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GSH efflux transporters include multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H\u002FR is required to advance these transporters as therapeutic targets. Our goal was to investigate, in vivo, regulation of Abcc1, Abcc2, and Abcc4 mRNA expression (i.e., genes encoding Mrp isoforms that transport GSH) by nuclear factor E2-related factor (Nrf2) using a well-established H\u002FR model. Female Sprague–Dawley rats (200–250 g) were subjected to normoxia (Nx, 21% O2, 60 min), hypoxia (Hx, 6% O2, 60 min) or H\u002FR (6% O2, 60 min followed by 21% O2, 10 min, 30 min, or 1 h) or were treated with the Nrf2 activator sulforaphane (25 mg\u002Fkg, i.p.) for 3 h. Abcc mRNA expression in brain microvessels was determined using quantitative real-time PCR. Nrf2 signaling activation was examined using an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) respectively. Data were expressed as mean ± SD and analyzed via ANOVA followed by the post hoc Bonferroni t test. We observed increased microvascular expression of Abcc1, Abcc2, and Abcc4 mRNA following H\u002FR treatment with reoxygenation times of 10 min, 30 min, and 1 h and in animals treated with sulforaphane. Using a biotinylated Nrf2 probe, we observed an upward band shift in brain microvessels isolated from H\u002FR animals or animals administered sulforaphane. ChIP studies showed increased Nrf2 binding to antioxidant response elements on Abcc1, Abcc2, and Abcc4 promoters following H\u002FR or sulforaphane treatment, suggesting a role for Nrf2 signaling in Abcc gene regulation. Our data show increased Abcc1, Abcc2, and Abcc4 mRNA expression at the BBB in response to H\u002FR stress and that Abcc gene expression is regulated by Nrf2 signaling. Since these Mrp isoforms transport GSH, these results may point to endogenous transporters that can be targeted for BBB protection during H\u002FR stress. Experiments are ongoing to examine functional implications of Nrf2-mediated increases in Abcc transcript expression. Such studies will determine utility of targeting Mrp isoforms for BBB protection in diseases with an H\u002FR component.",{"EN":170},"Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress",{"VOID":172},"[\"14887800813857542057\"]",{"VOID":174},"Ronaldson PT, Davis TP. Targeted drug delivery to treat pain and cerebral hypoxia. Pharmacol Rev. 2013;65:291–314.\nRonaldson PT, Davis TP. Targeting transporters: promoting blood–brain barrier repair in response to oxidative stress injury. Brain Res. 2015;1623:39–52.\nMark KS, Davis TP. Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol. 2002;282:H1485–94.\nMcCaffrey G, Willis CL, Staatz WD, Nametz N, Quigley CA, Hom S, Lochhead JJ, Davis TP. Occludin oligomeric assemblies at tight junctions of the blood–brain barrier are altered by hypoxia and reoxygenation stress. J Neurochem. 2009;110:58–71.\nLochhead JJ, McCaffrey G, Quigley CE, Finch J, DeMarco KM, Nametz N, Davis TP. Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation. J Cereb Blood Flow Metab. 2010;30:1625–36.\nWitt KA, Mark KS, Hom S, Davis TP. Effects of hypoxia-reoxygenation on rat blood–brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol. 2003;285:H2820–31.\nWillis CL, Meske DS, Davis TP. Protein kinase C activation modulates reversible increase in cortical blood–brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. J Cereb Blood Flow Metab. 2010;30:1847–59.\nWitt KA, Mark KS, Sandoval KE, Davis TP. Reoxygenation stress on blood–brain barrier paracellular permeability and edema in the rat. Microvasc Res. 2008;75:91–6.\nMichinaga S, Koyama Y. Pathogenesis of brain edema and investigation into anti-edema drugs. Int J Mol Sci. 2015;16:9949–75.\nAl Ahmad A, Gassmann M, Ogunshola OO. Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown. Microvasc Res. 2012;84:222–5.\nAgarwal R, Shukla GS. Potential role of cerebral glutathione in the maintenance of blood–brain barrier integrity in rat. Neurochem Res. 1999;24:1507–14.\nHirrlinger J, Dringen R. Multidrug resistance protein 1-mediated export of glutathione and glutathione disulfide from brain astrocytes. Methods Enzymol. 2005;400:395–409.\nHirrlinger J, Konig J, Keppler D, Lindenau J, Schulz JB, Dringen R. The multidrug resistance protein MRP1 mediates the release of glutathione disulfide from rat astrocytes during oxidative stress. J Neurochem. 2001;76:627–36.\nRonaldson PT, Bendayan R. HIV-1 viral envelope glycoprotein gp120 produces oxidative stress and regulates the functional expression of multidrug resistance protein-1 (Mrp1) in glial cells. J Neurochem. 2008;106:1298–313.\nBorst P, de Wolf C, van de Wetering K. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007;453:661–73.\nCopple IM. The Keap1-Nrf2 cell defense pathway—a promising therapeutic target? Adv Pharmacol. 2012;63:43–79.\nAleksunes LM, Slitt AL, Maher JM, Augustine LM, Goedken MJ, Chan JY, Cherrington NJ, Klaassen CD, Manautou JE. Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2. Toxicol Appl Pharmacol. 2008;226:74–83.\nMaher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, et al. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology. 2007;46:1597–610.\nWang X, Campos CR, Peart JC, Smith LK, Boni JL, Cannon RE, Miller DS. Nrf2 upregulates ATP binding cassette transporter expression and activity at the blood–brain and blood–spinal cord barriers. J Neurosci. 2014;34:8585–93.\nThompson BJ, Sanchez-Covarrubias L, Slosky LM, Zhang Y, Laracuente ML, Ronaldson PT. Hypoxia\u002Freoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood–brain barrier: relevance to CNS drug delivery. J Cereb Blood Flow Metab. 2014;34:699–707.\nChorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40:7416–29.\nHoque MT, Robillard KR, Bendayan R. Regulation of breast cancer resistant protein by peroxisome proliferator-activated receptor alpha in human brain microvessel endothelial cells. Mol Pharmacol. 2012;81:598–609.\nDallas S, Miller DS, Bendayan R. Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol Rev. 2006;58:140–61.\nMiller DS, Nobmann SN, Gutmann H, Toeroek M, Drewe J, Fricker G. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol. 2000;58:1357–67.\nLeggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24:7612–21.\nZhang Y, Schuetz JD, Elmquist WF, Miller DW. Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells. J Pharmacol Exp Ther. 2004;311:449–55.\nBandler PE, Westlake CJ, Grant CE, Cole SP, Deeley RG. Identification of regions required for apical membrane localization of human multidrug resistance protein 2. Mol Pharmacol. 2008;74:9–19.\nBauer B, Hartz AM, Lucking JR, Yang X, Pollack GM, Miller DS. Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood–brain barrier. J Cereb Blood Flow Metab. 2008;28:1222–34.\nUchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T. Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors. J Neurochem. 2011;117:333–45.\nSanchez-Covarrubias L, Slosky LM, Thompson BJ, Zhang Y, Laracuente ML, DeMarco KM, Ronaldson PT, Davis TP. P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac. PLoS ONE. 2014;9:e88516.\nAlfieri A, Srivastava S, Siow RC, Modo M, Fraser PA, Mann GE. Targeting the Nrf2-Keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol. 2011;589:4125–36.\nHayashi A, Suzuki H, Itoh K, Yamamoto M, Sugiyama Y. Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun. 2003;310:824–9.\nMa Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401–26.\nVollrath V, Wielandt AM, Iruretagoyena M, Chianale J. Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem J. 2006;395:599–609.\nXu S, Weerachayaphorn J, Cai SY, Soroka CJ, Boyer JL. Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression. Am J Physiol Gastrointest Liver Physiol. 2010;299:G126–35.\nFabian RH, Kent TA. Superoxide anion production during reperfusion is reduced by an antineutrophil antibody after prolonged cerebral ischemia. Free Radic Biol Med. 1999;26:355–61.\nHaddad JJ, Land SC. A non-hypoxic, ROS-sensitive pathway mediates TNF-α-dependent regulation of HIF-1α. FEBS Lett. 2001;505:269–74.\nZhao J, Moore AN, Redell JB, Dash PK. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci. 2007;27:10240–8.\nAlfieri A, Srivastava S, Siow RC, Cash D, Modo M, Duchen MR, Fraser PA, Williams SC, Mann GE. Sulforaphane preconditioning of the Nrf2\u002FHO-1 defense pathway protects the cerebral vasculature against blood–brain barrier disruption and neurological deficits in stroke. Free Radic Biol Med. 2013;65:1012–22.\nZhao Y, Fu B, Zhang X, Zhao T, Chen L, Zhang J, Wang X. Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice. Brain Res Bull. 2014;109:61–7.\nHirrlinger J, Schulz JB, Dringen R. Glutathione release from cultured brain cells: multidrug resistance protein 1 mediates the release of GSH from rat astroglial cells. J Neurosci Res. 2002;69:318–26.\nScheiber IF, Dringen R. Copper-treatment increases the cellular GSH content and accelerates GSH export from cultured rat astrocytes. Neurosci Lett. 2011;498:42–6.\nTadepalle N, Koehler Y, Brandmann M, Meyer N, Dringen R. Arsenite stimulates glutathione export and glycolytic flux in viable primary rat brain astrocytes. Neurochem Int. 2014;76:1–11.\nDringen R, Hirrlinger J. Glutathione pathways in the brain. Biol Chem. 2003;384:505–16.\nSlot AJ, Wise DD, Deeley RG, Monks TJ, Cole SP. Modulation of human multidrug resistance protein (MRP) 1 (ABCC1) and MRP2 (ABCC2) transport activities by endogenous and exogenous glutathione-conjugated catechol metabolites. Drug Metab Dispos. 2008;36:552–60.\nCole SP. Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annu Rev Pharmacol Toxicol. 2014;54:95–117.\nTachikawa M, Hosoya K, Terasaki T. Pharmacological significance of prostaglandin E2 and D2 transport at the brain barriers. Adv Pharmacol. 2014;71:337–60.\nStieger B, Gao B. Drug transporters in the central nervous system. Clin Pharmacokinet. 2015;54:225–42.\nMiller DS. Regulation of ABC transporters at the blood–brain barrier. Clin Pharmacol Ther. 2015;97:395–403.\nNies AT, Jedlitschky G, Konig J, Herold-Mende C, Steiner HH, Schmitt HP, Keppler D. Expression and immunolocalization of the multidrug resistance proteins, MRP1–MRP6 (ABCC1–ABCC6), in human brain. Neuroscience. 2004;129:349–60.\nRoberts LM, Black DS, Raman C, Woodford K, Zhou M, Haggerty JE, Yan AT, Cwirla SE, Grindstaff KK. Subcellular localization of transporters along the rat blood–brain barrier and blood–cerebral–spinal fluid barrier by in vivo biotinylation. Neuroscience. 2008;155:423–38.\nShawahna R, Uchida Y, Decleves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud PO, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8:1332–41.\nSoontornmalai A, Vlaming ML, Fritschy JM. Differential, strain-specific cellular and subcellular distribution of multidrug transporters in murine choroid plexus and blood–brain barrier. Neuroscience. 2006;138:159–69.",{"VOID":176},"10.1186\u002Fs12987-017-0055-4","PUBLICATION","VERIFIED","2024-05-16T15:07:23.658+00:00","Auto Verify","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-017-0055-4",[183,199,215],{"id":184,"sortIndex":19,"researcher":18,"roles":185,"affiliations":187,"properties":196,"displayName":198,"givenName":18,"familyName":18},"7f11b089-0592-4a6e-a557-cc7fc4faf188",[186],"AUTHOR",[188],{"id":189,"sortIndex":19,"affiliation":190,"properties":18},"a425005e-3389-4b73-8032-89ae24f60d6c",{"id":189,"createTime":18,"updateTime":18,"relativeEntities":191,"slug":18,"properties":192,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":195,"statistic":18},[],{"title":193},{"VI":194},"Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, USA",[],{"title":197},{"VI":198},"Kathryn Ibbotson",{"id":200,"sortIndex":201,"researcher":18,"roles":202,"affiliations":203,"properties":212,"displayName":214,"givenName":18,"familyName":18},"ea509979-ec67-4cd8-9e91-ea03ff635324",1,[186],[204],{"id":205,"sortIndex":19,"affiliation":206,"properties":18},"97135d7c-4430-4d78-927c-98ca68d851a7",{"id":205,"createTime":18,"updateTime":18,"relativeEntities":207,"slug":18,"properties":208,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":211,"statistic":18},[],{"title":209},{"VI":210},"Department of Pharmacology; College of Medicine, University of Arizona, Tucson, USA",[],{"title":213},{"VI":214},"Joshua Yell",{"id":216,"sortIndex":217,"researcher":18,"roles":218,"affiliations":219,"properties":226,"displayName":228,"givenName":18,"familyName":18},"350b3781-98c6-4620-aee2-31d63789e52e",2,[186],[220],{"id":205,"sortIndex":19,"affiliation":221,"properties":18},{"id":205,"createTime":18,"updateTime":18,"relativeEntities":222,"slug":18,"properties":223,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":225,"statistic":18},[],{"title":224},{"VI":210},[],{"title":227,"gsAuthor":229},{"VI":228},"Patrick T. Ronaldson",{"VOID":230},"[\"oCrqp0sAAAAJ\"]","ARTICLE",{"url":181,"publisher":233,"properties":286},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":234,"slug":10,"properties":235,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":238,"manageAffiliations":255,"indexDatabases":266,"url":18,"thumbnailPath":18,"statistic":281,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"issn":236,"title":237},{"VOID":13},{"EN":15},[239,243,247,251],{"id":22,"createTime":18,"updateTime":18,"relativeEntities":240,"label":241,"description":242,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":25},{},{"id":28,"createTime":18,"updateTime":18,"relativeEntities":244,"label":245,"description":246,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":31},{},{"id":34,"createTime":18,"updateTime":18,"relativeEntities":248,"label":249,"description":250,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":37},{},{"id":40,"createTime":18,"updateTime":18,"relativeEntities":252,"label":253,"description":254,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":43},{},[256,261],{"id":47,"createTime":18,"updateTime":18,"relativeEntities":257,"slug":18,"properties":258,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":260,"statistic":18},[],{"title":259},{"EN":51},[],{"id":54,"createTime":18,"updateTime":18,"relativeEntities":262,"slug":18,"properties":263,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":265,"statistic":18},[],{"title":264},{"EN":58},[],[267,274],{"id":62,"indexDatabase":268,"url":75,"indexYears":18,"academicFieldIds":273,"indexDatabaseRanking":18},{"id":64,"createTime":18,"updateTime":18,"relativeEntities":269,"label":270,"description":271,"key":71,"publicationTags":272,"standard":18},[],{"EN":67,"VI":67},{"EN":69,"VI":70},[73,74],[77],{"id":79,"indexDatabase":275,"url":90,"indexYears":91,"academicFieldIds":280,"indexDatabaseRanking":97},{"id":81,"createTime":18,"updateTime":18,"relativeEntities":276,"label":277,"description":278,"key":87,"publicationTags":279,"standard":18},[],{"EN":84,"VI":84},{"EN":84,"VI":86},[89],[93,94,95,96],{"impactFactor":19,"impactFactorByYear":282,"i10Index":112,"i10IndexLast5Year":113,"totalPublication":114,"totalPublicationByYear":283,"totalCitation":128,"totalCitationByYear":284,"totalCitationPerPublication":141,"totalCitationPerPublicationByYear":285,"hindexLast5Year":155,"hindex":155},{"2012":100,"2013":101,"2014":102,"2015":103,"2016":104,"2017":105,"2018":106,"2019":107,"2020":108,"2021":109,"2022":110,"2023":111},{"2011":113,"2012":116,"2013":117,"2014":118,"2015":119,"2016":120,"2017":117,"2018":121,"2019":122,"2020":123,"2021":124,"2022":125,"2023":126,"2024":127},{"2011":130,"2012":131,"2013":132,"2014":133,"2015":134,"2016":112,"2017":135,"2018":136,"2019":137,"2020":138,"2021":139,"2022":140},{"2011":143,"2012":144,"2013":145,"2014":146,"2015":147,"2016":148,"2017":149,"2018":150,"2019":151,"2020":152,"2021":153,"2022":154},{"pages":287,"volume":289},{"VOID":288},"1-10",{"VOID":290},"14",44,{"total":291,"publishYear":293,"statisticByYear":294},2017,{"2017":295,"2018":296,"2019":297,"2020":201,"2021":298,"2022":296,"2023":298,"2024":297,"2025":201,"2026":295},3,6,5,7,"2017-03-16","DONE_ANALYZE_CITATION","2026-07-25T13:06:40.238+00:00",[97,73],false,{"id":305,"createTime":306,"updateTime":307,"relativeEntities":308,"slug":309,"properties":310,"entityType":177,"verifyStatus":178,"verifyTime":321,"verifyNote":180,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":322,"fullTextUrl":18,"authors":323,"publicationType":231,"publisherRelationship":354,"citationCount":123,"citationInfo":413,"publishDate":418,"publishYear":414,"citationAnalyzeStatus":300,"lastCitationAnalyze":419,"indexDatabases":420,"openAccess":18,"references":18,"isForceReanalyzing":303},"bcf1784a-d2cb-4bf8-8165-a238a967cb26","2024-01-17T22:37:14.685+00:00","2026-07-23T23:53:52.553+00:00",[],"Brain-disposition-of-%CE%B1-Synuclein-roles-of-brain-barrier-systems-and-implications-for-Parkinson-s-disease",{"abstract":311,"title":313,"gsPaper":315,"references":317,"doi":319},{"EN":312},"Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-Synuclein (a-Syn) into Lewy body inclusions and the loss of dopaminergic neurons in the substantia nigra (SN). Accumulation of a-Syn can induce a progressive, cyclical pathology that results in the transmission of toxic, aggregated a-Syn species to healthy neurons, leading to further neurodegeneration such as occurs in PD. The blood–brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers (BCSFB) are responsible for regulating the access of nutrients and other molecules to the brain, but very little is known about their regulatory roles in maintaining the homeostasis of a-Syn in the CSF and brain parenchyma. This review analyzes the current literature reports on the transport of a-Syn by various brain cell types with a particular focus on the potential transport mechanisms of a-Syn at the BBB and BCSFB. The indication of altered a-Syn transport by brain barriers in PD pathoetiology and the perspectives in this research area are also discussed.",{"EN":314},"Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease",{"VOID":316},"[\"9872543272738690794\"]",{"VOID":318},"Kamel F: Paths from pesticides to Parkinson’s. Science. 2013, 341: 722-723.\nAuluck P, Caraveo G, Lindquist S: α-synuclein: membrane interactions and toxicity in Parkinson's disease. Ann Rev Cell Dev Biol. 2013, 26: 211-233.\nBraak H, Bohl JR, Müller CM, Rüb U, de Vos RAI, Del Tredici K: Stanley Fahn lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Movement Dis. 2006, 21: 2042-2051.\nDuda JE, Lee VMY, Trojanowski JQ: Neuropathy of synuclein aggregates: new insights into mechanisms of neurodegenerative diseases. J Neurosci Res. 2000, 61: 121-127.\nMurphy D, Rueter SM, Trojanowski JQ, Lee VMY: Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000, 20: 3214-3220.\nPerez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ: A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci. 2002, 22: 3090-3099.\nClayton DF, George JM: Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res. 1999, 58: 120-129.\nEllis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barceló-Coblijn GC, Nussbaum RL: Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking α-synuclein. Mol Cell Bio. 2005, 25: 10190-10201.\nWinklhofer KF, Haass C: Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 1802, 2010: 29-44.\nKalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE: α-synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2013, 73: 155-169.\nBodner CR, Maltsev AS, Dobson CM, Bax A: Differential phospholipid binding of α-synuclein variants implicated in Parkinson’s disease revealed by solution NMR spectroscopy. Biogeosciences. 2010, 49: 862-871.\nKirik D, Rosenblad C, Burger C, Lundberg C, Johanson TE, Muzyczka N, Mandel RJ, Björklund A: Parkinson-like neurodegeneration induced by targeted overexpression of α-synuclein in the nigrostriatal system. J Neurosci. 2002, 22: 2780-2791.\nKirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjòrklund A: Nigrostriatal a-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson’s disease. PNAS. 2003, 100: 2884-2889.\nGombash SE, Manfredsson FP, Kemp CJ, Kuhn NC, Fleming SM, Egan AE, Grant LM, Ciucci MR, MacKeigan JP, Sortwell CE: Morphological and behavioral impact of AAV2\u002F5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system. PLoS ONE. 2013, 8: 1-15.\nLee H, Patel S, Lee S: Intravesicular localization and exocytosis of α-synuclein and its aggregates. J Neurosci. 2005, 25: 6016-6024.\nLee H, Khoshaghideh F, Patel S, Lee S: Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004, 24: 1888-1896.\nLee H, Cho E, Lee KW, Kim J, Cho S, Lee S: Autophagic failure promotes the exocytosis and intracellular transfer of α-synuclein. Exp Mol Med. 2013, 45: 1-9.\nBrown PD, Davies SL, Speake T, Millar ID: Molecular mechanisms of cerebrospinal fluid production. Neurosci. 2004, 129: 957-970.\nSmith DE, Johanson CE, Keep RF: Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Del Rev. 2004, 56: 1765-1791.\nMcCaffrey G, Davis TP: Physiology and pathophysiology of the blood–brain barrier p-glycoprotein and occludin trafficking as therapeutic targets to optimize central nervous system drug delivery. J Investig Med. 2012, 60: 1131-1140.\nSobue K, Yamamoto N, Yoneda K, Hodgson ME, Yamashiro K, Tsuruoka N, Tsuda T, Katsuya H, Miura Y, Asai K, Kato T: Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res. 1999, 35: 155-164.\nAbbott NJ, Rönnbäck L, Hansson E: Astrocyte-endothelial interactions at the blood–brain barrier. Nature Rev. 2006, 7: 41-53.\nKim KS: Mechanisms of microbial traversal of the blood–brain barrier. Nature Rev. 2008, 6: 625-626.\nBernacki J, Dobrowolska A, Nierwińska K, Małecki A: Physiology and pharmacological role of the blood–brain barrier. Pharmacol Rep. 2008, 2008 (60): 600-622.\nZheng W, Aschner M, Ghersi-Egea J: Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol. 2003, 192: 1-11.\nJohanson CE, Duncan JA, Stopa EG, Baird A: Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharma Res. 2005, 22: 1011-1037.\nSpector R, Johanson CE: Sustained choroid plexus function in human elderly and Alzheimer’s disease patients. Fluids Barriers CNS. 2013, 10: 28-\nDesplats P, Lee H, Bae E, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee S: Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. PNAS. 2009, 106: 13010-13015.\nAngot E, Steiner JA, Lema Tomé CM, Ekström P, Mattson B, Björklund A, Brundin P: Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS ONE. 2012, 7: 1-11.\nLee H, Suk J, Bae E, Lee J, Paik SR, Lee S: Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int’l J Biochem Cell Bio. 2008, 40: 1835-1849.\nFreeman D, Cedilos R, Choyke S, Lukic Z, McGuire K, Marvin S, Burrage AM, Sudholt S, Rana A, O’Connor C, Wiethoff CM, Campbell EM: Alpha-synuclein induces lysosomal rupture and cathespin-dependent reactive oxidative species following endocytosis. PLoS ONE. 2013, 8: e62143-\nBüchel F, Saliger S, Dräger A, Hoffman S, Wrzodek C, Zell A, Kahle PJ: Parkinson’s disease: dopaminergic neuronal model is consistent with experimental finding of increased extracellular transport of α-synuclein. BMC Neurosci. 2013, 14: 1-12.\nWakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H: NACP\u002Fα-synuclein-positive filamentous inclusions in astrocytes, and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol. 2000, 99: 14-20.\nBraak H, Sastre M, Del Tredici K: Development of α-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol. 2007, 114: 231-241.\nLee H, Kim C, Lee S: Alpha-synuclein stimulation of astrocytes: potential role for neuroinflammation and neuroprotection. Oxid Med Cell Longev. 2010, 3: 283-287.\nLee H, Suk J, Patrick C, Bae E, Cho J, Rho S, Hwang D, Masliah E, Lee S: Direct transfer of a-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010, 285: 2962-9272.\nKim JN, Kim MK, Cho KS, Choi CS, Park SH, Yang S, Joo SH, Park JH, Bahn G, Shin CY, Lee H, Han S, Kwon KJ: Valproic acid regulates α-synuclein expression through JNK pathway in rat primary astrocytes. Biomol Ther. 2013, 21: 222-228.\nTamo W, Imaizumi T, Tanji K, Yoshi H, Mori F, Yoshimoto M, Takahashi H, Fukuda I, Wakabayashi K, Satoh K: Expression of α-synuclein, the precursor of non-amyloid β component of Alzheimer’s disease amyloid, in human cerebral blood vessels. Neurosci Lett. 2002, 326: 5-8.\nMollenhauer B, Trautmann E, Otte B, Ng J, Spreer A, Lange P, Sixel-Döring F, Hakimi M, VonSattel J, Nussbaum R, Trenkwalder C, Schlossmacher MG: α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system. J Neural Transm. 2012, 119: 739-746.\nFoulds PG, Diggle P, Mitchell JD, Parker A, Hasegawa M, Masuda-Suzukake M, Mann DMA, Allsop D: A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson’s disease. Sci Rep. 2013, 3: 2540-\nHong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J: DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain. 2010, 133: 713-726.\nMollenhauer B, Trautmann E, Taylor P, Manniger P, Sixel-Döring F, Ebentheuer J, Trenkwalder C, Schlossmacher MG: Total CSF α-synuclein is lower in de novo Parkinson patients than in healthy subjects. J Neurosci Lett. 2013, 532: 44-48.\nWalker SJ, Grant KA: Peripheral blood α-synuclein mRNA levels are elevated in cynomolgus monkeys that chronically self-administer ethanol. Alcohol. 2006, 38: 1-4.\nFauvet B, Kamdem MM, Fares MB, Desobry C, Michael S, Ardah MT, Tsika E, Coune P, Prudent M, Lion N, Eliezer D, Moore DJ, Schneider B, Aebischer P, El-Agnaf OM, Masliah E, Lashuel HA: Alpha-Synuclein in the central nervous system and from erythrocytes, mammalian cells and E. coli exists predominantly as a disordered monomer. J Biol Chem. 2012, 287: 15345-15364.\nGrathwohl SA, Steiner JA, Britschgi M, Brundin P: Mind the gut: secretion of α-synuclein by enteric neurons. J Neurochem. 2013, 125: 487-490.\nBates CA, Zheng G, Fu X, Zheng W: Expression and aggregation of α-synuclein in the blood-CSF barrier: Initial evidence for the influence of cellular manganese and copper status [abstract]. Toxicologist. 2013, 132: 1862-\nZheng W, Zhao Q: Establishment and characterization of an immortalized Z310 choroidal epithelial cell line from murine choroid plexus. Brain Res. 2002, 958: 371-380.\nMcMahon HT, Boucrot E: Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nature Rev Mol Biol. 2011, 12: 517-533.\nBates CA, Fu X, Ysselstein D, Rochet J, Zheng W: Transport of α-synuclein at the blood-cerebrospinal fluid barrier and effects of heavy metal toxicities: potential role in Parkinson’s disease pathoetiology [abstract]. Toxicologist. 2014, 138: 1349-\nAndré C, Truong TT, Robert JF, Guillaume YC: Effect of metals on herbicides-α-synuclein association: a possible factor in neurodegenerative disease studied by capillary electrophoresis. Electrophoresis. 2005, 26: 3256-3264.\nSantner A, Uversky VN: Metalloproteomics and metal toxicology of α-synuclein. Metallomics. 2010, 2: 378-392.\nCookson MR, Hardy J, Lewis PA: Genetic neuropathology of Parkinson’s disease. Int J Clin Exp Pathol. 2008, 1: 217-231.\nCovy JP, Giasson BI: α-synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson’s disease. Neurotox. 2011, 32: 622-629.\nYue Z, Yang XW: Dangerous duet: LRRK2 and α-synuclein jam at CMA. Nat Neurosci. 2013, 16: 375-377.\nKisos H, Puka K, Ben-Hur T, Richter-Landsberg C, Sharon R: Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. PLoS ONE. 2012, 7: e46817-\nLee H, Suk J, Bae E, Lee S: Clearance and deposition of extracellular α-synuclein aggregates in microglia. 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A1 là một phân tử kháng viêm mạnh mẽ đã được nghiên cứu rộng rãi trong hệ thống miễn dịch ngoại vi, nhưng chưa được khai thác như một mục tiêu\u002Fđại diện điều trị. Trong thập kỷ qua, chúng tôi đã tiến hành nghiên cứu phân tử này trong hệ thần kinh trung ương (CNS), đặc biệt tập trung vào giao diện chính giữa cơ thể ngoại vi và CNS: hàng rào máu-não. Trong bài đánh giá này, chúng tôi cung cấp một cái nhìn tổng quan về vai trò của phân tử này trong não, với sự nhấn mạnh đặc biệt vào chức năng của nó trong nội mô của hàng rào máu-não, và các tác động bảo vệ mà phân tử có thể thực hiện trong các bệnh viêm thần kinh, mạch máu thần kinh và chuyển hóa. Chúng tôi tập trung vào những con đường điều trị mới có thể được mở ra nhờ việc hiểu biết thêm về vai trò của annexin A1 trong hệ mạch CNS, cũng như tiềm năng của nó trong việc phục hồi tổn thương hàng rào máu-não trong bệnh tật và lão hóa.","Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune system, but has not as yet been exploited as a therapeutic target\u002Fagent. In the last decade, we have undertaken the study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. 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Development, maintenance and disruption of the blood–brain barrier. Nat Med. 2013;19:1584–96.",{"doi":607},{"id":603,"text":620,"url":605,"identifiers":621},"Chow BW, Gu C. The molecular constituents of the blood–brain barrier. Trends Neurosci. 2015;38:598–608.",{"doi":607},{"id":623,"text":624,"url":625,"identifiers":626},"2db5e9ee-31fd-40b4-b308-9b538a93e1fe","Sun H, Dai H, Shaik N, Elmquist WF. Drug efflux transporters in the CNS. Adv Drug Deliv Rev. 2003;55:83–105.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0169409X02001722",{"doi":627},"10.1016\u002Fs0169-409x(02)00172-2",{"id":603,"text":629,"url":605,"identifiers":630},"Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Davis TP, Ronaldson PT. Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? 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Drug transporters in the central nervous system. Clin Pharmacokinet. 2015;54:225–42.",{"doi":607},{"id":647,"text":648,"url":649,"identifiers":650},"42321ca6-3fc6-4b81-ae7b-16e9a0c2af59","Qosa H, Miller DS, Pasinelli P, Trotti D. Regulation of ABC efflux transporters at blood–brain barrier in health and neurological disorders. Brain Res. 2015;1628:298–316.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006899315005302",{"doi":651},"10.1016\u002Fj.brainres.2015.07.005",{"id":603,"text":653,"url":605,"identifiers":654},"Salameh TS, Banks WA. Delivery of therapeutic peptides and proteins to the CNS. Adv Pharmacol. 2014;71:277–99.",{"doi":607},{"id":603,"text":656,"url":605,"identifiers":657},"Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood–brain barrier. Neurobiol Dis. 2010;37:13–25.",{"doi":607},{"id":18,"text":659,"url":660,"identifiers":661},"Thomsen MS, Birkelund S, Burkhart A, Stensballe A, Moos T. Synthesis and deposition of basement membrane proteins by primary brain capillary endothelial cells in a murine model of the blood–brain barrier. J Neurochem. 2016. doi:10.1111\u002Fjnc.13747.","https:\u002F\u002Fdoi.org\u002F10.1111\u002Fjnc.13747",{"mag":662,"openalex":663,"pm":664,"doi":665},"2487534313","W2487534313","27456748","10.1111\u002Fjnc.13747",{"id":603,"text":667,"url":605,"identifiers":668},"Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM. Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev. 2005;85:979–1000.",{"doi":607},{"id":603,"text":670,"url":605,"identifiers":671},"Engelhardt B, Sorokin L. The blood–brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol. 2009;31:497–511.",{"doi":607},{"id":603,"text":673,"url":605,"identifiers":674},"del Zoppo GJ, Milner R. Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol. 2006;26:1966–75.",{"doi":607},{"id":603,"text":676,"url":605,"identifiers":677},"Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab NIH Public Access. 2007;27:1766–91.",{"doi":607},{"id":603,"text":679,"url":605,"identifiers":680},"Brkic M, Balusu S, Libert C, Vandenbroucke RE. Friends or foes: matrix metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediators Inflamm. 2015;2015:620581.",{"doi":607},{"id":603,"text":682,"url":605,"identifiers":683},"Bruschi F, Pinto B. The significance of matrix metalloproteinases in parasitic infections involving the central nervous system. Pathog. 2013;2:105–29.",{"doi":607},{"id":603,"text":685,"url":605,"identifiers":686},"Heo JH, Han SW, Lee SK. Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med. 2005;39:51–70.",{"doi":607},{"id":603,"text":688,"url":605,"identifiers":689},"Rosell A, Ortega-Aznar A, Alvarez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006;37:1399–406.",{"doi":607},{"id":603,"text":691,"url":605,"identifiers":692},"Muradashvili N, Benton RL, Saatman KE, Tyagi SC, Lominadze D. Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice. Metab Brain Dis. 2015;30:411–26.",{"doi":607},{"id":603,"text":694,"url":605,"identifiers":695},"Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60.",{"doi":607},{"id":603,"text":697,"url":605,"identifiers":698},"Armulik A, Abramsson A, Betsholtz C. Endothelial\u002Fpericyte interactions. Circ Res. 2005;97:512–23.",{"doi":607},{"id":603,"text":700,"url":605,"identifiers":701},"Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 2001;153:543–53.",{"doi":607},{"id":603,"text":703,"url":605,"identifiers":704},"Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, et al. Wnt\u002Fbeta-catenin signaling controls development of the blood–brain barrier. J Cell Biol. 2008\u002F10\u002F29 ed. 2008;183:409–17.",{"doi":607},{"id":603,"text":706,"url":605,"identifiers":707},"Liebner S, Plate KH, Ferguson J, Kelley R, Patterson C, Risau W, et al. Differentiation of the brain vasculature: the answer came blowing by the Wnt. J Angiogenes Res. 2010;2:1.",{"doi":607},{"id":603,"text":709,"url":605,"identifiers":710},"Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68:409–27.",{"doi":607},{"id":603,"text":712,"url":605,"identifiers":713},"Yao Y, Chen Z-L, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun. 2014;5:3413.",{"doi":607},{"id":603,"text":715,"url":605,"identifiers":716},"Janzer RC, Raff MC. Astrocytes induce blood–brain barrier properties in endothelial cells. Nature. 1987;325:253–7.",{"doi":607},{"id":603,"text":718,"url":605,"identifiers":719},"Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7:41–53.",{"doi":607},{"id":18,"text":721,"url":18,"identifiers":722},"Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H. Human astrocytes express aquaporin-1 and aquaporin-4 in vitro and in vivo. Neuropathology. 2007;27:245–56.",{},{"id":603,"text":724,"url":605,"identifiers":725},"Abbott NJ. Astrocyte-endothelial interactions and blood–brain barrier permeability. J Anat. 2002;200:629–38.",{"doi":607},{"id":603,"text":727,"url":605,"identifiers":728},"Asgari M, de Zélicourt D, Kurtcuoglu V. How astrocyte networks may contribute to cerebral metabolite clearance. Sci Rep. 2015;5:15024.",{"doi":607},{"id":730,"text":731,"url":732,"identifiers":733},"951e46f8-4178-4423-bae6-d9a4b3e111f3","Thal DR. The role of astrocytes in amyloid β-protein toxicity and clearance. Exp Neurol. 2012;236:1–5.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0014488612001938",{"doi":734},"10.1016\u002Fj.expneurol.2012.04.021",{"id":18,"text":736,"url":737,"identifiers":738},"da Fonseca ACC, Matias D, Garcia C, Amaral R, Geraldo LH, Freitas C, et al. The impact of microglial activation on blood-brain barrier in brain diseases. Front Cell Neurosci. 2014;8:362. doi:10.3389\u002Ffncel.2014.00362.","https:\u002F\u002Fdoi.org\u002F10.3389\u002Ffncel.2014.00362",{"mag":739,"pmc":740,"openalex":741,"pm":742,"doi":743},"2051140555","4217497","W2051140555","25404894","10.3389\u002Ffncel.2014.00362",{"id":603,"text":745,"url":605,"identifiers":746},"Sumi N, Nishioku T, Takata F, Matsumoto J, Watanabe T, Shuto H, et al. Lipopolysaccharide-activated microglia induce dysfunction of the blood–brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell Mol Neurobiol. 2010;30:247–53.",{"doi":607},{"id":603,"text":748,"url":605,"identifiers":749},"Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, et al. Tumor necrosis factor-alpha mediates the blood–brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. J Pharmacol Sci. 2010;112:251–4.",{"doi":607},{"id":603,"text":751,"url":605,"identifiers":752},"Andreone BJ, Lacoste B, Gu C. Neuronal and vascular interactions. Annu Rev Neurosci. 2015;38:25–46.",{"doi":607},{"id":754,"text":755,"url":756,"identifiers":757},"0999ad21-5db2-415b-a7f5-f1b050c96b12","Varatharaj A, Galea I. The blood–brain barrier in systemic inflammation. Immun: Brain Behav; 2016.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0889159116300551",{"doi":758},"10.1016\u002Fj.bbi.2016.03.010",{"id":603,"text":760,"url":605,"identifiers":761},"Lopez-Ramirez MA, Reijerkerk A, de Vries HE, Romero IA. Regulation of brain endothelial barrier function by microRNAs in health and neuroinflammation. FASEB J. 2016;30:2662–72.",{"doi":607},{"id":603,"text":763,"url":605,"identifiers":764},"Derada Troletti C, de Goede P, Kamermans A, de Vries HE. Molecular alterations of the blood–brain barrier under inflammatory conditions: the role of endothelial to mesenchymal transition. Biochim Biophys Acta Mol Basis Dis. 2016;1862:452–60.",{"doi":607},{"id":18,"text":766,"url":18,"identifiers":767},"Zenaro E, Piacentino G, Constantin G. The blood–brain barrier in Alzheimer’s disease. Dis: Neurobiol; 2016.",{},{"id":603,"text":769,"url":605,"identifiers":770},"Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol. 2012;33:579–89.",{"doi":607},{"id":603,"text":772,"url":605,"identifiers":773},"Zhou L, Yang B, Wang Y, Zhang H-L, Chen R-W, Wang Y-B. Bradykinin regulates the expression of claudin-5 in brain microvascular endothelial cells via calcium-induced calcium release. J Neurosci Res. 2014;92:597–606.",{"doi":607},{"id":603,"text":775,"url":605,"identifiers":776},"Schwaninger M, Sallmann S, Petersen N, Schneider A, Prinz S, Libermann TA, et al. Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-kappaB. J Neurochem. 1999;73:1461–6.",{"doi":607},{"id":778,"text":779,"url":780,"identifiers":781},"c2c6ece4-013b-4fcf-8f41-4090383dcc28","Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988;12:123–37.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0149763488800046",{"doi":782},"10.1016\u002Fs0149-7634(88)80004-6",{"id":603,"text":784,"url":605,"identifiers":785},"McCusker RH, Kelley KW. Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol. 2013;216:84–98.",{"doi":607},{"id":603,"text":787,"url":605,"identifiers":788},"Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood–brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302.",{"doi":607},{"id":603,"text":790,"url":605,"identifiers":791},"Taheri S, Gasparovic C, Huisa BN, Adair JC, Edmonds E, Prestopnik J, et al. Blood–brain barrier permeability abnormalities in vascular cognitive impairment. Stroke. 2011;42:2158–63.",{"doi":607},{"id":793,"text":794,"url":795,"identifiers":796},"ad610bd0-56d8-46b1-873f-a7221a34678c","Popescu BO, Toescu EC, Popescu LM, Bajenaru O, Muresanu DF, Schultzberg M, et al. Blood–brain barrier alterations in ageing and dementia. J Neurol Sci. 2009;283:99–106.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0022510X09004171",{"doi":797},"10.1016\u002Fj.jns.2009.02.321",{"id":603,"text":799,"url":605,"identifiers":800},"Wardlaw JM, Doubal FN, Valdes-Hernandez M, Wang X, Chappell FM, Shuler K, et al. Blood–brain barrier permeability and long-term clinical and imaging outcomes in cerebral small vessel disease. Stroke. 2013;44:525–7.",{"doi":607},{"id":603,"text":802,"url":605,"identifiers":803},"van de Haar HJ, Burgmans S, Hofman PAM, Verhey FRJ, Jansen JFA, Backes WH. Blood–brain barrier impairment in dementia: current and future in vivo assessments. Neurosci Biobehav Rev. 2015;49:71–81.",{"doi":607},{"id":603,"text":805,"url":605,"identifiers":806},"Raz L, Knoefel J, Bhaskar K. The neuropathology and cerebrovascular mechanisms of dementia. Blood Flow Metab: J Cereb; 2015.",{"doi":607},{"id":18,"text":808,"url":18,"identifiers":809},"Bowman GL, Kaye JA, Moore M, Waichunas D, Carlson NE, Quinn JF. Blood–brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology. 2007;68:1809–14.",{},{"id":811,"text":812,"url":813,"identifiers":814},"e8489ce4-ea50-4375-9699-f5043f5f5bbe","Rius-Pérez S, Tormos AM, Pérez S, Taléns-Visconti R. Vascular pathology: cause or effect in Alzheimer disease? Neurologia. 2015. doi:10.1016\u002Fj.nrl.2015.07.010.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0213485315001851",{"doi":815},"10.1016\u002Fj.nrl.2015.07.010",{"id":817,"text":818,"url":819,"identifiers":820},"64096293-81bf-4301-9e0f-881041dc7cb1","Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Acta: Biochim Biophys; 2015.","https:\u002F\u002Flinkinghub.elsevier.com\u002Fretrieve\u002Fpii\u002FS0925443915003701",{"doi":821},"10.1016\u002Fj.bbadis.2015.12.016",{"id":603,"text":823,"url":605,"identifiers":824},"Moheet A, Mangia S, Seaquist ER. Impact of diabetes on cognitive function and brain structure. Ann NY Acad Sci. 2015;1353:60–71.",{"doi":607},{"id":603,"text":826,"url":605,"identifiers":827},"Wang C, Chan JSY, Ren L, Yan JH. Obesity reduces cognitive and motor functions across the lifespan. Neural Plast. 2016;2016:2473081.",{"doi":607},{"id":829,"text":830,"url":831,"identifiers":832},"79f21b65-e2be-4e2e-a148-a90dd1acc484","Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012\u002F04\u002F03 ed. 2012;122:1164–71.","http:\u002F\u002Fwww.jci.org\u002Farticles\u002Fview\u002F58644",{"doi":833},"10.1172\u002Fjci58644",{"id":603,"text":835,"url":605,"identifiers":836},"Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012\u002F08\u002F21 ed. 2012;12:623–35.",{"doi":607},{"id":603,"text":838,"url":605,"identifiers":839},"Maggioli E, McArthur S, Mauro C, Kieswich J, Kusters DHMHM, Reutelingsperger CPMPM, et al. Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking. Brain Behav Immun. 2015;51:212–22.",{"doi":607},{"id":841,"text":842,"url":843,"identifiers":844},"03922c91-e162-4617-8354-bab7232380ec","Solito E, McArthur S, Christian H, Gavins F, Buckingham JC, Gillies GE. Annexin A1 in the brain–undiscovered roles? Trends Pharmacol Sci. 2008\u002F02\u002F12 ed. 2008;29:135–42.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0165614708000205",{"doi":845},"10.1016\u002Fj.tips.2007.12.003",{"id":847,"text":848,"url":849,"identifiers":850},"8e950f38-9def-4d0e-8dee-81e6849ad525","Parente L, Solito E. Annexin 1: more than an anti-phospholipase protein. Inflamm Res. 2004;53:125–32.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs00011-003-1235-z",{"doi":851},"10.1007\u002Fs00011-003-1235-z",{"id":603,"text":853,"url":605,"identifiers":854},"Perretti M, Flower RJ. Annexin 1 and the biology of the neutrophil. J Leukoc Biol. 2004;76:25–9.",{"doi":607},{"id":18,"text":856,"url":18,"identifiers":857},"Moss SE, Morgan RO. The annexins. Genome Biol. 2004;5:219.",{},{"id":18,"text":859,"url":18,"identifiers":860},"Solito E, Mulla A, Morris JF, Christian HC, Flower RJ, Buckingham JC. Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor, protein kinase C, phosphatidylinositol 3-kinase. Endocrinology. 2003\u002F03\u002F18 ed. 2003;144:1164–74.",{},{"id":603,"text":862,"url":605,"identifiers":863},"Solito E, Christian HC, Festa M, Mulla A, Tierney T, Flower RJ, et al. Post-translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface. Faseb J. 2006\u002F05\u002F25 ed. 2006;20:1498–500.",{"doi":607},{"id":603,"text":865,"url":605,"identifiers":866},"Cirino G, Cicala C, Sorrentino L, Ciliberto G, Arpaia G, Perretti M, et al. Anti-inflammatory actions of an N-terminal peptide from human lipocortin 1. Br J Pharmacol. 1993;108:573–4.",{"doi":607},{"id":603,"text":868,"url":605,"identifiers":869},"Kovacic RT, Tizard R, Cate RL, Frey AZ, Wallner BP. Correlation of gene and protein structure of rat and human lipocortin I. Biochemistry. 1991;30:9015–21.",{"doi":607},{"id":603,"text":871,"url":605,"identifiers":872},"Lopez-Ramirez MA, Wu D, Pryce G, Simpson JE, Reijerkerk A, King-Robson J, et al. MicroRNA-155 negatively affects blood–brain barrier function during neuroinflammation. FASEB J. 2014;28:2551–65.",{"doi":607},{"id":603,"text":874,"url":605,"identifiers":875},"Solito E, Romero IA, Marullo S, Russo-Marie F, Weksler BB. Annexin 1 binds to U937 monocytic cells and inhibits their adhesion to microvascular endothelium: involvement of the alpha 4 beta 1 integrin. J Immunol. 2000\u002F07\u002F21 ed. 2000;165:1573–81.",{"doi":607},{"id":603,"text":877,"url":605,"identifiers":878},"Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, et al. Feature Article: Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci USA. 2013\u002F01\u002F02 ed. 2013;110:832–41.",{"doi":607},{"id":603,"text":880,"url":605,"identifiers":881},"de la Fuente M, Parra AV. Vesicle aggregation by annexin I: role of a secondary membrane binding site. Biochemistry. 1995;34:10393–9.",{"doi":607},{"id":603,"text":883,"url":605,"identifiers":884},"McArthur S, Gobbetti T, Kusters DHM, Reutelingsperger CP, Flower RJ, Perretti M. Definition of a novel pathway centered on lysophosphatidic acid to recruit monocytes during the resolution phase of tissue inflammation. J Immunol. 2015;195:1500733.",{"doi":607},{"id":18,"text":886,"url":18,"identifiers":887},"Bena S, Brancaleone V, Wang JM, Perretti M, Flower RJ. Annexin A1 interaction with the FPR2\u002FALX receptor: identification of distinct domains and downstream associated signaling. J Biol Chem. 2012;287:24690–7.",{},{"id":603,"text":889,"url":605,"identifiers":890},"McArthur S, Yazid S, Christian H, Sirha R, Flower R, Buckingham J, et al. Annexin A1 regulates hormone exocytosis through a mechanism involving actin reorganization. Faseb J. 2009\u002F07\u002F25 ed. 2009;23:4000–10.",{"doi":607},{"id":603,"text":892,"url":605,"identifiers":893},"Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, et al. Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci USA. 2013;110:832–41.",{"doi":607},{"id":841,"text":895,"url":843,"identifiers":896},"Solito E, McArthur S, Christian H, Gavins F, Buckingham JC, Gillies GE. Annexin A1 in the brain–undiscovered roles? Trends Pharmacol Sci. 2008;29:135–42.",{"doi":845},{"id":603,"text":898,"url":605,"identifiers":899},"Luo ZZ, Gao Y, Sun N, Zhao Y, Wang J, Tian B, et al. Enhancing the interaction between annexin-1 and formyl peptide receptors regulates microglial activation to protect neurons from ischemia-like injury. J Neuroimmunol. 2014;276:24–36.",{"doi":607},{"id":603,"text":901,"url":605,"identifiers":902},"McArthur S, Cristante E, Paterno M, Christian H, Roncaroli F, Gillies GE, et al. Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J Immunol. 2010\u002F10\u002F22 ed. 2010;185:6317–28.",{"doi":607},{"id":603,"text":904,"url":605,"identifiers":905},"Solito E, Sastre M. Microglia function in Alzheimer’s disease. Front Pharmacol. 2012\u002F03\u002F01 ed. 2012;3:14.",{"doi":607},{"id":603,"text":907,"url":605,"identifiers":908},"Ek CJ, Dziegielewska KM, Habgood MD, Saunders NR. Barriers in the developing brain and neurotoxicology. Neurotoxicology. 2012;33:586–604.",{"doi":607},{"id":603,"text":910,"url":605,"identifiers":911},"Virgintino D, Errede M, Robertson D, Capobianco C, Girolamo F, Vimercati A, et al. Immunolocalization of tight junction proteins in the adult and developing human brain. Histochem Cell Biol. 2004;122:51–9.",{"doi":607},{"id":603,"text":913,"url":605,"identifiers":914},"Virgintino D, Errede M, Girolamo F, Capobianco C, Robertson D, Vimercati A, et al. Fetal blood–brain barrier P-glycoprotein contributes to brain protection during human development. J Neuropathol Exp Neurol. 2008;67:50–61.",{"doi":607},{"id":603,"text":916,"url":605,"identifiers":917},"D’Acunto CW, Gbelcova H, Festa M, Ruml T. The complex understanding of annexin A1 phosphorylation. Cell Signal. 2014;26:173–8.",{"doi":607},{"id":603,"text":919,"url":605,"identifiers":920},"Han G, Tian Y, Duan B, Sheng H, Gao H, Huang J. Association of nuclear annexin A1 with prognosis of patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7:751–9.",{"doi":607},{"id":603,"text":922,"url":605,"identifiers":923},"Farrall AJ, Wardlaw JM. Blood–brain barrier: ageing and microvascular disease–systematic review and meta-analysis. Neurobiol Aging. 2009;30:337–52.",{"doi":607},{"id":925,"text":926,"url":927,"identifiers":928},"67513773-4e3d-4270-9e63-9919b8d219cd","Elahy M, Jackaman C, Mamo JC, Lam V, Dhaliwal SS, Giles C, et al. Blood–brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. Immun Ageing. 2015;12:2.","https:\u002F\u002Fimmunityageing.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12979-015-0029-9",{"doi":929},"10.1186\u002Fs12979-015-0029-9",{"id":603,"text":931,"url":605,"identifiers":932},"Boraldi F, Bini L, Liberatori S, Armini A, Pallini V, Tiozzo R, et al. Proteome analysis of dermal fibroblasts cultured in vitro from human healthy subjects of different ages. Proteomics. 2003;3:917–29.",{"doi":607},{"id":603,"text":934,"url":605,"identifiers":935},"Leoni G, Neumann P-A, Kamaly N, Quiros M, Nishio H, Jones HR, et al. Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair. J Clin Invest. 2015;125:1215–27.",{"doi":607},{"id":603,"text":937,"url":605,"identifiers":938},"Monastyrskaya K, Babiychuk EB, Draeger A, Burkhard FC. Down-regulation of annexin A1 in the urothelium decreases cell survival after bacterial toxin exposure. J Urol. 2013;190:325–33.",{"doi":607},{"id":940,"text":941,"url":942,"identifiers":943},"09937774-e2a6-434b-b701-81d4efab789e","Gorlé N, Van Cauwenberghe C, Libert C, Vandenbroucke RE. The effect of aging on brain barriers and the consequences for Alzheimer’s disease development. Mamm Genome. 2016;27:407–20.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs00335-016-9637-8",{"doi":944},"10.1007\u002Fs00335-016-9637-8",{"id":603,"text":946,"url":605,"identifiers":947},"Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12:723–38.",{"doi":607},{"id":18,"text":949,"url":18,"identifiers":950},"Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV. Deficiency in mural vascular cells coincides with blood–brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013;23:303–10.",{},{"id":603,"text":952,"url":605,"identifiers":953},"Wang S, Voisin M-B, Larbi KY, Dangerfield J, Scheiermann C, Tran M, et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J Exp Med. 2006;203:1519–32.",{"doi":607},{"id":603,"text":955,"url":605,"identifiers":956},"Knott C, Stern G, Wilkin GP. Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci. 2000;16:724–39.",{"doi":607},{"id":18,"text":958,"url":18,"identifiers":959},"Eberhard DA, Brown MD, VandenBerg SR. Alterations of annexin expression in pathological neuronal and glial reactions. Immunohistochemical localization of annexins I, II (p36 and p11 subunits), IV, and VI in the human hippocampus. Am J Pathol. 1994;145:640–9.",{},{"id":603,"text":961,"url":605,"identifiers":962},"Perretti M, D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol. 2009;9:62–70.",{"doi":607},{"id":964,"text":965,"url":966,"identifiers":967},"f3938ca9-41f1-4c72-bf2f-e7cd848f26c4","Lee YH, Song GG. Genome-wide pathway analysis of a genome-wide association study on Alzheimer’s disease. Neurol Sci. 2015;36:53–9.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10072-014-1885-3",{"doi":968},"10.1007\u002Fs10072-014-1885-3",{"id":603,"text":970,"url":605,"identifiers":971},"Burgmans S, van de Haar HJ, Verhey FRJ, Backes WH. Amyloid-β interacts with blood–brain barrier function in dementia: a systematic review. J Alzheimers Dis. 2013;35:859–73.",{"doi":607},{"id":603,"text":973,"url":605,"identifiers":974},"Viggars AP, Wharton SB, Simpson JE, Matthews FE, Brayne C, Savva GM, et al. Alterations in the blood brain barrier in ageing cerebral cortex in relationship to Alzheimer-type pathology: a study in the MRC-CFAS population neuropathology cohort. Neurosci Lett. 2011;505:25–30.",{"doi":607},{"id":603,"text":976,"url":605,"identifiers":977},"Algotsson A, Winblad B. The integrity of the blood–brain barrier in Alzheimer’s disease. Acta Neurol Scand. 2007;115:403–8.",{"doi":607},{"id":603,"text":979,"url":605,"identifiers":980},"Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, et al. IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood–brain barrier neonatal Fc receptor. J Neurosci. 2005;25:11495–503.",{"doi":607},{"id":603,"text":982,"url":605,"identifiers":983},"Cignarella A, Bolego C, Pelosi V, Meda C, Krust A, Pinna C, et al. Distinct roles of estrogen receptor-alpha and beta in the modulation of vascular inducible nitric-oxide synthase in diabetes. J Pharmacol Exp Ther. 2009;328:174–82.",{"doi":607},{"id":603,"text":985,"url":605,"identifiers":986},"Deo AK, Borson S, Link JM, Domino K, Eary JF, Ke B, et al. Activity of P-glycoprotein, a β-amyloid transporter at the blood–brain barrier, is compromised in patients with mild Alzheimer disease. J Nucl Med. 2014;55:1106–11.",{"doi":607},{"id":603,"text":988,"url":605,"identifiers":989},"Pietronigro E, Zenaro E, Constantin G. Imaging of leukocyte trafficking in Alzheimer’s disease. Front Immunol. 2016;7:33.",{"doi":607},{"id":603,"text":991,"url":605,"identifiers":992},"Ortiz GG, Pacheco-Moisés FP, Macías-Islas MÁ, Flores-Alvarado LJ, Mireles-Ramírez MA, González-Renovato ED, et al. Role of the blood–brain barrier in multiple sclerosis. Arch Med Res. 2014;45:687–97.",{"doi":607},{"id":603,"text":994,"url":605,"identifiers":995},"Walter FR, Veszelka S, Deli MA. Role of the blood–brain barrier in the nutrition of the central nervous system. Arch Med Res. 2014;45:610–38.",{"doi":607},{"id":997,"text":998,"url":999,"identifiers":1000},"83827a83-a9a8-4040-9730-8499531d3334","Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta. 2011;1812:252–64.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0925443910001274",{"doi":1001},"10.1016\u002Fj.bbadis.2010.06.017",{"id":603,"text":1003,"url":605,"identifiers":1004},"Probst-Cousin S, Kowolik D, Kuchelmeister K, Kayser C, Neundorfer B, Heuss D. Expression of annexin-1 in multiple sclerosis plaques. Neuropathol Appl Neurobiol. 2002;28:292–300.",{"doi":607},{"id":603,"text":1006,"url":605,"identifiers":1007},"Gavins FNE, Dalli J, Flower RJ, Granger DN, Perretti M. Activation of the annexin 1 counter-regulatory circuit affords protection in the mouse brain microcirculation. FASEB J. 2007;21:1751–8.",{"doi":607},{"id":18,"text":1009,"url":18,"identifiers":1010},"Vital SA, Becker F, Holloway PM, Russell J, Perretti M, Granger DN, et al. Formyl-peptide receptor 2\u002F3\u002Flipoxin A4 receptor regulates neutrophil-platelet aggregation and attenuates cerebral inflammation: impact for therapy in cardiovascular disease. Circulation. 2016;133:2169–79.",{},{"id":603,"text":1012,"url":605,"identifiers":1013},"Liu J-H, Feng D, Zhang Y-F, Shang Y, Wu Y, Li X-F, et al. Chloral hydrate preconditioning protects against ischemic stroke via upregulating annexin A1. CNS Neurosci Ther. 2015;21:718–26.",{"doi":607},{"id":603,"text":1015,"url":605,"identifiers":1016},"Joseph C, Buga A-M, Vintilescu R, Balseanu AT, Moldovan M, Junker H, et al. Prolonged gaseous hypothermia prevents the upregulation of phagocytosis-specific protein annexin 1 and causes low-amplitude EEG activity in the aged rat brain after cerebral ischemia. J Cereb Blood Flow Metab. 2012;32:1632–42.",{"doi":607},{"id":603,"text":1018,"url":605,"identifiers":1019},"Gillies GE, McArthur S. Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev. 2010\u002F04\u002F16 ed. 2010;62:155–98.",{"doi":607},{"id":603,"text":1021,"url":605,"identifiers":1022},"Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol. 2009;30:201–11.",{"doi":607},{"id":1024,"text":1025,"url":1026,"identifiers":1027},"63b55e09-b501-4aa4-9fb3-3b634d6f0879","Nadkarni S, McArthur S. Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol. 2013;13:576–81.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1471489213000672",{"doi":1028},"10.1016\u002Fj.coph.2013.05.007",{"id":603,"text":1030,"url":605,"identifiers":1031},"Guo J, Krause DN, Horne J, Weiss JH, Li X, Duckles SP. Estrogen-receptor-mediated protection of cerebral endothelial cell viability and mitochondrial function after ischemic insult in vitro. J Cereb Blood Flow Metab. 2010;30:545–54.",{"doi":607},{"id":1033,"text":1034,"url":1035,"identifiers":1036},"f41bef68-5542-4aff-97cd-2d3f4176d3d2","Shin JA, Yoon JC, Kim M-S, Park E-M. Activation of classical estrogen receptor subtypes reduces tight junction disruption of brain endothelial cells under ischemia\u002Freperfusion injury. Med: Free Radic Biol; 2016.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0891584916000113",{"doi":1037},"10.1016\u002Fj.freeradbiomed.2016.01.010",{"id":603,"text":1039,"url":605,"identifiers":1040},"Shin JA, Yang SJ, Jeong SI, Park HJ, Choi Y-H, Park E-M. Activation of estrogen receptor β reduces blood–brain barrier breakdown following ischemic injury. Neuroscience. 2013;235:165–73.",{"doi":607},{"id":603,"text":1042,"url":605,"identifiers":1043},"Tu J, Jufri NF. Estrogen signaling through estrogen receptor beta and G-protein-coupled estrogen receptor 1 in human cerebral vascular endothelial cells: implications for cerebral aneurysms. Biomed Res Int. 2013;2013:524324.",{"doi":607},{"id":1045,"text":1046,"url":1047,"identifiers":1048},"59f47e68-0e10-4c48-b220-62833eb023b4","Burek M, Steinberg K, Förster CY. Mechanisms of transcriptional activation of the mouse claudin-5 promoter by estrogen receptor alpha and beta. Mol Cell Endocrinol. 2014;392:144–51.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0303720714001385",{"doi":1049},"10.1016\u002Fj.mce.2014.05.003",{"id":603,"text":1051,"url":605,"identifiers":1052},"Brailoiu E, Dun SL, Brailoiu GC, Mizuo K, Sklar LA, Oprea TI, et al. Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. J Endocrinol. 2007;193:311–21.",{"doi":607},{"id":603,"text":1054,"url":605,"identifiers":1055},"Razmara A, Sunday L, Stirone C, Wang XB, Krause DN, Duckles SP, et al. Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells. J Pharmacol Exp Ther. 2008;325:782–90.",{"doi":607},{"id":603,"text":1057,"url":605,"identifiers":1058},"Chen L-C, Lee W-S. Estradiol reduces ferrous citrate complex-induced NOS2 up-regulation in cerebral endothelial cells by interfering the nuclear factor kappa B transactivation through an estrogen receptor β-mediated pathway. PLoS ONE. 2013;8:e84320.",{"doi":607},{"id":603,"text":1060,"url":605,"identifiers":1061},"Nathan L, Chaudhuri G. Antioxidant and prooxidant actions of estrogens: potential physiological and clinical implications. Semin Reprod Endocrinol. 1998;16:309–14.",{"doi":607},{"id":603,"text":1063,"url":605,"identifiers":1064},"Burek M, Arias-Loza PA, Roewer N, Förster CY. Claudin-5 as a novel estrogen target in vascular endothelium. Arterioscler Thromb Vasc Biol. 2010;30:298–304.",{"doi":607},{"id":1066,"text":1067,"url":1068,"identifiers":1069},"c18c2fb7-eecd-4db2-a099-33af9096c0b6","Kang HS, Ahn HS, Kang HJ, Gye MC. Effect of estrogen on the expression of occludin in ovariectomized mouse brain. Neurosci Lett. 2006;402:30–4.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0304394006003193",{"doi":1070},"10.1016\u002Fj.neulet.2006.03.052",{"id":603,"text":1072,"url":605,"identifiers":1073},"Nourshargh S, Hordijk PL, Sixt M. Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nat Rev Mol Cell Biol. 2010;11:366–78.",{"doi":607},{"id":603,"text":1075,"url":605,"identifiers":1076},"Nilsson B-O. Modulation of the inflammatory response by estrogens with focus on the endothelium and its interactions with leukocytes. Inflamm Res. 2007;56:269–73.",{"doi":607},{"id":603,"text":1078,"url":605,"identifiers":1079},"Hartz AMS, Madole EK, Miller DS, Bauer B. Estrogen receptor beta signaling through phosphatase and tensin homolog\u002Fphosphoinositide 3-kinase\u002FAkt\u002Fglycogen synthase kinase 3 down-regulates blood–brain barrier breast cancer resistance protein. J Pharmacol Exp Ther. 2010;334:467–76.",{"doi":607},{"id":603,"text":1081,"url":605,"identifiers":1082},"Hartz AMS, Mahringer A, Miller DS, Bauer B. 17-β-estradiol: a powerful modulator of blood–brain barrier BCRP activity. J Cereb Blood Flow Metab. 2010;30:1742–55.",{"doi":607},{"id":603,"text":1084,"url":605,"identifiers":1085},"Mahringer A, Fricker G. BCRP at the blood–brain barrier: genomic regulation by 17β-estradiol. Mol Pharm. 2010;7:1835–47.",{"doi":607},{"id":603,"text":1087,"url":605,"identifiers":1088},"Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008;9:58–65.",{"doi":607},{"id":603,"text":1090,"url":605,"identifiers":1091},"Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, et al. Brain structure and obesity. Hum Brain Mapp. 2010;31:353–64.",{"doi":607},{"id":1093,"text":1094,"url":1095,"identifiers":1096},"75e45fa7-9ea2-49d8-8e47-34435fe5683e","van Bloemendaal L, Ijzerman RG, Ten Kulve JS, Barkhof F, Diamant M, Veltman DJ, et al. Alterations in white matter volume and integrity in obesity and type 2 diabetes. Metab Brain Dis. 2016;31:621–9.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs11011-016-9792-3",{"doi":1097},"10.1007\u002Fs11011-016-9792-3",{"id":603,"text":1099,"url":605,"identifiers":1100},"Pannacciulli N, Del Parigi A, Chen K, Le DSNT, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage. 2006;31:1419–25.",{"doi":607},{"id":603,"text":1102,"url":605,"identifiers":1103},"Tu Y-F, Tsai Y-S, Wang L-W, Wu H-C, Huang C-C, Ho C-J. Overweight worsens apoptosis, neuroinflammation and blood–brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation. J. Neuroinflammation. 2011;8:40.",{"doi":607},{"id":603,"text":1105,"url":605,"identifiers":1106},"Stranahan AM, Hao S, Dey A, Yu X, Baban B. Blood–brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice. Blood Flow Metab: J. Cereb; 2016.",{"doi":607},{"id":603,"text":1108,"url":605,"identifiers":1109},"Davidson TL, Monnot A, Neal AU, Martin AA, Horton JJ, Zheng W. The effects of a high-energy diet on hippocampal-dependent discrimination performance and blood–brain barrier integrity differ for diet-induced obese and diet-resistant rats. Physiol Behav. 2012;107:26–33.",{"doi":607},{"id":603,"text":1111,"url":605,"identifiers":1112},"Deng J, Zhang J, Feng C, Xiong L, Zuo Z. Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice. Cardiovasc Res. 2014;103:473–84.",{"doi":607},{"id":603,"text":1114,"url":605,"identifiers":1115},"Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, et al. Obesity in aging exacerbates blood–brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol Ser A. 2014;69:1212–26.",{"doi":607},{"id":603,"text":1117,"url":605,"identifiers":1118},"Kim DW, Glendining KA, Grattan DR, Jasoni CL. Maternal obesity in the mouse compromises the blood–brain barrier in the arcuate nucleus of offspring. Endocrinology. 2016;157:2229–42.",{"doi":607},{"id":603,"text":1120,"url":605,"identifiers":1121},"Buckman LB, Thompson MM, Moreno HN, Ellacott KLJ. Regional astrogliosis in the mouse hypothalamus in response to obesity. J Comp Neurol. 2013;521:1322–33.",{"doi":607},{"id":603,"text":1123,"url":605,"identifiers":1124},"Ouyang S, Hsuchou H, Kastin AJ, Wang Y, Yu C, Pan W. Diet-induced obesity suppresses expression of many proteins at the blood–brain barrier. J Cereb Blood Flow Metab. 2013;34:1–9.",{"doi":607},{"id":603,"text":1126,"url":605,"identifiers":1127},"Kanoski SE, Zhang Y, Zheng W, Davidson TL. The effects of a high-energy diet on hippocampal function and blood–brain barrier integrity in the rat. J Alzheimer’s Dis. 2010;21:207–19.",{"doi":607},{"id":603,"text":1129,"url":605,"identifiers":1130},"McColl BW, Rose N, Robson FH, Rothwell NJ, Lawrence CB. Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab. 2010;30:267–72.",{"doi":607},{"id":1132,"text":1133,"url":1134,"identifiers":1135},"5aa9696f-0c50-494c-b4d0-972c6b471b4c","Maysami S, Haley MJ, Gorenkova N, Krishnan S, McColl BW, Lawrence CB. Prolonged diet-induced obesity in mice modifies the inflammatory response and leads to worse outcome after stroke. J Neuroinflam. 2015;12:140.","https:\u002F\u002Fjneuroinflammation.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12974-015-0359-8",{"doi":1136},"10.1186\u002Fs12974-015-0359-8",{"id":1138,"text":1139,"url":1140,"identifiers":1141},"71fc5dfd-2fd9-4e8a-bbe5-33d492666eb5","Parimisetty A, Dorsemans A-C, Awada R, Ravanan P, Diotel N, Lefebvre d’Hellencourt C. Secret talk between adipose tissue and central nervous system via secreted factors-an emerging frontier in the neurodegenerative research. J Neuroinflam. 2016;13:67.","http:\u002F\u002Fjneuroinflammation.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12974-016-0530-x",{"doi":1142},"10.1186\u002Fs12974-016-0530-x",{"id":1144,"text":1145,"url":1146,"identifiers":1147},"2f817f22-c562-4b6c-8ce3-d24f3f0f2658","Kiliaan AJ, Arnoldussen IAC, Gustafson DR. Adipokines: a link between obesity and dementia? Lancet Neurol. 2014;13:913–23.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1474442214700857",{"doi":1148},"10.1016\u002Fs1474-4422(14)70085-7",{"id":603,"text":1150,"url":605,"identifiers":1151},"Kosicka A, Cunliffe AD, Mackenzie R, Zariwala MG, Perretti M, Flower RJ, et al. Attenuation of plasma annexin A1 in human obesity. FASEB J. 2013;27:368–78.",{"doi":607},{"id":603,"text":1153,"url":605,"identifiers":1154},"Kim H, Kang H, Heo RW, Jeon BT, Yi C, Shin HJ, et al. Caloric restriction improves diabetes-induced cognitive deficits by attenuating neurogranin-associated calcium signaling in high-fat diet-fed mice. J Cereb Blood Flow Metab. 2016;36:1098–110.",{"doi":607},{"id":603,"text":1156,"url":605,"identifiers":1157},"Wang H, Chen F, Zhong KL, Tang SS, Hu M, Long Y, et al. PPARγ agonists regulate bidirectional transport of amyloid-β across the blood–brain barrier and hippocampus plasticity in db\u002Fdb mice. Br J Pharmacol. 2016;173:372–85.",{"doi":607},{"id":18,"text":1159,"url":18,"identifiers":1160},"Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care. 2013;36:4036–42.",{},{"id":603,"text":1162,"url":605,"identifiers":1163},"Hoogenboom WS, Marder TJ, Flores VL, Huisman S, Eaton HP, Schneiderman JS, et al. Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes. Diabetes. 2014;63:728–38.",{"doi":607},{"id":1165,"text":1166,"url":1167,"identifiers":1168},"61b1b6e0-2b94-49fa-a0fa-2212ca06e87b","Van Duinkerken E, Schoonheim MM, Ijzerman RG, Klein M, Ryan CM, Moll AC, et al. Diffusion tensor imaging in type 1 diabetes: decreased white matter integrity relates to cognitive functions. Diabetologia. 2012;55:1218–20.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00125-012-2488-2",{"doi":1169},"10.1007\u002Fs00125-012-2488-2",{"id":603,"text":1171,"url":605,"identifiers":1172},"Roberts RO, Knopman DS, Przybelski SA, Mielke MM, Kantarci K, Preboske GM, et al. Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology. 2014;82:1132–41.",{"doi":607},{"id":603,"text":1174,"url":605,"identifiers":1175},"Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J. 2012;42:484–91.",{"doi":607},{"id":603,"text":1177,"url":605,"identifiers":1178},"Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry. 2010;67:505–12.",{"doi":607},{"id":18,"text":1180,"url":18,"identifiers":1181},"Saczynski JS, Siggurdsson S, Jonsson PV, Eiriksdottir G, Olafsdottir E, Kjartansson O, et al. Glycemic status and brain injury in older individuals: the age gene\u002Fenvironment susceptibility-Reykjavik study. Diabetes Care. 2009;32:1608–13.",{},{"id":603,"text":1183,"url":605,"identifiers":1184},"Mitchell AB, Cole JW, McArdle PF, Cheng Y-C, Ryan KA, Sparks MJ, et al. Obesity increases risk of ischemic stroke in young adults. Stroke. 2015;46:1690–2.",{"doi":607},{"id":603,"text":1186,"url":605,"identifiers":1187},"Pietrani NT, Ferreira CN, Rodrigues KF, Bosco AA, Oliveira MC, Teixeira AL, et al. Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy. Clin Chim Acta. 2014;436:181–2.",{"doi":607},{"id":603,"text":1189,"url":605,"identifiers":1190},"Price TO, Eranki V, Banks WA, Ercal N, Shah GN. Topiramate treatment protects blood–brain barrier pericytes from hyperglycemia-induced oxidative damage in diabetic mice. Endocrinology. 2012;153:362–72.",{"doi":607},{"id":603,"text":1192,"url":605,"identifiers":1193},"Hu P, Thinschmidt JS, Yan Y, Hazra S, Bhatwadekar A, Caballero S, et al. CNS inflammation and bone marrow neuropathy in type 1 diabetes. Am J Pathol. 2013;183:1608–20.",{"doi":607},{"id":1195,"text":1196,"url":1197,"identifiers":1198},"9b49b9a8-1ae8-4b00-94e0-c908d839853c","Luo Y, Kaur C, Ling EA. Neuronal and glial response in the rat hypothalamus-neurohypophysis complex with streptozotocin-induced diabetes. Brain Res. 2002;925:42–54.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006899301032589",{"doi":1199},"10.1016\u002Fs0006-8993(01)03258-9",{"id":603,"text":1201,"url":605,"identifiers":1202},"Jing YH, Chen KH, Kuo PC, Pao CC, Chen JK. Neurodegeneration in streptozotocin-induced diabetic rats is attenuated by treatment with resveratrol. Neuroendocrinology. 2013;98:116–27.",{"doi":607},{"id":603,"text":1204,"url":605,"identifiers":1205},"Yoo DY, Yim HS, Jung HY, Nam SM, Kim JW, Choi JH, et al. Chronic type 2 diabetes reduces the integrity of the blood–brain barrier by reducing tight junction proteins in the hippocampus. Sci: J Vet Med; 2016.",{"doi":607},{"id":1207,"text":1208,"url":1209,"identifiers":1210},"e2f33227-ec42-48c8-967e-36146523f886","Hawkins BT, Lundeen TF, Norwood KM, Brooks HL, Egleton RD. Increased blood–brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia. 2007;50:202–11.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00125-006-0485-z",{"doi":1211},"10.1007\u002Fs00125-006-0485-z",{"id":603,"text":1213,"url":605,"identifiers":1214},"Zanotto C, Simão F, Gasparin MS, Biasibetti R, Tortorelli LS, Nardin P, et al. Exendin-4 reverses biochemical and functional alterations in the blood–brain and blood-CSF barriers in diabetic rats. Mol Neurobiol. 2016;1–13.",{"doi":607},{"id":603,"text":1216,"url":605,"identifiers":1217},"Thrailkill KM, Bunn RC, Moreau CS, Cockrell GE, Simpson PM, Coleman HN, et al. Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care. 2007;30:2321–6.",{"doi":607},{"id":18,"text":1219,"url":18,"identifiers":1220},"Harris AK, Hutchinson JR, Sachidanandam K, Johnson MH, Dorrance AM, Stepp DW, et al. Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis: role of endothelin-1. Diabetes. 2005;54:2638–44.",{},{"id":1222,"text":1223,"url":1224,"identifiers":1225},"efe500fa-7893-4ccc-a1c6-c0e2bcd3ef4b","Shao B, Bayraktutan U. Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-βI and prooxidant enzyme NADPH oxidase. Redox Biol. 2014;2:694–701.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS2213231714000706",{"doi":1226},"10.1016\u002Fj.redox.2014.05.005",{"id":603,"text":1228,"url":605,"identifiers":1229},"Shimizu F, Sano Y, Tominaga O, Maeda T, Abe MA, Kanda T. Advanced glycation end-products disrupt the blood–brain barrier by stimulating the release of transforming growth factor-β by pericytes and vascular endothelial growth factor and matrix metalloproteinase-2 by endothelial cells in vitro. Neurobiol Aging. 2013;34:1902–12.",{"doi":607},{"id":603,"text":1231,"url":605,"identifiers":1232},"Aggarwal A, Khera A, Singh I, Sandhir R. S-nitrosoglutathione prevents blood–brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes. J Neurochem. 2015;132:595–608.",{"doi":607},{"id":1234,"text":1235,"url":1236,"identifiers":1237},"17c6d890-c0f1-4afc-90c4-c4a0cbdb515c","Kang H, Ko J, Jang S-W. The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells. Biochem Biophys Res Commun. 2012;423:188–94.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006291X12010042",{"doi":1238},"10.1016\u002Fj.bbrc.2012.05.114",{"id":603,"text":1240,"url":605,"identifiers":1241},"Tagoe CE, Marjanovic N, Park JY, Chan ES, Abeles AM, Attur M, et al. Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts. J Immunol. 2008;181:2813–20.",{"doi":607},{"id":603,"text":1243,"url":605,"identifiers":1244},"Liu Q-H, Shi M-L, Bai J, Zheng J-N. Identification of ANXA1 as a lymphatic metastasis and poor prognostic factor in pancreatic ductal adenocarcinoma. Asian Pac J Cancer Prev. 2015;16:2719–24.",{"doi":607},{"id":603,"text":1246,"url":605,"identifiers":1247},"Ghitescu LD, Gugliucci A, Dumas F. Actin and annexins I and II are among the main endothelial plasmalemma-associated proteins forming early glucose adducts in experimental diabetes. Diabetes. 2001;50:1666–74.",{"doi":607},{"id":603,"text":1249,"url":605,"identifiers":1250},"van Harten B, de Leeuw F-E, Weinstein HC, Scheltens P, Biessels GJ. Brain imaging in patients with diabetes: a systematic review. Diabetes Care. 2006;29:2539–48.",{"doi":607},{"id":603,"text":1252,"url":605,"identifiers":1253},"Doubal FN, MacGillivray TJ, Patton N, Dhillon B, Dennis MS, Wardlaw JM. Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke. Neurology. 2010;74:1102–7.",{"doi":607},{"id":603,"text":1255,"url":605,"identifiers":1256},"Smith HK, Gil CD, Oliani SM, Gavins FNE. Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke. FASEB J. 2015;29:2161–71.",{"doi":607},{"id":603,"text":1258,"url":605,"identifiers":1259},"Cooray SN, Gobbetti T, Montero-Melendez T, McArthur S, Thompson D, Clark AJL, et al. Ligand-specific conformational change of the G-protein-coupled receptor ALX\u002FFPR2 determines proresolving functional responses. Proc Natl Acad Sci USA. 2013;110:18232–7.",{"doi":607},{"id":603,"text":1261,"url":605,"identifiers":1262},"Headland SE, Jones HR, Norling LV, Kim A, Souza PR, Corsiero E, et al. Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Sci Transl Med. 2015;7:315ra190.",{"doi":607},{"id":603,"text":1264,"url":605,"identifiers":1265},"Fredman G, Kamaly N, Spolitu S, Milton J, Ghorpade D, Chiasson R, et al. Targeted nanoparticles containing the proresolving peptide Ac2–26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med. 2015;7:275ra20.",{"doi":607},{"id":1267,"createTime":1268,"updateTime":1269,"relativeEntities":1270,"slug":1271,"properties":1272,"entityType":177,"verifyStatus":178,"verifyTime":1283,"verifyNote":180,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":1284,"fullTextUrl":18,"authors":1285,"publicationType":231,"publisherRelationship":1358,"citationCount":117,"citationInfo":1417,"publishDate":1421,"publishYear":1418,"citationAnalyzeStatus":300,"lastCitationAnalyze":1269,"indexDatabases":1422,"openAccess":18,"references":18,"isForceReanalyzing":303},"4d40be7e-7931-4baa-8144-ddb64996c532","2023-12-19T21:03:25.922+00:00","2026-07-18T10:14:58.324+00:00",[],"Diagnostic-biomarker-kinetics-how-brain-derived-biomarkers-distribute-through-the-human-body-and-how-this-affects-their-diagnostic-significance-the-case-of-S100B",{"abstract":1273,"title":1275,"gsPaper":1277,"references":1279,"doi":1281},{"EN":1274},"Blood biomarkers of neurological diseases are often employed to rule out or confirm the presence of significant intracranial or cerebrovascular pathology or for the differential diagnosis of conditions with similar presentations (e.g., hemorrhagic vs. embolic stroke). More widespread utilization of biomarkers related to brain health is hampered by our incomplete understanding of the kinetic properties, release patterns, and excretion of molecules derived from the brain. This is, in particular, true for S100B, an astrocyte-derived protein released across the blood–brain barrier (BBB). We developed an open-source pharmacokinetic computer model that allows investigations of biomarker’s movement across the body, the sources of biomarker’s release, and its elimination. This model was derived from a general in silico model of drug pharmacokinetics adapted for protein biomarkers. We improved the model’s predictive value by adding realistic blood flow values, organ levels of S100B, lymphatic and glymphatic circulation, and glomerular filtration for excretion in urine. Three key variables control biomarker levels in blood or saliva: blood–brain barrier permeability, the S100B partition into peripheral organs, and the cellular levels of S100B in astrocytes. A small contribution to steady-state levels of glymphatic drainage was also observed; this mechanism also contributed to the uptake of organs of circulating S100B. This open-source model can also mimic the kinetic behavior of other markers, such as GFAP or NF-L. Our results show that S100B, after uptake by various organs from the systemic circulation, can be released back into systemic fluids at levels that do not significantly affect the clinical significance of venous blood or salivary levels after an episode of BBB disruption.",{"EN":1276},"Diagnostic biomarker kinetics: how brain-derived biomarkers distribute through the human body, and how this affects their diagnostic significance: the case of S100B",{"VOID":1278},"[\"5314074249840600644\"]",{"VOID":1280},"Segraves JM, Frishman WH. Highly sensitive cardiac troponin assays: a comprehensive review of their clinical utility. Cardiol Rev. 2015;23(6):282–9.\nJanigro D, Bailey DM, Lehmann S, Badaut J, O’Flynn R, Hirtz C, et al. Peripheral blood and salivary biomarkers of blood-brain barrier permeability and neuronal damage: clinical and applied concepts. Front Neurol. 2020;11: 577312.\nDadas A, Washington J, Marchi N, Janigro D. Improving the clinical management of traumatic brain injury through the pharmacokinetic modeling of peripheral blood biomarkers. Fluids Barriers CNS. 2016;13(1):21.\nBargerstock E, Puvenna V, Iffland P, Falcone T, Hossain M, Vetter S, et al. Is peripheral immunity regulated by blood-brain barrier permeability changes? PLoS ONE. 2014;9(7): e101477.\nPham N, Fazio V, Cucullo L, Teng Q, Biberthaler P, Bazarian JJ, et al. Extracranial sources of S100B do not affect serum levels. PLoS ONE. 2010;5(9): e12691.\nPreston E, Webster J, Small D. Characteristics of sustained blood-brain barrier opening and tissue injury in a model for focal trauma in the rat. J Neurotrauma. 2001;18(1):83–92.\nKanner AA, Marchi N, Fazio V, Mayberg MR, Koltz MT, Siomin V, et al. Serum S100beta: a noninvasive marker of blood-brain barrier function and brain lesions. Cancer. 2003;97(11):2806–13.\nMarchi N, Rasmussen P, Kapural M, Fazio V, Kight K, Mayberg MR, et al. Peripheral markers of brain damage and blood-brain barrier dysfunction. Restor Neurol Neurosci. 2003;21(3–4):109–21.\nMarchi N, Cavaglia M, Bhudia S, Hallene K, Janigro D. Peripheral markers of blood-brain barrier damage. Clin Chim Acta. 2004;342(1–2):1–12.\nFalcone T, Fazio V, Lee C, Simon B, Franco K, Marchi N, et al. Serum S100B: a potential biomarker for suicidality in adolescents? PLoS ONE. 2010;5(6): e11089.\nBouzat P, Francony G, Declety P, Brun J, Kaddour A, Renversez JC, et al. Can serum protein S100 beta predict neurological deterioration after moderate or minor traumatic brain injury? Annales Francaises D Anesthesie et de Reanimation. 2009;28(2):135–9.\nHasselblatt M, Mooren FC, von Ahsen N, Keyvani K, Fromme A, Schwarze-Eicker K, et al. Serum S100beta increases in marathon runners reflect extracranial release rather than glial damage. Neurology. 2004;62(9):1634–6.\nKorfias S, Stranjalis G, Papadimitriou A, Psachoulia C, Daskalakis G, Antsaklis A, et al. Serum S-100B protein as a biochemical marker of brain injury: a review of current concepts. Curr Med Chem. 2006;13(30):3719–31.\nPapa L, Silvestri S, Brophy GM, Giordano P, Falk JL, Braga CF, et al. GFAP out-performs S100beta in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J Neurotrauma. 2014;31(22):1815–22.\nSavola O, Pyhtinen J, Leino TK, Siitonen S, Niemela O, Hillbom M. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. J Trauma. 2004;56(6):1229–34.\nThelin EP, Jeppsson E, Frostell A, Svensson M, Mondello S, Bellander BM, et al. Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity. Crit Care. 2016;20:285.\nAnderson RE, Hansson LO, Nilsson O, Dijlai-Merzoug R, Settergren G. High serum S100B levels for trauma patients without head injuries. Neurosurgery. 2001;48(6):1255–8.\nPosti JP, Hossain I, Takala RS, Liedes H, Newcombe V, Outtrim J, et al. Glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are not specific biomarkers for mild CT-negative traumatic brain injury. J Neurotrauma. 2017. https:\u002F\u002Fdoi.org\u002F10.1089\u002Fneu.2016.4442.\nZhang Y, Zhu J, Xu H, Yi Q, Yan L, Ye L, et al. Time-dependent internalization of S100B by mesenchymal stem cells via the pathways of clathrin- and lipid raft-mediated endocytosis. Front Cell Dev Biol. 2021;9: 674995.\nPham N, Fazio V, Cucullo L, Teng Q, Biberthaler P, Bazarian JJ, et al. Extracranial sources of S100B do not affect serum levels. PLoS ONE. 2010. https:\u002F\u002Fdoi.org\u002F10.1371\u002Fjournal.pone.0012691.\nSteiner J, Schiltz K, Walter M, Wunderlich MT, Keilhoff G, Brisch R, et al. S100B serum levels are closely correlated with body mass index: an important caveat in neuropsychiatric research. Psychoneuroendocrinology. 2010;35(2):321–4.\nKawata K, Rubin LH, Takahagi M, Lee JH, Sim T, Szwanki V, et al. Subconcussive impact-dependent increase in plasma S100beta levels in collegiate football players. J Neurotrauma. 2017;34(14):2254–60.\nZonner SW, Ejima K, Bevilacqua ZW, Huibregtse ME, Charleston C, Fulgar C, et al. Association of increased serum S100B levels with high school football subconcussive head impacts. Front Neurol. 2019;10:327.\nTagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain. 2018;141(2):422–58.\nSchulte S, Podlog LW, Hamson-Utley JJ, Strathmann FG, Struder HK. A systematic review of the biomarker S100B: implications for sport-related concussion management. J Athl Train. 2014;49(6):830–50.\nMichetti F, Bruschettini M, Frigiola A, Abella R, Giamberti A, Marchese N, et al. Saliva S100B in professional sportsmen: high levels at resting conditions and increased after vigorous physical activity. Clin Biochem. 2011;44(2–3):245–7.\nWatson P, Shirreffs SM, Maughan RJ. Blood-brain barrier integrity may be threatened by exercise in a warm environment. Am J Physiol Regul Integr Comp Physiol. 2005;288(6):R1689–94.\nWatson P, Black KE, Clark SC, Maughan RJ. Exercise in the heat: effect of fluid ingestion on blood-brain barrier permeability. Med Sci Sports Exerc. 2006;38(12):2118–24.\nSchulte S, Schiffer T, Sperlich B, Kleinoder H, Holmberg HC. Serum concentrations of S100B are not affected by cycling to exhaustion with or without vibration. J Hum Kinet. 2011;30:59–63.\nKoh SX, Lee JK. S100B as a marker for brain damage and blood-brain barrier disruption following exercise. Sports Med. 2014;44(3):369–85.\nBailey DM, et al. Hypoxemia promotes blood-brain barrier destabilization of the neurovascular unit during extreme apnea in humans. J Cereb Blood Flow Metab. 2022. https:\u002F\u002Fdoi.org\u002F10.1177\u002F0271678X221075967.\nDadas A, Janigro D. The role and diagnostic significance of cellular barriers after concussive head trauma. Concussion. 2018;3(1):Cnc53.\nJanigro D, Kawata K, Silverman E, Marchi N, Diaz-Arrastia R. Is Salivary S100B a biomarker of traumatic brain injury? A pilot study. Front Neurol. 2020;11:528.\nMarchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D. Peripheral markers of blood-brain barrier damage. Clin Chim Acta. 2004;342(1–2):1–12.\nMarchi N, Rasmussen PA, Kapural M, Fazio V, Cavaglia M, Janigro D. Peripheral markers of brain damage and blood-brain barrier dysfunction. Restor Neurol Neurosci. 2003;21(3–4):109–21.\nPlog BA, Dashnaw ML, Hitomi E, Peng WG, Liao YH, Lou NH, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci. 2015;35(2):518–26.\nGill KL, Gardner I, Li L, Jamei M. A bottom-up whole-body physiologically based pharmacokinetic model to mechanistically predict tissue distribution and the rate of subcutaneous absorption of therapeutic proteins. AAPS J. 2016;18(1):156–70.\nHeizmann CW, Fritz G, Schafer BW. S100 proteins: structure, functions and pathology. Front Biosci. 2002;7:D1356–68.\nSepp A, Meno-Tetang G, Weber A, Sanderson A, Schon O, Berges A. Computer-assembled cross-species\u002Fcross-modalities two-pore physiologically based pharmacokinetic model for biologics in mice and rats. J Pharmacokinet Pharmacodyn. 2019;46(4):339–59.\nTiemann CA, Vanlier J, Oosterveer MH, Groen AK, Hilbers PA, van Riel NA. Parameter trajectory analysis to identify treatment effects of pharmacological interventions. PLoS Comput Biol. 2013;9(8): e1003166.\nShah DK, Betts AM. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn. 2012;39(1):67–86.\nMorquette P, Verdier D, Kadala A, Fethiere J, Philippe AG, Robitaille R, et al. An astrocyte-dependent mechanism for neuronal rhythmogenesis. Nat Neurosci. 2015;18(6):844–54.\nIverson GL, Posti JP, Ohman J, Blennow K, Zetterberg H, Luoto TM. Reliability of serum S100B measurement following mild traumatic brain injury: a comparison of assay measurements from two laboratories. Brain Inj. 2020;34(9):1237–44.\nBouvier D, Duret T, Rouzaire P, Jabaudon M, Rouzaire M, Nourrisson C, et al. Preanalytical, analytical, gestational and pediatric aspects of the S100B immuno-assays. Clin Chem Lab Med. 2016;54(5):833–42.\nRahim MA, Rahim ZH, Ahmad WA, Hashim OH. Can saliva proteins be used to predict the onset of acute myocardial infarction among high-risk patients? Int J Med Sci. 2015;12(4):329–35.\nJasim H, Olausson P, Hedenberg-Magnusson B, Ernberg M, Ghafouri B. The proteomic profile of whole and glandular saliva in healthy pain-free subjects. Sci Rep. 2016;6:39073.\nOkonkwo DO, Puffer RC, Puccio AM, Yuh EL, Yue JK, Diaz-Arrastia R, et al. Point-of-care platform blood biomarker testing of glial fibrillary acidic protein versus S100 calcium-binding protein B for prediction of traumatic brain injuries: a transforming research and clinical knowledge in traumatic brain injury study. J Neurotrauma. 2020. https:\u002F\u002Fdoi.org\u002F10.1089\u002Fneu.2020.7140.\nHladky SB, Barrand MA. The glymphatic hypothesis: the theory and the evidence. Fluids Barriers CNS. 2022;19(1):9.\nAbbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a “glymphatic” system? Acta Neuropathol. 2018;135(3):387–407.\nDadas A, Washington J, Janigro D. Cerebral waste accumulation and glymphatic clearance as mechanisms of human neurological diseases. J Neurol Neuromed. 2016;1(7):15–9.\nPlog BA, Nedergaard M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu Rev Pathol. 2017. https:\u002F\u002Fdoi.org\u002F10.1146\u002Fannurev-pathol-051217-111018.\nDadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. Neuropsychiatr Dis Treat. 2018;14:2989–3000.\nAzizi S, Hier DB, Allen B, Obafemi-Ajayi T, Olbricht GR, Thimgan MS, et al. A kinetic model for blood biomarker levels after mild traumatic brain injury. Front Neurol. 2021;12: 668606.\nSakatani S, Seto-Ohshima A, Shinohara Y, Yamamoto Y, Yamamoto H, Itohara S, et al. Neural-activity-dependent release of S100B from astrocytes enhances kainate-induced gamma oscillations in vivo. J Neurosci. 2008;28(43):10928–36.\nWinter CD, Clough GF, Pringle AK, Church MK. Outcome following severe traumatic brain injury TBI correlates with serum S100B but not brain extracellular fluid S100B: an intracerebral microdialysis study. World J Neurosci. 2013;3:93–9.\nSen J, Belli A, Petzold A, Russo S, Keir G, Thompson EJ, et al. Extracellular fluid S100B in the injured brain: a future surrogate marker of acute brain injury? Acta Neurochir. 2005;147(8):897–900.\nHajdukova L, Sobek O, Prchalova D, Bilkova Z, Koudelkova M, Lukaskova J, et al. Biomarkers of brain damage: S100B and NSE concentrations in cerebrospinal fluid—a normative study. Biomed Res Int. 2015;2015: 379071.\nReiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta. 2001;310(2):173–86.",{"VOID":1282},"10.1186\u002Fs12987-022-00329-9","2024-06-26T15:03:47.630+00:00","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-022-00329-9",[1286,1301,1318,1335],{"id":1287,"sortIndex":19,"researcher":18,"roles":1288,"affiliations":1289,"properties":1298,"displayName":1300,"givenName":18,"familyName":18},"fa59cba1-1239-417f-afb0-58985cf47595",[186],[1290],{"id":1291,"sortIndex":19,"affiliation":1292,"properties":18},"b4330cad-7aa9-4cee-9dfe-3c69fffed720",{"id":1291,"createTime":18,"updateTime":18,"relativeEntities":1293,"slug":18,"properties":1294,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1297,"statistic":18},[],{"title":1295},{"VI":1296},"FloTBI Inc., Cleveland, USA",[],{"title":1299},{"VI":1300},"Robert Murcko",{"id":1302,"sortIndex":201,"researcher":18,"roles":1303,"affiliations":1304,"properties":1313,"displayName":1315,"givenName":18,"familyName":18},"7852b6ed-1894-4202-b145-c2de75de29a0",[186],[1305],{"id":1306,"sortIndex":19,"affiliation":1307,"properties":18},"0c483b24-1fe8-4e83-aa7d-fdf987f39326",{"id":1306,"createTime":18,"updateTime":18,"relativeEntities":1308,"slug":18,"properties":1309,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1312,"statistic":18},[],{"title":1310},{"VI":1311},"Laboratory of Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS - U 1191 INSERM), University of Montpellier, Montpellier, France",[],{"title":1314,"gsAuthor":1316},{"VI":1315},"Nicola Marchi",{"VOID":1317},"[\"douRrCEAAAAJ\"]",{"id":1319,"sortIndex":217,"researcher":18,"roles":1320,"affiliations":1321,"properties":1330,"displayName":1332,"givenName":18,"familyName":18},"3063d39f-272b-4299-bbfd-79556ad870b1",[186],[1322],{"id":1323,"sortIndex":19,"affiliation":1324,"properties":18},"eb09b1b9-4b0a-4e77-95a7-87cc2f6b4d6d",{"id":1323,"createTime":18,"updateTime":18,"relativeEntities":1325,"slug":18,"properties":1326,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1329,"statistic":18},[],{"title":1327},{"VI":1328},"Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Newport, UK",[],{"title":1331,"gsAuthor":1333},{"VI":1332},"Damian Bailey",{"VOID":1334},"[\"BvgTqfQAAAAJ\"]",{"id":1336,"sortIndex":295,"researcher":18,"roles":1337,"affiliations":1338,"properties":1353,"displayName":1355,"givenName":18,"familyName":18},"4a6afc2d-7355-4b5d-bbe0-a5a7bd6a8a7d",[186],[1339,1345],{"id":1291,"sortIndex":19,"affiliation":1340,"properties":18},{"id":1291,"createTime":18,"updateTime":18,"relativeEntities":1341,"slug":18,"properties":1342,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1344,"statistic":18},[],{"title":1343},{"VI":1296},[],{"id":1346,"sortIndex":201,"affiliation":1347,"properties":18},"26a74323-a33e-4837-95a7-f9af6bd79569",{"id":1346,"createTime":18,"updateTime":18,"relativeEntities":1348,"slug":18,"properties":1349,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1352,"statistic":18},[],{"title":1350},{"VI":1351},"Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, USA",[],{"title":1354,"gsAuthor":1356},{"VI":1355},"Damir Janigro",{"VOID":1357},"[\"24ankW0AAAAJ\"]",{"url":1284,"publisher":1359,"properties":1412},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":1360,"slug":10,"properties":1361,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":1364,"manageAffiliations":1381,"indexDatabases":1392,"url":18,"thumbnailPath":18,"statistic":1407,"gsStatistic":18,"type":18,"analyzePriority":18},[],{"issn":1362,"title":1363},{"VOID":13},{"EN":15},[1365,1369,1373,1377],{"id":22,"createTime":18,"updateTime":18,"relativeEntities":1366,"label":1367,"description":1368,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":25},{},{"id":28,"createTime":18,"updateTime":18,"relativeEntities":1370,"label":1371,"description":1372,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":31},{},{"id":34,"createTime":18,"updateTime":18,"relativeEntities":1374,"label":1375,"description":1376,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":37},{},{"id":40,"createTime":18,"updateTime":18,"relativeEntities":1378,"label":1379,"description":1380,"parentId":18,"standard":18,"scholarHubFieldId":18},[],{"EN":43},{},[1382,1387],{"id":47,"createTime":18,"updateTime":18,"relativeEntities":1383,"slug":18,"properties":1384,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1386,"statistic":18},[],{"title":1385},{"EN":51},[],{"id":54,"createTime":18,"updateTime":18,"relativeEntities":1388,"slug":18,"properties":1389,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1391,"statistic":18},[],{"title":1390},{"EN":58},[],[1393,1400],{"id":62,"indexDatabase":1394,"url":75,"indexYears":18,"academicFieldIds":1399,"indexDatabaseRanking":18},{"id":64,"createTime":18,"updateTime":18,"relativeEntities":1395,"label":1396,"description":1397,"key":71,"publicationTags":1398,"standard":18},[],{"EN":67,"VI":67},{"EN":69,"VI":70},[73,74],[77],{"id":79,"indexDatabase":1401,"url":90,"indexYears":91,"academicFieldIds":1406,"indexDatabaseRanking":97},{"id":81,"createTime":18,"updateTime":18,"relativeEntities":1402,"label":1403,"description":1404,"key":87,"publicationTags":1405,"standard":18},[],{"EN":84,"VI":84},{"EN":84,"VI":86},[89],[93,94,95,96],{"impactFactor":19,"impactFactorByYear":1408,"i10Index":112,"i10IndexLast5Year":113,"totalPublication":114,"totalPublicationByYear":1409,"totalCitation":128,"totalCitationByYear":1410,"totalCitationPerPublication":141,"totalCitationPerPublicationByYear":1411,"hindexLast5Year":155,"hindex":155},{"2012":100,"2013":101,"2014":102,"2015":103,"2016":104,"2017":105,"2018":106,"2019":107,"2020":108,"2021":109,"2022":110,"2023":111},{"2011":113,"2012":116,"2013":117,"2014":118,"2015":119,"2016":120,"2017":117,"2018":121,"2019":122,"2020":123,"2021":124,"2022":125,"2023":126,"2024":127},{"2011":130,"2012":131,"2013":132,"2014":133,"2015":134,"2016":112,"2017":135,"2018":136,"2019":137,"2020":138,"2021":139,"2022":140},{"2011":143,"2012":144,"2013":145,"2014":146,"2015":147,"2016":148,"2017":149,"2018":150,"2019":151,"2020":152,"2021":153,"2022":154},{"pages":1413,"volume":1415},{"VOID":1414},"1-20",{"VOID":1416},"19",{"total":117,"publishYear":1418,"statisticByYear":1419},2022,{"2023":1420,"2024":297,"2025":298,"2026":296},8,"2022-05-11",[97,73],{"id":1424,"createTime":1425,"updateTime":1426,"relativeEntities":1427,"slug":1428,"properties":1429,"entityType":177,"verifyStatus":178,"verifyTime":1442,"verifyNote":180,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":1443,"fullTextUrl":18,"authors":1444,"publicationType":231,"publisherRelationship":1477,"citationCount":19,"citationInfo":1531,"publishDate":1534,"publishYear":1532,"citationAnalyzeStatus":17,"lastCitationAnalyze":1535,"indexDatabases":1536,"openAccess":18,"references":18,"isForceReanalyzing":303},"1004fbcf-ad2f-4322-808c-905e4ad5c043","2024-04-08T09:09:50.943+00:00","2026-07-15T22:39:02.944+00:00",[],"Recent-advances-in-human-iPSC-derived-models-of-the-blood-brain-barrier",{"abstract":1430,"title":1432,"gsPaper":1434,"keywords":1436,"references":1438,"doi":1440},{"EN":1431},"The blood–brain barrier (BBB) is a critical component of the central nervous system that protects neurons and other cells of the brain parenchyma from potentially harmful substances found in peripheral circulation. Gaining a thorough understanding of the development and function of the human BBB has been hindered by a lack of relevant models given significant species differences and limited access to in vivo tissue. However, advances in induced pluripotent stem cell (iPSC) and organ-chip technologies now allow us to improve our knowledge of the human BBB in both health and disease. This review focuses on the recent progress in modeling the BBB in vitro using human iPSCs.",{"EN":1433},"Recent advances in human iPSC-derived models of the blood–brain barrier",{"VOID":1435},"[\"14435456317483856878\"]",{"EN":1437},"",{"VOID":1439},"Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and Dysfunction of the blood–brain barrier. Cell. 2015;163:1064–78. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.cell.2015.10.067.\nSyvänen S, Lindhe Ö, Palner M, Kornum BR, Rahman O, Långström B, et al. Species differences in blood–brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos. 2009;37:635–43. https:\u002F\u002Fdoi.org\u002F10.1124\u002Fdmd.108.024745.\nWarren MS, Zerangue N, Woodford K, Roberts LM, Tate EH, Feng B, et al. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. Pharmacol Res. 2009;59:404–13.\nShawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8:1332–41.\nUchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors. J Neurochem. 2011;117:333–45.\nHoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T. Quantitative atlas of blood–brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci. 2013;102:3343–55. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fjps.23575.\nBernas MJ, Cardoso FL, Daley SK, Weinand ME, Campos AR, Ferreira AJG, et al. Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood–brain barrier. Nat Protoc. 2010;5:1265–72.\nWeksler BB, Subileau EA, Perrière N, Charneau P, Holloway K, Leveque M, et al. Blood–brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 2005;19:1872–4.\nRahman NA, Rasil ANHM, Meyding-Lamade U, Craemer EM, Diah S, Tuah AA, et al. Immortalized endothelial cell lines for in vitro blood-brain barrier models: a systematic review. Brain Res. 2016;1642:532–45.\nTakahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.\nYu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science (80−). 2007;318:1917–20. https:\u002F\u002Fdoi.org\u002F10.1126\u002Fscience.1151526.\nLippmann ES, Azarin SM, Kay JE, Nessler RA, Wilson HK, Al-Ahmad A, et al. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol. 2012;30:783–91. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnbt.2247.\nLippmann ES, Al-Ahmad A, Azarin SM, Palecek SP, Shusta EV. A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep. 2014;4:4160. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fsrep04160.\nStebbins MJ, Wilson HK, Canfield SG, Qian T, Palecek SP, Shusta EV. Differentiation and characterization of human pluripotent stem cell-derived brain microvascular endothelial cells. Methods. 2016;101:93–102. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ymeth.2015.10.016.\nStebbins MJ, Lippmann ES, Faubion MG, Daneman R, Palecek SP, Shusta EV. Activation of RARα, RARγ, or RXRα increases barrier tightness in human induced pluripotent stem cell-derived brain endothelial cells. Biotechnol J. 2018;13:1–12.\nWilson HK, Canfield SG, Hjortness MK, Palecek SP, Shusta EV. Exploring the effects of cell seeding density on the differentiation of human pluripotent stem cells to brain microvascular endothelial cells. Fluids Barriers CNS. 2015;12:1–12.\nHollmann EK, Bailey AK, Potharazu AV, Neely MD, Bowman AB, Lippmann ES. Accelerated differentiation of human induced pluripotent stem cells to blood–brain barrier endothelial cells. Fluids Barriers CNS. 2017;14:1–13.\nQian T, Maguire SE, Canfield SG, Bao X, Olson WR, Shusta EV, et al. Directed differentiation of human pluripotent stem cells to blood–brain barrier endothelial cells. Sci Adv. 2017;3:48–50.\nPark TE, Mustafaoglu N, Herland A, Hasselkus R, Mannix R, FitzGerald EA, et al. Hypoxia-enhanced blood–brain barrier chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat Commun. 2019;10:1–12. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41467-019-10588-0.\nNeal EH, Marinelli NA, Shi Y, McClatchey PM, Balotin KM, Gullett DR, et al. A simplified, fully defined differentiation scheme for producing blood–brain barrier endothelial cells from human iPSCs. Stem Cell Rep. 2019;12:1380–8. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.stemcr.2019.05.008.\nPraça C, Rosa SC, Sevin E, Cecchelli R, Dehouck MP, Ferreira LS. Derivation of brain capillary-like endothelial cells from human pluripotent stem cell-derived endothelial progenitor cells. Stem Cell Rep. 2019;13:599–611.\nWilson HK, Faubion MG, Hjortness MK, Palecek SP, Shusta EV. Cryopreservation of brain endothelial cells derived from human induced pluripotent stem cells is enhanced by rho-associated coiled coil-containing kinase inhibition. Tissue Eng Part C Methods. 2016;22:1085–94.\nGrifno GN, Farrell AM, Linville RM, Arevalo D, Kim JH, Gu L, et al. Tissue-engineered blood–brain barrier models via directed differentiation of human induced pluripotent stem cells. Sci Rep. 2019;9:1–13.\nAppelt-Menzel A, Cubukova A, Günther K, Edenhofer F, Piontek J, Krause G, et al. Establishment of a human blood–brain barrier co-culture model mimicking the neurovascular unit using induced pluri- and multipotent stem cells. Stem Cell Rep. 2017;8:894–906.\nDelsing L, Dönnes P, Sánchez J, Clausen M, Voulgaris D, Falk A, et al. Barrier properties and transcriptome expression in human iPSC-derived models of the blood–brain barrier. Stem Cells. 2018;36:1816–27.\nCanfield SG, Stebbins MJ, Morales BS, Asai SW, Vatine GD, Svendsen CN, et al. An isogenic blood–brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. J Neurochem. 2017;140:874–88.\nCanfield SG, Stebbins MJ, Faubion MG, Gastfriend BD, Palecek SP, Shusta EV. An isogenic neurovascular unit model comprised of human induced pluripotent stem cell-derived brain microvascular endothelial cells, pericytes, astrocytes, and neurons. Fluids Barriers CNS. 2019;16:1–12. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-019-0145-6.\nDelsing L, Kallur T, Zetterberg H, Hicks R, Synnergren J. Enhanced xeno-free differentiation of hiPSC-derived astroglia applied in a blood–brain barrier model. Fluids Barriers CNS. 2019;16:1–15. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-019-0147-4.\nStebbins MJ, Gastfriend BD, Canfield SG, Lee MS, Richards D, Faubion MG, et al. Human pluripotent stem cell-derived brain pericyte-like cells induce blood–brain barrier properties. Sci Adv. 2019;5:eaau7375.\nRibecco-Lutkiewicz M, Sodja C, Haukenfrers J, Haqqani AS, Ly D, Zachar P, et al. A novel human induced pluripotent stem cell blood-brain barrier model: applicability to study antibody-triggered receptor-mediated transcytosis. Sci Rep. 2018;8:1–17. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41598-018-19522-8.\nVatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, et al. Human iPSC-derived blood–brain barrier chips enable disease modeling and personalized medicine applications. Cell Stem Cell. 2019;24(995–1005):e6. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.stem.2019.05.011.\nJamieson JJ, Linville RM, Ding YY, Gerecht S, Searson PC. Role of iPSC-derived pericytes on barrier function of iPSC-derived brain microvascular endothelial cells in 2D and 3D. Fluids Barriers CNS. 2019;16:1–16. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-019-0136-7.\nSances S, Ho R, Vatine G, West D, Laperle A, Meyer A, et al. Human iPSC-derived endothelial cells and microengineered organ-chip enhance neuronal development. Stem Cell Rep. 2018;10:1222–36. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.stemcr.2018.02.012.\nZlokovic BV. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201.\nObermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013;19:1584–96.\nSweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–50. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnrneurol.2017.188.\nSweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood–brain barrier: from physiology to disease and back. Physiol Rev. 2019;99:21–78.\nVatine GD, Al-Ahmad A, Barriga BK, Svendsen S, Salim A, Garcia L, et al. Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood–brain barrier. Cell Stem Cell. 2017;20(831–843):e5. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.stem.2017.04.002.\nLim RG, Quan C, Reyes-Ortiz AM, Lutz SE, Kedaigle AJ, Gipson TA, et al. Huntington’s disease iPSC-derived brain microvascular endothelial cells reveal WNT-mediated angiogenic and blood–brain barrier deficits. Cell Rep. 2017;19:1365–77. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.celrep.2017.04.021.\nKatt ME, Mayo LN, Ellis SE, Mahairaki V, Rothstein JD, Cheng L, et al. The role of mutations associated with familial neurodegenerative disorders on blood-brain barrier function in an iPSC model. Fluids Barriers CNS. 2019;16:1–13. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-019-0139-4.\nLee CAA, Seo HS, Armien AG, Bates FS, Tolar J, Azarin SM. Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients. Fluids Barriers CNS. 2018;15:1–15. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-018-0094-5.\nAl-Ahmad AJ, Patel R, Palecek SP, Shusta EV. Hyaluronan impairs the barrier integrity of brain microvascular endothelial cells through a CD44-dependent pathway. J Cereb Blood Flow Metab. 2019;39:1759–75. https:\u002F\u002Fdoi.org\u002F10.1177\u002F0271678X18767748.\nShin Y, Choi SH, Kim E, Bylykbashi E, Kim JA, Chung S, et al. Blood–brain barrier dysfunction in a 3D in vitro model of alzheimer’s disease. Adv Sci. 2019;6:1900962. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fadvs.201900962.\nRieker C, Migliavacca E, Vaucher A, Mayer FC, Baud G, Marquis J, et al. Apolipoprotein E4 expression causes gain of toxic function in isogenic human induced pluripotent stem cell-derived endothelial cells. Arterioscler Thromb Vasc Biol. 2019;39:e195–207. https:\u002F\u002Fdoi.org\u002F10.1161\u002FATVBAHA.118.312261.\nMantle JL, Lee KH. A differentiating neural stem cell-derived astrocytic population mitigates the inflammatory effects of TNF-α and IL-6 in an iPSC-based blood–brain barrier model. Neurobiol Dis. 2018;119:113–20. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.nbd.2018.07.030.\nQosa H, Lichter J, Sarlo M, Markandaiah SS, McAvoy K, Richard JP, et al. Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P-Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1-linked amyotrophic lateral sclerosis. Glia. 2016;64:1298–313.\nMohamed LA, Markandaiah SS, Bonanno S, Pasinelli P, Trotti D. Excess glutamate secreted from astrocytes drives upregulation of P-glycoprotein in endothelial cells in amyotrophic lateral sclerosis. Exp Neurol. 2019;316:27–38. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.expneurol.2019.04.002.\nPage S, Raut S, Al-Ahmad A. Oxygen-glucose deprivation\u002Freoxygenation-induced barrier disruption at the human blood–brain barrier is partially mediated through the HIF-1 pathway. NeuroMolecular Med. 2019;21:414–31. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs12017-019-08531-z.\nKim BJ, Bee OB, McDonagh MA, Stebbins MJ, Palecek SP, Doran KS, et al. Modeling group B streptococcus and blood-brain barrier interaction by using induced pluripotent stem cell-derived brain endothelial cells. mSphere. 2017;2:1–12.\nKim BJ, McDonagh MA, Deng L, Gastfriend BD, Schubert-Unkmeir A, Doran KS, et al. Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells. Fluids Barriers CNS. 2019;16:1–10. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-019-0146-5.\nMartins Gomes SF, Westermann AJ, Sauerwein T, Hertlein T, Förstner KU, Ohlsen K, et al. Induced pluripotent stem cell-derived brain endothelial cells as a cellular model to study neisseria meningitidis infection. Front Microbiol. 2019;10:1–13. https:\u002F\u002Fdoi.org\u002F10.3389\u002Ffmicb.2019.01181.\nPatel R, Hossain MA, German N, Al-Ahmad AJ. Gliotoxin penetrates and impairs the integrity of the human blood–brain barrier in vitro. Mycotoxin Res. 2018;34:257–68.\nAlimonti JB, Ribecco-Lutkiewicz M, Sodja C, Jezierski A, Stanimirovic DB, Liu Q, et al. Zika virus crosses an in vitro human blood brain barrier model. Fluids Barriers CNS. 2018;15:1–9. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-018-0100-y.\nIngber DE. Developmentally inspired human ‘organs on chips’. Development. 2018;145:dev156125.\nRonaldson-Bouchard K, Vunjak-Novakovic G. Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell. 2018;22:310–24. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.stem.2018.02.011.\nZhang B, Korolj A, Lai BFL, Radisic M. Advances in organ-on-a-chip engineering. Nat Rev Mater. 2018;3:257–78. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41578-018-0034-7.\nCampisi M, Shin Y, Osaki T, Hajal C, Chiono V, Kamm RD. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials. 2018;180:117–29. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.biomaterials.2018.07.014.\nJagadeesan S, Workman MJ, Herland A, Svendsen CN, Vatine GD. Generation of a human iPSC-based blood–brain barrier chip. J Vis Exp. 2020. https:\u002F\u002Fdoi.org\u002F10.3791\u002F60925.\nFabre KM, Delsing L, Hicks R, Colclough N, Crowther DC, Ewart L. Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling: a case study for blood brain barrier research in a pharmaceutical setting. Adv Drug Deliv Rev. 2019;140:129–35. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.addr.2018.09.009.\nDeStefano JG, Xu ZS, Williams AJ, Yimam N, Searson PC. Effect of shear stress on iPSC-derived human brain microvascular endothelial cells (dhBMECs). Fluids Barriers CNS. 2017;14:1–15.\nLinville RM, DeStefano JG, Sklar MB, Xu Z, Farrell AM, Bogorad MI, et al. Human iPSC-derived blood–brain barrier microvessels: validation of barrier function and endothelial cell behavior. Biomaterials. 2018;2019(190–191):24–37. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.biomaterials.2018.10.023.\nKatt ME, Linville RM, Mayo LN, Xu ZS, Searson PC. Functional brain-specific microvessels from iPSC-derived human brain microvascular endothelial cells: the role of matrix composition on monolayer formation. Fluids Barriers CNS. 2018;15:7. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-018-0092-7.\nFaley SL, Neal EH, Wang JX, Bosworth AM, Weber CM, Balotin KM, et al. iPSC-derived brain endothelium exhibits stable, long-term barrier function in perfused hydrogel scaffolds. Stem Cell Rep. 2019;12:474–87. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.stemcr.2019.01.009.\nWang YI, Abaci HE, Shuler ML. Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol Bioeng. 2017;114:184–94.\nLee SWL, Campisi M, Osaki T, Possenti L, Mattu C, Adriani G, et al. Modeling nanocarrier transport across a 3D in vitro human blood-brain–barrier microvasculature. Adv Healthc Mater. 2020;1901486:1901486. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fadhm.201901486.\nMotallebnejad P, Thomas A, Swisher SL, Azarin SM. An isogenic hiPSC-derived BBB-on-a-chip. Biomicrofluidics. 2019;13:064119. https:\u002F\u002Fdoi.org\u002F10.1063\u002F1.5123476.\nLinville RM, DeStefano JG, Sklar MB, Chu C, Walczak P, Searson PC. Modeling hyperosmotic blood–brain barrier opening within human tissue-engineered in vitro brain microvessels. J Cereb Blood Flow Metab. 2019. https:\u002F\u002Fdoi.org\u002F10.1177\u002F0271678x19867980.\nPardridge WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2:3–14.\nOhshima M, Kamei S, Fushimi H, Mima S, Yamada T, Yamamoto T. Prediction of drug permeability using in vitro blood–brain barrier models with human induced pluripotent stem cell-derived brain microvascular endothelial cells. Biores Open Access. 2019;8:200–9. https:\u002F\u002Fdoi.org\u002F10.1089\u002Fbiores.2019.0026.\nAday S, Cecchelli R, Hallier-Vanuxeem D, Dehouck MP, Ferreira L. Stem cell-based human blood–brain barrier models for drug discovery and delivery. Trends Biotechnol. 2016;34:382–93. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.tibtech.2016.01.001.\nLi Y, Sun X, Liu H, Huang L, Meng G, Ding Y, et al. Development of human in vitro brain–blood barrier model from induced pluripotent stem cell-derived endothelial cells to predict the in vivo permeability of drugs. Neurosci Bull. 2019;35:996–1010. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs12264-019-00384-7.\nKurosawa T, Tega Y, Higuchi K, Yamaguchi T, Nakakura T, Mochizuki T, et al. Expression and functional characterization of drug transporters in brain microvascular endothelial cells derived from human induced pluripotent stem cells. Mol Pharm. 2018;15:5546–55.\nMantle JL, Min L, Lee KH. Minimum transendothelial electrical resistance thresholds for the study of small and large molecule drug transport in a human in vitro blood–brain barrier model. Mol Pharm. 2016;13:4191–8.\nLe Roux G, Jarray R, Guyot A-C, Pavoni S, Costa N, Théodoro F, et al. Proof-of-concept study of drug brain permeability between in vivo human brain and an in vitro iPSCs-human blood–brain barrier model. Sci Rep. 2019;9:16310. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41598-019-52213-6.\nPardridge WM. Drug and gene targeting to the brain with molecular trojan horses. Nat Rev Drug Discov. 2002;1:131–9. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnrd725.\nLu TM, Redmond D, Magdeldin T, Nguyen D-HT, Snead A, Sproul A, et al. Human induced pluripotent stem cell-derived neuroectodermal epithelial cells mistaken for blood-brain barrier-forming endothelial cells. bioRxiv. 2019:699173. https:\u002F\u002Fdoi.org\u002F10.1101\u002F699173.\nUrich E, Lazic SE, Molnos J, Wells I, Freskgård PO. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood–brain barrier models. PLoS ONE. 2012;7:e38149.\nAl-Ahmad AJ. Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC\u002FD3 cells. Am J Physiol Cell Physiol. 2017;313:C421–9.\nVanlandewijck M, He L, Mäe MA, Andrae J, Ando K, Del Gaudio F, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554:475–80.\nNoumbissi ME, Galasso B, Stins MF. Brain vascular heterogeneity: implications for disease pathogenesis and design of in vitro blood-brain barrier models. Fluids Barriers CNS. 2018;15:1–12. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-018-0097-2.\nDestefano JG, Jamieson JJ, Linville RM, Searson PC. Benchmarking in vitro tissue-engineered blood–brain barrier models. Fluids Barriers CNS. 2018;15:1–15. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12987-018-0117-2.\nPalmgrén JJ, Mönkkönen J, Korjamo T, Hassinen A, Auriola S. Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions. Eur J Pharm Biopharm. 2006;64:369–78. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejpb.2006.06.005.\nvan Meer BJ, de Vries H, Firth KSA, van Weerd J, Tertoolen LGJ, Karperien HBJ, et al. Small molecule absorption by PDMS in the context of drug response bioassays. Biochem Biophys Res Commun. 2017;482:323–8. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.bbrc.2016.11.062.\nPatel R, Alahmad AJ. Growth-factor reduced Matrigel source influences stem cell derived brain microvascular endothelial cell barrier properties. Fluids Barriers CNS. 2016;13:4–10.\nMantle JL, Lee KH. Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid-β and with neuroinflammatory cytokines. Biotechnol Bioeng. 2019;116(7):1752–61.",{"VOID":1441},"10.1186\u002Fs12987-020-00191-7","2024-05-10T15:11:05.139+00:00","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-020-00191-7",[1445,1462],{"id":1446,"sortIndex":19,"researcher":18,"roles":1447,"affiliations":1448,"properties":1457,"displayName":1459,"givenName":18,"familyName":18},"cf3fed8a-bbad-4cd9-85f0-a89dcb2f18e0",[186],[1449],{"id":1450,"sortIndex":19,"affiliation":1451,"properties":18},"5fc5a3ea-6a47-4567-9a98-b84e96515163",{"id":1450,"createTime":18,"updateTime":18,"relativeEntities":1452,"slug":18,"properties":1453,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1456,"statistic":18},[],{"title":1454},{"VI":1455},"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA",[],{"title":1458,"gsAuthor":1460},{"VI":1459},"Michael J. 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Hiện tại, bệnh hoạt động được xác định thông qua sự tái phát được xác nhận bởi bác sĩ hoặc phát hiện các tổn thương có tăng cường tương phản qua MRI, cho thấy tính thấm của BBB. Tuy nhiên, việc xác nhận lâm sàng về bệnh hoạt động có thể gặp nhiều khó khăn. Do đó, việc theo dõi bệnh trong MS có thể được hưởng lợi từ việc xác định một dấu ấn sinh học dễ tiếp cận cho bệnh hoạt động. Chúng tôi tin rằng các vesicle ngoại bào (EV) được tách ra từ huyết tương là những ứng cử viên xuất sắc để đáp ứng nhu cầu này. Bởi vì vai trò quan trọng của tính thấm BBB trong sinh bệnh học của MS và xác định bệnh hoạt động, chúng tôi đã tìm cách xác định EV có nguồn gốc từ tế bào nội mô hệ thần kinh trung ương (CNS) như là các dấu ấn sinh học của MS hoạt động. Vì các tế bào nội mô tiết ra nhiều EV hơn khi bị kích thích hoặc tổn thương, chúng tôi giả thuyết rằng nồng độ tuần hoàn của EV có nguồn gốc từ tế bào nội mô CNS sẽ tăng lên ở những bệnh nhân MS có bệnh hoạt động. Để kiểm tra điều này, chúng tôi đã phát triển một phương pháp mới để xác định EV có nguồn gốc từ tế bào nội mô CNS được tách ra từ huyết tương của bệnh nhân bằng cách sử dụng cytofluorometry. EV từ nội mô được xác định qua việc không có dấu ấn lymphocyte hoặc tiểu cầu CD3 và CD41, tương ứng, và biểu hiện dương tính của các dấu ấn pan-nội mô CD31, CD105 hoặc CD144. Để xác định xem EV có nguồn gốc từ tế bào nội mô CNS hay không, EV biểu thị CD31, CD105 hoặc CD144 đã được đánh giá để xác định sự biểu hiện của protein myelin và lymphocyte MAL, một protein được biểu hiện đặc biệt bởi các tế bào nội mô CNS so với các tế bào nội mô của các cơ quan ngoại vi. Các thí nghiệm kiểm soát chất lượng cho thấy rằng EV được phát hiện bằng phương pháp cytofluorometry của chúng tôi có kích thước từ 0,2 đến 1 micron. Phân tích cytofluorometry của EV tách ra từ 20 đối chứng khỏe mạnh, 16 bệnh nhân MS (RRMS) tái phát-điểm lại đang có bệnh hoạt động không nhận liệu pháp sửa đổi bệnh, 14 bệnh nhân RRMS có bệnh ổn định không nhận liệu pháp sửa đổi bệnh, 17 bệnh nhân RRMS tái phát ổn định đang nhận natalizumab, và 14 bệnh nhân RRMS ổn định đang nhận ocrelizumab cho thấy sự gia tăng đáng kể về nồng độ huyết tương của EV có nguồn gốc từ tế bào nội mô CNS ở những bệnh nhân có bệnh hoạt động so với tất cả các nhóm còn lại (p = 0.001). Kết luận: Lần đầu tiên, chúng tôi đã xác định được một phương pháp để nhận diện EV có nguồn gốc từ tế bào nội mô CNS trong huyết tương của mẫu máu người. Kết quả từ nghiên cứu pilot của chúng tôi cho thấy rằng mức độ tăng lên của EV có nguồn gốc từ tế bào nội mô CNS có thể là một dấu ấn sinh học của tính thấm BBB và bệnh hoạt động trong MS.","Multiple sclerosis (MS) is a complex, heterogenous disease characterized by inflammation, demyelination, and blood–brain barrier (BBB) permeability. Currently, active disease is determined by physician confirmed relapse or detection of contrast enhancing lesions via MRI indicative of BBB permeability. However, clinical confirmation of active disease can be cumbersome. As such, disease monitoring in MS could benefit from identification of an easily accessible biomarker of active disease. We believe extracellular vesicles (EV) isolated from plasma are excellent candidates to fulfill this need. Because of the critical role BBB permeability plays in MS pathogenesis and identification of active disease, we sought to identify EV originating from central nervous system (CNS) endothelial as biomarkers of active MS. Because endothelial cells secrete more EV when stimulated or injured, we hypothesized that circulating concentrations of CNS endothelial derived EV will be increased in MS patients with active disease. To test this, we developed a novel method to identify EV originating from CNS endothelial cells isolated from patient plasma using flow cytometry. Endothelial derived EV were identified by the absence of lymphocyte or platelet markers CD3 and CD41, respectively, and positive expression of pan-endothelial markers CD31, CD105, or CD144. To determine if endothelial derived EV originated from CNS endothelial cells, EV expressing CD31, CD105, or CD144 were evaluated for expression of the myelin and lymphocyte protein MAL, a protein specifically expressed by CNS endothelial cells compared to endothelial cells of peripheral organs. Quality control experiments indicate that EV detected using our flow cytometry method are 0.2 to 1 micron in size. Flow cytometry analysis of EV isolated from 20 healthy controls, 16 relapsing–remitting MS (RRMS) patients with active disease not receiving disease modifying therapy, 14 RRMS patients with stable disease not receiving disease modifying therapy, 17 relapsing-RRMS patients with stable disease receiving natalizumab, and 14 RRMS patients with stable disease receiving ocrelizumab revealed a significant increase in the plasma concentration of CNS endothelial derived EV in patients with active disease compared to all other groups (p = 0.001). Conclusions: For the first time, we have identified a method to identify CNS endothelial derived EV in circulation from human blood samples. Results from our pilot study indicate that increased levels of CNS endothelial derived EV may be a biomarker of BBB permeability and active disease in MS.",{"EN":1548,"VI":1549},"CNS endothelial derived extracellular vesicles are biomarkers of active disease in multiple sclerosis","Các vesicle ngoại bào nguồn gốc từ nội mô CNS là các dấu ấn sinh học của bệnh hoạt động trong bệnh đa xơ cứng",{"VOID":1551},"[\"17570826686466102869\"]",{"VI":1553},"đa xơ cứng, ngoại bào, tính thấm hàng rào máu-não, dấu ấn sinh học, nội mô CNS",{"VOID":1555},"10.1186\u002Fs12987-021-00299-4","2024-04-29T12:05:32.563+00:00",[442],"https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-021-00299-4",[1560,1577,1592,1605],{"id":1561,"sortIndex":19,"researcher":18,"roles":1562,"affiliations":1563,"properties":1572,"displayName":1574,"givenName":18,"familyName":18},"d9455836-8e7c-4fa4-a31d-e1069f84719e",[186],[1564],{"id":1565,"sortIndex":19,"affiliation":1566,"properties":18},"4bc2a523-a13e-41b0-a1e6-f5b8edf636ab",{"id":1565,"createTime":18,"updateTime":18,"relativeEntities":1567,"slug":18,"properties":1568,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1571,"statistic":18},[],{"title":1569},{"VI":1570},"The Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, New York, USA",[],{"title":1573,"gsAuthor":1575},{"VI":1574},"Michael Mazzucco",{"VOID":1576},"[\"PGBhOn4AAAAJ\"]",{"id":1578,"sortIndex":201,"researcher":18,"roles":1579,"affiliations":1580,"properties":1589,"displayName":1591,"givenName":18,"familyName":18},"87181f7f-bcbe-4e55-bceb-f7fd393ca6ee",[186],[1581],{"id":1582,"sortIndex":19,"affiliation":1583,"properties":18},"70bb3959-2c9e-4106-bff2-05e597920298",{"id":1582,"createTime":18,"updateTime":18,"relativeEntities":1584,"slug":18,"properties":1585,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1588,"statistic":18},[],{"title":1586},{"VI":1587},"Department of Neurology, Weill Cornell Medical College, New York, USA",[],{"title":1590},{"VI":1591},"William Mannheim",{"id":1593,"sortIndex":217,"researcher":18,"roles":1594,"affiliations":1595,"properties":1602,"displayName":1604,"givenName":18,"familyName":18},"9c7a6bd7-044d-484f-9f56-4570812036d3",[186],[1596],{"id":1565,"sortIndex":19,"affiliation":1597,"properties":18},{"id":1565,"createTime":18,"updateTime":18,"relativeEntities":1598,"slug":18,"properties":1599,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1601,"statistic":18},[],{"title":1600},{"VI":1570},[],{"title":1603},{"VI":1604},"Samantha V. Shetty",{"id":1606,"sortIndex":295,"researcher":18,"roles":1607,"affiliations":1608,"properties":1615,"displayName":1617,"givenName":18,"familyName":18},"fc24eb7d-9eaf-41d4-bb17-5b6a903854f6",[186],[1609],{"id":1565,"sortIndex":19,"affiliation":1610,"properties":18},{"id":1565,"createTime":18,"updateTime":18,"relativeEntities":1611,"slug":18,"properties":1612,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1614,"statistic":18},[],{"title":1613},{"VI":1570},[],{"title":1616},{"VI":1617},"Jennifer R. 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Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8(7):727.",{"doi":607},{"id":603,"text":1685,"url":605,"identifiers":1686},"Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.",{"doi":607},{"id":603,"text":1688,"url":605,"identifiers":1689},"Andaloussi SE, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12(5):347–57.",{"doi":607},{"id":603,"text":1691,"url":605,"identifiers":1692},"van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28.",{"doi":607},{"id":603,"text":1694,"url":605,"identifiers":1695},"Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.",{"doi":607},{"id":603,"text":1697,"url":605,"identifiers":1698},"Paolicelli RC, Bergamini G, Rajendran L. Cell-to-cell communication by extracellular vesicles: focus on microglia. Neuroscience. 2019;405:148–57.",{"doi":607},{"id":603,"text":1700,"url":605,"identifiers":1701},"Raposo G, Stahl PD. Extracellular vesicles: a new communication paradigm? Nat Rev Mol Cell Biol. 2019;20(9):509–10.",{"doi":607},{"id":603,"text":1703,"url":605,"identifiers":1704},"Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21(1):9–17.",{"doi":607},{"id":603,"text":1706,"url":605,"identifiers":1707},"Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol. 2018;6:18.",{"doi":607},{"id":603,"text":1709,"url":605,"identifiers":1710},"Saenz-Cuesta M, Osorio-Querejeta I, Otaegui D. Extracellular vesicles in multiple sclerosis: what are they telling us? Front Cell Neurosci. 2014;8:100.",{"doi":607},{"id":603,"text":1712,"url":605,"identifiers":1713},"Dolcetti E, Bruno A, Guadalupi L, Rizzo FR, Musella A, Gentile A, et al. Emerging role of extracellular vesicles in the pathophysiology of multiple sclerosis. Int J Mol Sci. 2020;21(19):7336.",{"doi":607},{"id":603,"text":1715,"url":605,"identifiers":1716},"Blonda M, Amoruso A, Martino T, Avolio C. New insights into immune cell-derived extracellular vesicles in multiple sclerosis. Front Neurol. 2018;9:604.",{"doi":607},{"id":603,"text":1718,"url":605,"identifiers":1719},"Barreca MM, Aliotta E, Geraci F. Extracellular vesicles in multiple sclerosis as possible biomarkers: dream or reality? Adv Exp Med Biol. 2017;958:1–9.",{"doi":607},{"id":603,"text":1721,"url":605,"identifiers":1722},"Kuhlmann T, Ludwin S, Prat A, Antel J, Bruck W, Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13–24.",{"doi":607},{"id":603,"text":1724,"url":605,"identifiers":1725},"Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJ, Reynolds R, Martin R. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci. 2015;16(3):147–58.",{"doi":607},{"id":603,"text":1727,"url":605,"identifiers":1728},"Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.",{"doi":607},{"id":603,"text":1730,"url":605,"identifiers":1731},"Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17(2):210–8.",{"doi":607},{"id":1733,"text":1734,"url":1735,"identifiers":1736},"7876aa37-78a1-49a3-8d83-88bdb0cb2cab","Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–93.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS147444221470256X",{"doi":1737},"10.1016\u002Fs1474-4422(14)70256-x",{"id":1739,"text":1740,"url":1741,"identifiers":1742},"ffcc47a7-797f-498b-a51c-fab93653d9f3","Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011;122(2):155–70.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00401-011-0840-0",{"doi":1743},"10.1007\u002Fs00401-011-0840-0",{"id":603,"text":1745,"url":605,"identifiers":1746},"Dobson R, Giovannoni G. Multiple sclerosis—a review. Eur J Neurol. 2019;26(1):27–40.",{"doi":607},{"id":603,"text":1748,"url":605,"identifiers":1749},"van der Valk P, De Groot CJ. Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol. 2000;26(1):2–10.",{"doi":607},{"id":603,"text":1751,"url":605,"identifiers":1752},"Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707–17.",{"doi":607},{"id":603,"text":1754,"url":605,"identifiers":1755},"Metz I, Weigand SD, Popescu BF, Frischer JM, Parisi JE, Guo Y, et al. Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann Neurol. 2014;75(5):728–38.",{"doi":607},{"id":603,"text":1757,"url":605,"identifiers":1758},"Gaetani L, Prosperini L, Mancini A, Eusebi P, Cerri MC, Pozzilli C, et al. 2017 revisions of McDonald criteria shorten the time to diagnosis of multiple sclerosis in clinically isolated syndromes. J Neurol. 2018;265(11):2684–7.",{"doi":607},{"id":603,"text":1760,"url":605,"identifiers":1761},"Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162–73.",{"doi":607},{"id":18,"text":1763,"url":18,"identifiers":1764},"Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet. 2018;391(10130):1622–36.",{},{"id":603,"text":1766,"url":605,"identifiers":1767},"Granziera C, Reich DS. Gadolinium should always be used to assess disease activity in MS—Yes. Mult Scler. 2020;26(7):765–6.",{"doi":607},{"id":603,"text":1769,"url":605,"identifiers":1770},"Bruck W, Bitsch A, Kolenda H, Bruck Y, Stiefel M, Lassmann H. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol. 1997;42(5):783–93.",{"doi":607},{"id":603,"text":1772,"url":605,"identifiers":1773},"Katz D, Taubenberger JK, Cannella B, McFarlin DE, Raine CS, McFarland HF. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol. 1993;34(5):661–9.",{"doi":607},{"id":603,"text":1775,"url":605,"identifiers":1776},"Lassmann H. The pathologic substrate of magnetic resonance alterations in multiple sclerosis. Neuroimaging Clin N Am. 2008;18(4):563–76, ix.",{"doi":607},{"id":603,"text":1778,"url":605,"identifiers":1779},"Li DK, Held U, Petkau J, Daumer M, Barkhof F, Fazekas F, et al. MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology. 2006;66(9):1384–9.",{"doi":607},{"id":18,"text":1781,"url":18,"identifiers":1782},"Khoury SJ, Guttmann CR, Orav EJ, Hohol MJ, Ahn SS, Hsu L, et al. Longitudinal MRI in multiple sclerosis: correlation between disability and lesion burden. Neurology. 1994;44(11):2120–4.",{},{"id":603,"text":1784,"url":605,"identifiers":1785},"Barkhof F. MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS). Mult Scler. 1999;5(4):283–6.",{"doi":607},{"id":603,"text":1787,"url":605,"identifiers":1788},"Gelibter S, Pisa M, Croese T, Finardi A, Mandelli A, Sangalli F, et al. Spinal fluid myeloid microvesicles predict disease course in multiple sclerosis. Ann Neurol. 2021;90(2):253–65.",{"doi":607},{"id":603,"text":1790,"url":605,"identifiers":1791},"Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F, et al. Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol. 2012;72(4):610–24.",{"doi":607},{"id":603,"text":1793,"url":605,"identifiers":1794},"Geraci F, Ragonese P, Barreca MM, Aliotta E, Mazzola MA, Realmuto S, et al. Differences in intercellular communication during clinical relapse and gadolinium-enhanced MRI in patients with relapsing remitting multiple sclerosis: a study of the composition of extracellular vesicles in cerebrospinal fluid. Front Cell Neurosci. 2018;12:418.",{"doi":607},{"id":603,"text":1796,"url":605,"identifiers":1797},"Masvekar R, Mizrahi J, Park J, Williamson PR, Bielekova B. Quantifications of CSF apoptotic bodies do not provide clinical value in multiple sclerosis. Front Neurol. 2019;10:1241.",{"doi":607},{"id":603,"text":1799,"url":605,"identifiers":1800},"Pieragostino D, Lanuti P, Cicalini I, Cufaro MC, Ciccocioppo F, Ronci M, et al. Proteomics characterization of extracellular vesicles sorted by flow cytometry reveals a disease-specific molecular cross-talk from cerebrospinal fluid and tears in multiple sclerosis. J Proteomics. 2019;204:103403.",{"doi":607},{"id":603,"text":1802,"url":605,"identifiers":1803},"Dalla Costa G, Croese T, Pisa M, Finardi A, Fabbella L, Martinelli V, et al. CSF extracellular vesicles and risk of disease activity after a first demyelinating event. Mult Scler. 2021;27(10):1606–10.",{"doi":607},{"id":603,"text":1805,"url":605,"identifiers":1806},"Doherty CM, Forbes RB. Diagnostic lumbar puncture. Ulster Med J. 2014;83(2):93–102.",{"doi":607},{"id":603,"text":1808,"url":605,"identifiers":1809},"Evans RW. Complications of lumbar puncture. Neurol Clin. 1998;16(1):83–105.",{"doi":607},{"id":603,"text":1811,"url":605,"identifiers":1812},"Grayev A, Schoepp M, Kuner A. A systematic review of procedural complications from transforaminal lumbar puncture for intrathecal nusinersen administration in patients with spinal muscular atrophy. AJNR Am J Neuroradiol. 2021;42(5):980–5.",{"doi":607},{"id":603,"text":1814,"url":605,"identifiers":1815},"Pitkanen M, Forster J. Complications caused by lumbar puncture. Duodecim. 2014;130(18):1834–42.",{"doi":607},{"id":1817,"text":1818,"url":1819,"identifiers":1820},"91c5a766-422a-4e81-a91b-49b3232df46a","Groen K, Maltby VE, Scott RJ, Tajouri L, Lechner-Scott J. Concentrations of plasma-borne extracellular particles differ between multiple sclerosis disease courses and compared to healthy controls. Mult Scler Relat Disord. 2020;45:102446.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS2211034820305216",{"doi":1821},"10.1016\u002Fj.msard.2020.102446",{"id":603,"text":1823,"url":605,"identifiers":1824},"Bhargava P, Nogueras-Ortiz C, Chawla S, Baek R, Jorgensen MM, Kapogiannis D. Altered levels of toll-like receptors in circulating extracellular vesicles in multiple sclerosis. Cells. 2019;8(9):1058.",{"doi":607},{"id":603,"text":1826,"url":605,"identifiers":1827},"Bhargava P, Nogueras-Ortiz C, Kim S, Delgado-Peraza F, Calabresi PA, Kapogiannis D. Synaptic and complement markers in extracellular vesicles in multiple sclerosis. Mult Scler. 2021;27(4):509–18.",{"doi":607},{"id":603,"text":1829,"url":605,"identifiers":1830},"Galazka G, Mycko MP, Selmaj I, Raine CS, Selmaj KW. Multiple sclerosis: serum-derived exosomes express myelin proteins. Mult Scler. 2018;24(4):449–58.",{"doi":607},{"id":603,"text":1832,"url":605,"identifiers":1833},"Moyano AL, Li G, Boullerne AI, Feinstein DL, Hartman E, Skias D, et al. Sulfatides in extracellular vesicles isolated from plasma of multiple sclerosis patients. J Neurosci Res. 2016;94(12):1579–87.",{"doi":607},{"id":603,"text":1835,"url":605,"identifiers":1836},"Saenz-Cuesta M, Irizar H, Castillo-Trivino T, Munoz-Culla M, Osorio-Querejeta I, Prada A, et al. Circulating microparticles reflect treatment effects and clinical status in multiple sclerosis. Biomark Med. 2014;8(5):653–61.",{"doi":607},{"id":603,"text":1838,"url":605,"identifiers":1839},"Lowery-Nordberg M, Eaton E, Gonzalez-Toledo E, Harris MK, Chalamidas K, McGee-Brown J, et al. The effects of high dose interferon-beta1a on plasma microparticles: correlation with MRI parameters. J Neuroinflammation. 2011;8:43.",{"doi":607},{"id":1841,"text":1842,"url":1843,"identifiers":1844},"a75e058c-5f64-45a4-a29a-70a60e310dfd","Marcos-Ramiro B, Oliva Nacarino P, Serrano-Pertierra E, Blanco-Gelaz MA, Weksler BB, Romero IA, et al. Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neurosci. 2014;15:110.","https:\u002F\u002Fbmcneurosci.biomedcentral.com\u002Farticles\u002F10.1186\u002F1471-2202-15-110",{"doi":1845},"10.1186\u002F1471-2202-15-110",{"id":1847,"text":1848,"url":1849,"identifiers":1850},"a6ffdd32-bf20-49c1-b147-a0984f4be783","Alexander JS, Chervenak R, Weinstock-Guttman B, Tsunoda I, Ramanathan M, Martinez N, et al. Blood circulating microparticle species in relapsing-remitting and secondary progressive multiple sclerosis. A case-control, cross sectional study with conventional MRI and advanced iron content imaging outcomes. J Neurol Sci. 2015;355(1–2):84–9.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0022510X15003093",{"doi":1851},"10.1016\u002Fj.jns.2015.05.027",{"id":603,"text":1853,"url":605,"identifiers":1854},"Zinger A, Latham SL, Combes V, Byrne S, Barnett MH, Hawke S, et al. Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients. Mult Scler. 2016;22(14):1883–7.",{"doi":607},{"id":603,"text":1856,"url":605,"identifiers":1857},"Sheremata WA, Jy W, Delgado S, Minagar A, McLarty J, Ahn Y. Interferon-beta1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis. J Neuroinflammation. 2006;3:23.",{"doi":607},{"id":603,"text":1859,"url":605,"identifiers":1860},"Jy W, Minagar A, Jimenez JJ, Sheremata WA, Mauro LM, Horstman LL, et al. Endothelial microparticles (EMP) bind and activate monocytes: elevated EMP-monocyte conjugates in multiple sclerosis. Front Biosci. 2004;9:3137–44.",{"doi":607},{"id":603,"text":1862,"url":605,"identifiers":1863},"Gaitan MI, Shea CD, Evangelou IE, Stone RD, Fenton KM, Bielekova B, et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann Neurol. 2011;70(1):22–9.",{"doi":607},{"id":603,"text":1865,"url":605,"identifiers":1866},"Kirk J, Plumb J, Mirakhur M, McQuaid S. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol. 2003;201(2):319–27.",{"doi":607},{"id":603,"text":1868,"url":605,"identifiers":1869},"McQuaid S, Cunnea P, McMahon J, Fitzgerald U. The effects of blood-brain barrier disruption on glial cell function in multiple sclerosis. Biochem Soc Trans. 2009;37(Pt 1):329–31.",{"doi":607},{"id":603,"text":1871,"url":605,"identifiers":1872},"Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9(6):540–9.",{"doi":607},{"id":603,"text":1874,"url":605,"identifiers":1875},"Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, Flores-Alvarado LJ, Mireles-Ramirez MA, Gonzalez-Renovato ED, et al. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res. 2014;45(8):687–97.",{"doi":607},{"id":1877,"text":1878,"url":1879,"identifiers":1880},"13cd4bf5-a40d-4ec0-9713-9e65a65e65c0","Ramirez SH, Andrews AM, Paul D, Pachter JS. Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers. Fluids Barriers CNS. 2018;15(1):19.","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-018-0104-7",{"doi":1881},"10.1186\u002Fs12987-018-0104-7",{"id":603,"text":1883,"url":605,"identifiers":1884},"Linden JR, Flores C, Schmidt EF, Uzal FA, Michel AO, Valenzuela M, et al. Clostridium perfringens epsilon toxin induces blood brain barrier permeability via caveolae-dependent transcytosis and requires expression of MAL. PLoS Pathog. 2019;15(11):e1008014.",{"doi":607},{"id":603,"text":1886,"url":605,"identifiers":1887},"Daneman R, Zhou L, Agalliu D, Cahoy JD, Kaushal A, Barres BA. The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS ONE. 2010;5(10):e13741.",{"doi":607},{"id":603,"text":1889,"url":605,"identifiers":1890},"Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM, et al. A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci U S A. 2015;112(23):7285–90.",{"doi":607},{"id":603,"text":1892,"url":605,"identifiers":1893},"Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016;89(1):37–53.",{"doi":607},{"id":603,"text":1895,"url":605,"identifiers":1896},"Song HW, Foreman KL, Gastfriend BD, Kuo JS, Palecek SP, Shusta EV. Transcriptomic comparison of human and mouse brain microvessels. Sci Rep. 2020;10(1):12358.",{"doi":607},{"id":603,"text":1898,"url":605,"identifiers":1899},"Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.",{"doi":607},{"id":1901,"text":1902,"url":1903,"identifiers":1904},"156eb43e-29aa-4f14-a20b-bffec468f860","Libregts S, Arkesteijn GJA, Nemeth A, Nolte-’t Hoen ENM, Wauben MHM. Flow cytometric analysis of extracellular vesicle subsets in plasma: impact of swarm by particles of non-interest. J Thromb Haemost. 2018;16(7):1423–36.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1538783622023406",{"doi":1905},"10.1111\u002Fjth.14154",{"id":603,"text":1907,"url":605,"identifiers":1908},"Veerman RE, Teeuwen L, Czarnewski P, Gucluler Akpinar G, Sandberg A, Cao X, et al. Molecular evaluation of five different isolation methods for extracellular vesicles reveals different clinical applicability and subcellular origin. J Extracell Vesicles. 2021;10(9):e12128.",{"doi":607},{"id":603,"text":1910,"url":605,"identifiers":1911},"Holcar M, Ferdin J, Sitar S, Tusek-Znidaric M, Dolzan V, Plemenitas A, et al. Enrichment of plasma extracellular vesicles for reliable quantification of their size and concentration for biomarker discovery. Sci Rep. 2020;10(1):21346.",{"doi":607},{"id":603,"text":1913,"url":605,"identifiers":1914},"Lobb RJ, Becker M, Wen SW, Wong CS, Wiegmans AP, Leimgruber A, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4:27031.",{"doi":607},{"id":603,"text":1916,"url":605,"identifiers":1917},"Vogel R, Coumans FA, Maltesen RG, Boing AN, Bonnington KE, Broekman ML, et al. A standardized method to determine the concentration of extracellular vesicles using tunable resistive pulse sensing. J Extracell Vesicles. 2016;5:31242.",{"doi":607},{"id":603,"text":1919,"url":605,"identifiers":1920},"Tian Y, Gong M, Hu Y, Liu H, Zhang W, Zhang M, et al. Quality and efficiency assessment of six extracellular vesicle isolation methods by nano-flow cytometry. J Extracell Vesicles. 2020;9(1):1697028.",{"doi":607},{"id":603,"text":1922,"url":605,"identifiers":1923},"Lucchetti D, Battaglia A, Ricciardi-Tenore C, Colella F, Perelli L, De Maria R, et al. Measuring extracellular vesicles by conventional flow cytometry: dream or reality? Int J Mol Sci. 2020;21(17):6257.",{"doi":607},{"id":1925,"text":1926,"url":1927,"identifiers":1928},"9b7a353b-c71e-458b-a6c9-1f1bffe24f5a","van der Pol E, van Gemert MJ, Sturk A, Nieuwland R, van Leeuwen TG. Single vs. swarm detection of microparticles and exosomes by flow cytometry. J Thromb Haemost. 2012;10(5):919–30.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1538783622062687",{"doi":1929},"10.1111\u002Fj.1538-7836.2012.04683.x",{"id":18,"text":1931,"url":1932,"identifiers":1933},"Inglis H, Norris P, Danesh A. Techniques for the analysis of extracellular vesicles using flow cytometry. J Vis Exp. 2015. https:\u002F\u002Fdoi.org\u002F10.3791\u002F52484.","https:\u002F\u002Fdoi.org\u002F10.3791\u002F52484",{"mag":1934,"pmc":1935,"openalex":1936,"pm":1937,"doi":1938},"2018636682","4401354","W2018636682","25867010","10.3791\u002F52484",{"id":603,"text":1940,"url":605,"identifiers":1941},"Osteikoetxea X, Sodar B, Nemeth A, Szabo-Taylor K, Paloczi K, Vukman KV, et al. Differential detergent sensitivity of extracellular vesicle subpopulations. Org Biomol Chem. 2015;13(38):9775–82.",{"doi":607},{"id":603,"text":1943,"url":605,"identifiers":1944},"Linden JR, Telesford K, Shetty S, Winokour P, Haigh S, Cahir-McFarland E, et al. A novel Panel of rabbit monoclonal antibodies and their diverse applications including inhibition of clostridium perfringens epsilon toxin oligomerization. Antibodies (Basel). 2018;7(4):37.",{"doi":607},{"id":603,"text":1946,"url":605,"identifiers":1947},"Lane RE, Korbie D, Hill MM, Trau M. Extracellular vesicles as circulating cancer biomarkers: opportunities and challenges. Clin Transl Med. 2018;7(1):14.",{"doi":607},{"id":603,"text":1949,"url":605,"identifiers":1950},"Tian J, Casella G, Zhang Y, Rostami A, Li X. Potential roles of extracellular vesicles in the pathophysiology, diagnosis, and treatment of autoimmune diseases. Int J Biol Sci. 2020;16(4):620–32.",{"doi":607},{"id":603,"text":1952,"url":605,"identifiers":1953},"Pardo F, Villalobos-Labra R, Sobrevia B, Toledo F, Sobrevia L. Extracellular vesicles in obesity and diabetes mellitus. Mol Aspects Med. 2018;60:81–91.",{"doi":607},{"id":603,"text":1955,"url":605,"identifiers":1956},"Xiao Y, Zheng L, Zou X, Wang J, Zhong J, Zhong T. Extracellular vesicles in type 2 diabetes mellitus: key roles in pathogenesis, complications, and therapy. J Extracell Vesicles. 2019;8(1):1625677.",{"doi":607},{"id":18,"text":1958,"url":18,"identifiers":1959},"Jansen F, Nickenig G, Werner N. Extracellular vesicles in cardiovascular disease: potential applications in diagnosis, prognosis, and epidemiology. Circ Res. 2017;120(10):1649–57.",{},{"id":603,"text":1961,"url":605,"identifiers":1962},"Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos M, Fuentes B, Diekhorst L, Diez-Tejedor E, et al. Role of exosomes as a treatment and potential biomarker for stroke. Transl Stroke Res. 2019;10(3):241–9.",{"doi":607},{"id":603,"text":1964,"url":605,"identifiers":1965},"van der Pol E, Coumans FA, Grootemaat AE, Gardiner C, Sargent IL, Harrison P, et al. Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J Thromb Haemost. 2014;12(7):1182–92.",{"doi":607},{"id":603,"text":1967,"url":605,"identifiers":1968},"van der Pol E, Hoekstra AG, Sturk A, Otto C, van Leeuwen TG, Nieuwland R. Optical and non-optical methods for detection and characterization of microparticles and exosomes. J Thromb Haemost. 2010;8(12):2596–607.",{"doi":607},{"id":1970,"text":1971,"url":1972,"identifiers":1973},"34f0d6cf-2fa6-4b4f-85fd-b24f51d9bada","van der Pol E, Sturk A, van Leeuwen T, Nieuwland R, Coumans F, group I-S-VW. Standardization of extracellular vesicle measurements by flow cytometry through vesicle diameter approximation. J Thromb Haemost. 2018;16(6):1236–45.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1538783622010972",{"doi":1974},"10.1111\u002Fjth.14009",{"id":603,"text":1976,"url":605,"identifiers":1977},"Arraud N, Linares R, Tan S, Gounou C, Pasquet JM, Mornet S, et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost. 2014;12(5):614–27.",{"doi":607},{"id":603,"text":1979,"url":605,"identifiers":1980},"Jamaly S, Ramberg C, Olsen R, Latysheva N, Webster P, Sovershaev T, et al. Impact of preanalytical conditions on plasma concentration and size distribution of extracellular vesicles using nanoparticle tracking analysis. Sci Rep. 2018;8(1):17216.",{"doi":607},{"id":603,"text":1982,"url":605,"identifiers":1983},"Abbo SR, Visser TM, Wang H, Goertz GP, Fros JJ, Abma-Henkens MHC, et al. The invasive Asian bush mosquito Aedes japonicus found in the Netherlands can experimentally transmit Zika virus and Usutu virus. PLoS Negl Trop Dis. 2020;14(4):e0008217.",{"doi":607},{"id":603,"text":1985,"url":605,"identifiers":1986},"Konoshenko MY, Lekchnov EA, Vlassov AV, Laktionov PP. Isolation of extracellular vesicles: general methodologies and latest trends. Biomed Res Int 2018; 2018: 8545347.",{"doi":607},{"id":1988,"text":1989,"url":1990,"identifiers":1991},"dff952c1-5997-44c0-afec-a67c22bb8fc9","Carnino JM, Lee H, Jin Y. Isolation and characterization of extracellular vesicles from Broncho-alveolar lavage fluid: a review and comparison of different methods. Respir Res. 2019;20(1):240.","https:\u002F\u002Frespiratory-research.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12931-019-1210-z",{"doi":1992},"10.1186\u002Fs12931-019-1210-z",{"id":1994,"text":1995,"url":1996,"identifiers":1997},"16534eb0-538b-4f72-936b-8e6c4e6bdeec","Xu R, Greening DW, Rai A, Ji H, Simpson RJ. Highly-purified exosomes and shed microvesicles isolated from the human colon cancer cell line LIM1863 by sequential centrifugal ultrafiltration are biochemically and functionally distinct. Methods. 2015;87:11–25.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1046202315001541",{"doi":1998},"10.1016\u002Fj.ymeth.2015.04.008",{"id":603,"text":2000,"url":605,"identifiers":2001},"Gardiner C, Shaw M, Hole P, Smith J, Tannetta D, Redman CW, et al. Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles. J Extracell Vesicles. 2014;3:25361.",{"doi":607},{"id":603,"text":2003,"url":605,"identifiers":2004},"van der Pol E, Coumans FA, Sturk A, Nieuwland R, van Leeuwen TG. Refractive index determination of nanoparticles in suspension using nanoparticle tracking analysis. Nano Lett. 2014;14(11):6195–201.",{"doi":607},{"id":2006,"text":2007,"url":2008,"identifiers":2009},"fdbd6bd8-487e-4c5a-926c-9514a0158469","van der Pol E, de Rond L, Coumans FAW, Gool EL, Boing AN, Sturk A, et al. Absolute sizing and label-free identification of extracellular vesicles by flow cytometry. Nanomedicine. 2018;14(3):801–10.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1549963417305907",{"doi":2010},"10.1016\u002Fj.nano.2017.12.012",{"id":603,"text":2012,"url":605,"identifiers":2013},"Linden JR, Ma Y, Zhao B, Harris JM, Rumah KR, Schaeren-Wiemers N, et al. Clostridium perfringens epsilon toxin causes selective death of mature oligodendrocytes and central nervous system demyelination. MBio. 2015;6(3):e02513.",{"doi":607},{"id":603,"text":2015,"url":605,"identifiers":2016},"Rumah KR, Ma Y, Linden JR, Oo ML, Anrather J, Schaeren-Wiemers N, et al. The myelin and lymphocyte protein MAL Is required for binding and activity of Clostridium perfringens epsilon-toxin. PLoS Pathog. 2015;11(5):e1004896.",{"doi":607},{"id":603,"text":2018,"url":605,"identifiers":2019},"Andrews AM, Lutton EM, Merkel SF, Razmpour R, Ramirez SH. Mechanical injury induces brain endothelial-derived microvesicle release: implications for cerebral vascular injury during traumatic brain injury. Front Cell Neurosci. 2016;10:43.",{"doi":607},{"id":603,"text":2021,"url":605,"identifiers":2022},"Figueira I, Godinho-Pereira J, Galego S, Maia J, Hasko J, Molnar K, et al. MicroRNAs and extracellular vesicles as distinctive biomarkers of precocious and advanced stages of breast cancer brain metastases development. Int J Mol Sci. 2021;22(10):5214.",{"doi":607},{"id":603,"text":2024,"url":605,"identifiers":2025},"Rom S, Heldt NA, Gajghate S, Seliga A, Reichenbach NL, Persidsky Y. Hyperglycemia and advanced glycation end products disrupt BBB and promote occludin and claudin-5 protein secretion on extracellular microvesicles. Sci Rep. 2020;10(1):7274.",{"doi":607},{"id":2027,"text":2028,"url":2029,"identifiers":2030},"8dfe03c5-3c9a-4a5a-bdd9-f64cf12eadee","Paul D, Baena V, Ge S, Jiang X, Jellison ER, Kiprono T, et al. Appearance of claudin-5(+) leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles. J Neuroinflammation. 2016;13(1):292.","https:\u002F\u002Fjneuroinflammation.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12974-016-0755-8",{"doi":2031},"10.1186\u002Fs12974-016-0755-8",{"id":603,"text":2033,"url":605,"identifiers":2034},"Martinez MC, Andriantsitohaina R. Extracellular vesicles in metabolic syndrome. Circ Res. 2017;120(10):1674–86.",{"doi":607},{"id":603,"text":2036,"url":605,"identifiers":2037},"Jansen F, Li Q, Pfeifer A, Werner N. Endothelial- and immune cell-derived extracellular vesicles in the regulation of cardiovascular health and disease. JACC Basic Transl Sci. 2017;2(6):790–807.",{"doi":607},{"id":603,"text":2039,"url":605,"identifiers":2040},"Alonso MA, Weissman SM. cDNA cloning and sequence of MAL, a hydrophobic protein associated with human T-cell differentiation. Proc Natl Acad Sci U S A. 1987;84(7):1997–2001.",{"doi":607},{"id":603,"text":2042,"url":605,"identifiers":2043},"Frank M. MAL, a proteolipid in glycosphingolipid enriched domains: functional implications in myelin and beyond. Prog Neurobiol. 2000;60(6):531–44.",{"doi":607},{"id":603,"text":2045,"url":605,"identifiers":2046},"Schaeren-Wiemers N, Schaefer C, Valenzuela DM, Yancopoulos GD, Schwab ME. Identification of new oligodendrocyte- and myelin-specific genes by a differential screening approach. J Neurochem. 1995;65(1):10–22.",{"doi":607},{"id":603,"text":2048,"url":605,"identifiers":2049},"Schaeren-Wiemers N, Valenzuela DM, Frank M, Schwab ME. Characterization of a rat gene, rMAL, encoding a protein with four hydrophobic domains in central and peripheral myelin. J Neurosci. 1995;15(8):5753–64.",{"doi":607},{"id":2051,"text":2052,"url":2053,"identifiers":2054},"d127e2cc-43de-45c3-bb12-33208a0a1c7b","Zacchetti D, Peranen J, Murata M, Fiedler K, Simons K. VIP17\u002FMAL, a proteolipid in apical transport vesicles. FEBS Lett. 1995;377(3):465–9.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0014579395013962",{"doi":2055},"10.1016\u002F0014-5793(95)01396-2",{"id":603,"text":2057,"url":605,"identifiers":2058},"Kim T, Fiedler K, Madison DL, Krueger WH, Pfeiffer SE. Cloning and characterization of MVP17: a developmentally regulated myelin protein in oligodendrocytes. J Neurosci Res. 1995;42(3):413–22.",{"doi":607},{"id":603,"text":2060,"url":605,"identifiers":2061},"Erne B, Sansano S, Frank M, Schaeren-Wiemers N. Rafts in adult peripheral nerve myelin contain major structural myelin proteins and myelin and lymphocyte protein (MAL) and CD59 as specific markers. J Neurochem. 2002;82(3):550–62.",{"doi":607},{"id":603,"text":2063,"url":605,"identifiers":2064},"Frank M, Schaeren-Wiemers N, Schneider R, Schwab ME. Developmental expression pattern of the myelin proteolipid MAL indicates different functions of MAL for immature Schwann cells and in a late step of CNS myelinogenesis. J Neurochem. 1999;73(2):587–97.",{"doi":607},{"id":603,"text":2066,"url":605,"identifiers":2067},"Schaeren-Wiemers N, Bonnet A, Erb M, Erne B, Bartsch U, Kern F, et al. The raft-associated protein MAL is required for maintenance of proper axon–glia interactions in the central nervous system. J Cell Biol. 2004;166(5):731–42.",{"doi":607},{"id":603,"text":2069,"url":605,"identifiers":2070},"Millan J, Puertollano R, Fan L, Rancano C, Alonso MA. The MAL proteolipid is a component of the detergent-insoluble membrane subdomains of human T-lymphocytes. Biochem J. 1997;321(Pt 1):247–52.",{"doi":607},{"id":603,"text":2072,"url":605,"identifiers":2073},"Caduff J, Sansano S, Bonnet A, Suter U, Schaeren-Wiemers N. Characterization of GFP-MAL expression and incorporation in rafts. Microsc Res Tech. 2001;52(6):645–55.",{"doi":607},{"id":603,"text":2075,"url":605,"identifiers":2076},"Magal LG, Yaffe Y, Shepshelovich J, Aranda JF, de Marco MC, Gaus K, et al. Clustering and lateral concentration of raft lipids by the MAL protein. Mol Biol Cell. 2009;20(16):3751–62.",{"doi":607},{"id":603,"text":2078,"url":605,"identifiers":2079},"Millan J, Puertollano R, Fan L, Alonso MA. Caveolin and MAL, two protein components of internal detergent-insoluble membranes, are in distinct lipid microenvironments in MDCK cells. Biochem Biophys Res Commun. 1997;233(3):707–12.",{"doi":607},{"id":603,"text":2081,"url":605,"identifiers":2082},"Ramnarayanan SP, Tuma PL. MAL, but not MAL2, expression promotes the formation of cholesterol-dependent membrane domains that recruit apical proteins. Biochem J. 2011;439(3):497–504.",{"doi":607},{"id":603,"text":2084,"url":605,"identifiers":2085},"Ventimiglia LN, Alonso MA. Biogenesis and function of T cell-derived exosomes. Front Cell Dev Biol. 2016;4:84.",{"doi":607},{"id":603,"text":2087,"url":605,"identifiers":2088},"Ventimiglia LN, Fernandez-Martin L, Martinez-Alonso E, Anton OM, Guerra M, Martinez-Menarguez JA, et al. Cutting edge: regulation of exosome secretion by the integral MAL protein in T cells. J Immunol. 2015;195(3):810–4.",{"doi":607},{"id":603,"text":2090,"url":605,"identifiers":2091},"Anton O, Batista A, Millan J, Andres-Delgado L, Puertollano R, Correas I, et al. An essential role for the MAL protein in targeting Lck to the plasma membrane of human T lymphocytes. J Exp Med. 2008;205(13):3201–13.",{"doi":607},{"id":603,"text":2093,"url":605,"identifiers":2094},"Anton OM, Andres-Delgado L, Reglero-Real N, Batista A, Alonso MA. MAL protein controls protein sorting at the supramolecular activation cluster of human T lymphocytes. J Immunol. 2011;186(11):6345–56.",{"doi":607},{"id":603,"text":2096,"url":605,"identifiers":2097},"Wankel B, Ouyang J, Guo X, Hadjiolova K, Miller J, Liao Y, et al. Sequential and compartmentalized action of Rabs, SNAREs, and MAL in the apical delivery of fusiform vesicles in urothelial umbrella cells. Mol Biol Cell. 2016;27(10):1621–34.",{"doi":607},{"id":603,"text":2099,"url":605,"identifiers":2100},"Verma S, Nakaoke R, Dohgu S, Banks WA. Release of cytokines by brain endothelial cells: a polarized response to lipopolysaccharide. Brain Behav Immun. 2006;20(5):449–55.",{"doi":607},{"id":18,"text":2102,"url":18,"identifiers":2103},"Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annu Rev Neurosci. 1999;22:11–28.",{},{"id":603,"text":2105,"url":605,"identifiers":2106},"Blanch M, Dorca-Arevalo J, Not A, Cases M, Gomez de Aranda I, Martinez-Yelamos A, et al. The cytotoxicity of epsilon toxin from Clostridium perfringens on lymphocytes is mediated by mal protein expression. Mol Cell Biol. 2018;38(19):e00086-18.",{"doi":607},{"id":603,"text":2108,"url":605,"identifiers":2109},"Adler D, Linden JR, Shetty SV, Ma Y, Bokori-Brown M, Titball RW, et al. Clostridium perfringens epsilon toxin compromises the blood-brain barrier in a humanized Zebrafish model. iScience. 2019;15:39–54.",{"doi":607},{"id":603,"text":2111,"url":605,"identifiers":2112},"Rumah KR, Linden J, Fischetti VA, Vartanian T. Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease. PLoS ONE. 2013;8(10):e76359.",{"doi":607},{"id":603,"text":2114,"url":605,"identifiers":2115},"Geng Z, Huang J, Kang L, Gao S, Yuan Y, Li Y, et al. Clostridium perfringens epsilon toxin binds to erythrocyte MAL receptors and triggers phosphatidylserine exposure. J Cell Mol Med. 2020;24(13):7341–52.",{"doi":607},{"id":2117,"text":2118,"url":2119,"identifiers":2120},"4773caf9-92a0-4631-afa4-d09d644168d3","Geng Z, Kang L, Huang J, Gao S, Wang J, Yuan Y, et al. Epsilon toxin from Clostridium perfringens induces toxic effects on skin tissues and HaCaT and human epidermal keratinocytes. Toxicon. 2021;198:102–10.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0041010121001471",{"doi":2121},"10.1016\u002Fj.toxicon.2021.05.002",{"id":603,"text":2123,"url":605,"identifiers":2124},"Dorca-Arevalo J, Blanch M, Pradas M, Blasi J. Epsilon toxin from Clostridium perfringens induces cytotoxicity in FRT thyroid epithelial cells. Anaerobe. 2018;53:43–9.",{"doi":607},{"id":2126,"text":2127,"url":2128,"identifiers":2129},"f11c678a-edee-451f-a17e-07b4a8ccd4fd","Dorca-Arevalo J, Dorca E, Torrejon-Escribano B, Blanch M, Martin-Satue M, Blasi J. Lung endothelial cells are sensitive to epsilon toxin from Clostridium perfringens. Vet Res. 2020;51(1):27.","https:\u002F\u002Fveterinaryresearch.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs13567-020-00748-2",{"doi":2130},"10.1186\u002Fs13567-020-00748-2",{"id":603,"text":2132,"url":605,"identifiers":2133},"Skryabin GO, Komelkov AV, Savelyeva EE, Tchevkina EM. Lipid rafts in exosome biogenesis. Biochemistry (Mosc). 2020;85(2):177–91.",{"doi":607},{"id":603,"text":2135,"url":605,"identifiers":2136},"Pollet H, Conrard L, Cloos AS, Tyteca D. Plasma membrane lipid domains as platforms for vesicle biogenesis and shedding? Biomolecules. 2018;8(3):94.",{"doi":607},{"id":603,"text":2138,"url":605,"identifiers":2139},"de Jong OG, Verhaar MC, Chen Y, Vader P, Gremmels H, Posthuma G, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles. 2012;1:18936.",{"doi":607},{"id":603,"text":2141,"url":605,"identifiers":2142},"Dozio V, Sanchez JC. Characterisation of extracellular vesicle-subsets derived from brain endothelial cells and analysis of their protein cargo modulation after TNF exposure. J Extracell Vesicles. 2017;6(1):1302705.",{"doi":607},{"id":603,"text":2144,"url":605,"identifiers":2145},"Yamamoto S, Niida S, Azuma E, Yanagibashi T, Muramatsu M, Huang TT, et al. Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes. Sci Rep. 2015;5:8505.",{"doi":607},{"id":603,"text":2147,"url":605,"identifiers":2148},"Yun JW, Barzegar M, Boyer CJ, Minagar A, Couraud PO, Alexander JS. Brain endothelial cells release apical and basolateral microparticles in response to inflammatory cytokine stimulation: relevance to neuroinflammatory stress? Front Immunol. 2019;10:1455.",{"doi":607},{"id":603,"text":2150,"url":605,"identifiers":2151},"Pan Q, He C, Liu H, Liao X, Dai B, Chen Y, et al. Microvascular endothelial cells-derived microvesicles imply in ischemic stroke by modulating astrocyte and blood brain barrier function and cerebral blood flow. Mol Brain. 2016;9(1):63.",{"doi":607},{"id":603,"text":2153,"url":605,"identifiers":2154},"Hazelton I, Yates A, Dale A, Roodselaar J, Akbar N, Ruitenberg MJ, et al. Exacerbation of acute traumatic brain injury by circulating extracellular vesicles. J Neurotrauma. 2018;35(4):639–51.",{"doi":607},{"id":603,"text":2156,"url":605,"identifiers":2157},"Haqqani AS, Delaney CE, Tremblay TL, Sodja C, Sandhu JK, Stanimirovic DB. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS. 2013;10(1):4.",{"doi":607},{"id":603,"text":2159,"url":605,"identifiers":2160},"Kimura K, Hohjoh H, Fukuoka M, Sato W, Oki S, Tomi C, et al. Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis. Nat Commun. 2018;9(1):17.",{"doi":607},{"id":603,"text":2162,"url":605,"identifiers":2163},"Selmaj I, Cichalewska M, Namiecinska M, Galazka G, Horzelski W, Selmaj KW, et al. Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis. Ann Neurol. 2017;81(5):703–17.",{"doi":607},{"id":603,"text":2165,"url":605,"identifiers":2166},"Ebrahimkhani S, Vafaee F, Young PE, Hur SSJ, Hawke S, Devenney E, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.",{"doi":607},{"id":603,"text":2168,"url":605,"identifiers":2169},"Niwald M, Migdalska-Sek M, Brzezianska-Lasota E, Miller E. Evaluation of selected microRNAs expression in remission phase of multiple sclerosis and their potential link to cognition, depression, and disability. J Mol Neurosci. 2017;63(3–4):275–82.",{"doi":607},{"id":603,"text":2171,"url":605,"identifiers":2172},"Manna I, Iaccino E, Dattilo V, Barone S, Vecchio E, Mimmi S, et al. Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients. FASEB J. 2018;32(8):4241–6.",{"doi":607},{"id":603,"text":2174,"url":605,"identifiers":2175},"Saenz-Cuesta M, Alberro A, Munoz-Culla M, Osorio-Querejeta I, Fernandez-Mercado M, Lopetegui I, et al. The first dose of fingolimod affects circulating extracellular vesicles in multiple sclerosis patients. Int J Mol Sci. 2018;19(8):2448.",{"doi":607},{"id":2177,"createTime":2178,"updateTime":2179,"relativeEntities":2180,"slug":2181,"properties":2182,"entityType":177,"verifyStatus":178,"verifyTime":2191,"verifyNote":180,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":2192,"fullTextUrl":18,"authors":2193,"publicationType":231,"publisherRelationship":2322,"citationCount":19,"citationInfo":2380,"publishDate":2383,"publishYear":2381,"citationAnalyzeStatus":17,"lastCitationAnalyze":2179,"indexDatabases":2384,"openAccess":18,"references":2385,"isForceReanalyzing":303},"095eae83-902e-4ca6-8081-ef74dbfb8f37","2023-12-24T13:56:45.439+00:00","2026-03-18T20:00:49.331+00:00",[],"The-CXCL13-CXCR5-chemokine-axis-in-neuroinflammation-evidence-of-CXCR5-CD4-T-cell-recruitment-to-CSF",{"abstract":2183,"title":2185,"gsPaper":2187,"doi":2189},{"EN":2184},"C-X-C chemokine ligand 13 (CXCL13) is frequently elevated in cerebrospinal fluid (CSF) in a variety of inflammatory central nervous system (CNS) diseases, has been detected in meningeal B cell aggregates in brain tissues of multiple sclerosis patients, and proposedly recruits B cells into the inflamed CNS. Besides B cells also follicular helper T (Tfh) cells express the cognate receptor C-X-C chemokine receptor type 5 (CXCR5) and follow CXCL13 gradients in lymphoid tissues. These highly specialized B cell helper T cells are indispensable for B cell responses to infection and vaccination and involved in autoimmune diseases. Phenotypically and functionally related circulating CXCR5+CD4 T cells occur in blood. Their co-recruitment to the inflamed CSF is feasible but unresolved. We approached this question with a retrospective study including data of all patients between 2017 and 2019 of whom immune phenotyping data of CXCR5 expression and CSF CXCL13 concentrations were available. Discharge diagnoses and CSF laboratory parameters were retrieved from records. Patients were categorized as pyogenic\u002Faseptic meningoencephalitis (ME, n = 29), neuroimmunological diseases (NIMM, n = 22), and non-inflammatory neurological diseases (NIND, n = 6). ANOVA models and Spearman’s Rank-Order correlation were used for group comparisons and associations of CXCL13 levels with immune phenotyping data. In fact, intrathecal CXCL13 elevations strongly correlated with CXCR5+CD4 T cell frequencies in the total cohort (p \u003C 0.0001, r = 0.59), and ME (p = 0.003, r = 0.54) and NIMM (p = 0.043, r = 0.44) patients. Moreover, the ratio of CSF-to-peripheral blood (CSF\u002FPB) frequencies of CXCR5+CD4 T cells strongly correlated with CXCL13 levels both in the total cohort (p = 0.001, r = 0.45) and ME subgroup (p = 0.005, r = 0.50), indicating selective accumulation. ME, NIMM and NIND groups differed with regard to CSF cell counts, albumin quotient, intrathecal IgG, CXCL13 elevations and CXCR5+CD4 T cells, which were higher in inflammatory subgroups. The observed link between intrathecal CXCL13 elevations and CXCR5+CD4 T cell frequencies does not prove but suggests recruitment of possible professional B cell helpers to the inflamed CSF. This highlights CSF CXCR5+CD4 T cells a key target and potential missing link to the poorly understood phenomenon of intrathecal B cell and antibody responses with relevance for infection control, chronic inflammation and CNS autoimmunity.",{"EN":2186},"The CXCL13\u002FCXCR5-chemokine axis in neuroinflammation: evidence of CXCR5+CD4 T cell recruitment to 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G, Steger R, Wipfler P, Otto F, Afazel S, Haschke-Becher E, et al. Beyond LNB: real life data on occurrence and extent of CSF CXCL13 in neuroinflammatory diseases. J Neuroimmunol. 2020;338:577087.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0165572819301080",{"doi":2391},"10.1016\u002Fj.jneuroim.2019.577087",{"id":2393,"text":2394,"url":2395,"identifiers":2396},"bbe0fb63-db18-4da1-9306-57ce7757c954","Dersch R, Hottenrott T, Senel M, Lehmensiek V, Tumani H, Rauer S, et al. The chemokine CXCL13 is elevated in the cerebrospinal fluid of patients with neurosyphilis. Fluids Barriers CNS. 2015;12:12.","http:\u002F\u002Fwww.fluidsbarrierscns.com\u002Fcontent\u002F12\u002F1\u002F12",{"doi":2397},"10.1186\u002Fs12987-015-0008-8",{"id":603,"text":2399,"url":605,"identifiers":2400},"Hytonen J, Kortela E, Waris M, Puustinen J, Salo J, Oksi J. CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation. J Neuroinflammation. 2014;11:103.",{"doi":607},{"id":2402,"text":2403,"url":2404,"identifiers":2405},"14fa6291-7cc9-4c05-ae0a-d42e83b50b07","Wagner JN, Weis S, Kubasta C, Panholzer J, von Oertzen TJ. CXCL13 as a diagnostic marker of neuroborreliosis and other neuroinflammatory disorders in an unselected group of patients. J Neurol. 2018;265(1):74–81.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs00415-017-8669-7",{"doi":2406},"10.1007\u002Fs00415-017-8669-7",{"id":2408,"text":2409,"url":2410,"identifiers":2411},"a847d4a0-eda1-491c-9e0c-32e1692df0d6","Kowarik MC, Cepok S, Sellner J, Grummel V, Weber MS, Korn T, et al. CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflammation. 2012;9:93.","https:\u002F\u002Fjneuroinflammation.biomedcentral.com\u002Farticles\u002F10.1186\u002F1742-2094-9-93",{"doi":2412},"10.1186\u002F1742-2094-9-93",{"id":603,"text":2414,"url":605,"identifiers":2415},"Yu Q, Cheng Y, Wang Y, Wang C, Lu H, Guan Z, et al. Aberrant humoral immune responses in neurosyphilis: CXCL13\u002FCXCR5 play a pivotal role for B-cell recruitment to the cerebrospinal fluid. J Infect Dis. 2017;216(5):534–44.",{"doi":607},{"id":603,"text":2417,"url":605,"identifiers":2418},"Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14(2):164–74.",{"doi":607},{"id":603,"text":2420,"url":605,"identifiers":2421},"Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(Pt 4):1089–104.",{"doi":607},{"id":603,"text":2423,"url":605,"identifiers":2424},"Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisäkk P, Ransohoff RM, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain. 2006;129(Pt 1):200–11.",{"doi":607},{"id":2426,"text":2427,"url":2428,"identifiers":2429},"79df8e72-55a5-4777-8993-e056cb45757e","Aloisi F, Columba-Cabezas S, Franciotta D, Rosicarelli B, Magliozzi R, Reynolds R, et al. Lymphoid chemokines in chronic neuroinflammation. J Neuroimmunol. 2008;198(1–2):106–12.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0165572808001136",{"doi":2430},"10.1016\u002Fj.jneuroim.2008.04.025",{"id":603,"text":2432,"url":605,"identifiers":2433},"Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1\u002FCXCR5. J Exp Med. 1998;187(4):655–60.",{"doi":607},{"id":603,"text":2435,"url":605,"identifiers":2436},"Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol. 2004;5(9):943–52.",{"doi":607},{"id":603,"text":2438,"url":605,"identifiers":2439},"Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000;192(11):1553–62.",{"doi":607},{"id":603,"text":2441,"url":605,"identifiers":2442},"Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41(4):529–42.",{"doi":607},{"id":603,"text":2444,"url":605,"identifiers":2445},"Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21.",{"doi":607},{"id":18,"text":2447,"url":18,"identifiers":2448},"Rao DA. T Cells That Help B Cells in Chronically Inflamed Tissues. Front Immunol. 2018;9:1924.",{},{"id":603,"text":2450,"url":605,"identifiers":2451},"Ueno H, Banchereau J, Vinuesa CG. Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol. 2015;16(2):142–52.",{"doi":607},{"id":603,"text":2453,"url":605,"identifiers":2454},"Heit A, Schmitz F, Gerdts S, Flach B, Moore MS, Perkins JA, et al. Vaccination establishes clonal relatives of germinal center T cells in the blood of humans. J Exp Med. 2017;214(7):2139–52.",{"doi":607},{"id":603,"text":2456,"url":605,"identifiers":2457},"Herati RS, Muselman A, Vella L, Bengsch B, Parkhouse K, Del Alcazar D, et al. Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells. Sci Immunol. 2017;2(8):eaag2152.",{"doi":607},{"id":603,"text":2459,"url":605,"identifiers":2460},"Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nature medicine. 262020. p. 453–5.",{"doi":607},{"id":603,"text":2462,"url":605,"identifiers":2463},"Koutsakos M, Wheatley AK, Loh L, Clemens EB, Sant S, Nüssing S, et al. Circulating T(FH) cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. Sci Transl Med. 2018;10(428):eaan8405.",{"doi":607},{"id":603,"text":2465,"url":605,"identifiers":2466},"Bentebibel SE, Khurana S, Schmitt N, Kurup P, Mueller C, Obermoser G, et al. ICOS(+)PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. Sci Rep. 2016;6:26494.",{"doi":607},{"id":18,"text":2468,"url":18,"identifiers":2469},"Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med. 2013;5(176):176ra32.",{},{"id":603,"text":2471,"url":605,"identifiers":2472},"Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758–69.",{"doi":607},{"id":2474,"text":2475,"url":2476,"identifiers":2477},"853d7a64-1aaf-4aa4-aa1f-563bc0e36f64","Xiao H, Luo G, Son H, Zhou Y, Zheng W. Upregulation of peripheral CD4+CXCR5+ T cells in osteosarcoma. Tumour Biol. 2014;35(6):5273–9.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs13277-014-1686-6",{"doi":2478},"10.1007\u002Fs13277-014-1686-6",{"id":603,"text":2480,"url":605,"identifiers":2481},"Ashida S, Ochi H, Hamatani M, Fujii C, Kimura K, Okada Y, et al. immune skew of circulating follicular helper T cells associates with myasthenia gravis severity. Neurol Neuroimmunol Neuroinflamm. 2021;8(2):e945.",{"doi":607},{"id":603,"text":2483,"url":605,"identifiers":2484},"Reiber H. Cerebrospinal fluid–physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler. 1998;4(3):99–107.",{"doi":607},{"id":603,"text":2486,"url":605,"identifiers":2487},"Harrer A, Pilz G, Wipfler P, Oppermann K, Sellner J, Hitzl W, et al. High interindividual variability in the CD4\u002FCD8 T cell ratio and natalizumab concentration levels in the cerebrospinal fluid of patients with multiple sclerosis. Clin Exp Immunol. 2015;180(3):383–92.",{"doi":607},{"id":2489,"text":2490,"url":2491,"identifiers":2492},"d399856e-9cd3-4dc1-8c8f-96f5ebeb0926","Markowicz M, Schötta AM, Kundi M, Bogovič P, Ogrinc K, Strle F, et al. CXCL13 concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other neurological disorders determined by Luminex and ELISA. Ticks Tick Borne Dis. 2018;9(5):1137–42.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1877959X17305964",{"doi":2493},"10.1016\u002Fj.ttbdis.2018.04.008",{"id":603,"text":2495,"url":605,"identifiers":2496},"Reiber H. Cerebrospinal fluid data compilation and knowledge-based interpretation of bacterial, viral, parasitic, oncological, chronic inflammatory and demyelinating diseases. Diagnostic patterns not to be missed in neurology and psychiatry. Arq Neuropsiquiatr. 2016;74(4):337–50.",{"doi":607},{"id":2498,"text":2499,"url":2500,"identifiers":2501},"35d7a719-18bb-4c2d-92b8-3ed56ee25371","Pilz G, Wipfler P, Otto F, Hitzl W, Afazel S, Haschke-Becher E, et al. Cerebrospinal fluid CXLC13 indicates disease course in neuroinfection: an observational study. J Neuroinflammation. 2019;16(1):13.","https:\u002F\u002Fjneuroinflammation.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12974-019-1405-8",{"doi":2502},"10.1186\u002Fs12974-019-1405-8",{"id":603,"text":2504,"url":605,"identifiers":2505},"Crotty S. T follicular helper cell biology: a decade of discovery and diseases. Immunity. 2019;50(5):1132–48.",{"doi":607},{"id":603,"text":2507,"url":605,"identifiers":2508},"Corcione A, Casazza S, Ferretti E, Giunti D, Zappia E, Pistorio A, et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci U S A. 2004;101(30):11064–9.",{"doi":607},{"id":2510,"text":2511,"url":2512,"identifiers":2513},"e4cc07cc-30ea-4268-8dbe-6ec209fa43c9","Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014;6(248):248ra107.","https:\u002F\u002Fwww.science.org\u002Fdoi\u002F10.1126\u002Fscitranslmed.3008879",{"doi":2514},"10.1126\u002Fscitranslmed.3008879",{"id":603,"text":2516,"url":605,"identifiers":2517},"Palanichamy A, Apeltsin L, Kuo TC, Sirota M, Wang S, Pitts SJ, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med. 2014;6(248):248ra106.",{"doi":607},{"id":603,"text":2519,"url":605,"identifiers":2520},"Negron A, Stuve O, Forsthuber TG. Ectopic lymphoid follicles in multiple sclerosis: centers for disease control? Front Neurol. 2020;11:607766.",{"doi":607},{"id":603,"text":2522,"url":605,"identifiers":2523},"Mitsdoerffer M, Peters A. Tertiary lymphoid organs in central nervous system autoimmunity. Front Immunol. 2016;7:451.",{"doi":607},{"id":603,"text":2525,"url":605,"identifiers":2526},"DiSano KD, Royce DB, Gilli F, Pachner AR. Central nervous system inflammatory aggregates in the theiler’s virus model of progressive multiple sclerosis. Front Immunol. 2019;10:1821.",{"doi":607},{"id":603,"text":2528,"url":605,"identifiers":2529},"Schafflick D, Xu CA, Hartlehnert M, Cole M, Schulte-Mecklenbeck A, Lautwein T, et al. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat Commun. 2020;11(1):247.",{"doi":607},{"id":603,"text":2531,"url":605,"identifiers":2532},"Enose-Akahata Y, Azodi S, Smith BR, Billioux BJ, Vellucci A, Ngouth N, et al. Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases. PLoS Pathog. 2018;14(4):e1007042.",{"doi":607},{"id":2534,"text":2535,"url":2536,"identifiers":2537},"6770860a-d9d7-4bf4-b020-04c8898d7cf9","Lee S, Shin Y, Marler J, Levin MC. Post-translational glycosylation of target proteins implicate molecular mimicry in the pathogenesis of HTLV-1 associated neurological disease. J Neuroimmunol. 2008;204(1–2):140–8.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0165572808003093",{"doi":2538},"10.1016\u002Fj.jneuroim.2008.07.020",{"id":603,"text":2540,"url":605,"identifiers":2541},"Levin MC, Lee SM, Kalume F, Morcos Y, Dohan FC Jr, Hasty KA, et al. Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med. 2002;8(5):509–13.",{"doi":607},{"id":603,"text":2543,"url":605,"identifiers":2544},"Pratama A, Vinuesa CG. Control of TFH cell numbers: why and how? Immunol Cell Biol. 2014;92(1):40–8.",{"doi":607},{"id":603,"text":2546,"url":605,"identifiers":2547},"Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmestrom C, et al. Cerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosis. Mult Scler. 2017;23(1):62–71.",{"doi":607},{"id":603,"text":2549,"url":605,"identifiers":2550},"Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmeström C, et al. Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis. J Neurochem. 2017;141(2):296–304.",{"doi":607},{"id":603,"text":2552,"url":605,"identifiers":2553},"Piccio L, Naismith RT, Trinkaus K, Klein RS, Parks BJ, Lyons JA, et al. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. 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               \u003Cjats:title>Background\u003C\u002Fjats:title>\n                \u003Cjats:p>Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1, and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of a mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs).\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>\u003Cjats:sec>\n                \u003Cjats:title>Methods\u003C\u002Fjats:title>\n                \u003Cjats:p>\n  iPSC lines from patients suffering from a familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporter activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1, and lysosomal acidification by acridine orange.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>\u003Cjats:sec>\n                \u003Cjats:title>Results\u003C\u002Fjats:title>\n                \u003Cjats:p>iPSC-derived BMECs from the FAD patient presenting a mutation in the PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to the control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Aβ1–40 peptides compared to control-BMECs.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>\u003Cjats:sec>\n                \u003Cjats:title>Conclusions\u003C\u002Fjats:title>\n                \u003Cjats:p>Our study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMEC metabolism. In particular, mutation in the \u003Cjats:italic>PSEN1\u003C\u002Fjats:italic> gene was associated with a more detrimental phenotype than mutation in \u003Cjats:italic>PSEN2\u003C\u002Fjats:italic>, as noted by a reduced barrier function, reduced drug efflux pump activity, and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>",{"EN":2704},"Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro",{"VOID":2706},"33413468",{"VOID":2708},"10.1186\u002Fs12987-020-00235-y","2024-05-08T18:44:57.551+00:00",[2711],"EN","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-020-00235-y",[2714,2733,2750],{"id":2715,"sortIndex":19,"researcher":18,"roles":2716,"affiliations":2717,"properties":2726,"displayName":2730,"givenName":18,"familyName":18},"e342c2f2-64a6-402b-a01f-afc82269f696",[],[2718],{"id":2719,"sortIndex":19,"affiliation":2720,"properties":18},"0f0e74cd-1dbd-440f-ae53-0170459065b7",{"id":2719,"createTime":18,"updateTime":18,"relativeEntities":2721,"slug":18,"properties":2722,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":2725,"statistic":18},[],{"title":2723},{"EN":2724},"Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, 1300 South Coulter Street, Amarillo, TX, 79106, USA",[],{"orcid":2727,"title":2729,"openalex":2731},{"VOID":2728},"https:\u002F\u002Forcid.org\u002F0000-0001-8550-7684",{"EN":2730},"Snehal Raut",{"VOID":2732},"A5047910951",{"id":2734,"sortIndex":201,"researcher":18,"roles":2735,"affiliations":2736,"properties":2743,"displayName":2747,"givenName":18,"familyName":18},"e8604ead-1391-4d8f-a438-76c76e1deeb6",[],[2737],{"id":2719,"sortIndex":19,"affiliation":2738,"properties":18},{"id":2719,"createTime":18,"updateTime":18,"relativeEntities":2739,"slug":18,"properties":2740,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":2742,"statistic":18},[],{"title":2741},{"EN":2724},[],{"orcid":2744,"title":2746,"openalex":2748},{"VOID":2745},"https:\u002F\u002Forcid.org\u002F0000-0001-6782-6470",{"EN":2747},"Ronak 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LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80(19):1778–83.",{"doi":2831},"10.1212\u002FWNL.0b013e31828726f5",{"id":18,"text":2833,"url":18,"identifiers":2834},"Mehta PD, Pirttila T, Patrick BA, Barshatzky M, Mehta SP. Amyloid beta protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett. 2001;304(1–2):102–6.",{"doi":2835},"10.1016\u002FS0304-3940(01)01754-2",{"id":18,"text":2837,"url":18,"identifiers":2838},"Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595–608.",{"doi":2839},"10.15252\u002Femmm.201606210",{"id":18,"text":2841,"url":18,"identifiers":2842},"Alonso AD, Beharry C, Corbo CP, Cohen LS. Molecular mechanism of prion-like tau-induced neurodegeneration. Alzheimers Dement. 2016;12(10):1090–7.",{"doi":2843},"10.1016\u002Fj.jalz.2015.12.014",{"id":18,"text":2845,"url":18,"identifiers":2846},"Chong FP, Ng KY, Koh RY, Chye SM. Tau proteins and tauopathies in alzheimer’s disease. Cell Mol Neurobiol. 2018;38(5):965–80.",{"doi":2847},"10.1007\u002Fs10571-017-0574-1",{"id":18,"text":2849,"url":18,"identifiers":2850},"Dorszewska J, Prendecki M, Oczkowska A, Dezor M, Kozubski W. Molecular basis of familial and sporadic alzheimer’s disease. Curr Alzheimer Res. 2016;13(9):952–63.",{"doi":2851},"10.2174\u002F1567205013666160314150501",{"id":18,"text":2853,"url":18,"identifiers":2854},"Garcia-Leon JA, Cabrera-Socorro A, Eggermont K, Swijsen A, Terryn J, Fazal R, et al. Generation of a human induced pluripotent stem cell-based model for tauopathies combining three microtubule-associated protein TAU mutations which displays several phenotypes linked to neurodegeneration. Alzheimers Dement. 2018;14(10):1261–80.",{"doi":2855},"10.1016\u002Fj.jalz.2018.05.007",{"id":18,"text":2857,"url":18,"identifiers":2858},"Braidy N, Munoz P, Palacios AG, Castellano-Gonzalez G, Inestrosa NC, Chung RS, et al. Recent rodent models for Alzheimer’s disease: clinical implications and basic research. J Neural Transm (Vienna). 2012;119(2):173–95.",{"doi":2859},"10.1007\u002Fs00702-011-0731-5",{"id":18,"text":2861,"url":18,"identifiers":2862},"Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37.",{"doi":2863},"10.1186\u002Falzrt269",{"id":18,"text":2865,"url":18,"identifiers":2866},"Jung YW, Hysolli E, Kim KY, Tanaka Y, Park IH. Human induced pluripotent stem cells and neurodegenerative disease: prospects for novel therapies. Curr Opin Neurol. 2012;25(2):125–30.",{"doi":2867},"10.1097\u002FWCO.0b013e3283518226",{"id":18,"text":2869,"url":18,"identifiers":2870},"Mohamet L, Miazga NJ, Ward CM. Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology. World J Stem Cells. 2014;6(2):239–47.",{"doi":2871},"10.4252\u002Fwjsc.v6.i2.239",{"id":18,"text":2873,"url":18,"identifiers":2874},"Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, et al. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet. 2011;20(23):4530–9.",{"doi":2875},"10.1093\u002Fhmg\u002Fddr394",{"id":18,"text":2877,"url":18,"identifiers":2878},"Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimers Dement. 2019;15(1):158–67.",{"doi":2879},"10.1016\u002Fj.jalz.2018.07.222",{"id":18,"text":2881,"url":18,"identifiers":2882},"Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid-beta blood–brain barrier transcytosis and clearance. Nat Neurosci. 2015;18(7):978–87.",{"doi":2883},"10.1038\u002Fnn.4025",{"id":18,"text":2885,"url":18,"identifiers":2886},"Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci. 2015;18(4):521–30.",{"doi":2887},"10.1038\u002Fnn.3966",{"id":18,"text":2889,"url":18,"identifiers":2890},"Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015;11(8):457–70.",{"doi":2891},"10.1038\u002Fnrneurol.2015.119",{"id":18,"text":2893,"url":18,"identifiers":2894},"Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932.",{"doi":2895},"10.1038\u002Fncomms3932",{"id":18,"text":2897,"url":18,"identifiers":2898},"Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12(12):723–38.",{"doi":2899},"10.1038\u002Fnrn3114",{"id":18,"text":2901,"url":18,"identifiers":2902},"Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: a matter of blood-brain barrier dysfunction? J Exp Med. 2017;214(11):3151–69.",{"doi":2903},"10.1084\u002Fjem.20171406",{"id":18,"text":2905,"url":18,"identifiers":2906},"Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990;250(4978):279–82.",{"doi":2907},"10.1126\u002Fscience.2218531",{"id":18,"text":2909,"url":18,"identifiers":2910},"Do Carmo S, Cuello AC. Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener. 2013;8(1):37.",{"doi":2911},"10.1186\u002F1750-1326-8-37",{"id":18,"text":2913,"url":18,"identifiers":2914},"Lippmann ES, Al-Ahmad A, Azarin SM, Palecek SP, Shusta EV. A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep. 2014;4:4160.",{"doi":2915},"10.1038\u002Fsrep04160",{"id":18,"text":2917,"url":18,"identifiers":2918},"Lippmann ES, Azarin SM, Kay JE, Nessler RA, Wilson HK, Al-Ahmad A, et al. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol. 2012;30(8):783–91.",{"doi":2919},"10.1038\u002Fnbt.2247",{"id":18,"text":2921,"url":18,"identifiers":2922},"Patel R, Page S, Al-Ahmad AJ. Isogenic blood-brain barrier models based on patient-derived stem cells display inter-individual differences in cell maturation and functionality. J Neurochem. 2017;142(1):74–88.",{"doi":2923},"10.1111\u002Fjnc.14040",{"id":18,"text":2925,"url":18,"identifiers":2926},"Thome MP, Filippi-Chiela EC, Villodre ES, Migliavaca CB, Onzi GR, Felipe KB, et al. Ratiometric analysis of Acridine Orange staining in the study of acidic organelles and autophagy. J Cell Sci. 2016;129(24):4622–32.",{"doi":2927},"10.1242\u002Fjcs.195057",{"id":18,"text":2929,"url":18,"identifiers":2930},"Checler F, Goiran T, Alves da Costa C. Presenilins at the crossroad of a functional interplay between PARK2\u002FPARKIN and PINK1 to control mitophagy: implication for neurodegenerative diseases. Autophagy. 2017;13(11):2004–5.",{"doi":2931},"10.1080\u002F15548627.2017.1363950",{"id":18,"text":2933,"url":18,"identifiers":2934},"Martin-Maestro P, Sproul A, Martinez H, Paquet D, Gerges M, Noggle S, et al. Autophagy induction by bexarotene promotes mitophagy in presenilin 1 familial alzheimer’s disease iPSC-derived neural stem cells. Mol Neurobiol. 2019;56(12):8220–36.",{"doi":2935},"10.1007\u002Fs12035-019-01665-y",{"id":18,"text":2937,"url":18,"identifiers":2938},"Fedeli C, Filadi R, Rossi A, Mammucari C, Pizzo P. PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca(2+) homeostasis. Autophagy. 2019;15(12):2044–62.",{"doi":2939},"10.1080\u002F15548627.2019.1596489",{"id":18,"text":2941,"url":18,"identifiers":2942},"Sarasija S, Norman KR. A gamma-secretase independent role for presenilin in calcium homeostasis impacts mitochondrial function and morphology in Caenorhabditis elegans. Genetics. 2015;201(4):1453–66.",{"doi":2943},"10.1534\u002Fgenetics.115.182808",{"id":18,"text":2945,"url":18,"identifiers":2946},"Sarasija S, Laboy JT, Ashkavand Z, Bonner J, Tang Y, Norman KR. Presenilin mutations deregulate mitochondrial Ca(2+) homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans. Elife. 2018;7:e33052.",{"doi":2947},"10.7554\u002FeLife.33052",{"id":18,"text":2949,"url":18,"identifiers":2950},"Xu Y, Duan C, Kuang Z, Hao Y, Jeffries JL, Lau GW. Pseudomonas aeruginosa pyocyanin activates NRF2-ARE-mediated transcriptional response via the ROS-EGFR-PI3K-AKT\u002FMEK-ERK MAP kinase signaling in pulmonary epithelial cells. PLoS One. 2013;8(8):e72528.",{"doi":2951},"10.1371\u002Fjournal.pone.0072528",{"id":18,"text":2953,"url":18,"identifiers":2954},"Giau VV, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Sci Rep. 2019;9(1):8368.",{"doi":2955},"10.1038\u002Fs41598-019-44848-2",{"id":18,"text":2957,"url":18,"identifiers":2958},"Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23(4):213–27.",{"doi":2959},"10.1177\u002F0891988710383571",{"id":18,"text":2961,"url":18,"identifiers":2962},"Yang J, Zhao H, Ma Y, Shi G, Song J, Tang Y, et al. Early pathogenic event of Alzheimer’s disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget. 2017;8(5):7900–13.",{"doi":2963},"10.18632\u002Foncotarget.13776",{"id":18,"text":2965,"url":18,"identifiers":2966},"Katt ME, Mayo LN, Ellis SE, Mahairaki V, Rothstein JD, Cheng L, et al. The role of mutations associated with familial neurodegenerative disorders on blood-brain barrier function in an iPSC model. Fluids Barriers CNS. 2019;16(1):20.",{"doi":2967},"10.1186\u002Fs12987-019-0139-4",{"id":18,"text":2969,"url":18,"identifiers":2970},"Shea YF, Chu LW, Chan AO, Ha J, Li Y, Song YQ. A systematic review of familial Alzheimer’s disease: differences in presentation of clinical features among three mutated genes and potential ethnic differences. J Formos Med Assoc. 2016;115(2):67–75.",{"doi":2971},"10.1016\u002Fj.jfma.2015.08.004",{"id":18,"text":2973,"url":18,"identifiers":2974},"Meyer K, Kirchner M, Uyar B, Cheng JY, Russo G, Hernandez-Miranda LR, et al. Mutations in disordered regions can cause disease by creating dileucine motifs. Cell. 2018;175(1):239–53. e17.",{"doi":2975},"10.1016\u002Fj.cell.2018.08.019",{"id":18,"text":2977,"url":18,"identifiers":2978},"Sifat AE, Vaidya B, Kaisar MA, Cucullo L, Abbruscato TJ. Nicotine and electronic cigarette (E-Cig) exposure decreases brain glucose utilization in ischemic stroke. J Neurochem. 2018;147(2):204–21.",{"doi":2979},"10.1111\u002Fjnc.14561",{"id":18,"text":2981,"url":18,"identifiers":2982},"Al-Ahmad AJ. Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC\u002FD3 cells. Am J Physiol Cell Physiol. 2017;313(4):C421-C9.",{"doi":2983},"10.1152\u002Fajpcell.00116.2017",{"id":18,"text":2985,"url":18,"identifiers":2986},"Nijland PG, Michailidou I, Witte ME, Mizee MR, van der Pol SM, van Het Hof B, et al. Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions. Glia. 2014;62(7):1125–41.",{"doi":2987},"10.1002\u002Fglia.22667",{"id":18,"text":2989,"url":18,"identifiers":2990},"Meireles M, Martel F, Araujo J, Santos-Buelga C, Gonzalez-Manzano S, Duenas M, et al. Characterization and modulation of glucose uptake in a human blood-brain barrier model. J Membr Biol. 2013;246(9):669–77.",{"doi":2991},"10.1007\u002Fs00232-013-9583-2",{"id":18,"text":2993,"url":18,"identifiers":2994},"Zandl-Lang M, Fanaee-Danesh E, Sun Y, Albrecher NM, Gali CC, Cancar I, et al. Regulatory effects of simvastatin and apoJ on APP processing and amyloid-beta clearance in blood-brain barrier endothelial cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863(1):40–60.",{"doi":2995},"10.1016\u002Fj.bbalip.2017.09.008",{"id":18,"text":2997,"url":18,"identifiers":2998},"Chen W, Chan Y, Wan W, Li Y, Zhang C. Abeta1-42 induces cell damage via RAGE-dependent endoplasmic reticulum stress in bEnd.3 cells. Exp Cell Res. 2018;362(1):83–9.",{"doi":2999},"10.1016\u002Fj.yexcr.2017.11.005",{"id":18,"text":3001,"url":18,"identifiers":3002},"Hartz AM, Zhong Y, Wolf A, LeVine H, Miller DS, Bauer B. Abeta40 reduces P-glycoprotein at the blood-brain barrier through the ubiquitin-proteasome pathway. J Neurosci. 2016;36(6):1930–41.",{"doi":3003},"10.1523\u002FJNEUROSCI.0350-15.2016",{"id":18,"text":3005,"url":18,"identifiers":3006},"Shackleton B, Crawford F, Bachmeier C. Inhibition of ADAM10 promotes the clearance of Abeta across the BBB by reducing LRP1 ectodomain shedding. Fluids Barriers CNS. 2016;13(1):14.",{"doi":3007},"10.1186\u002Fs12987-016-0038-x",{"id":18,"text":3009,"url":18,"identifiers":3010},"Van Gassen G, De Jonghe C, Nishimura M, Yu G, Kuhn S, St George-Hyslop P, et al. Evidence that the beta-catenin nuclear translocation assay allows for measuring presenilin 1 dysfunction. Mol Med. 2000;6(7):570–80.",{"doi":3011},"10.1007\u002FBF03401795",{"id":18,"text":3013,"url":18,"identifiers":3014},"Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA. Wnt\u002Fbeta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci USA. 2009;106(2):641–6.",{"doi":3015},"10.1073\u002Fpnas.0805165106",{"id":18,"text":3017,"url":18,"identifiers":3018},"Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, et al. Wnt\u002Fbeta-catenin signaling controls development of the blood-brain barrier. J Cell Biol. 2008;183(3):409–17.",{"doi":3019},"10.1083\u002Fjcb.200806024",{"id":18,"text":3021,"url":18,"identifiers":3022},"Sarasija S, Norman KR. Role of presenilin in mitochondrial oxidative stress and neurodegeneration in Caenorhabditis elegans. Antioxidants (Basel). 2018;7(9):111.",{"doi":3023},"10.3390\u002Fantiox7090111",{"id":18,"text":3025,"url":18,"identifiers":3026},"Kinarivala N, Morsy A, Patel R, Carmona AV, Sajib MS, Raut S, et al. An iPSC-derived neuron model of CLN3 disease facilitates small molecule phenotypic screening. ACS Pharmacol Transl Sci. 2020;3(5):931–47.",{"doi":3027},"10.1021\u002Facsptsci.0c00077",{"id":18,"text":3029,"url":18,"identifiers":3030},"Lim RG, Quan C, Reyes-Ortiz AM, Lutz SE, Kedaigle AJ, Gipson TA, et al. Huntington’s disease iPSC-derived brain microvascular endothelial cells reveal WNT-mediated angiogenic and blood-brain barrier deficits. Cell Rep. 2017;19(7):1365–77.",{"doi":3031},"10.1016\u002Fj.celrep.2017.04.021",{"id":18,"text":3033,"url":18,"identifiers":3034},"Vatine GD, Al-Ahmad A, Barriga BK, Svendsen S, Salim A, Garcia L, et al. Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood-brain barrier. Cell Stem Cell. 2017;20(6):831–43. e5.",{"doi":3035},"10.1016\u002Fj.stem.2017.04.002",{"id":18,"text":3037,"url":18,"identifiers":3038},"Martinez A, Al-Ahmad AJ. Effects of glyphosate and aminomethylphosphonic acid on an isogeneic model of the human blood-brain barrier. Toxicol Lett. 2019;304:39–49.",{"doi":3039},"10.1016\u002Fj.toxlet.2018.12.013",{"id":3041,"createTime":3042,"updateTime":3043,"relativeEntities":3044,"slug":3045,"properties":3046,"entityType":177,"verifyStatus":178,"verifyTime":3055,"verifyNote":180,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":3056,"fullTextUrl":18,"authors":3057,"publicationType":231,"publisherRelationship":3090,"citationCount":3147,"citationInfo":3148,"publishDate":3152,"publishYear":595,"citationAnalyzeStatus":17,"lastCitationAnalyze":3153,"indexDatabases":3154,"openAccess":18,"references":3155,"isForceReanalyzing":303},"15496f40-a2d9-4547-8035-2cdf16b71c1a","2024-01-16T04:16:14.003+00:00","2025-08-04T12:42:25.413+00:00",[],"Nonsurgical-therapy-for-hydrocephalus-a-comprehensive-and-critical-review",{"abstract":3047,"title":3049,"gsPaper":3051,"doi":3053},{"EN":3048},"Pharmacological interventions have been tested experimentally and clinically to prevent hydrocephalus and avoid the need for shunting beginning in the 1950s. Clinical trials of varied quality have not demonstrated lasting and convincing protective effects through manipulation of cerebrospinal fluid production, diuresis, blood clot fibrinolysis, or manipulation of fibrosis in the subarachnoid compartment, although there remains some promise in the latter areas. Acetazolamide bolus seems to be useful for predicting shunt response in adults with hydrocephalus. Neuroprotection in the situation of established hydrocephalus has been tested experimentally beginning more recently. Therapies designed to modify blood flow or pulsation, reduce inflammation, reduce oxidative damage, or protect neurons are so far of limited success; more experimental work is needed in these areas. As has been recommended for preclinical studies in stroke and brain trauma, stringent conditions should be met for preclinical studies in hydrocephalus.",{"EN":3050},"Nonsurgical therapy for hydrocephalus: a comprehensive and critical review",{"VOID":3052},"[\"18312182339705279383\"]",{"VOID":3054},"10.1186\u002Fs12987-016-0025-2","2024-05-02T13:46:50.020+00:00","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs12987-016-0025-2",[3058,3075],{"id":3059,"sortIndex":19,"researcher":18,"roles":3060,"affiliations":3061,"properties":3070,"displayName":3072,"givenName":18,"familyName":18},"372ae4d2-4a1d-4a98-8679-3cacd2349c2e",[186],[3062],{"id":3063,"sortIndex":19,"affiliation":3064,"properties":18},"01ef327d-10ff-4979-93b6-ca98b6b86acb",{"id":3063,"createTime":18,"updateTime":18,"relativeEntities":3065,"slug":18,"properties":3066,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":3069,"statistic":18},[],{"title":3067},{"VI":3068},"Department of Pathology, University of Manitoba; Children’s Hospital Research Institute of Manitoba, Diagnostic Services Manitoba, Winnipeg, Canada",[],{"title":3071,"gsAuthor":3073},{"VI":3072},"Marc R. Del Bigio",{"VOID":3074},"[\"kL0kkYwAAAAJ\"]",{"id":3076,"sortIndex":201,"researcher":18,"roles":3077,"affiliations":3078,"properties":3087,"displayName":3089,"givenName":18,"familyName":18},"8f6009bc-b709-4b02-beca-0cff0ae2b3eb",[186],[3079],{"id":3080,"sortIndex":19,"affiliation":3081,"properties":18},"0c811550-8c01-4925-88b0-be1618a82630",{"id":3080,"createTime":18,"updateTime":18,"relativeEntities":3082,"slug":18,"properties":3083,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":3086,"statistic":18},[],{"title":3084},{"VI":3085},"Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada",[],{"title":3088},{"VI":3089},"Domenico L. 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A contemporary definition and classification of hydrocephalus. Semin Pediatr Neurol. 2009;16:9–15.",{"doi":607},{"id":3160,"text":3161,"url":3162,"identifiers":3163},"2c3f5bba-4146-4cb9-be62-8ed0ad97af50","Rekate HL. A consensus on the classification of hydrocephalus: its utility in the assessment of abnormalities of cerebrospinal fluid dynamics. Childs Nerv Syst. 2011;27:1535–41.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00381-011-1558-y",{"doi":3164},"10.1007\u002Fs00381-011-1558-y",{"id":3166,"text":3167,"url":3168,"identifiers":3169},"fb08a7b6-0ee3-48ed-999f-d07aa395f485","Aschoff A, Kremer P, Hashemi B, Kunze S. The scientific history of hydrocephalus and its treatment. Neurosurg Rev. 1999;22:67–93.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs101430050035",{"doi":3170},"10.1007\u002Fs101430050035",{"id":18,"text":3172,"url":18,"identifiers":3173},"Wu Y, Green NL, Wrensch MR, Zhao S, Gupta N. Ventriculoperitoneal shunt complications in California: 1990–2000. Neurosurgery. 2007;61:557–562, discussion 562–3.",{},{"id":603,"text":3175,"url":605,"identifiers":3176},"Riva-Cambrin J, Kestle JR, Holubkov R, Butler J, Kulkarni AV, Drake J, Whitehead WE, Wellons JC 3rd, Shannon CN, Tamber MS, Limbrick DD, Jr., Rozzelle C, Browd SR, Simon TD: Risk factors for shunt malfunction in pediatric hydrocephalus: a multicenter prospective cohort study. J Neurosurg Pediatr. 2015;1–9.",{"doi":607},{"id":18,"text":3178,"url":18,"identifiers":3179},"Limbrick DD Jr, Baird LC, Klimo P Jr, Riva-Cambrin J, Flannery AM, Pediatric Hydrocephalus Systematic R, Evidence-Based Guidelines Task F. Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 4: Cerebrospinal fluid shunt or endoscopic third ventriculostomy for the treatment of hydrocephalus in children. J Neurosurg Pediatr. 2014;14(Suppl 1):30–4.",{},{"id":603,"text":3181,"url":605,"identifiers":3182},"Rasul FT, Marcus HJ, Toma AK, Thorne L, Watkins LD. Is endoscopic third ventriculostomy superior to shunts in patients with non-communicating hydrocephalus? A systematic review and meta-analysis of the evidence. Acta Neurochir (Wien). 2013;155:883–9.",{"doi":607},{"id":603,"text":3184,"url":605,"identifiers":3185},"Tudor KI, Tudor M, McCleery J, Car J. Endoscopic third ventriculostomy (ETV) for idiopathic normal pressure hydrocephalus (iNPH). Cochrane Database Syst Rev. 2015;7:CD010033.",{"doi":607},{"id":603,"text":3187,"url":605,"identifiers":3188},"Kazui H, Miyajima M, Mori E, Ishikawa M, Investigators S. Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial. Lancet Neurol. 2015;14:585–94.",{"doi":607},{"id":603,"text":3190,"url":605,"identifiers":3191},"Del Bigio MR, Kanfer JN, Zhang YW. Myelination delay in the cerebral white matter of immature rats with kaolin-induced hydrocephalus is reversible. J Neuropathol Exp Neurol. 1997;56:1053–66.",{"doi":607},{"id":603,"text":3193,"url":605,"identifiers":3194},"Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244–50.",{"doi":607},{"id":18,"text":3196,"url":18,"identifiers":18},"(STAIR) STAIR. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30:2752–8.",{"id":603,"text":3198,"url":605,"identifiers":3199},"Diaz-Arrastia R, Kochanek PM, Bergold P, Kenney K, Marx CE, Grimes CJ, Loh LT, Adam LT, Oskvig D, Curley KC, Salzer W. Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma. 2014;31:135–58.",{"doi":607},{"id":603,"text":3201,"url":605,"identifiers":3202},"Poca MA, Sahuquillo J. Short-term medical management of hydrocephalus. Expert Opin Pharmacother. 2005;6:1525–38.",{"doi":607},{"id":3204,"text":3205,"url":3206,"identifiers":3207},"c9b53fca-b1e5-43fb-98c4-3f459864afeb","Spector R, Keep RF, Snodgrass SR, Smith QR, Johanson CE. A balanced view of choroid plexus structure and function: focus on adult humans. Exp Neurol. 2015;267:78–86.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS001448861500062X",{"doi":3208},"10.1016\u002Fj.expneurol.2015.02.032",{"id":603,"text":3210,"url":605,"identifiers":3211},"Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015;16:445–57.",{"doi":607},{"id":603,"text":3213,"url":605,"identifiers":3214},"Damkier HH, Brown PD, Praetorius J. Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev. 2013;93:1847–92.",{"doi":607},{"id":603,"text":3216,"url":605,"identifiers":3217},"Nagelhus EA, Ottersen OP. Physiological roles of aquaporin-4 in brain. Physiol Rev. 2013;93:1543–62.",{"doi":607},{"id":3219,"text":3220,"url":3221,"identifiers":3222},"400d3753-c010-4f65-b6f5-81ec05f9e26f","Bulat M, Klarica M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Res Rev. 2011;65:99–112.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0165017310000895",{"doi":3223},"10.1016\u002Fj.brainresrev.2010.08.002",{"id":603,"text":3225,"url":605,"identifiers":3226},"Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40:2583.",{"doi":607},{"id":3228,"text":3229,"url":3230,"identifiers":3231},"fae75b4b-4194-435c-91d6-23839eb8e9c3","Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:10.","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002F2045-8118-11-10",{"doi":3232},"10.1186\u002F2045-8118-11-10",{"id":3234,"text":3235,"url":3236,"identifiers":3237},"b5e975c9-958c-4c65-9dcf-f1a23986ec42","Hladky SB, Barrand MA. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS. 2014;11:26.","http:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002F2045-8118-11-26",{"doi":3238},"10.1186\u002F2045-8118-11-26",{"id":603,"text":3240,"url":605,"identifiers":3241},"Carare RO, Hawkes CA, Weller RO. Afferent and efferent immunological pathways of the brain. Anatomy, function and failure. Brain Behav Immun. 2014;36:9–14.",{"doi":607},{"id":18,"text":3243,"url":18,"identifiers":3244},"Marriott WM. The use of theobromin sodio salicylate (diuretin) in the treatment of hydrocephalus. Am J Dis Child. 1924;28:479–83.",{},{"id":603,"text":3246,"url":605,"identifiers":3247},"Wise BL, Mathis JL, Wright JH. Experimental use of isosorbide: an oral osmotic agent to lower cerebrospinal pressure and reduce brain bulk. J Neurosurg. 1966;25:183–8.",{"doi":607},{"id":603,"text":3249,"url":605,"identifiers":3250},"Hayden PW, Foltz EL, Shurtleff DB. Effect of on oral osmotic agent on ventricular fluid pressure of hydrocephalic children. Pediatrics. 1968;41:955–67.",{"doi":607},{"id":603,"text":3252,"url":605,"identifiers":3253},"Shurtleff DB, Hayden PW. The treatment of hydrocephalus with isosorbide, and oral hyperosmotic agent. J Clin Pharmacol New Drugs. 1972;12:108–14.",{"doi":607},{"id":3255,"text":3256,"url":3257,"identifiers":3258},"b64cd291-54ba-4771-aedf-0f7b84fff77d","Shurtleff DB, Hayden PW, Weeks R, Laurence KM. Temporary treatment of hydrocephalus and myelodysplasia with isosorbide: preliminary report. J Pediatr. 1973;83:651–7.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0022347673802355",{"doi":3259},"10.1016\u002Fs0022-3476(73)80235-5",{"id":603,"text":3261,"url":605,"identifiers":3262},"Hayden PW, Shurtleff DB. The medical management of hydrocephalus. Dev Med Child Neurol Suppl. 1972;27:52–8.",{"doi":607},{"id":603,"text":3264,"url":605,"identifiers":3265},"Lorber J. The use of isosorbide in the treatment of hydrocephalus. Dev Med Child Neurol Suppl. 1972;27:87–93.",{"doi":607},{"id":603,"text":3267,"url":605,"identifiers":3268},"Lorber J. Isosorbide in the medical treatment of infantile hydrocephalus. J Neurosurg. 1973;39:702–11.",{"doi":607},{"id":603,"text":3270,"url":605,"identifiers":3271},"Lorber J. Isosorbide in treatment of infantile hydrocephalus. Arch Dis Child. 1975;50:431–6.",{"doi":607},{"id":603,"text":3273,"url":605,"identifiers":3274},"Lorber J, Salfield S, Lonton T. Isosorbide in the management of infantile hydrocephalus. Dev Med Child Neurol. 1983;25:502–11.",{"doi":607},{"id":18,"text":3276,"url":18,"identifiers":3277},"Liptak GS, Gellerstedt ME, Klionsky N. Isosorbide in the medical management of hydrocephalus in children with myelodysplasia. Dev Med Child Neurol. 1992;34:150–4.",{},{"id":18,"text":3279,"url":18,"identifiers":3280},"Johnson V, Carlson AJ, Johnson A. Studies on the physiological action of glycerol on the animal organism. Am J Physiol. 1933;103:517–34.",{},{"id":603,"text":3282,"url":605,"identifiers":3283},"Cantore G, Guidetti B, Virno M. Oral glycerol for the reduction of intracranial pressure. J Neurosurg. 1964;21:278–83.",{"doi":607},{"id":603,"text":3285,"url":605,"identifiers":3286},"Hill A, Volpe JJ. Normal pressure hydrocephalus in the newborn. Pediatrics. 1981;68:623–9.",{"doi":607},{"id":3288,"text":3289,"url":3290,"identifiers":3291},"6534d159-0e1b-4205-afca-a50edea7c534","Yamanaka R, Koga H, Yamamoto Y, Yamada S, Sano T, Fukushige T. Characteristics of patients with brain metastases from lung cancer in a palliative care center. Support Care Cancer. 2011;19:467–73.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00520-010-0838-5",{"doi":3292},"10.1007\u002Fs00520-010-0838-5",{"id":18,"text":3294,"url":18,"identifiers":3295},"Shimoda M, Oda S, Shibata M, Masuko A, Sato O. Change in regional cerebral blood flow following glycerol administration predicts. Clinical result from shunting in normal pressure hydrocephalus. Acta Neurochir (Wien). 1994;129:171–6.",{},{"id":603,"text":3297,"url":605,"identifiers":3298},"Mase M, Ueda Y, Nagai H. Effect of NIK-242 inj. (20 % erythritol) on intracranial pressure in dogs with acute obstructive hydrocephalus. No To Shinkei. 1990;42:79–85.",{"doi":607},{"id":603,"text":3300,"url":605,"identifiers":3301},"Diringer MN, Edwards DF, Zazulia AR. Hydrocephalus: a previously unrecognized predictor of poor outcome from supratentorial intracerebral hemorrhage. Stroke. 1998;29:1352–7.",{"doi":607},{"id":603,"text":3303,"url":605,"identifiers":3304},"Tschirgi RD, Frost RW, Taylor JL. Inhibition of cerebrospinal fluid formation by a carbonic anhydrase inhibitor, 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide (diamox). Proc Soc Exp Biol Med. 1954;87:373–6.",{"doi":607},{"id":603,"text":3306,"url":605,"identifiers":3307},"Maren TH, Robinson B. The pharmacology of acetazolamide as related to cerebrospinal fluid and the treatment of hydrocephalus. Bull Johns Hopkins Hosp. 1960;106:1–24.",{"doi":607},{"id":3309,"text":3310,"url":3311,"identifiers":3312},"f9f70e4d-816c-40c2-86aa-874e49687fd0","Domer FR. Effects of diuretics on cerebrospinal fluid formation and potassium movement. Exp Neurol. 1969;24:54–64.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0014488669900053",{"doi":3313},"10.1016\u002F0014-4886(69)90005-3",{"id":603,"text":3315,"url":605,"identifiers":3316},"Swenson ER: Pharmacology of acute mountain sickness: old drugs and newer thinking. J Appl Physiol 2016;120:204–15.",{"doi":607},{"id":603,"text":3318,"url":605,"identifiers":3319},"Gao F, Liu F, Chen Z, Hua Y, Keep RF, Xi G. Hydrocephalus after intraventricular hemorrhage: the role of thrombin. J Cereb Blood Flow Metab. 2014;34:489–94.",{"doi":607},{"id":603,"text":3321,"url":605,"identifiers":3322},"Gao F, Zheng M, Hua Y, Keep RF, Xi G. Acetazolamide attenuates thrombin-induced hydrocephalus. Acta Neurochir Suppl. 2016;121:373–7.",{"doi":607},{"id":3324,"text":3325,"url":3326,"identifiers":3327},"59fdbbb5-f1e5-4a35-8a9c-cd4b374dba95","Kolecka M, Ondreka N, Moritz A, Kramer M, Schmidt MJ. Effect of acetazolamide and subsequent ventriculo-peritoneal shunting on clinical signs and ventricular volumes in dogs with internal hydrocephalus. Acta Vet Scand. 2015;57:49.","https:\u002F\u002Factavetscand.biomedcentral.com\u002Farticles\u002F10.1186\u002Fs13028-015-0137-8",{"doi":3328},"10.1186\u002Fs13028-015-0137-8",{"id":603,"text":3330,"url":605,"identifiers":3331},"Elvidge AR, Branch CL, Thompson GB. Observations in a case of hydrocephalus treated with Diamox. J Neurosurg. 1957;14:628–38.",{"doi":607},{"id":603,"text":3333,"url":605,"identifiers":3334},"Ricci G, Copaitich T. Trial acetazolamide therapy of hydrocephalus in tuberculous meningitis. Clin Ter. 1959;16:20–32.",{"doi":607},{"id":18,"text":3336,"url":18,"identifiers":3337},"Huttenlocher PR. Treatment of hydrocephalus with acetazolamide: results in 15 cases. J Pediatr. 1965;66:1023–30.",{},{"id":603,"text":3339,"url":605,"identifiers":3340},"Birzis L, Carter CH, Maren TH. Effects of acetazolamide on CSF pressure and electrolytes in hydrocephalus. Neurology. 1958;8:522–8.",{"doi":607},{"id":603,"text":3342,"url":605,"identifiers":3343},"Mercuri E, Faundez JC, Cowan F, Dubowitz L. Acetazolamide without frusemide in the treatment of post-haemorrhagic hydrocephalus. Acta Paediatr. 1994;83:1319–21.",{"doi":607},{"id":3345,"text":3346,"url":3347,"identifiers":3348},"72a03323-3f4f-4e4b-afb1-b196ccbf6540","Miner ME. Acetazolamide treatment of progressive hydrocephalus secondary to intraventricular hemorrhage in a preterm infant. Childs Nerv Syst. 1986;2:105–6.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002FBF00286232",{"doi":3349},"10.1007\u002FBF00286232",{"id":603,"text":3351,"url":605,"identifiers":3352},"Nalin A, Gatti G: Effects of treatment with acetazolamide (Diamox) in cases of non tumourous hydrocephalus early diagnosed and controlled by encephalography. Acta Univ Carol Med Monogr. 1976:170–3.",{"doi":607},{"id":18,"text":3354,"url":18,"identifiers":3355},"Cutler RW, Page L, Galicich J, Watters GV. Formation and absorption of cerebrospinal fluid in man. Brain. 1968;91:707–20.",{},{"id":603,"text":3357,"url":605,"identifiers":3358},"Schain RJ. Carbonic anhydrase inhibitors in chronic infantile hydrocephalus. Am J Dis Child. 1969;117:621–5.",{"doi":607},{"id":3360,"text":3361,"url":3362,"identifiers":3363},"555c68e9-8802-4811-844b-9bcb17df1717","Mealey J Jr, Barker DT. Failure of oral acetazolamide to avert hydrocephalus in infants with myelomeningocele. J Pediatr. 1968;72:257–9.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0022347668803191",{"doi":3364},"10.1016\u002Fs0022-3476(68)80319-1",{"id":603,"text":3366,"url":605,"identifiers":3367},"Aimard G, Vighetto A, Gabet JY, Bret P, Henry E. Acetazolamide: an alternative to shunting in normal pressure hydrocephalus? Preliminary results. Rev Neurol (Paris). 1990;146:437–9.",{"doi":607},{"id":603,"text":3369,"url":605,"identifiers":3370},"Miyake H, Ohta T, Kajimoto Y, Deguchi J. Diamox challenge test to decide indications for cerebrospinal fluid shunting in normal pressure hydrocephalus. Acta Neurochir (Wien). 1999;141:1187–93.",{"doi":607},{"id":603,"text":3372,"url":605,"identifiers":3373},"Chang CC, Kuwana N, Ito S, Ikegami T. Impairment of cerebrovascular reactivity to acetazolamide in patients with normal pressure hydrocephalus. Nuclear Med Commun. 2000;21:139–41.",{"doi":607},{"id":603,"text":3375,"url":605,"identifiers":3376},"Chang CC, Asada H, Mimura T, Suzuki S. A prospective study of cerebral blood flow and cerebrovascular reactivity to acetazolamide in 162 patients with idiopathic normal-pressure hydrocephalus. J Neurosurg. 2009;111:610–7.",{"doi":607},{"id":603,"text":3378,"url":605,"identifiers":3379},"Yamada SM, Masahira N, Kawanishi Y, Fujimoto Y, Shimizu K. Preoperative acetazolamide SPECT is useful for predicting outcome of shunt operation in idiopathic normal pressure hydrocephalus patients. Clin Nucl Med. 2013;38:671–6.",{"doi":607},{"id":603,"text":3381,"url":605,"identifiers":3382},"Alperin N, Oliu CJ, Bagci AM, Lee SH, Kovanlikaya I, Adams D, Katzen H, Ivkovic M, Heier L, Relkin N. Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH. Neurology. 2014;82:1347–51.",{"doi":607},{"id":603,"text":3384,"url":605,"identifiers":3385},"Ivkovic M, Reiss-Zimmermann M, Katzen H, Preuss M, Kovanlikaya I, Heier L, Alperin N, Hoffmann KT, Relkin N. MRI assessment of the effects of acetazolamide and external lumbar drainage in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS. 2015;12:9.",{"doi":607},{"id":603,"text":3387,"url":605,"identifiers":3388},"Supuran CT. Acetazolamide for the treatment of idiopathic intracranial hypertension. Expert Rev Neurother. 2015;15:851–6.",{"doi":607},{"id":603,"text":3390,"url":605,"identifiers":3391},"Piper RJ, Kalyvas AV, Young AM, Hughes MA, Jamjoom AA, Fouyas IP. Interventions for idiopathic intracranial hypertension. Cochrane Database Syst Rev. 2015;8:CD003434.",{"doi":607},{"id":603,"text":3393,"url":605,"identifiers":3394},"Miller TB, Wilkinson HA, Rosenfeld SA, Furuta T. Intracranial hypertension and cerebrospinal fluid production in dogs: effects of furosemide. Exp Neurol. 1986;94:66–80.",{"doi":607},{"id":603,"text":3396,"url":605,"identifiers":3397},"McCarthy KD, Reed DJ. The effect of acetazolamide and furosemide on cerebrospinal fluid production and choroid plexus carbonic anhydrase activity. J Pharmacol Exp Ther. 1974;189:194–201.",{"doi":607},{"id":603,"text":3399,"url":605,"identifiers":3400},"Lorenzo AV, Hornig G, Zavala LM, Boss V, Welch K. Furosemide lowers intracranial pressure by inhibiting CSF production. Z Kinderchir. 1986;41(Suppl 1):10–2.",{"doi":607},{"id":18,"text":3402,"url":18,"identifiers":3403},"Vinas F, De Cabrera C, De Vinas MS. Tratamiento de la hidrocefalia con un derivado del acido sulfamoilantranilico. Comunicacion previa. Prensa Med Argent. 1967;54:496–9.",{},{"id":603,"text":3405,"url":605,"identifiers":3406},"Chaplin ER, Goldstein GW, Myerberg DZ, Hunt JV, Tooley WH. Posthemorrhagic hydrocephalus in the preterm infant. Pediatrics. 1980;65:901–9.",{"doi":607},{"id":603,"text":3408,"url":605,"identifiers":3409},"Shinnar S, Gammon K, Bergman EW Jr, Epstein M, Freeman JM. Management of hydrocephalus in infancy: use of acetazolamide and furosemide to avoid cerebrospinal fluid shunts. J Pediatr. 1985;107:31–7.",{"doi":607},{"id":603,"text":3411,"url":605,"identifiers":3412},"Libenson MH, Kaye EM, Rosman NP, Gilmore HE. Acetazolamide and furosemide for posthemorrhagic hydrocephalus of the newborn. Pediatr Neurol. 1999;20:185–91.",{"doi":607},{"id":603,"text":3414,"url":605,"identifiers":3415},"Pouplard F, Pineau P. Use of acetazolamide in external hydrocephalus in infants. Ann Pediatr (Paris). 1990;37:310–2.",{"doi":607},{"id":603,"text":3417,"url":605,"identifiers":3418},"Kennedy CR, Ayers S, Campbell MJ, Elbourne D, Hope P, Johnson A. Randomized, controlled trial of acetazolamide and furosemide in posthemorrhagic ventricular dilation in infancy: follow-up at 1 year. Pediatrics. 2001;108:597–607.",{"doi":607},{"id":603,"text":3420,"url":605,"identifiers":3421},"International PHVD Drug Trial Group. International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy. Lancet. 1998;352:433–40.",{"doi":607},{"id":603,"text":3423,"url":605,"identifiers":3424},"Whitelaw A, Kennedy CR, Brion LP: Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database Syst Rev. 2001:CD002270.",{"doi":607},{"id":603,"text":3426,"url":605,"identifiers":3427},"Hack M, Cohen AR. Acetazolamide plus furosemide for periventricular dilatation: lessons for drug therapy in children. Lancet. 1998;352:418–9.",{"doi":607},{"id":18,"text":3429,"url":18,"identifiers":3430},"Neblett CR, Waltz TA Jr, McNeel DP, Harrison GM. Effect of cardiac glycosides on human cerebrospinal-fluid production. Lancet. 1972;2:1008–9.",{},{"id":603,"text":3432,"url":605,"identifiers":3433},"Allonen H, Anderson KE, Iisalo E, Kanto J, Stromblad LG, Wettrell G. Passage of digoxin into cerebrospinal fluid in man. Acta Pharmacol Toxicol (Copenh). 1977;41:193–202.",{"doi":607},{"id":603,"text":3435,"url":605,"identifiers":3436},"Bass NH, Fallstrom SP, Lundborg P. Digoxin-induced arrest of the cerebrospinal fluid circulation in the infant rat: implications for medical treatment of hydrocephalus during early postnatal life. Pediatr Res. 1979;13:26–30.",{"doi":607},{"id":603,"text":3438,"url":605,"identifiers":3439},"Penisson-Besnier I, Cesbron JG, L’Heveder G, Laine-Cessac P, Dubas F. Efficacy of triamterene in hydrocephalus in adults. Presse Med. 1993;22:224–5.",{"doi":607},{"id":603,"text":3441,"url":605,"identifiers":3442},"Narita K, Sasamoto S, Koizumi S, Okazaki S, Nakamura H, Inoue T, Takeda S. TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport. FASEB J. 2015;29:2247–59.",{"doi":607},{"id":18,"text":3444,"url":18,"identifiers":3445},"Gattone V, Blazer-Yost B: Use of TRPV4 antagonists to ameliorate hydrocephalus and related materials and methods. WO 2014089013 A1. USA: Indiana University Research And Technology Corporation; 2014.",{},{"id":603,"text":3447,"url":605,"identifiers":3448},"Lindvall-Axelsson M, Hedner P, Owman C. Corticosteroid action on choroid plexus: reduction in Na+ –K+ –ATPase activity, choline transport capacity, and rate of CSF formation. Exp Brain Res. 1989;77:605–10.",{"doi":607},{"id":603,"text":3450,"url":605,"identifiers":3451},"Weiss MH, Nulsen FE. The effect of glucocorticoids on CSF flow in dogs. J Neurosurg. 1970;32:452–8.",{"doi":607},{"id":603,"text":3453,"url":605,"identifiers":3454},"Sato O. The effect of dexamethasone on cerebrospinal fluid production rate in the dog. No To Shinkei. 1967;19:485–92.",{"doi":607},{"id":603,"text":3456,"url":605,"identifiers":3457},"Gomez-Sanchez CE, de Rodriguez AF, Romero DG, Estess J, Warden MP, Gomez-Sanchez MT, Gomez-Sanchez EP. Development of a panel of monoclonal antibodies against the mineralocorticoid receptor. Endocrinology. 2006;147:1343–8.",{"doi":607},{"id":3459,"text":3460,"url":3461,"identifiers":3462},"9598e8f7-174d-43c8-8f2b-5d324de19ba4","Fattal-Valevski A, Beni-Adani L, Constantini S. Short-term dexamethasone treatment for symptomatic slit ventricle syndrome. Childs Nerv Syst. 2005;21:981–4.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00381-004-1132-y",{"doi":3463},"10.1007\u002Fs00381-004-1132-y",{"id":18,"text":3465,"url":18,"identifiers":3466},"Dandy WE. Extirpation of the choroid plexus of the lateral ventricles in communicating hydrocephalus. Ann Surg. 1918;68:569–79.",{},{"id":603,"text":3468,"url":605,"identifiers":3469},"Warf BC. Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg. 2005;103:475–81.",{"doi":607},{"id":603,"text":3471,"url":605,"identifiers":3472},"Weiss MH, Roessmann U. Radioactive tissue changes induced to control experimental hydrocephalus. J Neurosurg. 1972;36:266–9.",{"doi":607},{"id":603,"text":3474,"url":605,"identifiers":3475},"Weiss MH, Nulsen FE, Kaufman B. Selective radionecrosis of the choroid plexus for control of experimental hydrocephalus. J Neurosurg. 1972;36:270–5.",{"doi":607},{"id":603,"text":3477,"url":605,"identifiers":3478},"Rish BL, Meacham WF. Experimental study of the intraventricular instillation of radioactive gold. J Neurosurg. 1967;27:15–20.",{"doi":607},{"id":3480,"text":3481,"url":3482,"identifiers":3483},"f4fe26e4-cf22-4b50-9859-57ea2a1bd074","Bardfeld PA, Shulman K. Rhenium-188 therapy of experimental hydrocephalus. Exp Neurol. 1976;50:777–85.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0014488676900431",{"doi":3484},"10.1016\u002F0014-4886(76)90043-1",{"id":18,"text":3486,"url":18,"identifiers":3487},"Bernstein GA, Fingerhut AG, Becker D. Pertechnetate in the treatment of hydrocephalus. J Nuc Med. 1969;10:322.",{},{"id":18,"text":3489,"url":18,"identifiers":3490},"Christensen J. Gonzalez Toledo EC: Radioisotope treatment of hydrocephalus. Preliminary report. Arch Fund Roux Ocefa. 1971;5:87–8.",{},{"id":603,"text":3492,"url":605,"identifiers":3493},"Surash S, Nemeth P, Chakrabarty A, Chumas P. The conjugation of an AQP1-directed immunotoxin in the study of site-directed therapy within the CNS. Childs Nerv Syst. 2011;27:811–8.",{"doi":607},{"id":603,"text":3495,"url":605,"identifiers":3496},"Timothy J, Chumas P, Chakrabarty A, Drake JM, Morrison E. Destruction of choroid plexus cells in vitro: a new concept for the treatment of hydrocephalus? Neurosurgery. 2004;54:727–32.",{"doi":607},{"id":603,"text":3498,"url":605,"identifiers":3499},"Halperin JJ, Kurlan R, Schwalb JM, Cusimano MD, Gronseth G, Gloss D. Practice guideline: idiopathic normal pressure hydrocephalus: response to shunting and predictors of response: report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology. Neurology. 2015;85:2063–71.",{"doi":607},{"id":603,"text":3501,"url":605,"identifiers":3502},"Strahle J, Garton HJ, Maher CO, Muraszko KM, Keep RF, Xi G. Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res. 2012;3:25–38.",{"doi":607},{"id":603,"text":3504,"url":605,"identifiers":3505},"Berman PH, Banker BQ. Neonatal meningitis. A clinical and pathological study of 29 cases. Pediatrics. 1966;38:6–24.",{"doi":607},{"id":603,"text":3507,"url":605,"identifiers":3508},"Cherian S, Whitelaw A, Thoresen M, Love S. The pathogenesis of neonatal post-hemorrhagic hydrocephalus. Brain Pathol. 2004;14:305–11.",{"doi":607},{"id":603,"text":3510,"url":605,"identifiers":3511},"Massicotte EM, Del Bigio MR. Human arachnoid villi response to subarachnoid hemorrhage: possible relationship to chronic hydrocephalus. J Neurosurg. 1999;91:80–4.",{"doi":607},{"id":603,"text":3513,"url":605,"identifiers":3514},"Sajant J, Heikkinen E, Majamaa K. Rapid induction of meningeal collagen synthesis in the cerebral cisternal and ventricular compartments after subarachnoid hemorrhage. Acta Neurochir (Wien). 2001;143:821–6.",{"doi":607},{"id":603,"text":3516,"url":605,"identifiers":3517},"Pepper MS. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol. 2001;21:1104–17.",{"doi":607},{"id":603,"text":3519,"url":605,"identifiers":3520},"Keramati M, Mianroodi RA, Memarnejadian A, Mirzaie A, Sazvari S, Aslani MM, Roohvand F. Towards a superior streptokinase for fibrinolytic therapy of vascular thrombosis. Cardiovasc Hematol Agents Med Chem. 2013;11:218–29.",{"doi":607},{"id":603,"text":3522,"url":605,"identifiers":3523},"Gurman P, Miranda OR, Nathan A, Washington C, Rosen Y, Elman NM. Recombinant tissue plasminogen activators (rtPA): a review. Clin Pharmacol Ther. 2015;97:274–85.",{"doi":607},{"id":3525,"text":3526,"url":3527,"identifiers":3528},"f12f0f42-9b86-4a40-8927-a1c98546ffdb","Lemarchant S, Docagne F, Emery E, Vivien D, Ali C, Rubio M. tPA in the injured central nervous system: different scenarios starring the same actor? Neuropharmacology. 2012;62:749–56.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0028390811004758",{"doi":3529},"10.1016\u002Fj.neuropharm.2011.10.020",{"id":18,"text":3531,"url":18,"identifiers":3532},"Julow J. Prevention of subarachnoid fibrosis after subarachnoid haemorrhage with urokinase. Scanning electron microscopic study in the dog. Acta Neurochir (Wien). 1979;51:51–63.",{},{"id":3534,"text":3535,"url":3536,"identifiers":3537},"1324a516-ed33-4a28-a929-f1ea6865e0c8","Julow J, Ishii M, Iwabuchi T. Scanning electron microscopy of the subarachnoid macrophages after subarachnoid haemorrhage, and their possible role in the formation of subarachnoid fibrosis. Acta Neurochir (Wien). 1979;50:273–80.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002FBF01808524",{"doi":3538},"10.1007\u002FBF01808524",{"id":18,"text":3540,"url":18,"identifiers":3541},"Pang D, Sclabassi RJ, Horton JA. Lysis of intraventricular blood clot with urokinase in a canine model: Part 3. Effects of intraventricular urokinase on clot lysis and posthemorrhagic hydrocephalus. Neurosurgery. 1986;19:553–72.",{},{"id":18,"text":3543,"url":18,"identifiers":3544},"Brinker T, Seifert V, Dietz H. Subacute hydrocephalus after experimental subarachnoid hemorrhage: its prevention by intrathecal fibrinolysis with recombinant tissue plasminogen activator. Neurosurgery. 1992;31:306–11.",{},{"id":18,"text":3546,"url":18,"identifiers":3547},"Mayfrank L, Kissler J, Raoofi R, Delsing P, Weis J, Kuker W, Gilsbach JM. Ventricular dilatation in experimental intraventricular hemorrhage in pigs. Characterization of cerebrospinal fluid dynamics and the effects of fibrinolytic treatment. Stroke. 1997;28:141–8.",{},{"id":3549,"text":3550,"url":3551,"identifiers":3552},"f2da0f9d-2390-4f1c-8d9c-5c5d682d50d8","Mayfrank L, Kim Y, Kissler J, Delsing P, Gilsbach JM, Schroder JM, Weis J. Morphological changes following experimental intraventricular haemorrhage and intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator. Acta Neuropathol. 2000;100:561–7.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs004010000219",{"doi":3553},"10.1007\u002Fs004010000219",{"id":603,"text":3555,"url":605,"identifiers":3556},"Gaberel T, Montagne A, Lesept F, Gauberti M, Lemarchand E, Orset C, Goulay R, Bertrand T, Emery E, Vivien D. Urokinase versus Alteplase for intraventricular hemorrhage fibrinolysis. Neuropharmacology. 2014;85:158–65.",{"doi":607},{"id":603,"text":3558,"url":605,"identifiers":3559},"Hudgins RJ, Boydston WR, Hudgins PA, Adler SR. Treatment of intraventricular hemorrhage in the premature infant with urokinase. A preliminary report. Pediatr Neurosurg. 1994;20:190–7.",{"doi":607},{"id":603,"text":3561,"url":605,"identifiers":3562},"Hudgins RJ, Boydston WR, Hudgins PA, Morris R, Adler SM, Gilreath CL. Intrathecal urokinase as a treatment for intraventricular hemorrhage in the preterm infant. Pediatr Neurosurg. 1997;26:281–7.",{"doi":607},{"id":603,"text":3564,"url":605,"identifiers":3565},"Hansen AR, Volpe JJ, Goumnerova LC, Madsen JR. Intraventricular urokinase for the treatment of posthemorrhagic hydrocephalus. Pediatr Neurol. 1997;17:213–7.",{"doi":607},{"id":603,"text":3567,"url":605,"identifiers":3568},"Whitelaw A, Mowinckel MC, Abildgaard U. Low levels of plasminogen in cerebrospinal fluid after intraventricular haemorrhage: a limiting factor for clot lysis? Acta Paediatr. 1995;84:933–6.",{"doi":607},{"id":603,"text":3570,"url":605,"identifiers":3571},"Whitelaw A, Saliba E, Fellman V, Mowinckel MC, Acolet D, Marlow N. Phase I study of intraventricular recombinant tissue plasminogen activator for treatment of posthaemorrhagic hydrocephalus. Arch Dis Child Fetal Neonatal Ed. 1996;75:F20–6.",{"doi":607},{"id":603,"text":3573,"url":605,"identifiers":3574},"Whitelaw A, Pople I, Cherian S, Evans D, Thoresen M. Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy. Pediatrics. 2003;111:759–65.",{"doi":607},{"id":603,"text":3576,"url":605,"identifiers":3577},"Whitelaw A, Evans D, Carter M, Thoresen M, Wroblewska J, Mandera M, Swietlinski J, Simpson J, Hajivassiliou C, Hunt LP, Pople I. Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics. 2007;119:e1071.",{"doi":607},{"id":603,"text":3579,"url":605,"identifiers":3580},"Whitelaw A, Jary S, Kmita G, Wroblewska J, Musialik-Swietlinska E, Mandera M, Hunt L, Carter M, Pople I. Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics. 2010;125:e852–8.",{"doi":607},{"id":603,"text":3582,"url":605,"identifiers":3583},"Jary S, De Carli A, Ramenghi LA, Whitelaw A. Impaired brain growth and neurodevelopment in preterm infants with posthaemorrhagic ventricular dilatation. Acta Paediatr. 2012;101:743–8.",{"doi":607},{"id":603,"text":3585,"url":605,"identifiers":3586},"Whitelaw A, Rivers RP, Creighton L, Gaffney P. Low dose intraventricular fibrinolytic treatment to prevent posthaemorrhagic hydrocephalus. Arch Dis Child. 1992;67:12–4.",{"doi":607},{"id":3588,"text":3589,"url":3590,"identifiers":3591},"a7142583-1695-47cd-ad3e-57b4a74bf597","Luciano R, Velardi F, Romagnoli C, Papacci P, De Stefano V, Tortorolo G. Failure of fibrinolytic endoventricular treatment to prevent neonatal post-haemorrhagic hydrocephalus. A case-control trial. Childs Nerv Syst. 1997;13:73–6.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs003810050045",{"doi":3592},"10.1007\u002Fs003810050045",{"id":3594,"text":3595,"url":3596,"identifiers":3597},"b209939a-f193-477d-be21-b9b1c3eff6f1","Yapicioglu H, Narli N, Satar M, Soyupak S, Altunbasak S. Intraventricular streptokinase for the treatment of posthaemorrhagic hydrocephalus of preterm. J Clin Neurosci. 2003;10:297–9.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0967586803000286",{"doi":3598},"10.1016\u002Fs0967-5868(03)00028-6",{"id":3600,"text":3601,"url":3602,"identifiers":3603},"f78a9c71-f2a0-4623-a995-eed31633d7b2","Haines SJ, Lapointe M. Fibrinolytic agents in the management of posthemorrhagic hydrocephalus in preterm infants: the evidence. Childs Nerv Syst. 1999;15:226–34.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs003810050378",{"doi":3604},"10.1007\u002Fs003810050378",{"id":603,"text":3606,"url":605,"identifiers":3607},"Whitelaw A, Odd D. Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database Syst Rev. 2007;4:CD000498.",{"doi":607},{"id":603,"text":3609,"url":605,"identifiers":3610},"Todo T, Usui M, Takakura K. Treatment of severe intraventricular hemorrhage by intraventricular infusion of urokinase. J Neurosurg. 1991;74:81–6.",{"doi":607},{"id":603,"text":3612,"url":605,"identifiers":3613},"Tung MYY, Ong PL, Seow WT, Tan KK. A study on the efficacy of intraventricular urokinase in the treatment of intraventricular haemorrhage. Br J Neurosurg. 1998;12:234–9.",{"doi":607},{"id":603,"text":3615,"url":605,"identifiers":3616},"Torres A, Plans G, Martino J, Godino O, Garcia I, Gracia B, Acebes JJ. Fibrinolytic therapy in spontaneous intraventricular haemorrhage: efficacy and safety of the treatment. Br J Neurosurg. 2008;22:269–74.",{"doi":607},{"id":603,"text":3618,"url":605,"identifiers":3619},"Wang B, Huang Q, Liu H, Yang H: Intrathecal injection of urokinase: a promising therapeutic method for acute hydrocephalus? Med Hypotheses. 2009;74:955.",{"doi":607},{"id":603,"text":3621,"url":605,"identifiers":3622},"Mayfrank L, Lippitz B, Groth M, Bertalanffy H, Gilsbach JM. Effect of recombinant tissue plasminogen activator on clot lysis and ventricular dilatation in the treatment of severe intraventricular haemorrhage. Acta Neurochir (Wien). 1993;122:32–8.",{"doi":607},{"id":603,"text":3624,"url":605,"identifiers":3625},"Staykov D, Huttner HB, Struffert T, Ganslandt O, Doerfler A, Schwab S, Bardutzky J. Intraventricular fibrinolysis and lumbar drainage for ventricular hemorrhage. Stroke. 2009;40:3275–80.",{"doi":607},{"id":603,"text":3627,"url":605,"identifiers":3628},"Staykov D, Huttner HB, Lunkenheimer J, Volbers B, Struffert T, Doerfler A, Ganslandt O, Juettler E, Schwab S, Bardutzky J. Single versus bilateral external ventricular drainage for intraventricular fibrinolysis in severe ventricular haemorrhage. J Neurol Neurosurg Psychiatry. 2010;81:105–8.",{"doi":607},{"id":603,"text":3630,"url":605,"identifiers":3631},"Staykov D, Wagner I, Volbers B, Huttner HB, Doerfler A, Schwab S, Bardutzky J. Dose effect of intraventricular fibrinolysis in ventricular hemorrhage. Stroke. 2011;42:2061–4.",{"doi":607},{"id":603,"text":3633,"url":605,"identifiers":3634},"Ramakrishna R, Sekhar LN, Ramanathan D, Temkin N, Hallam D, Ghodke BV, Kim LJ. Intraventricular tissue plasminogen activator for the prevention of vasospasm and hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010;67:110–7.",{"doi":607},{"id":603,"text":3636,"url":605,"identifiers":3637},"Ziai WC, Tuhrim S, Lane K, McBee N, Lees K, Dawson J, Butcher K, Vespa P, Wright DW, Keyl PM, Mendelow AD, Kase C, Wijman C, Lapointe M, John S, Thompson R, Thompson C, Mayo S, Reilly P, Janis S, Awad I, Hanley DF, Investigators CI. A multicenter, randomized, double-blinded, placebo-controlled phase III study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (Clear III). Int J Stroke. 2014;9:536–42.",{"doi":607},{"id":18,"text":3639,"url":18,"identifiers":3640},"Dey M, Stadnik A, Riad F, Zhang L, McBee N, Kase C, Carhuapoma JR, Ram M, Lane K, Ostapkovich N, Aldrich F, Aldrich C, Jallo J, Butcher K, Snider R, Hanley D, Ziai W, Awad IA, Investigators CIT. Bleeding and infection with external ventricular drainage: a systematic review in comparison with adjudicated adverse events in the ongoing Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-III IHV) trial. Neurosurgery. 2015;76:291–300 (discussion 301).",{},{"id":603,"text":3642,"url":605,"identifiers":3643},"Whitelaw A, Aquilina K. Management of posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed. 2012;97:F229–3.",{"doi":607},{"id":603,"text":3645,"url":605,"identifiers":3646},"Shooman D, Portess H, Sparrow O. A review of the current treatment methods for posthaemorrhagic hydrocephalus of infants. Cerebrospinal Fluid Res. 2009;6:1.",{"doi":607},{"id":603,"text":3648,"url":605,"identifiers":3649},"Mazzola CA, Choudhri AF, Auguste KI, Limbrick DD Jr, Rogido M, Mitchell L, Flannery AM. Pediatric hydrocephalus: systematic literature review and evidence-based guidelines Part 2 Management of posthemorrhagic hydrocephalus in premature infants. J Neurosurg Pediatr. 2014;14(Suppl 1):8–23.",{"doi":607},{"id":603,"text":3651,"url":605,"identifiers":3652},"Shi L, Xu L, Shi L, Brandon D, Chen S, Zhang J: Intraventricular recombinant tissue plasminogen activator in treatment of aneurysmal intraventricular hemorrhage: a meta-analysis. Curr Drug Targets 2015 [Epub ahead of print].",{"doi":607},{"id":603,"text":3654,"url":605,"identifiers":3655},"Gerner ST, Kuramatsu JB, Abel H, Kloska SP, Lucking H, Eyupoglu IY, Doerfler A, Schwab S, Huttner HB. Intraventricular fibrinolysis has no effects on shunt dependency and functional outcome in endovascular-treated aneurysmal SAH. Neurocrit Care. 2014;21:435–43.",{"doi":607},{"id":603,"text":3657,"url":605,"identifiers":3658},"Kramer AH, Jenne CN, Zygun DA, Roberts DJ, Hill MD, Holodinsky JK, Todd S, Kubes P, Wong JH. Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial. J Cereb Blood Flow Metab. 2015;35:1241–8.",{"doi":607},{"id":603,"text":3660,"url":605,"identifiers":3661},"Scheld WM, Dacey RG, Winn HR, Welsh JE, Jane JA, Sande MA. Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone. J Clin Invest. 1980;66:243–53.",{"doi":607},{"id":603,"text":3663,"url":605,"identifiers":3664},"Wilkinson HA, Wilson RB, Patel PP, Esmaili M. Corticosteroid therapy of experimental hydrocephalus after intraventricular-subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 1974;37:224–9.",{"doi":607},{"id":603,"text":3666,"url":605,"identifiers":3667},"Julow J. The influence of dexamethasone on subarachnoid fibrosis after subarachnoid haemorrhage Scanning electron microscopic study in the dog. Acta Neurochir (Wien). 1979;51:43–51.",{"doi":607},{"id":603,"text":3669,"url":605,"identifiers":3670},"Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2015;9:CD004405.",{"doi":607},{"id":603,"text":3672,"url":605,"identifiers":3673},"Sporrborn JL, Knudsen GB, Solling M, Seieroe K, Farre A, Lindhardt BO, Benfield T, Brandt CT. Brain ventricular dimensions and relationship to outcome in adult patients with bacterial meningitis. BMC Infect Dis. 2015;15:367.",{"doi":607},{"id":603,"text":3675,"url":605,"identifiers":3676},"Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2013;13:223–37.",{"doi":607},{"id":603,"text":3678,"url":605,"identifiers":3679},"Prasad K, Singh MB: Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008:CD002244.",{"doi":607},{"id":603,"text":3681,"url":605,"identifiers":3682},"Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics. 1997;99:226–31.",{"doi":607},{"id":3684,"text":3685,"url":3686,"identifiers":3687},"ca80a596-dd4b-444b-b8eb-2b98d114ac13","Shah I, Meshram L. High dose versus low dose steroids in children with tuberculous meningitis. J Clin Neurosci. 2014;21:761–4.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0967586813004955",{"doi":3688},"10.1016\u002Fj.jocn.2013.07.021",{"id":3690,"text":3691,"url":3692,"identifiers":3693},"5cd9eb32-7828-49bf-b57f-0bf7c5addbb8","Rigante D, Ansuini V, Caldarelli M, Bertoni B, La Torraca I, Stabile A. Hydrocephalus in CINCA syndrome treated with anakinra. Childs Nerv Syst. 2006;22:334.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00381-006-1280-3",{"doi":3694},"10.1007\u002Fs00381-006-1280-3",{"id":603,"text":3696,"url":605,"identifiers":3697},"Kitazawa K, Tada T. Elevation of transforming growth factor-beta 1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke. 1994;25:1400–4.",{"doi":607},{"id":603,"text":3699,"url":605,"identifiers":3700},"Douglas MR, Daniel M, Lagord C, Akinwunmi J, Jackowski A, Cooper C, Berry M, Logan A. High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus. J Neurol Neurosurg Psychiatry. 2009;80:545–50.",{"doi":607},{"id":603,"text":3702,"url":605,"identifiers":3703},"Whitelaw A, Christie S, Pople I. Transforming growth factor-beta1: a possible signal molecule for posthemorrhagic hydrocephalus? Pediatr Res. 1999;46:576–80.",{"doi":607},{"id":603,"text":3705,"url":605,"identifiers":3706},"Heep A, Stoffel-Wagner B, Bartmann P, Benseler S, Schaller C, Groneck P, Obladen M, Felderhoff-Mueser U. Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus. Pediatr Res. 2004;56:768–74.",{"doi":607},{"id":603,"text":3708,"url":605,"identifiers":3709},"Kaestner S, Dimitriou I. TGF beta1 and TGF beta2 and their role in posthemorrhagic hydrocephalus following SAH and IVH. J Neurol Surg A Cent Eur Neurosurg. 2013;74:279–84.",{"doi":607},{"id":603,"text":3711,"url":605,"identifiers":3712},"Cherian S, Thoresen M, Silver IA, Whitelaw A, Love S. Transforming growth factor-betas in a rat model of neonatal posthaemorrhagic hydrocephalus. Neuropathol Appl Neurobiol. 2004;30:585–600.",{"doi":607},{"id":603,"text":3714,"url":605,"identifiers":3715},"Kanaji M, Tada T, Kobayashi S. A murine model of communicating hydrocephalus: role of TGF-beta1. J Clin Neurosci. 1997;4:51–6.",{"doi":607},{"id":603,"text":3717,"url":605,"identifiers":3718},"Tada T, Kanaji M, Kobayashi S. Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor-beta 1. J Neuroimmunol. 1994;50:153–8.",{"doi":607},{"id":603,"text":3720,"url":605,"identifiers":3721},"Nitta J, Tada T. Ultramicroscopic structures of the leptomeninx of mice with communicating hydrocephalus induced by human recombinant transforming growth factor-beta 1. Neurol Med Chir (Tokyo). 1998;38:819–24.",{"doi":607},{"id":603,"text":3723,"url":605,"identifiers":3724},"Tada T, Zhan H, Tanaka Y, Hongo K, Matsumoto K, Nakamura T. Intraventricular administration of hepatocyte growth factor treats mouse communicating hydrocephalus induced by transforming growth factor beta1. Neurobiol Dis. 2006;21:576–86.",{"doi":607},{"id":603,"text":3726,"url":605,"identifiers":3727},"Galbreath E, Kim SJ, Park K, Brenner M, Messing A. Overexpression of TGF-beta 1 in the central nervous system of transgenic mice results in hydrocephalus. J Neuropathol Exp Neurol. 1995;54:339–49.",{"doi":607},{"id":603,"text":3729,"url":605,"identifiers":3730},"Wyss-Coray T, Feng L, Masliah E, Ruppe MD, Lee HS, Toggas SM, Rockenstein EM, Mucke L. Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1. Am J Pathol. 1995;147:53–67.",{"doi":607},{"id":603,"text":3732,"url":605,"identifiers":3733},"Moinuddin SM, Tada T. Study of cerebrospinal fluid flow dynamics in TGF-beta 1 induced chronic hydrocephalic mice. Neurol Res. 2000;22:215–22.",{"doi":607},{"id":603,"text":3735,"url":605,"identifiers":3736},"Hayashi N, Leifer DW, Cohen AR. Chronologic changes of cerebral ventricular size in a transgenic model of hydrocephalus. Pediatr Neurosurg. 2000;33:182–7.",{"doi":607},{"id":603,"text":3738,"url":605,"identifiers":3739},"Cohen AR, Leifer DW, Zechel M, Flaningan DP, Lewin JS, Lust WD. Characterization of a model of hydrocephalus in transgenic mice. J Neurosurg. 1999;91:978–88.",{"doi":607},{"id":603,"text":3741,"url":605,"identifiers":3742},"Aquilina K, Hobbs C, Tucker A, Whitelaw A, Thoresen M. Do drugs that block transforming growth factor beta reduce posthaemorrhagic ventricular dilatation in a neonatal rat model? Acta Paediatr 2008;97:1181–6.",{"doi":607},{"id":603,"text":3744,"url":605,"identifiers":3745},"Li T, Zhang P, Yuan B, Zhao D, Chen Y, Zhang X. Thrombin-induced TGF-beta1 pathway: a cause of communicating hydrocephalus post subarachnoid hemorrhage. Int J Mol Med. 2013;31:660–6.",{"doi":607},{"id":603,"text":3747,"url":605,"identifiers":3748},"Botfield H, Gonzalez AM, Abdullah O, Skjolding AD, Berry M, McAllister JP 2nd, Logan A. Decorin prevents the development of juvenile communicating hydrocephalus. Brain. 2013;136:2842–58.",{"doi":607},{"id":603,"text":3750,"url":605,"identifiers":3751},"Yan H, Chen Y, Li L, Jiang J, Wu G, Zuo Y, Zhang JH, Feng H, Yan X, Liu F. Decorin alleviated chronic hydrocephalus via inhibiting TGF-beta1\u002FSmad\u002FCTGF pathway after subarachnoid hemorrhage in rats. Brain Res. 2016;1630:241–53.",{"doi":607},{"id":603,"text":3753,"url":605,"identifiers":3754},"Piersma B, Bank RA, Boersema M. Signaling in fibrosis: tGF-beta, WNT, and YAP\u002FTAZ converge. Front Med. 2015;2:59.",{"doi":607},{"id":603,"text":3756,"url":605,"identifiers":3757},"Xu H, Xu B, Wang Z, Tan G, Shen S. Inhibition of Wnt\u002Fbeta-catenin signal is alleviated reactive gliosis in rats with hydrocephalus. Childs Nerv Syst. 2015;31:227.",{"doi":607},{"id":603,"text":3759,"url":605,"identifiers":3760},"Hatta J, Hatta T, Moritake K, Otani H. Heavy water inhibiting the expression of transforming growth factor-beta1 and the development of kaolin-induced hydrocephalus in mice. J Neurosurg. 2006;104:251–8.",{"doi":607},{"id":603,"text":3762,"url":605,"identifiers":3763},"Manaenko A, Lekic T, Barnhart M, Hartman R, Zhang JH. Inhibition of transforming growth factor-beta attenuates brain injury and neurological deficits in a rat model of germinal matrix hemorrhage. Stroke. 2014;45:828–34.",{"doi":607},{"id":3765,"text":3766,"url":3767,"identifiers":3768},"5da787c7-aac6-4771-be13-199669de47d8","Darwish SF, El-Bakly WM, El-Naga RN, Awad AS, El-Demerdash E. Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: impact on interferon therapy. Biochem Pharmacol. 2015;98:231–42.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006295215005742",{"doi":3769},"10.1016\u002Fj.bcp.2015.09.001",{"id":603,"text":3771,"url":605,"identifiers":3772},"Belur PK, Chang JJ, He S, Emanuel BA, Mack WJ. Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury. Neurosurg Focus. 2013;34:E9.",{"doi":607},{"id":603,"text":3774,"url":605,"identifiers":3775},"Zhao J, Chen Z, Xi G, Keep RF, Hua Y. Deferoxamine attenuates acute hydrocephalus after traumatic brain injury in rats. Transl Stroke Res. 2014;5:586–94.",{"doi":607},{"id":603,"text":3777,"url":605,"identifiers":3778},"Meng H, Li F, Hu R, Yuan Y, Gong G, Hu S, Feng H. Deferoxamine alleviates chronic hydrocephalus after intraventricular hemorrhage through iron chelation and Wnt1\u002FWnt3a inhibition. Brain Res. 2015;1602:44–52.",{"doi":607},{"id":603,"text":3780,"url":605,"identifiers":3781},"Chen Q, Tang J, Tan L, Guo J, Tao Y, Li L, Chen Y, Liu X, Zhang JH, Chen Z, Feng H. Intracerebral hematoma contributes to hydrocephalus after intraventricular hemorrhage via aggravating iron accumulation. Stroke. 2015;46:2902.",{"doi":607},{"id":603,"text":3783,"url":605,"identifiers":3784},"Aya KL, Stern R. Hyaluronan in wound healing: rediscovering a major player. Wound Repair Regen. 2014;22:579–93.",{"doi":607},{"id":603,"text":3786,"url":605,"identifiers":3787},"Sonnemann KJ, Bement WM. Wound repair: toward understanding and integration of single-cell and multicellular wound responses. Annu Rev Cell Dev Biol. 2011;27:237–63.",{"doi":607},{"id":603,"text":3789,"url":605,"identifiers":3790},"Vinukonda G, Zia MT, Bhimavarapu BB, Hu F, Feinberg M, Bokhari A, Ungvari Z, Fried VA, Ballabh P. Intraventricular hemorrhage induces deposition of proteoglycans in premature rabbits, but their in vivo degradation with chondroitinase does not restore myelination, ventricle size and neurological recovery. Exp Neurol. 2013;247:630–44.",{"doi":607},{"id":603,"text":3792,"url":605,"identifiers":3793},"Gourie-Devi M, Satish P. Hyaluronidase as an adjuvant in the treatment of cranial arachnoiditis (hydrocephalus and optochiasmatic arachnoiditis) complicating tuberculous meningitis. Acta Neurol Scand. 1980;62:368–81.",{"doi":607},{"id":3795,"text":3796,"url":3797,"identifiers":3798},"cd72216e-a2f2-401e-865b-3c3c7627b5a6","Bhagwati SN, George K. Use of intrathecal hyaluronidase in the management of tuberculous meningitis with hydrocephalus. Childs Nerv Syst. 1986;2:20–5.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002FBF00274028",{"doi":3799},"10.1007\u002Fbf00274028",{"id":603,"text":3801,"url":605,"identifiers":3802},"Gegalian L. Use of hyaluronidase in the central nervous system. Surg Neurol. 1979;12:3–5.",{"doi":607},{"id":603,"text":3804,"url":605,"identifiers":3805},"Schoeman J, Donald P, van Zyl L, Keet M, Wait J. Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Dev Med Child Neurol. 1991;33:396–405.",{"doi":607},{"id":603,"text":3807,"url":605,"identifiers":3808},"Garg RK, Paliwal V, Malhotra HS. Tuberculous optochiasmatic arachnoiditis: a devastating form of tuberculous meningitis. Expert Rev Anti Infect Ther. 2011;9:719–29.",{"doi":607},{"id":603,"text":3810,"url":605,"identifiers":3811},"Zhang S, Chen D, Huang C, Bao J, Wang Z. Expression of HGF, MMP-9 and TGF-beta1 in the CSF and cerebral tissue of adult rats with hydrocephalus. Int J Neurosci. 2013;123:392–9.",{"doi":607},{"id":603,"text":3813,"url":605,"identifiers":3814},"Zechel J, Gohil H, Lust WD, Cohen A. Alterations in matrix metalloproteinase-9 levels and tissue inhibitor of matrix metalloproteinases-1 expression in a transforming growth factor-beta transgenic model of hydrocephalus. J Neurosci Res. 2002;69:662–8.",{"doi":607},{"id":603,"text":3816,"url":605,"identifiers":3817},"Okamoto T, Takahashi S, Nakamura E, Nagaya K, Hayashi T, Shirai M, Fujieda K. Increased expression of matrix metalloproteinase-9 and hepatocyte growth factor in the cerebrospinal fluid of infants with posthemorrhagic hydrocephalus. Early Hum Dev. 2010;86:251–4.",{"doi":607},{"id":3819,"text":3820,"url":3821,"identifiers":3822},"a16dc5d9-2e4e-4e54-b39b-c0f9682a8ad0","Okamoto T, Takahashi S, Nakamura E, Nagaya K, Hayashi T, Shirai M, Fujieda K. Matrix metalloproteinases in infants with posthemorrhagic hydrocephalus. Early Hum Dev. 2008;84:137–9.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0378378207001387",{"doi":3823},"10.1016\u002Fj.earlhumdev.2007.08.006",{"id":603,"text":3825,"url":605,"identifiers":3826},"Yeom KW, Lober RM, Alexander A, Cheshier SH, Edwards MS. Hydrocephalus decreases arterial spin-labeled cerebral perfusion. Am J Neuroradiol. 2014;35:1433–9.",{"doi":607},{"id":603,"text":3828,"url":605,"identifiers":3829},"Owler BK, Pickard JD. Normal pressure hydrocephalus and cerebral blood flow: a review. Acta Neurol Scand. 2001;104:325–42.",{"doi":607},{"id":603,"text":3831,"url":605,"identifiers":3832},"Del Bigio MR. Neuropathology and structural changes in hydrocephalus. Dev Disabil Res Rev. 2010;16:16–22.",{"doi":607},{"id":603,"text":3834,"url":605,"identifiers":3835},"Del Bigio MR. Morphology of astroglial swelling in culture and in the edematous brain: an adaptive response to a disturbed microenvironment. In: Fedoroff S, Juurlink BHJ, Doucette R, editors. Biology and pathology of astrocyte-neuron interactions. New York: Plenum Press; 1993. p. 347–58.",{"doi":607},{"id":603,"text":3837,"url":605,"identifiers":3838},"Krauss JK, Regel JP, Vach W, Droste DW, Borremans JJ, Mergner T. Vascular risk factors and arteriosclerotic disease in idiopathic normal-pressure hydrocephalus of the elderly. Stroke. 1996;27:24–9.",{"doi":607},{"id":603,"text":3840,"url":605,"identifiers":3841},"Boon AJ, Tans JT, Delwel EJ, Egeler-Peerdeman SM, Hanlo PW, Wurzer HA, Hermans J. Dutch Normal-Pressure Hydrocephalus Study: the role of cerebrovascular disease. J Neurosurg. 1999;90:221–6.",{"doi":607},{"id":603,"text":3843,"url":605,"identifiers":3844},"Wagshul ME, Eide PK, Madsen JR. The pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. Fluids Barriers CNS. 2011;8:5.",{"doi":607},{"id":603,"text":3846,"url":605,"identifiers":3847},"Park EH, Dombrowski S, Luciano M, Zurakowski D, Madsen JR. Alterations of pulsation absorber characteristics in experimental hydrocephalus. J Neurosurg Pediatr. 2010;6:159–70.",{"doi":607},{"id":18,"text":3849,"url":18,"identifiers":3850},"Fuller CK. Some observations on chronic hydrocephalus with report of a case apparently arrested. Can Med Assoc J. 1927;17:675–7.",{},{"id":603,"text":3852,"url":605,"identifiers":3853},"Del Bigio MR. Calcium-mediated proteolytic damage in white matter of hydrocephalic rats? J Neuropathol Exp Neurol. 2000;59:946–54.",{"doi":607},{"id":603,"text":3855,"url":605,"identifiers":3856},"Del Bigio MR, Massicotte EM. Protective effect of nimodipine on behavior and white matter of rats with hydrocephalus. J Neurosurg. 2001;94:788–94.",{"doi":607},{"id":603,"text":3858,"url":605,"identifiers":3859},"Khan OH, Enno T, Del Bigio MR. Magnesium sulfate therapy is of mild benefit to young rats with kaolin-induced hydrocephalus. Pediatr Res. 2003;53:970–6.",{"doi":607},{"id":603,"text":3861,"url":605,"identifiers":3862},"Khan OH, McPhee LC, Moddemann LN, Del Bigio MR. Calcium antagonism in neonatal rats with kaolin-induced hydrocephalus. J Child Neurol. 2007;22:1161–6.",{"doi":607},{"id":3864,"text":3865,"url":3866,"identifiers":3867},"6f49b0f8-c542-46f7-954b-db7dd96e2089","Di Curzio DL, Buist RJ, Del Bigio MR. Reduced subventricular zone proliferation and white matter damage in juvenile ferrets with kaolin-induced hydrocephalus. Exp Neurol. 2013;248:112–28.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0014488613001775",{"doi":3868},"10.1016\u002Fj.expneurol.2013.06.004",{"id":603,"text":3870,"url":605,"identifiers":3871},"Nieto Barrera M, Candau Fernandez Mensaque R, Rufo Campos M, Rodriguez Criado G, Barrionuevo Gallo B. El tratamiento de la hidrocefalia infantil con dinitrato de isosorbide [Treatment of infantile hydrocephalus with isosorbide dinitrate]. An Esp Pediatr. 1977;10:843–56.",{"doi":607},{"id":603,"text":3873,"url":605,"identifiers":3874},"Schmidt JF, Albeck M, Gjerris F. The effect of nimodipine on ICP and CBF in patients with normal-pressure hydrocephalus. Acta Neurochir (Wien). 1990;102:11–3.",{"doi":607},{"id":603,"text":3876,"url":605,"identifiers":3877},"Olsen KS, Albeck M, Agerlin N, Schmidt JF. The effect of ketanserin on ICP and CBF in patients with normal-pressure hydrocephalus. J Neurosurg Anesthesiol. 1996;8:216–9.",{"doi":607},{"id":603,"text":3879,"url":605,"identifiers":3880},"Greitz D, Greitz T, Hindmarsh T. A new view on the CSF-circulation with the potential for pharmacological treatment of childhood hydrocephalus. Acta Paediatr. 1997;86:125–32.",{"doi":607},{"id":603,"text":3882,"url":605,"identifiers":3883},"Nilsson F, Nilsson T, Edvinsson L, Bjorkman S, Nordstrom CH. Effects of dihydroergotamine and sumatriptan on isolated human cerebral and peripheral arteries and veins. Acta Anaesthesiol Scand. 1997;41:1257–62.",{"doi":607},{"id":603,"text":3885,"url":605,"identifiers":3886},"Andersen AR, Tfelt-Hansen P, Lassen NA. The effect of ergotamine and dihydroergotamine on cerebral blood flow in man. Stroke. 1987;18:120–3.",{"doi":607},{"id":603,"text":3888,"url":605,"identifiers":3889},"Asgeirsson B, Grande PO, Nordstrom CH, Messeter K, Sjoholm H. Cerebral haemodynamic effects of dihydroergotamine in patients with severe traumatic brain lesions. Acta Anaesthesiol Scand. 1995;39:922–30.",{"doi":607},{"id":603,"text":3891,"url":605,"identifiers":3892},"Bundgaard H, von Oettingen G, Jorgensen HA, Jensen K, Cold GE. Effects of dihydroergotamine on intracranial pressure, cerebral blood flow, and cerebral metabolism in patients undergoing craniotomy for brain tumors. J Neurosurg Anesthesiol. 2001;13:195–201.",{"doi":607},{"id":3894,"text":3895,"url":3896,"identifiers":3897},"a892e29a-73cc-4716-8389-3a0ca2eec4a8","Licht T, Keshet E. Delineating multiple functions of VEGF-A in the adult brain. Cell Mol Life Sci. 2013;70:1727–37.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs00018-013-1280-x",{"doi":3898},"10.1007\u002Fs00018-013-1280-x",{"id":603,"text":3900,"url":605,"identifiers":3901},"Wittko-Schneider IM, Schneider FT, Plate KH. Brain homeostasis: VEGF receptor 1 and 2-two unequal brothers in mind. Cell Mol Life Sci. 2013;70:1705–25.",{"doi":607},{"id":3903,"text":3904,"url":3905,"identifiers":3906},"89ce9a56-6802-4ddd-a176-54940034becd","Yang J, Dombrowski SM, Deshpande A, Krajcir N, Luciano MG. VEGF\u002FVEGFR-2 changes in frontal cortex, choroid plexus, and CSF after chronic obstructive hydrocephalus. J Neurol Sci. 2010;296:39–46.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0022510X10002601",{"doi":3907},"10.1016\u002Fj.jns.2010.06.012",{"id":603,"text":3909,"url":605,"identifiers":3910},"Deshpande A, Dombrowski SM, Leichliter A, Krajcir N, Zingales N, Inoue M, Schenk S, Fukamachi K, Luciano MG. Dissociation between vascular endothelial growth factor receptor-2 and blood vessel density in the caudate nucleus after chronic hydrocephalus. J Cereb Blood Flow Metab. 2009;29:1806–15.",{"doi":607},{"id":603,"text":3912,"url":605,"identifiers":3913},"Del Bigio MR, Wilson MJ, Enno T. Chronic hydrocephalus in rats and humans: white matter loss and behavior changes. Ann Neurol. 2003;53:337–46.",{"doi":607},{"id":603,"text":3915,"url":605,"identifiers":3916},"Dombrowski SM, Deshpande A, Dingwall C, Leichliter A, Leibson Z, Luciano MG. Chronic hydrocephalus-induced hypoxia: increased expression of VEGFR-2+ and blood vessel density in hippocampus. Neuroscience. 2008;152:346–59.",{"doi":607},{"id":3918,"text":3919,"url":3920,"identifiers":3921},"de690af8-f6f1-4247-8667-d28d7e4d7de4","Yang J, Shanahan KJ, Shriver LP, Luciano MG: Exercise-induced changes of cerebrospinal fluid vascular endothelial growth factor in adult chronic hydrocephalus patients. J Clin Neurosci. 2015, in press.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS096758681500452X",{"doi":3922},"10.1016\u002Fj.jocn.2015.08.019",{"id":603,"text":3924,"url":605,"identifiers":3925},"Shim JW, Sandlund J, Han CH, Hameed MQ, Connors S, Klagsbrun M, Madsen JR, Irwin N. VEGF, which is elevated in the CSF of patients with hydrocephalus, causes ventriculomegaly and ependymal changes in rats. Exp Neurol. 2013;247:703–9.",{"doi":607},{"id":3927,"text":3928,"url":3929,"identifiers":3930},"a1e6e056-1a7b-4efd-9bd3-10a6b41db4c8","Shim JW, Sandlund J, Madsen JR. VEGF: a potential target for hydrocephalus. Cell Tissue Res. 2014;358:667–83.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00441-014-1978-6",{"doi":3931},"10.1007\u002Fs00441-014-1978-6",{"id":3933,"text":3934,"url":3935,"identifiers":3936},"8aeff6dd-4214-4991-8851-334966de080f","Del Bigio MR. Neuropathological changes caused by hydrocephalus. Acta Neuropathol (Berl). 1993;85:573–85.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002FBF00334666",{"doi":3937},"10.1007\u002FBF00334666",{"id":603,"text":3939,"url":605,"identifiers":3940},"Wu Q, Chen W, Sinha B, Tu Y, Manning S, Thomas N, Zhou S, Jiang H, Ma H, Kroessler DA, Yao J, Li Z, Inder TE, Wang X. Neuroprotective agents for neonatal hypoxic-ischemic brain injury. Drug Discov Today. 2015;20:1372.",{"doi":607},{"id":603,"text":3942,"url":605,"identifiers":3943},"Deren KE, Packer M, Forsyth J, Milash B, Abdullah OM, Hsu EW, McAllister JP 2nd. Reactive astrocytosis, microgliosis and inflammation in rats with neonatal hydrocephalus. Exp Neurol. 2010;226:110–9.",{"doi":607},{"id":3945,"text":3946,"url":3947,"identifiers":3948},"b69cc3bd-0803-4c51-9d36-1d60d30780db","Ulfig N, Bohl J, Neudorfer F, Rezaie P. Brain macrophages and microglia in human fetal hydrocephalus. Brain Dev. 2004;26:307–15.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0387760403001724",{"doi":3949},"10.1016\u002Fs0387-7604(03)00172-4",{"id":603,"text":3951,"url":605,"identifiers":3952},"Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J. Microglia and neuronal cell death. Neuron Glia Biol. 2011;7:25–40.",{"doi":607},{"id":603,"text":3954,"url":605,"identifiers":3955},"Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. 2010;119:89–105.",{"doi":607},{"id":603,"text":3957,"url":605,"identifiers":3958},"Fernandes A, Miller-Fleming L, Pais TF. Microglia and inflammation: conspiracy, controversy or control? Cell Mol Life Sci. 2014;71:3969–85.",{"doi":607},{"id":603,"text":3960,"url":605,"identifiers":3961},"Li C, Yuan K, Schluesener H. Impact of minocycline on neurodegenerative diseases in rodents: a meta-analysis. Rev Neurosci. 2013;24:553–62.",{"doi":607},{"id":18,"text":3963,"url":18,"identifiers":3964},"Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, Blacker D. Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke. 2013;44:2493–9.",{},{"id":3966,"text":3967,"url":3968,"identifiers":3969},"bdea76a3-3459-47f2-bcf1-22dffd41f4f2","McAllister JP 2nd, Miller JM. Minocycline inhibits glial proliferation in the H-Tx rat model of congenital hydrocephalus. Cerebrospinal Fluid Res. 2010;7:7.","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002F1743-8454-7-7",{"doi":3970},"10.1186\u002F1743-8454-7-7",{"id":3972,"text":3973,"url":3974,"identifiers":3975},"29e94055-96df-41ba-a6be-74221d18929b","Xu H, Tan G, Zhang S, Zhu H, Liu F, Huang C, Zhang F, Wang Z. Minocycline reduces reactive gliosis in the rat model of hydrocephalus. BMC Neurosci. 2012;13:148.","https:\u002F\u002Fbmcneurosci.biomedcentral.com\u002Farticles\u002F10.1186\u002F1471-2202-13-148",{"doi":3976},"10.1186\u002F1471-2202-13-148",{"id":603,"text":3978,"url":605,"identifiers":3979},"Guo J, Chen Q, Tang J, Zhang J, Tao Y, Li L, Zhu G, Feng H, Chen Z. Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage. Brain Res. 2015;1594:115–24.",{"doi":607},{"id":603,"text":3981,"url":605,"identifiers":3982},"Sanchez AR, Rogers RS 3rd, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol. 2004;43:709–15.",{"doi":607},{"id":3984,"text":3985,"url":3986,"identifiers":3987},"7a845ddc-07ee-4171-b9ab-0c07b4495dd3","Lacombe P, Mathews PM, Schmidt SD, Breidert T, Heneka MT, Landreth GE, Feinstein DL, Galea E. Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised. J Neuroinflammation. 2004;1:11.","http:\u002F\u002Fjneuroinflammation.biomedcentral.com\u002Farticles\u002F10.1186\u002F1742-2094-1-11",{"doi":3988},"10.1186\u002F1742-2094-1-11",{"id":603,"text":3990,"url":605,"identifiers":3991},"Kurt G, Cemil B, Borcek AO, Borcek P, Akyurek N, Sepici A, Ceviker N. Infliximab administration reduces neuronal apoptosis on the optic pathways in a rabbit hydrocephalus model: a preliminary report. Br J Neurosurg. 2010;24:275–9.",{"doi":607},{"id":603,"text":3993,"url":605,"identifiers":3994},"Del Bigio MR, Khan OH, da Silva Lopes L, Juliet PA. Cerebral white matter oxidation and nitrosylation in young rodents with kaolin-induced hydrocephalus. J Neuropathol Exp Neurol. 2012;71:274–88.",{"doi":607},{"id":603,"text":3996,"url":605,"identifiers":3997},"Tarnaris A, Watkins LD, Kitchen ND. Biomarkers in chronic adult hydrocephalus. Cerebrospinal Fluid Res. 2006;3:11.",{"doi":607},{"id":18,"text":3999,"url":18,"identifiers":4000},"Etus V, Gazioglu N, Belce A. N-acetylcystein reduces cerebral lipid peroxidation in a rat model of infantile hydrocephalus. J Neurol Sci (Turk). 2001;18:2.",{},{"id":603,"text":4002,"url":605,"identifiers":4003},"Etus V, Altug T, Belce A, Ceylan S. Green tea polyphenol (-)-epigallocatechin gallate prevents oxidative damage on periventricular white matter of infantile rats with hydrocephalus. Tohoku J Exp Med. 2003;200:203–9.",{"doi":607},{"id":4005,"text":4006,"url":4007,"identifiers":4008},"0504b096-1e22-4bb7-8361-6ee23b5b528d","Turgut M, Erdogan S, Ergin K, Serter M. Melatonin ameliorates blood-brain barrier permeability, glutathione, and nitric oxide levels in the choroid plexus of the infantile rats with kaolin-induced hydrocephalus. Brain Res. 2007;1175:117–25.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006899307017416",{"doi":4009},"10.1016\u002Fj.brainres.2007.07.056",{"id":4011,"text":4012,"url":4013,"identifiers":4014},"5271c16b-0bc9-4bd1-8c3b-bda957b5e1ff","Di Curzio DL, Turner-Brannen E, Del Bigio MR. Oral antioxidant therapy for juvenile rats with kaolin-induced hydrocephalus. Fluids Barriers CNS. 2014;11:23.","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002F2045-8118-11-23",{"doi":4015},"10.1186\u002F2045-8118-11-23",{"id":603,"text":4017,"url":605,"identifiers":4018},"Catalao CH, Correa DA, Saito ST, Lopes LD. Camellia sinensis neuroprotective role in experimentally induced hydrocephalus in Wistar rats. Childs Nerv Syst. 2013;30:591.",{"doi":607},{"id":18,"text":4020,"url":18,"identifiers":4021},"Feng S, Yang Q, Liu M, Li W, Yuan W, Zhang S, Wu B, Li J: Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev. 2011:CD007230.",{},{"id":603,"text":4023,"url":605,"identifiers":4024},"Chen Z, Zhang J, Chen Q, Guo J, Zhu G, Feng H. Neuroprotective effects of edaravone after intraventricular hemorrhage in rats. NeuroReport. 2014;25:635–40.",{"doi":607},{"id":603,"text":4026,"url":605,"identifiers":4027},"Wenk GL, Parsons CG, Danysz W. Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol. 2006;17:411–24.",{"doi":607},{"id":603,"text":4029,"url":605,"identifiers":4030},"Cabuk B, Etus V, Bozkurt SU, Sav A, Ceylan S. Neuroprotective effect of memantine on hippocampal neurons in infantile rat hydrocephalus. Turk Neurosurg. 2011;21:352–8.",{"doi":607},{"id":603,"text":4032,"url":605,"identifiers":4033},"Taveira KV, Carraro KT, Catalao CH, Lda Lopes S. Morphological and morphometric analysis of the hippocampus in Wistar rats with experimental hydrocephalus. Pediatr Neurosurg. 2012;48:163–7.",{"doi":607},{"id":603,"text":4035,"url":605,"identifiers":4036},"Shim I, Ha Y, Chung JY, Lee HJ, Yang KH, Chang JW. Association of learning and memory impairments with changes in the septohippocampal cholinergic system in rats with kaolin-induced hydrocephalus. Neurosurgery. 2003;53:416–25.",{"doi":607},{"id":4038,"text":4039,"url":4040,"identifiers":4041},"d3bb9efd-cc92-42ec-95a2-60b342477cea","Ding Y, McAllister JP II, Yao B, Yan N, Canady AI. Neuron tolerance during hydrocephalus. Neuroscience. 2001;106:659–67.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS030645220100166X",{"doi":4042},"10.1016\u002Fs0306-4522(01)00166-x",{"id":603,"text":4044,"url":605,"identifiers":4045},"Kokturk S, Ceylan S, Etus V, Yasa N, Ceylan S. Morinda citrifolia L. (noni) and memantine attenuate periventricular tissue injury of the fourth ventricle in hydrocephalic rabbits. Neural Regen Res. 2013;8:773–82.",{"doi":607},{"id":603,"text":4047,"url":605,"identifiers":4048},"Khan OH, Enno T, Del Bigio MR. Tacrolimus and cyclosporine A are of no benefit to young rats with kaolin-induced hydrocephalus. Pediatr Neurosurg. 2003;39:309–13.",{"doi":607},{"id":603,"text":4050,"url":605,"identifiers":4051},"Del Bigio MR, Wang X, Wilson MJ. Sodium channel-blocking agents are not of benefit to rats with kaolin-induced hydrocephalus. Neurosurgery. 2002;51:460–7.",{"doi":607},{"id":603,"text":4053,"url":605,"identifiers":4054},"Malm J, Kristensen B, Ekstedt J, Wester P. CSF concentration gradients of monoamine metabolites in patients with hydrocephalus. J Neurol Neurosurg Psychiatr. 1994;57:1026–33.",{"doi":607},{"id":603,"text":4056,"url":605,"identifiers":4057},"Miyake H, Eghwrudjakpor P, Sakamoto T, Kurisaka M, Mori K. Neurotransmitter changes in hydrocephalus: effects of cerebral metabolic activator on kaolin-induced hydrocephalus. In: Matsumoto S, Tamaki N, editors. Hydrocephalus: pathogenesis and treatment. Tokyo: Springer-Verlag; 1991. p. 68–74.",{"doi":607},{"id":603,"text":4059,"url":605,"identifiers":4060},"Keenan S, Mavaddat N, Iddon J, Pickard JD, Sahakian BJ. Effects of methylphenidate on cognition and apathy in normal pressure hydrocephalus: a case study and review. Br J Neurosurg. 2005;19:46–50.",{"doi":607},{"id":603,"text":4062,"url":605,"identifiers":4063},"Wheeler GA, Young SA. Use of methylphenidate in a case of mild, inoperative, idiopathic, normal pressure hydrocephalus. Gen Hosp Psychiatry. 1994;16:361–3.",{"doi":607},{"id":603,"text":4065,"url":605,"identifiers":4066},"Anderson B. Relief of akinetic mutism from obstructive hydrocephalus using bromocriptine and ephedrine. Case report. J Neurosurg. 1992;76:152–5.",{"doi":607},{"id":18,"text":4068,"url":18,"identifiers":4069},"Mateo-Sierra O, Gutierrez FA, Fernandez-Carballal C, Pinilla D, Mosqueira B, Iza B, Carrillo R. Akinetic mutism related to hydrocephalus and cerebellar surgery treated with bromocriptine and ephedrine. A pathophysiological review. Neurocirugia (Astur). 2005;16:134–141; discussion 141.",{},{"id":603,"text":4071,"url":605,"identifiers":4072},"Mashiko H, Yokoyama H, Matsumoto H, Niwa S. Trazodone for aggression in an adolescent with hydrocephalus. Psychiatry Clin Neurosci. 1996;50:133–6.",{"doi":607},{"id":603,"text":4074,"url":605,"identifiers":4075},"Owen-Lynch PJ, Draper CE, Mashayekhi F, Bannister CM, Miyan JA. Defective cell cycle control underlies abnormal cortical development in the hydrocephalic Texas rat. Brain. 2003;126:623–31.",{"doi":607},{"id":603,"text":4077,"url":605,"identifiers":4078},"Yung YC, Mutoh T, Lin ME, Noguchi K, Rivera RR, Choi JW, Kingsbury MA, Chun J. Lysophosphatidic Acid signaling may initiate fetal hydrocephalus. Sci Transl Med. 2011;3:99ra87.",{"doi":607},{"id":603,"text":4080,"url":605,"identifiers":4081},"Lategan B, Chodirker BN, Del Bigio MR. Fetal hydrocephalus caused by cryptic intraventricular hemorrhage. Brain Pathol. 2010;20:391–8.",{"doi":607},{"id":603,"text":4083,"url":605,"identifiers":4084},"Del Bigio MR. Cell proliferation in human ganglionic eminence and suppression after prematurity-associated haemorrhage. Brain. 2011;134:1344–61.",{"doi":607},{"id":603,"text":4086,"url":605,"identifiers":4087},"Stoddard NC, Chun J. Promising pharmacological directions in the world of lysophosphatidic acid signaling. Biomol Ther (Seoul). 2015;23:1–11.",{"doi":607},{"id":18,"text":4089,"url":18,"identifiers":4090},"Jones HC, Bucknall RM. Inherited prenatal hydrocephalus in the H-Tx rat: a morphological study. Neuropathol Appl Neurobiol. 1988;14:263–74.",{},{"id":4092,"text":4093,"url":4094,"identifiers":4095},"b0266505-bae7-4890-9d04-3633597101cf","Jones HC, Depelteau JS, Carter BJ, Lopman BA, Morel L. Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat. Mamm Genome. 2001;12:22–6.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs003350010226",{"doi":4096},"10.1007\u002Fs003350010226",{"id":603,"text":4098,"url":605,"identifiers":4099},"Cains S, Shepherd A, Nabiuni M, Owen-Lynch PJ, Miyan J. Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus. J Neuropathol Exp Neurol. 2009;68:404–16.",{"doi":607},{"id":603,"text":4101,"url":605,"identifiers":4102},"Tsubokawa T, Katayama Y, Miyazaki S, Ogawa H, Kawamata T, Iwasaki M, Sako Y. Raphe-cell transplantation into the hippocampus of the hydrocephalic rat brain. Brain Inj. 1988;2:67–74.",{"doi":607},{"id":603,"text":4104,"url":605,"identifiers":4105},"Ahn SY, Chang YS, Sung DK, Sung SI, Yoo HS, Lee JH, Oh WI, Park WS. Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage. Stroke. 2013;44:497.",{"doi":607},{"id":603,"text":4107,"url":605,"identifiers":4108},"Ahn SY, Chang YS, Sung DK, Sung SI, Yoo HS, Im GH, Choi SJ, Park WS. Optimal route for mesenchymal stem cells transplantation after severe intraventricular hemorrhage in newborn rats. PLoS One. 2015;10:e0132919.",{"doi":607},{"id":603,"text":4110,"url":605,"identifiers":4111},"Del Bigio MR. Future directions for therapy of childhood hydrocephalus: a view from the laboratory. Pediatr Neurosurg. 2001;34:172–81.",{"doi":607},{"id":603,"text":4113,"url":605,"identifiers":4114},"Brouwer AJ, Brouwer MJ, Groenendaal F, Benders MJ, Whitelaw A, de Vries LS. European perspective on the diagnosis and treatment of posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed. 2012;97:F50–5.",{"doi":607},{"id":603,"text":4116,"url":605,"identifiers":4117},"Brouwer AJ, Groenendaal F, Benders MJ, de Vries LS. Early and late complications of germinal matrix-intraventricular haemorrhage in the preterm infant: what is new? Neonatology. 2014;106:296–303.",{"doi":607},{"id":4119,"text":4120,"url":4121,"identifiers":4122},"51f6e6ec-b5f1-4050-b7aa-a427e80fc0d5","Garrido-Mesa N, Zarzuelo A, Galvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169:337–52.","https:\u002F\u002Fbpspubs.onlinelibrary.wiley.com\u002Fdoi\u002F10.1111\u002Fbph.12139",{"doi":4123},"10.1111\u002Fbph.12139",{"id":603,"text":4125,"url":605,"identifiers":4126},"Juul SE, Pet GC. Erythropoietin and neonatal neuroprotection. Clin Perinatol. 2015;42:469–81.",{"doi":607},{"id":603,"text":4128,"url":605,"identifiers":4129},"Neubauer AP, Voss W, Wachtendorf M, Jungmann T. Erythropoietin improves neurodevelopmental outcome of extremely preterm infants. Ann Neurol. 2010;67:657–66.",{"doi":607},{"id":603,"text":4131,"url":605,"identifiers":4132},"Ye R, Zhao G, Liu X. Ginsenoside Rd for acute ischemic stroke: translating from bench to bedside. Expert Rev Neurother. 2013;13:603–13.",{"doi":607},{"id":603,"text":4134,"url":605,"identifiers":4135},"Del Zoppo GJ. Why do all drugs work in animals but none in stroke patients? 1. Drugs promoting cerebral blood flow. J Intern Med. 1995;237:79–88.",{"doi":607},{"id":603,"text":4137,"url":605,"identifiers":4138},"Grotta J. Why do all drugs work in animals but none in stroke patients? 2. Neuroprotective therapy. J Intern Med. 1995;237:89–94.",{"doi":607},{"id":603,"text":4140,"url":605,"identifiers":4141},"Dirnagl U. Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab. 2006;26:1465–78.",{"doi":607},{"id":18,"text":4143,"url":18,"identifiers":4144},"O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–77.",{},{"id":603,"text":4146,"url":605,"identifiers":4147},"Tosetti P, Hicks RR, Theriault E, Phillips A, Koroshetz W, Draghia-Akli R, Workshop P. Toward an international initiative for traumatic brain injury research. J Neurotrauma. 2013;30:1211–22.",{"doi":607},{"id":4149,"text":4150,"url":4151,"identifiers":4152},"547dce8c-7332-4e61-933b-1adaf507e06b","Del Bigio MR, Slobodian I, Schellenberg AE, Buist RJ, Kemp-Buors TL. Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus. Fluids Barriers CNS. 2011;8:22.","https:\u002F\u002Ffluidsbarrierscns.biomedcentral.com\u002Farticles\u002F10.1186\u002F2045-8118-8-22",{"doi":4153},"10.1186\u002F2045-8118-8-22"]