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Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ). We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number. PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects. Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.",{"EN":280},"Cannabidiol effect in pentylenetetrazole-induced seizures depends on PI3K",{"VOID":282},"[\"3876813160252435677\"]",{"VOID":284},"Milligan TA. Epilepsy: a clinical overview. Am J Med. 2021;134:840–7. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.AMJMED.2021.01.038.\nFisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55:475–82. https:\u002F\u002Fdoi.org\u002F10.1111\u002FEPI.12550.\nKwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9. https:\u002F\u002Fdoi.org\u002F10.1056\u002FNEJM200002033420503.\nHakami T, Tahir HC. Neuropharmacology of antiseizure drugs. Neuropsychopharmacol Rep. 2021;41:336–51. https:\u002F\u002Fdoi.org\u002F10.1002\u002FNPR2.12196.\nPerucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11:792–802. https:\u002F\u002Fdoi.org\u002F10.1016\u002FS1474-4422(12)70153-9.\nDavis BH, Beasley TM, Amaral M, Szaflarski JP, Gaston T, Perry Grayson L, et al. Pharmacogenetic predictors of cannabidiol response and tolerability in treatment-resistant epilepsy. Clin Pharmacol Ther. 2021;110:1368–80. https:\u002F\u002Fdoi.org\u002F10.1002\u002FCPT.2408.\nTito PAL, de Bernardino TCS, Bellozi PMQ, da Silva MCM, de Miranda AS, Vieira ÉLM, et al. Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain. Pharmacol Rep. 2021;73:1680–93. https:\u002F\u002Fdoi.org\u002F10.1007\u002FS43440-021-00301-8.\nThiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: a placebo-controlled randomized clinical trial. JAMA Neurol. 2021;78:285–92. https:\u002F\u002Fdoi.org\u002F10.1001\u002FJAMANEUROL.2020.4607.\nSzaflarski JP, Bebin EM, Cutter G, DeWolfe J, Dure LS, Gaston TE, et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018;87:131–6. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.YEBEH.2018.07.020.\nSilvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E. Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules. 2019;24:1459. https:\u002F\u002Fdoi.org\u002F10.3390\u002FMOLECULES24081459.\nFattorusso A, Matricardi S, Mencaroni E, Dell’Isola GB, Di Cara G, Striano P, et al. The pharmacoresistant epilepsy: an overview on existant and new emerging therapies. Front Neurol. 2021;12: 674483. https:\u002F\u002Fdoi.org\u002F10.3389\u002FFNEUR.2021.674483.\nUliel-Sibony S, Hausman-Kedem M, Fattal-Valevski A, Kramer U. Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist? Brain Dev. 2021;43:89–96. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.BRAINDEV.2020.06.018.\nde Lima IVA, Bellozi PMQ, Batista EM, Vilela LR, Brandão IL, Ribeiro FM, et al. Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway. Neuropharmacology. 2020;176:108156. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.NEUROPHARM.2020.108156.\nGobira PH, Vilela LR, Gonçalves BDC, Santos RPM, de Oliveira AC, Vieira LB, et al. Cannabidiol, a cannabis sativa constituent, inhibits cocaine-induced seizures in mice: possible role of the mTOR pathway and reduction in glutamate release. Neurotoxicology. 2015;50:116–21. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.NEURO.2015.08.007.\nLin B, Gao Y, Li Z, Zhang Z, Lin X, Gao J. Cannabidiol alleviates hemorrhagic shock-induced neural apoptosis in rats by inducing autophagy through activation of the PI3K\u002FAKT pathway. Fundam Clin Pharmacol. 2020;34:640–9. https:\u002F\u002Fdoi.org\u002F10.1111\u002FFCP.12557.\nGiacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K\u002FAkt\u002FmTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia. 2017;116:77–84. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.FITOTE.2016.11.010.\nLöscher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res. 2016;126:157–84. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.EPLEPSYRES.2016.05.016.\nShimada T, Yamagata K. Pentylenetetrazole-Induced Kindling Mouse Model. J Vis Exp. 2018;2018:56573. https:\u002F\u002Fdoi.org\u002F10.3791\u002F56573.\nJones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, et al. Cannabidiol displays antiepileptiform and antiseizure properties In Vitro and In Vivo. J Pharmacol Exp Ther. 2010;332:569–77. https:\u002F\u002Fdoi.org\u002F10.1124\u002FJPET.109.159145.\nKlein BD, Jacobson CA, Metcalf CS, Smith MD, Wilcox KS, Hampson AJ, et al. Evaluation of cannabidiol in animal seizure models by the epilepsy therapy screening program (ETSP). Neurochem Res. 2017;42:1939–48. https:\u002F\u002Fdoi.org\u002F10.1007\u002FS11064-017-2287-8\u002FFIGURES\u002F4.\nConsroe P, Benedito MAC, Leite JR, Carlini EA, Mechoulam R. Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol. 1982;83:293–8. https:\u002F\u002Fdoi.org\u002F10.1016\u002F0014-2999(82)90264-3.\nVilela LR, Lima IV, Kunsch ÉB, Pinto HPP, de Miranda AS, Vieira ÉLM, et al. Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels. Epilepsy Behav. 2017;75:29–35. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.YEBEH.2017.07.014.\nBellozi PMQ, de Lima IVA, Dória JG, Vieira ÉLM, Campos AC, Candelario-Jalil E, et al. Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1–42 induced neurotoxicity and memory impairment. Sci Rep. 2016. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fsrep25226.\nZanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SRL. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159:122–8. https:\u002F\u002Fdoi.org\u002F10.1111\u002FJ.1476-5381.2009.00521.X.\nSánchez-Alegría K, Flores-León M, Avila-Muñoz E, Rodríguez-Corona N, Arias C. PI3K Signaling in neurons: a central node for the control of multiple functions. Int J Mol Sci. 2018;19:3725. https:\u002F\u002Fdoi.org\u002F10.3390\u002FIJMS19123725.\nGross C, Bassell GJ. Neuron-specific regulation of class I PI3K catalytic subunits and their dysfunction in brain disorders. Front Mol Neurosci. 2014. https:\u002F\u002Fdoi.org\u002F10.3389\u002FFNMOL.2014.00012.\nde Lima IVA, Campos AC, Miranda AS, Vieira ÉLM, Amaral-Martins F, Vago JP, et al. PI3Kγ deficiency enhances seizures severity and associated outcomes in a mouse model of convulsions induced by intrahippocampal injection of pilocarpine. Exp Neurol. 2015;267:123–34. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.EXPNEUROL.2015.02.021.\nZhang B, Wong M. Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia. 2012;53:506–11. https:\u002F\u002Fdoi.org\u002F10.1111\u002FJ.1528-1167.2011.03384.X.\nHan T, Qin Y, Mou C, Wang M, Jiang M, Liu B. Seizure induced synaptic plasticity alteration in hippocampus is mediated by IL-1β receptor through PI3K\u002FAkt pathway. Am J Transl Res. 2016;8:4499.\nCarter AN, Born HA, Levine AT, Dao AT, Zhao AJ, Lee WL, et al. Wortmannin attenuates seizure-induced hyperactive pi3k\u002Fakt\u002Fmtor signaling, impaired memory, and spine dysmorphology in rats. ENeuro. 2017;4:354–70. https:\u002F\u002Fdoi.org\u002F10.1523\u002FENEURO.0354-16.2017.\nYang B, Wang J, Zhang N. Effect of nobiletin on experimental model of epilepsy. Transl Neurosci. 2018;9:211–9. https:\u002F\u002Fdoi.org\u002F10.1515\u002FTNSCI-2018-0031.\nHaller J, Bakos N, Szirmay M, Ledent C, Freund TF. The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci. 2002;16:1395–8. https:\u002F\u002Fdoi.org\u002F10.1046\u002FJ.1460-9568.2002.02192.X.\nGuscott M, Bristow LJ, Hadingham K, Rosahl TW, Beer MS, Stanton JA, et al. Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology. 2005;48:492–502. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.NEUROPHARM.2004.11.015.\nReynolds DS. The value of genetic and pharmacological approaches to understanding the complexities of GABA (A) receptor subtype functions: the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav. 2008;90:37–42. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.PBB.2008.03.015.\nVanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci. 2005;30:194–204. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.TIBS.2005.02.008.\nLazarini-Lopes W, Do Val-da Silva RA, da Silva-Júnior RMP, Leite JP, Garcia-Cairasco N. The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: From behavior and mechanisms to clinical insights. Neurosci Biobehav Rev. 2020;111:166–82. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.NEUBIOREV.2020.01.014.\nAsth L, Iglesias LP, De Oliveira AC, Moraes MFD, Moreira FA. Exploiting cannabinoid and vanilloid mechanisms for epilepsy treatment. Epilepsy Behav. 2021;121:106832. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.YEBEH.2019.106832.\nShahbazi F, Grandi V, Banerjee A, Trant JF. Cannabinoids and cannabinoid receptors: the story so far. IScience. 2020;23:101301. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.ISCI.2020.101301.\nBisogno T, Hanuš L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845–52. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fsj.bjp.0704327.\nCao Q, Liu X, Yang F, Wang H. CB2R induces a protective response for epileptic seizure via the PI3K 110α-AKT signaling pathway. Exp Ther Med. 2018;16:4784–90. https:\u002F\u002Fdoi.org\u002F10.3892\u002FETM.2018.6788.\nFranco-Vadillo A, Toledo-Blass M, Rivera-Herrera Z, Guevara-Balcazar G, Orihuela-Rodriguez O, Morales-Carmona JA, et al. Cannabidiol-mediated RISK PI3K\u002FAKT and MAPK\u002FERK pathways decreasing reperfusion myocardial damage. Pharmacol Res Perspect. 2021. https:\u002F\u002Fdoi.org\u002F10.1002\u002FPRP2.784.\nGu Z, Singh S, Niyogi RG, Lamont GJ, Wang H, Lamont RJ, et al. Marijuana-derived cannabinoids trigger a CB2\u002FPI3K axis of suppression of the innate response to oral pathogens. Front Immunol. 2019;10:2288. https:\u002F\u002Fdoi.org\u002F10.3389\u002FFIMMU.2019.02288.\nSánchez MG, Ruiz-Llorente L, Sánchez AM, Díaz-Laviada I. Activation of phosphoinositide 3-kinase\u002FPKB pathway by CB(1) and CB(2) cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. Cell Signal. 2003;15:851–9. https:\u002F\u002Fdoi.org\u002F10.1016\u002FS0898-6568(03)00036-6.\nGalve-Roperh I, Chiurchiù V, Díaz-Alonso J, Bari M, Guzmán M, Maccarrone M. Cannabinoid receptor signaling in progenitor\u002Fstem cell proliferation and differentiation. Prog Lipid Res. 2013;52:633–50. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.PLIPRES.2013.05.004.\nMlost J, Bryk M, Starowicz K. Cannabidiol for pain treatment: focus on pharmacology and mechanism of action. Int J Mol Sci. 2020;21:1–22. https:\u002F\u002Fdoi.org\u002F10.3390\u002FIJMS21228870.\nIuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA. Neuroprotective effect of cannabidiol, a non-psychoactive component from cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 2004;89:134–41. https:\u002F\u002Fdoi.org\u002F10.1111\u002FJ.1471-4159.2003.02327.X.\nMolina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ. Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. J Neurosci Res. 2002;67:829–36. https:\u002F\u002Fdoi.org\u002F10.1002\u002FJNR.10165.\nMolina-Holgado F, Pinteaux E, Heenan L, Moore JD, Rothwell NJ, Gibson RM. Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase\u002FAKT signaling. Mol Cell Neurosci. 2005;28:189–94. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.MCN.2004.09.004.\nTrazzi S, Steger M, Mitrugno VM, Bartesaghi R, Ciani E. CB1 cannabinoid receptors increase neuronal precursor proliferation through AKT\u002Fglycogen synthase kinase-3beta\u002Fbeta-catenin signaling. J Biol Chem. 2010;285:10098–109. https:\u002F\u002Fdoi.org\u002F10.1074\u002FJBC.M109.043711.\nPalazuelos J, Ortega Z, Díaz-Alonso J, Guzmán M, Galve-Roperh I. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J Biol Chem. 2012;287:1198–209. https:\u002F\u002Fdoi.org\u002F10.1074\u002FJBC.M111.291294.\nLee G, Huang Y, Washington JM, Briggs NW, Zuo Z. Carbamazepine enhances the activity of glutamate transporter type 3 via phosphatidylinositol 3-kinase. Epilepsy Res. 2005;66:145–53. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.EPLEPSYRES.2005.08.003.\nRyu JH, Lee PB, Kim JH, Do SH, Kim CS. Effects of pregabalin on the activity of glutamate transporter type 3. Br J Anaesth. 2012;109:234–9. https:\u002F\u002Fdoi.org\u002F10.1093\u002FBJA\u002FAES120.\nXu E, Müller-Taubenberger A, Adley KE, Pawolleck N, Lee VWY, Wiedemann C, et al. Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid. Eukaryot Cell. 2007;6:899–906. https:\u002F\u002Fdoi.org\u002F10.1128\u002FEC.00104-06\u002FSUPPL_FILE\u002FXU_SUP_DATA_2B.ZIP.\nPuighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci. 2009;12:1152–8. https:\u002F\u002Fdoi.org\u002F10.1038\u002FNN.2369.\nAmbrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Di Palma M, et al. Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E. Biochim Biophys Acta-Mol Basis Dis. 2019;1865:1098–112. https:\u002F\u002Fdoi.org\u002F10.1016\u002FJ.BBADIS.2019.01.026.\nChang P, Walker MC, Williams RSB. Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid. 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showed that estrogen-progestin oral contraceptive (COC) or tobacco smoking causes increased risk of cardiovascular diseases (CVD) in premenopausal women. Studies also suggest that nicotine, a major tobacco alkaloid, may worsen or improve atherothrombotic CVD. Altered hemorheology, prothrombotic and pro-inflammatory biomarkers, have been implicated in the development of atherothrombotic CVD events. However, the effect of non-smoking nicotine exposure on these biomarkers during COC treatment is not yet established. We therefore sought to determine the effects of nicotine exposure during COC treatment on these biomarkers, and also tested the hypothesis that the nicotine effects would be glucocorticoid-dependent. Female Sprague-Dawley rats aged 10 weeks were given (po) vehicle, low-dose nicotine (0.1 mg\u002Fkg) or high-dose nicotine (1.0 mg\u002Fkg) with or without COC steroids (5.0 μg\u002Fkg ethinylestradiol and 25.0 μg\u002Fkg levonorgestrel) daily for 6 weeks. COC treatment or nicotine exposure led to increased insulin resistance (IR), hemorheological (blood viscosity, hematocrit and plasma viscosity), prothrombotic (plasminogen activator inhibitor-1), pro-inflammatory (uric acid, C-reactive protein, neutrophil\u002Flymphocyte and platelet\u002Flymphocyte ratios) biomarkers and corticosterone. However, these effects except that on corticosterone were abrogated by nicotine exposure during COC treatment. Our study indicates that nicotine- or COC-induced IR may be mediated via inflammatory\u002Fthrombotic pathway. The results imply that nicotine exposure could impact negatively on atherothrombotic biomarkers in COC non-users, whereas the impact in COC users could be positive. 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Eur J Pharmacol 2014;735:97–104.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0014299914003033",{"doi":795},"10.1016\u002Fj.ejphar.2014.04.019",{"id":797,"createTime":798,"updateTime":799,"relativeEntities":800,"slug":801,"properties":802,"entityType":177,"verifyStatus":178,"verifyTime":811,"verifyNote":180,"languages":22,"translateLanguages":22,"viewCount":23,"primaryUrl":812,"fullTextUrl":22,"authors":813,"publicationType":212,"publisherRelationship":842,"citationCount":23,"citationInfo":894,"publishDate":897,"publishYear":895,"citationAnalyzeStatus":898,"lastCitationAnalyze":799,"indexDatabases":899,"openAccess":22,"references":22,"isForceReanalyzing":269},"23c7632a-c27d-4fff-8098-703e72d1e8d0","2024-02-08T06:27:20.808+00:00","2026-07-28T14:46:36.352+00:00",[],"Inhibitors-of-type-2-sodium-glucose-co-transporters-a-new-strategy-for-diabetes-treatment",{"title":803,"gsPaper":805,"references":807,"doi":809},{"EN":804},"Inhibitors of type 2 sodium glucose co-transporters – a new strategy for diabetes treatment",{"VOID":806},"[\"14110282534235371570\"]",{"VOID":808},"2008, American Diabetes Association: Standards of medical care in diabetes 2008, Diabetes Care, 31, S12\nBell, 2004, Type 2 diabetes mellitus: what is the optimal treatment regimen?, Am J Med, 116, 23S, 10.1016\u002Fj.amjmed.2003.10.017\nCalado, 2006, Familial renal glucosuria: SGLC5A2 mutation analysis and evidence of salt-wasting, Kidney Int, 69, 852, 10.1038\u002Fsj.ki.5000194\nDluhy, 2008, Intensive glycemic control in the ACCORD and ADVANCE trials, N Engl J Med, 358, 2630, 10.1056\u002FNEJMe0804182\nEhrenkranz, 2005, Phlorizin: a review, Diabetes Metab Res Rev, 21, 31, 10.1002\u002Fdmrr.532\nFujimori, 2008, Remogliflozin etabonate, in a novel category of selective low-affinity\u002Fhigh-capacity sodium glucose cotransporter (SGLT-2) inhibitors, exhibits antidiabetic efficacy in rodent models, J Pharmacol Exp Ther, 327, 268, 10.1124\u002Fjpet.108.140210\nGaede, 2003, Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes, N Engl J Med, 348, 383, 10.1056\u002FNEJMoa021778\nGeerlings, 2000, Diabetes Women Asymptomatic Bacteriuria Utrecht Study Group: Risk factors for symptomatic urinary tract infections in women with diabetes, Diabetes Care, 23, 1737, 10.2337\u002Fdiacare.23.12.1737\nGrigoriou, 2006, Prevalence of clinical vaginal candidiasis in a university hospital and possible risk factors, Eur J Obstet Gynecol Reprod Biol, 126, 121, 10.1016\u002Fj.ejogrb.2005.09.015\nHan, 2008, Dapagliflozin, a selective SGLT-2 inhibitor, improves glucose homeostasis in normal and diabetic rats, Diabetes, 57, 1723, 10.2337\u002Fdb07-1472\nHandlon, 2005, Sodium glucose co-transporter 2 (SGLT-2) inhibitors as potential antidiabetic agents, Expert Opin Ther Pat, 15, 1531, 10.1517\u002F13543776.15.11.1531\nIsaji, 2007, Sodium-glucose cotransporter inhibitors for diabetes, Curr Opin Investig Drugs, 8, 285\nJabbour, 2008, Sodium-glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes, Int J Clin Pract, 62, 1279, 10.1111\u002Fj.1742-1241.2008.01829.x\nJohnson & Johnson Pharmaceutical Research & Development, L.L.C.: A randomized, double-blind, placebocontrolled, double-dummy, parallel group, multicenter, dose-ranging study in subjects with type 2 diabetes mellitus to evaluate the efficacy, safety, and tolerability of orally administered SGLT2 inhibitor JNJ-28431754 with sitagliptin as a reference arm. NCT00642278.\nKahn, 1991, Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression, J Clin Invest, 87, 561, 10.1172\u002FJCI115031\nKanai, 1994, The human kidney low affinity Na+\u002Fglucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose, J Clin Invest, 93, 397, 10.1172\u002FJCI116972\nKatsuno, 2007, Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level, J Pharmacol Exp Ther, 320, 323, 10.1124\u002Fjpet.106.110296\nL’Abbate, 2005, Large and micro coronary vascular involvement in diabetes, Pharmacol Rep, 57, 3\nLee, 2007, Regulatory mechanisms of Na+\u002Fglucose cotransporters in renal proximal tubule cells, Kidney Int Suppl, 106, S27, 10.1038\u002Fsj.ki.5002383\nList, 2009, Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes mellitus, Diabetes Care, 32, 650, 10.2337\u002Fdc08-1863\nMadej, 2005, Plasma concentrations of adhesion molecules and chemokines in patients with essential hypertension, Pharmacol Rep, 57, 81\nMalatiali, 2008, Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats, Exp Diabetes Res, 10.1155\u002F2008\u002F305403\nNathan, 2006, Management of hyperglycaemia in type 2 diabetes: A consensus alghoritm for the initiation and adjustment of therapy, A consensus statement for the American Diabetes Association and the European Association for the Study of Diabetes, 49, 1711\nOkopien, 2005, Hypolipidemic drugs affect monocyte IL-β gene expression and release in patients with IIa and IIb dyslipidemia, J Cardiovasc Pharmacol, 45, 160, 10.1097\u002F01.fjc.0000151895.80508.c9\nPajor, 2008, Inhibitor binding in the human renal low- and high-affinity Na+\u002Fglucose cotransporters, J Pharmacol Exp Ther, 324, 985, 10.1124\u002Fjpet.107.129825\nRahmoune, 2005, Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non–insulin-dependent diabetes, Diabetes, 54, 3427, 10.2337\u002Fdiabetes.54.12.3427\nSanter, 2003, Molecular analysis of the SGLT2 gene in patients with renal glucosuria, J Am Soc Nephrol, 14, 2873, 10.1097\u002F01.ASN.0000092790.89332.D2\nStratton, 2000, Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study BMJ, 321, 405\n2008, Tanabe Seiyaku Co. Ltd.: Annual Report 2008, Mitsubishi Chemical Holdings Corporation, 28.\nVallon, 1999, Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption, J Am Soc Nephrol, 10, 2569, 10.1681\u002FASN.V10122569\nVan den Heuvel, 2002, Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2), Hum Genet, 111, 544, 10.1007\u002Fs00439-002-0820-5\nWild, 2004, Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030, Diabetes Care, 27, 1047, 10.2337\u002Fdiacare.27.5.1047\n2008, World Health Organization: International Nonproprietary Names for Pharmaceutical Substances (INN), Recommended International Nonproprietary Names: List 59, 22, 50\n2008, World Health Organization: International Nonproprietary Names for Pharmaceutical Substances (INN), Recommended International Nonproprietary Names: List 59, 22, 66\nWright, 2007, Active sugar transport in health and disease, J Intern Med, 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with long-acting local anesthetic effects did not cause system toxicity as fast as bupivacaine, while catecholamines (i.e., epinephrine) with the vasoconstrictive characteristics enhanced the effects of local anesthetic drugs. The objective of the experiment was to examine the synergistic effect of local dopamine (a catecholamine) injection on cutaneous antinociception of dextrorphan. The panniculus reflex in response to skin stimulation with a needle was used as the primary endpoint when dextrorphan (1.50, 2.61, 5.46, 10.20 and 20.40 μmol) alone, dopamine (16.20, 32.40, 51.60, 60.00 and 81.60 μmol) alone, or dopamine + dextrorphan (a ratio of ED50vs. ED50) was injected subcutaneously on the rat’s back. We used an isobolographic modelling approach to determine whether a synergistic effect would be observed. We showed that dextrorphan, dopamine, or the mixture of dopamine and dextrorphan produced dose-related skin antinociception. The potency (ED50, 50% effective dose) for cutaneous antinociception was dextrorphan [6.02 (5.93–6.14) μmol] greater than dopamine [48.91 (48.80–49.06) μmol] (p \u003C 0.01). The duration of nociceptive inhibition induced by dopamine was longer than that induced by dextrorphan (p \u003C 0.01) based on their equipotent doses (ED25, ED50, and ED75). Enhancement and prolongation of skin antinociception occurred after co-administration of dopamine with dextrorphan. When compared to dopamine, dextrorphan was more potent and had a shorter duration of skin nociceptive block. 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Dextromethorphan or dextrorphan have a local anesthetic effect on infiltrative cutaneous analgesia in rats. Anesth Analg 2007;104:1251–5.",{"doi":628},{"id":1117,"text":1118,"url":1119,"identifiers":1120},"9017a8b8-1d2a-4517-81b6-e48882ef1f71","Chen YW, Chen YC, Lin CN, Chu CC, Lin MT, Wang JJ, et al. The spinal anaesthetic effect of dextromethorphan, dextrorphan, and 3-methoxymorphinan. Eur J Pharmacol 2007;569:188–93.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS001429990700619X",{"doi":1121},"10.1016\u002Fj.ejphar.2007.05.019",{"id":1123,"text":1124,"url":1125,"identifiers":1126},"7a9ffec2-cde2-412a-948e-4377f3b53385","Chen YW, Wang JJ, Liu TY, Chen YC, Hung CH. Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses. Can J Anaesth 2011;58:55–61.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs12630-010-9408-z",{"doi":1127},"10.1007\u002Fs12630-010-9408-z",{"id":624,"text":1129,"url":626,"identifiers":1130},"Tam KW, Chen SY, Huang TW, Lin CC, Su CM, Li CL, et al. Effect of wound infiltration with ropivacaine or bupivacaine analgesia in breast cancer surgery: a meta-analysis of randomized controlled trials. Int J Surg 2015;22:79–85.",{"doi":628},{"id":22,"text":1132,"url":22,"identifiers":1133},"Ventham NT, O’Neill S, Johns N, Brady RR, Fearon KC. Evaluation of novel local anesthetic wound infiltration techniques for postoperative pain following colorectal resection surgery: a meta-analysis. Dis Colon Rectum 2014;57:237–50.",{},{"id":624,"text":1135,"url":626,"identifiers":1136},"Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. 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Exp Neurol 2007;205:536–46.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0014488607001276",{"doi":1148},"10.1016\u002Fj.expneurol.2007.03.010",{"id":624,"text":1150,"url":626,"identifiers":1151},"Ross M. Dopamine-induced localized cutaneous vasoconstriction and piloerection. Arch Dermatol 1991;127:586–7.",{"doi":628},{"id":22,"text":1153,"url":22,"identifiers":1154},"Tallarida RJ, Porreca F, Cowan A. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci 1989;45:947–61.",{},{"id":1156,"text":1157,"url":1158,"identifiers":1159},"0ba0aa46-1839-421a-baf5-44d5925345d9","Han MM, Chiu CC, Wang JJ, Chen YW, Hung CH. Mexiletine co-injected with clonidine increases the quality and duration of cutaneous analgesia in response to skin pinpricks in the rat. Neurosci Lett 2017;654:23–7.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0304394017305025",{"doi":1160},"10.1016\u002Fj.neulet.2017.06.022",{"id":624,"text":1162,"url":626,"identifiers":1163},"Chen YW, Shieh JP, Liu KS, Wang JJ, Hung CH. Naloxone prolongs cutaneous nociceptive block by lidocaine in rats. Fundam Clin Pharmacol 2017;31:636–42.",{"doi":628},{"id":1165,"text":1166,"url":1167,"identifiers":1168},"14e41aed-310d-4cfc-8dae-c74cb71660ff","Petruska JC, Barker DF, Garraway SM, Trainer R, Fransen JW, Seidman PA, et al. Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity. J Comp Neurol 2014;522:1048–71.","https:\u002F\u002Fonlinelibrary.wiley.com\u002Fdoi\u002F10.1002\u002Fcne.23461",{"doi":1169},"10.1002\u002Fcne.23461",{"id":624,"text":1171,"url":626,"identifiers":1172},"Theriault E, Diamond J. Nociceptive cutaneous stimuli evoke localized contractions in a skeletal muscle. J Neurophysiol 1988;60:446–62.",{"doi":628},{"id":624,"text":1174,"url":626,"identifiers":1175},"Chen YW, Chiu CC, Kan CD, Wang JJ, Hung CH. The addition of epinephrine to proxymetacaine or oxybuprocaine solution increases the depth and duration of cutaneous analgesia in rats. Reg Anesth Pain Med 2016;41:601–6.",{"doi":628},{"id":624,"text":1177,"url":626,"identifiers":1178},"Chou AK, Chiu CC, Chen YW, Wang JJ, Hung CH. Phentolamine reverses epinephrine-enhanced skin antinociception of dibucaine in rats. Anesth Analg 2018.",{"doi":628},{"id":1180,"text":1181,"url":1182,"identifiers":1183},"3ac6627c-aa3d-4744-9f12-2eb8344e6c73","Chen YW, Chen CM, Liu KS, Wang JJ, Hung CH. 2-Adamantanamine produces prolonged spinal block in rats. Neurosci Lett 2017;653:168–72.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0304394017304391",{"doi":1184},"10.1016\u002Fj.neulet.2017.05.043",{"id":624,"text":1186,"url":626,"identifiers":1187},"Tzeng JI, Wang JN, Wang JJ, Chen YW, Hung CH. Cutaneous synergistic analgesia of bupivacaine in combination with dopamine in rats. Neurosci Lett 2016;620:88–92.",{"doi":628},{"id":624,"text":1189,"url":626,"identifiers":1190},"Minkin S, Kundhal K. Likelihood-based experimental design for estimation of ED50. Biometrics 1999;55:1030–7.",{"doi":628},{"id":624,"text":1192,"url":626,"identifiers":1193},"Tzeng JI, Kan CD, Wang JN, Wang JJ, Lin HT, Hung CH. Intrathecal amantadine for prolonged spinal blockade of sensory and motor functions in rats. Fundam Clin Pharmacol 2016;30:357–63.",{"doi":628},{"id":1195,"text":1196,"url":1197,"identifiers":1198},"0af7b9cc-85c5-4f74-b483-20b30fb6bf43","Tzeng JI, Chiu CC, Wang JJ, Chen YW, Hung CH. Isobolographic analysis of the cutaneous antinociceptive interaction between bupivacaine co-injected with serotonin in rats. Pharmacol Rep 2017;69:846–50.","https:\u002F\u002Flinkinghub.elsevier.com\u002Fretrieve\u002Fpii\u002FS1734114016303097",{"doi":1199},"10.1016\u002Fj.pharep.2017.03.017",{"id":624,"text":1201,"url":626,"identifiers":1202},"Chen YW, Chiu CC, Lin HT, Wang JJ, Hung CH. Adding dopamine to proxymetacaine or oxybuprocaine solutions potentiates and prolongs the cutaneous antinociception in rats. Anesth Analg 2018;126:1721–8.",{"doi":628},{"id":624,"text":1204,"url":626,"identifiers":1205},"Chen YW, Chu CC, Chen YC, Hung CH, Hsueh MI, Wang JJ. Clonidine as adjuvant for oxybuprocaine, bupivacaine or dextrorphan has a significant peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats. Neurosci Lett 2011;496:186–90.",{"doi":628},{"id":624,"text":1207,"url":626,"identifiers":1208},"Camponovo C, Wulf H, Ghisi D, Fanelli A, Riva T, Cristina D, et al. Intrathecal 1% 2-chloroprocaine vs. 0.5% bupivacaine in ambulatory surgery: a prospective, observer-blinded, randomised, controlled trial. Acta Anaesthesiol Scand 2014;58:560–6.",{"doi":628},{"id":624,"text":1210,"url":626,"identifiers":1211},"Camponovo C. Spinal 1% 2-Chloroprocaine versus general anesthesia for ultra-short outpatient procedures: a retrospective analysis. Acta Biomed 2014;85:265–8.",{"doi":628},{"id":624,"text":1213,"url":626,"identifiers":1214},"Khan MA, Gerner P, Kuo Wang G. Amitriptyline for prolonged cutaneous analgesia in the rat. Anesthesiology 2002;96:109–16.",{"doi":628},{"id":624,"text":1216,"url":626,"identifiers":1217},"Hung CH, Wang JJ, Chen YC, Chu CC, Chen YW. Intrathecal oxybuprocaine and proxymetacaine produced potent and long-lasting spinal anesthesia in rats. Neurosci Lett 2009;454:249–53.",{"doi":628},{"id":624,"text":1219,"url":626,"identifiers":1220},"Cameron AE, Cross FW. Pain and mobility after inguinal herniorrhaphy: ineffectiveness of subcutaneous bupivacaine. Br J Surg 1985;72:68–9.",{"doi":628},{"id":1222,"text":1223,"url":1224,"identifiers":1225},"2e80871f-70c4-4b42-a4ec-46d64d32a4f1","Newton DJ, Burke D, Khan F, McLeod GA, Belch JJ, McKenzie M, et al. Skin blood flow changes in response to intradermal injection of bupivacaine and levobupivacaine, assessed by laser Doppler imaging. Reg Anesth Pain Med 2000;25:626–31.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS1098733900094426",{"doi":1226},"10.1053\u002Frapm.2000.9853",{"id":22,"text":1228,"url":22,"identifiers":1229},"Eley KA, Young JD, Watt-Smith SR. Epinephrine, norepinephrine, dobutamine, and dopexamine effects on free flap skin blood flow. Plast Reconstr Surg 2012;130:564–70.",{},{"id":624,"text":1231,"url":626,"identifiers":1232},"Leis S, Drenkhahn S, Schick C, Arnolt C, Schmelz M, Birklein F, et al. Catecholamine release in human skin-a microdialysis study. Exp Neurol 2004;188:86–93.",{"doi":628},{"id":1234,"text":1235,"url":1236,"identifiers":1237},"e4a8a34a-e02f-46f6-bd32-8b3d4989c1c3","Elayan H, Kennedy B, Ziegler MG. Epinephrine synthesis in rat skin by an N-methyltransferase. Arch Dermatol Res 1990;282:194–7.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002FBF00372622",{"doi":1238},"10.1007\u002Fbf00372622",{"id":624,"text":1240,"url":626,"identifiers":1241},"Chen YW, Liu KS, Wang JJ, Chou W, Hung CH. Isobolographic analysis of epinephrine with bupivacaine, dextromethorphan, 3-methoxymorphinan, or dextrorphan on infiltrative anesthesia in rats: dose-response studies. Reg Anesth Pain Med 2008;33:115–21.",{"doi":628},{"id":624,"text":1243,"url":626,"identifiers":1244},"Hung CH, Chiu CC, Liu KS, Chen YW, Wang JJ. Synergistic effects of serotonin or dopamine combined with lidocaine at producing nociceptive block in rats. Reg Anesth Pain Med 2017;42:351–6.",{"doi":628},{"id":624,"text":1246,"url":626,"identifiers":1247},"Morgan MJ, Franklin KB. Dopamine receptor subtypes and formalin test analgesia. Pharmacol Biochem Behav 1991;40:317–22.",{"doi":628},{"id":624,"text":1249,"url":626,"identifiers":1250},"Musazzi UM, Matera C, Dallanoce C, Vacondio F, De Amici M, Vistoli G, et al. On the selection of an opioid for local skin analgesia: structure-skin permeability relationships. Int J Pharm 2015;489:177–85.",{"doi":628},{"id":22,"text":1252,"url":22,"identifiers":1253},"Schadel M, Wu D, Otton SV, Kalow W, Sellers EM. Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol 1995;15:263–9.",{},{"id":1255,"createTime":1256,"updateTime":1257,"relativeEntities":1258,"slug":1259,"properties":1260,"entityType":177,"verifyStatus":178,"verifyTime":1271,"verifyNote":180,"languages":22,"translateLanguages":22,"viewCount":23,"primaryUrl":1272,"fullTextUrl":22,"authors":1273,"publicationType":212,"publisherRelationship":1315,"citationCount":22,"citationInfo":22,"publishDate":1367,"publishYear":1368,"citationAnalyzeStatus":1369,"lastCitationAnalyze":1370,"indexDatabases":1371,"openAccess":22,"references":22,"isForceReanalyzing":269},"a8292111-5937-4e90-8172-ab14b9433262","2023-12-17T18:26:26.464+00:00","2026-07-23T18:34:35.586+00:00",[],"Effect-of-neuroleptics-on-cytochrome-P450-2C11-CYP2C11-in-rat-liver",{"abstract":1261,"title":1263,"gsPaper":1265,"references":1267,"doi":1269},{"EN":1262},"The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of cytochrome P450 2C11 (CYP2C11), measured as a rate of testosterone 2a- and 16a-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in the microsomes of rats treated intraperitoneally (ip) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine and perazine 10 mg\u002Fkg; chlorpromazine 3 mg\u002Fkg; haloperidol 0.3 mg\u002Fkg; risperidone 0.1 mg\u002Fkg; sertindole 0.05 mg\u002Fkg) for one day or two weeks (twice a day), in the absence of the neuroleptics in vitro. The investigated neuroleptics added to control liver microsomes produced some inhibitory effects on CYP2C11 activity, which were moderate (thioridazine: Ki = 55), modest (sertindole and perazine: Ki = 76 and 94 μM, respectively) or week (promazine, levomepromazine, haloperidol and chlorpromazine: Ki = 285, 280, 223 and 157 μM, respectively). Risperidone had the weakest inhibitory effect on the CYP2C11 activity (K, = 641 μM). One-day exposure of rats to the neuroleptics did not significantly change the activity of CYP2C11 in liver microsomes. Of the neuroleptics studied, only chronic treatment with levomepromazine, perazine and thioridazine diminished CYP2C11 activity; those effects were positively correlated with the observed decreases in the protein level of the enzyme. The in vivo inhibition of CYP2C11 by chronic treatment with the three phenothiazines suggests their influence on the enzyme regulation. A possible mechanism of CYP2C11 regulation by the neuroleptics and its pharmacological significance are discussed.",{"EN":1264},"Effect of neuroleptics on cytochrome P450 2C11 (CYP2C11)in rat liver",{"VOID":1266},"[]",{"VOID":1268},"Agrawal AK, Shapiro BH: Differential expression of gender-dependent hepatic isoforms of cytochrome P-450 by pulse signals in the circulating masculine episodic growth hormone profile of the rat. J Pharmacol Exp Ther, 2000, 292, 228–237.\nAzarpira N, Namazi S, Hendijani F, Banan M, Darai M: Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran. Pharmacol Rep, 2010, 62, 740–746.\nBadger TM, Ronis MJJ, Lumpkin CK, Valentine CR, Shahare M, Irby D, Huang J, Mercado C et al.: Effects of chronic ethanol on growth hormone secretion and hepatic cytochrome P450 isoenzymes of the rat. J Pharmacol Exp Ther, 1993, 264, 438–447.\nBarbosa-Sicard, E, Markovic M, Honeck H, Christ B, Muller DN, Schunck WH: Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily. Biochem Biophys Res Commun, 2005, 329, 1275–1281.\nBelic A, Temesvári M, Kohalmy K, Vrzal R, Dvorak Z, Rozman D, Monostory K: Investigation of the CYP2C9 induction profile in human hepatocytes by combining experimental and modelling approaches. 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Eur Neuropsychopharmacol, 2005, 15, 103–110.\nDaniel W A, Syrek M, Haduch A, Wójcikowski J: Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants. Br J Pharmacol, 2000, 131, 287–295.\nDaniel WA, Syrek M, Wójcikowski J: The influence of selective serotonin reuptake inhibitors on the plasma and brain pharmacokinetics of the simplest phenothiazine neuroleptic promazine in the rat. Eur Neuropsychopharmacol, 1999, 9, 337–344.\nDaniel WA, Wójcikowski J: Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs. Pharmacol Toxicol, 1997, 80, 62–68.\nDe Mol NJ, Becht ABC, Koenen J, Lodder G: Irreversible binding with biological macromolecules and effect of bacterial mutagenity tests on the radical cation of promethazine and photoactivated promethazine. Comparison with chlorpromazine. Chem Biol Interact, 1986, 57, 73–83.\nHaduch A, Ogórka T, Boksa J, Daniel WA: Interactions between neuroleptics and CYP2C6 in rat liver - in vitro and ex vivo study. Pharmacol Rep, 2005, 57, 872–877.\nHaduch A, Wójcikowski J, Daniel WA: Direct effects of neuroleptics on the activity of CYP2A in the liver of rats. Pharmacol Rep, 2005, 57, 867–871.\nHaduch A, Wójcikowski J, Daniel WA: The activity of cytochrome P450 CYP2B in rat liver during neuroleptic treatment. Pharmacol Rep, 2007, 59, 606–612.\nHanagama M, Inoue H, Kamiya M, Shinone K, Nata M: Gene expression on liver toxicity induced by administration of haloperidol in rats with severe fatty liver. Leg Med, 2008, 10, 177–184.\nIber H, Chen Q, Sewer M, Morgan ET: Regulation of hepatic cytochrome P450 2C11 by glucocorticoids. Arch Biochem Biophys, 1997, 343, 305–310.\nKelder PP, Fischer MJE, De Mol NJ, Janssen LHM: Oxidation of chlorpromazine by methemoglobin in the presence of hydrogen peroxide. Formation of chlorpromazine radical cation and its covalent binding to methemoglobin. Arch Biochem Biophys, 1991, 284, 313–319.\nKobayashi K, Urashima K, Shimada N, Chiba K: Substrate specificity for rat cytochrome P450 (CYP) iso-forms: screening with cDNA-expressed systems oft he rat. Biochem Pharmacol, 2002, 63, 889–896.\nLegraverend C, Mode A, Westin S, Strom A, Eguchi H, Zaphiropoulos PG, Gustafsson JA: Transcriptional regulation of rat P-450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion. Mol Endocrinol, 1992, 6, 259–266.\nLevine M, Law EYW, Bandiera SM, Chang TKH, Bellward GD: In vivo cimetidine inhibits hepatic CYP2C6 and CYP2C11 but not CYP1A1 in adult male rats. J Pharmacol Exp Ther, 1998, 284, 493–499.\nLewis DFV: Substrate selectivity and metabolism. In: Cytochromes P450. Structures and function. Taylor & Francis, London and New York, 2001, 76–117.\nMasubuchi Y, Ose A, Horie T: Mechanism-based inacti-vation of CYP2C11 by diclofenac. Drug Metab Dispos, 2001, 29, 1190–1195.\nMonostory K, Dvorak Z: Steroid regulation of drug-metabolizing cytochrome P450. Curr Drug Metab, 2011, 12, 154–172.\nMorgan ET, MacGeogh C, Gustafsson J-A: Hormonal and developmental regulation of the expression of the hepatic microsomal steroid 16α-hydroxylase cytochrome P-450 apoprotein in the rat. J Biol Chem, 1985, 260, 11895–11898.\nMurray M: Inhibition and induction of cytochrome P450 2B1 in rat liver by promazine and chlorpromazine. Biochem Pharmacol, 1992, 44, 1219–1222.\nNedelcheva V, Gut I: P450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer. Xenobiotica, 1994, 24, 1151–1175.\nPampori NA, Agrawal AK, Shapiro BH: Infusion of gender-dependent plasma growth hormone profiles into intact rats: effects of subcutaneous, intraperitoneal, and intravenous routes of rat and human growth hormone on endogenous circulating growth hormone profiles and expression of sexually dimorphic hepatic CYP isoforms. Drug Metab Dispos, 2001, 29, 8–16.\nPascussi JM, Gerbal Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem MJ, Maurel P: The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol, 2008, 48, 1–32.\nRahmaniyan M, Patrick K, Bell NH: Characterization of recombinant CYP2C11: a vitamin D 25-hydroxylase and 24-hydroxylase. Am J Physiol Endocrinol Metab, 2005, 288, 753–760.\nRane A, Liu Z, Levol R, Bjelfman C, Thyr C, Ericson H, Hansson T et al.: Differential effects of neuroleptic agents on hepatic cytochrome P-450 isoenzymes in the male rat. Biochim Biophys Acta, 1996, 1291, 60–66.\nRendic S, Di Carlo FJ: Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab Rev, 1997, 29, 413–580.\nRichelson E, Nelson A: Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro. Eur J Pharmacol, 1984, 103, 197–204.\nRoman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev, 2002, 82, 131–185.\nRyan DE, Levin W: Purification and characterization of hepatic microsomal cytochrome P-450. Pharmacol Ther, 1990, 45, 153–239.\nSonderfan AJ, Arlotto MP, Dutton DR, McMillen SK, Parkonson A: Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P-450. Arch Biochem Biophys, 1987, 255, 27–41.\nSouèek P, Gut I: Cytochromes P-450 in rats: structures, functions, properties and relevant human forms. Xenobiotica, 1992, 22, 83–103.\nSundseth SS, Alberta JA, Waxman DJ: Sex-specific, growth hormone-regulated transcription of the cytochrome P450 2C11 and 2C12 genes. J Biol Chem, 1992, 267, 3907–3914.\nTateishi T, Kumai T, Watanabe M, Tanaka M, Kobayashi S: A comparison of the effect of five phenothiazines on hepatic CYP isoenzymes in rats. Pharmacol. Toxicol, 1999, 85, 252–256.\nTinel M, Elkahwaji J, Robin MA, Fardel N, Descatoire V, Haouzi D, Berson A, Pessayre D: Interleukin-2 over-expresses c-myc and down-regulates cytochrome P-450 in rat hepatocytes. J Pharmacol Exp Ther, 1999, 289, 649–655.\nVečeřa R, Zachařová A, Orolin J, Strojil J, Škottová N, Anzenbacher P: Fenofibrate-induced decrease of expression of CYP2C11 and CYP2C6 in rat. Biopharm Drug Dispos, 2011, 32, 482–487.\nWaxman DJ: Interactins of hepatic cytochromes P450 with steroid hormones. Biochem Pharmacol, 1988, 37, 71–84.\nWaxman DJ, Holloway MG: Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol, 2009, 76, 215–228.\nWaxman DJ, O’Connor C: Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol, 2006, 20, 2613–2629.\nWong SL, Cao G, Mack RJ, Granneman GR: Pharma-cokinetics of sertrindole in healthy young and elderly male and female subjects. Clin Pharmacol Ther, 1997, 62, 157–164.\nWójcikowski J, Daniel WA: Distribution interactions between perazine and antidepressant drugs. In vivo studies. Pol J Pharmacol, 2000, 52, 449–457.\nWójcikowski J, Daniel WA: Identification of factors mediating the effects of the brain dopaminergic system on the expression of cytochrome P450 in the liver. Pharmacol Rep, 2008, 60, 966–971.\nWójcikowski J, Daniel WA: The brain dopaminergic system as an important center regulating liver cytochrome P450 in the rat. Expert Opin Drug Metab Toxicol, 2009, 5, 631–645.\nWójcikowski J, Daniel WA: The role of the nervous system in the regulation of liver cytochrome P450. Curr Drug Metab, 2011, 12, 124–138.\nWójcikowski J, Daniel WA: Thioridazine-fluoxetine interaction at the level of the distribution process in vivo. Pol J Pharmacol, 2002, 54, 647–654.\nWójcikowski J, Gołembiowska K, Daniel WA: Regulation of liver cytochrome P450 by activation of brain do-paminergic system: physiological and pharmacological implications. Biochem Pharmacol, 2008, 76, 258–267.\nWójcikowski J, Gołembiowska K, Daniel WA: The regulation of liver cytochrome P450 by the brain dopaminergic system. Curr Drug Metab, 2007, 8, 631–638.",{"VOID":1270},"10.1016\u002FS1734-1140(11)70713-7","2024-09-04T20:56:12.429+00:00","https:\u002F\u002Flinkinghub.elsevier.com\u002Fretrieve\u002Fpii\u002FS1734114011707137",[1274,1289,1302],{"id":1275,"sortIndex":23,"researcher":22,"roles":1276,"affiliations":1277,"properties":1286},"acba74a7-fb07-40ed-bb24-5dc6bb53dd03",[186],[1278],{"id":1279,"sortIndex":23,"affiliation":1280,"properties":22},"e005fddf-4a74-4f4f-a43b-3e30895bab2d",{"id":1279,"createTime":22,"updateTime":22,"relativeEntities":1281,"slug":22,"properties":1282,"entityType":22,"verifyStatus":22,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":22,"url":22,"parentIds":1285,"statistic":22},[],{"title":1283},{"VI":1284},"Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland",[],{"title":1287},{"VI":1288},"Anna Haduch",{"id":1290,"sortIndex":139,"researcher":22,"roles":1291,"affiliations":1292,"properties":1299},"30423a58-aca2-4c6e-9ab1-b162e5373d55",[186],[1293],{"id":1279,"sortIndex":23,"affiliation":1294,"properties":22},{"id":1279,"createTime":22,"updateTime":22,"relativeEntities":1295,"slug":22,"properties":1296,"entityType":22,"verifyStatus":22,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":22,"url":22,"parentIds":1298,"statistic":22},[],{"title":1297},{"VI":1284},[],{"title":1300},{"VI":1301},"Jacek Wójcikowski",{"id":1303,"sortIndex":288,"researcher":22,"roles":1304,"affiliations":1305,"properties":1312},"9f5064bf-5abc-4057-abdd-88435649bdd0",[186],[1306],{"id":1279,"sortIndex":23,"affiliation":1307,"properties":22},{"id":1279,"createTime":22,"updateTime":22,"relativeEntities":1308,"slug":22,"properties":1309,"entityType":22,"verifyStatus":22,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":22,"url":22,"parentIds":1311,"statistic":22},[],{"title":1310},{"VI":1284},[],{"title":1313},{"VI":1314},"Władysława A. Daniel",{"url":1272,"publisher":1316,"properties":1362},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":1317,"slug":10,"properties":1318,"entityType":20,"verifyStatus":21,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":23,"subjectFields":1322,"manageAffiliations":1331,"indexDatabases":1342,"url":22,"thumbnailPath":22,"statistic":1357,"gsStatistic":22,"type":159,"analyzePriority":22},[],{"issn":1319,"title":1320,"eissn":1321},{"VOID":15},{"EN":17},{"VOID":13},[1323,1327],{"id":26,"createTime":22,"updateTime":22,"relativeEntities":1324,"label":1325,"description":1326,"parentId":22,"standard":22,"scholarHubFieldId":22},[],{"EN":29},{},{"id":32,"createTime":22,"updateTime":22,"relativeEntities":1328,"label":1329,"description":1330,"parentId":22,"standard":22,"scholarHubFieldId":22},[],{"EN":35},{},[1332,1337],{"id":39,"createTime":22,"updateTime":22,"relativeEntities":1333,"slug":22,"properties":1334,"entityType":22,"verifyStatus":22,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":22,"url":22,"parentIds":1336,"statistic":22},[],{"title":1335},{"EN":43},[45],{"id":47,"createTime":22,"updateTime":22,"relativeEntities":1338,"slug":22,"properties":1339,"entityType":22,"verifyStatus":22,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":22,"url":22,"parentIds":1341,"statistic":22},[],{"title":1340},{"EN":51},[],[1343,1350],{"id":55,"indexDatabase":1344,"url":66,"indexYears":67,"academicFieldIds":1349,"indexDatabaseRanking":71},{"id":57,"createTime":22,"updateTime":22,"relativeEntities":1345,"label":1346,"description":1347,"key":63,"publicationTags":1348,"standard":22},[],{"EN":60,"VI":60},{"EN":60,"VI":62},[65],[69,70],{"id":73,"indexDatabase":1351,"url":86,"indexYears":22,"academicFieldIds":1356,"indexDatabaseRanking":22},{"id":75,"createTime":22,"updateTime":22,"relativeEntities":1352,"label":1353,"description":1354,"key":82,"publicationTags":1355,"standard":22},[],{"EN":78,"VI":78},{"EN":80,"VI":81},[84,85],[88],{"impactFactor":23,"impactFactorByYear":1358,"i10Index":102,"i10IndexLast5Year":103,"totalPublication":104,"totalPublicationByYear":1359,"totalCitation":122,"totalCitationByYear":1360,"totalCitationPerPublication":140,"totalCitationPerPublicationByYear":1361,"hindexLast5Year":158,"hindex":158},{"2012":91,"2013":92,"2014":93,"2015":94,"2016":95,"2017":96,"2018":97,"2019":93,"2020":98,"2021":99,"2022":100,"2023":101},{"2009":106,"2010":107,"2011":108,"2012":109,"2013":110,"2014":111,"2015":112,"2016":113,"2017":114,"2018":115,"2019":116,"2020":117,"2021":118,"2022":119,"2023":120,"2024":121},{"2009":124,"2010":125,"2011":126,"2012":127,"2013":128,"2014":129,"2015":130,"2016":131,"2017":132,"2018":133,"2019":134,"2020":135,"2021":136,"2022":137,"2023":138,"2024":139},{"2009":142,"2010":143,"2011":144,"2012":145,"2013":146,"2014":147,"2015":148,"2016":149,"2017":150,"2018":151,"2019":152,"2020":153,"2021":154,"2022":155,"2023":156,"2024":157},{"pages":1363,"volume":1365},{"VOID":1364},"1491-1499",{"VOID":1366},"63","2011-12-30",2011,"ERROR_IN_GET_PLATFORM_ID","2026-07-23T18:34:35.585+00:00",[84,71],{"id":1373,"createTime":1374,"updateTime":1375,"relativeEntities":1376,"slug":1377,"properties":1378,"entityType":177,"verifyStatus":178,"verifyTime":1388,"verifyNote":180,"languages":22,"translateLanguages":22,"viewCount":23,"primaryUrl":1389,"fullTextUrl":22,"authors":1390,"publicationType":212,"publisherRelationship":1406,"citationCount":22,"citationInfo":22,"publishDate":1458,"publishYear":1459,"citationAnalyzeStatus":1369,"lastCitationAnalyze":1375,"indexDatabases":1460,"openAccess":22,"references":22,"isForceReanalyzing":269},"a638216f-0048-4fce-815d-dc01dbbfa34b","2023-12-25T02:22:23.620+00:00","2026-07-22T05:24:28.859+00:00",[],"Analysis-of-the-excitatory-motor-response-evoked-by-nicotinic-and-muscarinic-blockade-of-ovine-small-bowel",{"abstract":1379,"title":1381,"gsPaper":1383,"references":1384,"doi":1386},{"EN":1380},"It has been reported that the administration of anticholinergic drugs evokes inhibitory and excitatory responses, but the precise character of the latter has not yet been defined. This study was thus devoted to analyzing its occurrence following various doses of hexamethonium (Hx) and atropine (At) administration in the course of different phases of the small-intestinal migrating motor complex (MMC) in fasted and non-fasted sheep and to further characterize the excitatory responses in comparison with individual phases of the MMC. Two basic types of excitatory response were found. In the course of chronic experiments, various doses of Hx and At evoked rebound excitation (RE, i.e., irregular contractions or spike bursts evoked in response to the anticholinergic drug) alternating with phase 3-like activity (not the organized phase 3 of the MMC or its parts). The intensity of these changes varied and was related to the drug dose. Thus intense and non-intense RE activity were distinguished. In non-fasted sheep, these alterations were slightly less pronounced than in fasted animals. When the drug was given during phase 1 of the MMC, RE did not occur or was greatly reduced and its arrival was delayed. Hx triggered RE mostly in the duodenum, while the action of At was most effective in the jejunum. It is concluded that Hx and At initially hamper small-intestinal motility and just after that evoke a secondary stimulatory response, i.e., phase 3-like activity and RE of different intensity, duration, and repeatability in fasted and non-fasted sheep. These stimulatory effects may resemble unorganized phases of the MMC.",{"EN":1382},"Analysis of the excitatory motor response evoked by nicotinic and muscarinic blockade of ovine small bowel",{"VOID":1266},{"VOID":1385},"Aeberhard P, Bedi BS: Effects of proximal gastric vagotomy (PGV) followed by total vagotomy (TV) on postprandial and fasting myoelectrical activity of the canine stomach and duodenum. Gut, 1977, 18, 515–523.\nAndrews PLR: Central organization of the vagal drive to the nonadrenergic noncholinergic neurones controlling gastric motility. Arch Int Pharmacodyn, 1990, 303, 167–198.\nBaccari MC, Calamai F, Staderini G: The influence of the vagally induced rebound contractions on the non-adrenergic, non-cholinergic (NANC) inhibitory motility of the rabbit. J Auton Nerv Syst, 1992, 37, 125–135.\nBayguinov O, Vogalis F, Morris B, Sanders KM: Patterns of electrical activity and neural responses in canine proximal duodenum. Am J Physiol, 1992, 263, G887–G894.\nBehrns KE, Sarr MG: Duodenal nutrients inhibit canine jejunal fasting motor patterns through a hormonal mechanism. Dig Dis Sci, 1994, 39, 1665–1671.\nBrown EN, Galligan JJ: Muscarinic receptors couple to modulation of nicotinic ACh receptor desensitization in myenteric neurons. Am J Physiol, 2003, 285, G37–G44.\nBueno L, Praddaude F: Electrical activity of the gallbladder and biliary tract in sheep and its relationships with antral and duodenal motility. Ann Biol Anim Biochim Biophys, 1979, 19, 1109–1121.\nBueno L, Ruckebusch Y: Effect of anticholinergic drugs on the electrical activity of the antrum and duodenojejunum in sheep. J Vet Pharmacol Ther, 1978, 1, 225–232.\nBurks TF: Neurotransmission and neurotransmitters. In: Physiology of the Gastrointestinal Tract. Ed. Johnson LR, Raven Press, New York, 1994, 211–242.\nCaulfield MP, Birdsall NJM: International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev, 1998, 50, 279–290.\nCode CF, Marlett JA: The interdigestive myoelectric complex of the stomach and small bowel of dogs. J Physiol (Lond), 1975, 246, 289–309.\nCottrell DF: Vagal reflex inhibition of motility in the abomasal body of sheep by antral and duodenal tension receptors. Vet Res Commun, 1994, 18, 319–330.\nDaniel EE: Pharmacology of adrenergic, cholinergic, and drugs acting on other receptors in gastrointestinal muscle. In: Handbook of Experimental Pharmacology. Ed. Bertaccini G, Springer-Verlag, Berlin, 1982, 249–322.\nDelbro D, Gustafsson BI: Vagally induced hexamethonium-resistant jejunal contractions in the cat. Acta Physiol Scand, 1989, 136, 143–144.\nDent J, Dodds WJ, Sekiguchi T, Hogan WJ, Arndorfer RC: Interdigestive phasic contractions of the human lower esophageal sphincter. Gastroenterology, 1983, 84, 453–460.\nDujic Z, Roerig DL, Schedewie HK, Kampine JP, Bosnjak ZJ: Presynaptic modulation of ganglionic ACh release by muscarinic and nicotinic receptors. Am J Physiol, 1990, 259, R288–R293.\nEglen RM, Michel AD, Kunysz EA, Cornett CM, Whiting RL: Analysis of the interaction of hexamethonium with muscarinic receptors in vitro. Br J Pharmacol, 1988, 9, 511P.\nEl-Sharkawy TY, Markus H, Diamant NE: Neural control of the intestinal migrating myoelectric complex. A pharmacological analysis. Can J Physiol Pharmacol, 1982, 60, 794–804.\nHasler WL: Small intestinal motility. In: Physiology of the Gastrointestinal Tract. Ed. Johnson LR, Academic Press, Amsterdam, 2006, 935–964.\nIto S, Kimura A, Ohga A: Development of non-cholinergic, non-adrenergic excitatory and inhibitory responses to intramural nerve stimulation in rat stomach. Br J Pharmacol, 1989, 93, 684–692.\nKatschinski M, Dahmen G, Reinshagen M, Beglinger C, Koop H, Nustede R, Adler G: Cephalic stimulation of gastrointestinal secretory and motor responses in humans. Gastroenterology, 1992, 103, 383–391.\nKay AW, Smith RN: The action of atropine and hexamethonium in combination on gastric secretion and motility. Br J Pharmacol, 1956, 11, 231–235.\nLang IM, Sarna SK: All intense bursts of rhythmic activity may not be phase III activity. Am J Physiol, 1987, 252, G592–G593.\nMandl P, Kiss JP: Role of presynaptic nicotinic acetylcholine receptors in the regulation of gastrointestinal motility. Brain Res Bull, 2007, 72, 194–200.\nMellander A, Abrahamsson H, Sjövall H: The migrating motor complex — the motor component of a cholinergic enteric secretomotor programme? Acta Physiol Scand, 1995, 154, 329–341.\nNelson DK, Pieramico O, Dahmen G, Dominguez-Muñoz JE, Malfertheiner P, Adler G: M1-muscarinic mechanisms regulate interdigestive cycling of motor and secretory activity in human upper gut. Dig Dis Sci, 1996, 41, 2006–2015.\nRees WDW, Malagelada J-R, Miller LJ, Go VLW: Human interdigestive and postprandial gastrointestinal motor and gastrointestinal hormone patterns. Dig Dis Sci, 1982, 27, 321–329.\nRomański KW: Changes in amplitude and duration of the spike bursts within phase 3 of the migrating myoelectric complex in the small bowel of fasted, non-fasted and fed sheep. Bull Vet Inst Pulawy, 2006, 50, 239–245.\nRomański KW: Character and cholinergic control of myoelectric activity in ovine duodenal bulb: relationships to adjacent regions. Vet Archiv, 2003, 73, 1–16.\nRomański KW: Characteristics and cholinergic control of the ‘minute rhythm’ in ovine antrum, small bowel and gallbladder. J Vet Med A, 2002, 49, 313–320.\nRomański KW: Regional differences in the effects of various doses of cerulein upon the small-intestinal migrating motor complex in fasted and non-fasted sheep. J Anim Physiol Anim Nutr, 2007, 91, 29–39.\nRomański KW: The effect of cholecystokinin-octapeptide and cerulein on phasic and tonic components in ovine duodenum with special reference to the ‘minute rhythm’. Acta Vet Brno, 2007, 76, 17–25.\nRomański KW: The rebound excitation triggered by anticholinergic drugs from ovine pyloric antrum, small bowel and gallbladder. J Physiol Pharmacol, 2003a, 54, 121–133.\nRomański KW: The role of muscarinic and nicotinic receptors in the control of the ovine pyloric antral myoelectric response to nutrients during individual phases of the migrating myoelectric complex. Small Ruminant Res, 2005, 57, 121–131.\nRomański KW, Sławuta P: Cholinergic control of pacemaker initiating phase 3 of the migrating myoelectric complex in sheep. J Anim Feed Sci, 2002, 11, 637–650.\nRuckebusch Y: Gastrointestinal motor functions in ruminants. In: Handbook of Physiology. The Gastrointestinal System. vol. 1, Ed. Schultz SG, American Physiological Society, Bethesda, 1989, 1225–1282.\nRuckebusch Y, Bueno L: Origin of migrating myoelectric complex in sheep. Am J Physiol, 1977, 233, E483–E487.\nRuckebusch Y, Malbert CH, Crichlow EC: Hexamethonium: a probe to assess autonomic nervous system involvement in upper gastrointestinal functions in conscious sheep. Vet Res Commun, 1987, 11, 293–303.\nSarna SK, Daniel EE: Threshold curves and refractoriness properties of gastric relaxation oscillators. Am J Physiol, 1974, 226, 749–755.\nSarna SK, Lang IM, Gleysteen JJ, Otterson MF: Central vs. enteric neural control of small intestinal migrating motor complexes. In: Nerves and the Gastrointestinal Tract. Ed. Singer MV, Goebell H, MTP Press Ltd., Lancaster, 1989, 746–752.\nSarna SK, Otterson MF: Small intestinal physiology and pathophysiology. Gastroenterol Clin North Am, 1989, 18, 375–405.\nSchiavone A, Sagrada A, Pagani F, Giachetti A: Role of muscarinic receptor subtypes in the regulation of migrating myoelectric complex in the dog. Gastroenterology, 1989, 96, 116–121.\nSkok VI: Nicotinic acetylcholine receptors in autonomic ganglia. Auton Neurosci Basic Clin, 2002, 97, 1–11.\nSnedecor GW, Cochran WG: Statistical Methods. The Iowa State University Press, Ames, 1971.\nTarbrook D: On the rebound. Nurs Times, 1997, 93, 60–62.\nTitchen DA. Gastrointestinal peptide hormone distribution, release, and action in ruminants. In: Control of Digestion and Metabolism in Ruminants. A Reston Book, Prentice Hall, Englewood Cliffs, 1986, 227–248.\nTohara K, Uchida Y, Suzuki H, Itoh Z: Initiation of phase III contractions in the jejunum by atropine, hexamethonium and xylocaine in conscious dogs. Neurogastroenterol Motil, 2000, 12, 11–21.\nTorsoli A, Severi C: The neuroendocrine control of gastrointestinal motor activity. J Physiol (Paris), 1993, 87, 367–374.\nZonta F, Dondi G, Lucchelli A, Santagostino-Barbone MG, Grana E: Antimuscarinic action of hexamethonium. Med Sci Res, 1987, 15, 513–514.",{"VOID":1387},"10.1016\u002FS1734-1140(10)70269-3","2024-06-25T21:55:02.477+00:00","https:\u002F\u002Flinkinghub.elsevier.com\u002Fretrieve\u002Fpii\u002FS1734114010702693",[1391],{"id":1392,"sortIndex":23,"researcher":22,"roles":1393,"affiliations":1394,"properties":1403},"4962eeab-3f51-418d-8a9c-4de0e67c0c88",[186],[1395],{"id":1396,"sortIndex":23,"affiliation":1397,"properties":22},"774f7d64-1329-4cfc-8d04-4d9b0d7be6fe",{"id":1396,"createTime":22,"updateTime":22,"relativeEntities":1398,"slug":22,"properties":1399,"entityType":22,"verifyStatus":22,"verifyTime":22,"verifyNote":22,"languages":22,"translateLanguages":22,"viewCount":22,"url":22,"parentIds":1402,"statistic":22},[],{"title":1400},{"VI":1401},"Department of Biostructure and Animal Physiology, Veterinary Faculty, Wroclaw University of Environmental and Life Sciences, Wroctaw, Poland",[],{"title":1404},{"VI":1405},"Krzysztof W. 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Environ Toxicol Pharmacol, 33, 92, 10.1016\u002Fj.etap.2011.09.005\nLaemmli, 1970, Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature, 227, 680, 10.1038\u002F227680a0\nTowbin, 1979, Electrophoretic transfer of proteins from polyarylamide gels to nitrocellulose sheets: procedure and some applications, Proc Natl Acad Sci U S A, 76, 4350, 10.1073\u002Fpnas.76.9.4350\nPfaffl, 2001, A new mathematical model for relative quantification in real-time RT-PCR, Nucleic Acids Res, 9\nSebolt-Leopold, 2004, Targeting the mitogen-activated protein kinase cascade to treat cancer, Nat Rev Cancer, 4, 937, 10.1038\u002Fnrc1503\nSticozzi, 2013, Antiproliferative effect of two novel COX-2 inhibitors on human keratinocytes, Eur J Pharm Sci, 49, 133, 10.1016\u002Fj.ejps.2013.02.009\nHursting, 1999, Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice, J Natl Cancer Inst, 91, 215, 10.1093\u002Fjnci\u002F91.3.215\nGerhäuser, 2003, Mechanism-based in vitro screening of potential cancer chemopreventive agents, Mutat Res, 523–524, 163, 10.1016\u002FS0027-5107(02)00332-9\nChaturvedi, 2001, Abnormal NF-kappaB signaling pathway with enhanced susceptibility to apoptosis in immortalized keratinocytes, J Dermatol Sci, 26, 67, 10.1016\u002FS0923-1811(00)00157-2\nRidd, 2010, Defective TPA signalling compromises HaCaT cells as a human in vitro skin carcinogenesis model, Toxicol In Vitro, 24, 910, 10.1016\u002Fj.tiv.2009.11.017\nYang, 2007, Design and synthesis of compounds that extend yeast replicative lifespan, Aging Cell, 6, 35, 10.1111\u002Fj.1474-9726.2006.00259.x\nPark, 2013, Do sirtuins promote mammalian longevity?: a critical review on its relevance to the longevity effect induced by calorie restriction, Mol Cells, 35, 474, 10.1007\u002Fs10059-013-0130-x\nPastore, 2011, Differential modulation of stress-inflammation responses by plant polyphenols in cultured normal human keratinocytes and immortalized HaCaT cells, J Dermatol Sci, 63, 104\nZykova, 2008, Resveratrol directly targets COX-2 to inhibit carcinogenesis, Mol Carcinog, 47, 797, 10.1002\u002Fmc.20437\nShin, 2011, The ETS family transcription factor ELK-1 regulates induction of the cell cycle-regulatory gene p21(Waf1\u002FCip1) and the BAX gene in sodium arsenite-exposed human keratinocyte HaCaT cells, J Biol Chem, 286, 26860, 10.1074\u002Fjbc.M110.216721\nHsu, 2000, Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis, Free Radic Biol Med, 28, 1338, 10.1016\u002FS0891-5849(00)00220-3\nFuchs, 1996, Phosphorylation-dependent targeting of c-Jun ubiquitination by Jun N-kinase, Oncogene, 13, 1531\nMusti, 1997, Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases, Science, 275, 400, 10.1126\u002Fscience.275.5298.400\nYang, 2013, c-Jun-mediated anticancer mechanisms of tylophorine, Carcinogenesis, 34, 1304, 10.1093\u002Fcarcin\u002Fbgt039\nvan 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               \u003Cjats:title>Background\u003C\u002Fjats:title>\n                \u003Cjats:p>The results of our previous studies demonstrated that low sensitivity to negative feedback (NF) is associated with increased vulnerability to the development of compulsive alcohol-seeking in rats. In the present study, we investigated the molecular underpinnings of this relationship.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>\u003Cjats:sec>\n                \u003Cjats:title>Methods\u003C\u002Fjats:title>\n                \u003Cjats:p>Using TaqMan Gene Expression Array Cards, we analyzed the expression of the genes related to NF sensitivity and alcohol metabolism in three cortical regions (medial prefrontal cortex [mPFC], anterior cingulate cortex [ACC], orbitofrontal cortex [OFC]) and two subcortical regions (nucleus accumbens [Nacc], amygdala [Amy]). Gene expression differences were confirmed at the protein level with Western blot.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>\u003Cjats:sec>\n                \u003Cjats:title>Results\u003C\u002Fjats:title>\n                \u003Cjats:p>Sensitivity to NF was characterized by differences in \u003Cjats:italic>Gad2\u003C\u002Fjats:italic>, \u003Cjats:italic>Drd2\u003C\u002Fjats:italic>, and \u003Cjats:italic>Slc6a4\u003C\u002Fjats:italic> expression in the ACC, \u003Cjats:italic>Maoa\u003C\u002Fjats:italic> in the mPFC, and \u003Cjats:italic>Gria1\u003C\u002Fjats:italic>, \u003Cjats:italic>Htr3a\u003C\u002Fjats:italic>, and \u003Cjats:italic>Maoa\u003C\u002Fjats:italic> in the OFC. Chronic alcohol consumption was associated with differences in the expression of \u003Cjats:italic>Comt\u003C\u002Fjats:italic> and \u003Cjats:italic>Maoa\u003C\u002Fjats:italic> in the ACC, \u003Cjats:italic>Comt\u003C\u002Fjats:italic>, \u003Cjats:italic>Adh1\u003C\u002Fjats:italic>, and \u003Cjats:italic>Htr2b\u003C\u002Fjats:italic> in the mPFC, \u003Cjats:italic>Adh1,\u003C\u002Fjats:italic> and \u003Cjats:italic>Slc6a4\u003C\u002Fjats:italic> in the Nacc, \u003Cjats:italic>Gad2,\u003C\u002Fjats:italic> and \u003Cjats:italic>Htr1a\u003C\u002Fjats:italic> in the OFC, and \u003Cjats:italic>Drd2\u003C\u002Fjats:italic> in the Amy. Interactions between the sensitivity to NF and alcohol consumption were observed in the expression of \u003Cjats:italic>Gabra1\u003C\u002Fjats:italic>, \u003Cjats:italic>Gabbr2\u003C\u002Fjats:italic>, \u003Cjats:italic>Grin2a\u003C\u002Fjats:italic>, \u003Cjats:italic>Grin2b\u003C\u002Fjats:italic>, and \u003Cjats:italic>Grm3\u003C\u002Fjats:italic> in the ACC, and \u003Cjats:italic>Grin2a\u003C\u002Fjats:italic> in the OFC. The observed differences were confirmed at the protein level for MAO-A in the mPFC, and ADH1 in the mPFC and Nacc.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>\u003Cjats:sec>\n                \u003Cjats:title>Conclusions\u003C\u002Fjats:title>\n                \u003Cjats:p>Our findings contribute to a better understanding of the molecular mechanisms underlying the relationship between trait sensitivity to NF and compulsive alcohol consumption.\u003C\u002Fjats:p>\n              \u003C\u002Fjats:sec>",{"EN":1645},"Identification of genes regulated by trait sensitivity to negative feedback and prolonged alcohol consumption in 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