The neurogliovascular unit in hepatic encephalopathy

Bustamante, 1999, Prognostic significance of hepatic encephalopathy in patients with cirrhosis, J Hepatol, 30, 890, 10.1016/S0168-8278(99)80144-5 Vilstrup, 2014, Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases, J Hepatol, 61, 642, 10.1016/j.jhep.2014.05.042 Lopez-Franco, 2021, Cognitive impairment after resolution of hepatic encephalopathy: a systematic review and meta-analysis, Front Neurosci, 15, 11 Ochoa-Sanchez, 2021, Hepatic encephalopathy: from metabolic to neurodegenerative, Neurochem Res, 10.1007/s11064-021-03372-4 Tapper, 2015, Refining the ammonia hypothesis, Mayo Clin Proc, 90, 646, 10.1016/j.mayocp.2015.03.003 Clària, 2016, Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure, Hepatology, 64, 1249, 10.1002/hep.28740 Trebicka, 2020, The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology, J Hepatol, 73, 842, 10.1016/j.jhep.2020.06.013 Rolando, 2000, The systemic inflammatory response syndrome in acute liver failure, Hepatology, 32, 734, 10.1053/jhep.2000.17687 Shawcross, 2011, Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis, J Hepatol, 54, 640, 10.1016/j.jhep.2010.07.045 Chen, 2021, The role of intestinal bacteria and gut–brain Axis in hepatic encephalopathy, Front Cell Infect Microbiol, 10, 595759, 10.3389/fcimb.2020.595759 Lattanzi, 2019, Hepatic encephalopathy and sarcopenia: two faces of the same metabolic alteration, J Clin Exp Hepatol, 9, 125, 10.1016/j.jceh.2018.04.007 Gluud, 2017, Branched-chain amino acids for people with hepatic encephalopathy, Cochrane Database Syst Rev, 5, CD001939 Hassouneh, 2021, Gut microbiota modulation and fecal transplantation: an overview on innovative strategies for hepatic encephalopathy treatment, J Clin Med, 10, 330 Jayakumar, 2016, Glutamine synthetase: role in neurological disorders, Adv Neurobiol, 13, 327, 10.1007/978-3-319-45096-4_13 Norenberg, 1987, The role of astrocytes in hepatic encephalopathy, Neurochem Pathol, 6, 13, 10.1007/BF02833599 Ahmad, 2020, The role of neurovascular system in neurodegenerative diseases, Mol Neurobiol, 57, 4373, 10.1007/s12035-020-02023-z Huang, 2019, Astrocyte signaling in the neurovascular unit after central nervous system injury, Int J Mol Sci, 20, 282, 10.3390/ijms20020282 Sweeney, 2019, Blood-brain barrier: from physiology to disease and back, Physiol Rev, 99, 21, 10.1152/physrev.00050.2017 De Bock, 2014, The dual face of connexin-based astroglial Ca2+ communication: a key player in brain physiology and a prime target in pathology, Biochim Biophys Acta BBA - Mol Cell Res, 1843, 2211, 10.1016/j.bbamcr.2014.04.016 Abbott, 2006, Astrocyte–endothelial interactions at the blood–brain barrier, Nat Rev Neurosci, 7, 41, 10.1038/nrn1824 Sofroniew, 2010, Astrocytes: biology and pathology, Acta Neuropathol (Berl), 119, 7, 10.1007/s00401-009-0619-8 Zhou, 2008, Altered blood–brain barrier integrity in adult aquaporin-4 knockout mice, NeuroReport, 19, 1, 10.1097/WNR.0b013e3282f2b4eb Sheeler, 2020, Glia in neurodegeneration: the housekeeper, the defender and the perpetrator, Int J Mol Sci, 21, 9188, 10.3390/ijms21239188 Hickman, 2018, Microglia in neurodegeneration, Nat Neurosci, 21, 1359, 10.1038/s41593-018-0242-x Rasmussen, 2018, The glymphatic pathway in neurological disorders, Lancet Neurol, 17, 1016, 10.1016/S1474-4422(18)30318-1 Liddelow, 2017, Neurotoxic reactive astrocytes are induced by activated microglia, Nature, 541, 481, 10.1038/nature21029 Oja, 2017, Neurotoxicity of ammonia, Neurochem Res, 42, 713, 10.1007/s11064-016-2014-x Rama Rao, 2012, Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy, Neurochem Int, 60, 697, 10.1016/j.neuint.2011.09.007 Murthy, 2001, Ammonia-induced production of free radicals in primary cultures of rat astrocytes, J Neurosci Res, 66, 282, 10.1002/jnr.1222 Reinehr, 2007, Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices, Glia, 55, 758, 10.1002/glia.20504 Norenberg, 1994, Astrocyte swelling in liver failure: role of glutamine and benzodiazepines, Acta Neurochir Suppl (Wien), 60, 24 Ong, 2003, Correlation between ammonia levels and the severity of hepatic encephalopathy, Am J Med, 114, 188, 10.1016/S0002-9343(02)01477-8 Shalimar, 2019, Prognostic role of ammonia in patients with cirrhosis, Hepatology, 70, 982, 10.1002/hep.30534 Jayakumar, 2015, Neuroinflammation in hepatic encephalopathy: mechanistic aspects, J Clin Exp Hepatol, 5, S21, 10.1016/j.jceh.2014.07.006 Hadjihambi, 2018, Hepatic encephalopathy: a critical current review, Hepatol Int, 12, 135, 10.1007/s12072-017-9812-3 Nicolao, 2003, Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy, J Hepatol, 38, 441, 10.1016/S0168-8278(02)00436-1 Trebicka, 2019, Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis, Front Immunol, 10, 476, 10.3389/fimmu.2019.00476 Arroyo, 2020, The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis, J Hepatol Bélanger, 2011, Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation, Cell Metab, 14, 724, 10.1016/j.cmet.2011.08.016 Pellerin, 2007, Activity-dependent regulation of energy metabolism by astrocytes: an update, Glia, 55, 1251, 10.1002/glia.20528 Bosoi, 2014, Elevated cerebral lactate: implications in the pathogenesis of hepatic encephalopathy, Metab Brain Dis, 29, 919, 10.1007/s11011-014-9573-9 Dhanda, 2018, Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy, Metab Brain Dis, 33, 209, 10.1007/s11011-017-0136-8 Weiss, 2016, Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy, J Hepatol, 65, 1120, 10.1016/j.jhep.2016.07.046 Bjerring, 2018, Cerebral blood flow and metabolism in hepatic encephalopathy—a meta-analysis, J Clin Exp Hepatol, 8, 286, 10.1016/j.jceh.2018.06.002 Ponziani, 2019, Minimal hepatic encephalopathy is associated with increased cerebral vascular resistance. A transcranial Doppler ultrasound study, Sci Rep, 9, 15373, 10.1038/s41598-019-51867-6 Moreau, 2020, Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF, J Hepatol, 72, 688, 10.1016/j.jhep.2019.11.009 Zaccherini, 2021, Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF, J Hepatol, 74, 1117, 10.1016/j.jhep.2020.11.035 Dabos, 2015, 1H nuclear magnetic resonance spectroscopy-based metabonomic study in patients with cirrhosis and hepatic encephalopathy, World J Hepatol, 7, 1701, 10.4254/wjh.v7.i12.1701 Jiménez, 2010, Serum metabolic signature of minimal hepatic encephalopathy by 1H-nuclear magnetic resonance, J Proteome Res, 9, 5180, 10.1021/pr100486e Bernal, 2015, Acute liver failure: a curable disease by 2024?, J Hepatol, 62, S112, 10.1016/j.jhep.2014.12.016 Braissant, 2019, Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy, J Hepatol, 71, 505, 10.1016/j.jhep.2019.05.022 Cudalbu, 2019, Brain edema in chronic hepatic encephalopathy, J Clin Exp Hepatol, 9, 362, 10.1016/j.jceh.2019.02.003 Bosoi, 2014, Increased brain lactate is central to the development of brain edema in rats with chronic liver disease, J Hepatol, 60, 554, 10.1016/j.jhep.2013.10.011 Rackayova, 2016, 1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism, Metab Brain Dis, 31, 1303, 10.1007/s11011-015-9715-8 Clària, 2019, Orchestration of tryptophan-kynurenine pathway, acute decompensation, and acute-on-chronic liver failure in cirrhosis, Hepatology, 69, 1686, 10.1002/hep.30363 Montagnese, 2021, A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy, J Hepatol, 75, 98, 10.1016/j.jhep.2021.03.012 Lockwood, 1991, Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy, J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab, 11, 337, 10.1038/jcbfm.1991.67 Keiding, 2006, Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography, Hepatol Baltim Md, 43, 42, 10.1002/hep.21001 Nguyen, 2012, Blood–brain barrier in acute liver failure, Neurochem Int, 60, 676, 10.1016/j.neuint.2011.10.012 Cauli, 2011, Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats, Gastroenterology, 140, 638, 10.1053/j.gastro.2010.10.043 Grant, 2018, Direct comparison of the thioacetamide and azoxymethane models of type A hepatic encephalopathy in mice, Gene Expr, 18, 171, 10.3727/105221618X15287315176503 Shimojima, 2008, Altered expression of zonula occludens-2 precedes increased blood–brain barrier permeability in a murine model of fulminant hepatic failure, J Invest Surg, 21, 101, 10.1080/08941930802043565 Nguyen, 2006, Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice, J Hepatol, 44, 1105, 10.1016/j.jhep.2005.09.019 Dhanda, 2018, Blood-brain barrier permeability is exacerbated in experimental model of hepatic encephalopathy via MMP-9 activation and downregulation of tight junction proteins, Mol Neurobiol, 55, 3642 Wright, 2010, Role of aquaporin-4 in the development of brain oedema in liver failure, J Hepatol, 53, 91, 10.1016/j.jhep.2010.02.020 Quinn, 2014, Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms, Dig Liver Dis, 46, 527, 10.1016/j.dld.2014.01.159 Wright, 2007, Endotoxemia produces coma and brain swelling in bile duct ligated rats, Hepatology, 45, 1517, 10.1002/hep.21599 Bosoi, 2012, Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure, Free Radic Biol Med, 52, 1228, 10.1016/j.freeradbiomed.2012.01.006 Xu, 2016, Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats, Acta Pharmacol Sin, 37, 1129, 10.1038/aps.2016.25 Chen, 2012, Alterations in NADPH oxidase expression and blood–brain barrier in bile duct ligation-treated young rats: effects of melatonin, Neurochem Int, 60, 751, 10.1016/j.neuint.2012.03.021 Faropoulos, 2010, Altered occludin expression in brain capillaries induced by obstructive jaundice in rats, Brain Res, 1325, 121, 10.1016/j.brainres.2010.02.020 Chen, 2013, TIMP-1 attenuates blood–brain barrier permeability in mice with acute liver failure, J Cereb Blood Flow Metab, 33, 1041, 10.1038/jcbfm.2013.45 McMillin, 2015, TGFβ1 exacerbates blood–brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5, Lab Invest, 95, 903, 10.1038/labinvest.2015.70 Wang, 2011, Tumor necrosis factor-α affects blood–brain barrier permeability in acetaminophen-induced acute liver failure, Eur J Gastroenterol Hepatol, 23, 552, 10.1097/MEG.0b013e3283470212 Lv, 2010, Tumour necrosis factor-α affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure: blood-brain barrier in liver failure, Liver Int, 30, 1198, 10.1111/j.1478-3231.2010.02211.x Qosa, 2015, Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders, Brain Res, 1628, 298, 10.1016/j.brainres.2015.07.005 Zhang, 2014, Hyperammonemia enhances the function and expression of P-glycoprotein and Mrp2 at the blood-brain barrier through NF-κB, J Neurochem, 131, 791, 10.1111/jnc.12944 Jin, 2013, P-glycoprotein and multidrug resistance-associated protein 2 are oppositely altered in brain of rats with thioacetamide-induced acute liver failure, Liver Int, 33, 274, 10.1111/j.1478-3231.2012.02862.x Liu, 2018, Altered function and expression of ABC transporters at the blood–brain barrier and increased brain distribution of phenobarbital in acute liver failure mice, Front Pharmacol, 9, 190, 10.3389/fphar.2018.00190 Li, 2016, Acute liver failure impairs function and expression of breast cancer-resistant protein (BCRP) at rat blood-brain barrier partly via ammonia-ROS-ERK1/2 activation, J Neurochem, 138, 282, 10.1111/jnc.13666 Jördens, 2015, Multidrug resistance-associated protein 4 expression in ammonia-treated cultured rat astrocytes and cerebral cortex of cirrhotic patients with hepatic encephalopathy: mrp4 Expression Changes in Hepatic Encephalopathy, Glia, 63, 2092, 10.1002/glia.22879 Sørensen, 2013, Update on cerebral uptake of blood ammonia, Metab Brain Dis, 28, 155, 10.1007/s11011-013-9395-1 Jover, 2006, Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: a model of hepatic encephalopathy in cirrhosis, Hepatology, 43, 1257, 10.1002/hep.21180 Norenberg, 1991, Ammonia-induced astrocyte swelling in primary culture, Neurochem Res, 16, 833, 10.1007/BF00965694 Rivera-Mancía, 2009, Morphological changes of rat astrocytes induced by liver damage but not by manganese chloride exposure, Metab Brain Dis, 24, 243, 10.1007/s11011-009-9138-5 Back, 2011, Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model, Neurol Res, 33, 1100, 10.1179/1743132811Y.0000000046 Chavarria, 2015, Magnetic resonance imaging and spectroscopy in hepatic encephalopathy, J Clin Exp Hepatol, 5, S69, 10.1016/j.jceh.2013.10.001 Cordoba, 2003, 1H magnetic resonance in the study of hepatic encephalopathy in humans, Metab Brain Dis, 15 Zeng, 2020, Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy, Neurology, 94, e1147, 10.1212/WNL.0000000000008899 Rama Rao, 2014, Glutamine in the pathogenesis of hepatic encephalopathy: the trojan Horse hypothesis revisited, Neurochem Res, 39, 593, 10.1007/s11064-012-0955-2 Rangroo Thrane, 2013, Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering, Nat Med, 19, 1643, 10.1038/nm.3400 Eefsen, 2012, Cerebral expression of NKCC1 in rats with acute and chronic hyperammonemia, J Liver Dis Transpl, 01 Jayakumar, 2008, Na-K-Cl cotransporter-1 in the mechanism of ammonia-induced astrocyte swelling, J Biol Chem, 283, 33874, 10.1074/jbc.M804016200 Jayakumar, 2011, The Na–K–Cl cotransporter in the brain edema of acute liver failure, J Hepatol, 54, 272, 10.1016/j.jhep.2010.06.041 Jayakumar, 2014, Sulfonylurea receptor 1 contributes to the astrocyte swelling and brain edema in acute liver failure, Transl Stroke Res, 5, 28, 10.1007/s12975-014-0328-z Stokum, 2015, Mechanisms of astrocyte-mediated cerebral edema, Neurochem Res, 40, 317, 10.1007/s11064-014-1374-3 Rama Rao, 2003, Increased aquaporin-4 expression in ammonia-treated cultured astrocytes, Neuroreport, 14, 2379, 10.1097/00001756-200312190-00018 Rama Rao, 2010, Brain aquaporin-4 in experimental acute liver failure, J Neuropathol Exp Neurol, 69, 869, 10.1097/NEN.0b013e3181ebe581 Thumburu, 2014, Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure, J Neurochem, 128, 617, 10.1111/jnc.12511 Rama Rao, 2014, Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure, Neurobiol Dis, 63, 222, 10.1016/j.nbd.2013.11.018 Hadjihambi, 2019, Impaired brain glymphatic flow in experimental hepatic encephalopathy, J Hepatol, 70, 40, 10.1016/j.jhep.2018.08.021 Görg, 2010, Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy, Hepatology, 52, 256, 10.1002/hep.23656 Görg, 2013, Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy, Hepatology, 57, 2436, 10.1002/hep.26265 Görg, 2008, Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo, Hepatology, 48, 567, 10.1002/hep.22345 Singh, 2014, Acute liver failure in rats activates glutamine-glutamate cycle but declines antioxidant enzymes to induce oxidative stress in cerebral cortex and cerebellum, PloS One, 9, 10.1371/journal.pone.0095855 Faleiros, 2014, Up-regulation of brain cytokines and chemokines mediates neurotoxicity in early acute liver failure by a mechanism independent of microglial activation, Brain Res, 1578, 49, 10.1016/j.brainres.2014.07.001 Chroni, 2006, Brain oxidative stress induced by obstructive jaundice in rats, J Neuropathol Exp Neurol, 65, 193, 10.1097/01.jnen.0000200152.98259.4e Wang, 2013, Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy, Mol Med Rep, 8, 67, 10.3892/mmr.2013.1472 Haack, 2014, Dysbalance of astrocyte calcium under hyperammonemic conditions, PloS One, 9, 10.1371/journal.pone.0105832 Lachmann, 2013, Precipitants of hepatic encephalopathy induce rapid astrocyte swelling in an oxidative stress dependent manner, Arch Biochem Biophys, 536, 143, 10.1016/j.abb.2013.05.004 Görg, 2019, O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy, J Hepatol, 71, 930, 10.1016/j.jhep.2019.06.020 Lu, 2019, Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes, EBioMedicine, 48, 539, 10.1016/j.ebiom.2019.09.058 Görg, 2018, Hepatic encephalopathy and astrocyte senescence, J Clin Exp Hepatol, 8, 294, 10.1016/j.jceh.2018.05.003 Heidari, 2019, Brain mitochondria as potential therapeutic targets for managing hepatic encephalopathy, Life Sci, 218, 65, 10.1016/j.lfs.2018.12.030 Görg, 2013, Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy, Arch Biochem Biophys, 536, 158, 10.1016/j.abb.2013.03.010 Görg, 2015, Ammonia-induced senescence in cultured rat astrocytes and in human cerebral cortex in hepatic encephalopathy, Glia, 63, 37, 10.1002/glia.22731 Bobermin, 2020, Ammonia-induced glial-inflammaging, Mol Neurobiol, 57, 3552, 10.1007/s12035-020-01985-4 Wright, 2007, Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension, Metab Brain Dis, 22, 375, 10.1007/s11011-007-9071-4 Zemtsova, 2011, Microglia activation in hepatic encephalopathy in rats and humans, Hepatology, 54, 204, 10.1002/hep.24326 Dennis, 2014, Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy, Metab Brain Dis, 29, 1027, 10.1007/s11011-013-9469-0 Karababa, 2017, Ammonia attenuates LPS-induced upregulation of pro-inflammatory cytokine mRNA in Co-cultured astrocytes and microglia, Neurochem Res, 42, 737, 10.1007/s11064-016-2060-4 Hsu, 2021, Enhanced meningeal lymphatic drainage ameliorates neuroinflammation and hepatic encephalopathy in cirrhotic rats, Gastroenterology, 160, 10.1053/j.gastro.2020.11.036 Rangroo Thrane, 2012, Real-time analysis of microglial activation and motility in hepatic and hyperammonemic encephalopathy, Neuroscience, 220, 247, 10.1016/j.neuroscience.2012.06.022 McMillin, 2017, Bile acid-mediated sphingosine-1-phosphate receptor 2 signaling promotes neuroinflammation during hepatic encephalopathy in mice, Front Cell Neurosci, 11, 191, 10.3389/fncel.2017.00191 McMillin, 2014, Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline, J Neuroinflam, 11, 121, 10.1186/1742-2094-11-121 McMillin, 2015, TGR5 signaling reduces neuroinflammation during hepatic encephalopathy, J Neurochem, 135, 565, 10.1111/jnc.13243 McMillin, 2016, Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice, J Neuroinflam, 13, 198, 10.1186/s12974-016-0674-8 Jiang, 2009, Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline, J Neurochem, 109, 485, 10.1111/j.1471-4159.2009.05981.x Chastre, 2012, Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications, PloS One, 7, 10.1371/journal.pone.0049670 Zhang, 2017, Neuron-derived CCL2 contributes to microglia activation and neurological decline in hepatic encephalopathy, Biol Res, 50, 26, 10.1186/s40659-017-0130-y Cauli, 2007, Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts, Hepatology, 46, 514, 10.1002/hep.21734 Agusti, 2017, Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy, CNS Neurosci Ther, 23, 386, 10.1111/cns.12688 Dadsetan, 2016, Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy, J Neuroinflammation, 13, 245, 10.1186/s12974-016-0710-8 Wright, 2014, Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis, Liver Int, 34, 1184, 10.1111/liv.12481 D’Mello, 2009, Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor signaling during peripheral organ inflammation, J Neurosci, 29, 2089, 10.1523/JNEUROSCI.3567-08.2009 Chen, 2014, Morphological changes of cortical pyramidal neurons in hepatic encephalopathy, BMC Neurosci, 15, 15, 10.1186/1471-2202-15-15 Rodrigo, 2010, Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy, Gastroenterology, 139, 675, 10.1053/j.gastro.2010.03.040 D’Mello, 2017, Interactions between platelets and inflammatory monocytes affect sickness behavior in mice with liver inflammation, Gastroenterology, 153, 1416, 10.1053/j.gastro.2017.08.011 Balzano, 2020, Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway, J Neuroinflam, 17, 70, 10.1186/s12974-020-01746-z Taoro-González, 2019, Differential role of interleukin-1β in neuroinflammation-induced impairment of spatial and nonspatial memory in hyperammonemic rats, FASEB J, 33, 9913, 10.1096/fj.201900230RR Hoogland, 2015, Systemic inflammation and microglial activation: systematic review of animal experiments, J Neuroinflam, 12, 114, 10.1186/s12974-015-0332-6 Balzano, 2020, Chronic hyperammonemia induces peripheral inflammation that leads to cognitive impairment in rats: reversed by anti-TNF-a treatment, J Hepatol, 73, 12, 10.1016/j.jhep.2019.01.008 Bémeur, 2010, IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure, Neurochem Int, 56, 213, 10.1016/j.neuint.2009.11.010 McMillin, 2019, Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice, J Neuroinflam, 16, 69, 10.1186/s12974-019-1455-y Xie, 2018, Dysregulated bile acid signaling contributes to the neurological impairment in murine models of acute and chronic liver failure, EBioMedicine, 37, 294, 10.1016/j.ebiom.2018.10.030 Horvatits, 2017, Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis, Liver Int, 37, 224, 10.1111/liv.13201 Agusti, 2011, p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts, Gut, 60, 1572, 10.1136/gut.2010.236083 Agusti, 2014, Rats with minimal hepatic encephalopathy due to portacaval shunt show differential increase of translocator protein (18 kDa) binding in different brain areas, which is not affected by chronic MAP-kinase p38 inhibition, Metab Brain Dis, 29, 955, 10.1007/s11011-013-9461-8 Engelmann, 2021, Pathophysiology of decompensated cirrhosis: portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction, J Hepatol, 75, S49, 10.1016/j.jhep.2021.01.002 Demorrow, 2021, 2021 ISHEN guidelines on animal models of hepatic encephalopathy, Liver Int, 41, 1474, 10.1111/liv.14911