{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:57:15Z","timestamp":1792429035329,"version":"4.5.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Type C hepatic encephalopathy (type C HE) is increasingly suspected in children with chronic liver disease (CLD), and believed to underlie long-term neurocognitive difficulties. The molecular underpinnings of type C HE in both adults and children are incompletely understood. In the present study we combined the experimental advantages of <jats:italic>in vivo<\/jats:italic> high field <jats:sup>1<\/jats:sup>H magnetic resonance spectroscopy with immunohistochemistry to follow longitudinally over 8 weeks the neurometabolic changes in the hippocampus of animals having undergone bile duct ligation as pups. Rats who develop CLD early in life displayed pronounced neurometabolic changes in the hippocampus characterized by a progressive increase in glutamine concentration which correlated with plasma ammonia levels and a rapid decrease in brain myo-inositol. Other neurometabolic findings included a decrease in other organic osmolytes (taurine, choline-containing compounds and creatine), ascorbate and glutamate. At the cellular level, we observed an increase in glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4) expression in the hippocampus at 4 weeks post bile duct ligation (BDL), together with astrocytic morphological alterations. These findings differ from observations in the brain of adult rats following BDL, and are in keeping with the commonly accepted theory of age-dependent vulnerability.<\/jats:p>","DOI":"10.1038\/s41598-020-64416-3","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T10:02:48Z","timestamp":1588672968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Longitudinal osmotic and neurometabolic changes in young rats with chronic cholestatic liver disease"],"prefix":"10.1038","volume":"10","author":[{"given":"Veronika","family":"Rackayova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8068-3344","authenticated-orcid":false,"given":"Olivier","family":"Braissant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1785-792X","authenticated-orcid":false,"given":"Anne-Laure","family":"Rougemont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Cudalbu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0711-687X","authenticated-orcid":false,"given":"Val\u00e9rie A.","family":"McLin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,5]]},"reference":[{"key":"64416_CR1","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1097\/MPG.0b013e318259ed20","volume":"55","author":"SE Caudle","year":"2012","unstructured":"Caudle, S. E., Katzenstein, J. M., Karpen, S. & McLin, V. Developmental assessment of infants with biliary atresia: differences between boys and girls. J Pediatr Gastroenterol Nutr 55, 384\u2013389, https:\/\/doi.org\/10.1097\/MPG.0b013e318259ed20 (2012).","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"64416_CR2","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1016\/j.jpeds.2009.12.014","volume":"156","author":"SE Caudle","year":"2010","unstructured":"Caudle, S. E., Katzenstein, J. M., Karpen, S. J. & McLin, V. A. Language and motor skills are impaired in infants with biliary atresia before transplantation. J Pediatr 156, 936\u2013940 e931, https:\/\/doi.org\/10.1016\/j.jpeds.2009.12.014 (2010).","journal-title":"J Pediatr"},{"key":"64416_CR3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jpeds.2014.03.032","volume":"165","author":"LG Sorensen","year":"2014","unstructured":"Sorensen, L. G. et al. Longitudinal study of cognitive and academic outcomes after pediatric liver transplantation. J Pediatr 165, 65\u201372 e62, https:\/\/doi.org\/10.1016\/j.jpeds.2014.03.032 (2014).","journal-title":"J Pediatr"},{"key":"64416_CR4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/lt.25634","volume":"26","author":"D Ohnemus","year":"2020","unstructured":"Ohnemus, D. et al. Health-Related Quality of Life and Cognitive Functioning in Pediatric Liver Transplant Recipients. Liver Transpl 26, 45\u201356, https:\/\/doi.org\/10.1002\/lt.25634 (2020).","journal-title":"Liver Transpl"},{"key":"64416_CR5","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1111\/pan.12255","volume":"23","author":"JJ Moser","year":"2013","unstructured":"Moser, J. J., Veale, P. M., McAllister, D. L. & Archer, D. P. A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses. Paediatr Anaesth 23, 1084\u20131096, https:\/\/doi.org\/10.1111\/pan.12255 (2013).","journal-title":"Paediatr Anaesth"},{"key":"64416_CR6","doi-asserted-by":"publisher","first-page":"9810","DOI":"10.1523\/JNEUROSCI.22-22-09810.2002","volume":"22","author":"O Braissant","year":"2002","unstructured":"Braissant, O. et al. Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci 22, 9810\u20139820 (2002).","journal-title":"J Neurosci"},{"issue":"Suppl 1","key":"64416_CR7","doi-asserted-by":"publisher","first-page":"S58","DOI":"10.1016\/j.ymgme.2003.11.016","volume":"81","author":"AL Gropman","year":"2004","unstructured":"Gropman, A. L. & Batshaw, M. L. Cognitive outcome in urea cycle disorders. Mol Genet Metab 81(Suppl 1), S58\u201362, https:\/\/doi.org\/10.1016\/j.ymgme.2003.11.016 (2004).","journal-title":"Mol Genet Metab"},{"key":"64416_CR8","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.brainresrev.2007.06.026","volume":"56","author":"L Cagnon","year":"2007","unstructured":"Cagnon, L. & Braissant, O. Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev 56, 183\u2013197, https:\/\/doi.org\/10.1016\/j.brainresrev.2007.06.026 (2007).","journal-title":"Brain Res Rev"},{"issue":"Pt 14","key":"64416_CR9","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1242\/jcs.110.14.1603","volume":"110","author":"T Hirase","year":"1997","unstructured":"Hirase, T. et al. Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110(Pt 14), 1603\u20131613 (1997).","journal-title":"J Cell Sci"},{"key":"64416_CR10","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1007\/s11011-013-9452-9","volume":"29","author":"L Chavarria","year":"2014","unstructured":"Chavarria, L. & Cordoba, J. Magnetic resonance of the brain in chronic and acute liver failure. Metab Brain Dis 29, 937\u2013944, https:\/\/doi.org\/10.1007\/s11011-013-9452-9 (2014).","journal-title":"Metab Brain Dis"},{"key":"64416_CR11","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.abb.2013.05.006","volume":"536","author":"S Keiding","year":"2013","unstructured":"Keiding, S. & Pavese, N. Brain metabolism in patients with hepatic encephalopathy studied by PET and MR. Arch Biochem Biophys 536, 131\u2013142, https:\/\/doi.org\/10.1016\/j.abb.2013.05.006 (2013).","journal-title":"Arch Biochem Biophys"},{"key":"64416_CR12","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1111\/liv.12032","volume":"33","author":"L Chavarria","year":"2013","unstructured":"Chavarria, L. et al. Brain magnetic resonance in experimental acute-on-chronic liver failure. Liver Int 33, 294\u2013300, https:\/\/doi.org\/10.1111\/liv.12032 (2013).","journal-title":"Liver Int"},{"key":"64416_CR13","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s11011-012-9368-9","volume":"28","author":"C Cudalbu","year":"2013","unstructured":"Cudalbu, C. In vivo studies of brain metabolism in animal models of Hepatic Encephalopathy using (1)H Magnetic Resonance Spectroscopy. Metab Brain Dis 28, 167\u2013174, https:\/\/doi.org\/10.1007\/s11011-012-9368-9 (2013).","journal-title":"Metab Brain Dis"},{"key":"64416_CR14","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1007\/s11011-015-9715-8","volume":"31","author":"V Rackayova","year":"2016","unstructured":"Rackayova, V. et al. (1)H and (31)P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism. Metab Brain Dis 31, 1303\u20131314, https:\/\/doi.org\/10.1007\/s11011-015-9715-8 (2016).","journal-title":"Metab Brain Dis"},{"key":"64416_CR15","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.3174\/ajnr.A1652","volume":"30","author":"BR Foerster","year":"2009","unstructured":"Foerster, B. R., Conklin, L. S., Petrou, M., Barker, P. B. & Schwarz, K. B. Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy. AJNR Am J Neuroradiol 30, 1610\u20131613, https:\/\/doi.org\/10.3174\/ajnr.A1652 (2009).","journal-title":"AJNR Am J Neuroradiol"},{"key":"64416_CR16","doi-asserted-by":"publisher","first-page":"4064","DOI":"10.1007\/s00330-017-4808-x","volume":"27","author":"S Hanquinet","year":"2017","unstructured":"Hanquinet, S. et al. Globus pallidus MR signal abnormalities in children with chronic liver disease and\/or porto-systemic shunting. Eur Radiol 27, 4064\u20134071, https:\/\/doi.org\/10.1007\/s00330-017-4808-x (2017).","journal-title":"Eur Radiol"},{"key":"64416_CR17","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.jhep.2016.10.026","volume":"66","author":"A Srivastava","year":"2017","unstructured":"Srivastava, A. et al. Minimal hepatic encephalopathy in children with chronic liver disease: Prevalence, pathogenesis and magnetic resonance-based diagnosis. J Hepatol 66, 528\u2013536, https:\/\/doi.org\/10.1016\/j.jhep.2016.10.026 (2017).","journal-title":"J Hepatol"},{"key":"64416_CR18","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.jhep.2019.05.022","volume":"71","author":"O Braissant","year":"2019","unstructured":"Braissant, O. et al. Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy. J Hepatol 71, 505\u2013515, https:\/\/doi.org\/10.1016\/j.jhep.2019.05.022 (2019).","journal-title":"J Hepatol"},{"key":"64416_CR19","doi-asserted-by":"publisher","first-page":"7368","DOI":"10.1523\/JNEUROSCI.5746-12.2013","volume":"33","author":"AD Workman","year":"2013","unstructured":"Workman, A. D., Charvet, C. J., Clancy, B., Darlington, R. B. & Finlay, B. L. Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci 33, 7368\u20137383, https:\/\/doi.org\/10.1523\/JNEUROSCI.5746-12.2013 (2013).","journal-title":"J Neurosci"},{"key":"64416_CR20","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1126\/science.7777856","volume":"268","author":"BL Finlay","year":"1995","unstructured":"Finlay, B. L. & Darlington, R. B. Linked regularities in the development and evolution of mammalian brains. Science 268, 1578\u20131584, https:\/\/doi.org\/10.1126\/science.7777856 (1995).","journal-title":"Science"},{"key":"64416_CR21","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1111\/j.1478-3231.2009.02034.x","volume":"29","author":"RF Butterworth","year":"2009","unstructured":"Butterworth, R. F. et al. Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29, 783\u2013788, https:\/\/doi.org\/10.1111\/j.1478-3231.2009.02034.x (2009).","journal-title":"Liver Int"},{"key":"64416_CR22","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.bbi.2019.08.184","volume":"82","author":"X Sun","year":"2019","unstructured":"Sun, X. et al. Corticosterone-mediated microglia activation affects dendritic spine plasticity and motor learning functions in minimal hepatic encephalopathy. Brain Behav Immun 82, 178\u2013187, https:\/\/doi.org\/10.1016\/j.bbi.2019.08.184 (2019).","journal-title":"Brain Behav Immun"},{"key":"64416_CR23","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.neuint.2009.01.021","volume":"55","author":"P Monfort","year":"2009","unstructured":"Monfort, P. et al. Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications. Neurochem Int 55, 106\u2013112, https:\/\/doi.org\/10.1016\/j.neuint.2009.01.021 (2009).","journal-title":"Neurochem Int"},{"key":"64416_CR24","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1002\/nbm.1528","volume":"23","author":"M Terpstra","year":"2010","unstructured":"Terpstra, M., Rao, R. & Tkac, I. Region-specific changes in ascorbate concentration during rat brain development quantified by in vivo (1)H NMR spectroscopy. NMR Biomed 23, 1038\u20131043, https:\/\/doi.org\/10.1002\/nbm.1528 (2010).","journal-title":"NMR Biomed"},{"key":"64416_CR25","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1002\/mrm.10497","volume":"50","author":"I Tkac","year":"2003","unstructured":"Tkac, I., Rao, R., Georgieff, M. K. & Gruetter, R. Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo 1H NMR spectroscopy. Magn Reson Med 50, 24\u201332, https:\/\/doi.org\/10.1002\/mrm.10497 (2003).","journal-title":"Magn Reson Med"},{"key":"64416_CR26","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1007\/s10545-012-9546-2","volume":"36","author":"O Braissant","year":"2013","unstructured":"Braissant, O., McLin, V. A. & Cudalbu, C. Ammonia toxicity to the brain. J Inherit Metab Dis 36, 595\u2013612, https:\/\/doi.org\/10.1007\/s10545-012-9546-2 (2013).","journal-title":"J Inherit Metab Dis"},{"key":"64416_CR27","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1007\/s11011-016-9938-3","volume":"32","author":"S Dasarathy","year":"2017","unstructured":"Dasarathy, S. et al. Ammonia toxicity: from head to toe? Metab Brain Dis 32, 529\u2013538, https:\/\/doi.org\/10.1007\/s11011-016-9938-3 (2017).","journal-title":"Metab Brain Dis"},{"issue":"Pt 3","key":"64416_CR28","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1042\/bj2770697","volume":"277","author":"RA Hawkins","year":"1991","unstructured":"Hawkins, R. A. & Jessy, J. Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis. Biochem J 277(Pt 3), 697\u2013703, https:\/\/doi.org\/10.1042\/bj2770697 (1991).","journal-title":"Biochem J"},{"key":"64416_CR29","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.neuroscience.2004.10.045","volume":"131","author":"H Tanigami","year":"2005","unstructured":"Tanigami, H. et al. Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuroscience 131, 437\u2013449, https:\/\/doi.org\/10.1016\/j.neuroscience.2004.10.045 (2005).","journal-title":"Neuroscience"},{"key":"64416_CR30","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1046\/j.1471-4159.2002.01041.x","volume":"82","author":"SK Fisher","year":"2002","unstructured":"Fisher, S. K., Novak, J. E. & Agranoff, B. W. Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J Neurochem 82, 736\u2013754, https:\/\/doi.org\/10.1046\/j.1471-4159.2002.01041.x (2002).","journal-title":"J Neurochem"},{"key":"64416_CR31","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1093\/jn\/116.1.50","volume":"116","author":"SH Zeisel","year":"1986","unstructured":"Zeisel, S. H., Char, D. & Sheard, N. F. Choline, phosphatidylcholine and sphingomyelin in human and bovine milk and infant formulas. J Nutr 116, 50\u201358, https:\/\/doi.org\/10.1093\/jn\/116.1.50 (1986).","journal-title":"J Nutr"},{"key":"64416_CR32","doi-asserted-by":"publisher","first-page":"528S","DOI":"10.1080\/07315724.2000.10718976","volume":"19","author":"SH Zeisel","year":"2000","unstructured":"Zeisel, S. H. Choline: needed for normal development of memory. J Am Coll Nutr 19, 528S\u2013531S, https:\/\/doi.org\/10.1080\/07315724.2000.10718976 (2000).","journal-title":"J Am Coll Nutr"},{"key":"64416_CR33","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/jcbfm.2009.8","volume":"29","author":"H Lei","year":"2009","unstructured":"Lei, H., Berthet, C., Hirt, L. & Gruetter, R. Evolution of the neurochemical profile after transient focal cerebral ischemia in the mouse brain. J Cereb Blood Flow Metab 29, 811\u2013819, https:\/\/doi.org\/10.1038\/jcbfm.2009.8 (2009).","journal-title":"J Cereb Blood Flow Metab"},{"key":"64416_CR34","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/s1734-1140(10)70256-5","volume":"62","author":"MW Oliveira","year":"2010","unstructured":"Oliveira, M. W. et al. Scavenging and antioxidant potential of physiological taurine concentrations against different reactive oxygen\/nitrogen species. Pharmacol Rep 62, 185\u2013193, https:\/\/doi.org\/10.1016\/s1734-1140(10)70256-5 (2010).","journal-title":"Pharmacol Rep"},{"key":"64416_CR35","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1152\/advan.00034.2004","volume":"28","author":"K Strange","year":"2004","unstructured":"Strange, K. Cellular volume homeostasis. Adv Physiol Educ 28, 155\u2013159, https:\/\/doi.org\/10.1152\/advan.00034.2004 (2004).","journal-title":"Adv Physiol Educ"},{"key":"64416_CR36","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1007\/s11011-007-9063-4","volume":"22","author":"KV Rama Rao","year":"2007","unstructured":"Rama Rao, K. V. & Norenberg, M. D. Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis 22, 265\u2013275, https:\/\/doi.org\/10.1007\/s11011-007-9063-4 (2007).","journal-title":"Metab Brain Dis"},{"key":"64416_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0505-y","volume":"13","author":"V Hernandez-Rabaza","year":"2016","unstructured":"Hernandez-Rabaza, V. et al. Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane. J Neuroinflammation 13, 41, https:\/\/doi.org\/10.1186\/s12974-016-0505-y (2016).","journal-title":"J Neuroinflammation"},{"key":"64416_CR38","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.acthis.2016.03.003","volume":"118","author":"OE Hiba","year":"2016","unstructured":"Hiba, O. E., Elgot, A., Ahboucha, S. & Gamrani, H. Differential regional responsiveness of astroglia in mild hepatic encephalopathy: An Immunohistochemical approach in bile duct ligated rat. Acta Histochem 118, 338\u2013346, https:\/\/doi.org\/10.1016\/j.acthis.2016.03.003 (2016).","journal-title":"Acta Histochem"},{"key":"64416_CR39","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1002\/hep.21180","volume":"43","author":"R Jover","year":"2006","unstructured":"Jover, R. et al. Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: A model of hepatic encephalopathy in cirrhosis. Hepatology 43, 1257\u20131266, https:\/\/doi.org\/10.1002\/hep.21180 (2006).","journal-title":"Hepatology"},{"key":"64416_CR40","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1111\/liv.12481","volume":"34","author":"GA Wright","year":"2014","unstructured":"Wright, G. A. et al. Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis. Liver Int 34, 1184\u20131191, https:\/\/doi.org\/10.1111\/liv.12481 (2014).","journal-title":"Liver Int"},{"key":"64416_CR41","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1111\/jnc.12810","volume":"131","author":"AR Jayakumar","year":"2014","unstructured":"Jayakumar, A. R. et al. Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies. J Neurochem 131, 333\u2013347, https:\/\/doi.org\/10.1111\/jnc.12810 (2014).","journal-title":"J Neurochem"},{"key":"64416_CR42","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1111\/j.1460-9568.2008.06126.x","volume":"27","author":"O Braissant","year":"2008","unstructured":"Braissant, O. et al. Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency. Eur J Neurosci 27, 1673\u20131685, https:\/\/doi.org\/10.1111\/j.1460-9568.2008.06126.x (2008).","journal-title":"Eur J Neurosci"},{"key":"64416_CR43","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/s0306-4522(97)00347-3","volume":"82","author":"ME Rice","year":"1998","unstructured":"Rice, M. E. & Russo-Menna, I. Differential compartmentalization of brain ascorbate and glutathione between neurons and glia. Neuroscience 82, 1213\u20131223, https:\/\/doi.org\/10.1016\/s0306-4522(97)00347-3 (1998).","journal-title":"Neuroscience"},{"key":"64416_CR44","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.abb.2013.03.010","volume":"536","author":"B Gorg","year":"2013","unstructured":"Gorg, B., Schliess, F. & Haussinger, D. Osmotic and oxidative\/nitrosative stress in ammonia toxicity and hepatic encephalopathy. Arch Biochem Biophys 536, 158\u2013163, https:\/\/doi.org\/10.1016\/j.abb.2013.03.010 (2013).","journal-title":"Arch Biochem Biophys"},{"key":"64416_CR45","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1023\/a:1023858902184","volume":"18","author":"KV Rama Rao","year":"2003","unstructured":"Rama Rao, K. V., Jayakumar, A. R. & Norenberg, D. M. Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis 18, 113\u2013127, https:\/\/doi.org\/10.1023\/a:1023858902184 (2003).","journal-title":"Metab Brain Dis"},{"key":"64416_CR46","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1007\/s00726-011-0875-5","volume":"40","author":"P Sestili","year":"2011","unstructured":"Sestili, P. et al. Creatine as an antioxidant. Amino Acids 40, 1385\u20131396, https:\/\/doi.org\/10.1007\/s00726-011-0875-5 (2011).","journal-title":"Amino Acids"},{"key":"64416_CR47","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/0301-0082(94)90052-3","volume":"43","author":"GV Rebec","year":"1994","unstructured":"Rebec, G. V. & Pierce, R. C. A vitamin as neuromodulator: ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission. Prog Neurobiol 43, 537\u2013565, https:\/\/doi.org\/10.1016\/0301-0082(94)90052-3 (1994).","journal-title":"Prog Neurobiol"},{"key":"64416_CR48","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/s0166-2236(99)01543-x","volume":"23","author":"ME Rice","year":"2000","unstructured":"Rice, M. E. Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci 23, 209\u2013216, https:\/\/doi.org\/10.1016\/s0166-2236(99)01543-x (2000).","journal-title":"Trends Neurosci"},{"key":"64416_CR49","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1515\/BC.2003.059","volume":"384","author":"R Dringen","year":"2003","unstructured":"Dringen, R. & Hirrlinger, J. Glutathione pathways in the brain. Biol Chem 384, 505\u2013516, https:\/\/doi.org\/10.1515\/BC.2003.059 (2003).","journal-title":"Biol Chem"},{"key":"64416_CR50","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1053\/j.gastro.2010.03.040","volume":"139","author":"R Rodrigo","year":"2010","unstructured":"Rodrigo, R. et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139, 675\u2013684, https:\/\/doi.org\/10.1053\/j.gastro.2010.03.040 (2010).","journal-title":"Gastroenterology"},{"key":"64416_CR51","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.abb.2013.04.005","volume":"536","author":"OA Sergeeva","year":"2013","unstructured":"Sergeeva, O. A. GABAergic transmission in hepatic encephalopathy. Arch Biochem Biophys 536, 122\u2013130, https:\/\/doi.org\/10.1016\/j.abb.2013.04.005 (2013).","journal-title":"Arch Biochem Biophys"},{"issue":"1359-1367","key":"64416_CR52","doi-asserted-by":"publisher","first-page":"e1351","DOI":"10.1053\/j.gastro.2008.12.057","volume":"136","author":"O Cauli","year":"2009","unstructured":"Cauli, O., Mansouri, M. T., Agusti, A. & Felipo, V. Hyperammonemia increases GABAergic tone in the cerebellum but decreases it in the rat cortex. Gastroenterology 136(1359-1367), e1351\u20131352, https:\/\/doi.org\/10.1053\/j.gastro.2008.12.057 (2009).","journal-title":"Gastroenterology"},{"key":"64416_CR53","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1111\/j.1471-4159.2011.07244.x","volume":"117","author":"R Leke","year":"2011","unstructured":"Leke, R. et al. Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy. J Neurochem 117, 824\u2013832, https:\/\/doi.org\/10.1111\/j.1471-4159.2011.07244.x (2011).","journal-title":"J Neurochem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64416-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64416-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64416-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T10:06:42Z","timestamp":1670321202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64416-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,5]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["64416"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-64416-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,5]]},"assertion":[{"value":"11 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7536"}}