{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T09:26:43Z","timestamp":1784366803671,"version":"3.55.0"},"reference-count":59,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP 130556"],"award-info":[{"award-number":["MOP 130556"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied by various perioperative factors such as blood loss and hypotension which could influence outcomes post\u2010LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension\u2010induced neuronal cell death. Six\u2010week bile duct\u2010ligated (BDL) rats with MHE and respective SHAM\u2010controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90\u00a0mm\u00a0Hg) were induced via blood withdrawal from the femoral artery and maintained for 120\u00a0min. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia\u2010lowering strategy ornithine phenylacetate (OP; MNK\u20106105), administered orally (1\u00a0g\/kg) for 3\u00a0weeks before induction of hypotension. Hypotension 30 and 60\u00a0mm\u00a0Hg (not 90\u00a0mm\u00a0Hg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM\u2010operated controls as well as non\u2010hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase\u20103, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonaemia, improved anxiety and activity, and protected the brain against hypotension\u2010induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension\u2010induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post\u2010transplant and that treating for MHE pre\u2010LT might reduce this risk.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15290-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15290","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T10:57:00Z","timestamp":1609412220000},"page":"561-573","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Bile\u2010duct ligation renders the brain susceptible to hypotension\u2010induced neuronal degeneration: Implications of ammonia"],"prefix":"10.1111","volume":"157","author":[{"given":"Marc\u2010Andr\u00e9","family":"Cl\u00e9ment","sequence":"first","affiliation":[{"name":"Hepato\u2010Neuro Laboratory CRCHUM Universit\u00e9 de Montr\u00e9al Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2235-6019","authenticated-orcid":false,"given":"Cristina R.","family":"Bosoi","sequence":"additional","affiliation":[{"name":"Hepato\u2010Neuro Laboratory CRCHUM Universit\u00e9 de Montr\u00e9al Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana M.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Hepato\u2010Neuro Laboratory CRCHUM Universit\u00e9 de Montr\u00e9al Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5395-5853","authenticated-orcid":false,"given":"M\u00e9lanie","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Hepato\u2010Neuro Laboratory CRCHUM Universit\u00e9 de Montr\u00e9al Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-5958","authenticated-orcid":false,"given":"Chantal","family":"B\u00e9meur","sequence":"additional","affiliation":[{"name":"Hepato\u2010Neuro Laboratory CRCHUM Universit\u00e9 de Montr\u00e9al Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9854-6834","authenticated-orcid":false,"given":"Christopher F.","family":"Rose","sequence":"additional","affiliation":[{"name":"Hepato\u2010Neuro Laboratory CRCHUM Universit\u00e9 de Montr\u00e9al Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.54.155"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2007.05.004"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-016-9843-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24273"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-008-9112-7"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2013.01.015"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2012.01.006"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-14-32"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-011-0822-5"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-007-9072-3"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-010-9183-0"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-017-0155-5"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22897"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000088056"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.332"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-007-9020-4"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16649196"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/lt.22197"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.4103\/bc.bc_27_16","article-title":"Prospective clinical biomarkers of caspase\u2010mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration","volume":"3","author":"Glushakova O. 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