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Abnormal brain oxygen homeostasis in an animal model of liver disease

Hadjihambi, Anna; Cudalbu, Cristina; Pierzchala, Katarzyna; Simicic, Dunja; Donnelly, Chris; Konstantinou, Christos; Davies, Nathan; ... Hosford, Patrick S; + view all (2022) Abnormal brain oxygen homeostasis in an animal model of liver disease. JHEP Reports , 4 (8) , Article 100509. 10.1016/j.jhepr.2022.100509. Green open access

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Abstract

Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive dysfunction. We hypothesise that HE is associated with reduced brain oxygenation and explored the potential role of ammonia as an underlying pathophysiological factor. / Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement and proton magnetic resonance spectroscopy were used to investigate how hyperammonemia impacts oxygenation and metabolic substrate availability in the CNS. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, USA) was used as an experimental treatment to reduce ammonia concentration in plasma. / Results: In BDL animals, glucose, lactate and tissue oxygen concentrations in the cerebral cortex were significantly lower compared to sham-operated controls. OP treatment corrected the hyperammonemia and restored brain tissue oxygen. While BDL animals were hypotensive, cortical tissue oxygen was significantly improved by treatments which increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. / Conclusions: These data suggest that hyperammonemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE aiming to restore normal brain blood flow alongside ammonia-reducing strategies.

Type: Article
Title: Abnormal brain oxygen homeostasis in an animal model of liver disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jhepr.2022.100509
Publisher version: https://doi.org/10.1016/j.jhepr.2022.100509
Language: English
Additional information: Copyright © 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an Open Access article published under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/).
Keywords: Oxygen, ornithine phenylacetate, chronic liver disease, hyperammonemia, phenylephrine
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10149826
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