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Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease

Hadjihambi, A; De Chiara, F; Hosford, PS; Habtetion, A; Karagiannis, A; Davies, N; Gourine, AV; (2017) Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease. Hepatology , 65 (4) pp. 1306-1318. 10.1002/hep.29031. Green open access

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Abstract

The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte-neuron lactate shuttle hypothesis suggests that neuronal activity is fuelled (at least in part) by lactate provided by neighbouring astrocytes. We hypothesised that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced-hyperammonemia [HA]) and also evaluated the effect of ammonia-lowering treatment (ornithine phenylacetate, OP). Plasma ammonia concentration in BDL rats was indeed significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia-induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. CONCLUSION: The results of the present study demonstrate that HE is associated with CNS hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel-mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. This article is protected by copyright. All rights reserved.

Type: Article
Title: Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/hep.29031
Publisher version: https://doi.org/10.1002/hep.29031
Language: English
Additional information: © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Astrocyte, hepatic encephalopathy, lactate, neuron, ornithine phenylacetate
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
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
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
URI: http://discovery.ucl.ac.uk/id/eprint/1535972
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