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.
Preview |
Text
Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease.pdf - Published Version Download (5MB) | Preview |
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.
Archive Staff Only
 |
View Item |
