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

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 fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized 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) and also evaluated the effect of ammonia-lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was 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 central nervous system 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. (Hepatology 2017;65:1306-1318).

• Authors: Anna Hadjihambi, Francesco De Chiara, Patrick S Hosford, Abeba Habtetion, Anastassios Karagiannis, Nathan Davies, Alexander V Gourine, Rajiv Jalan
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 65 Issue 4 Pg. 1306-1318 (04 2017) ISSN: 1527-3350 [Electronic] United States
• PMID: 28066916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

Chemical References

• Biomarkers
• Lactates
• Connexin 26
• Ammonia

Topics

• Ammonia (metabolism)
• Analysis of Variance
• Animals
• Bile Ducts (surgery)
• Biomarkers (metabolism)
• Blotting, Western
• Cerebral Cortex (metabolism)
• Chronic Disease
• Connexin 26 (metabolism)
• Disease Models, Animal
• Hepatic Encephalopathy (metabolism, physiopathology)
• Hyperammonemia (metabolism, physiopathology)
• Lactates (metabolism)
• Ligation
• Liver Cirrhosis (metabolism, physiopathology)
• Male
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Statistics, Nonparametric