title: 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.
  
  
  
  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.affiliation: UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom.|Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Hadjihambi
authors.affiliation: UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Chiara
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Hosford
authors.affiliation: UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom.
authors.forename: Abeba
authors.initials: A
authors.lastname: Habtetion
authors.affiliation: Neurocentre Magendie, INSERM U1215, Bordeaux, France, University of Bordeaux, Bordeaux, France.
authors.forename: Anastassios
authors.initials: A
authors.lastname: Karagiannis
authors.affiliation: UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom.
authors.forename: Nathan
authors.initials: N
authors.lastname: Davies
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
authors.affiliation: UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
mesh_terms: D000641:Ammonia / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000378:metabolism*; D002908:Chronic Disease; D000072259:Connexin 26 / Q000378:metabolism*; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000378:metabolism / Q000503:physiopathology*; D022124:Hyperammonemia / Q000378:metabolism* / Q000503:physiopathology; D007773:Lactates / Q000378:metabolism; D008026:Ligation; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers; D007773:Lactates; D000072259:Connexin 26; D000641:Ammonia