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)

Impaired brain glymphatic flow in experimental hepatic encephalopathy

“…1 The prevailing hypothesis proposes that this occurs because of metabolic and transporter defects induced by hyperammonaemia, inflammation and alterations in blood brain barrier function. 2,3 In the periphery, the lymphatic system is responsible for interstitial fluid (ISF) clearance, a mechanism that is critical for maintaining tissue homeostasis. Although neuronal function is exquisitely sensitive to alterations in the extracellular environment, until recently, the brain was believed to be devoid of a lymphatic drainage/clearance system.…”

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

“…While Cx26 levels also drop, Cx43 production rather increases in cholestatic animals (Table ) . Interestingly, bile duct ligation in rat leads to dysfunction of cortical connexin hemichannels, mediated by ammonia, which could underlie the hepatic encephalopathy frequently occurring in chronic liver disease . Recently, bile duct ligated Panx1 ‐/‐ mice were found to display increased hepatocellular injury and antioxidant enzyme activity with a predominant immune response …”

Brain metabolic sensing and metabolic signaling at the level of an astrocyte

“…Third, exogenous ATP and l ‐lactate induced potent excitation of C1 neurons in vitro and triggered sympathoexcitatory effects similar to those observed following optogenetic activation of brainstem astrocytes or brain hypoxia in vivo (Sun, Wahlestedt, & Reis, ; Horiuchi, Potts, Tagawa, & Dampney, ; Ralevic, ; Marina et al, ). Finally, hypoxia facilitated release of both ATP (Gourine et al, ) and lactate (Karagiannis et al, ; Hadjihambi et al, ) in brainstem regions containing populations of pre‐sympathetic neurons. While the effect of ATP on C1 neuronal activity is mediated by P2X and P2Y receptors (Sun et al, ; Ralevic, ; Wenker, Sobrinho, Takakura, Mulkey, & Moreira, ), the mechanisms underlying the excitatory effects of lactate remain unknown but appear to involve activation of as yet uncharacterized lactate‐sensitive G s coupled receptor (Tang et al, ).…”