Abstract
Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABAA receptors can modulate cerebellar neuroinflammation. The GABAA antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABAA receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABAA receptors could be a suitable target for improving neuroinflammation in MHE.
Highlights
Introduction published maps and institutional affilPatients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE) characterized by mild cognitive impairment, attention deficits, and psychomotor slowing, which impair quality of life, reduce life span, and increase the risks of accidents, falls, and hospitalization
control with vehicle (CV), controlinvehicle; CB, Asare peripheral inflammation induces neuroinflammation the cerebellum of control treated with bicuculline; HA, hyperammonemic rats with vehicle; HB, hyperammonemic rats ammonemic rats, we evaluated the effect of bicuculline on cerebellar neuroinflamm treated with bicuculline
Our results suggest that bicuculline-induced peripheral inflammation, microglial activation in the cerebellum, and a decrease in the membrane expression of GAT-1, leading to a small increase in extracellular GABA, were not sufficient to lead to significant impairment of motor coordination in control rats (Figure 8a)
Summary
Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE) characterized by mild cognitive impairment, attention deficits, and psychomotor slowing, which impair quality of life, reduce life span, and increase the risks of accidents, falls, and hospitalization. MHE affects several million people and is a serious health, social, and economic problem [1]. Hyperammonemia and peripheral inflammation play synergistic roles in inducing cognitive and motor alterations in MHE [2,3,4]. Chronic hyperammonemia per se is enough to induce neuroinflammation with the activation of microglia increasing inflammatory markers in the brain associated with the impairment of cognitive function. Reducing neuroinflammation with ibuprofen restored the learning of a discrimination task in the Y maze in hyperammonemic rats. Chronic hyperammonemia induces peripheral inflammation, increasing TNFα and iations
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