Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology. Butterworth Roger F Drugs Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex. 10.1007/s40265-018-1017-0

GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. Hata Toshiyuki,Rehman Fatima,Hori Tomohide,Nguyen Justin H The Journal of surgical research BACKGROUND:Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS:To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 μg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS:We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS:Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation. 10.1016/j.jss.2018.11.047

Increased GABA signaling in liver macrophage promotes HBV replication in HBV-carrier mice. Virus research Gamma-aminobutyric acid (GABA) signals in various non-neuronal cells including hepatocytes and some immune cells. Studies, including ours, show that type A GABA receptors (GABARs)-mediated signaling occurs in macrophages regulating tissue-specific functions. Our recent study reveals that activation of GABARs in liver macrophages promotes their M2-like polarization and increases HBV replication in mice. This short article briefly summarizes the GABA signaling system in macrophages and discusses potential mechanisms by which GABA signaling promotes HBV replication. 10.1016/j.virusres.2024.199366