Therapeutic effects of berberine on hyperammonemia-associated neuroinflammation in thioacetamide-induced hepatic encephalopathy.

Persistent hyperammonaemia and neuroinflammation are the hallmarks of hepatic encephalopathy (HE), a severe central nervous system (CNS) disorder. Berberine (BBR) showed potent anti-inflammatory activities in various diseases. However, its underlying mechanisms and potential therapeutic benefits in HE remain unclear, necessitating further mechanistic studies. In the current investigation, we evaluated the therapeutic effects of BBR on neurobehavior, blood-brain barrier (BBB) permeability and brain histology in TAA-induced HE rats. The animal model of HE was induced by three repeated doses of TAA 300 mg/kg i.p. Animals were treated with BBR 100 mg/kg orally once daily for 3 days. The administration of TAA aggravated neurobehavioral alterations, ammonia, cerebral edema and impaired BBB permeability. The cortex and hippocampus tissue showed significant microglial and astrocyte activation, increased inflammatory markers such as IL-1β, TNF-α, IL-6, and NLRP3 inflammasome signalling cascade (caspase-1, ASC, NLRP3, and NF-κB) in TAA group compared to control. Moreover, increased tissue injury and expression of gasdermin-D and reduced neuronal markers (NeuN and MAP-2) were detected in cortex and hippocampus of TAA group. To this end, BBR post-treatment averted the TAA-induced behavioral alterations, cerebral edema and BBB leakage. Additionally, BBR reduced the TAA-induced aforementioned neuroinflammatory and histopathological changes in the cortex and hippocampus. In conclusion, this study demonstrates that BBR post-treatment significantly inhibits the progression of HE by modulating HMGB1/NF-κB/NLRP3 signalling pathway. Overall, these findings highlight the potential of BBR as a promising therapeutic agent to manage HE.