Berberine and Lactulose Combination Therapy Attenuates Neuroinflammation and Hepatic Injury in Thioacetamide-Induced Hepatic Encephalopathy in Rats

Hepatic encephalopathy (HE) represents a severe neuropsychiatric manifestation secondary to advanced hepatic dysfunction, predominantly driven by hyperammonaemia and associated neuroinflammatory processes. Although lactulose remains a mainstay in the clinical management of HE due to its ammonia-lowering properties, its limited efficacy in attenuating neuroinflammation necessitates the use of adjunctive therapeutic strategies. Previously, we identified berberine, a plant-derived isoquinoline alkaloid, as an anti-HE agent via the reduction of neuroinflammation and NLRP3 inflammasome activation. Therefore, in the present study, we investigated the potential beneficial effects of co-administering berberine and lactulose in a rat model of thioacetamide (TAA)-induced hepatic encephalopathy. HE was induced via intraperitoneal injections of TAA (200 mg/kg) on alternate days for one week. Animals received oral pre-treatment with lactulose (8 mL/kg) alone or in combination with berberine (100 mg/kg) for 14 consecutive days. Comprehensive behavioural assessments were conducted alongside biochemical quantification of systemic ammonia, hepatic transaminases (ALT, AST), and oxidative stress markers (MDA, GSH) in both hepatic and cerebral tissues. Histopathological evaluations of the liver and brain further corroborated the biochemical findings. Notably, combination therapy significantly ameliorated cognitive deficits, reduced systemic ammonia burden, normalised liver and brain enzyme profiles, and markedly attenuated central neuroinflammatory signalling, as evidenced by reduced hippocampal NF-κB activation and GFAP immunoreactivity, in addition to suppressing hepatic NF-κB expression, surpassing the effects observed with monotherapy. Histological analyses revealed reduced neuronal degeneration and hepatic architectural disruption. These findings underscore the therapeutic potential of berberine-lactulose co-treatment in mitigating both hepatic and neuroinflammatory pathologies associated with HE, offering a promising adjunctive strategy for improving neurocognitive outcomes in liver failure. Berberine potentiates lactulose efficacy in thioacetamide-induced hepatic encephalopathy. Combination therapy reduces hyperammonemia and improves neurobehavioral deficits. Berberine-lactulose co-treatment attenuates hepatic injury, fibrosis, and oxidative stress. Combination therapy suppresses hippocampal NF-κB activation and reactive astrogliosis while reducing hepatic inflammation. Combined therapy offers superior hepato-neuroprotection over lactulose monotherapy.