Neuroprotective effects of zingerone on the thioacetamide-induced hepatic encephalopathy in rats. Insights from oxidative stress, ER stress, BDNF signaling and apoptosis.

This study investigated the protective effects of zingerone (ZIN) against thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats (n = 10 per group). HE was induced by TAA (200 mg/kg, intraperitoneally (i.p.)) on days 1 and 3, and rats were treated with ZIN (25 or 50 mg/kg/day, intragastric gavage (i.g.)) for 14 days. Serum biochemistry, oxidative stress, inflammatory markers, ER stress-related proteins, apoptosis indicators, histopathology, and behavioral outcomes were evaluated TAA administration markedly increased whole-blood ammonia concentrations together with serum activities of the hepatic injury biomarkers ALT, AST, ALP, GGT, and LDH compared with the Control group, while ZIN treatment significantly improved these parameters. ZIN reduced malondialdehyde (MDA) levels and restored antioxidant defenses (SOD and GSH) in both liver and brain tissues. Pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were elevated after TAA exposure, whereas IL-10 was reduced; ZIN dose-dependently reversed these changes. In addition, TAA increased ER stress markers (GRP78, CHOP, ATF6, XBP1, IRE1, and PERK) and apoptosis-related Bax and caspase-3 expression, which were significantly suppressed by ZIN. In brain tissue, ZIN preserved BDNF expression and reduced GFAP immunoreactivity. Behavioral impairments, including anxiety-like behavior and locomotor deficits, were significantly improved at 50 mg/kg. Overall, ZIN exhibited dose-dependent hepatoprotective and neuroprotective effects in TAA-induced hepatic encephalopathy, as evidenced by attenuation of oxidative stress, inflammation, ER stress, and apoptosis. This study provides an integrated evaluation of ZIN in hepatic encephalopathy, extending prior findings in other hepatotoxicity models, including CCl₄ and cadmium-induced injury, as well as related phytochemical studies in HE.