Hesperidin mitigates cognitive and anxiety-like deficits by enhancing hippocampal antioxidant defenses, reducing neuroinflammation, and preventing neuronal apoptosis in a third-trimester-equivalent rat model of developmental ethanol neurotoxicity

Ethanol exposure during brain development has been associated with hippocampal oxidative stress, neuroinflammation, and apoptosis, resulting in lasting cognitive and emotional deficits characteristic of fetal alcohol spectrum disorders (FASD). This study evaluated the neuroprotective potential of Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory actions, against developmental ethanol neurotoxicity. Neonatal Wistar rats received ethanol (5.25g/kg/day; 11.9% v/v) from postnatal days 2–10 and were subsequently treated intraperitoneally with Hesperidin (25, 50, or 100mg/kg). Behavioral testing on days 39–45 using the Elevated Plus Maze (EPM) and Morris Water Maze (MWM) showed that ethanol markedly decreased open arm time (OAT%) and entries (OAE%) (P < 0.001, P < 0.01 vs Control), increased escape latency (P < 0.001), and reduced probe target time (P < 0.001 vs Control). Hesperidin at 50 and 100mg/kg improved all indices (P < 0.05–0.01 vs Ethanol). Ethanol elevated hippocampal MDA and TNF-α (P < 0.001) while decreasing SOD (P < 0.01) and GSH-Px (P < 0.001), Hesperidin normalized these values (P < 0.01–0.001 vs Ethanol). GFAP and cleaved caspase-3 immunoreactivity were also reduced by hesperidin (P < 0.001 vs Ethanol). Overall, Hesperidin afforded dose-dependent neuroprotection by mitigating oxidative stress, inflammation, and apoptosis, thereby improving ethanol-induced behavioral impairments.