Neuroprotective effect of ferulic acid in valproic acid induced autism like behaviour in zebrafish via modulation of PI3K/AKT/mTOR pathway.

Valproic acid (VPA), a widely used antiepileptic and mood stabilizing drug, is known to induce autism-like features when administered during neurodevelopment. Recent evidence suggests that VPA exposure during adulthood may also elicit autism spectrum disorder (ASD)-like features by altering key signalling pathways, such as phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K-AKT-mTOR), and cause behavioural and neuromorphological deficits. The study explored the neuroprotective properties of ferulic acid (FA) in VPA-induced cognitive and behavioural impairments. Zebrafish were exposed to VPA at 500 μM for four consecutive days to induce ASD-like features. After 4 days of VPA exposure, they were treated with FA (50, 100, and 200 mg/kg) and risperidone (0.5 mg/kg) for 4 days. Behavioural (T-maze, Novel Tank Driving Test (NTDT), and social interaction), biochemical (oxidative markers), molecular changes (PI3K, mTOR by ELISA, and AKT by immunohistochemistry), and histopathological analyses were performed to confirm the neuroprotective properties of ferulic acid (FA). VPA (500 μM) exposure significantly deteriorated behavioural and molecular alteration levels (p < 0.001 vs. normal control group) in zebrafish. However, FA (100 and 200 mg/kg) significantly improved cognitive and behavioural alterations, as well as oxidative marker and neurotransmitter levels (p < 0.05 vs. VPA group) in zebrafish. Treatment also improved histopathological changes and AKT levels (p < 0.001 vs. the VPA group) in zebrafish. Our results demonstrated that the therapeutic effect of FA in VPA induced autism like symptoms in zebrafish was mediated by its antioxidant, anti-inflammatory, and anti-apoptotic properties through modulation of the PI3K-AKT-mTOR pathway, offering a promising therapeutic strategy for ASD-like symptoms.