Rosiglitazone Mitigates Valproic Acid-Induced Neurotoxicity in Zebrafish Larvae via Activation of the PPAR Pathway

Valproic acid (VPA), a commonly used treatment for epilepsy and psychiatric disorders, is associated with neurodevelopmental toxicity and an elevated risk of autism spectrum disorder (ASD). This study investigates the protective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR) agonist, against VPA-induced neurotoxicity in zebrafish larvae. Zebrafish embryos were exposed to VPA (50, 75, 100 μM) from 0.5-h postfertilization (hpf) to 120 hpf, with or without RGZ cotreatment. VPA exposure significantly reduced locomotor activity, evidenced by decreased swimming distance and velocity, and disrupted neurotransmitter homeostasis, with elevated norepinephrine and L-glutamic acid levels. Transcriptomic analysis and qRT-PCR revealed that VPA downregulated PPAR pathway genes (ppara, pparg, pck1, and fabp1), while RGZ cotreatment partially restored locomotor activity, normalized neurotransmitter levels, and rescued PPAR pathway gene expression. These findings demonstrate that RGZ mitigates VPA-induced neurotoxicity by activating PPAR signaling, restoring metabolic balance, and improving motor function, suggesting PPAR agonists as potential therapeutic agents for VPA-induced neurotoxicity and ASD-related deficits.