Comparative Analysis of Cannabidiol and Risperidone on Behavioral and Neurochemical Outcomes, and Neurodevelopment Markers in a Zebrafish Model of Embryonic Exposure to Sodium Valproate

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, repetitive behaviors, and sensory abnormalities. Sodium valproate (VPA) exposure during embryonic development is a well-established preclinical model for ASD, leading to increased oxidative stress in the developing brain, including lipid peroxidation, which affects cell proliferation and organization. This study aimed to investigate the potential therapeutic effects of cannabidiol (CBD) and risperidone (RISP) in reversing ASD-like behaviors and associated neurobiological alterations induced by embryonic VPA exposure in a zebrafish model. Zebrafish embryos were exposed to 125 μM VPA for 2 days post-fertilization (dpf). At 3-4 dpf, embryos were treated with 0.06 μM CBD or 1 μM RISP. Behavioral assays were conducted to assess hyperlocomotion and aggressive behavior. At 7 dpf, lipid peroxidation levels were measured, and expression of glial fibrillary acidic protein (GFAP) and calcium/calmodulin (CaM) were analyzed to evaluate neurobiological changes. VPA exposure resulted in increased hyperlocomotion and aggression. CBD treatment effectively reversed these behaviors, while RISP showed limited efficacy. Additionally, CBD reduced lipid peroxidation and restored anandamide levels, whereas RISP did not exhibit these effects. CBD also normalized GFAP and CaM expression, indicating restoration of glial function and excitatory/inhibitory balance. CBD demonstrated a better efficacy and safety profile compared to RISP in reversing ASD-like behaviors and associated neurobiological alterations in the zebrafish model. These findings suggest that CBD may offer a safer and more effective therapeutic alternative for managing ASD-related symptoms.