Neuroprotective Efficacy of Fisetin Against VPA-Induced Autistic Neurobehavioral Alterations by Targeting Dysregulated Redox Homeostasis

Autism is a neurodevelopmental condition, and it's associated pathophysiology, viz., oxidative stress and altered cellular homeostasis, has been extensively intertwined with behavioral impairments. Therefore, targeting oxidative stress and redox cellular homeostasis could be beneficial in relieving autistic-like symptoms. For this purpose, we examined a library of nutraceutical compounds that led us to a bioflavonoid fisetin. Autism-like neurobehavior was induced by subjecting the pregnant rodents to valproic acid at the time of neural tube closure (GD12.5). In this novel study, fisetin was evaluated for its neuroprotective potential at gestational (GD13 until delivery) and post-weaning developmental windows (PND 23–32) in VPA-induced rodent model of autism. Developmental VPA exposure increased intracellular ROS production, oxidative stress, altered AChE and ATPases in brain regions, and induced autistic-like behavioral impairments (social, repetitive, stereotyped, and sensorimotor). The present findings suggested that gestational and post-weaning fisetin treatment significantly improved the behavioral impairments by attenuating elevated oxidative stress, ROS, lipid peroxidation, and re-establishing redox homeostasis. Also, it effectively reinstated the reduced levels of endogenous antioxidants, glutathione, AChE, and ATPases by its antioxidant potential. Therefore, fisetin with its properties could be used as a potential therapeutic agent in overcoming the symptoms associated with autism.

Graphical Abstract