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

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Abstract

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.

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Acknowledgements

We are thankful to the Council of Scientific and Industrial Research (CSIR) for providing financial assistance to Ms. Sweety Mehra to carry out the research work. A vote of thanks goes to the Department of Zoology, Panjab University, Chandigarh, where the above-mentioned experimental work was carried out. Special thanks to Dr. Surbhi Kaushal and Dr. Naveed Pervaiz for their constant support during the research work.

Funding

Ms. Sweety Mehra received CSIR Research fellowship to carry out the mentioned work (09/135/2017 (790)-EMR-I).

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  1. Cell and Molecular Biology Lab, Department of Zoology, Panjab University, Chandigarh, 160014, India

    Sweety Mehra, Aitizaz Ul Ahsan, Madhu Sharma, Muskan Budhwar & Mani Chopra

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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Sweety Mehra, Aitizaz Ul Ahsan, Madhu Sharma, Muskan Budhwar, and Mani Chopra. The first draft of the manuscript (along with figures) was prepared by Sweety Mehra, and all the authors commented on all versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Mani Chopra.

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The study was approved by the Institutional Animal Ethics Committee (Approval No: (PU/45/99/CPCSEA/IAEC/2019/271). All experiments were conducted in compliance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA).

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Mehra, S., Ahsan, A.U., Sharma, M. et al. Neuroprotective Efficacy of Fisetin Against VPA-Induced Autistic Neurobehavioral Alterations by Targeting Dysregulated Redox Homeostasis. J Mol Neurosci 73, 403–422 (2023). https://doi.org/10.1007/s12031-023-02127-w

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