Evaluation of Beta cateninwnt signaling axis inrodent model of autism by assessing blood brain barrier integrity implications and therapeutic targeting by fisetin

Abstract

Autism is a neurodevelopmental disorder and its pathophysiology has been extensively intertwined with impaired behavioural habits, mitochondrial dysfunction, BBB disruption, and various other mechanisms. Altered canonical Wnt signaling is one of the primary mechanisms that can contribute to the pathophysiology of autism. This study aimed to investigate the role of canonical Wnt signaling in the development of autism-associated symptoms and its therapeutic targeting by bioflavonoid fisetin in prenatal VPA model of autism. For this, dams were subjected to valproic acid sodium salt (VPA) at the time of neural tube closure i.e., gestational day 12.5 (GD 12.5) to induce autism in F1 generation. Fisetin was administered in two treatment regimens i.e., gestational (GD 13 till delivery) and post-weaning fisetin (PND 23-32). Our observations confirmed that developmental VPA exposure increased reactive oxygen species, dysregulated mitochondria functioning and generated oxidative stress in the cerebrum and cerebellum. This ROS-induced mitochondrial damage dysregulated the canonical Wnt signaling which further instigated the blood-brain barrier (BBB) disruption, apoptosis, and neuronal damage in the prenatal VPA model of autism. These mechanisms blended and resulted in developmental delays and behavioural impairments which are the defining characteristics of autism. Gestational and post-weaning fisetin treatments effectively attenuated the elevated ROS, mitochondrial damage, and over-activated Wnt signaling. Regulation of the mitochondrial directed-Wnt signaling axis restored the BBB permeability and improved neurodevelopmental impairments resulting in relieving autism-like behaviour. Collectively, our findings revealed that fisetin evoked modulation of the mitochondria-Wnt signaling cascade successfully relieved the associated symptoms of autism in the prenatal VPA model of autism and could be used as a potential bioceutical against autism. newline