Neuroprotective effect of PPAR gamma agonist in rat model of autism spectrum disorder: Role of Wnt/β-catenin pathway.

Background: The clinical manifestation of autism spectrum disorder (ASD) is linked to the disruption of fundamental neurodevelopmental pathways. Emerging evidences claim to have an upregulation of canonical Wnt/β-catenin pathway while downregulation of PPARγ pathway in ASD. This study aims to investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in rat model of ASD. The study further explores the possible role of PPARγ and Wnt/β-catenin pathway and their interaction in ASD by using their modulators.

Material And Methods: Pregnant female Wistar rats received 600 mg/kg of valproic acid (VPA) to induce autistic symptoms in pups. Pioglitazone (10 mg/kg) was used to evaluate neurobehaviors, relative mRNA expression of inflammatory (IL-1β, IL-6, IL-10, TNF-α), apoptotic markers (Bcl-2, Bax, & Caspase-3) and histopathology (H&E, Nissl stain, Immunohistochemistry). Effect of pioglitazone was evaluated on Wnt pathway and 4 μg/kg dose of 6-BIO (Wnt modulator) was used to study the PPARγ pathway.

Results: ASD model was established in pups as indicated by core autistic symptoms, increased neuroinflammation, apoptosis and histopathological neurodegeneration in cerebellum, hippocampus and amygdala. Pioglitazone significantly attenuated these alterations in VPA-exposed rats. The expression study results indicated an increase in key transcription factor, β-catenin in VPA-rats suggesting an upregulation of canonical Wnt pathway in them. Pioglitazone significantly downregulated the Wnt signaling by suppressing the expression of Wnt signaling-associated proteins. The inhibiting effect of Wnt pathway on PPARγ activity was indicated by downregulation of PPARγ-associated protein in VPA-exposed rats and those administered with 6-BIO.

Conclusion: In the present study, upregulation of canonical Wnt/β-catenin pathway was demonstrated in ASD rat model. Pioglitazone administration significantly ameliorated these symptoms potentially through its neuroprotective effect and its ability to downregulate the Wnt/β-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.