Guggulsterone Mediated JAK/STAT and PPAR-Gamma Modulation Prevents Neurobehavioral and Neurochemical Abnormalities in Propionic Acid-Induced Experimental Model of Autism.

Rishabh Khera,Sumit Kumar,Satya Sai Sadhu,Sonalika Bhalla,Abdulrahman Alshammari,Sidharth Mehan,Metab Alharbi

doi:10.3390/molecules27030889

Abstract

Autism spectrum disorder is a neurodevelopmental disorder marked by repetitive behaviour, challenges in verbal and non-verbal communication, poor socio-emotional health, and cognitive impairment. An increased level of signal transducer and activator of transcription 3 (STAT3) and a decreased level of peroxisome proliferator-activated receptor (PPAR) gamma have been linked to autism pathogenesis. Guggulsterone (GST) has a neuroprotective effect on autistic conditions by modulating these signalling pathways. Consequently, the primary objective of this study was to examine potential neuroprotective properties of GST by modulating JAK/STAT and PPAR-gamma levels in intracerebroventricular propionic acid (ICV PPA) induced experimental model of autism in adult rats. In this study, the first 11 days of ICV-PPA injections in rats resulted in autism-like behavioural, neurochemical, morphological, and histopathological changes. The above modifications were also observed in various biological samples, including brain homogenate, CSF, and blood plasma. GST was also observed to improve autism-like behavioural impairments in autistic rats treated with PPA, including locomotion, neuromuscular coordination, depression-like behaviour, spatial memory, cognition, and body weight. Prolonged GST treatment also restored neurochemical deficits in a dose-dependent manner. Chronic PPA administration increased STAT3 and decreased PPAR gamma in autistic rat brain, CSF, and blood plasma samples, which were reversed by GST. GST also restored the gross and histopathological alterations in PPA-treated rat brains. Our results indicate the neuroprotective effects of GST in preventing autism-related behavioural and neurochemical alterations.

Highlights

The current work sought to investigate the protective effect of signal transducer and activator of transcription 3 (STAT3) and peroxisome proliferator-activated receptor (PPAR) gamma modulator GST on restoring behavioural and neurochemical abnormalities in autistic rats treated with propionic acid
This study strongly suggested that GST had neuroprotective effects in autistic rats treated with propionic acid
Based on our histological findings, we may conclude that the degeneration of numerous neuronal cells in the cerebral cortex region of the rat brain determines the significant neuropathological abnormalities in autism

Summary

Introduction

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by persistent social difficulties and restricted and repetitive behavioural patterns [1]. ASD is a spectrum disorder because it manifests differently in each patient. These issues frequently appear in early childhood and tend to hinder functioning in various circumstances [2]. According to the Centers for Disease Control and Prevention, one out of every 54 children is affected by this increasingly widespread condition [3]. Early-onset autism symptoms begin immediately after birth, while regressive autism symptoms start around the age of two and progress slows down [4]

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