Effects of Metformin and Risperidone on Autistic Like Behaviors and Brain Neurodegenerative changes in Valproic Acid Rat Model of Autism

Abstract

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology that arise during early childhood, characterized by clinical and behavioral diversity and a varying developmental course that are a common challenge in understanding its exact neuro-pathophysiology. Prenatal VPA exposure is a well-established rat model of autism allowing us to investigate the neurobiology underlying autistic-like changes and illustrate new treatment potentials. Recently, PPAR-α activation was found to play a fundamental role in neuroprotection and improving autistic-like behaviors through alleviating neuroinflammation, oxidative stress, astrocyte reactivity, tauopathy in addition to its favorable role in metabolic regulation, thus attracting attention in the treatment of ASD. Aim: This study aims to investigate the role of PPAR-α, astrocytic dysfunction and tauopathy in ASD and detect the possible neuroprotective effects of MET, through PPAR-α activation, and RIS either monotherapy or in combination in alleviating autistic-like changes at the behavioral and neurobiological levels. Methods: Pregnant female Wistar rats received 600mg/kg VPA on G12.5 to induce autistic-like behavioral and neurobiological alterations in their offspring. Chronic intraperitoneal MET (100mg/kg/day) and RIS (1mg/kg/day) either monotherapy or in combination started directly after weaning till the end of experiment. Results: Prenatal VPA exposure simulated the autistic core behaviors associated with neurochemical and histopathological neurodegenerative changes. Both MET and RIS either monotherapy or in combination were able to reverse these changes, and the effect of MET was comparable to RIS. In addition, MET was able to alleviate the RIS induced weight gain and improving cognitive functions highlighting its promising adjunctive role in alleviating ASD pathophysiology. Conclusion: Our study shed the light on the favorable effects of MET and RIS monotherapy and in combination in alleviating the autistic-like changes and proposed PPAR-α activation along with restoring astrocytes homeostasis as promising targets in novel therapeutic strategies in ASD.