Novel Role of Peroxisome Proliferator Activated Receptor-Α in Valproic Acid Rat Model of Autism: Mechanistic Study of Risperidone and Metformin Monotherapy Versus Combination.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology exhibiting a chal-lenge in understanding its exact neuro-pathophysiology. Recently, peroxisome proliferator activated receptor (PPAR)-alpha activation was found to play a fundamental role in neuroprotection and improving autistic-like-behaviors in experimental animal models of ASD through alleviating neuroinflammation, oxidative-stress, astrocyte reactivity, tauopathy in addition to its favorable role in metabolic regulation, thus attracting atten-tion as a possible target in treatment of ASD.This study aimed to investigate the role of PPAR-alpha, astrocytic dysfunction and tauopathy in ASD and detect the possible neuroprotective effects of metformin (MET), through PPAR-alpha activation, and risperidone (RIS) either monotherapy or in combination in alleviating autistic-like-changes at behavioral and neurobiological levels in male Wistar rats.Pregnant female Wistar rats received valproic-acid (VPA) to induce autistic-like-behavioral and neurobio-logical alterations in their offspring. Chronic intra-peritoneal MET (100 mg/kg/day) and RIS (1 mg/kg/day) either monotherapy or in combination started from postnatal day (PND) 24 till PND61 (38 days). Prenatal VPA exposure simulated the autistic core behaviors associated with neurochemical and histopatho-logical neurodevelopmental degenerative changes. Both MET and RIS either monotherapy or in combination were able to reverse these changes. The effect of MET was comparable to RIS. Moreover, MET was able to alleviate the RIS induced weight gain and improve cognitive functions highlighting its promising adjunctive role in alleviating ASD pathophysiology.Our study highlighted the favorable effects of MET and RIS both in monotherapy and in combination in alleviating the autistic-like-changes and proposed PPAR-alpha activation along with restoring astrocytes homeostasis as promising targets in novel therapeutic strategies in ASD.