Novel role of peroxisome proliferator activated receptor-α in valproic acid rat model of autism: Mechanistic study of risperidone and metformin monotherapy versus combination.

Scientists studied autism-like behaviors in rats by giving pregnant mothers valproic acid. They then treated the baby rats with two medications - metformin and risperidone - either alone or together. Both treatments helped reduce autism-like behaviors and brain changes. Metformin worked as well as risperidone and helped prevent weight gain that risperidone can cause. The study suggests these medications might work by activating specific brain pathways.

This animal study investigated the role of PPAR-α activation in autism using a valproic acid rat model. Researchers examined the effects of metformin and risperidone, both individually and in combination, on autistic-like behaviors and neurobiological changes. The study found that prenatal valproic acid exposure induced autistic core behaviors and neurodevelopmental changes in offspring. Both metformin and risperidone treatments were able to reverse these changes, with metformin showing comparable effects to risperidone.

Notably, metformin helped alleviate risperidone-induced weight gain and improved cognitive functions. The research suggests PPAR-α activation and astrocyte homeostasis restoration as potential therapeutic targets for autism spectrum disorder.

Results suggest potential for metformin as monotherapy or adjunctive treatment in autism, particularly for managing risperidone-related weight gain. PPAR-α pathway represents a novel therapeutic target. Human clinical trials needed to validate these animal model findings.

Animal model study using rats; sample size not reported; unclear methodology details; limited generalizability to human autism; short-term treatment duration; single autism model used.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology exhibiting a challenge in understanding its exact neuro-pathophysiology. Recently, peroxisome proliferator activated receptor (PPAR)-α 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 attention as a possible target in treatment of ASD. This study aimed to investigate the role of PPAR-α, astrocytic dysfunction and tauopathy in ASD and detect the possible neuroprotective effects of metformin (MET), through PPAR-α 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 neurobiological 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 histopathological 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-α activation along with restoring astrocytes homeostasis as promising targets in novel therapeutic strategies in ASD.