الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Background: Autism spectrum disorder (ASD) is characterized by impaired communication, deficits in social interaction, restricted interests and stereotyped behavior. ASD is a multi-factorial disorder that results from interaction between genetic and environmental factors. Moreover, prenatal exposure to valproic acid (VPA) contributes to the increased risk of ASD. Risperidone and aripiprazole are the only FDA approved antipsychotics for the treatment of ASD associated irritability. Risperidone is approved in children more than 5 years old, while aripiprazole is approved for children at least 6 years old. Autophagy is a process in which intracellular components and dysfunctional organelles are transported to the lysosome for degradation and recycling. The role of metformin is mainly linked to activation of adenosine monophosphate protein kinase (AMPK). So, metformin can enhance autophagy. The aim of the work: To evaluate the possible effect of postnatal risperidone and metformin administration on treatment of ASD, in an experimental model of prenatal valproic acid-induced autism in rats. Additionally, we aimed to assess autophagy process in ASD model and the outcome of metformin (autophagy enhancer) on the disease characteristics.
Materials and Methods: VPA-induced autistic model was obtained by a single intraperitoneal (i.p.) injection of VPA (500 mg/kg) dissolved in 0.9 saline at E12.5. Pregnant female rats were allowed to continue pregnancy and male offspring were either left untreated (8 rats) or treated with risperidone (0.5 mg/kg PO once /day),or metformin (200 mg/kg PO once /day) starting from P 21 to P 51 (8 rats each).Development of ASD was assessed by behavioral tests, histo-pathological examination of Nissl granules in the hippocampi and Real Time Polymerase Chain Reaction (RT-PCR) for detection of changes in LC3 mRNA gene expression in rat hippocampi to assess the autophagy process. Results: postnatal metformin treatment improved social impairments and restored normal behavior, reduced repetitive behaviors in VPA-autistic rats and significantly decreased the time spent in dark by VPA-autistic rats. Additionally, after metformin treatment the anxiety levels of rats tended to be lower. enhanced autophagy marker (LC3 mRNA gene expression) and greatly improved the histopathological abnormalities in the rat hippocampi. Conclusion: metformin effectively ameliorates the core symptoms and abnormal histopathology of ASD through induction of autophagy.