Novel potential benefit of metformin on valproic acid-induced autism spectrum disorder in rats

[Speaker] Olufunmilayo O Adeyemi:1
[Co-author] Aishat O Balogun:1, Ismail O Ishola:1
1:Department of Pharmacology, Therapeutics and Toxicology, College of Medicine University of Lagos, Nigeria

Autism is a lifelong neurodevelopmental disorder characterized by impairments in social interaction and repetitive patterns of behaviour. Prenatal exposure to valproic acid (VPA) has been shown to increase the risk of autism in children. In this study, we examined the effect of metformin on VPA-induced autism spectrum disorders in rats. Pregnant albino rats administered VPA (500 mg/kg, i.p.) or normal saline (10 ml/kg, i.p.; vehicle-control) on gestational day 12.5. The pups were given metformin (5, 50 or 500 mg/kg, p.o.) or vehicle (10 ml/kg, p.o.) daily from postnatal day 21 to 50. Social behaviour, spatial learning/ reference memory, repetitive behaviour and anxiety were assessed using the three-chamber social assay, Morris water maze, Y- maze and elevated plus maze (EPM), respectively. Postnatal day 50, the animals were sacrificed and brains removed for biochemical assay. Pretreatment of rats pups with VPA caused a reduction in sociability index (P< 0.001, 0.21± 0.03) when compared to the control animals (3.56± 0.36) which was dose dependently and significantly ameliorated by metformin. Moreover, VPA reduced social preference evidenced in significant increase in time spent in the familiar chamber and reduction in time spent in the novel chamber compared to the control animals in the three-chamber social behaviour apparatus. Metformin administration caused dose dependent increase in time spent in novel chamber suggestive of improvement in social behaviour. In the Morris water maze task, VPA caused deficit in spatial learning ability which was dose dependently ameliorated by metformin evidenced in significant reduction of escape latency time and increase in time spent at quadrant location indicative of improvement in spatial learning and reference memory, respectively. Prenatal VPA increased repetitive (Y-maze) and anxiety (EPM) behaviours which were significantly attenuated by metformin treatment. VPA-induced increase in malondialdehyde level and deficit in antioxidant enzymes activities as well as increase in acetylcholinesterase activity in the hippocampus and prefrontal cortex were attenuated by metformin treatment.
Findings from this study showed that post natal administration of metformin prevented valproic acid-induced autistic behaviour. Hence, metformin could be a potential drug in the management of autism spectrum disorders

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