The comparative effectiveness of metformin and risperidone in a rat model of valproic acid-induced autism, Potential role for enhanced autophagy.

Researchers tested two medications - metformin (a diabetes drug) and risperidone (an autism-approved medication) - in rats with autism-like behaviors. Both medications helped reduce anxiety, social problems, and repetitive behaviors. The study found that these medications work by improving a brain cleaning process called autophagy in the hippocampus (memory center). Metformin was more effective at improving this brain cleaning process than risperidone, which may explain why it worked better overall.

This preclinical study compared metformin and risperidone effectiveness in treating autism-like behaviors in rats exposed to valproic acid during pregnancy. Both medications successfully reduced anxiety, social impairment, and stereotyped behaviors in the rat model. The research identified suppressed hippocampal autophagy (cellular cleanup process) as a potential mechanism underlying autism-like behaviors. Metformin showed superior effectiveness in enhancing autophagy markers (increased LC3B expression, reduced P62 accumulation) compared to risperidone, which correlated with better behavioral outcomes and neuronal survival.

This suggests that metformin's therapeutic effects may be mediated through its autophagy-enhancing properties, providing new insights into potential mechanisms of action for autism interventions.

While promising, this preclinical research requires human studies before clinical application. The findings suggest autophagy enhancement as a potential therapeutic target and support investigating metformin's role in autism treatment, complementing existing risperidone therapy.

This is a preclinical animal study using a VPA-induced autism model, which may not fully represent human autism. Sample size not reported. Results require validation in human studies before clinical translation.

Risperidone is the first antipsychotic to be approved by Food and Drug Administration (FDA) for treating autism spectrum disorder (ASD). The potential efficacy of metformin in preventing and/or controlling ASD behavioral deficits was also recently reported. Suppression of hippocampus autophagy was suggested as a potential pathologic mechanism in ASD. Is metformin's ability to improve ASD clinical phenotype driven by its autophagy-enhancing properties?

And does hippocampus autophagy enhancement underlie risperidone's efficacy as well? Both questions are yet to be answered. The effectiveness of metformin on alleviation of ASD-like behavioral deficits in adolescent rats exposed prenatally to valproic acid (VPA) was compared to that of risperidone. The potential modulatory effects of risperidone on hippocampal autophagic activity were also assessed and compared to those of metformin.

Male offspring exposed to VPA during gestation exhibited marked anxiety, social impairment and aggravation of stereotyped grooming; such deficits were efficiently rescued by postnatal risperidone or metformin therapy. This autistic phenotype was associated with suppressed hippocampal autophagy; as evidenced by reduced gene/dendritic protein expression of LC3B (microtubule-associated proteins 1 light chain 3B) and increased somatic P62 (Sequestosome 1) protein aggregates. Interestingly, compared to risperidone, the effectiveness of metformin in controlling ASD symptoms and improving hippocampal neuronal survival was well correlated to its ability to markedly induce pyramidal neuronal LC3B expression while lowering P62 accumulation. Our work highlights, for the first time, positive modulation of hippocampus autophagy as potential mechanism underlying improvements in autistic behaviors, observed with metformin, as well as risperidone, therapy.