Early-Life Melatonin Supplementation Reduces the Long-Term Behavioral, Morphological, and Molecular Alterations in a Rat Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by significant challenges in social interactions and repetitive behaviors. Its prevalence is high, with males affected at a rate four times higher than females. Among various comorbidities associated with ASD, sleep disorders and abnormal melatonin levels have emerged as critical areas of concern. Melatonin, a potent endogenous hormone, plays essential roles as a circadian regulator, anti-inflammatory, and antioxidant agent through the release of pro- and anti-inflammatory cytokines and stimulation of endogenous antioxidant enzymes. This study sets out to examine the effects of melatonin administration during gestation and lactation on ASD-related behaviors, focusing on sex-specific differences in a well-established ASD model. Pregnant rats received an intraperitoneal injection of valproic acid (VPA) or saline at gestational day 12.5 (E12.5) and were treated with melatonin or vehicle from E13 until weaning. Our results indicated that chronic melatonin supplementation effectively reversed behavioral, circadian, and morphological abnormalities in male offspring. In females, melatonin prevented the inflammatory responses induced by VPA. Furthermore, chronic melatonin treatment restored the altered profile of serum melatonin observed in VPA animals and also restored the circadian expression of enzymes critical for its synthesis. These findings highlight sex-specific alterations prevalent in this model and strongly suggest that melatonin represents a promising therapeutic approach for mitigating ASD-related behaviors in the VPA model, warranting further investigation to assess its clinical relevance.