Abstract
BACKGROUND: Prenatal stress (PNS) is a significant risk factor impacting the lifelong health of offspring, and it has been widely recognized as being closely linked to the increased prevalence of neurodevelopmental disorders and psychiatric illnesses. However, effective pharmacological interventions to mitigate its detrimental effects remain limited. Melatonin (Mel), an endogenous hormone, has demonstrated considerable potential in treating neurological diseases due to its anti-inflammatory, antioxidant, and neuroprotective properties, as well as its favorable safety profile and broad clinical applicability. OBJECTIVE: This study aims to investigate the protective effects and mechanisms of melatonin on neurodevelopmental and behavioral abnormalities in offspring induced by prenatal stress. METHODS: Using a prenatal stress mouse model, we evaluated the effects of melatonin on emotional and cognitive deficits in offspring. Neurogenesis and synaptic development were assessed, and RNA sequencing was performed to analyze microglial gene enrichment and immune-related pathways. Both in vivo and in vitro experiments were conducted to validate the findings, focusing on the PI3K/AKT/NF-κB signaling pathway in microglia. RESULTS: Melatonin administration alleviated emotional and cognitive deficits in offspring mice exposed to prenatal stress, addressing abnormalities in neurogenesis and synaptic development. Additionally, RNA sequencing revealed that melatonin suppresses microglial gene enrichment and the upregulation of immune-related pathways. Both in vivo and in vitro validation indicated that melatonin modulates the PI3K/AKT/NF-κB signaling pathway in microglia, reducing the elevated expression of CXCL10 in the dentate gyrus, thereby restoring normal neuro-supportive functions and optimizing the neurodevelopmental environment. CONCLUSION: These findings suggest that melatonin significantly improves neurodevelopmental disorders and behavioral abnormalities caused by prenatal stress by inhibiting pathological microglial activation and promoting hippocampal neurogenesis and synaptic plasticity. This provides new insights into melatonin's potential as a neuroprotective agent for treating prenatal stress-related disorders.