Wu Dong, Du Jingyi, Zhao Tiantian, Li Naigang, Qiao Xinghui, Peng Fan, Wang Dongshuang, Shi Jiaming, Zhang Shu, Diao Can, Wang Liyan, Zhou Wenjuan, Hao Aijun
Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Mental Disorders and Intelligent Control, Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
CNS Neurosci Ther. 2025 Mar;31(3):e70347. doi: 10.1111/cns.70347.
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.
This study aims to investigate the protective effects and mechanisms of melatonin on neurodevelopmental and behavioral abnormalities in offspring induced by prenatal stress.
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.
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.
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.
产前应激（PNS）是影响后代终身健康的重要风险因素，已被广泛认为与神经发育障碍和精神疾病患病率的增加密切相关。然而，减轻其有害影响的有效药物干预措施仍然有限。褪黑素（Mel）作为一种内源性激素，由于其抗炎、抗氧化和神经保护特性，以及良好的安全性和广泛的临床适用性，在治疗神经系统疾病方面已显示出相当大的潜力。
本研究旨在探讨褪黑素对产前应激诱导的后代神经发育和行为异常的保护作用及机制。
使用产前应激小鼠模型，我们评估了褪黑素对后代情绪和认知缺陷的影响。评估神经发生和突触发育，并进行RNA测序以分析小胶质细胞基因富集和免疫相关途径。进行体内和体外实验以验证这些发现，重点关注小胶质细胞中的PI3K/AKT/NF-κB信号通路。
给予褪黑素可减轻暴露于产前应激的后代小鼠的情绪和认知缺陷，解决神经发生和突触发育异常问题。此外，RNA测序显示褪黑素抑制小胶质细胞基因富集和免疫相关途径的上调。体内和体外验证均表明，褪黑素调节小胶质细胞中的PI3K/AKT/NF-κB信号通路，降低齿状回中CXCL10的升高表达，从而恢复正常的神经支持功能并优化神经发育环境。
这些发现表明，褪黑素通过抑制病理性小胶质细胞激活并促进海马神经发生和突触可塑性，显著改善产前应激引起的神经发育障碍和行为异常。这为褪黑素作为治疗产前应激相关疾病的神经保护剂的潜力提供了新的见解。
