Melatonin modulates the differentiation of neural stem cells exposed to manganese via SIRT1/β-catenin signaling.

Excessive exposure of children to manganese (Mn) in the environment has a bearing on developmental neurotoxicity. Although melatonin (Mel) can play a neuroprotective role by modulating the differentiation of neural stem cells (NSCs) in the developing brain, its specific mechanism under Mn overexposure remains to be explored. Here, we cultured primary NSCs as an available model to investigate the relevant molecular mechanism of Mel mitigation on Mn-induced disorder of NSCs differentiation through sirtuin 1 (SIRT1)/β-catenin pathway. It was found that Mel could facilitate the differentiation of Mn-treated NSCs into neurons. Further, our results uncovered that the pro-differentiation mechanism of Mel depended upon ascending the activity of SIRT1, thereby weakening β-catenin acetylation and increasing phosphorylation of β-catenin ser675 in the cytoplasm, which facilitates the nuclear translocation of β-catenin. Furthermore, the role of SIRT1 in Mel-mediated signal transduction was investigated through the pretreatment of NSCs using a highly specific SIRT1 inhibitor, EX527. After EX527 pretreatment, Mel could not maintain its protective effect. Overall, our results revealed that Mel could alleviate Mn-induced disorder of NSCs differentiation through the activation of the SIRT1/β-catenin pathway.