Mechanism of arsenic regulation of mitochondrial damage and autophagy induced synaptic damage through SIRT1 and protective effect of melatonin in HT22 cell

Arsenic (As), a widespread environmental pollutant, can induce severe neurological damage worldwide; however, the underlying mechanisms remain unclear. Sirtuin 1 (SIRT1) has been reported to exert neuroprotective effects against various neurological diseases by resisting mitochondrial damage and autophagy through deacetylation. In this study, we established a model of HT22 cells exposed to NaAsO₂ and examined the levels of mitochondrial, autophagy, and synaptic damage in HT22 cells and HT22 cells with high expression of SIRT1 (pre-treated with the agonist SRT1720) 24 h after exposure. Our results suggest that NaAsO₂ exposure induces down-regulation of SIRT1, causing mitochondrial damage and activation of autophagy, which in turn leads to synaptic damage. Notably, melatonin (Mel) intervention upregulated SIRT1 and attenuated mitochondrial damage and autophagy, restoring synaptic damage. In conclusion, the results of the present study indicate that As causes neurotoxicity by decreasing SIRT1 production, causing mitochondrial damage and activating autophagy, which provides fundamental data for further study of arsenic neurotoxicity. In addition, blocking this pathway attenuated the synaptic damage of arsenic exposure, which provides a new therapeutic avenue for arsenic neurotoxicity.