Sesamol alleviates manganese-induced neuroinflammation and cognitive impairment via regulating the microglial cGAS-STING/NF-zB pathway

Toxic effects of excessive manganese (Mn) from occupational or environmental exposure cause harm to human health. Excessive Mn exposure is intimately associated with neurodegeneration and cognitive dysfunction. In-flammatory responses mediated by microglia are essential contributors to the pathogenesis of Mn-induced neurotoxicity. Inhibition of microglia-mediated inflammation has been shown to alleviate Mn-induced neuro-toxicity. Sesamol, derived from sesame, has neuroprotective properties in various disease models, including neurological diseases. Whether sesamol protects against Mn-induced neurological injuries has not been deter-mined. Here, both in vivo and in vitro Mn exposure models were established to address the beneficial effects of sesamol on Mn-induced neurotoxicity. We showed that administration of sesamol mitigated learning and memory deficits of mice treated by Mn. Furthermore, sesamol reduced Mn-induced microglial activation and the expression of proinflammatory mediators (TNF-alpha, iNOS, and Cxcl10), while exerting a marginal effect on anti-inflammation and microglial phagocytosis. Mn exposure activated the microglial cGAS-STING pathway and sesamol inhibited this pathway by reducing the phosphorylation of STING and NF-zB, concomitantly decreasing IFN-alpha and IFN-beta synthesis. In summary, our novel results indicated that sesamol exerted its protective effects on Mn-induced neuroinflammation and cognitive impairment via the microglial cGAS-STING/NF-zB pathway, providing evidence that sesamol may serve as an effective therapeutic for preventing and treating Mn-induced neurotoxicity.