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. Inflammatory 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 neurotoxicity.
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 determined. 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-α, 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-κB, concomitantly decreasing IFN-α and IFN-β 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-κB pathway, providing evidence that
sesamol may serve as an effective therapeutic for preventing and treating Mn-induced neurotoxicity.