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

Abstract

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.

Keywords: Manganese; Microglia; Neuroinflammation; Sesamol; cGAS-STING pathway.