Resveratrol Attenuated Manganese-Induced Learning and Memory Impairments in Mice Through PGC-1Alpha-Mediated Autophagy and Microglial M1/M2 Polarization

Overexposure to manganese (Mn) can induce cognitive deficits, but the underlying mechanisms are unclear. Microglial dysfunction and autophagic dysfunction have been implicated in Mn neurotoxicity. The neuroprotective effects of resveratrol (RSV) have been studied extensively, but the potential protective effects of RSV against Mn-induced cognitive dysfunction have not been evaluated. We investigated the effects of RSV on Mn-induced changes in PGC-1α, microglial M1/M2 polarization, and autophagy in vivo and in vitro. Kunming mice were treated with saline, MnCl2, RSV, or MnCl2 + RSV. The results showed that RSV improved cognitive dysfunction, suppressed release of inflammatory cytokines, promoted M2 microglial polarization, and increased autophagy in the hippocampi of Mn-treated mice. Furthermore, we also showed that Mn treatment significantly decreased the expression of PGC-1α, ULK1, BDNF, and activated NF-κB signaling. These effects were reversed by RSV pretreatment. In addition, RSV inhibited STAT6 acetylation, but did not affect ULK1 acetylation. Knockdown of PGC-1α using LV-PGC-1α shRNA reversed RSV-induced increases in the expression levels of PGC-1α, ULK1, LC3-II, and mitigated the RSV-induced decrease in the expression level of p62, in Mn-treated BV2 cells. Resveratrol-induced M2 polarization and autophagic flux were abolished by LV-PGC-1α shRNA pretreatment. These results showed that RSV exerted neuroprotective effects against Mn-induced learning and memory impairment partially through PGC-1α-mediated microglial M1/M2 polarization and autophagy.