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Published on: January 22, 2017
Resveratrol Attenuated Manganese-Induced Learning and Memory Impairments in Mice Through PGC-1Alpha-Mediated
Jing Lang1, Liang Gao1, Jie Wu1
1School of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, China.
Abstract:
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.
Insights
Resveratrol (RSV) protects against manganese (Mn)-induced cognitive deficits by enhancing microglial M2 polarization and autophagy, partly through PGC-1α signaling. This study reveals a novel neuroprotective mechanism for RSV against heavy metal neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese (Mn) overexposure causes cognitive deficits, with microglial and autophagic dysfunction implicated in its neurotoxicity.
- Resveratrol (RSV) is known for neuroprotective effects, but its role in mitigating Mn-induced cognitive impairment is unexamined.
Purpose of the Study:
- To investigate the neuroprotective effects of RSV against Mn-induced cognitive dysfunction.
- To explore RSV's impact on PGC-1α expression, microglial polarization, and autophagy in the context of Mn neurotoxicity.
Main Methods:
- Mice were treated with saline, MnCl2, RSV, or MnCl2 + RSV.
- In vitro studies used BV2 cells with PGC-1α knockdown via LV-PGC-1α shRNA.
- Evaluated cognitive function, inflammatory cytokines, microglial polarization (M1/M2), autophagy markers (ULK1, LC3-II, p62), PGC-1α, BDNF, and NF-κB signaling.
Main Results:
- RSV treatment improved cognitive function, reduced inflammation, promoted M2 microglial polarization, and enhanced autophagy in Mn-exposed mice.
- Mn exposure decreased PGC-1α, ULK1, and BDNF expression while activating NF-κB; RSV reversed these changes.
- Knockdown of PGC-1α abolished RSV's beneficial effects on M2 polarization and autophagy in vitro.
Conclusions:
- Resveratrol exerts neuroprotective effects against Mn-induced learning and memory impairment.
- These effects are mediated, in part, by PGC-1α-dependent regulation of microglial M1/M2 polarization and autophagy.
- RSV offers a potential therapeutic strategy for Mn neurotoxicity.
