Donepezil Regulates 1-Methyl-4-phenylpyridinium-Induced Microglial Polarization in Parkinson鈥檚 Disease

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• 作者：Teng Chen ; Ruihua Hou ; Shujun Xu ; Chengyuan Wu
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：October 21, 2015
• 年：2015
• 卷：6
• 期：10
• 页码：1708-1714
• 全文大小：357K
• ISSN：1948-7193

文摘

1-Methyl-4-phenylpyridinium (MPP+) induces microglial activation and degeneration of dopaminergic (DAergic) neurons. Donepezil is a well-known acetylcholinesterase inhibitor used clinically to treat cognitive dysfunction in Alzheimer鈥檚 disease (AD). In the present study, we tested the hypothesis that MPP+ promotes microglial M1 polarization and suppresses M2 polarization and that this can be restored by donepezil. Results indicate that MPP+ treatment in microglial BV2 cells promotes microglial polarization toward the M1 state. However, pretreatment with donepezil inhibited MPP+-induced M1 polarization in microglia by suppressing the release of interleukin (IL)-6, IL-1尾, or tumor necrosis factor (TNF)-伪. Importantly, we found that MPP+ inhibited microglial M2 polarization by suppressing expression of Arg-1, Fizz1, and Ym1, which was also rescued by pretreatment with donepezil. In addition, IL-4-mediated induction of anti-inflammatory marker genes IL-10, IL-13, and transforming growth factor-尾2 (TGF-尾2) were significantly attenuated by MPP+ in BV2 cells, which was restored by pretreatment with donepezil in a concentration-dependent manner. Mechanistically, we found that the addition of MPP+ reduced the intensity of phosphorylated signal transducer and activator of transcription 6 (STAT6) but not total STAT6 in IL-4-stimulated BV2 cells. Importantly, pretreatment of microglial BV2 cells with donepezil 3 h prior to administration of MPP+ rescued the reduction of STAT6 phosphorylation induced by MPP+.