Donepezil regulates 1-Methyl-4-phenylpyridinium-induced microglial polarization in Parkinson’s Disease

Chen, Teng, Hou, Ruihua, Xu, Shujun and Wu, Chengyuan (2015) Donepezil regulates 1-Methyl-4-phenylpyridinium-induced microglial polarization in Parkinson’s Disease. ACS Chemical Neuroscience, 6 (10), 1708-1714. (doi:10.1021/acschemneuro.5b00026). (PMID:26114860)

Abstract

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’s 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?, or tumor necrosis factor (TNF)-?. 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-?2 (TGF-?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+.

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Contributors

Author: Ruihua Hou

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