title: Donepezil Regulates 1-Methyl-4-phenylpyridinium-Induced Microglial Polarization in Parkinson's Disease.
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-1β, or tumor necrosis factor (TNF)-α. 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-β2 (TGF-β2) 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+.
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University , Ji'nan 250012, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Chen
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton , Southampton SO14 3DT, U.K.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Hou
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University , Ji'nan 250012, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University , Ji'nan 250012, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Wu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D016764:Cell Polarity / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D006540:Herbicides; D007189:Indans; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D018697:Nootropic Agents; D010880:Piperidines; D012333:RNA, Messenger; C413576:Retnla protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D000077265:Donepezil; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases; C544448:Arg1 protein, mouse; D001119:Arginase; D015655:1-Methyl-4-phenylpyridinium
keywords: Donepezil; MPP+; STAT6; arginase-1 (Arg-1); microglia M2 polarization