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: Teng Chen, Ruihua Hou, Shujun Xu, Chengyuan Wu
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 6 Issue 10 Pg. 1708-14 (Oct 21 2015) ISSN: 1948-7193 [Electronic] United States
• PMID: 26114860 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Herbicides
• Indans
• Intercellular Signaling Peptides and Proteins
• Lectins
• Nootropic Agents
• Piperidines
• RNA, Messenger
• Retnla protein, mouse
• STAT6 Transcription Factor
• Stat6 protein, mouse
• Donepezil
• Chil3 protein, mouse
• beta-N-Acetylhexosaminidases
• Arg1 protein, mouse
• Arginase
• 1-Methyl-4-phenylpyridinium

Topics

• 1-Methyl-4-phenylpyridinium (pharmacology)
• Analysis of Variance
• Animals
• Arginase (genetics, metabolism)
• Cell Line, Transformed
• Cell Polarity (drug effects)
• Cell Survival (drug effects)
• Cytokines (genetics, metabolism)
• Donepezil
• Dose-Response Relationship, Drug
• Herbicides (pharmacology)
• Indans (pharmacology)
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Lectins (genetics, metabolism)
• Macrophages (drug effects)
• Mice
• Microglia (drug effects)
• Nootropic Agents (pharmacology)
• Piperidines (pharmacology)
• RNA, Messenger (metabolism)
• STAT6 Transcription Factor (metabolism)
• beta-N-Acetylhexosaminidases (genetics, metabolism)