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

Donepezil regulates 1-Methyl-4-phenylpyridinium-induced microglial polarization in Parkinson’s Disease
Donepezil regulates 1-Methyl-4-phenylpyridinium-induced microglial polarization in Parkinson’s Disease
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+.
1948-7193
1708-1714
Chen, Teng
85bd8bf1-284e-4fc5-ab58-c8de35ea0eaa
Hou, Ruihua
470bdcbc-93a9-4dad-aac5-26d455c34376
Xu, Shujun
da49fbd1-bddd-48b5-a020-5211c9fe5a58
Wu, Chengyuan
dcd472ae-e574-43e8-aa5f-b9ae66d85766
Chen, Teng
85bd8bf1-284e-4fc5-ab58-c8de35ea0eaa
Hou, Ruihua
470bdcbc-93a9-4dad-aac5-26d455c34376
Xu, Shujun
da49fbd1-bddd-48b5-a020-5211c9fe5a58
Wu, Chengyuan
dcd472ae-e574-43e8-aa5f-b9ae66d85766

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)

Record type: Article

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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More information

e-pub ahead of print date: 26 June 2015
Published date: 21 October 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 402659
URI: http://eprints.soton.ac.uk/id/eprint/402659
ISSN: 1948-7193
PURE UUID: ac22fe5a-a4e2-485d-92a8-e746bdaeb9af
ORCID for Ruihua Hou: ORCID iD orcid.org/0000-0001-6127-1478

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Date deposited: 14 Nov 2016 12:30
Last modified: 15 Mar 2024 03:28

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Contributors

Author: Teng Chen
Author: Ruihua Hou ORCID iD
Author: Shujun Xu
Author: Chengyuan Wu

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