The University of Southampton
University of Southampton Institutional Repository

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+.
0002-7863
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. Journal of the American Chemical Society, 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+.

Full text not available from this repository.

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: https://eprints.soton.ac.uk/id/eprint/402659
ISSN: 0002-7863
PURE UUID: ac22fe5a-a4e2-485d-92a8-e746bdaeb9af

Catalogue record

Date deposited: 14 Nov 2016 12:30
Last modified: 15 Jul 2019 19:55

Export record

Altmetrics

Contributors

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

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×