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Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia
BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer’s disease (AD) is related to the inflammatory responses mediated by mi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741946/ https://www.ncbi.nlm.nih.gov/pubmed/29273047 http://dx.doi.org/10.1186/s12974-017-1033-0 |
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author | Haraguchi, Yoshinori Mizoguchi, Yoshito Ohgidani, Masahiro Imamura, Yoshiomi Murakawa-Hirachi, Toru Nabeta, Hiromi Tateishi, Hiroshi Kato, Takahiro A. Monji, Akira |
author_facet | Haraguchi, Yoshinori Mizoguchi, Yoshito Ohgidani, Masahiro Imamura, Yoshiomi Murakawa-Hirachi, Toru Nabeta, Hiromi Tateishi, Hiroshi Kato, Takahiro A. Monji, Akira |
author_sort | Haraguchi, Yoshinori |
collection | PubMed |
description | BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer’s disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca(2+) signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca(2+) signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca(2+) mobilization in microglial cells. METHODS: We examined whether pretreatment with donepezil affects the intracellular Ca(2+) mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. RESULTS: In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca(2+) elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca(2+) elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca(2+) elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca(2+) elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. CONCLUSIONS: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-017-1033-0) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5741946 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57419462018-01-03 Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia Haraguchi, Yoshinori Mizoguchi, Yoshito Ohgidani, Masahiro Imamura, Yoshiomi Murakawa-Hirachi, Toru Nabeta, Hiromi Tateishi, Hiroshi Kato, Takahiro A. Monji, Akira J Neuroinflammation Research BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer’s disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca(2+) signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca(2+) signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca(2+) mobilization in microglial cells. METHODS: We examined whether pretreatment with donepezil affects the intracellular Ca(2+) mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. RESULTS: In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca(2+) elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca(2+) elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca(2+) elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca(2+) elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. CONCLUSIONS: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-017-1033-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-22 /pmc/articles/PMC5741946/ /pubmed/29273047 http://dx.doi.org/10.1186/s12974-017-1033-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Haraguchi, Yoshinori Mizoguchi, Yoshito Ohgidani, Masahiro Imamura, Yoshiomi Murakawa-Hirachi, Toru Nabeta, Hiromi Tateishi, Hiroshi Kato, Takahiro A. Monji, Akira Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia |
title | Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia |
title_full | Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia |
title_fullStr | Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia |
title_full_unstemmed | Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia |
title_short | Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia |
title_sort | donepezil suppresses intracellular ca(2+) mobilization through the pi3k pathway in rodent microglia |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741946/ https://www.ncbi.nlm.nih.gov/pubmed/29273047 http://dx.doi.org/10.1186/s12974-017-1033-0 |
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