Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia

Authors: Yoshinori Haraguchi, Yoshito Mizoguchi, Masahiro Ohgidani, Yoshiomi Imamura, Toru Murakawa-Hirachi, Hiromi Nabeta, Hiroshi Tateishi, Takahiro A. Kato, Akira Monji

Published in: Journal of Neuroinflammation | Issue 1/2017

Login to get access

Abstract

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 Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells.

Methods

We examined whether pretreatment with donepezil affects the intracellular Ca2+ 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 Ca2+ 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 Ca2+ elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca2+ 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.
Appendix
Available only for authorised users
Literature
1.
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.CrossRefPubMed
2.
Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science. 2013;11:156–61.CrossRef
3.
Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia. 2013;61:71–90.CrossRefPubMed
4.
Monji A, Kato TA, Mizoguchi Y, Horikawa H, Seki Y, Kasai M, Yamauchi Y, Yamada S, Kanba S. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:115–21.CrossRef
5.
Mizoguchi Y, Kato TA, Horikawa H, Monji A. Microglial intracellular Ca(2+) signaling as a target of antipsychotic actions for the treatment of schizophrenia. Front Cell Neurosci. 2014;8:370.CrossRefPubMedPubMedCentral
6.
7.
Mizoguchi Y, Monji A. Microglial intracellular Ca2+ signaling in synaptic development and its alterations in neurodevelopmental disorders. Front Cell Neurosci. 2017;11:69.CrossRefPubMedPubMedCentral
8.
Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. World Alzheimer report: the global impact of dementia (Alzheimer’s Disease International), Alzheimer’s Disease International (ADI), London. 2015.
9.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.CrossRefPubMed
10.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.CrossRefPubMed
11.
12.
13.
Ohgidani M, Kato TA, Sagata N, Hayakawa K, Shimokawa N, Sato-Kasai M, Kanba S. TNF-α from hippocampal microglia induces working memory deficits by acute stress in mice. Brain Behav Immun. 2016;55:17–24.CrossRefPubMed
14.
Decourt B, Lahiri DK, Sabbagh MN. Targeting tumor necrosis factor alpha for Alzheimer’s disease. Curr Alzheimer Res. 2017;14:412–25.CrossRefPubMed
15.
16.
17.
McLarnon JG, Choi HB, Lue LF, Walker DG, Kim SU. Perturbations in calcium-mediated signal transduction in microglia from Alzheimer’s disease patients. J Neurosci Res. 2005;81:426–35.CrossRefPubMed
18.
Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P. Donepezil Nordic study group. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:489–95.CrossRefPubMed
19.
Asomugha CO, Linn DM, Linn CL. ACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs. J Neurochem. 2010;112:214–26.CrossRefPubMed
20.
Guo HB, Cheng YF, Wu JG, Wang CM, Wang HT, Zhang C, Qiu ZK, Xu JP. Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience. 2015;290:530–42.CrossRefPubMed
21.
Hwang J, Hwang H, Lee HW, Suk K. Microglia signaling as a target of donepezil. Neuropharmacology. 2010;58:1122–9.CrossRefPubMed
22.
Kim HG, Moon M, Choi JG, Park G, Kim AJ, Hur J, Lee KT, Oh MS. Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo. Neurotoxicology. 2014;40:23–32.CrossRefPubMed
23.
Kikuchi T, Okamura T, Arai T, Obata T, Fukushi K, Irie T, Shiraishi T. Use of a novel radiometric method to assess the inhibitory effect of donepezil on acetylcholinesterase activity in minimally diluted tissue samples. Br J Pharmacol. 2010;159:1732–42.CrossRefPubMedPubMedCentral
24.
Cheepsunthorn P, Radov L, Menzies S, Reid J, Connor JR. Characterization of a novel brain-derived microglial cell line isolated from neonatal rat brain. Glia. 2011;35:53–62.CrossRef
25.
Mizoguchi Y, Kato TA, Seki Y, Ohgidani M, Sagata N, Horikawa H, Yamauchi Y, Sato-Kasai M, Hayakawa K, Inoue R, Kanba S, Monji A. Brain-derived neurotrophic factor (BDNF) induces sustained intracellular Ca2+ elevation through the up-regulation of surface transient receptor potential 3 (TRPC3) channels in rodent microglia. J Biol Chem. 2014;289:18549–55.CrossRefPubMedPubMedCentral
26.
Mizoguchi Y, Monji A, Kato T, Seki Y, Gotoh L, Horikawa H, Suzuki SO, Iwaki T, Yonaha M, Hashioka S, Kanba S. Brain-derived neurotrophic factor induces sustained elevation of intracellular Ca2+ in rodent microglia. J Immunol. 2009;183:7778–86.CrossRefPubMed
27.
Sato-Kasai M, Kato TA, Ohgidani M, Mizoguchi Y, Sagata N, Inamine S, Horikawa H, Hayakawa K, Shimokawa N, Kyuragi S, Seki Y, Monji A, Kanba S. Aripiprazole inhibits polyI:C-induced microglial activation possibly via TRPM7. Schizophr Res. 2016;178:35–43.CrossRefPubMed
28.
Kato T, Mizoguchi Y, Monji A, Horikawa H, Suzuki SO, Seki Y, Iwaki T, Hashioka S, Kanba S. Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro. J Neurochem. 2008;106:815–25.CrossRefPubMed
29.
Kojima H, Nakatsubo N, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, Hirata Y, Nagano T. Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins. Anal Chem. 1998;70:2446–53.CrossRefPubMed
30.
Patel VH, Brack KE, Coote JH, Ng GA. A novel method of measuring nitric-oxide-dependent fluorescence using 4,5-diaminofluorescein (DAF-2) in the isolated Langendorff-perfused rabbit heart. Pflugers. Archiv. 2008;456:635–45.
31.
Kuno R, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A. Autocrine activation of microglia by tumor necrosis factor-alpha. J Neuroimmunol. 2005;162:89–96.CrossRefPubMed
32.
Veroni C, Gabriele L, Canini I, Castiello L, Coccia E, Remoli ME, Columba-Cabezas S, Aricò E, Aloisi F, Agresti C. Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways. Mol Cell Neurosci. 2010;45:234–44.CrossRefPubMed
33.
Vuong B, Hogan-Cann AD, Alano CC, Stevenson M, Chan WY, Anderson CM, Swanson RA, Kauppinen TM. NF-κB transcriptional activation by TNFα requires phospholipase C, extracellular signal-regulated kinase 2 and poly(ADP-ribose) polymerase-1. J Neuroinflammation. 2015;12:229.CrossRefPubMedPubMedCentral
34.
De Simone R, Ajmone-Cat MA, Carnevale D, Minghetti L. Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammation. 2005;2:4.CrossRefPubMedPubMedCentral
35.
Yu CR, Role LW. Functional contribution of the alpha7 subunit to multiple subtypes of nicotinic receptors in embryonic chick sympathetic neurones. J Physiol. 1998;509:651–65.CrossRefPubMedPubMedCentral
36.
Kato K, Hayako H, Ishihara Y, Marui S, Iwane M, Miyamoto M. TAK-147, an acetylcholinesterase inhibitor, increases choline acetyltransferase activity in cultured rat septal cholinergic neurons. Neurosci Lett. 1999;260:5–8.CrossRefPubMed
37.
Ruscher K, Inácio AR, Valind K, Rowshan Ravan A, Kuric E, Wieloch T. Effects of the sigma-1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydro-chloride on inflammation after stroke. PLoS One. 2012;7:e45118.CrossRefPubMedPubMedCentral
38.
Hall AA, Herrera Y, Ajmo CT Jr, Cuevas J, Pennypacker KR. Sigma receptors suppress multiple aspects of microglial activation. Glia. 2009;57:744–54.CrossRefPubMed
39.
Matsumoto RR, Bowen WD, Tom MA, Vo VN, Truong DD, De Costa BR. Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur J Pharmacol. 1995;280:301–10.CrossRefPubMed
40.
Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H, Akaike A. Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology. 2006;51:474–86.CrossRefPubMed
41.
Dong H, Zhang X, Dai X, Lu S, Gui B, Jin W, Zhang S, Zhang S, Qian Y. Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway. J Neuroinflammation. 2014;11:140.CrossRefPubMedPubMedCentral
42.
Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994;269:5241–8.PubMed
43.
Irino Y, Nakamura Y, Inoue K, Kohsaka S, Ohsawa K. Akt activation is involved in P2Y12 receptor-mediated chemotaxis of microglia. J Neurosci Res. 2008;86:1511–9.CrossRefPubMed
44.
Yule DI, Williams JA. U73122 inhibits Ca2+ oscillations in response to cholecystokinin and carbachol but not to JMV-180 in rat pancreatic acinar cells. J Biol Chem. 1992;267:13830–5.PubMed
45.
Ferreira R, Wong R, Schlichter LC. KCa3.1/IK1 channel regulation by cGMP-dependent protein kinase (PKG) via reactive oxygen species and CaMKII in microglia: an immune modulating feedback system? Front Immunol. 2015;8:153.
46.
Tokumitsu H, Chijiwa T, Hagiwara M, Mizutani A, Terasawa M, Hidaka H. KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1990;265:4315–20.PubMed
47.
Jiang Y, Liu Y, Zhu C, Ma X, Ma L, Zhou L, Huang Q, Cen L, Pi R, Chen X. Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice. Neurobiol Learn Mem. 2015;121:20–9.CrossRefPubMed
48.
Bhat NR, Zhang P, Lee JC, Hogan EL. Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci. 1998;18:1633–41.PubMed
49.
Park JS, Woo MS, Kim SY, Kim WK, Kim HS. Repression of interferon-gamma-induced inducible nitric oxide synthase (iNOS) gene expression in microglia by sodium butyrate is mediated through specific inhibition of ERK signaling pathways. J Neuroimmunol. 2005;168:56–64.CrossRefPubMed
50.
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995;17:27489–94.CrossRef
51.
52.
Kalinchuk AV, McCarley RW, Porkka-Heiskanen T, Basheer R. Sleep deprivation triggers inducible nitric oxide-dependent nitric oxide production in wake-active basal forebrain neurons. J Neurosci. 2010;30:13254–64.CrossRefPubMedPubMedCentral
53.
Moore WM, Webber RK, Jerome GM, Tjoeng FS, Misko TP, Currie MG. L-N6-(1-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J Med Chem. 1994;37:3886–8.CrossRefPubMed
54.
Takada Y, Yonezawa A, Kume T, Katsuki H, Kaneko S, Sugimoto H, Akaike A. Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther. 2003;306:772–7.CrossRefPubMed
55.
Tabet N. Acetylcholinesterase inhibitors for Alzheimer’s disease: anti-inflammatories in acetylcholine clothing. Age Ageing. 2006;35:336–8.CrossRefPubMed
56.
Arikawa M, Kakinuma Y, Noguchi T, Todaka H, Sato T. Donepezil, an acetylcholinesterase inhibitor, attenuates LPS-induced inflammatory response in murine macrophage cell line RAW 264.7 through inhibition of nuclear factor kappa B translocation. Eur J Pharmacol. 2016;789:17–26.CrossRefPubMed
57.
Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A. alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem. 2001;276:13541–6.CrossRefPubMed
58.
Takata K, Kitamura Y, Saeki M, Terada M, Kagitani S, Kitamura R, Fujikawa Y, Maelicke A, Tomimoto H, Taniguchi T, Shimohama S. Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem. 2010;285:40180–91.CrossRefPubMedPubMedCentral
59.
Katayama T, Kobayashi H, Okamura T, Yamasaki-Katayama Y, Kibayashi T, Kimura H, Ohsawa K, Kohsaka S, Minami M. Accumulating microglia phagocytose injured neurons in hippocampal slice cultures: involvement of p38 MAP kinase. PLoS One. 2012;7:e40813.CrossRefPubMedPubMedCentral
60.
61.
Vodovotz Y, Lucia MS, Flanders KC, Chesler L, Xie QW, Smith TW, Weidner J, Mumford R, Webber R, Nathan C, Roberts AB, Lippa CF, Sporn MB. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med. 1996;184:1425–33.CrossRefPubMed
62.
Nathan C, Calingasan N, Nezezon J, Ding A, Lucia MS, La Perle K, Fuortes M, Lin M, Ehrt S, Kwon NS, Chen J, Vodovotz Y, Kipiani K, Beal MF. Protection from Alzheimer’s-like disease in the mouse by genetic ablation of inducible nitric oxide synthase. J Exp Med. 2005;202:1163–9.CrossRefPubMedPubMedCentral
63.
Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, König S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron. 2011;71:833–44.CrossRefPubMed
64.
Schott JM, Revesz T. Inflammation in Alzheimer’s disease: insights from immunotherapy. Brain. 2013;136:2654–6.CrossRefPubMed
65.
Streit WJ, Xue QS, Tischer J, Bechmann I. Microglial pathology. Acta Neuropathol Commun. 2014;26:142.CrossRef
Metadata
Title
Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia
Authors
Yoshinori Haraguchi
Yoshito Mizoguchi
Masahiro Ohgidani
Yoshiomi Imamura
Toru Murakawa-Hirachi
Hiromi Nabeta
Hiroshi Tateishi
Takahiro A. Kato
Akira Monji
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1033-0

Other articles of this Issue 1/2017

Journal of Neuroinflammation 1/2017 Go to the issue

Research

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis

Research

Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function

Research

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Research

Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress

Research

Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes

Research

microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells