title: Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo.
abstract: Recent studies on Alzheimer's disease (AD) have focused on soluble oligomeric forms of amyloid-beta (Aβ oligomer, AβO) that are directly associated with AD-related pathologies, such as cognitive decline, neurodegeneration, and neuroinflammation. Donepezil is a well-known anti-dementia agent that increases acetylcholine levels through inhibition of acetylcholinesterase. However, a growing body of experimental and clinical studies indicates that donepezil may also provide neuroprotective and disease-modifying effects in AD. Additionally, donepezil has recently been demonstrated to have anti-inflammatory effects against lipopolysaccharides and tau pathology. However, it remains unknown whether donepezil has anti-inflammatory effects against AβO in cultured microglial cells and the brain in animals. Further, the effects of donepezil against AβO-mediated neuronal death, astrogliosis, and memory impairment have also not yet been investigated. Thus, in the present study, we examined the anti-inflammatory effect of donepezil against AβO and its neuroinflammatory mechanisms. Donepezil significantly attenuated the release of inflammatory mediators (prostaglandin E2, interleukin-1 beta, tumor necrosis factor-α, and nitric oxide) from microglia. Donepezil also decreased AβO-induced up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 protein and phosphorylation of p38 mitogen-activated protein kinase as well as translocation of nuclear factor-kappa B. We next showed that donepezil suppresses activated microglia-mediated toxicity in primary hippocampal cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In intrahippocampal AβO-injected mice, donepezil significantly inhibited microgliosis and astrogliosis. Furthermore, behavioral tests revealed that donepezil (2 mg/kg/day, 5 days, p.o.) significantly ameliorated AβO-induced memory impairment. These results suggest that donepezil directly inhibits microglial activation induced by AβO through blocking MAPK and NF-κB signaling and, in part, contributing to the amelioration of neurodegeneration and memory impairment.
authors.affiliation: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Hyo Geun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Jin Gyu
authors.initials: JG
authors.lastname: Choi
authors.affiliation: Department of Life and Nanopharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Gunhyuk
authors.initials: G
authors.lastname: Park
authors.affiliation: The Graduate School of Alternative Medicine, Kyunggi University, 71 Chungjeong-ro-2-ga, Seodaemun-gu, Seoul 120-837, Republic of Korea.
authors.forename: Ae-Jung
authors.initials: AJ
authors.lastname: Kim
authors.affiliation: Department of Brain Korea 21 Project Center, School of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Life and Nanopharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea; Department of Life and Nanopharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: msohok@khu.ac.kr.
authors.forename: Myung Sook
authors.initials: MS
authors.lastname: Oh
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000077265:Donepezil; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D007189:Indans; D018836:Inflammation Mediators; D010880:Piperidines; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D000077265:Donepezil; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Alzheimer's disaese; Amyloid-beta oligomer; Donepezil; Inflammation; Microglia