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상위피인용논문

조회477

김효근Hyo Geun Kim

경희대학교

Neurotoxicology., 2014 Jan;40:23-32 | https://doi.org/10.1016/j.neuro.2013.10.004 Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo

Hyo Geun Kim^{a 1}, Minho Moon ^{b 1 2}, Jin Gyu Choi ^a, Gunhyuk Park ^c, Ae-Jung Kim ^d, Jinyoung Hur ^{e 3}, Kyung-Tae Lee ^c, Myung Sook Oh ^{a c *}

^aDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
^bDepartment of Pharmacology, School of Medicine, Kyung Hee University, 26 Kyungheedae ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
^cDepartment 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
^dThe Graduate School of Alternative Medicine, Kyunggi University, 71 Chungjeong-ro-2-ga, Seodaemun-gu, Seoul 120-837, Republic of Korea
^eDepartment of Brain Korea 21 Project Center, School of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea

¹These authors contributed equally to this work.
²Present address: Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, MA 02478, United States.
³Present address: Division of Metabolism and Functionality Research, Korea Food Research Institute, Seongnam-si, Gyeonggi-do, Republic of Korea.

^*Corresponding author: correspondence to Myung Sook Oh

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.

논문정보

형식Research article
게재일2014년 01월 (BRIC 등록일 2023-08-24)
연구진국내 연구진
분야 의약학 > 약학
피인용횟수120회 이상 인용된 논문

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