Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo.

Article Details

Citation

Copy to clipboard

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 Jan;40:23-32. doi: 10.1016/j.neuro.2013.10.004. Epub 2013 Nov 1.

PubMed ID

24189446 [ View in PubMed

]

Abstract

Recent studies on Alzheimer's disease (AD) have focused on soluble oligomeric forms of amyloid-beta (Abeta oligomer, AbetaO) 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 AbetaO in cultured microglial cells and the brain in animals. Further, the effects of donepezil against AbetaO-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 AbetaO and its neuroinflammatory mechanisms. Donepezil significantly attenuated the release of inflammatory mediators (prostaglandin E2, interleukin-1 beta, tumor necrosis factor-alpha, and nitric oxide) from microglia. Donepezil also decreased AbetaO-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 AbetaO-injected mice, donepezil significantly inhibited microgliosis and astrogliosis. Furthermore, behavioral tests revealed that donepezil (2 mg/kg/day, 5 days, p.o.) significantly ameliorated AbetaO-induced memory impairment. These results suggest that donepezil directly inhibits microglial activation induced by AbetaO through blocking MAPK and NF-kappaB signaling and, in part, contributing to the amelioration of neurodegeneration and memory impairment.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Donepezil	Nuclear factor NF-kappa-B (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details