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

Recent studies on Alzheimer's disease (AD) have focused on soluble oligomeric forms of amyloid-beta (A beta oligomer, A beta O) 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 A beta O in cultured microglial cells and the brain in animals. Further, the effects of donepezil against A beta O-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 A beta O and its neuroinflammatory mechanisms. Donepezil significantly attenuated the release of inflammatory mediators (prostaglandin E-2, interleukin-1 beta, tumor necrosis factor-alpha, and nitric oxide) from microglia. Donepezil also decreased A beta O-induced upregulation 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 A beta O-injected mice, donepezil significantly inhibited microgliosis and astrogliosis. Furthermore, behavioral tests revealed that donepezil (2 mg/kg/day, 5 days, p.o.) significantly ameliorated A beta O-induced memory impairment. These results suggest that donepezil directly inhibits microglial activation induced by A beta O through blocking MAPK and NF-kappa B signaling and, in part, contributing to the amelioration of neurodegeneration and memory impairment. (C) 2013 Elsevier Inc. All rights reserved.