Microglia signaling as a target of donepezil

被引:101
作者
Hwang, Jaegyu [1 ]
Hwang, Heehong [1 ]
Lee, Ho-Won [2 ]
Suk, Kyoungho [1 ]
机构
[1] Kyungpook Natl Univ, Sch Med, Dept Pharmacol, Brain Sci & Engn Inst,CMRI, Taegu 700422, South Korea
[2] Kyungpook Natl Univ, Sch Med, Dept Neurol, Brain Sci & Engn Inst,CMRI, Taegu, South Korea
关键词
Donepezil; Microglia; Neuroinflammation; Neuroprotection; Acetylcholine; NICOTINIC ACETYLCHOLINE-RECEPTOR; ALZHEIMERS-DISEASE; INFLAMMATORY RESPONSE; CHOLINERGIC SYSTEM; NITRIC-OXIDE; NEUROPROTECTION; ACTIVATION; CELLS; INHIBITOR; CYTOKINES;
D O I
10.1016/j.neuropharm.2010.02.003
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Donepezil is a reversible and noncompetitive cholinesterase inhibitor. The drug is considered as a first-line treatment in patients with mild to moderate Alzheimer's disease. Recently, anti-inflammatory and neuroprotective effects of the drug have been reported. "Cholinergic anti-inflammation pathway" has major implications in these effects. Here, we present evidence that donepezil at 5-20 mu M directly acts on microglial cells to inhibit their inflammatory activation. Our conclusion is based on the measurement of nitric oxide and proinflammatory mediators using purified microglia cultures and microglia cell lines: donepezil attenuated microglial production of nitric oxide and tumor necrosis factor (TNF)-alpha, and suppressed the gene expression of inducible nitric oxide synthase, interleukin-1 beta, and TNF-alpha. Subsequent studies showed that donepezil inhibited a canonical inflammatory NF-kappa B signaling. Microglia/neuroblastoma coculture and animal experiments supported the anti-inflammatory effects of donepezil. Based on the studies using nicotinic acetylcholine receptor antagonists, the donepezil inhibition of microglial activation was independent of acetylcholine and its receptor. Thus, inflammatory activation signaling of microglia may be one of the direct targets of donepezil in the central nervous system. It should be noted, however, that there is a large gap between the therapeutic dose of the drug used clinically and the concentration of the drug that exerts the direct action on microglial cells. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1122 / 1129
页数:8
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