期刊
NEUROPHARMACOLOGY
卷 95, 期 -, 页码 29-36出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2015.02.020
关键词
Alzheimer's disease; Donepezil; Amyloid-beta; Oligomer; Mitochondrial dysfunction
资金
- National Natural Science Foundation of China [81173034, 81072646]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China [2012ZX09301001-004]
- Ministry of Science and Technology of China [2011CB510004]
The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-beta (A beta)-associated mitochondrial dysfunction, in order to gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease (AD) drug. First, our study verifies the ameliorative effects of donepezil on behavioral deficits in both working memory and anxiety in APP/PS1 double transgenic mice, at a time point that AChE is not inhibited. Meanwhile, we demonstrate that donepezil enhances the resistance of brain mitochondria of APP/PS1 mice to the induction of rnitochondrial permeability transition (MPT) by calcium ions. Moreover, the level of mitochondrial A beta in the brain of donepezil-treated APP/PS1 transgenic mice is significantly lower than that of vehicle-treated APP/PS1 mice. Our in vitro study using isolated mitochondria from rat brains, which is expected as an AChE-free subcellular system, further confirms the ameliorative effects of donepezil on oligomeric AP(1-42) induced mitochondrial swelling and ATP reduction. In addition, donepezil treatment also significantly blocks the A beta accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against A beta-associated mitochondrial dysfunction are closely associated with the reduction of A beta accumulation in the mitochondria. Above observation led us to assume that, besides potent AChE inhibitory effect, other non-cholinergic mechanisms may be involved in the neuroprotective profiles of donepezil. (C) 2015 Elsevier Ltd. All rights reserved.
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