Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice.
OBJECTIVE
Donepezil, a reversible acetylcholinesterase inhibitor, improves cognitive function of Alzheimer's disease. Stimulation of cholinergic system was reported to improve long-term survival of rats with chronic heart failure and to attenuate inflammatory response in mice with lipopolysaccharide-induced sepsis. We sought to determine whether the pharmacological stimulation of cholinergic system by donepezil reduces atherogenesis in apolipoprotein (Apo) E-knockout (KO) mice.


RESULTS
Male ApoE-KO mice (10-week-old) were fed a high-fat diet and received infusion of angiotensin (Ang) II (490 ng/kg/day). Donepezil or physostigmine was administered for 4 weeks. Oral administration of donepezil (5 mg/kg/day) or infusion of physostigmine (2 mg/kg/day) significantly attenuated atherogenesis (Oil Red O-positive area) without significant changes in heart rate, blood pressure and total cholesterol levels. Administration of donepezil suppressed expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α, NADPH oxidase activity and production of reactive oxygen species in the aorta.


CONCLUSIONS
The present study revealed novel anti-oxidative and anti-atherosclerotic effects of pharmacological stimulation of cholinergic system by donepezil. Donepezil may be used as a novel therapeutics for the atherosclerotic cardiovascular diseases.
Inanaga
Keita
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Ichiki
Toshihiro
T
Miyazaki
Ryohei
R
Takeda
Kotaro
K
Hashimoto
Toru
T
Matsuura
Hirohide
H
Sunagawa
Kenji
K
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000201:enzymology*; D002318:Cardiovascular Diseases; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D000077265:Donepezil; D007189:Indans / Q000494:pharmacology; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010880:Piperidines / Q000494:pharmacology; D018805:Sepsis
D001057:Apolipoproteins E; D002800:Cholinesterase Inhibitors; D016207:Cytokines; D007189:Indans; D008070:Lipopolysaccharides; D010880:Piperidines; D000077265:Donepezil