Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Atherosclerosis. 2010 Nov;213(1):52-8. doi: 10.1016/j.atherosclerosis.2010.07.027. Epub 2010 Jul 27.
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.
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.
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.
多奈哌齐是一种可逆的乙酰胆碱酯酶抑制剂，可改善阿尔茨海默病患者的认知功能。有报道称，刺激胆碱能系统可改善慢性心力衰竭大鼠的长期生存率，并减轻脂多糖诱导的脓毒症小鼠的炎症反应。我们试图确定多奈哌齐对胆碱能系统的药理学刺激是否可减少载脂蛋白（Apo）E 敲除（KO）小鼠的动脉粥样硬化形成。
雄性 ApoE-KO 小鼠（10 周龄）给予高脂肪饮食，并输注血管紧张素（Ang）II（490ng/kg/天）。多奈哌齐或毒扁豆碱治疗 4 周。多奈哌齐（5mg/kg/天）口服或毒扁豆碱（2mg/kg/天）输注可显著减轻动脉粥样硬化形成（油红 O 阳性面积），而心率、血压和总胆固醇水平无明显变化。多奈哌齐可抑制单核细胞趋化蛋白-1和肿瘤坏死因子-α的表达、NADPH 氧化酶活性和主动脉中活性氧的产生。
本研究揭示了多奈哌齐对胆碱能系统的药理学刺激的新型抗氧化和抗动脉粥样硬化作用。多奈哌齐可作为治疗动脉粥样硬化性心血管疾病的新疗法。
