Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice.

Abstract

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.

METHODS AND 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.

CONCLUSION:

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.

• Authors: Keita Inanaga, Toshihiro Ichiki, Ryohei Miyazaki, Kotaro Takeda, Toru Hashimoto, Hirohide Matsuura, Kenji Sunagawa
• Journal: Atherosclerosis (Atherosclerosis) Vol. 213 Issue 1 Pg. 52-8 (Nov 2010) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 20723895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apolipoproteins E
• Cholinesterase Inhibitors
• Cytokines
• Indans
• Lipopolysaccharides
• Piperidines
• Donepezil

Topics

• Alzheimer Disease (drug therapy)
• Animals
• Apolipoproteins E (genetics)
• Atherosclerosis (enzymology)
• Cardiovascular Diseases
• Cholinesterase Inhibitors (pharmacology)
• Cytokines (metabolism)
• Donepezil
• Indans (pharmacology)
• Inflammation
• Lipopolysaccharides (metabolism)
• Male
• Mice
• Mice, Knockout
• Oxidative Stress
• Piperidines (pharmacology)
• Sepsis