Abstract 5322: Donepezil, an Acetylcholinesterase Inhibitor, Attenuates Atherogenesis in Apolipoprotein E Knockout Mice Through Antioxidative and Anti-inflammatory Effects

Abstract

Objective Donepezil, a reversible acetylcholinesterase inhibitor, improves cognitive function of Alzheimer’s disease. Vagus nerve stimulation is known to attenuate inflammatory responses in mice with lipopolysaccharide-induced sepsis, which is designated cholinergic anti-inflammatory system. We investigated whether the pharmacological stimulation of cholinergic system by donepezil affects atherogenesis in apolipoprotein (Apo) E-knockout (KO) mice. Methods and Results Male ApoE-KO mice (10-week-old) were fed a high fat diet (HFD) and received infusion of angiotensin (Ang) II (1.9 mg/kg/day). Oral administration of donepezil (5 mg/kg/day) or infusion of physostigmine (2mg/kg/day), another acetylcholinesterase inhibitor, for 4 weeks did not change hemodynamics or cholesterol level, but significantly reduced Oil Red O-positive area of en face aorta (Control 3.8±0.4%, AngII + HFD 13.6±2.2%, AngII + HFD and donepezil 6.9±0.9%*, AngII + HFD and physostigmine 8.2±0.6%*, *P<0.05 vs AngII + HFD) and macrophage infiltration into the aortic root (p<0.05). Donepezil also decreased monocyte chemoattractant protein (MCP)-1-positive area by 45% (p<0.05) in the aortic sinus. Donepezil administration also attenuated atherogenesis in ApoE-KO mice fed a HFD for 8 weeks without AngII infusion. Quantitative RT-PCR revealed that administration of donepezil to ApoE-KO mice treated with AngII and a HFD significantly suppressed expression of MCP-1 and tumor necrosis factor-alpha 52% and 70% reduction, respectively, P<0.05) in the aorta. Donepezil significantly suppressed NADPH oxidase activity (43% reduction, P<0.05) and production of reactive oxygen species in the aorta. Preincubation with acetylcholine completely inhibited AngII-induced NADPH oxidase 1 expression in cultured vascular smooth muscle cells (P<0.05). Conclusion The present study revealed a novel anti-atherosclerotic effect of pharmacological stimulation of cholinergic system by donepezil. Donepezil may increase acetylcholine availability and downregulate NADPH oxidase followed by suppression of inflammatory cytokine production and atherogenesis. Cholinergic stimulation may be a novel therapeutic strategy for atherosclerotic cardiovascular diseases.