Abstract 819: Donepezil, an Acetylcholiesterase inhibitor Against Alzheimer’s Dementia, Promotes Angiogenesis in an Ischemic Limb Model of Nicotinic α7 ΚO Mice
Introduction: Previous studies demonstrated that chronic administration of donepezil, an acetylcholinesterase (ChE) inhibitor against Alzheimer’s Dementia, improved the survival and cardiac function of rats with chronic heart failure comparably with chronic vagal nerve stimulation. These results suggest that intervention for the cholinergic system in hearts plays a beneficial role in cardioprotection. However, its precise mechanism remains elucidated.
Hypothesis: We assessed the hypothesis that donepezil possesses angiogenic promoting potency.
Methods: Initially, we evaluated a signaling pathway of donepezil and the angiogenic properties. In vitro study, by using donepezil-treated human umbilical vein endothelial cells (HUVECs), signals responsible for angiogenesis were evaluated. The effects on tube formation cultured on Matrigel were also studied. To evaluate in vivo angiogenic effects, fluorescent angiography and thermography were utilized in a murine ischemic hindlimb model including nicotinic α7 receptor deleted mice (α7KO), another model with impaired angiogenesis. Immunohistochemical and molecular analyses were also conducted. They were treated with donepezil for 4 weeks, after the left femoral artery ligation in the wild type mice (WT) or α7KO.
Results: Compared to the untreated WT (n=10), donepezil-treated WT (n=10) exhibited rich capillaries and recovery of perfusion in the ischemic hindlimbs. Ischemic muscle atrophy in the affected limb was significantly prevented by donepezil. Such a beneficial effect was associated with enhanced VEGF immunoreactivities in the affected limb. Surprisingly, even in α7KO, donepezil (5mg/kg/day n = 10, 83μg/kg/day n = 14 ) exerted its beneficial effect. Donepezil comparably promotes angiogenesis between WT and α7KO in terms of angiogenesis, perfusion, and biochemical markers in ischemic limb. In HUVECs, donepezil directly upregulated angiogenic proteins such as HIF-1α, VEGF and phosphorylated Flk-1, and significantly accelerated tube formation of HUVECs (p<0.05, n=8), suggesting that donepezil modulated non-central cholinergic system in HUVECs promote angiogenesis.
Conclusion: The present results suggest that donepezil is a potential candidate for a new angiogenic drug.