Donepezil Can Improve Ischemic Muscle Atrophy by Activating Angiomyogenic Properties of Satellite Cells

Background: Saving more limbs of patients with peripheral arterial disease (PAD) from amputation by accelerating angiogenesis in affected limbs has been anticipated for years. We hypothesized that an anti-Alzheimer drug, donepezil (DPZ), can activate angiomyogenic properties of satellite cells, myogenic progenitors, and thus be an additional pharmacological therapy against PAD. Methods and Results: In a murine hindlimb ischemia model, we investigated the angiogenic effects of a clinical dose of DPZ (0.2mg kg(-1) day(-1)) and its combination with cilostazol, a platelet aggregation inhibitor and a conventional therapeutic drug against PAD. The combination therapy most effectively improved skin coldness and most effectively upregulated vascular endothelial growth factor (VEGF)-producing satellite cells in ischemic hindlimbs. Computed tomography revealed that DPZ remarkably attenuated ischemic muscle atrophy and induced super-restoration in affected hindlimbs. The in vitro study with human aortic endothelial cells showed that DPZ or its combination with cilostazol effectively upregulated the expression of pAkt, hypoxia inducible factor-1 alpha, and VEGF protein. Likewise, in primary cultured satellite cells, DPZ, alone or in combination, upregulated the expression of VEGF, interleukin-1 beta, and fibroblast growth factor 2 protein. Conclusions: The present results suggest that a clinical dosage of DPZ accelerates angiomyogenesis by directly acting on both endothelial and satellite cells. Therefore, DPZ is a potential additional choice for conventional drug therapy against PAD.