title: Donepezil can improve ischemic muscle atrophy by activating angiomyogenic properties of satellite cells.
abstract: 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 (0.2 mg·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-1α, and VEGF protein. Likewise, in primary cultured satellite cells, DPZ, alone or in combination, upregulated the expression of VEGF, interleukin-1β, 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.
authors: Department of Cardiovascular Control, Kochi Medical School.
authors: Tatsuya
authors: T
authors: Noguchi
authors: Yoshihiko
authors: Y
authors: Kakinuma
authors: Mikihiko
authors: M
authors: Arikawa
authors: Kayo
authors: K
authors: Okazaki
authors: Eri
authors: E
authors: Hoshino
authors: Tatsuo
authors: T
authors: Iiyama
authors: Toru
authors: T
authors: Kubo
authors: Hiroaki
authors: H
authors: Kitaoka
authors: Yoshinori
authors: Y
authors: Doi
authors: Takayuki
authors: T
authors: Sato
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000077265:Donepezil; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D024510:Muscle Development / Q000187:drug effects*; D009133:Muscular Atrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C508585:IL1B protein, human; C587672:IL1B protein, mouse; D007189:Indans; D053583:Interleukin-1beta; D018697:Nootropic Agents; D010880:Piperidines; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; D000077265:Donepezil