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Acetylcholinesterase inhibitors attenuate angiogenesis
Ryohei Miyazaki1, Toshihiro Ichiki, Toru Hashimoto
1Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Clinical Science (London, England : 1979)
|February 29, 2012
Summary
Donepezil, an Alzheimer's drug, was found to suppress blood vessel formation (angiogenesis) in a mouse model of hindlimb ischemia. This effect is linked to reduced interleukin-1β and vascular endothelial growth factor expression, suggesting potential anti-angiogenic therapy applications.
Area of Science:
- Pharmacology
- Vascular Biology
- Molecular Medicine
Background:
- Donepezil is an acetylcholinesterase inhibitor used for Alzheimer's disease.
- Donepezil reduces inflammatory cytokine production in peripheral blood mononuclear cells.
- Muscle-derived inflammatory cytokines are crucial for neovascularization in hindlimb ischemia models.
Purpose of the Study:
- To investigate the effect of donepezil on angiogenesis in a hindlimb ischemia model.
- To elucidate the molecular mechanisms underlying donepezil's impact on neovascularization.
Main Methods:
- A hindlimb ischemia model was induced by unilateral femoral artery ligation in mice.
- Blood flow recovery was assessed using laser Doppler perfusion imaging.
- Capillary density was evaluated by CD31 staining; cytokine and protein expression analyzed via Western blot and RT-PCR.
Main Results:
- Donepezil and physostigmine significantly decreased blood flow recovery and capillary density in ischemic hindlimbs.
- Donepezil treatment reduced interleukin-1β and vascular endothelial growth factor expression.
- Interleukin-1β administration reversed donepezil's anti-angiogenic effects and VEGF down-regulation.
Conclusions:
- Cholinergic stimulation via acetylcholinesterase inhibitors suppresses angiogenesis.
- This suppression occurs through PI3K-mediated inhibition of IL-1β induction, leading to reduced VEGF expression.
- Acetylcholinesterase inhibitors represent a potential novel anti-angiogenic therapy.
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