Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia
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RESEARCH
Open Access
Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia Jiunn-Jye Sheu1, Kun-Chen Lin2, Ching-Yen Tsai3, Tzu-Hsien Tsai4, Steve Leu5, Chia-Hung Yen6, Yung-Lung Chen4, Hsueh-Wen Chang7, Cheuk-Kwan Sun8, Sarah Chua4, Jenq-Lin Yang5 and Hon-Kan Yip4,9*
Abstract Background and aim: Procedural failure and untoward clinical outcomes after surgery remain problematic in critical limb ischemia (CLI) patients. This study tested a clopidogrel-cilostazol combination treatment compared with either treatment alone in attenuating CLI and improving CLI-region blood flow in rats. Methods: Male Sprague–Dawley rats (n = 40) were equally divided into five groups: control, CLI induction only, CL I + cilostazol (12.0 mg/day/kg), CLI + clopidogrel (8.0 mg/kg/day) and CLI + combined cilostazol-clopidogrel. After treatment for 21 days, Laser Doppler imaging was performed. Results: On day 21, the untreated CLI group had the lowest ratio of ischemic/normal blood flow (p < 0.001). Inflammation measured by VCAM-1 protein expression; oxidative stress; PAI-1, MMP-9 and TNF-α mRNA expressions; and immunofluorescence staining (IF) of CD68+ cells was lower with combined treatment than with the other treatments, and lower in the two single-treatment groups than the untreated CLI group (all p < 0.01). Antiinflammatory mRNA expression of interleukin-10, and eNOS showed a reverse pattern among these groups. Apoptosis measured by Bax, caspase-3 and PARP; and muscle damage measured by cytosolic cytochrome-C, and serum and muscle micro-RNA-206 were all lowest with combination treatment, and the two single-treatment groups showed lower values than the untreated group (all p < 0.001). Angiogenesis measured by eNOS, IF staining of CD31+ and vWF + cells; and number of vessels in CLI region were highest with combination treatment and higher in the single-treatment groups than the untreated group (all p < 0.001). Conclusion: Combined cilostazol-clopidogrel therapy is superior to either agent alone in improving ischemia in rodent CLI. Keywords: Critical limb ischemia, Apoptosis, Inflammation, Pharmacomodulation, Angiogenesis
Background Some of the most important risk factors for atherosclerosis are hypercholesterolemia, hypertension, and diabetes mellitus. Peripheral arterial disease (PAD) is characterized by atherosclerotic occlusion of the lower extremities and is a common manifestation of systemic atherosclerosis [1]. Patients with PAD have approximately the same relative risk of death from cardiovascular causes as those * Correspondence: [email protected] 4 Division of Cardiology, Department of Internal Medicine; Chang Gung Memorial Hospital- Kaohsiung Medical Center, Chang Gung University College of Medicine, Gueishan, Taiwan 9 Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung 123, Ta Pei Road, Niao Sung Dist, Kaohsiung City 83301, Taiwan Full list of author information is available at the end of the article
with a history of coronary or cerebrovascular dis
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