Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia

• Main Authors: Sheu Jiunn-Jye, Lin Kun-Chen, Tsai Ching-Yen, Tsai Tzu-Hsien, Leu Steve, Yen Chia-Hung, Chen Yung-Lung, Chang Hsueh-Wen, Sun Cheuk-Kwan, Chua Sarah, Yang Jenq-Lin, Yip Hon-Kan
• Format: Article
• Language: English
• Published: BMC 2012-08-01
• Series: Journal of Translational Medicine
• Subjects: Critical limb ischemia; Apoptosis; Inflammation; Pharmacomodulation; Angiogenesis
• Online Access: http://www.translational-medicine.com/content/10/1/164

<p>Abstract</p> <p>Background and aim</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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). Anti-inflammatory 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).</p> <p>Conclusion</p> <p>Combined cilostazol-clopidogrel therapy is superior to either agent alone in improving ischemia in rodent CLI.</p>