Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia


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. 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. 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). Combined cilostazol-clopidogrel therapy is superior to either agent alone in improving ischemia in rodent CLI.

DOI: 10.1186/1479-5876-10-164

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@inproceedings{Sheu2012CombinationOC, title={Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia}, author={Jiunn-Jye Sheu and Kun-Chen Lin and Ching-Yen Tsai and Tzu-hsien Tsai and Steve Leu and Chia-Hung Yen and Yung-Lung Chen and Hsueh-wen Chang and Cheuk-Kwan Sun and Sarah Chua and Jenq-Lin Yang and Hon-Kan Yip}, booktitle={Journal of Translational Medicine}, year={2012} }