Journal Article

Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia

Tsai, Ching-Yen, Chua, Sarah, Yang, Jenq-Lin, Yen, Chia-Hung, Chang, Hsueh-Wen, Chen, Yung-Lung, Sun, Cheuk-Kwan, Yip, Hon-Kan, Sheu, Jiunn-Jye, Lin, Kun-Chen, Tsai, Tzu-Hsien, Leu, Steve

2012

Overview

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

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Angiogenesis / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Blotting, Western / Colleges & universities / Combination strategies / Comparative analysis / Critical limb ischemia / Drug therapy / Drug Therapy, Combination / Extremities - blood supply / Flow Cytometry / Hospitals / Immunohistochemistry / Inflammation / Interleukins / Ischemia / Ischemia - prevention & control / Male / Medical research / Medicine, Experimental / Medicine/Public Health / Mortality / Oxidative Stress / Pharmacomodulation / Rats / Rats, Sprague-Dawley / Real-Time Polymerase Chain Reaction / RNA / Rodents / Tetrazoles - administration & dosage / Tetrazoles - therapeutic use / Ticlopidine - administration & dosage / Ticlopidine - analogs & derivatives / Ticlopidine - therapeutic use