![]() | Only 14 pages are availabe for public view |
Abstract Cisplatin (CP) a highly effective anti-neoplastic agent, CP therapy is limited by severe side-effects in normal tissues (Brock et al., 2012). CP accumulates in the kidney, contributing to CP nephrotoxicity and hence restricts its clinical utilization (sultana et al., 2012). Renal injury by CP has been associated with oxidative stress, inflammation, and apoptosis (Kiymaz et al., 2008). In the present study, a quantitative evaluation of CP-induced structural and functional alterations in the kidneys was performed by histopathological and biochemical analyses in order to determine the potential beneficial effects of sildenafil and / or gemfibrozil either separately or in combination on CP induced nephrotoxicity either before cisplatin treatment as a prophylactic measure or after CP treatment as a therapeutic measure. In this study, 72 adult male albino rats were divided into 9 equal groups (G) of rats, 8 rats for each group; G1: treated with saline (control), G2A: vehicle before CP (5 mg⁄kg, intraperitoneally, i.p.); G2B: vehicle after CP, for detecting spontaneous recovery, died at day 5 after CP; G3, G4, G5 received sildenafil, gemfibrozil and both 14 days before cisplatin, respectively; G6, G7, G8 received sildenafil, gemfibrozil and both for 14 days after cisplatin, respectively. At day 17, the end of the experimental period, Creatinine (Cr) and urea were measured. All animals were sacrificed and kidney was taken for histopathology. Another piece of kidney tissue was taken to measure heme oxygenase activity, reduced glutathione, Quantitative RT-PCR for gene expression of tumor necrosis factor alpha (TNF-α) and endothelial nitric oxide synthase (ENOS) level in kidney tissues. Cisplatin group (G2A) developed AKI with significantly high urea and creatinine. Histopathological examination showed severe diffuse (80- 90%) tubular necrosis in G2A. while the best result was shown in G8 which received post-cisplatin combination therapy (< 10% tubular necrosis) while G5 which received pre-cisplatin combination therapy showed mild degree of tubular necrosis (10-20%). Other groups showed moderate degree of tubular necrosis (20-40%). TNF-α was highly and significantly elevated in G2A compared to control group and other groups while remaining measured parameters were significantly reduced in G2A. All tissue markers did not significantly differ between G1 and G8. There was a significant positive correlation between Cr and TNF-α while there were significant negative correlation between Cr and other tissue markers in G1 and G2 and also we got same result of correlation when G2 and G8 were done. Linear regression analysis demonstrated that heme oxygenase was the independent predictor of AKI demonstrated by elevated Cr among G1 and G2A (P =0.002). Improved tissue heme oxygenase was also the independent predictor of improvement of Cr among G2A and G8. This current work adds gemfibrozil and sildenafil to the growing list of pharmaceutical agents tested in cisplatin nephrotoxicity. |