الفهرس 
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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.