Zileuton alleviates acute cisplatin nephrotoxicity: Inhibition of lipoxygenase pathway favorably modulates the renal oxidative/inflammatory/caspase-3 axis.

摘要: Abstract Objective The current study investigated for the first time possible beneficial effect of zileuton, a selective 5-lipoxygenase inhibitor (5-LOX), against cisplatin-induced acute renal failure. Methodology Male Sprague-Dawley rats (180–200 g) were administered cisplatin once (5 mg/kg, i.p.) alone or combined with oral zileuton (10 mg/kg, given twice; 1 h before and 12 h after cisplatin). Results Compared control rats, administration caused significant increases BUN (33.76 ± 7.74 vs 61.88 ± 11.35 mg/dl), serum creatinine (0.61 ± 0.21 1.56 ± 0.28 mg/dl), levels MDA (6.40 ± 1.04 20.52 ± 2.18 nmol/g tissue), NOx (3.45 ± 1.20 17.70 ± 2.27 nmol/g TNF-α (6.71 ± 0.66 23.71 ± 3.41 pg/g MPO (0.87 ± 0.09 3.12 ± 0.41 U/mg tissue protein) caspase-3 activity (2.81 ± 0.37 12.70 ± 2.94 U/mg protein). Whereas, total SOD (1.99 ± 0.53 0.79 ± 0.06 U/mg IL-10 (110.98 ± 19.70 62.34 ± 14.42 pg/g tissue) significantly decreased. Cisplatin-induced nephrotoxicity was further confirmed histopathologically (tubular necrosis, cystic dilatation tubules, vacuolar degeneration tubular epithelium perivascular oedema, interstitial fibrosis). These changes accompanied by alteration in 5-LOX pathway manifested as elevated 5-LOX, LTD4 LTB4. Simultaneous to cisplatin-treated reversed deleterious insults restored measured parameters near values. Conclusions data establish experimental evidence that abrogates probably via inhibition detrimental actions products, thus favorably affecting oxidative/inflammatory/caspase-3 axis. Based on findings, therapeutic prospect this purpose is recommended.