Zileuton Alleviates Acute Cisplatin Nephrotoxicity: Inhibition of Lipoxygenase Pathway Favorably Modulates the Renal Oxidative/inflammatory/caspase-3 Axis.

Objective: The current study investigated for the first time the 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 with control rats, acute cisplatin administration caused significant increases of BUN (33.76 +/- 7.74 vs 61.88 +/- 11.35 mg/di), serum creatinine (0.61 +/- 0.21 vs 1.56 +/- 0.28 mg/dl), renal levels of MDA (6.40 +/- 1.04 vs 20.52 +/- 2.18 nmol/g tissue), NOx (3.45 +/- 1.20 vs 17.70 +/- 2.27 nmol/g tissue), TNF-alpha (6.71 +/- 0.66 vs 23.71 +/- 3.41 pg/g tissue), MPO (0.87 +/- 0.09 vs 3.12 +/- 0.41 U/mg tissue protein) and renal caspase-3 activity (2.81 +/- 0.37 vs 12.70 +/- 2.94 U/mg tissue protein). Whereas, total SOD activity (1.99 +/- 0.53 vs 0.79 0.06 U/mg tissue protein) and IL-10 (110.98 +/- 19.70 vs 62.34 +/- 14.42 pg/g tissue) were significantly decreased. Cisplatin-induced nephrotoxicity was further confirmed histopathologically (tubular necrosis, cystic dilatation of renal tubules, vacuolar degeneration of renal tubular epithelium with perivascular oedema, and interstitial fibrosis). These changes were accompanied by alteration in 5-LOX pathway manifested as elevated renal levels of 5-LOX, LTD4 and LTB4. Simultaneous administration of zileuton to the cisplatin-treated rats reversed the deleterious renal insults and restored the measured parameters near to control values. Conclusions: These data establish the first experimental evidence that zileuton abrogates cisplatin nephrotoxicity in rats probably via the inhibition of detrimental actions of 5-LOX products, thus favorably affecting renal oxidative/inflammatory/caspase-3 axis. Based on current findings, the therapeutic prospect of zileuton for this purpose is recommended.