Mai M Helmy1, Amel A Hashim2, Samar M Mouneir3. 1. Pharmacology and Toxicology Department, Faculty of Pharmacy, Alexandria University, Egypt. Electronic address: meeshoo7@hotmail.com. 2. Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Egypt. Electronic address: weiss_rosa@yahoo.com. 3. Pharmacology Department, Faculty of Veterinary Medicine, Cairo University, Egypt.
Abstract
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/dl), 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-α (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.
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/dl), 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-α (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 cisplatinnephrotoxicity 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.
Authors: Sherien A Abdelhady; Mennatallah A Ali; Tamer A Al-Shafie; Ebtsam M Abdelmawgoud; Dalia M Yacout; Mahmoud M El-Mas Journal: Inflamm Res Date: 2021-08-11 Impact factor: 4.575
Authors: Florencia Lorenzetti; Marina Cecilia Vera; María Paula Ceballos; María Teresa Ronco; Gerardo Bruno Pisani; Juan Alberto Monti; Alvaro Lucci; Carla Gabriela Comanzo; Thierry Tordjmann; María Cristina Carrillo; Ariel Darío Quiroga; María de Luján Alvarez Journal: Sci Rep Date: 2019-12-03 Impact factor: 4.379