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Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.
Naunyn Schmiedebergs Arch Pharmacol. 2016 Aug; 389(8):819-30.NS

Abstract

The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. georgeshehatou@gmail.com.Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27215580

Citation

Fahmi, Alaa N A., et al. "Febuxostat Exerts Dose-dependent Renoprotection in Rats With Cisplatin-induced Acute Renal Injury." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 389, no. 8, 2016, pp. 819-30.
Fahmi AN, Shehatou GS, Shebl AM, et al. Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(8):819-30.
Fahmi, A. N., Shehatou, G. S., Shebl, A. M., & Salem, H. A. (2016). Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury. Naunyn-Schmiedeberg's Archives of Pharmacology, 389(8), 819-30. https://doi.org/10.1007/s00210-016-1258-y
Fahmi AN, et al. Febuxostat Exerts Dose-dependent Renoprotection in Rats With Cisplatin-induced Acute Renal Injury. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(8):819-30. PubMed PMID: 27215580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury. AU - Fahmi,Alaa N A, AU - Shehatou,George S G, AU - Shebl,Abdelhadi M, AU - Salem,Hatem A, Y1 - 2016/05/23/ PY - 2016/01/29/received PY - 2016/05/09/accepted PY - 2016/5/25/entrez PY - 2016/5/25/pubmed PY - 2017/2/22/medline KW - Cisplatin KW - Febuxostat KW - Inflammation KW - Kidney injury KW - Oxidative stress KW - TNF-α SP - 819 EP - 30 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch Pharmacol VL - 389 IS - 8 N2 - The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy. SN - 1432-1912 UR - https://www.unboundmedicine.com/medline/citation/27215580/Febuxostat_exerts_dose_dependent_renoprotection_in_rats_with_cisplatin_induced_acute_renal_injury_ L2 - https://dx.doi.org/10.1007/s00210-016-1258-y DB - PRIME DP - Unbound Medicine ER -