Benzbromarone mitigates cisplatin nephrotoxicity involving enhanced peroxisome proliferator-activated receptor-alpha (PPAR-α) expression

Aim: Despite the great efficacy reported for cisplatin as a widely used chemotherapeutic agent, its clinical use is limited by the challenge of facing its serious side effect; nephrotoxicity. In this study, the effect of the benzbromarone on peroxisome proliferator-activated receptor-alpha (PPAR-α) was investigated against cisplatin nephrotoxicity.

Main methods: Rats were administered benzbromarone (10 mg/kg/day; p.o.) for 14 days, and cisplatin (6.5 mg/kg; i.p.) as a single dose on the 10th day. Blood and kidney tissue samples were collected for determination of kidney function, biochemical and molecular markers, as well as histopathological investigation.

Key findings: Benzbromarone improved kidney function, that was evidenced by reduced serum creatinine and blood urea nitrogen to nearly the half, compared to the group administered cisplatin alone. The protein expression of PPAR-α was enhanced with benzbromarone treatment, along with a considerable suppression of oxidative stress as benzbromarone reduced mRNA expression of NADPH Oxidase, while increased the anti-oxidant HO-1 protein expression associated with enhancing Nrf2. Besides, it displayed a marked anti-inflammatory effect involved suppression of p38 MAPK/NF-κB p65 signaling pathway and its downstream targets. Moreover, benzbromarone retarded Apoptosis associated with reducing the pro-apoptotic (Bax) and enhancing the anti-apoptotic (Bcl-2) protein expressions. The protective effects of benzbromarone were also confirmed by histopathological results.

Significance: Our data confirm the relation between PPAR-α, and the deleterious effects induced by cisplatin. It can also be suggested that enhancing PPAR-α expression by benzbromarone is a promising therapeutic approach that overcomes cisplatin nephrotoxicity, involving regulation of different signaling pathways: Nrf2/HO-1, p38 MAPK/NF-κB p65, and Bax/Bcl-2.

Bax/Bcl-2; Benzbromarone; Cisplatin nephrotoxicity; Nrf2/HO-1; PPAR-α expression; p38 MAPK/NF-κB p65.