Carvedilol protects against cisplatin-induced oxidative stress, redox state unbalance and apoptosis in rat kidney mitochondria.
Cisplatin is a highly effective chemotherapeutic agent which causes severe nephrotoxicity. Studies have suggested that reactive oxygen species, mainly generated in mitochondria, play a central role in cisplatin-induced renal damage. A wide range of antioxidants have been evaluated as possible protective agents against cisplatin-induced nephrotoxicity; however a safe and efficacious compound has not yet been found. The present study is the first to evaluate the protective potential of carvedilol, a beta-blocker with strong antioxidant properties, against the mitochondrial oxidative stress and apoptosis in kidney of rats treated with cisplatin. The following cisplatin-induced toxic effects were prevented by carvedilol: increased plasmatic levels of creatinine and blood urea nitrogen (BUN); lipid peroxidation, oxidation of cardiolipin; oxidation of protein sulfhydryls; depletion of the non-enzymatic antioxidant defense and increased activity of caspase-3. Carvedilol per se did not present any effect on renal mitochondria. It was concluded that carvedilol prevents mitochondrial dysfunction and renal cell death through the protection against the oxidative stress and redox state unbalance induced by cisplatin. The association of carvedilol to cisplatin chemotherapy was suggested as a possible strategy to minimize the nephrotoxicity induced by this antitumor agent.
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n, Ribeirão Preto, SP, Brazil.
M A Carvalho
MA
Rodrigues
J L
JL
Rodrigues
N M
NM
Martins
F
F
Barbosa
C
C
Curti
N A G
NA
Santos
A C
AC
Santos
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004347:Drug Interactions; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D008315:Malondialdehyde; D003404:Creatinine; D002945:Cisplatin