Abstract
The platinum compound cisplatin is one of the most potent chemotherapy agents available to treat various malignancies. Nephrotoxicity is a common complication of cisplatin chemotherapy, which involves increased oxidative and nitrosative stress, limiting its clinical use. In this study, we have investigated the effects of a nonpsychoactive cannabinoid cannabidiol, which was reported to exert antioxidant effects and has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients in a mouse model of cisplatin-induced nephropathy. Cisplatin induced increased expression of superoxide-generating enzymes RENOX (NOX4) and NOX1, enhanced reactive oxygen species generation, inducible nitric-oxide synthase expression, nitrotyrosine formation, apoptosis (caspase-3/7 activity, DNA fragmentation, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), poly(ADP-ribose) polymerase activity, and inflammation (tumor necrosis factor-α and interleukin-1β) in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum blood urea nitrogen and creatinine levels) 72 h after the administration of the drug. Treatment of mice with cannabidiol markedly attenuated the cisplatin-induced oxidative/nitrosative stress, inflammation, and cell death in the kidney, and it improved renal function. Thus, our results suggest that cannabidiol may represent a promising new protective strategy against cisplatin-induced nephrotoxicity.
Footnotes
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This study was supported by the Intramural Research Program of National Institutes of Health National Institute on Alcohol Abuse and Alcoholism.
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H.P. and P.M. contributed equally to this work.
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doi:10.1124/jpet.108.147181.
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ABBREVIATIONS: PARP, poly(ADP-ribose) polymerase; TNF, tumor necrosis factor; IL, interleukin; CB, cannabinoid; CBD, cannabidiol; BUN, blood urea nitrogen; iNOS, inducible nitric-oxide synthase; PAS, periodic acid-Schiff; ROS, reactive oxygen species; MDA, malondialdehyde; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; CP, cisplatin; NT, 3-nitrotyrosine.
- Received October 8, 2008.
- Accepted December 11, 2008.
- U.S. Government work not protected by U.S. copyright
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