Cannabidiol Attenuates Cisplatin-Induced Nephrotoxicity by Decreasing oxidative/nitrosative Stress, Inflammation, and Cell Death

J Pharmacol Exp Ther. 2009 Mar;328(3):708-14. doi: 10.1124/jpet.108.147181. Epub 2008 Dec 12.

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-alpha and interleukin-1beta) 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cannabidiol / pharmacology*
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Caspase 7 / drug effects
  • Caspase 7 / metabolism
  • Cell Death / drug effects*
  • Cisplatin / antagonists & inhibitors
  • Cisplatin / toxicity*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Inflammation / prevention & control*
  • Kidney / drug effects
  • Kidney / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADH, NADPH Oxidoreductases / genetics
  • NADPH Oxidase 1
  • NADPH Oxidase 4
  • NADPH Oxidases / drug effects
  • NADPH Oxidases / genetics
  • Oxidative Stress / drug effects*

Substances

  • Cannabidiol
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX1 protein, mouse
  • Nox4 protein, mouse
  • Caspase 3
  • Caspase 7
  • Cisplatin