PREVENTION & TREATMENT OF CISPLATIN- RHABDOMYOLYSIS- INDUCED NEPHROTOXICITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Prevention & Treatment of Cisplatin- Rhabdomyolysis- Induced Nephrotoxicity Using Metal Complexes The objective of this proposal is to synthesize, characterize, and test several new metal (copper and zinc) complexes of salicylic acid and aminothiol derivatives as catalytic antioxidants that scavenge a wide range of reactive oxygen species (ROS). Several compounds in this class have been shown to be efficacious in a variety of ways in in vitro and in vivo oxidative stress models of human diseases. Our preliminary data strongly indicate that these metal complexes satisfy many of the criteria for prevention and treatment of cisplatin-induced nephrotoxicity (an ROS-mediated injury), as they are active, stable, and nontoxic antioxidants. Since rhabdomyolysis-induced nephrotoxicity is also ROS-mediated, these compounds also satisfy many of the criteria for prevention and treatment of kidney injury due to this disease. We hypothesize that copper and zinc complexes can be synthesized that combine the cytoprotective effects of antioxidant ligands with the cytorecovery effects of the essential metals in order to protect kidney tubular epithelial cells from toxicity due to cisplatin administration or the development of rhabdomyolysis. The proposal has two specific aims: Specific Aim 1: Synthesize, characterize, and evaluate antioxidant properties of several copper and zinc complexes. The focus will be on ligands, which have or contribute to cytoprotective activity. We will examine ligands from the substituted salicylate and aminothiol classes. Several such compounds have been synthesized in our laboratory and have shown favorable activity in several in vitro models. This Specific Aim will focus on chemical studies of several new compounds, as well as some previously known but not fully characterized compounds. All new compounds will be tested for antioxidant properties using standard antioxidant assays and cyclic voltammetry. Specific Aim 2: Assess the nephroprotective activity of metal complexes in vitro and in vivo. The stable water-soluble compounds with the highest antioxidant activities will be tested for cytoprotection against cisplatin and rhabdomyolysis injuries using cultured tubular epithelial cells in vitro and in a mouse model. Experiments will be done to determine the effect of metal complexes on caspase activation and caspase-dependent or -independent endonuclease activation. Better agents for the prevention and treatment of cisplatin- and rhabdomyolysis-induced nephrotoxicities are greatly needed to reduce treatment-related and comorbid renal dysfunction. The compounds proposed in this study have molecular features that combine the cytoprotective effects of antioxidant ligands with the cytorecovery effects of the essential metals, zinc, and copper.