CHARACTERIZATION OF THE CYTOPROTECTIVE ACTION OF PEROXYNITRITE DECOMPOSITION CATALYSTS

The formation of the powerful oxidant peroxynitrite (PN) from the reac tion of superoxide anion with nitric oxide has been shown to be a kine tically favored reaction contributing to cellular injury and death at sites of tissue inflammation. The PN molecule is highly reactive causi ng lipid peroxidation as well as nitration of both free and protein-bo und tyrosine. We present evidence for the pharmacological manipulation of PN with decomposition catalysts capable of converting it to nitrat e. hs target cells challenged with exogenously added synthetic PN, a s eries of metalloporphyrin catalysts 2,4,6-trimethyl-3,3-disulfonatophe nyl)porphyrinato iron (III) (FeTMPS); 5,10,15,20-tetrakis(4-sulfonatop henyl)porphyrinato iron (III) (FeTPPS); 10,15,20-tetrakis(N-methyl-4'- pyridyl)porphyrinato iron (III) (FeTMPyP)) provided protection against PN-mediated injury with EC50 values for each compound 30-50-fold belo w the final concentration of PN added. Cytoprotection was correlated w ith a reduction in the level of measurable nitrotyrosine. In addition, we found our catalysts to be cytoprotective against endogenously gene rated PN in endotoxin-stimulated RAW 264.7 cells as well as in dissoci ated cultures of hippocampal neurons and glia that had been exposed to cytokines. Our studies thus provide compelling evidence for the invol vement of peroxynitrite in cytokine-mediated cellular injury and sugge st the therapeutic potential of PN decomposition catalysts in reducing cellular damage at sites of inflammation.