Therapeutic manipulations of peroxynitrite.
Interest in peroxynitrite (PN) chemistry soared after recognition in 1987 of the biological role of nitric oxide, and PN has recently emerged as a possible key mediator of in vivo oxidative stress and disease. The role of PN in disease processes can be dissected both pharmacologically and biochemically, and several laboratories have examined the cellular production of peroxynitrite. In vitro demonstrations of PN-mediated cellular injury have served to strengthen the case for peroxynitrite's proposed role in the pathogenesis of human neurodegenerative disorders as examined in animal models and in diseased human tissue. Among the nervous system disorders in which PN is strongly implicated in pathology are stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. Pathologies driven by the formation of PN are amenable to pharmacological intervention at either the reactant (nitric oxide, superoxide anions) or the product (peroxynitrite). Strategies for blocking the deleterious biochemistry of peroxynitrite must aim to decrease either the flux or the intrinsic lifetime of the peroxynitrite; three particular tactics would accomplish such purposes. A novel class of antiinflammatory agents has recently been identified: PN decomposition catalysts. Identification of these catalysts offers the scientific community the opportunity to elucidate and further our understanding of the roles of peroxynitrite in animal models of diseases, which may lead to a major breakthrough in understanding the physiopathological importance of this molecule.
Salvemini
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Discovery Pharmacology, G.D. Searle, St. Louis, Missouri 63017, USA.
Jensen
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MP
Riley
D P
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Misko
T P
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