Superoxide, superoxide dismutase and ischemic injury.
Oxidative stress results from an oxidant/antioxidant imbalance: an excess of oxidants relative to the antioxidant capacity. Recent evidence strongly suggests that oxidant stress plays a major role in several aspects of ischemia and reperfusion. Immunohistochemical and biochemical evidence demonstrate the significant role of reactive oxygen species, in particular superoxide and its reaction product peroxynitrite, formed by the interaction of superoxide and nitric oxide, in endothelial and tissue injury associated with ischemia and reperfusion. Endothelial cell damage, neutrophil activation and infiltration into tissues, lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels and other oxidative protein modifications contribute to the cytotoxic effect of superoxide and peroxynitrite. In addition, superoxide and peroxynitrite trigger DNA strand breakage, with subsequent activation of the nuclear enzyme poly-ADP ribosyl synthetase, a pathway which contributes to the cellular injury in ischemia and reperfusion. In vivo, removal of superoxide (and thus of peroxynitrite) by superoxide dismutase mimetics (SODm), which mimic the catalytic activity of the human superoxide dismutase enzymes, prevent the cellular energetic failure and tissue damage associated with ischemia and reperfusion and exert an overall beneficial effect in this situation. The role(s) of superoxide and the potential utility of SODm will be discussed in this review.
MetaPhore Pharmaceuticals Inc, St Louis, MO 63114, USA. dsalvemini@metaphore.com
Daniela
D
Salvemini
Salvatore
S
Cuzzocrea
D000818:Animals; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D008345:Manganese; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism* / Q000627:therapeutic use; D013481:Superoxides / Q000037:antagonists & inhibitors*
D016166:Free Radical Scavengers; C426066:M40401; D009942:Organometallic Compounds; D013481:Superoxides; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase