[Peroxynitrite production in cerebral ischemia]

Peroxynitrite, generated by the reaction of nitric oxide and superoxide, has toxic effects including oxidation of sulfhydryls, lipid peroxidation and nitration of amino acid residues. So far peroxynitrite has not yet been detected in the ischemic brain because of its short half-life. Recently, we have succeeded in detecting 3-nitro-L-tyrosine, which is considered to be a footprint of peroxynitrite, in ischemic brain. Production of nitrotyrosine started during the ischemic period, increased after reperfusion, peaked at 48 hours, then declined up to 72 hours. Nitrotyrosine level was highest in the peri-infarct region, second highest in the core-of-infarct region, and lowest in the caudoputamen and the non-infarct region. Studies using pharmacological agents including MK-801, 7-nitroindazole and aminoguanidine suggest that peroxynitrite production originates from nNOS in the early phase of reperfusion, and from iNOS in the later phase of reperfusion. Further, the immunohistochemical study indicates that iNOS, located mainly in vascular cells, is predominantly responsible for nitrotyrosine production. Thus, peroxynitrite production depends on the stage of evolution of the ischemic process and on the cell type producing NO. These findings have important implications for the therapeutic time window and choice of NOS inhibitors in patients with cerebral infarction.