REPERFUSION INJURY AS THE MECHANISM OF BRAIN-DAMAGE AFTER PERINATAL ASPHYXIA

Upon reperfusion of ischemic tissues, reactive oxygen metabolites are generated and are responsible for much of the organ damage. Experiment al studies have revealed two main sources of these metabolites: 1) the oxidation of hypoxanthine to xanthine and on to uric acid by the oxid ase form of xanthine oxidoreductase and 2) neutrophils accumulating in ischemic and reperfused tissue. Blocking either source will reduce re perfusion damage in a number of experimental situations. Although xant hine oxidoreductase activity may be unmeasurably low in organs other t han liver and intestine, it may be involved in reperfusion injury else where because of its localization in capillary endothelial cells. Time course considerations suggest that substrate accumulation and NADH in hibition of dehydrogenase activity may be more important in the pathog enesis than conversion of xanthine dehydrogenase into the oxidase form . Neutrophil accumulation may be partly due to oxidants in the first p lace, suggesting a link between the two sources of reactive oxygen met abolites. In the clinical context, many of the sequelae of perinatal a sphyxia may be accounted for by reperfusion damage to organs such as b rain, kidney, heart, liver, and lungs. During asphyxia, substrates of xanthine oxidase accumulate, upon resuscitation the cosubstrate oxygen is introduced, and evidence for oxidant production and effects has be en obtained. In the pathogenesis of brain damage after asphyxia, both microvascular injury and parenchymal cell damage are important. Oxygen metabolites are involved in the former, but in the latter process the ir role is less clear because ischemia-reperfusion triggers not only o xidant production but many other phenomena, including gene activation, ATP depletion, glutamate accumulation, and increase of intracellular calcium. A severe insult results in cell necrosis, but more moderate a sphyxia may cause delayed neuronal death through apoptosis. The time c ourse of the changes in high energy phosphates as well as of selective neuronal death suggest that in the first hours of life there is a ''t herapeutic window,'' with future possibilities for prevention of perma nent damage.