Recent data from our laboratory suggest that the developing brain responds differently to hypoxia-ischemia (H-I) than the mature brain, therefore requiring different strategies for neuroprotection. Our preliminary data suggest that the developing brain exposed to H-I is more susceptible than the adult brain to injury caused by free radicals, including nitric oxide and hydrogen peroxide. It is our hypothesis that the neonatal brain is more vulnerable than the mature brain because of a greater susceptibility to oxidative stress. This oxidative stress is due to hydrogen peroxide accumulation and sensitivity. To explore this hypothesis we will show that the immature brain accumulates more hydrogen peroxide than the mature brain after H-I, and that the maturity of the nervous system determines the differential responsivity. We will measure hydrogen peroxide accumulation in vivo and in vitro in response to H-I and correlate this with the location and type of cell death. Since the susceptibility to oxidative stress may be due to inadequate scavenging systems in the immature brain, we will measure glutathione peroxidase activity and localization and assess the effect of overexpression of this enzyme on neurological outcome. We will test whether differences in the regulation of glutathione levels and extent of oxidation between immature and mature brain account for differences in susceptibility to oxidative stress. We hypothesize that one mechanism for increased damage with hydrogen peroxide accumulation may be through the formation of hydroxyl ions as a result of the Fenton reaction. This mechanism is particularly important in the immature brain because of the increased amount of free iron. We will measure the localization and concentration of redox available iron and measure hydroxyl formation and outcome after iron chelation. The significance of the findings lies in the clinical application. Prenatal and perinatal hypoxia-ischemia are major causes of severe handicaps in neurologically impaired children. If blockade of free radicals can diminish perinatal H-I injury, development of specific inhibitors may lead to safe, easily administered therapies that could significantly reduce the burden for families and society in caring for these unfortunate children. The ability to identify therapies specific to the immature brain is of utmost importance and relevance to proper therapy.
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