: This competitive renewal application proposes experiments to dissect mechanisms by which hypoxic ischemia damages the neonatal brain, using a one-week-old rat model. This model replicates many important features of hypoxic-ischemic encephalopathy and brain injury seen in human neonates. Work funded by this application in the past has established that excessive stimulation of N-methyl-aspartate (NMDA) type glutamate receptors is an important trigger for the chain of events leading to delayed neuronal damage in the model. Over the last period of support, we examined events downstream of NMDA receptor stimulation and established that 7-nitroindazole, an antagonist of neuronal nitric oxide synthase (nNOS), is neuroprotective. We also found that nNOS-immunoreactive fibers increase strikingly over the week after injury in regions of the brain, such as the thalamus, that are selectively vulnerable. We found that neurodegeneration in this model includes a mixture of necrotic, apoptotic and hybrid morphologies and that apoptosis and caspase-3 immunoreactivity persist for more than a week after the insult. We hypothesize that delayed neurodegeneration is mediated in part by production of nitric oxide, which in turn is associated with activation of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP-l). To explore this hypothesis at a molecular level, we adapted the rat model to neonatal mice, in order to take advantage of gene knockout models and technology for determining coordinate changes in mRNA expression. These studies are important for developing practical ways to salvage brain tissue in infants and young children who have suffered hypoxic-ischemic injuries.
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