This competitive renewal application proposes experiments to dissect the mechanisms by which hypoxia-ischemia damages the neonatal brain. In the last period of support we used a one week old rat model of hypoxia-ischemia to demonstrate that overstimulation of N-methyl- D-aspartate (NMDA) receptors plays a major role in the chain of events leading to neuronal damage in the corpus striatum, hippocampus and neocortex. We found that the noncompetitive NMDA antagonist dizocilpine (MK-801) is very neuroprotective in the model and stereotaxic injection of the NMDA agonists NMDA and quinolinic acid into the neonatal brain replicates the neuropathology seen in hypoxic- ischemic injury. New experiments will focus on NMDA receptor triggered events that evolve in the post-insult period of hypoxic- ischemic encephalopathy (HIE) to find interventions that can be used clinically. Hypothesis I states that mild post-insult cooling can slow down the cascade of events to lengthen the temporal window for NMDA antagonist efficacy. Hypothesis II states that induction of neuronal nitric oxide synthase (nNOS) over 24 hours post-insult contributes to evolving neuronal damage from necrosis and/or apoptosis and inhibition of nNOS activity in this period can be neuroprotective. Hypothesis III states the administration of N-acetylcysteine or glutathione can also extend the therapeutic window for NMDA antagonists by enhancing brain glutathionine levels and lowering concentrations of reactive oxygen species produced by oxidative stress and NOS activation during HIE. Hypothesis IV states that activation of the immediate early gene product cyclooxygenase-2 (COX-2) also contributes to damage during the evolution of HIE and inhibition of this enzyme provides neuroprotection.
Specific aims to test these hypotheses use the techniques of quantitative morphometry, in vitro receptor autoradiography, immunocytochemistry, in situ hybridization histochemistry, microdialysis and measurement of glutathionine levels. The application presents preliminary data to support these hypotheses and the methods that will be used to test them. The information gained from these experiments is very important for developing practical neuroprotective therapies for fetuses, infants and young children.
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