A model of asphyxic cardiac arrest was developed in one-week old piglets in which the pattern of selective injury involving basal ganglia, sensorimotor cortex and thalamic sensory nuclei resembles that in human neonatal hypoxic-ischemic encephalopathy. The present application is focused on mechanisms of injury in striatum, where injury evolves rapidly, is most severe, and requires early therapeutic intervention. Because the morphology of striatal injury and the markers of cellular oxidative stress evolve over the first 6 hours of recovery in a manner analogous to N-methyl-D-aspartate (NMDA) excitotoxicity, the aims of the present proposal investigate possible strategies to modulate NMDA receptor signal/transduction pathways and their downstream consequences. Dopamine is known to amplify NMDA responses, possibly by receptor phosphorylation.
In Aim 1, dopamine antagonists will be used to determine if increased NMDA receptor phosphorylation and decreased Na,K-ATPase, normally observed after resuscitation, can be prevented and if striatal neurons are protected. Sigma receptor ligands are known to reduce NMDA responses. In Project 1 of this grant, a sigma ligand was found previously to decrease nitric oxide production evoked by NMDA and focal ischemia, and to reduce focal ischemic striatal injury in mature brain.
In Aim 2, this sigma ligand will be tested in immature brain to determine if neuroprotection from global ischemia occurs in striatum in association with decreased protein nitration and decreased NMDA receptor phosphorylation. Oxidative stress was found to progress rapidly after reoxygenation as indicated by decreased glutathione, increased protein carbonyl formation, and hydroxyl radical damage to DNA and RNA.
In Aim 3, the effect of immediate and delayed antioxidant treatment on striatal injury and markers of cellular oxidative stress will be determined. Inducing mild hypothermia immediately after resuscitation for a 24 hour period was found to provide complete, long-term striatal protection in piglets.
In Aim 4, the impact of using a more clinically relevant delay in instituting hypothermia will be evaluated, and the efficacy of early antioxidant treatment in extending the therapeutic window for hypothermia will be assessed. These studies will provide unique mechanistic insights into the cause of rapid neurodegeneration in immature basal ganglia using a large animal model of asphyxia cardiac arrest and resuscitation. These results will permit translation into clinical therapeutic approaches to help prevent the devastating consequences of neonatal hypoxic-ischemic encephalopathy.
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