There is compelling evidence that excessive activation of receptors for the excitatory amino acids glutamate and aspartate leads to at least a portion of the neuronal damage seen with brain hypoxia and ischemia (H/I). The experiments in this project will examine certain specific questions related to excitatory amino acid receptors and the pathophysiology and therapy of cerebral H/I in the newborn. First, we will determine the developmental profile of excitotoxic neuronal injury, concentrating specifically on the N-methyl-D-aspartate (NMDA) receptor at different pre- and post-natal ages. We expect that NMDA toxicity is not constant through development and that there may be windows of extreme sensitivity. We will utilize the NMDA agonist cysteine, which freely crosses the placenta and replicates the neurotoxicity of NMDA. We also wish to extend preliminary observations that overactivation of NMDA receptors can cause brain hemorrhage in young animals, suggesting another link between excitotoxicity and neonatal brain damage. Second, we will examine the developmental profile of NMDA antagonist neurotoxicity. Many neurobiologists believe that these drugs may protect the brain from H/I, but are concerned that they also harbor toxic potential. We have preliminary evidence that they are relatively nontoxic in young animals and want to determine the therapeutic window for these drugs more accurately. If we verify the safety of this class of drugs in the newborn, the may have widespread therapeutic use in early treatment of H/I. Third, using new calcium-sensitive fluorescent dyes, we plan to examine the role of excitatory amino acid receptors in controlling the rise in ionized intracellular calcium, and presumably neuronal injury, in hypoxic human brain slices obtained from focal cortical resections. These will be the first experiments to directly test the hypothesis that overactivation of excitatory amino acid receptors plays a role in the pathophysiology of human H/I brain injury.
Showing the most recent 10 out of 11 publications
