Necrotic neuron death in the hippocampus, as occurs following hypoxia- ischemia, seizure, or hypoglycemia, appears to involve an excess of synaptic glutamate accumulation, of free cytosolic calcium, and pathologic overactivation of calcium-dependent degenerative events, such as oxygen radical formation. Furthermore, the de generative features of this cascade are worsened by the energy depletion that accompanies these neurological insults. Based on this knowledge, we will design a gene transfer strategy to protect hippocampal neurons from these insults; this will involve the transfer and overexpression of genes to enhance glucose uptake, calcium binding, or oxygen radical scavenging. We will use herpes simplex virus vectors to carry out such gene transfers with vectors carrying the gene for a) the rat brain glucose transporter, b) for calbindin DD-28K, or c) for bcl-2). We have already constructed these vectors and our pilot data indicate neuroprotective potential of each.
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