DEFECTIVE HERPES-SIMPLEX VIRUS VECTORS EXPRESSING THE RAT-BRAIN GLUCOSE-TRANSPORTER PROTECT CULTURED NEURONS FROM NECROTIC INSULTS

Because neurons are postmitotic, they are irreplaceable once they succ umb to necrotic insults such as hypoglycemia, ischemia, and seizure. A paucity of energy can exacerbate the toxicities of these insults; thu s, a plausible route to protect neurons from necrotic injury would be to enhance their glucose uptake capability. We have demonstrated previ ously that defective herpes simplex virus (HSV) vectors overexpressing the rat brain glucose transporter (GT) gene (gt) can enhance glucose uptake in adult rat hippocampus and in hippocampal cultures. Furthermo re, we have observed that such vectors can maintain neuronal metabolis m during hypoglycemia and reduce kainic acid-induced seizure damage. I n this study, we have developed bicistronic Vectors that coexpressed g t and Escherichia coli lacZ as a reporter gene, which allows us to ide ntify directly neurons that are infected with the vectors. Overexpress ion of GT from these vectors protected cultured hippocampal, spinal co rd, and septal neurons against various necrotic insults, including hyp oglycemia, glutamate, and 3-nitropropionic acid. Our observations demo nstrate the feasibility of using HSV vectors to protect neurons from n ecrotic insults. Although this study has concentrated on the delivery of gt, other genes with therapeutic or protective capability might als o be used.