Herpes Simplex Virus Vectors Overexpressing the Glucose Transporter Gene Protect Against Seizure-Induced Neuron Loss

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-08, Vol.92 (16), p.7247-7251
• Main Authors: Lawrence, Matthew S., Ho, Dora Y., Dash, Rajesh, Sapolsky, Robert M.
• Format: Article
• Language: English
• Subjects: Animals; Brain; Brain damage; Cercopithecus aethiops; Escherichia coli; Gene Expression; Gene Transfer Techniques; Genes; Genetic Vectors; Glucose Transporter Type 1; herpes simplex virus; Herpes viruses; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Hypoglycemia; Hypoglycemia - metabolism; Hypoglycemia - pathology; In Vitro Techniques; Infections; Kainic Acid - toxicity; Male; Metabolism; Monosaccharide Transport Proteins - genetics; Neurology; Neurons; Neurons - metabolism; Neurons - pathology; Neuroscience; Rats; Rats, Sprague-Dawley; Rodents; Seizures; Seizures - metabolism; Seizures - pathology; Seizures - prevention & control; Simplexvirus; Simplexvirus - genetics; Vero Cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.16.7247

We have generated herpes simplex virus (HSV) vectors vIE1GT and vα4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV α4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypoglycemia. Microinfusion of GT vectors into the rat hippocampus also reduces kainic acid-induced seizure damage in the CA3 cell field. Furthermore, delivery of the vector even after onset of the seizure is protective, suggesting that HSV-mediated gene transfer for neuroprotection need not be carried out in anticipation of neurologic crises. Using the bicistronic vector vα22βgalα4GT, which coexpresses both GT and the Escherichia coli lacZ marker gene, we further demonstrate an inverse correlation between the extent of vector expression in the dentate and the amount of CA3 damage resulting from the simultaneous delivery of kainic acid.