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 succumb to necrotic insults such as hypoglycemia, ischemia, and seizure. A paucity of energy can exacerbate the toxicities of these insults; thus, a plausible route to protect neurons from necrotic injury would be to enhance their glucose uptake capability. We have demonstrated previously 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. Furthermore, we have observed that such vectors can maintain neuronal metabolism during hypoglycemia and reduce kainic acid-induced seizure damage. In this study, we have developed bicistronic vectors that coexpressed gt and Escherichia coli lacZ as a reporter gene, which allows us to identify directly neurons that are infected with the vectors. Overexpression of GT from these vectors protected cultured hippocampal, spinal cord, and septal neurons against various necrotic insults, including hypoglycemia, glutamate, and 3-nitropropionic acid. Our observations demonstrate the feasibility of using HSV vectors to protect neurons from necrotic insults. Although this study has concentrated on the delivery of gt, other genes with therapeutic or protective capability might also be used.
Ho
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Department of Biological Sciences, Stanford University, CA 94305-5120, USA.
Saydam
T C
TC
Fink
S L
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Lawrence
M S
MS
Sapolsky
R M
RM
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops; D003673:Defective Viruses / Q000235:genetics*; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D018698:Glutamic Acid / Q000494:pharmacology; D007003:Hypoglycemia / Q000473:pathology; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D011401:Promoter Regions, Genetic; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics*; D014709:Vero Cells
D009004:Monosaccharide Transport Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D018698:Glutamic Acid; C015392:3-nitropropionic acid