A herpes simplex virus vector overexpressing the glucose transporter gene protects the rat dentate gyrus from an antimetabolite toxin.

The use of herpes simplex virus vectors offers an attractive means for the in vitro and in vivo transfer of novel genes into postmitotic neurons. Such an approach allows for the introduction of genes with the potential to protect neurons from necrotic insults. Toward that end, we have previously constructed a bicistronic herpes viral vector expressing the gene for the Glut-1 rat brain glucose transporter (GT), along with the Escherichia coli lacZ reporter gene. We observed that this vector enhances glucose uptake both in primary hippocampal cultures and in the hippocampus itself. Moreover, we have found that this vector will protect a variety of types of cultured neurons from necrotic insults and protect hippocampal neurons in vivo from seizure-induced damage. In the present report, we further demonstrate the neuroprotective potential of this GT-expressing vector. 3-Acetylpyridine, an electron transport uncoupler which is preferentially toxic to the dentate gyrus, was microinfused into the dorsal hippocampus of rats. Infection of dentate neurons with GT vectors at the time of exposure to the toxin significantly decreased damage, whereas infection with a physiologically neutral control vector did not. Moreover, there was a window of opportunity for this intervention, as microinfusion of the GT-expressing vector up to 1 h, but not 4 h, after the insult was still neuroprotective.