Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo.
Previous studies have demonstrated that overexpression of the proto-oncogene bcl-2 can protect neuron and neuron-like cell lines from growth factor deprivation, calcium ionophores, glutamate excitotoxicity, hypoglycemia, free radicals, and lipid peroxidation. To determine whether Bcl-2 exhibits a similar protective effect in CNS neurons, we generated defective herpes simplex virus (HSV) vectors capable of overexpressing Bcl-2 in primary cultures and in the intact brain. Infection of hippocampal cultures with Bcl-2 vectors enhanced neuron survivorship after exposure to adriamycin, a potent oxygen radical generator. Furthermore, dichlorofluorescein measurements indicated that there was a significant reduction in the accumulation of oxygen radicals associated with this insult. Bcl-2 vectors also enhanced survival in cultured neurons after exposure to glutamate and hypoglycemia. Most significantly, the in vivo delivery of the vector protected neurons against adriamycin toxicity in the dorsal horn of the dentate gyrus and focal ischemia in the striatum.
Lawrence
M S
MS
Department of Biological Sciences, Stanford University, California 94305, USA.
Ho
D Y
DY
Sun
G H
GH
Steinberg
G K
GK
Sapolsky
R M
RM
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018698:Glutamic Acid; D004317:Doxorubicin