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-on cogene bcl-2 can protect neuron and neuron-like cell lines from growth factor deprivation, calcium ionophores, glutamate excitotoxicity, hyp oglycemia, free radicals, and lipid peroxidation. To determine whether Bcl-2 exhibits a similar protective effect in CNS neurons, we generat ed defective herpes simplex virus (HSV) vectors capable of overexpress ing Bcl-2 in primary cultures and in the intact brain. Infection of hi ppocampal cultures with Bcl-2 vectors enhanced neuron survivorship aft er exposure to adriamycin, a potent oxygen radical generator. Furtherm ore, dichlorofluorescein measurements indicated that there was a signi ficant reduction in the accumulation of oxygen radicals associated wit h this insult. Bcl-2 vectors also enhanced survival in cultured neuron s after exposure to glutamate and hypoglycemia. Most significantly, th e 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.