Glutamate excitotocicity occurs in several neurodegenerative diseases such as stroke, Alzheimer's, Parkinson's and Huntington's diseases. Currently, no effective treatments exist for these pathological conditions. Therapeutic approaches for blocking glutamate-induced apoptosis may include introduction of genes that activate survival pathways. Previously, we have shown that the HSV-2 gene ICP10PK inhibits apoptosis in cultured neurons by activating the Ras/MEK/ERK signaling pathway. The current studies examine the neuroprotective activity of ICP10PK in a model of NMDA-induced excitotoxic injury, in vivo and in vitro.;For in vivo experiments, mice were given intrastriatal NMDA injections bilaterally. In the left striatum, NMDA was diluted in PBS; in the right striatum it was combined with an HSV-2 vector delivering ICP10PK (DeltaRR). The data indicate that DeltaRR is not toxic and does not induce an inflammatory response, which is likely related to its failure to replicate in the brain. DeltaRR decreases NMDA-induced lesion volume and increases cell survival by inhibiting caspase-3 cleavage, thus protecting neurons from apoptosis even when given up to four hours after NMDA. Neuroprotection is conferred by the phosphorylation/activation of ERK by MEK. Additionally, behavioral testing showed that protected neurons retained function. An ICP10PK-negative vector (DeltaPK) did not activate ERK or protect neurons from apoptosis or behavioral abnormalities.;For in vitro experiments, organotypic striatal cultures were used to determine the specific neuroprotective mechanism induced by DeltaRR. Employing specific protein kinase inhibitors demonstrates that protection from apoptosis is dependent on the activation of the Ras/MEK/ERK and PI3-K/AKT pathways as well as the inhibiton of the pro-apoptosic JNK pathway and cleavages of caspase-3 and PARP. Neuroprotection also involves the induction of anti-apoptosic Bag-1 and the inhibition pro-apoptosic Bad.;These studies show that ICP10PK delivered by DeltaRR reduces apoptosis induced by an excitotoxin in vivo and in vitro. Neuroprotection is accomplished by activating the Ras/MEK/ERK and P13-K pathways. The data suggest that ICP10PK has anti-apoptosic activity in vivo and is a potential gene therapy for neurodegenerative diseases of the CNS.