The HSV-2 protein ICP10PK prevents neuronal apoptosis and loss of function in an in vivo model of neurodegeneration associated with glutamate excitotoxicity.

Excessive glutamate receptor activation results in neuronal death, a process known as excitotoxicity. Intrastriatal injection of N-methyl-d-aspartate (NMDA) is a model of excitotoxicity. We used this model to examine whether excitotoxic injury is inhibited by the anti-apoptotic herpes simplex virus type 2 (HSV-2) protein, ICP10PK, delivered by the replication incompetent HSV-2 vector, DeltaRR. Intrastriatal DeltaRR administration (2500 plaque forming units) was nontoxic and did not induce microglial activation 5 days after injection. Intrastriatal injection of DeltaRR with NMDA or 4 h after NMDA injection showed increased neuronal survival and decreased mitochondrial damage compared to injection of NMDA alone. Neuroprotection was due to the inhibition of NMDA-induced apoptosis through ERK activation. DeltaRR-treated mice did not develop NMDA-associated behavioral deficits. The data suggest that DeltaRR is a promising platform for treatment of acute neuronal injury.