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.
Golembewski
Erin K
EK
Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, MD 20742, USA.
Wales
Samantha Q
SQ
Aurelian
Laure
L
Yarowsky
Paul J
PJ
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002522:Chlorocebus aethiops; D004396:Coloring Agents; D018491:Dopamine Agonists / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D018846:Excitatory Amino Acids / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D007267:Injections; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D016202:N-Methylaspartate / Q000633:toxicity*; D017072:Neostriatum; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents; D010640:Phenothiazines; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000494:pharmacology*; D014709:Vero Cells
D004396:Coloring Agents; D018491:Dopamine Agonists; D018846:Excitatory Amino Acids; D007202:Indicators and Reagents; D018696:Neuroprotective Agents; D010640:Phenothiazines; D018698:Glutamic Acid; D016202:N-Methylaspartate; C100671:ICP10 protein, herpes simplex virus type 2; D012264:Ribonucleotide Reductases; D003576:Electron Transport Complex IV; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D001058:Apomorphine; C009469:thionine