Your browser version may not work well with NCBI's Web applications. More information here...
1: Genet Vaccines Ther. 2008 Jan 7;6:1.Click here to read Click here to read Links

DeltaRR vaccination protects from KA-induced seizures and neuronal loss through ICP10PK-mediated modulation of the neuronal-microglial axis.

Laing JM, Aurelian L.

Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore, MD 21201, USA. laurelia@umaryland.edu.

ABSTRACT: Ischemic brain injury and epilepsy are common neurodegenerative diseases caused by excitotoxicity. Their pathogenesis includes microglial production of inflammatory cytokines. Our studies were designed to examine whether a growth compromised HSV-2 mutant (DeltaRR) prevents excitotoxic injury through modulation of microglial responses by the anti-apoptotic HSV-2 protein ICP10PK. EOC2 and EOC20 microglial cells, which are differentially activated, were infected with DeltaRR or the ICP10PK deleted virus (DeltaPK) and examined for virus-induced neuroprotective activity. Both cell lines were non-permissive for virus growth, but expressed ICP10PK (DeltaRR) or the PK deleted ICP10 protein p95 (DeltaPK). Conditioned medium (CM) from DeltaRR-, but not DeltaPK-infected cells prevented N-methyl-D-aspartate (NMDA)-induced apoptosis of primary hippocampal cultures, as determined by TUNEL and caspase-3 activation (76.9 +/- 5.3% neuroprotection). Neuroprotection was associated with inhibition of TNF-alpha and RANTES and production of IL-10. The CM from DeltaPK-infected EOC2 and EOC20 cells did not contain IL-10, but it contained TNF-alpha and RANTES. IL-10 neutralization significantly (p < 0.01) decreased, but did not abrogate, the neuroprotective activity of the CM from DeltaRR-infected microglial cultures indicating that ICP10PK modulates the neuronal-microglial axis, also through induction of various microglial neuroprotective factors. Rats given DeltaRR (but not DeltaPK) by intranasal inoculation were protected from kainic acid (KA)-induced seizures and neuronal loss in the CA1 hippocampal fields. Protection was associated with a significant (p < 0.001) increase in the numbers of IL-10+ microglia (CD11b+) as compared to DeltaPK-treated animals. DeltaRR is a promising vaccination/therapy platform for neurodegeneration through its pro-survival functions in neurons as well as microglia modulation.

PMID: 18179717 [PubMed - in process]

PMCID: PMC2268933