4.5 Article

Multi-targeted neuroprotection by the HSV-2 gene ICP10PK includes robust bystander activity through PI3-K/Akt and/or MEK/ERK-dependent neuronal release of vascular endothelial growth factor and fractalkine

Journal

JOURNAL OF NEUROCHEMISTRY
Volume 112, Issue 3, Pages 662-676

Publisher

WILEY
DOI: 10.1111/j.1471-4159.2009.06475.x

Keywords

chemokines; cytokines; excitotoxicity; growth factors; microglia; SOD1

Funding

  1. NINDS
  2. National Institutes of Health (NIH) [NS45169]

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P>Hippocampal cultures infected with the delta RR vector for the HSV-2 anti-apoptotic gene ICP10PK survive cell death triggered by a wide variety of insults. Survival includes robust protection of uninfected neurons, but the mechanism of this bystander activity is still unclear. Here we report that ICP10PK+ neurons release soluble factors that protect uninfected neurons from NMDA and MPP+-induced apoptosis. Release depends on ICP10PK-mediated activation of the Ras signaling pathways MEK/ERK and PI3-K/Akt, and it was not seen for cultures infected with the ICP10PK negative vector delta PK. The released neuroprotective factors include vascular endothelial growth factor (VEGF) and fractalkine, the levels of which were significantly higher in conditioned media from hippocampal cultures infected with delta RR (NCM delta RR) than delta PK or phosphate-buffered saline (mock infection). VEGF neutralization inhibited the neuroprotective activity of NCM delta RR, indicating that the VEGF protective function is through neuron-neuron cross-talk. NCM delta RR also stimulated microglia to release increased levels of IL-10 and decreased levels of TNF-alpha that were protective for uninfected neurons. These release patterns were not seen for microglia given NCM delta RR in which fractalkine was neutralized, indicating that the fractalkine protective function is through bidirectional neuron-microglia communication. Collectively, the data indicate that delta RR is a multiple target strategy to rescue neurons from excitotoxic injury.

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