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HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption

Gene Therapy volume 9, pages 214–219 (2002)Cite this article

Abstract

Studies utilizing gene delivery to the nervous system indicate that various strategies are protective following acute neurological insults such as seizure and stroke. We have found that inhibitors of apoptosis are protective against excitotoxicity and heat stress but not energetic impairment in vitro. Here we studied the neuroprotective efficacy in vivo of these mediators: viral genes (crmA, p35, γ34.5 KsBcl-2) that have evolved to suppress suicidal host responses to infection, by inhibiting apoptosis. We investigated these effects by utilizing modified herpes vectors to deliver the anti-apoptotic agents intracerebrally and examined them in the face of excitotoxic and metabolic insults. We found that p35 and γ34.5 reduced by 45% a hippocampal CA3 lesion caused by kainic acid, while crmA and KsBcl-2 did not. None of the inhibitors protected the dentate gyrus of the hippocampus following 3-acetylpyridine, a hypoglycemia model, but we found crmA to worsen the damage. These data are similar to our results in neuronal cultures where the inhibitors protected against the excitotoxin domoic acid, but not against the metabolic poison, cyanide. Together, the results suggest that inhibitors of various apoptotic elements are capable of protecting under acute insult conditions both in vitro and in vivo, suggesting possible future therapeutic applications.

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Acknowledgements

The authors wish to thank Dr Ted Dumas for his advice on the project. This work was supported by NIH RO1 NS32848 and the TDRDP of the State of California to RMS and an Undergraduate Research Opportunity Howard Hughes’ Grant to JJH.

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  1. M Roy and JJ Hom: The first two authors contributed equally to this work

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  1. Department of Biological Sciences, Stanford University, Stanford, CA, USA

    M Roy, JJ Hom & RM Sapolsky

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Roy, M., Hom, J. & Sapolsky, R. HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption. Gene Ther 9, 214–219 (2002). https://doi.org/10.1038/sj.gt.3301642

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