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Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury

Gene Therapy volume 14, pages 621–625 (2007)Cite this article

Abstract

Gene therapy may be a promising approach for treatment of brain ischemia. We and others previously demonstrated that increased activity of matrix metalloproteinases (MMPs) contributes to the tissue damage that results from ischemic injury. The proteolysis of MMPs is tightly controlled by tissue inhibitors of MMPs (TIMPs). In this study, we examined whether adenoviral-mediated gene transfer of TIMP-1 and TIMP-2 could protect against neuronal damage induced by global cerebral ischemia in mice. An adenovirus expressing TIMP-1 or TIMP-2 (AdTIMP-1 or AdTIMP-2) or a control adenovirus (RAd60) or vehicle was injected into the striatum 3 days before transient global cerebral ischemia. The extent of neuronal damage was quantified 3 days post-ischemia. There was no significant difference in the extent of neuronal damage in vehicle as compared to RAd60-treated mice. In contrast, neuronal damage was reduced, by approximately 50%, after gene transfer of AdTIMP-1 (P<0.001) and AdTIMP-2 (P< 0.01) as compared to controls. This study provides the first in vivo evidence of the protective effects of TIMP-1 and TIMP-2 via gene transfer in global ischemia.

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Acknowledgements

We gratefully acknowledge the support of the Wellcome Trust (KH is supported by a Wellcome Trust University Award) and the MRC (GJ is supported by MRC Industrial studentship with Organon.

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Authors and Affiliations

  1. Centre for Neuroscience Research, University of Edinburgh, Edinburgh, UK

    S Magnoni, S Thomson, G Jordan, J McCulloch & K Horsburgh

  2. Department of Anaesthesia and Intensive Care, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, IRCCS, Milan, Italy

    S Magnoni

  3. Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, UK

    A Baker

  4. Bristol Heart Institute, Bristol Royal Infirmary, Bristol, UK

    S J George

  5. Division of Neuroscience, Faculty of Life Sciences, University of Manchester, Manchester, UK

    B W McColl

  6. Astellas CNS Research in Edinburgh, University of Edinburgh, Edinburgh, UK

    J McCulloch

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  1. S Magnoni
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Correspondence to S Magnoni.

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Magnoni, S., Baker, A., Thomson, S. et al. Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury. Gene Ther 14, 621–625 (2007). https://doi.org/10.1038/sj.gt.3302894

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  • DOI: https://doi.org/10.1038/sj.gt.3302894

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