Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat

W.B. Veldhuis, J.W. Derksen, S. Floris, P.H. Meide, van der, H.E. Vries, de, J. Schepers, C.D. Dijkstra, L.J. Kappelle, K. Nicolaij, P.R. Bär

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    Abstract

    The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN- treatment reduced lesion volume on diffusion-weighted MRI by 70% (P <0.01) at 1 day after stroke. IFN- attenuated the leakage of contrast agent through the blood–brain barrier (P <0.005), indicating a better-preserved blood–brain barrier integrity. Both control and IFN--treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN- was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN- treatment resulted in an 85% reduction (P <0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN- almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN- affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN- has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.
    Original languageEnglish
    Pages (from-to)1029-1039
    JournalJournal of Cerebral Blood Flow and Metabolism
    Volume23
    DOIs
    Publication statusPublished - 2003

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