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.
|Tijdschrift||Journal of Cerebral Blood Flow and Metabolism|
|Status||Gepubliceerd - 2003|