Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat.
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-beta), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-beta treatment reduced lesion volume on diffusion-weighted MRI by 70% (P < 0.01) at 1 day after stroke. IFN-beta 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-beta-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-beta was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-beta 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-beta 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-beta affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-beta has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.
Veldhuis
Wouter B
WB
Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands. veldhuis@invivonmr.uu.nl
Derksen
Joris W
JW
Floris
Sarah
S
Van Der Meide
Peter H
PH
De Vries
Helga E
HE
Schepers
Janneke
J
Vos
Ine M P
IM
Dijkstra
Christien D
CD
Kappelle
L Jaap
LJ
Nicolay
Klaas
K
Bär
Peter R
PR
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology*; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000494:pharmacology; D020521:Stroke / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9