Interferon-Beta Blocks Infiltration of Inflammatory Cells and Reduces Infarct Volume after Ischemic Stroke in the Rat

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-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.

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

“…In the CNS, both astrocytes and microglia express MMP9 (28), and it is also expressed by infiltrating macrophages (44). It has been shown that type I IFN inhibits MMP9 expression in astrocytes and microglia and reduces leukocyte infiltration to the CNS (29,43,(45)(46)(47). We find that in the absence of type I IFN signaling, MMP9 was significantly increased.…”

Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo

“…IFNβ is an important downstream chemical product of TLR3 and TLR4 via TRIF. It has been shown that direct administration of IFNβ reduced ischemic brain damage in both rat and rabbit models of ischemic stroke [27][28][29] . The protective effects of IFNβ are associated with both preventing neutrophil infiltration and attenuating blood-brain barrier damage [28] .…”

Kinetic Changes of COX-2 Expression during Reperfusion Period after Ischemic Preconditioning Play a Role in Protection Against Ischemic Damage in Rat Brain

“…Some macrophage and microglial response after injury is necessary for scavenging the necrotic debris facilitating plasticity (Danton and Dietrich, 2003). However, excess infiltration of leukocytes into the brain is detrimental and therapies that prevent leukocyte infiltration during the acute phase after ischemia are neuroprotective (Yrjanheikki et al, 1999;Veldhuis et al, 2003;Yenari et al, 2005;Garau et al, 2005). Individual inflammatory mediators play a complex role in promoting protection as well as destruction after brain injury.…”