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特別演講 - Jui-Hung (Jimmy) Yen, Ph.D.
Title:
Interferon beta modulates neuroinflammation and extends tPA therapeutic window in ischemic stroke


Abstract
Stroke is a leading cause of death and results in permanent disability in up to 30% of survivors. Among them, ischemic stroke accounts for about 87 percent of all cases. Tissue plasminogen activator (tPA) is the only effective treatment for ischemic stroke but has a very limited therapeutic window of 3-4.5h. Undesirably, delayed tPA treatment beyond 3-4.5h disease onset increases risk of blood brain barrier (BBB) disruption and
hemorrhagic transformation (HT) that further exacerbates brain injury. In addition, tPA has been shown to aggravate neuroinflammation by enhancing microglia (MG) activation. Thus, there is a critical need to develop a therapeutic approach to attenuate brain inflammation and widen the tPA therapeutic window following ischemic stroke. Interferon beta (IFNβ), a cytokine with immunomodulatory properties, was approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS) for more than a decade. It has been well-established that IFNβ suppresses CNS inflammation in MS, thereby suggesting that IFNβ might have a therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in ischemic stroke using the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in the ischemic brain but also lessened neurological deficit in ischemic stroke animals. Furthermore, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced CNS infiltration of monocytes/macrophages, neutrophils, CD4+ T cells and γδT cells, inhibited the production of inflammatory mediators, suppressed the expression of adhesion molecules on brain endothelial cells, and repressed microglia activation in the ischemic brain. More importantly, we found that IFNβ alleviated BBB disruption and HT, and significantly reduced mortality rate in stroke animals with delayed tPA treatment. In conclusion, our study provides strong evidence that IFNβ can be developed as a novel therapy to alleviate neuroinflammation and mitigate adverse effect of delayed tPA treatment in ischemic stroke that would ultimately lead to a new venue of medical intervention for cerebral ischemia.
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