Interleukin-1 alpha as a novel treatment for ischemic stroke

项目概要/摘要 中风是全球死亡和残疾的主要原因，迫切需要更有效的治疗方法。 不幸的是，所有针对脑损伤引起的神经元损伤的主要机制的临床试验， 缺血（CI）（即氧化应激和兴奋性毒性）已经失败。CI还诱导了有效的局部炎症反应。 导致缺血半暗带进行性损伤的反应。然而，新的证据表明， 炎症也可能启动关键的中风后修复过程，包括血管生成， 功能恢复基于这些原因，我们认为炎症是治疗中风的一个有吸引力的靶点 复苏为了支持这一点，我们最近表明，中风后内源性脑上调， 促炎细胞因子白细胞介素-1（IL-1）亚型IL-1 β以细胞特异性方式（小胶质细胞）受到严格调节 急性和慢性血小板）表明它在损伤和修复中起重要作用， 分别此外，我们现在证明，中风后延迟（3天）给予IL-1， 促进了小鼠中风后的血管生成。这可能发生，至少部分是由于IL-1 β诱导的 产生促血管生成的细胞外基质片段串珠素LG3。此外，正如LG3所知， 神经保护作用，我们假设IL-1 β可能是神经保护和神经恢复， 缺血性中风为了支持这一假设，初步结果表明，IL-1 β全身给药， (IV)或动脉内（IA）再灌注后立即在小鼠短暂大脑中动脉 闭塞耐受良好，具有深刻的神经保护作用和功能恢复作用。因此，我们假设 提示IL-1 β可能是治疗缺血性脑卒中新的神经保护剂。 探讨IL-1 β对实验性缺血性脑卒中的神经保护作用及其机制， 我们提出以下目标： 目的1：探讨急性和慢性内源性IL-1 β在缺血性脑卒中中的作用。 目的2：探讨IL-1 β对实验性缺血性脑卒中的治疗作用。 目的3：探讨IL-1拮抗神经保护作用的机制。 这些研究的成功完成将增加我们对内源性IL-1受体的作用的理解。 在中风后的不同阶段，确定其治疗潜力和作用机制，并支持IL-1治疗。 作为一种有前途的新型中风疗法。

PROJECT SUMMARY/ABSTRACT Stroke is a major cause of death and disability worldwide and more effective therapies are urgently needed. Unfortunately, all clinical trials that have targeted the primary mechanisms of neuronal injury caused by cerebral ischemia (CI) (i.e. oxidative stress and excitotoxicity) have failed. CI also induces a potent local inflammatory response that leads to progressive damage in the ischemic penumbra. However, emerging evidence suggest that inflammation may also initiate key post-stroke repair processes including angiogenesis leading to long-term functional recovery. For these reasons we propose that inflammation is an attractive therapeutic target for stroke recovery. In support of this, we have recently shown that endogenous post-stroke brain upregulation of the proinflammatory cytokine interleukin-1 (IL-1) isoform IL-1 is tightly regulated in a cell-specific fashion (microglia acutely and platelets chronically) suggesting that it could play important roles in both injury and repair, respectively. Furthermore, we now demonstrate that delayed (3 day) post-stroke administration of IL-1 promoted post-stroke angiogenesis in mice. This may occur, at least in part, as the result of IL-1-induced generation of the proangiogenic extracellular matrix fragment perlecan LG3. Furthermore, as LG3 has known neuroprotective actions, we hypothesize that IL-1 could be both neuroprotective and neurorestorative in ischemic stroke. In support of this hypothesis, preliminary results suggest that IL-1 administered systemically (IV) or intra-arterially (IA) immediately after reperfusion in mice subjected to transient middle cerebral artery occlusion is well tolerated, profoundly neuroprotective and functionally restorative. Therefore, we hypothesize that IL-1 may represent a novel neuroprotective agent for ischemic stroke. To investigate the neuroprotective potential and mechanism(s) of action of IL-1 in experimental ischemic stroke, we propose the following aims: Aim 1: Determine the role of acute and chronic endogenous IL-1 in ischemic stroke. Aim 2: Determine the therapeutic potential of IL-1 in experimental ischemic stroke. Aim 3: Determine the neuroprotective mechanism(s) of IL-1 action. Successful completion of these studies will increase our understanding of the role of endogenous IL-1 at different stages after stroke, determine its therapeutic potential and mechanism(s) of action, and support IL-1 as a promising novel stroke therapy.