Interleukin-1 alpha as a novel treatment for ischemic stroke

Interleukin-1 alpha 作为缺血性中风的新型治疗方法

• 批准号: 9986329
• 负责人: Gregory Jaye Bix
• 金额: $ 31.51万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986329
• 关键词: Interleukin; alpha; novel; treatment; ischemic

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.

项目摘要/摘要 中风是全世界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，所有针对脑损伤主要机制的临床试验 缺血(CI)(即氧化应激和兴奋性毒性)已失效。CI还会引起强烈的局部炎症 导致缺血半暗带进行性损害的反应。然而，新出现的证据表明， 这种炎症还可能启动关键的中风后修复过程，包括血管生成，导致长期 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。 恢复。为了支持这一点，我们最近表明，中风后内源性大脑上调 促炎细胞因子IL-1(IL-1)亚型IL-1以细胞特异性方式(小胶质细胞 急性和慢性的血小板)表明它在损伤和修复中都可能发挥重要作用， 分别进行了分析。此外，我们现在证明卒中后延迟(3天)给药IL-1 促进小鼠卒中后血管生成。这可能至少部分是由于IL-1诱导的结果 促血管生成细胞外基质片段Perlecan LG3的产生。此外，正如LG3所知， 神经保护作用，我们假设IL-1可能具有神经保护和神经修复作用。 缺血性中风。为了支持这一假设，初步结果表明，IL-1是全身给药的 (IV)或动脉内注射(IA)造成小鼠大脑中动脉短暂性缺血再灌注 闭塞具有良好的耐受性，具有深刻的神经保护和功能恢复作用。因此，我们假设 IL-1可能是治疗缺血性卒中的一种新的神经保护剂。 目的：探讨IL-1对实验性缺血性卒中的神经保护作用及其机制(S)。 我们提出以下目标： 目的1：探讨急性和慢性内源性IL-1在缺血性卒中中的作用。 目的2：探讨IL-1对实验性缺血性卒中的治疗作用。 目的：探讨IL-1作用的神经保护机制(S)。 这些研究的成功完成将增加我们对内源性IL-1作用的理解 卒中后不同阶段，确定其治疗潜力和作用机制(S)，并支持IL-1 作为一种很有前途的新型中风疗法。