Novel combinatory therapy for experimental ischemic stroke

项目摘要/摘要 中风是导致死亡和永久性残疾的主要原因，对公共卫生造成的影响估计为73.7美元 在美国每年10亿美元。缺血性卒中占卒中病例的85%以上。治疗性的 治疗缺血性中风的选择有限。早期应用重组组织型纤溶酶原激活剂(TPA)治疗 只有一小部分患者受益。此外，这种治疗并不针对免疫炎症事件。 在中风期间。脑缺血再灌注损伤与多种神经炎性因子的调节失调有关 信号通路对神经元回路造成不可逆转的损害，从而导致影响 中风幸存者。我们的多PI团队具有广泛、互补和独特的专业知识和访问权限 多种研究工具将使用大鼠模型来研究一种新的药理学方法的有效性 解决实验性缺血性卒中引发的神经炎性中断，从而保护神经元 改善网络完整性，促进神经功能恢复。我们的中心假设是阻止亲- 炎性血小板活化因子受体(PAFR)与二十二碳二烯联用 将导致持续的神经恢复并保护初级运动皮质的神经元回路 缺血性卒中后。令人信服的初步数据支持这一假设。我们已经确定了一个低点 分子量PAFR拮抗剂LAU-0901，将与阿司匹林触发的药物一起使用 (AT)异构体AT-NPD1(阿司匹林触发的神经保护素D1)，我们的先导二十二烷类化合物，在为 这个应用程序。我们预测，我们针对运动机制的新的实验性联合疗法 通过阻断促炎PAF信号对电路的损伤将减少损伤并提高存活率 确保大脑中动脉后可获得促进分解和神经保护的脂质介质 闭塞(MCAO)。我们提出了两个具体的目标：1)检验以下假设：联合阻断亲神经。 炎症性PAF加用二十二碳二烯类化合物治疗MCAO后将导致持续的神经恢复， 以及2)检验联合治疗恢复体内平衡的脂质介质通路的预测 用于实验性缺血性中风。提出研究的科学前提是识别关键网络 适应性大脑可塑性中的过程，这可能有助于预测功能结果，也可能导致 开发治疗干预措施以支持和促进中风后的康复。这是一项创新 治疗方法也可能适用于其他神经系统疾病的治疗 炎性成分，如阿尔茨海默病、帕金森氏病等。

PROJECT SUMMARY / ABSTRACT Stroke is a leading cause of death and permanent disability, with an estimated impact on public health of $73.7 billion per year in the United States. Ischemic stroke accounts for over 85% of stroke cases. Therapeutic options for ischemic stroke are limited. Early treatment with recombinant tissue-plasminogen activator (tPA) only benefits a fraction of patients. In addition, this treatment does not target immuno-inflammatory events during stroke. Ischemia-reperfusion damage is associated with dysregulation of multiple neuroinflammatory signaling pathways that causes irreversible damage to neuronal circuits resulting in the pathologies that affect stroke survivors. Our multi-PI team with extensive, complementary, and unique expertise and access to multiple research tools will use a rat model to investigate the efficacy of a novel approach to pharmacologically resolve neuroinflammatory disruptions triggered by experimental ischemic stroke and thus preserve neuronal network integrity and promote neurologic recovery. Our central hypothesis is that blocking pro- inflammatory platelet activating factor receptor (PAFR) together with administration of docosanoids will lead to sustained neurological recovery and protect neuronal circuits in the primary motor cortex after ischemic stroke. Compelling preliminary data support this hypothesis. We have identified a low molecular weight PAFR antagonist, LAU-0901, which will be administered together with the aspirin-triggered (AT) isomer, AT-NPD1 (aspirin-triggered neuroprotectin D1), our lead docosanoid, in the studies proposed for this application. We predict that our new experimental combination therapy that targets mechanisms of motor circuit damage by blocking pro-inflammatory PAF signaling will reduce damage and enhance survival by ensuring the availability of pro-resolving and neuroprotective lipid mediators following middle cerebral artery occlusion (MCAo). We propose two specific aims: 1) To test the hypothesis that combined blocking of pro- inflammatory PAF plus treatment with docosanoids after MCAo will lead to sustained neurological recovery, and 2) Test the prediction that pro-homeostatic lipid mediator pathways are restored by combination treatment for experimental ischemic stroke. The scientific premise of the proposed research is to identify key network processes in adaptive brain plasticity, which may help to predict functional outcome and may also lead to development of therapeutic interventions to support and promote recovery after stroke. This innovative therapeutic approach may also be applicable to the treatment of other neurological diseases with an inflammatory component such as Alzheimer's disease, Parkinson's disease and others.