Novel combinatory therapy for experimental ischemic stroke

实验性缺血性中风的新型组合疗法

• 批准号: 10093153
• 负责人: Nicolas G. Bazan
• 金额: $ 32.77万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093153
• 关键词: Acute; Address; Affect; Aftercare; Alteplase; Alzheimer' s Disease; Aspirin; Attenuated; Behavioral; Bioavailable; Blood - brain barrier anatomy; Brain; Brain Injuries; Cause of Death; Cell Survival; Cerebral Ischemia; Cerebrovascular Disorders; Clinical Research; Combined Modality Therapy; Data; Dose; Early treatment; Eicosanoids; Ensure; Equilibrium; Event; Goals; Histologic; Homeostasis; Immune response; Inflammation; Inflammatory; Inflammatory Response; Interneurons; Investigational Therapies; Ischemia; Ischemic Penumbra; Ischemic Stroke; Isomerism; Lead; Longevity; Mediating; Microglia; Middle Cerebral Artery Occlusion; Modeling; Molecular Weight; Motor; Motor Cortex; Neurons; Parkinson Disease; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Process; Public Health; Rattus; Recovery; Recovery of Function; Reperfusion Injury; Research; Resolution; Signal Pathway; Signal Transduction; Silicon; Site; Stroke; Testing; Therapeutic; Therapeutic Intervention; United States; aged; angiogenesis; brain cell; disability; functional outcomes; fundamental research; in vivo; indexing; innovation; lipid mediator; macrophage; nervous system disorder; neural network; neurogenesis; neuroinflammation; neurological recovery; neuronal circuitry; neuronal survival; neuroprotectin D1; neuroprotection; neurovascular unit; novel; novel strategies; platelet activating factor receptor; post stroke; preservation; primary outcome; repaired; response; small molecule; stroke model; stroke survivor; stroke therapy; synergism; targeted treatment; therapeutic development; tool; translational impact

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.

项目总结/摘要 中风是导致死亡和永久性残疾的主要原因，对公共卫生的影响估计为73.7美元。 在美国每年10亿。缺血性中风占中风病例的85%以上。治疗 缺血性中风的选择有限。重组组织纤溶酶原激活剂（tPA）的早期治疗 只对一小部分病人有益此外，这种治疗不针对免疫炎症事件 在中风期间。缺血-再灌注损伤与多种神经炎症因子的失调有关 信号通路，导致神经元回路的不可逆损伤，导致影响 中风幸存者我们的多PI团队拥有广泛、互补和独特的专业知识， 多种研究工具将使用大鼠模型来研究一种新的方法来治疗糖尿病的有效性。 解决由实验性缺血性中风引发的神经炎性破坏， 网络完整性和促进神经恢复。我们的中心假设是，阻断亲- 炎性血小板活化因子受体（PAFR）与给予类二十二烷 将导致持续的神经恢复，并保护初级运动皮层的神经回路 在缺血性中风之后。令人信服的初步数据支持这一假设。我们发现了一个 分子量PAFR拮抗剂LAU-0901，将与阿司匹林触发的 (AT)异构体，AT-NPD 1（阿司匹林触发的神经保护素D1），我们的铅类二十二烷，在研究中提出的， 这个应用程序。我们预测，我们的新的实验性联合治疗，目标机制的运动 通过阻断促炎性PAF信号传导而造成的回路损伤将通过以下方式减少损伤并提高存活率： 确保大脑中动脉灌注后促消退和神经保护性脂质介质的可用性 闭塞（MCAo）。我们提出了两个具体的目标：1）为了检验这一假设，结合阻断亲- MCAo后炎性PAF加用二十二烷类化合物治疗将导致持续的神经恢复， 和2）测试通过组合治疗恢复促稳态脂质介质途径的预测 实验性缺血性中风提出研究的科学前提是确定关键网络 适应性大脑可塑性的过程，这可能有助于预测功能结果，也可能导致 制定治疗干预措施，以支持和促进中风后的恢复。这一创新 治疗方法也可适用于治疗其它神经系统疾病， 炎性成分如阿尔茨海默病、帕金森病等。