Neuroprotection of Remotely Administered Hypothermia on Spleen in Ischemic Stroke

远程低温对缺血性中风脾脏的神经保护作用

• 批准号: 10809221
• 负责人: YUCHUAN DING
• 金额: $ 42.35万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809221
• 关键词: Acute; Acute Brain Injuries; Animals; Anti-Inflammatory Agents; Area; Basic Science; Brain; Brain Injuries; Brain Ischemia; Brain region; CCL2 gene; Cells; Cerebral Ischemia; Clinical; Clinical Research; Coagulation Process; Data; Development; Encephalitis; Evaluation; Excision; FDA approved; Foundations; Goals; Heart Arrest; Hemorrhage; Immune; Immune system; Immunity; In Situ; Infarction; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Leukocytes; Lymphocyte; Macrophage; Macrophage Activation; Methods; Middle Cerebral Artery Occlusion; Modeling; Neurological outcome; Outcome; Patients; Phase; Procedures; Radiation; Rattus; Reaction; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Retrieval; Spleen; Splenectomy; Splenocyte; Stroke; TNF gene; Techniques; Testing; Therapeutic; Translating; acute stroke; body system; brain tissue; clinical translation; clinically relevant; cytokine; effective therapy; functional improvement; high reward; high risk; improved; innovation; knowledge translation; monocyte; natural hypothermia; neuroprotection; neutrophil; novel; novel strategies; novel therapeutics; post stroke; preservation; prevent; remote administration; side effect; stroke clinical trials; stroke model; stroke outcome; stroke patient; stroke therapy; theories; therapeutic target; thrombolysis

In spite of decades of research, stroke therapies are limited to recanalization therapies that can only be used on < 10% of stroke patients; the vast majority of stroke patients cannot be treated by these methods. Even if recanalization is successful, the outcome is often poor due to subsequent reperfusion injury. A major damage mechanism operating in stroke is inflammatory injury due to excessive pro-inflammatory cascades. Our long- term research goal is to develop effective neuroprotection strategies to lengthen the therapeutic window and prevent brain damage after reperfusion. We propose here a novel, high risk/high reward approach of Remotely Administered Hypothermia (RAH) to mitigate inflammatory injury by inducing spleen hypothermia to suppress pro-inflammatory mediators in the acute phase of stroke, and thereby reduce brain injury and improve functional outcomes. Many studies have shown that, after stroke, splenic inflammatory cells, including neutrophils, monocytes/macrophages, and lymphocytes, are released and infiltrate the brain, heightening brain inflammation and exacerbating ischemia/reperfusion injury. Clinical studies have observed spleen contraction in acute stroke patients where functional outcome improved with the gradual recovery of spleen volume. These observations are supported by stroke animal studies showing spleen volume decrease during the acute phase of middle cerebral artery occlusion (MCAO), and transfer of splenocytes to stroke-injured brain areas. Activation and release of splenic cells is upstream of excessive brain inflammation in stroke. Therefore, regulation of splenic activity offers a therapeutic target for decreasing brain inflammation and improving stroke outcomes . Animal studies however, often use irreversible manipulations of the spleen, such as splenectomy or radiation-induced inhibition of spleen function, which clearly are not clinically practical. Here we use the rat MCAO model to investigate our novel approach to reversibly suppresses spleen inflammatory activity in the acute phase of stroke by administering spleen hypothermia to mitigate excessive brain inflammation. The powerful neuroprotective effect of hypothermia has long been recognized in focal ischemic stroke. However, the clinical use of whole-body hypothermia is limited due to adverse side effects. Our novel RAH of spleen does not have these adverse side effects and is effective at decreasing brain inflammation, reducing infarct volume, and improving functional outcomes. This high risk/high reward approach, in which contemporaneous in situ reperfusion and remote administration of neuroprotective therapy (spleen hypothermia) is readily clinically translatable. Successful completion of the proposed studies will lay the foundation for treating stroke patients with a reversible inhibition of proinflammatory spleen function that will preserve the positive benefits of spleen function in the post-acute phase of stroke.

尽管经过了数十年的研究，但中风治疗仅限于再通治疗， 用于< 10%的中风患者;绝大多数中风患者不能用这些方法治疗。甚至 如果再通成功，由于随后的再灌注损伤，结果通常很差。一个重大的损害 在中风中起作用的机制是由于过度的促炎级联反应引起的炎性损伤。我们长久以来- 长期研究目标是开发有效的神经保护策略，以延长治疗窗口， 防止再灌注后的脑损伤。我们在这里提出了一种新颖的，高风险/高回报的远程方法， 给药低温（RAH）通过诱导脾脏低温抑制炎症反应来减轻炎症损伤。 促炎介质在中风的急性期，从而减少脑损伤和改善功能 结果。 许多研究表明，中风后，脾脏炎性细胞，包括中性粒细胞， 单核细胞/巨噬细胞和淋巴细胞被释放并浸润大脑，加剧大脑炎症 并加重缺血/再灌注损伤。临床研究已经观察到急性中风时脾脏收缩 随着脾脏体积的逐渐恢复，功能结局改善的患者。这些观察结果 中风动物研究显示，在急性期， 脑动脉闭塞（MCAO），以及将脾细胞转移到中风损伤的脑区域。激活和 脾细胞的释放是中风中过度脑炎症的上游。因此，调节脾 活动提供了减少脑炎症和改善中风结果的治疗靶点。动物 然而，研究经常使用脾的不可逆操作，例如脾切除术或放射诱导的脾切除术。 抑制脾功能，这显然在临床上不实用。 在这里，我们使用大鼠MCAO模型来研究我们的可逆性抑制脾脏的新方法。 通过给予脾低温以减轻过度的炎症活动， 脑部炎症低温的强大神经保护作用早已被认识到在局灶性 缺血性中风然而，由于不良副作用，全身低温的临床使用受到限制。我们 新的脾脏RAH没有这些不良副作用并且有效减少脑炎症， 减少梗死体积和改善功能结果。这种高风险/高回报的方法，其中 同时原位再灌注和远程神经保护治疗（脾低温） 很容易在临床上转化。成功完成拟议的研究将奠定基础， 中风患者具有可逆的促炎性脾功能抑制， 脾功能在中风后急性期的益处。