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

基本信息

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
项目类别：
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

项目摘要

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，中风治疗仅限于血管再通治疗，而这些治疗只能通过用于<10%的中风患者；绝大多数中风患者无法通过这些方法进行治疗。甚至即使再通成功，由于随后的再灌注损伤，结果往往很差。重大损害中风的作用机制是过度促炎级联导致的炎症损伤。我们的长期短期研究目标是开发有效的神经保护策略，以延长治疗窗口和防止再灌注后脑损伤。我们在这里提出一种新颖的、高风险/高回报的远程方法给予低温（RAH）通过诱导脾低温抑制炎症损伤来减轻炎症损伤中风急性期的促炎介质，从而减少脑损伤并改善功能结果。许多研究表明，中风后，脾脏炎症细胞，包括中性粒细胞，单核细胞/巨噬细胞和淋巴细胞被释放并渗入大脑，加剧大脑炎症并加剧缺血/再灌注损伤。临床研究观察到急性中风时脾脏收缩随着脾脏体积的逐渐恢复，功能结果得到改善的患者。这些观察得到中风动物研究的支持，显示中风中期急性期脾脏体积减少脑动脉闭塞（MCAO），以及将脾细胞转移到中风损伤的大脑区域。激活和脾细胞的释放是中风中过度脑部炎症的上游。因此，调节脾活动为减少大脑炎症和改善中风结果提供了治疗目标。动物然而，研究经常使用不可逆的脾脏操作，例如脾切除术或放射诱导抑制脾功能，这显然在临床上不实用。在这里，我们使用大鼠 MCAO 模型来研究我们可逆性抑制脾脏的新方法通过低温脾脏来减轻中风急性期的炎症活动脑部炎症。低温的强大神经保护作用早已在局灶性脑损伤中得到认可。缺血性中风。然而，由于不良副作用，全身低温的临床应用受到限制。我们的新型脾脏 RAH 没有这些不良副作用，并且可以有效减少脑部炎症，减少梗塞体积并改善功能结果。这种高风险/高回报的方法，其中同期原位再灌注和远程神经保护治疗（脾低温）易于临床转化。拟议研究的成功完成将为治疗奠定基础中风患者可逆性抑制促炎性脾功能，从而保留积极的功能脾脏功能在中风后急性期的益处。