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.

尽管进行了数十年的研究，但中风疗法仅限用于<10％的中风患者；绝大多数中风患者无法通过这些方法来治疗。甚至如果重新定性成功，则由于随后的再灌注损伤，结果通常很差。重大伤害在中风中运行的机制是由于过度促炎的级联反应而导致的炎症损伤。我们的长期术语研究目标是制定有效的神经保护策略，以延长治疗窗口和再灌注后脑损伤。我们在这里提出了一种小说，高风险/高奖励方法通过诱导脾脏体温过低以抑制抑制脾在中风的急性阶段，促炎性介体，从而减少脑损伤并提高功能结果。许多研究表明，中风后，脾炎细胞，包括中性粒细胞，单核细胞/巨噬细胞和淋巴细胞释放并浸润大脑，增加了脑部炎症并加剧缺血/再灌注损伤。临床研究观察到急性中风的脾脏收缩随着脾脏体积逐渐恢复，功能结果改善的患者。这些观察中风动物研究支持，表明中间急性期脾脏的体积减少脑动脉闭塞（MCAO），并将脾细胞转移到中风受损害的大脑区域。激活和脾细胞的释放是中风中过度脑部炎症的上游。因此，脾脏的调节活动为减少脑部炎症和改善中风结果提供了治疗靶标。动物但是，研究经常使用脾脏的不可逆操纵，例如脾切除术或辐射诱导抑制脾脏功能，显然在临床上是不实际的。在这里，我们使用大鼠MCAO模型研究我们的新方法可逆抑制脾脏通过施用脾脏体温过低以减轻过度大脑炎症。长期以来，体温过低的强大神经保护作用已在局灶性中得到认可缺血性中风。但是，由于副作用不良，全身低温的临床使用受到限制。我们的新型脾脏没有这些不良副作用，并且有效减少脑部炎症，减少梗塞量并改善功能结果。这种高风险/高奖励方法，其中同时的原位再灌注和神经保护疗法的远程给药（脾脏体温过低）很容易在临床上翻译。拟议研究的成功完成将为治疗奠定基础中风患者对促炎性脾脏功能的可逆抑制作用将保留阳性脾脏功能在中风后阶段的好处。