Neuroprotection of Remotely Administered Hypothermia on Spleen in Ischemic Stroke

尽管经过几十年的研究，中风疗法仅限于再通疗法，而这些疗法只能 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。连 如果再通成功，由于随后的再灌注损伤，结果往往很差。一次重大破坏 卒中的作用机制是由于过度的促炎性级联反应造成的炎性损伤。我们的长- 学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 预防再灌流后的脑损伤。我们在这里提出了一种新颖的、高风险/高回报的远程 应用低温(RAH)诱导脾低温抑制炎性损伤 促炎症介质在中风急性期，从而减少脑损伤，改善功能 结果。 许多研究表明，中风后，包括中性粒细胞在内的脾脏炎症细胞， 单核/巨噬细胞和淋巴细胞被释放并渗透到大脑中，加剧了脑部炎症。 加重缺血/再灌流损伤。临床研究观察到急性卒中患者的脾收缩 功能结果随着脾体积逐渐恢复而改善的患者。这些观察结果 中风动物研究表明，在中期急性期脾体积减少 大脑动脉闭塞(MCAO)，以及脾细胞转移到中风损伤的脑区。激活和 脾细胞的释放是中风患者过度脑部炎症的上游。因此，调理脾， 活动为减少脑部炎症和改善中风预后提供了一个治疗目标。动物 然而，研究经常使用不可逆的脾操作，如脾切除或辐射诱导。 抑制脾功能，这显然在临床上并不实用。 在这里，我们使用大鼠大脑中动脉阻塞模型来研究我们的可逆性抑制脾的新方法 脾低温缓解中风急性期炎症活动的实验研究 脑部发炎。低温的强大神经保护作用早已被认为是局灶性脑损伤。 缺血性中风。然而，由于全身低温的不良反应，其临床应用受到限制。我们的 新的脾RAH没有这些不良副作用，在减轻脑部炎症方面有效， 减少梗死体积，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) 在临床上很容易被翻译。成功完成拟议的研究将为治疗奠定基础 中风患者具有可逆性抑制促炎症反应的脾功能即可保留阳性 卒中后急性期脾功能的益处。

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.