Stroke Therapy

描述（由申请人提供）： 中风是死亡、长期残疾和社会经济成本的主要原因，突出了对更有效治疗的迫切需求。组织型纤溶酶原激活剂（t-PA）静脉给药是FDA批准的唯一一种重建脑血流的治疗方法。但由于卒中后3 h以上出血风险增加，很少有卒中患者（1-2%）受益于t-PA; t-PA具有神经毒性作用，也可通过增加血脑屏障（BBB）通透性加重再灌注损伤的程度。需要一种替代策略来延长干预窗口，最大限度地减少再灌注损伤的损害，并促进脑修复，从而实现神经功能的恢复。缺血后即刻、再灌注期间及其后产生的活性氧被认为是缺血性损伤的主要介质。我们的初步研究表明，纳米颗粒介导的抗氧化酶超氧化物歧化酶（SOD）向大脑的递送减轻了ROS的影响，保护了BBB，并显着减少了中风模型中的再灌注损伤。基于这些结果，我们设想，一种有效的抗氧化剂输送系统（纳米SOD/过氧化氢酶）与t-PA的组合，可以克服目前的t-PA单独治疗的局限性。我们假设纳米SOD/过氧化氢酶具有持续的神经保护作用和减少对BBB的再灌注损伤，将1）最大限度地减少t-PA的损伤，同时保留其溶栓活性以延长治疗窗口，2）通过中和ROS的有害作用抑制神经炎症，3）创造有利于神经元修复的条件以恢复神经功能。该提案的四个具体目标是：目标1：开发神经保护性纳米SOD/过氧化氢酶系统。目的2：分析纳米SOD/过氧化氢酶对缺血性脑损伤的保护作用。目的3：评价纳米SOD/过氧化氢酶对神经功能恢复和运动功能的影响，并探讨其预防性应用。目的4：探讨纳米SOD/CAT对脑缺血损伤的修复机制。有效的治疗可以使更多的中风患者受益，而不是单独使用t-PA治疗，因为治疗窗口延长，出血并发症的风险降低。此外，由于神经元的修复，它可以显着改善脑卒中后的残疾。

DESCRIPTION (provided by applicant): Stroke is a leading cause of death, long-term disability, and socioeconomic costs, highlighting the urgent need for more effective treatments. Intravenous administration of tissue plasminogen activator (t-PA) is the only FDA-approved therapy to re-establish cerebral blood flow. But because of increased risk of hemorrhage beyond 3 h post stroke, few stroke patients (1-2%) benefit from t-PA; t-PA, which has neurotoxic effects, can also aggravate the extent of reperfusion injury by increasing blood-brain barrier (BBB) permeability. An alternative strategy is needed to extend the window of intervention, minimize damage from reperfusion injury, and promote brain repair leading to neurological recovery. Reactive oxygen species (ROS), generated soon after ischemia and during reperfusion and thereafter, are considered the main mediators of ischemic injury. Our preliminary studies show that nanoparticle-mediated delivery of the antioxidant enzyme superoxide dismutase (SOD) to the brain mitigates the effects of ROS, protects the BBB, and significantly reduces reperfusion injury in stroke model. Based on these results, we envision that an efficient antioxidant delivery system to the brain (nano-SOD/catalase) in combination with t-PA could overcome the limitations of current therapy with t-PA alone. We hypothesize that nano-SOD/catalase, with its sustained neuroprotective effects and reduced reperfusion injury to the BBB, would 1) minimize damage from t-PA while retaining its thrombolytic activity to extend the window of treatment, 2) inhibit neuroinflammation by neutralizing the deleterious effects of ROS, and 3) create conditions favorable to neuronal repair to regain neurologic functions. The proposal's four specific aims are: AIM 1: To develop a neuroprotective nano-SOD/catalase system. AIM 2: To analyze the neuroprotective efficacy of nano-SOD/catalase against ischemic injury. AIM 3: To evaluate the extent of neurological recovery and motor functions with nano-SOD/catalase and to explore its prophylactic use. AIM 4: To confirm the brain repair mechanisms of nano-SOD/catalase following ischemic injury. An effective treatment could benefit more stroke patients than can be treated with t-PA alone because of the extended window of treatment and reduced risk of hemorrhagic complications. Furthermore, it could significantly improve the post-stroke disability because of neuronal repair.