Stroke Therapy

描述(由申请人提供)： 中风是导致死亡、长期残疾和社会经济成本的主要原因，突显了对更有效治疗的迫切需要。静脉注射组织型纤溶酶原激活剂(t-PA)是FDA批准的唯一重建脑血流的治疗方法。但由于卒中后3h以上出血的风险增加，很少有中风患者(1-2%)受益于t-PA；t-PA具有神经毒性作用，也可以通过增加血脑屏障(BBB)的通透性来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造成的损害，并促进大脑修复，从而导致神经恢复。活性氧(ROS)被认为是脑缺血损伤的主要介质，在缺血后不久、再灌流过程中及之后产生。我们的初步研究表明，在卒中模型中，纳米颗粒介导的抗氧化酶超氧化物歧化酶(SOD)脑内传递可以减轻ROS的影响，保护血脑屏障，并显著减少再灌注损伤。基于这些结果，我们设想一种有效的抗氧化剂输送系统(纳米超氧化物歧化酶/过氧化氢酶)与t-PA相结合可以克服目前单独使用t-PA治疗的局限性。我们推测，纳米超氧化物歧化酶/过氧化氢酶具有持续的神经保护作用和减少对血脑屏障的再灌注损伤，将1)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的有害影响抑制神经炎症；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：开发具有神经保护作用的纳米SOD/过氧化氢酶系统。目的：分析纳米超氧化物歧化酶/过氧化氢酶对脑缺血损伤的神经保护作用。目的：评价纳米超氧化物歧化酶/过氧化氢酶对大鼠神经功能恢复和运动功能的影响，并探讨其预防作用。目的：探讨纳米超氧化物歧化酶/过氧化氢酶在脑缺血损伤修复中的作用机制。有效的治疗可能比单独使用t-PA治疗更多的中风患者受益，因为治疗窗口延长了，出血并发症的风险降低了。此外，它还能显著改善中风后因神经元修复而导致的残疾。 公共卫生相关性： 项目叙事中风是导致死亡、长期残疾和社会经济成本的主要原因，突显了对更有效治疗的迫切需要。静脉注射组织型纤溶酶原激活剂(t-PA)是FDA批准的唯一重建脑血流的治疗方法，但它不能用于大多数中风患者，因为中风后3h以上出血的风险增加，其神经毒性作用，也可以加重再灌注损伤的程度。在拟议的研究中，我们将开发高效的抗氧化剂递送系统(纳米超氧化物歧化酶/过氧化氢酶)来保护大脑免受再灌注损伤。有效的治疗可能比单独使用t-PA治疗更多的中风患者受益，因为治疗窗口延长了，出血并发症的风险降低了。此外，纳米超氧化物歧化酶/过氧化氢酶可以预防神经炎症，促进神经元修复机制，从而显著改善卒中后的恢复。

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. PUBLIC HEALTH RELEVANCE: Project Narrative 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 it cannot be used in most stroke patients because of increased risk of hemorrhage beyond 3 h post stroke, its neurotoxic effects, can also aggravate the extent of reperfusion injury. In the proposed study, we will develop efficient antioxidant delivery system (nano- SOD/catalase) to protect brain from reperfusion 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. Further, nano-SOD/catalase could prevent neuroinflammation and facilitate neuronal repair mechanisms that could significantly improve the post-stroke recovery.