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Therapeutic use of bryostatin-1 to extend tPA time window following MCAO

使用苔藓抑素-1 来延长 MCAO 后 tPA 时间窗的治疗用途

基本信息

批准号：
9914347
负责人：
JASON D HUBER
金额：
$ 32.81万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914347
关键词：
Acute Alteplase Apoptotic Area Attenuated Basic Science Behavioral Biochemical Biological Assay Blood Vessels Brain Injuries Brain region Cerebral Edema Cerebral Infarction Cerebral hemisphere hemorrhage Cerebrum Clinical Clinical Trials Cognitive Dangerousness Data Dose Edema FDA approved Failure Functional disorder Future Goals Health Hemorrhage Human Incidence Infarction Injury Ischemic Brain Injury Ischemic Stroke Isoenzymes Knowledge Link Measures Medical Middle Cerebral Artery Occlusion Mission National Institute of Neurological Disorders and Stroke Necrosis Nervous System Trauma Neurological Models Neurons Perfusion Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Pre-Clinical Model Prevalence Protein Kinase C Public Health Rattus Recovery of Function Reperfusion Therapy Research Research Personnel Risk Safety Signal Pathway Stroke Structure Swelling Testing Therapeutic Therapeutic Uses Thrombolytic Therapy Time Tissues Training Translating United States Food and Drug Administration United States National Institutes of Health Work aged behavior measurement biochemical tools blood-brain barrier permeabilization brain endothelial cell bryostatin cerebral microvasculature cerebrovascular clinically relevant endothelial dysfunction experience improved innovation mild traumatic brain injury neurotoxicity novel therapeutics post stroke pre-clinical preference response restoration stroke model stroke outcome stroke patient stroke therapy therapeutic target thrombolysis

项目摘要

There is a tremendous clinical need for improved treatment of acute ischemic stroke. Currently, recombinant tissue plasminogen activator (tPA) is the only FDA approved drug for treatment of acute ischemic stroke. However, less than 5% of people suffering an ischemic stroke receive tPA due to increased risk of secondary cerebral hemorrhage and edema formation. Thus, an unmet need exists to develop novel therapeutics that work in combination with tPA to improve stroke outcome, reduce secondary complications, and extend the time window for administering tPA. Bryostatin-1, an ultrapotent PKC modulator, may provide substantial benefit for treatment of acute ischemic stroke. The long-term goal of our research is to identify and develop therapeutics that markedly improve the safety profile of tPA so that more victims of ischemic stroke are eligible for thrombolysis. The objective of this proposal is to determine if tPA time window can be extended in aged rats co- administered bryostatin-1 with tPA. The central hypothesis is that PKCϵ activation by administration of bryostatin-1 during the acute phase of ischemic cerebral infarction attenuates cerebral endothelium dysfunction; thus, decreasing the degree of injury & increasing the window, in which reperfusion can be safely accomplished. Rationale is that using two separate models of neurological injury (MCAO & mild traumatic brain injury), administration of bryostatin-1 reduced hemispheric swelling & BBB permeability with improved survival & functional recovery. Using our clinically relevant ischemic stroke model, we will use biochemical, neuropathological, and behavioral measures, to test our central hypothesis and accomplish the objective of this proposal, as described in these two specific aims: (1) Identify optimal dose of bryostatin-1 & validate PKCϵ as a therapeutic target & (2) identify therapeutic target of bryostatin-1 that improves cerebrovascular function post- MCAO. Specific aim 1 tests the working hypothesis that co-administration of bryostatin-1 with tPA at 6 h after MCAO will selectively activate PKCe in neurons & cerebral microvessels & it will be lower doses of bryostatin-1 (10-30 mcg/m2) that produce the most efficacious stroke outcome. Specific aim 2 test the working hyothesis that co-administration of bryostatin-1 with tPA at 6 h after MCAO reduces cerebral swelling, mitigates hemorrhagic transformation & improves stroke outcome by selective PKCε activation in cerebral endothelial cells attenuating BBB dysfunction in the infarcted hemisphere. Due to the prevalence & debilitating effects of ischemic stroke, the need for better therapeutic strategies cannot be overstated. Unfortunately, the ability to translate promising preclinical findings into effective drugs that clinically mitigate post-stroke brain damage has, to date, failed. This proposal will determine if co-administration of bryostatin-1 with tPA improves stroke outcome & extends the tPA time window following acute ischemic stroke. Results from this proposal have the translational potential to vastly improve the way ischemic stroke is treated.

临床迫切需要改善急性缺血性中风的治疗。目前，重组组织纤溶酶原激活剂（tPA）是 FDA 唯一批准用于治疗急性缺血性中风的药物。然而，由于继发性中风风险增加，只有不到 5% 的缺血性中风患者接受了 tPA 脑出血和水肿形成。因此，开发有效的新疗法的需求尚未得到满足与 tPA 联合使用可改善中风结果、减少继发并发症并延长中风时间管理 tPA 的窗口。 Bryostatin-1 是一种超强 PKC 调节剂，可为治疗急性缺血性中风。我们研究的长期目标是确定和开发治疗方法显着提高 tPA 的安全性，使更多的缺血性中风患者有资格获得治疗溶栓。该提案的目的是确定是否可以延长老年大鼠的 tPA 时间窗将苔藓抑素-1 与 tPA 一起施用。中心假设是 PKCϵ 通过施用苔藓抑素-1在缺血性脑梗死急性期可减轻脑内皮功能障碍；因此，减少损伤程度并增加可以安全完成再灌注的窗口。基本原理是使用两种不同的神经损伤模型（MCAO 和轻度创伤性脑损伤），施用苔藓抑素-1 可减少半球肿胀和 BBB 通透性，并提高存活率和功能恢复。使用我们临床相关的缺血性中风模型，我们将使用生化、神经病理学和行为测量，以检验我们的中心假设并实现这一目标提案，如这两个具体目标所述：(1) 确定苔藓抑素-1 的最佳剂量并验证 PKCϵ 为治疗靶点 & (2) 确定苔藓抑素-1 改善脑血管功能的治疗靶点 MCAO 后。具体目标 1 测试了苔藓抑素-1 与 tPA 在 6 时共同给药的工作假设 MCAO 后一小时将选择性激活神经元和脑微血管中的 PKCe，且剂量较低苔藓抑素-1 (10-30 mcg/m2) 可产生最有效的中风结果。具体目标2测试工作假设是在 MCAO 后 6 小时同时给予苔藓抑素-1 和 tPA 可减轻脑肿胀，通过选择性激活大脑中的 PKCε 来减轻出血性转化并改善中风结果内皮细胞减轻梗死半球的 BBB 功能障碍。由于流行和衰弱由于缺血性中风的影响，对更好的治疗策略的需求无论如何强调都不为过。不幸的是，能够将有希望的临床前发现转化为临床上缓解中风后大脑的有效药物迄今为止，损害尚未成功。该提案将确定苔藓抑素-1 与 tPA 联合给药是否会改善卒中结果并延长急性缺血性卒中后的 tPA 时间窗。该提案的结果极大改善缺血性中风治疗方式的转化潜力。