Endogenous and exogenous protection of the BBB in stroke

中风时血脑屏障的内源性和外源性保护

• 批准号: 7769522
• 负责人: Richard F Keep
• 金额: $ 33.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-25 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769522
• 关键词: Address; Affect; Alteplase; Antioxidants; Astrocytes; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrum; Cystine; Data; Defense Mechanisms; Disease; Edema; Endothelial Cells; Endothelium; Event; Exposure to; Ferritin; Fibroblasts; Free Radicals; Functional disorder; Glucose; Glutamates; Glutathione; H ferritin; Hemin; Hemoglobin; In Vitro; Inflammation; Inflammation Mediators; Injury; Ischemia; Ischemic Preconditioning; Ischemic Stroke; Leukocytes; Link; Lipopolysaccharides; Messenger RNA; Methods; Molecular; NF-E2-related factor 2; NQO1 gene; Oxidative Stress; Oxidoreductase; Oxygen; Production; Protein Biosynthesis; Proteins; Quinine; Regulation; Reperfusion Therapy; Role; Small Interfering RNA; Stimulus; Stress; Stroke; Sulforaphane; System; Therapeutic; Tight Junctions; Up-Regulation; cell injury; cell type; cruciferous vegetable; deprivation; design; heme oxygenase-1; in vivo; interest; killings; migration; nervous system disorder; neurotoxic; neurovascular unit; preconditioning; prevent; protective effect; public health relevance; therapeutic target; transcription factor; uptake; Address; Affect; Alteplase; Antioxidants; Astrocytes; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrum; Cystine; Data; Defense Mechanisms; Disease; Edema; Endothelial Cells; Endothelium; Event; Exposure to; Ferritin; Fibroblasts; Free Radicals; Functional disorder; Glucose; Glutamates; Glutathione; H ferritin; Hemin; Hemoglobin; In Vitro; Inflammation; Inflammation Mediators; Injury; Ischemia; Ischemic Preconditioning; Ischemic Stroke; Leukocytes; Link; Lipopolysaccharides; Messenger RNA; Methods; Molecular; NF-E2-related factor 2; NQO1 gene; Oxidative Stress; Oxidoreductase; Oxygen; Production; Protein Biosynthesis; Proteins; Quinine; Regulation; Reperfusion Therapy; Role; Small Interfering RNA; Stimulus; Stress; Stroke; Sulforaphane; System; Therapeutic; Tight Junctions; Up-Regulation; cell injury; cell type; cruciferous vegetable; deprivation; design; heme oxygenase-1; in vivo; interest; killings; migration; nervous system disorder; neurotoxic; neurovascular unit; preconditioning; prevent; protective effect; public health relevance; therapeutic target; transcription factor; uptake

DESCRIPTION (provided by applicant): Endogenous and exogenous protection of the BBB in stroke. Blood-brain barrier (BBB) dysfunction occurs in a wide variety of neurological diseases and injuries (e.g. stroke). Such dysfunction may participate in those states by enhancing the influx of leukocytes into the brain, allowing the entry of potentially neurotoxic blood components and causing vasogenic edema. In addition, it may affect disease treatment (e.g. hemorrhagic transformation is a major limiting factor for the use of tissue plasminogen activator-induced reperfusion therapy for ischemic stroke). There is, therefore, a great need for methods to protect the BBB. Therapeutic targets may potentially be identified by examining which endogenous mechanisms are altered in disease states. We have shown that preconditioning stimuli can protect the BBB and cerebral endothelial cells in vivo and in vitro. We have also shown that stroke-related factors cause a marked increase in the expression of the cystine/glutamate exchanger (system xc-), a regulator of intracellular glutathione, in cerebral endothelial cells. This exchanger is regulated by nrf2 (an anti-oxidant transcription factor) and xc- can be markedly upregulated by exposure to sulforaphane, an activator of Nrf2 and a component of cruciferous vegetables. These results have led us to hypothesize that: Nrf2 and the proteins it regulates (e.g. xCT, heme oxygenase 1 and ferritin) may be a target for protecting the BBB. As Nrf2 regulation of these proteins requires protein synthesis, we also hypothesize that the function of this system is to protect against delayed BBB disruption, particularly due to migrating leukocytes in ischemia. These hypotheses will be examined in five specific aims: 1+2) Determine whether upregulation of system xc- by stroke-related factors, inflammatory mediators or sulforaphane is protective. 3+4) Determine whether Nrf2 is activated in the cerebral endothelium after stroke or inflammation and whether its activation and the upregulation of downstream proteins will protect the cerebral endothelium. 5) Examines whether treatment with sulforaphane can protect the BBB in vivo. These specific aims will be examined in vitro, to allow elucidation of molecular mechanisms, and in vivo, to determine pathophysiological relevance. The results should highlight endogenous BBB protective mechanisms and the potential exogenous compounds to activate or inhibit those mechanisms. PUBLIC HEALTH RELEVANCE: Brain blood vessels have very specialized functions, forming a blood-brain barrier. Disuption of that barrier occurs in many neurological disorders and injuries, contributing to brain dysfunction. This proposal examines natural defense mechanisms that may protect the blood-brain barrier, how to activate those mechanisms or prevent their inactivation therapeutically.

描述（由申请人提供）：中风中BBB的内源性和外源性保护。血脑屏障（BBB）功能障碍发生在多种神经系统疾病和损伤中（例如中风）。这种功能障碍可以通过增强白细胞流入大脑的流入，从而进入潜在的神经毒性血成分并引起血管性水肿，从而参与这些状态。此外，它可能会影响疾病治疗（例如，出血转化是使用组织纤溶酶原激活剂诱导的缺血性中风的再灌注疗法的主要限制因素）。因此，需要方法来保护BBB。可以通过检查哪些内源性机制在疾病状态下改变了治疗靶标。我们已经表明，预处理刺激可以在体内和体外保护BBB和脑内皮细胞。我们还表明，与中风相关的因素导致大脑内皮细胞中细胞内谷胱甘肽的调节剂（System XC-）的表达显着增加。该交换器受NRF2（一种抗氧化剂转录因子）的调节，并且可以通过暴露于NRF2的激活剂和十字花科蔬菜的成分来明显上调XC-。这些结果使我们假设：NRF2及其调节的蛋白质（例如XCT，血红素氧酶1和铁蛋白）可能是保护BBB的靶标。由于这些蛋白质的NRF2调节需要蛋白质合成，因此我们还假设该系统的功能是预防延迟的BBB破坏，特别是由于缺血中的白细胞迁移。这些假设将以五个特定的目的进行检查：1+2）确定与中风相关因素，炎症介体或硫磺烷对系统XC-的上调是否具有保护性。 3+4）确定中风或炎症后是否在脑内皮中激活NRF2，以及其激活和下游蛋白的上调是否会保护脑内皮。 5）检查使用硫烷治疗是否可以在体内保护BBB。这些特定目标将在体外检查，以阐明分子机制和体内，以确定病理生理的相关性。结果应强调内源性BBB保护机制以及激活或抑制这些机制的潜在外源化合物。公共卫生相关性：脑血管具有非常专业的功能，形成了血脑屏障。该障碍的破裂发生在许多神经系统疾病和损伤中，导致脑功能障碍。该提案研究了可以保护血脑屏障的自然防御机制，如何激活这些机制或防止其灭活治疗。