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

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）：中风时血脑屏障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（例如中风）中。这种功能障碍可能通过增加白细胞流入大脑来参与这些状态，从而允许潜在的神经毒性血液成分进入并引起血管源性水肿。此外，它还可能影响疾病治疗（例如，出血转化是使用组织纤溶酶原激活剂诱导的再灌注疗法治疗缺血性中风的主要限制因素）。因此，非常需要保护 BBB 的方法。通过检查疾病状态下哪些内源机制发生改变，可以潜在地确定治疗靶点。我们已经证明，预处理刺激可以在体内和体外保护血脑屏障和脑内皮细胞。我们还发现，中风相关因素会导致脑内皮细胞中胱氨酸/谷氨酸交换器（系统 xc-）（细胞内谷胱甘肽的调节剂）的表达显着增加。这种交换器受 nrf2（一种抗氧化转录因子）调节，并且 xc- 可以通过暴露于萝卜硫素（Nrf2 的激活剂和十字花科蔬菜的成分）而显着上调。这些结果使我们推测：Nrf2 及其调节的蛋白质（例如 xCT、血红素加氧酶 1 和铁蛋白）可能是保护 BBB 的目标。由于 Nrf2 对这些蛋白质的调节需要蛋白质合成，因此我们还假设该系统的功能是防止延迟性 BBB 破坏，特别是由于缺血中白细胞迁移所致。这些假设将在五个具体目标中进行检验：1+2) 确定中风相关因素、炎症介质或萝卜硫素对系统 xc- 的上调是否具有保护作用。 3+4)确定Nrf2在中风或炎症后脑内皮中是否被激活，以及其激活和下游蛋白的上调是否会保护脑内皮。 5) 检查萝卜硫素处理是否可以保护体内的BBB。这些具体目标将在体外进行检查，以阐明分子机制，并在体内进行检查，以确定病理生理学相关性。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：脑血管具有非常特殊的功能，形成血脑屏障。该屏障的破坏发生在许多神经系统疾病和损伤中，导致大脑功能障碍。该提案研究了可能保护血脑屏障的自然防御机制，以及如何激活这些机制或通过治疗防止其失活。