Perivascular astrocyte swelling after BBB disruption

BBB破坏后血管周围星形胶质细胞肿胀

• 批准号: 9062538
• 负责人: Richard F Keep
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062538
• 关键词: Address; Aspartate; Aspartic Acid; Astrocytes; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Edema; Brain hemorrhage; Cell Volumes; Cells; Cerebral Edema; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Clot retraction; Data; Edema; Event; Excitatory Amino Acids; Exposure to; Extracellular Space; Extravasation; Failure; Functional disorder; Glutamates; Health; Hematoma; Hemorrhage; In Vitro; Injury; Ischemia; Liquid substance; Mediating; Movement; Neurologic; Neuronal Injury; Neurons; Patients; Plasma; Potassium; Protamine Sulfate; Risk; Serum; Stroke; Swelling; Testing; Therapeutic Agents; Thrombin; Vascular Diseases; Water; brain parenchyma; cerebrovascular; extracellular; high risk; in vivo; inhibitor/antagonist; insight; migration; neurotoxic; prevent; response; therapeutic target

 DESCRIPTION (provided by applicant): There is marked swelling of perivascular endfeet after cerebral ischemia. This has been thought to result from parenchymal injury. However, our preliminary studies have found that plasma and serum both cause marked rapid astrocyte swelling in vitro, suggesting that ischemia-induced blood-brain barrier (BBB) disruption and an entry of plasma constituents may contribute to astrocyte swelling. In normal brain, there is a marked L-glutamate and L-aspartate gradient between plasma and brain extracellular space, with plasma concentrations being ~10 fold higher. These excitatory amino acids can cause astrocyte swelling, an effect blocked by excitatory amino acid transport (EAAT1/2 mediated) inhibition. Such inhibition also reduces serum-induced astrocyte swelling, suggesting that an influx of these excitatory amino acids from blood after BBB disruption may contribute to astrocyte swelling. The aim of this proposal is to extend these findings in vivo and to examine whether serum/plasma-induced astrocyte swelling may form a cuff that limits the occurrence of hemorrhage after BBB disruption but which may also contribute to brain edema formation. In particular, we will: 1) examine whether BBB disruption without ischemia causes endfeet swelling and whether this can be blocked by an EAAT1/2 inhibitor; and 2) determine whether there is swelling of perihematomal astrocytes after intracerebral hemorrhage (ICH) which forms a perihematomal cuff and whether blocking astrocyte swelling with a EAAT1/2 inhibitor prevents cuff formation increasing hematoma size but limiting ICH-induced edema formation. A greater understanding of astrocyte endfeet swelling after BBB disruption and ischemic/ hemorrhagic stroke may provide insights into how to treat brain edema and limit cerebral hemorrhage (hematoma expansion). In addition, these results may be of importance to the many other neurological conditions associated with BBB dysfunction.

 描述（申请人提供）：脑缺血后血管末足明显肿胀。这被认为是由于实质损伤造成的。然而，我们的初步研究发现，血浆和血清均会在体外引起星形胶质细胞明显快速肿胀，这表明缺血引起的血脑屏障（BBB）破坏和血浆成分的进入可能导致星形胶质细胞肿胀。在正常大脑中，血浆和大脑细胞外空间之间存在明显的 L-谷氨酸和 L-天冬氨酸梯度，血浆浓度高出约 10 倍。这些兴奋性氨基酸会导致星形胶质细胞肿胀，这种效应会被兴奋性氨基酸转运（EAAT1/2 介导的）抑制所阻断。这种抑制作用还可以减少血清诱导的星形胶质细胞肿胀，这表明血脑屏障破坏后这些兴奋性氨基酸从血液中涌入可能会导致星形胶质细胞肿胀。该提案的目的是在体内扩展这些发现，并检查血清/血浆诱导的星形胶质细胞肿胀是否可能形成袖带，限制血脑屏障破坏后出血的发生，但也可能导致脑水肿的形成。特别是，我们将：1）检查没有缺血的 BBB 破坏是否会导致足末肿胀，以及是否可以通过 EAAT1/2 抑制剂来阻断； 2) 确定脑出血（ICH）后血肿周围星形胶质细胞是否肿胀，形成血肿周围袖带，以及用 EAAT1/2 抑制剂阻断星形胶质细胞肿胀是否可以防止袖带形成，增加血肿大小，但限制 ICH 诱导的水肿形成。 更好地了解血脑屏障破坏和缺血性/出血性中风后星形胶质细胞足端肿胀可能会为如何治疗脑水肿和限制脑出血（血肿扩张）提供见解。此外，这些结果可能对于与 BBB 功能障碍相关的许多其他神经系统疾病也很重要。

项目成果

Endocytosis of tight junction proteins and the regulation of degradation and recycling.

• DOI: 10.1111/nyas.13346
• 发表时间: 2017-06
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Stamatovic SM;Johnson AM;Sladojevic N;Keep RF;Andjelkovic AV
• 通讯作者: Andjelkovic AV