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: 8959648
• 负责人: Richard F Keep
• 金额: $ 19.39万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959648
• 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; DL-TBOA; Data; Edema; Event; Excitatory Amino Acids; Exposure to; Extracellular Space; Extravasation; Failure; Functional disorder; Glutamates; 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; cerebrovascular; extracellular; high risk; in vivo; inhibitor/antagonist; insight; migration; neurotoxic; prevent; public health relevance; 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（由申请人提供）：脑缺血后血管周围终足明显肿胀。这被认为是由实质损伤引起的。然而，我们的初步研究发现，血浆和血清都引起显着的快速星形胶质细胞肿胀在体外，这表明缺血诱导的血脑屏障（BBB）的破坏和血浆成分的进入可能有助于星形胶质细胞肿胀。在正常脑中，血浆和脑细胞外空间之间存在显著的L-谷氨酸和L-天冬氨酸梯度，血浆浓度高约10倍。这些兴奋性氨基酸可以引起星形胶质细胞肿胀，这种作用被兴奋性氨基酸转运（EAAT 1/2介导的）抑制所阻断。这种抑制也减少了血清诱导的星形胶质细胞肿胀，表明血脑屏障破坏后这些兴奋性氨基酸从血液中流入可能有助于星形胶质细胞肿胀。本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限制BBB破坏后出血发生但也可能导致脑水肿形成的袖带。我们尤其会：1）检查没有缺血的BBB破坏是否引起终足肿胀，以及这是否可以被EAAT 1/2抑制剂阻断;和2）确定在脑出血（ICH）后是否存在形成血肿周围袖带的血肿周围星形胶质细胞的肿胀，以及用EAAT 1/2抑制剂阻断星形胶质细胞肿胀是否防止袖带形成，增加血肿大小但限制ICH诱导的水肿形成。 对BBB破坏和缺血性/出血性卒中后星形胶质细胞终足肿胀的更深入了解可能为如何治疗脑水肿和限制脑出血（血肿扩大）提供见解。此外，这些结果可能对与BBB功能障碍相关的许多其他神经系统疾病具有重要意义。