Perivascular astrocyte swelling after BBB disruption

 描述(申请人提供)：脑缺血后血管周围终足明显肿胀。这被认为是实质损伤造成的。然而，我们的初步研究发现，血浆和血清在体外都能引起星形胶质细胞显著的快速肿胀，这表明缺血诱导的血脑屏障(BBB)破坏和血浆成分进入可能是星形胶质细胞肿胀的原因之一。在正常脑组织中，血浆与脑细胞外间隙之间存在明显的L-谷氨酸和L-天冬氨酸梯度，其血浆浓度约高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运输(EAAT1/2介导)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，这表明这些兴奋性氨基酸在血脑屏障破坏后从血液中涌入可能有助于星形胶质细胞肿胀。这项建议的目的是在活体内推广这些发现，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，限制血脑屏障中断后出血的发生，但也可能导致脑水肿的形成。特别是，我们将：1)检查在没有缺血的情况下破坏BBB是否会导致终足肿胀，以及EAAT1/2抑制剂是否可以阻止这种情况；以及2)确定脑出血(ICH)后是否有血肿周围星形胶质细胞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。对血脑屏障破坏和脑缺血/出血性卒中后星形胶质细胞终足肿胀的更多了解可能会为如何治疗脑水肿和限制脑出血(血肿扩大)提供见解。此外，这些结果可能对与血脑屏障功能障碍相关的许多其他神经系统疾病具有重要意义。

 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.