White Matter Injury After Subarachnoid Hemorrhage: Role of Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9.
White Matter Injury After Subarachnoid Hemorrhage: Role of Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9.
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DOI：
10.1161/strokeaha.115.010351
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发表时间：
2015-10
期刊：
影响因子：
8.3
通讯作者：
Xi G
中科院分区：
文献类型：
--
作者：
Egashira Y;Zhao H;Hua Y;Keep RF;Xi G
我们最近观察到实验性蛛网膜下腔出血（SAH）后早期白质损伤，但潜在机制尚不确定。本研究调查了基质金属蛋白酶 (MMP)-9 在血脑屏障 (BBB) 破坏和随之而来的白质损伤中的潜在作用。 SAH 是由成年雄性小鼠的血管内穿孔引起的。设计了以下三个实验：（1）SAH后24小时对小鼠进行MRI检查并安乐死，以确定白质中的BBB破坏和MMP-9激活； (2) 为了研究 MMP-9 在 BBB 破坏中的作用，比较 SAH 后 24 小时野生型 (WT) 和 MMP-9 敲除 (MMP-9−/−) 小鼠的 MRI 病灶体积； (3) WT 和 MMP-9−/− 小鼠在 SAH 后 1 天和 8 天接受 MRI，以检测脑损伤的时间依赖性变化。大脑被用来研究白质中髓磷脂的完整性。在患有 SAH 的 WT 小鼠中，MRI 上白质显示 BBB 破坏（白蛋白渗漏）和 T2 高信号。 SAH 后 24 小时 MMP-9 活性升高。 MMP-9−/− 小鼠 SAH 后白质 T2 高信号少于 WT 小鼠。 SAH 后 8 天，WT 小鼠髓磷脂完整性降低，MMP-9−/− 小鼠白质损伤减少。 SAH 会导致 BBB 破坏，进而导致白质损伤。 MMP-9 在这些病理学中发挥着重要作用，并且可能成为 SAH 引起的白质损伤的治疗靶点。
We recently observed early white matter injury after experimental subarachnoid hemorrhage (SAH) but the underlying mechanisms are uncertain. This study investigated the potential role of matrix metalloproteinase (MMP)-9 in blood-brain barrier (BBB) disruption and consequent white matter injury. SAH was induced by endovascular perforation in adult male mice. The following three experiments were devised: (1) mice underwent MRI at 24 h after SAH and were euthanized to determine BBB disruption and MMP-9 activation in white matter; (2) to investigate the role of MMP-9 in BBB disruption, lesion volumes on MRI were compared between wild-type (WT) and MMP-9-knockout (MMP-9−/−) mice at 24 h after SAH; (3) WT and MMP-9−/− mice underwent MRI at 1 and 8 days after SAH to detect time-dependent changes in brain injury. Brains were used to investigate myelin integrity in white matter. In WT mice with SAH, white matter showed BBB disruption (albumin leakage) and T2-hyperintensity on MRI. MMP-9 activity was elevated at 24 h after SAH. MMP-9−/− mice had less white matter T2-hyperintensity after SAH than WT mice. At 8 days after SAH, WT mice had decreased myelin integrity and MMP-9−/− mice developed less white matter injury. SAH causes BBB disruption and consequent injury in white matter. MMP-9 plays an important role in those pathologies and could be a therapeutic target for SAH-induced white matter injury.