Blood-Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit.
Blood-Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit.
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DOI：
10.1523/eneuro.0123-18.2018
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发表时间：
2018-05
期刊：
影响因子：
3.4
通讯作者：
Härtig W
中科院分区：
文献类型：
--
作者：
Bankstahl M;Breuer H;Leiter I;Märkel M;Bascuñana P;Michalski D;Bengel FM;Löscher W;Meier M;Bankstahl JP;Härtig W
脑损伤后血脑屏障（BBB）通透性增加导致血浆蛋白的局部外渗，并可能对癫痫的发病机制起关键作用。在这里，我们全面探讨了白蛋白这一主要外渗成分的时空演变，并阐明了神经血管单元（NVU）对早期癫痫性神经病理的相关反应。我们在广泛应用的大鼠匹罗卡品癫痫持续状态（SE）模型中应用了体内翻译磁共振成像和互补免疫组织化学分析。观察到的快速血脑屏障渗漏影响主要癫痫发生相关的脑区，在se后1 ~ 2 d达到峰值，此后迅速下降，并伴有脑水肿，一般遵循相同的时间过程。在血脑屏障渗漏的高峰期，血清白蛋白与NVU成分（如血管成分、神经元和脑免疫细胞）共定位。令人惊讶的是，星形胶质细胞标记物没有与白蛋白共定位，水通道蛋白-4 （AQP4）在漏血脑屏障区域明显减少，表明星形胶质细胞介导的内皮-神经元偶联受到严重干扰。此外，NVU血管系统明显的适应性重组过程发生在白蛋白存在的部位，内皮细胞免疫反应性降低和血管基底膜标志物的改变证实了这一点。综上所述，NVU水平的退行性事件，影响血管、星形胶质细胞和神经元，似乎超过了重建过程。考虑到快速发生的血脑屏障泄漏和随后的NVU损伤，我们的数据支持迅速恢复血脑屏障治疗的必要性，作为合理治疗干预的一个组成部分，以防止癫痫发生和SE的其他有害后遗症的发展。
Increased permeability of the blood–brain barrier (BBB) following cerebral injury results in regional extravasation of plasma proteins and can critically contribute to the pathogenesis of epilepsy. Here, we comprehensively explore the spatiotemporal evolution of a main extravasation component, albumin, and illuminate associated responses of the neurovascular unit (NVU) contributing to early epileptogenic neuropathology. We applied translational in vivo MR imaging and complementary immunohistochemical analyses in the widely used rat pilocarpine post–status epilepticus (SE) model. The observed rapid BBB leakage affected major epileptogenesis-associated brain regions, peaked between 1 and 2 d post-SE, and rapidly declined thereafter, accompanied by cerebral edema generally following the same time course. At peak of BBB leakage, serum albumin colocalized with NVU constituents, such as vascular components, neurons, and brain immune cells. Surprisingly, astroglial markers did not colocalize with albumin, and aquaporin-4 (AQP4) was clearly reduced in areas of leaky BBB, indicating a severe disturbance of astrocyte-mediated endothelial-neuronal coupling. In addition, a distinct adaptive reorganization process of the NVU vasculature apparently takes place at sites of albumin presence, substantiated by reduced immunoreactivity of endothelial and changes in vascular basement membrane markers. Taken together, degenerative events at the level of the NVU, affecting vessels, astrocytes, and neurons, seem to outweigh reconstructive processes. Considering the rapidly occurring BBB leakage and subsequent impairment of the NVU, our data support the necessity of a prompt BBB-restoring treatment as one component of rational therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of SE.