Departments of Physiology and Cell Biology, Brain and Cognitive Sciences, The Inter-Faculty Brain Science School, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva Israel.
Neurology Residency Training Program, McGill University, Montreal, QC, Canada.
Epilepsy Behav. 2019 Dec;101(Pt B):106285. doi: 10.1016/j.yebeh.2019.04.038. Epub 2019 Nov 8.
The blood-brain barrier (BBB), a unique anatomical and physiological interface between the central nervous system (CNS) and the peripheral circulation, is essential for the function of neural circuits. Interactions between the BBB, cerebral blood vessels, neurons, astrocytes, microglia, and pericytes form a dynamic functional unit known as the neurovascular unit (NVU). The NVU-BBB crosstalk plays a key role in the regulation of blood flow, response to injury, neuronal firing, and synaptic plasticity. Blood-brain barrier dysfunction (BBBD), a hallmark of brain injury, is a prominent finding in status epilepticus. Blood-brain barrier dysfunction is observed within the first hour of status epilepticus, and in epileptogenic brain regions, may last for months. Blood-brain barrier dysfunction was shown to have a role in astroglial dysfunction, neuroinflammation, increasing neural excitability, reduction of seizure threshold, excitatory synaptogenesis, impaired plasticity, and epileptogenesis. A key signaling pathway associated with BBBD-induced neurovascular dysfunction is the transforming growth factor beta (TGF-β) proinflammatory pathway, activated by the extravasation of serum albumin into the brain when BBB functions are compromised. Specific small molecules blocking TGF-β, and the nonspecific, Food and Drug Administration (FDA) approved blocker and angiotensin antagonist losartan, were shown to reduce BBBD and block epileptogenesis. With these encouraging preclinical data, we have developed imaging approach to quantitatively assess BBBD as a diagnostic, predictive, and pharmacodynamic biomarker after brain injury. Clinical trials in the foreseen future are expected to test the feasibility of BBB-targeted diagnostic coupled therapy in status epileptics and seizure disorders. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
血脑屏障（BBB）是中枢神经系统（CNS）和外周循环之间独特的解剖和生理界面，对于神经回路的功能至关重要。BBB、脑血管、神经元、星形胶质细胞、小胶质细胞和周细胞之间的相互作用形成了一个动态的功能单元，称为神经血管单元（NVU）。NVU-BBB 串扰在调节血流、对损伤的反应、神经元放电和突触可塑性方面起着关键作用。血脑屏障功能障碍（BBBD）是脑损伤的标志，也是癫痫持续状态的突出发现。在癫痫持续状态的第一个小时内就观察到血脑屏障功能障碍，在致痫脑区，可能持续数月。血脑屏障功能障碍被证明在星形胶质细胞功能障碍、神经炎症、增加神经兴奋性、降低癫痫发作阈值、兴奋性突触形成、可塑性受损和癫痫发生中起作用。与 BBBD 诱导的神经血管功能障碍相关的一个关键信号通路是转化生长因子β（TGF-β）促炎途径，当 BBB 功能受损时，血清白蛋白外渗进入大脑会激活该途径。特异性阻断 TGF-β的小分子，以及非特异性的、美国食品和药物管理局（FDA）批准的阻滞剂和血管紧张素拮抗剂氯沙坦，已被证明可减少 BBBD 并阻断癫痫发生。有了这些令人鼓舞的临床前数据，我们已经开发出了一种成像方法，用于定量评估脑损伤后的血脑屏障功能障碍作为一种诊断、预测和药效学生物标志物。预计在不久的将来会进行临床试验，以测试针对血脑屏障的诊断联合治疗在癫痫持续状态和癫痫发作障碍中的可行性。本文是第 7 届伦敦-因斯布鲁克癫痫持续状态和急性发作学术研讨会特刊的一部分。
