Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands.
Epilepsia. 2024 Sep;65(9):2519-2536. doi: 10.1111/epi.18072. Epub 2024 Aug 5.
Stroke is a major contributor to mortality and morbidity worldwide and the most common cause of epilepsy in the elderly in high income nations. In recent years, it has become increasingly evident that both ischemic and hemorrhagic strokes induce dysfunction of the blood-brain barrier (BBB), and that this impairment can contribute to epileptogenesis. Nevertheless, studies directly comparing BBB dysfunction and poststroke epilepsy (PSE) are largely absent. Therefore, this review summarizes the role of BBB dysfunction in the development of PSE in animal models and clinical studies. There are multiple mechanisms whereby stroke induces BBB dysfunction, including increased transcytosis, tight junction dysfunction, spreading depolarizations, astrocyte and pericyte loss, reactive astrocytosis, angiogenesis, matrix metalloproteinase activation, neuroinflammation, adenosine triphosphate depletion, oxidative stress, and finally cell death. The degree to which these effects occur is dependent on the severity of the ischemia, whereby cell death is a more prominent mechanism of BBB disruption in regions of critical ischemia. BBB dysfunction can contribute to epileptogenesis by increasing the risk of hemorrhagic transformation, increasing stroke size and the amount of cerebral vasogenic edema, extravasation of excitatory compounds, and increasing neuroinflammation. Furthermore, albumin extravasation after BBB dysfunction contributes to epileptogenesis primarily via increased transforming growth factor β signaling. Finally, seizures themselves induce BBB dysfunction, thereby contributing to epileptogenesis in a cyclical manner. In repairing this BBB dysfunction, pericyte migration via platelet-derived growth factor β signaling is indispensable and required for reconstruction of the BBB, whereby astrocytes also play a role. Although animal stroke models have their limitations, they provide valuable insights into the development of potential therapeutics designed to restore the BBB after stroke, with the ultimate goal of improving outcomes and minimizing the occurrence of PSE. In pursuit of this goal, rapamycin, statins, losartan, semaglutide, and metformin show promise, whereby modulation of pericyte migration could also be beneficial.
中风是全球范围内导致死亡率和发病率的主要原因，也是高收入国家中老年人癫痫的最常见原因。近年来，越来越明显的是，缺血性和出血性中风都会导致血脑屏障（BBB）功能障碍，而这种损害可能导致癫痫发作。然而，直接比较 BBB 功能障碍和中风后癫痫（PSE）的研究在很大程度上仍然缺乏。因此，本综述总结了 BBB 功能障碍在动物模型和临床研究中导致 PSE 的作用。中风诱导 BBB 功能障碍的机制有多种，包括跨细胞转运增加、紧密连接功能障碍、扩散性去极化、星形胶质细胞和周细胞丢失、反应性星形胶质细胞增生、血管生成、基质金属蛋白酶激活、神经炎症、三磷酸腺苷耗竭、氧化应激，最终是细胞死亡。这些效应的发生程度取决于缺血的严重程度，其中细胞死亡是严重缺血区域 BBB 破坏的更主要机制。BBB 功能障碍通过增加出血性转化的风险、增加中风大小和脑血管源性水肿的量、兴奋性化合物的外渗以及增加神经炎症，从而促进癫痫发作。此外，BBB 功能障碍后的白蛋白外渗主要通过增加转化生长因子 β 信号传导促进癫痫发作。最后，癫痫发作本身会诱导 BBB 功能障碍，从而以循环方式促进癫痫发作。在修复这种 BBB 功能障碍时，血小板衍生生长因子 β 信号转导的周细胞迁移是必不可少的，也是重建 BBB 所必需的，星形胶质细胞也发挥作用。尽管动物中风模型存在局限性，但它们为设计旨在中风后恢复 BBB 的潜在治疗方法提供了有价值的见解，最终目标是改善结果并最大程度地减少 PSE 的发生。为了实现这一目标，雷帕霉素、他汀类药物、洛沙坦、司美格鲁肽和二甲双胍显示出希望，调节周细胞迁移也可能有益。
