Sarvari Sajad, Moakedi Faezeh, Hone Emily, Simpkins James W, Ren Xuefang
Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
Department of Biochemistry, West Virginia University, Morgantown, WV, USA.
Metab Brain Dis. 2020 Aug;35(6):851-868. doi: 10.1007/s11011-020-00573-8. Epub 2020 Apr 15.
Stroke is the leading cause of disability among adults as well as the 2nd leading cause of death globally. Ischemic stroke accounts for about 85% of strokes, and currently, tissue plasminogen activator (tPA), whose therapeutic window is limited to up to 4.5 h for the appropriate population, is the only FDA approved drug in practice and medicine. After a stroke, a cascade of pathophysiological events results in the opening of the blood-brain barrier (BBB) through which further complications, disabilities, and mortality are likely to threaten the patient's health. Strikingly, tPA administration in eligible patients might cause hemorrhagic transformation and sustained damage to BBB integrity. One must, therefore, delineate upon stroke onset which cellular and molecular factors mediate BBB permeability as well as what key roles BBB rupture plays in the pathophysiology of stroke. In this review article, given our past findings of mechanisms underlying BBB opening in stroke animal models, we elucidate cellular, subcellular, and molecular factors involved in BBB permeability after ischemic stroke. The contribution of each factor to stroke severity and outcome is further discussed. Determinant factors in BBB permeability and stroke include mitochondria, miRNAs, matrix metalloproteinases (MMPs), immune cells, cytokines, chemokines, and adhesion proteins. Once these factors are interrogated and their roles in the pathophysiology of stroke are determined, novel targets for drug discovery and development can be uncovered in addition to novel therapeutic avenues for human stroke management.
中风是成年人残疾的主要原因，也是全球第二大死因。缺血性中风约占中风病例的85%，目前，组织型纤溶酶原激活剂（tPA）是美国食品药品监督管理局（FDA）实际批准使用的唯一药物，其治疗窗口对合适的人群限制在4.5小时以内。中风后，一系列病理生理事件会导致血脑屏障（BBB）开放，进而可能引发更多并发症、残疾和死亡，威胁患者健康。引人注目的是，对符合条件的患者使用tPA可能会导致出血性转化，并持续损害血脑屏障的完整性。因此，必须在中风发作时就明确哪些细胞和分子因素介导血脑屏障通透性，以及血脑屏障破裂在中风病理生理学中起什么关键作用。在这篇综述文章中，鉴于我们过去在中风动物模型中对血脑屏障开放机制的研究发现，我们阐明了缺血性中风后涉及血脑屏障通透性的细胞、亚细胞和分子因素。我们还进一步讨论了每个因素对中风严重程度和预后的影响。血脑屏障通透性和中风的决定性因素包括线粒体、微小RNA（miRNA）、基质金属蛋白酶（MMP）、免疫细胞、细胞因子、趋化因子和黏附蛋白。一旦对这些因素进行深入研究并确定它们在中风病理生理学中的作用，除了为人类中风治疗开辟新的治疗途径外，还可以发现药物研发的新靶点。
