Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter, Amarillo, Texas, 79106, USA.
AAPS J. 2017 Jul;19(4):957-972. doi: 10.1208/s12248-017-0091-7. Epub 2017 May 8.
The blood-brain barrier (BBB) is a vital component of the neurovascular unit (NVU) containing tight junctional (TJ) proteins and different ion and nutrient transporters which maintain normal brain physiology. BBB disruption is a major pathological hallmark in the course of ischemic stroke which is regulated by the actions of different factors working at different stages of cerebral ischemia including matrix metalloproteinases (MMPs), inflammatory modulators, vesicular trafficking, oxidative pathways, and junctional-cytoskeletal interactions. These components interact further to disrupt maintenance of both the paracellular and transport barriers of the central nervous system (CNS) to worsen ischemic brain injury and the propensity for hemorrhagic transformation (HT) associated with injury and/or thrombolytic therapy with tissue-type plasminogen activator (tPA). We propose that these complex molecular pathways should be evaluated further so that they could be targeted alone or in combination to protect the BBB during cerebral ischemia. These types of novel interventions should be guided by advanced imaging techniques for better diagnosis of BBB damage which may exert significant therapeutic benefit including the extension of therapeutic window of tPA. This review will focus on the different stages and mechanisms of BBB damage in acute ischemic stroke and novel therapeutic strategies to target those pathways for better therapeutic outcome in stroke.
血脑屏障（BBB）是神经血管单元（NVU）的重要组成部分，包含紧密连接（TJ）蛋白和不同的离子和营养转运体，它们维持着正常的大脑生理学。BBB 破坏是缺血性中风过程中的主要病理标志，受不同因素在脑缺血不同阶段的作用调节，包括基质金属蛋白酶（MMPs）、炎症调节剂、囊泡转运、氧化途径和连接细胞骨架相互作用。这些成分进一步相互作用，破坏中枢神经系统（CNS）的细胞旁和转运屏障的维持，导致缺血性脑损伤恶化，并增加与损伤和/或组织型纤溶酶原激活物（tPA）溶栓治疗相关的出血性转化（HT）的倾向。我们提出，应该进一步评估这些复杂的分子途径，以便单独或联合靶向这些途径，在脑缺血期间保护 BBB。这些新型干预措施应该由先进的成像技术指导，以便更好地诊断 BBB 损伤，这可能会产生显著的治疗益处，包括延长 tPA 的治疗窗口。本综述将重点介绍急性缺血性中风中 BBB 损伤的不同阶段和机制，以及针对这些途径的新型治疗策略，以获得更好的中风治疗效果。
