Ronaldson Patrick T, Davis Thomas P
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724-5050, USA.
Pharmaceutics. 2022 Jul 20;14(7):1501. doi: 10.3390/pharmaceutics14071501.
Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have reported positive results for neuroprotective agents; however, only one compound (3K3A-activated protein C (3K3A-APC)) has advanced to Phase III clinical trial evaluation. One reason for these many failures is the lack of consideration of transport mechanisms at the blood-brain barrier (BBB) and neurovascular unit (NVU). These endogenous transport processes function as a "gateway" that is a primary determinant of efficacious brain concentrations for centrally acting drugs. Despite the knowledge that some neuroprotective agents (i.e., statins and memantine) are substrates for these endogenous BBB transporters, preclinical stroke studies have largely ignored the role of transporters in CNS drug disposition. Here, we review the current knowledge on specific BBB transporters that either limit drug uptake into the brain (i.e., ATP-binding cassette (ABC) transporters) or can be targeted for optimized drug delivery (i.e., solute carrier (SLC) transporters). Additionally, we highlight the current knowledge on transporter expression in astrocytes, microglia, pericytes, and neurons with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain.
缺血性中风是美国乃至全球发病和死亡的主要原因。事实上，一些研究项目已试图发现新药或重新利用现有疗法来推进中风药物治疗。许多这类临床前中风研究报告了神经保护剂的阳性结果；然而，只有一种化合物（3K3A 活化蛋白 C（3K3A-APC））进入了 III 期临床试验评估阶段。这些众多失败案例的一个原因是缺乏对血脑屏障（BBB）和神经血管单元（NVU）转运机制的考虑。这些内源性转运过程起着“门户”的作用，是中枢作用药物有效脑内浓度的主要决定因素。尽管已知一些神经保护剂（即他汀类药物和美金刚）是这些内源性血脑屏障转运体的底物，但临床前中风研究在很大程度上忽略了转运体在中枢神经系统药物处置中的作用。在此，我们综述了关于特定血脑屏障转运体的现有知识，这些转运体要么限制药物进入脑内（即 ATP 结合盒（ABC）转运体），要么可作为优化药物递送的靶点（即溶质载体（SLC）转运体）。此外，我们着重介绍了目前关于星形胶质细胞、小胶质细胞、周细胞和神经元中转运体表达的知识，重点关注这些细胞类型中可影响药物在脑内分布的转运机制。
