Transport Mechanisms at the Blood-Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs.
Transport Mechanisms at the Blood-Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs.
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DOI：
10.3390/pharmaceutics14071501
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发表时间：
2022-07-20
期刊：
影响因子：
5.4
通讯作者：
Davis, Thomas P.
中科院分区：
文献类型：
--
作者：
Ronaldson, Patrick T.;Davis, Thomas P.
关键词：
缺血性卒中是美国和世界各地发病率和死亡率的主要原因。事实上，一些研究项目已经试图发现新的药物或重新利用现有的治疗方法来推进中风药物治疗。许多临床前中风研究报告了神经保护剂的积极结果;然而，只有一种化合物（3 K3 A活化蛋白C（3 K3 A-APC））已进入III期临床试验评估。这些许多失败的原因之一是缺乏对血脑屏障（BBB）和神经血管单元（NVU）的转运机制的考虑。这些内源性转运过程起着“通道”的作用，是中枢作用药物有效脑浓度的主要决定因素。尽管知道一些神经保护剂（即，他汀类药物和美金刚）是这些内源性BBB转运蛋白的底物，但临床前卒中研究在很大程度上忽略了转运蛋白在CNS药物处置中的作用。在这里，我们回顾了目前关于特定BBB转运蛋白的知识，这些转运蛋白限制药物摄取到大脑中（即，ATP结合盒（ABC）转运蛋白）或可被靶向以优化药物递送（即，溶质载体（SLC）转运蛋白）。此外，我们强调了目前的知识转运蛋白表达星形胶质细胞，小胶质细胞，周细胞和神经元的运输机制，在这些细胞类型，可以影响药物在大脑中的分布的重点。
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.
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影响因子：
2.6
作者：
Banks WA
通讯作者：
Banks WA
血脑屏障与人类认知障碍和阿尔茨海默氏病的联系。
DOI：
10.1038/s44161-021-00014-4
发表时间：
2022-03
期刊：
NATURE CARDIOVASCULAR RESEARCH
影响因子：
--
作者：
Barisano, Giuseppe;Montagne, Axel;Kisler, Kassandra;Schneider, Julie A;Wardlaw, Joanna M;Zlokovic, Berislav V
通讯作者：
Zlokovic, Berislav V
影响因子：
5.3
作者：
Bernstein, Hans-Gert;Hoelzl, Gloria;Pahnke, Jens
通讯作者：
Pahnke, Jens
影响因子：
6.7
作者：
Billington, Sarah;Salphati, Laurent;Unadkat, Jashvant D.
通讯作者：
Unadkat, Jashvant D.
影响因子：
5.5
作者：
Abdullahi, Wazir;Tripathi, Dinesh;Ronaldson, Patrick T.
通讯作者：
Ronaldson, Patrick T.