Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University.
Biol Pharm Bull. 2021;44(4):465-473. doi: 10.1248/bpb.b21-00001.
From the viewpoint of drug discovery, it is an important issue to elucidate the drug permeability at the human central nervous system (CNS) barriers and the molecular mechanisms in the cells forming CNS barriers especially during CNS diseases. I introduced quantitative proteomics techniques into the blood-brain barrier (BBB) study, then quantitatively investigated the transport system at the human BBB and clarified the quantitative differences in protein expression levels and functions of transporters and receptors between animals and humans, or in vitro and in vivo. Based on the difference in the absolute expression level of transporters between in vitro and in vivo, I demonstrated that the drug efflux activity of P-glycoprotein (P-gp) at in vivo BBB can be accurately reconstructed from the in vitro system, not only in mouse models but also monkeys similar to humans and pathological conditions. Furthermore, I discovered Claudin-11 as another tight junction molecule expressed at the CNS barriers, and clarified that it contributes to the disruption of the CNS barriers in multiple sclerosis. Furthermore, it was also elucidated that the P-gp dysfunction causes excessive brain entry of glucocorticoid which causes a nerve damage in cerebral infarct, and it can be suppressed by targeting Abl/Src kinases. These suggest that targeting the tight junctions and transporters, which are important molecules at the CNS barriers, would potentially lead to the treatment of CNS diseases. In this review, I would like to introduce a new CNS barrier study opened by quantitative proteomics research.
从药物发现的角度来看，阐明人类中枢神经系统 (CNS) 屏障的药物通透性以及形成 CNS 屏障的细胞中的分子机制是一个重要的问题，尤其是在 CNS 疾病期间。我将定量蛋白质组学技术引入血脑屏障 (BBB) 研究中，然后定量研究了人 BBB 的转运系统，阐明了动物与人、体外与体内之间转运体和受体的蛋白表达水平和功能的定量差异。基于体外和体内之间转运体的绝对表达水平的差异，我证明了 P-糖蛋白 (P-gp) 在体内 BBB 的药物外排活性可以从体外系统准确重建，不仅在小鼠模型中，而且在类似于人类的猴子和病理条件下也是如此。此外，我发现 Claudin-11 是另一种在 CNS 屏障上表达的紧密连接分子，并阐明它有助于多发性硬化症中 CNS 屏障的破坏。此外，还阐明了 P-gp 功能障碍导致糖皮质激素过度进入大脑，从而导致脑梗死中的神经损伤，并且可以通过靶向 Abl/Src 激酶来抑制。这表明针对重要的 CNS 屏障分子——紧密连接和转运体，可能会为 CNS 疾病的治疗带来新的希望。在这篇综述中，我将介绍定量蛋白质组学研究开辟的新的 CNS 屏障研究。
