Tachikawa Masanori, Uchida Yasuo, Terasaki Tetsuya
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Brain Nerve. 2013 Feb;65(2):121-36.
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) possess a variety of carrier-mediated transport systems to support and protect brain function. Multidisciplinary research conducted on these transport systems has provided a foundation not only for understanding the pathophysiological role of the brain barriers better but also for the development of rational drug delivery and targeting strategies for the central nervous system (CNS). Drugs recognized by the blood-to-brain influx transport systems, e.g., an amino acid transporter LAT1/SLC7A5 and an unidentified organic cation transporter, are expected to have a great potential for CNS delivery. Nevertheless, drugs recognized by efflux transporters, including ATP-binding cassette transporters such as P-glycoprotein (MDR1/ABCB1), breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistant protein 4 (MRP4/ABCC4), show low permeability across the brain barriers, resulting in low distribution to the brain. The brain-to-blood efflux transport systems also play an important role in the cerebral clearance of endogenous neurotoxic compounds such as prostaglandins and β-amyloid, the reduction of which is related to disorders of the CNS. Recently, we developed a method based on quantitative targeted absolute proteomics (QTAP) to determine the absolute expression levels of transporters of the human brain barriers. Data on absolute expression levels of transporters together with data on intrinsic transporter activity enables reconstruction of in vivo brain barrier transport function in humans. This review covers cutting-edge knowledge and methodologies related to transport systems at the BBB and BCSFB, which contribute to the knowledge regarding the management of endogenous and xenobiotic compounds by the brain, and the importance of these transport systems for CNS drug delivery and therapeutics.
血脑屏障（BBB）和血脑脊液屏障（BCSFB）拥有多种载体介导的转运系统，以支持和保护脑功能。对这些转运系统进行的多学科研究不仅为更好地理解脑屏障的病理生理作用奠定了基础，也为开发合理的中枢神经系统（CNS）药物递送和靶向策略奠定了基础。被血脑流入转运系统识别的药物，例如氨基酸转运体LAT1/SLC7A5和一种未明确的有机阳离子转运体，有望在CNS递送方面具有巨大潜力。然而，被外排转运体识别的药物，包括ATP结合盒转运体，如P-糖蛋白（MDR1/ABCB1）、乳腺癌耐药蛋白（BCRP/ABCG2）和多药耐药蛋白4（MRP4/ABCC4），在脑屏障中的通透性较低，导致在脑中的分布较少。脑血外排转运系统在前列腺素和β-淀粉样蛋白等内源性神经毒性化合物的脑清除中也起着重要作用，这些化合物的减少与CNS疾病有关。最近，我们开发了一种基于定量靶向绝对蛋白质组学（QTAP）的方法来确定人脑屏障转运体的绝对表达水平。转运体绝对表达水平的数据以及转运体固有活性的数据能够重建人体体内脑屏障的转运功能。本综述涵盖了与BBB和BCSFB转运系统相关的前沿知识和方法，这些知识有助于了解脑对内源性和外源性化合物的管理，以及这些转运系统对CNS药物递送和治疗的重要性。
