Farthing Christine A, Sweet Douglas H
Virginia Commonwealth University, School of Pharmacy, Department of Pharmaceutics, 401 N 12th Street, Richmond, VA, 23298, USA.
Curr Pharm Des. 2014;20(10):1472-86. doi: 10.2174/13816128113199990456.
A major function of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB) is to exert selective control over the flux of organic cations and anions into and out of the CNS compartment. These barriers are dynamic tissues that accomplish this task by expressing dozens of transporter proteins representing numerous transporter families. One such family, belonging to the Solute Carrier (SLC) superfamily, is the organic cation/anion/zwitterion (SLC22) family of transporters, which includes the organic cation transporters (OCTs/OCTNs) and organic anion transporters (OATs). SLC22 transporters interact with a broad range of compounds that include drugs of abuse, environmental toxins/toxicants, opioid analgesics, antidepressant and anxiolytic agents and neurotransmitters and their metabolites. Defining the transport mechanisms controlling the CNS penetration, disposition and clearance of such compounds is fundamental to advancing our understanding of the underlying mechanisms that regulate CNS homeostasis and impact neuronal health. Such information might help direct efforts to improve the efficacy and clinical outcomes of current and future therapeutic agents used in the treatment of CNS disorders. This review focuses on highlighting the identification of the SLC22 transporter family, current knowledge of OCT and OAT expression within the CNS (including brain capillaries, choroid plexus and brain regions relevant to monoaminergic neuronal signaling), and recent data regarding behavioral changes related to mood and anxiety disorders and altered responses to stimulants and antidepressants in SLC22 loss of functions models (knockout/knockdown). In vitro and in vivo evidence of SLC22 localization and transport characteristics within the CNS compartment are summarized.
血脑屏障（BBB）和血脑脊液屏障（BCSFB）的一个主要功能是对有机阳离子和阴离子进出中枢神经系统（CNS）部分的通量进行选择性控制。这些屏障是动态组织，通过表达代表众多转运蛋白家族的数十种转运蛋白来完成这项任务。溶质载体（SLC）超家族中的一个这样的家族是有机阳离子/阴离子/两性离子（SLC22）转运蛋白家族，其中包括有机阳离子转运蛋白（OCTs/OCTNs）和有机阴离子转运蛋白（OATs）。SLC22转运蛋白与广泛的化合物相互作用，这些化合物包括滥用药物、环境毒素/毒物、阿片类镇痛药、抗抑郁药和抗焦虑药以及神经递质及其代谢产物。确定控制此类化合物中枢神经系统渗透、分布和清除的转运机制，对于增进我们对调节中枢神经系统稳态和影响神经元健康的潜在机制的理解至关重要。这些信息可能有助于指导努力提高当前和未来用于治疗中枢神经系统疾病的治疗药物的疗效和临床结果。本综述重点强调了SLC22转运蛋白家族的鉴定、中枢神经系统内OCT和OAT表达的现有知识（包括脑毛细血管、脉络丛和与单胺能神经元信号相关的脑区），以及关于SLC22功能丧失模型（敲除/敲低）中与情绪和焦虑障碍相关的行为变化以及对兴奋剂和抗抑郁药反应改变的最新数据。总结了中枢神经系统部分内SLC22定位和转运特征的体外和体内证据。
