Löscher Wolfgang, Gericke Birthe
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany.
Center for Systems Neuroscience, D-30559 Hannover, Germany.
Pharmaceutics. 2020 Oct 14;12(10):966. doi: 10.3390/pharmaceutics12100966.
The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.
血脑屏障（BBB）限制了几种脑部疾病的药物治疗。除了血脑屏障的结构和代谢特征外，ATP驱动的药物外排转运蛋白P-糖蛋白（Pgp）是血脑屏障的选择性守门人；因此，它是药物输送到大脑的主要障碍。在此，我们综述血脑屏障处Pgp表达和功能活性的复杂调控，重点关注我们实验室的最新研究。除了诸如Pgp表达和功能的转录调控以及转录后或翻译后修饰等传统过程外，还讨论了诸如血脑屏障内皮细胞内和细胞间Pgp转运以及细胞内Pgp介导的溶酶体隔离随后由血液中性粒细胞清除等新机制。血脑屏障处这些主动药物外排的内在机制是潜在的治疗靶点，可用于调节P-糖蛋白活性以治疗脑部疾病并增强药物向大脑的输送。
