L-type Amino Acid Transporter 1 (SLC7A5)-Mediated Transport of Pregabalin at the Rat Blood-Spinal Cord Barrier and its Sensitivity to Plasma Branched-Chain Amino Acids |
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| Institution: | 1. Department of Chemical Engineering, Indian Institute of Technology, Delhi 110016, India;2. Chemical Engineering Department, Loughborough University, Loughborough LE11 3TU, Leicestershire, United Kingdom;1. School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China;2. School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, PR China;3. College of Environmental and Chemical Engineering, Zhaoqing University, Zhaoqing, 526061, PR China;1. Centro de Excelencia en Productos y Procesos de Córdoba (CEPROCOR), Argentina;2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina;3. Facultad de Ciencias Químicas - Universidad Nacional de Córdoba, Argentina;4. Laboratorio de Biotecnología - Facultad de Ciencias Químicas - Universidad Católica de Córdoba, Argentina;1. Department of Chemistry, Centre College, Danville, KY 40422, United States;2. Department of Chemistry and Biochemistry, DePauw University, Greencastle, IN 46135, United States;3. Department of Chemical Engineering, University of Kentucky, Lexington, KY 40506, United States;1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20903, USA;2. Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA |
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| Abstract: | Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs. |
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