Temporal expression of transporters and receptors in a rat primary co-culture blood–brain barrier model. (October 2014)

• Record Type: Journal Article
• Authors: Liu, Houfu; Li, Yang; Lu, Sijie; Wu, Yiwen; Sahi, Jasminder
• Is Part Of: Xenobiotica. Volume 44:Number 10(2014:Oct.)
• Page Start: 941
• Page End: 951
• Publication Date: 2014-10
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.919430
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. The more relevant primary co-cultures of brain microvessel endothelial cells and astrocytes (BMEC) are less utilized for screening of potential CNS uptake when compared to intestinal and renal cell lines.</p> <p>2. In this study, we characterized the temporal mRNA expression of major CNS transporters and receptors, including the transporter regulators <italic>Pxr, Ahr</italic> and <italic>Car</italic> in a rat BMEC co-cultured model. Permeability was compared with the Madin–Darby canine kidney (MDCKII)-MDR1 cell line and rat brain <italic>in situ</italic> perfusion model.</p> <p>3. Our data demonstrated differential changes in expression of individual transporters and receptors over the culture period. Expression of ATP-binding cassette transporters was better retained than that of solute carrier transporters. The insulin receptor (IR) was best maintained among investigated receptors. <italic>AhR</italic> demonstrated high mRNA expression in rat brain capillaries and expression was better retained than <italic>Pxr</italic> or <italic>Car</italic> in culture. <italic>Mdr1b</italic> expression was up-regulated during primary culture, albeit Mdr1a mRNA levels were much higher. P-gp and Bcrp-1 were highly expressed and functional in this <italic>in vitro</italic> system.</p> <p>4. Permeability measurements with 18 CNS marketed drugs demonstrated weak correlation between rBMEC model and rat <italic>in situ</italic> permeability and moderate correlation with MDCKII-MDR1 cells.</p> <p>5. We have provided appropriate methodologies, as well as detailed and quantitative characterization data to facilitate improved understanding and rational use of this <italic>in vitro</italic> rat BBB model.</p> </abstract>