期刊
PHARMACEUTICAL RESEARCH
卷 -, 期 -, 页码 -出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-023-03598-7
关键词
blood-CSF barrier; breast cancer resistance protein; CNS pharmacokinetics; drug transport; P-glycoprotein
This study investigates the functional activity of P-gp and Bcrp at the murine blood-cerebrospinal fluid barrier (BCSFB) using live tissue imaging. The results show that Bcrp has functional activity at the apical membrane of the BCSFB, and P-gp may also have additional contributions.
PurposeThe brain is protected from circulating metabolites and xenobiotics by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Previous studies report that P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are expressed apically or subapically at the blood-CSF barrier (BCSFB), implying a paradoxical function to mediate blood-to-CSF transport of xenobiotics. As evidence of P-gp and Bcrp activity at the BCSFB is limited, the goal of this study is to investigate functional activity of P-gp and Bcrp at the murine BCSFB using a live tissue imaging approach.MethodsThe choroid plexuses (CP) forming the BCSFB were freshly isolated from mouse brain ventricles and incubated with fluorescent probes calcein-AM and BODIPY FL-Prazosin. Using quantitative fluorescence microscopy, the functional contributions of Bcrp and P-gp were examined using inhibitors and mice with targeted deletion of the Abcb1a/b or Abcg2 gene.ResultsApical transport of calcein-AM in choroid plexus epithelial (CPE) cells is sensitive to inhibition by elacridar and Ko143 but is unaffected by P-gp deletion. In wild-type mice, elacridar increased CPE accumulation of BODIPY FL-Prazosin by 220% whereas deletion of Bcrp increased BODIPY FL-Prazosin accumulation by 43%. There was no change in Mdr1a/1b mRNA expression in CP tissues from the Bcrp-/- mice.ConclusionsThis study demonstrated functional activity of Bcrp at the BCSFB apical membrane and provided evidence supporting an additional contribution by P-gp. These findings contribute to the understanding of transport mechanisms that regulate CSF drug concentrations, which may benefit future predictions of CNS drug disposition, efficacy, and toxicity.
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