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P‑Glycoprotein, Breast Cancer Resistance Protein, Organic Anion Transporter 3, and Transporting Peptide 1a4 during Blood–Brain Barrier Maturation: Involvement of Wnt/β-Catenin and Endothelin‑1 Signaling
journal contribution
posted on 2016-02-19, 10:03 authored by Rania Harati, Henri Benech, Anne Sophie Villégier, Aloïse MabondzoOur current knowledge about drug transporters in the
maturational
brain is very limited. In this study, we provide a comprehensive overview
of the expression and activity profile of P-glycoprotein (P-gp), Breast
Cancer Resistance Protein (bcrp), Organic Anion Transporter 3 (oat3),
and Transporting Peptide 1a4 (oatp1a4) transporters during blood–brain
barrier (BBB) maturation. Gene and protein expressions of the analyzed
transporters increase as the brain matures, with no variation in their
activity for P-gp and bcrp, while the transport activity of oat3 and
oatp1a4 increases during brain maturation from preterm up to adulthood.
For the first time, we illustrate a downregulation of nuclear β-catenin
expression in brain capillaries when bcrp, P-gp, oat3, and oatp1a4
transporters are at their highest expression levels. In vivo activation of β-catenin in rat brains, by intracerebroventricular
(ICV) injection of a GSK-3 inhibitor, enhances the activity of P-gp,
bcrp, oat3, and oatp1a4. Interestingly, in an in vitro BBB model consisting of a coculture of primary endothelial brain
cells with astrocytes or in vivo, activation of β-catenin
enhances the mRNA expression of ET-1. Interestingly, blocking the
ETA receptor for endothelin-1 in vivo by ICV injection
of a ETA antagonist decreases transporter activity mediated by the
activation of β-catenin. These findings shed light on the role
of an interaction between β-catenin and endothelin-1 signaling
in the regulation of these transporters at the BBB.