P-glycoprotein, breast cancer resistance protein, Organic Anion Transporter 3, and Transporting Peptide 1a4 during blood-brain barrier maturation: involvement of Wnt/ß-catenin and endothelin-1 signaling.

ABSTRACT

Our 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 ß-catenin expression in brain capillaries when bcrp, P-gp, oat3, and oatp1a4 transporters are at their highest expression levels. In vivo activation of ß-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 ß-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 ß-catenin. These findings shed light on the role of an interaction between ß-catenin and endothelin-1 signaling in the regulation of these transporters at the BBB.