Comparison of Multidrug Resistance Protein-1 (MRP-1) and P-Glycoprotein (PGP) Expression in The Developing Human Central Nervous System: Cellular and Tissue Localization.

Abstract

Background: MRP-1 and Pgp are multidrug efflux pumps that share substantial overlap in substrate specificity including their possible transport of unconjugated bilirubin. Although Pgp is reportedly expressed on endothelial cells and perivascular astrocytes of the blood-brain barrier (BBB) in human newborns, the pattern of MRP-1 expression in the CNS of human neonates has not been characterized. Objective: To test the hypothesis that MRP-1 is expressed in a regionally specific, developmentally modulated fashion in human CNS and compare the pattern of MRP-1 cellular and tissue localization with that of Pgp. Design/Methods: Paraffin embedded postmortem brain tissue sections from infants born at 23–42 weeks gestation were subjected to antigen retrieval in 10 mM sodium citrate at 97°C and immunostained for MRP-1 and Pgp using the monoclonal antibodies MRPr1 (Kamiya) and C219 (Signet) respectively. Immunostaining as a function of age, cell type and brain region was semiquantified. Results: MRP-1 was expressed in choroids plexus epithelium, ependymal cells of the lateral ventricles, oligo-dendroglial cells, neurons in selected brainstem nuclei, and large pyramidal cells of the cerebellum. MRP-1 immunostaining did not change between 23 and 42 weeks gestation. MRP-1 was not observed in capillary endothelial cells or astrocytes. In contrast, Pgp immunostaining was prominent in capillary endothelial cells and perivascular astrocytes of the BBB and observed in choroids plexus epithelium and large pyramidal cells of the cerebellum; Pgp immunostaining increased with gestational age from 23–42 weeks. Conclusions: We conclude that MRP-1 and Pgp are expressed in a regional and cell specific fashion in the human CNS. Pgp is primarily expressed in endothelial cells and perivascular astrocytes of the BBB; cells that do not express MRP-1. MRP-1 is expressed in choroids plexus epithelium and ependymal cells of the ventricles, elements of the blood-CSF barrier. Both Pgp and MRP-1 are expressed in selected parenchymal neurons most notably, large pyramidal cells of the cerebellum. We speculate that the complementary pattern of MRP-1 (blood-CSF barrier) and Pgp (BBB) expression may serve together to limit CNS bilirubin levels during neonatal hyperbilirubinemia. Disclosure: Funded by NINDS (038993), 25 Club of Magee-Womens Hospital, and Mario Lemieux Centers for Patient Care and Research.