Developmental expression of multidrug resistance phosphoglycoprotein (P-gp) in the mouse fetal brain and glucocorticoid regulation

The multidrug resistance gene (Abcb1) protein product, phosphoglycoprotein (P-gp) is expressed on the luminal surface of capillary endothelial cells of the adult blood-brain barrier (bbb). P-gp is critical for neuroprotection as it actively pumps substrates back into the capillary lumen. The fetal brain represents a primary target for many P-gp substrates; however, the developmental expression, function and regulation of Abcb1 in the fetal brain are not well understood. Approximately 10% of pregnant women undergo synthetic glucocorticoid therapy for the management of preterm labor (PTL), though the effects of synthetic glucocorticoid on P-gp in the fetal brain are not known. We hypothesize that in the fetal brain: 1) expression and function of Abcb1 will increase with advancing gestation; 2) synthetic glucocorticoids will up-regulate the expression of Abcb1 and 3) this increased expression will correspond to a decrease in brain accumulation of P-gp substrates. Pregnant FVB dams were euthanized on embryonic day (E) 15.5 or E18.5 and fetal brains were collected and analyzed for [H-3]digoxin accumulation or P-gp expression. In another group, pregnant FVB dams were injected daily with either dexamethasone (DEX; 0.1 mg/kg or 1 mg/kg) or vehicle from E9.5-E15.5 (mid-gestation) or E12.5-E18.5 (late-gestation) and analyzed on E15.5 or E18.5. Abcb1a mRNA (P<0.01) and P-gp protein increased near term, corresponding to decreased [H-3]digoxin accumulation in the fetal brain (P<0.001). DEX treatment during mid-gestation modified Abcb1 mRNA expression and P-gp function in a dose-, gestational age-, and sex-specific manner. In conclusion, P-gp mediated protection of the fetal brain increases with advancing gestation in an isoform-specific manner. Synthetic glucocorticoid exposure can modify expression and function of multidrug-resistance in the fetal brain, and this will likely have clinical implication given the extensive use of synthetic glucocorticoid in the management of PTL. (C) 2010 Elsevier B.V. All rights reserved.