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

Abstract

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 [ 3H]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 [ 3H]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.