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Developmental expression of multidrug resistance phosphoglycoprotein (P-gp) in the mouse fetal brain and
Sophie Petropoulos1, William Gibb, Stephen G Matthews
1Department of Physiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada.
Insights
The fetal brain
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The blood-brain barrier (BBB) protects the fetal brain from harmful substances.
- Phosphoglycoprotein (P-gp), a multidrug resistance protein, is crucial for BBB function.
- Understanding P-gp in the fetal brain is vital due to its vulnerability to substrates and the use of synthetic glucocorticoids in preterm labor.
Purpose of the Study:
- To investigate the developmental expression and function of Abcb1 (P-gp) in the fetal brain.
- To determine the effects of synthetic glucocorticoids on fetal brain P-gp.
- To assess the impact of these changes on the accumulation of P-gp substrates in the fetal brain.
Main Methods:
- Analysis of Abcb1 mRNA and P-gp protein expression in fetal brains at different gestational ages (E15.5, E18.5).
- Measurement of [(3)H]digoxin accumulation in fetal brains to assess P-gp function.
- Administration of dexamethasone (DEX) to pregnant dams at various doses and gestational periods, followed by fetal brain analysis.
Main Results:
- Abcb1 mRNA and P-gp protein levels increased significantly near term (E18.5).
- Fetal brain accumulation of [(3)H]digoxin decreased as gestation advanced, indicating enhanced P-gp function.
- Dexamethasone treatment altered Abcb1 mRNA and P-gp function in a dose-, gestational age-, and sex-specific manner.
Conclusions:
- P-gp mediated neuroprotection in the fetal brain strengthens with advancing gestation.
- Synthetic glucocorticoids can modulate multidrug resistance in the fetal brain.
- These findings have significant clinical implications for managing preterm labor with synthetic glucocorticoids.
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 [(3)H]digoxin accumulation or P-gp expression. In another group, pregnant FVB dams were injected daily with either dexamethasone (DEX; 0.1mg/kg or 1mg/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 [(3)H]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.
