Glucocorticoids modulate drug transporter function in human fetal brain endothelial cells

Area of Science:

• Neuroscience
• Pharmacology
• Developmental Biology

Background:

• Synthetic glucocorticoids (sGC) are used during pregnancy, but their impact on the fetal blood-brain barrier (BBB) drug transporters is unknown.
• Key BBB drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are modulated by glucocorticoids in animal models.
• Cortisol is crucial for fetal BBB maturation, but its effect on drug transporter function in humans is not understood.

Purpose of the Study:

• To investigate the effects of dexamethasone (sGC) and cortisol on drug transporter function and expression in the human fetal BBB.
• To determine if these effects are dependent on gestational age (early vs. mid-gestation).

Main Methods:

• Primary human fetal brain endothelial cells (hfBECs) from early and mid-gestation were cultured.
• Cells were treated with dexamethasone and cortisol in vitro.
• P-gp and BCRP efflux activity, protein levels, and mRNA expression were measured.

Main Results:

• Dexamethasone and cortisol increased P-gp and BCRP efflux activity in a time-, dose-, and age-dependent manner.
• Mid-gestation hfBECs showed greater relative increases in transporter activity compared to early gestation.
• Dexamethasone increased P-gp and BCRP protein levels in early gestation cells but not in mid-gestation cells, suggesting a non-genomic mechanism.

Conclusions:

• Glucocorticoids significantly increase P-gp and BCRP activity in the human fetal BBB, with effects varying by gestational age.
• The observed changes in transporter activity may occur via non-genomic pathways, potentially involving glucocorticoid receptor and pregnane X receptor signaling.
• Altered glucocorticoid levels during gestation could dysregulate the transport of substances into the developing brain, impacting neurodevelopment.