scholarly journals Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

2017 ◽  
Vol 41 (3) ◽  
pp. 1044-1050 ◽  
Author(s):  
Enrrico Bloise ◽  
Sophie Petropoulos ◽  
Majid Iqbal ◽  
Alisa Kostaki ◽  
Tania Maria Ortiga-Carvalho ◽  
...  
Keyword(s):  
Viral Infection ◽  
Blood Brain Barrier ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Environmental Toxins ◽  
Brain Barrier ◽  
Fetal Blood ◽  
Maternal Circulation ◽  
P Glycoprotein ◽  
Blood Brain

Background/Aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain. Methods: Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [3H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, ‘fetal-units’ (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected. Results: PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [3H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed. Conclusion: Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.

scholarly journals Corticosteroid Regulation of P-Glycoprotein in the Developing Blood-Brain Barrier

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1067-1079 ◽  
Author(s):  
Majid Iqbal ◽  
William Gibb ◽  
Stephen G. Matthews
Keyword(s):  
Blood Brain Barrier ◽  
Fetal Brain ◽  
Late Gestation ◽  
Brain Barrier ◽  
Protective Capacity ◽  
Maternal Circulation ◽  
Acetoxymethyl Ester ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Brain Microvessel

The early fetal brain is susceptible to teratogens in the maternal circulation, because brain microvessel expression of drug efflux transporter, P-glycoprotein (P-gp), is very low. However, there is a dramatic up-regulation of brain microvessel P-gp in late gestation. This study investigated the role of cortisol and dexamethasone in this up-regulation of fetal brain microvessel P-gp expression. Primary brain endothelial cell (BEC) cultures derived from gestational d (GD)40, GD50, GD65 (term, ∼68 d) and postnatal d 14 male guinea pigs were treated with varying doses (10−8 to 10−5m) of cortisol, dexamethasone, and aldosterone. After treatment, P-gp function was assessed using calcein-acetoxymethyl ester (P-gp substrate; 1 μm for 1 h) and measuring BEC accumulation of calcein. Corticosteroid treatment of BECs derived from postnatal d 14 resulted in increased P-gp activity. BECs derived from GD65 (near term) responded similarly, but these cells were extremely sensitive to the effects of mineralocorticoid receptor agonists (cortisol and aldosterone). BECs derived from GD50 displayed dose-dependent increases in P-gp function with dexamethasone (P &lt; 0.05) and a trend towards increased function with cortisol. Cells derived from GD40 were unresponsive to all treatments. In conclusion, P-gp function in BECs is more responsive to glucocorticoids (GCs) in late gestation. Therefore, the late gestational surge in fetal plasma GCs, which parallels the increase in brain microvessel P-gp expression, may contribute to this P-gp up-regulation. Further, synthetic GCs (administered to pregnant women at risk of preterm delivery) may increase the protective capacity of the developing fetal blood-brain barrier, depending on the timing of GC exposure.

scholarly journals TGF-β1 Regulation of Multidrug Resistance P-glycoprotein in the Developing Male Blood-Brain Barrier

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 475-484 ◽  
Author(s):  
Stephanie Baello ◽  
Majid Iqbal ◽  
Enrrico Bloise ◽  
Mohsen Javam ◽  
William Gibb ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Fetal Brain ◽  
Cell Types ◽  
Brain Barrier ◽  
Dependent Manner ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Age Dependent ◽  
Tgf Β1

P-glycoprotein (P-gp), an efflux transporter encoded by the abcb1 gene, protects the developing fetal brain. Levels of P-gp in endothelial cells of the blood-brain barrier (BBB) increase dramatically during the period of peak brain growth. This is coincident with increased release of TGF-β1 by astrocytes and neurons. Although TGF-β1 has been shown to modulate P-gp activity in a number of cell types, little is known about how TGF-β1 regulates brain protection. In the present study, we hypothesized that TGF-β1 increases abcb1 expression and P-gp activity in fetal and postnatal BBB in an age-dependent manner. We found TGF-β1 to potently regulate abcb1 mRNA and P-gp function. TGF-β1 increased P-gp function in brain endothelial cells (BECs) derived from fetal and postnatal male guinea pigs. These effects were more pronounced earlier in gestation when compared with BECs derived postnatally. To investigate the signaling pathways involved, BECs derived at gestational day 50 and postnatal day 14 were exposed to ALK1 and ALK5 inhibitors and agonists. Through inhibition of ALK5, we demonstrated that ALK5 is required for the TGF-β1 effects on P-gp function. Activation of ALK1, by the agonist BMP-9, produced similar results to TGF-β1 on P-gp function. However, TGF-β1 signaling through the ALK1 pathway is age-dependent as dorsomorphin, an ALK1 inhibitor, attenuated TGF-β1-mediated effects in BECs derived at postnatal day 14 but not in those derived at gestational day 50. In conclusion, TGF-β1 regulates P-gp at the fetal and neonatal BBB and both ALK5 and ALK1 pathways are implicated in the regulation of P-gp function. Aberrations in TGF-β1 levels at the developing BBB may lead to substantial changes in fetal brain exposure to P-gp substrates, triggering consequences for brain development.

scholarly journals Fetal Blood-Brain Barrier P-Glycoprotein Contributes to Brain Protection During Human Development

2008 ◽  
Vol 67 (1) ◽  
pp. 50-61 ◽  
Author(s):  
Daniela Virgintino ◽  
Mariella Errede ◽  
Francesco Girolamo ◽  
Carmen Capobianco ◽  
David Robertson ◽  
...  
Keyword(s):  
Human Development ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Fetal Blood ◽  
Brain Protection ◽  
P Glycoprotein ◽  
Blood Brain
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