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

Abstract

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.

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

“…Some studies have shown that chemoresistance may be attributed to expression of the multidrug resistance gene ( MDR1 ) and its encoded protein P-gp, which has been found to reduce drug uptake [28]. In our study, after treatment of A549/DDP cells with AA alone or with a combination of DDP with AA, the expression of MDR1 (P-gp) significantly decreased.…”

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

“…A decrease in P-gp protein expression in PTDC may be associated with fetal accumulation of P-gp substrates, such as endogenous and synthetic glucocorticoids, estrogens and pro-inflammatory compounds. This possibility is supported by the evidence that LPS and polyI:C inhibited P-gp activity and increased fetal drug exposure in pregnant mice [8, 54]. P-gp also transports important classes of drugs such as angiotensin receptor blockers, antibiotics, antiepileptics, antihistamines, antiretrovirals, NSAIDs and statins1.…”

Malaria in pregnancy regulates P‐glycoprotein (P‐gp/Abcb1a) and ABCA1 efflux transporters in the Mouse Visceral Yolk Sac

“…C57BL/6 mice exposed to sublethal (foetal) LPS in mid-pregnancy, exhibited impaired placental P-gp activity, 18 while polyinosinic:polycytidylic acid (PolyI:C, a viral mimic) had no effect on placental P-gp activity. 36 Human first-trimester placentae exposed to lipopolysaccharide (LPS, a bacterial antigen) exhibited decreased P-gp/ABCB1 and BCRP/ABCG2 levels. 37 In contrast, human chorioamnionitis in 2nd trimester, often resulting from polymicrobial infection, 38 resulted in decreased P-gp levels but elevated BCRP expression.…”