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Perinatal Maturation of Drug Transporters and Claudin-5 at the Blood-Brain Barrier
Laetitia Federici1,2, Salvatore Cisternino1,2, Sylvain Auvity1,2
1Université Paris Cité, INSERM, Optimisation thérapeutique en neuropharmacologie OTEN U1144, Paris, France.
Insights
The blood-brain barrier (BBB) matures postnatally, with P-glycoprotein (P-gp) enhancing efflux transport and gatekeeper functions. This postnatal maturation impacts brain susceptibility to P-gp substrates, especially in preterm infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The blood-brain barrier (BBB) protects the brain by regulating molecular transport.
- Cerebral capillary endothelial cells (EC) are key components of the BBB.
- Understanding BBB development is crucial for neonatal and maternal health.
Purpose of the Study:
- To investigate the developmental changes in BBB integrity and transport function.
- To assess the role of P-glycoprotein (P-gp/ABCB1) in postnatal BBB maturation.
- To evaluate the implications for drug delivery and brain susceptibility in infants.
Main Methods:
- Immunohistochemistry of human cortical samples for P-gp expression.
- Quantitative PCR (qPCR) and Western Blot analysis of mouse brain microvessels.
- In vivo assessment of BBB integrity using [14C]sucrose and transport activity using [3H]verapamil and [3H]rosuvastatin in mice.
Main Results:
- P-gp expression reached mature levels in the early human postnatal period.
- Mouse BBB integrity was established by postnatal day 5 (P5).
- Expression of claudin-5, P-gp, and Oatp1a4 increased until postnatal day 30 (P30) in mice, with decreased brain transport of verapamil and rosuvastatin, indicating enhanced efflux capacity.
Conclusions:
- BBB integrity is established early, but maturation, particularly efflux transport, continues postnatally.
- P-glycoprotein (P-gp) plays a critical role in developing the BBB's gatekeeper functions.
- Immature BBB in preterm infants may increase brain susceptibility to P-gp substrates, influencing treatment strategies.
Aim:
Cerebral capillary endothelial cells (EC) form the blood-brain barrier (BBB), which regulates molecular exchange between the blood and the brain. Understanding their function during brain development is essential for optimizing treatments in neonates, children, as well as pregnant and breastfeeding women.
Methods:
P-glycoprotein (P-gp/ABCB1) expression during brain development was assessed by immunohistochemistry in human cortical samples. In mice, postnatal brain microvessels were analyzed using qPCR and Western Blot, and BBB function was evaluated in vivo using [14C]sucrose to assess barrier integrity, and [3H]verapamil or [3H]rosuvastatin to assess transport activity.
Results:
In humans, P-gp reached mature levels in the early postnatal period. In mice, BBB integrity was established by postnatal day 5 (P5), but the expression of claudin-5, P-gp, and Oatp1a4 increased until P30. Brain transport of verapamil and rosuvastatin significantly decreased between P15 and P30, indicating enhanced efflux capacity.
Conclusions:
Although BBB integrity is established at birth, BBB continues maturing throughout the postnatal period, with a predominant efflux transport. Our findings underscore the critical role of P-gp in the acquisition of BBB gatekeeper properties. The immature BBB may result in a higher brain susceptibility to P-gp substrates in preterm infants.
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