Perinatal Maturation of Drug Transporters and Claudin-5 at the Blood-Brain Barrier.

Abstract

<h4>Aim</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.