Federici Laetitia, Cisternino Salvatore, Auvity Sylvain, Gelot Antoinette, Becmeur-Lefebvre Mathilde, Favier Maryline, Letort Gaelle, Mailly Philippe, Cohen-Salmon Martine, Boulay Anne-Cécile
Université Paris Cité, INSERM, Optimisation thérapeutique en neuropharmacologie OTEN U1144, Paris, France.
Service Pharmacie, Assistance Publique - Hôpitaux de Paris, AP-HP, Hôpital Universitaire Necker - Enfants Malades, Paris, France.
CNS Neurosci Ther. 2025 Sep;31(9):e70614. doi: 10.1111/cns.70614.
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.
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 [C]sucrose to assess barrier integrity, and [H]verapamil or [H]rosuvastatin to assess transport activity.
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.
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.
脑毛细血管内皮细胞形成血脑屏障，该屏障调节血液与脑之间的分子交换。了解其在脑发育过程中的功能对于优化新生儿、儿童以及孕妇和哺乳期妇女的治疗至关重要。
通过免疫组织化学评估人皮质样本在脑发育过程中P-糖蛋白（P-gp/ABCB1）的表达。在小鼠中，使用qPCR和蛋白质免疫印迹法分析出生后脑微血管，并在体内使用[C]蔗糖评估屏障完整性，使用[H]维拉帕米或[H]瑞舒伐他汀评估转运活性来评价血脑屏障功能。
在人类中，P-gp在出生后早期达到成熟水平。在小鼠中，出生后第5天（P5）建立了血脑屏障完整性，但紧密连接蛋白-5、P-gp和有机阴离子转运多肽1a4（Oatp1a4）的表达在P30之前持续增加。维拉帕米和瑞舒伐他汀的脑转运在P15至P30之间显著降低，表明外排能力增强。
尽管出生时血脑屏障完整性已建立，但血脑屏障在出生后时期持续成熟，主要是外排转运。我们的研究结果强调了P-gp在获得血脑屏障守门人特性中的关键作用。未成熟的血脑屏障可能导致早产儿脑对P-gp底物的易感性更高。
