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Developmental patterns in human blood–brain barrier and blood–cerebrospinal fluid barrier ABC drug transporter expression

Authors
  • Verscheijden, L. F. M.1
  • van Hattem, A. C.1
  • Pertijs, J. C. L. M.1
  • de Jongh, C. A.1
  • Verdijk, R. M.2
  • Smeets, B.3
  • Koenderink, J. B.1
  • Russel, F. G. M.1
  • de Wildt, S. N.1, 4
  • 1 Radboud University Medical Center, Institutes for Molecular Life and Health Sciences,
  • 2 Erasmus MC University Medical Center,
  • 3 Radboud University Medical Center,
  • 4 Erasmus MC-Sophia Children’s Hospital,
Type
Published Article
Journal
Histochemistry and Cell Biology
Publisher
Springer Berlin Heidelberg
Publication Date
May 24, 2020
Volume
154
Issue
3
Pages
265–273
Identifiers
DOI: 10.1007/s00418-020-01884-8
PMID: 32448916
PMCID: PMC7502061
Source
PubMed Central
Keywords
License
Unknown

Abstract

When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9–39 weeks), 17 neonates (GA range 24.6–41.3 weeks, PNA range 0.004–3.5 weeks), 8 children (PNA range 0.1–3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation. Electronic supplementary material The online version of this article (10.1007/s00418-020-01884-8) contains supplementary material, which is available to authorized users.

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