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ATP-binding cassette (ABC) drug transporters in the developing blood–brain barrier: role in fetal brain protection

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Abstract

The blood–brain barrier (BBB) provides essential neuroprotection from environmental toxins and xenobiotics, through high expression of drug efflux transporters in endothelial cells of the cerebral capillaries. However, xenobiotic exposure, stress, and inflammatory stimuli have the potential to disrupt BBB permeability in fetal and post-natal life. Understanding the role and ability of the BBB in protecting the developing brain, particularly with respect to drug/toxin transport, is key to promoting long-term brain health. Drug transporters, particularly P-gp and BCRP are expressed in early gestation at the developing BBB and have a crucial role in developmental homeostasis and fetal brain protection. We have highlighted several factors that modulate drug transporters at the developing BBB, including synthetic glucocorticoid (sGC), cytokines, maternal infection, and growth factors. Some factors have the potential to increase expression and function of drug transporters and increase brain protection (e.g., sGC, transforming growth factor [TGF]-β). However, others inhibit drug transporters expression and function at the BBB, increasing brain exposure to xenobiotics (e.g., tumor necrosis factor [TNF], interleukin [IL]-6), negatively impacting brain development. This has implications for pregnant women and neonates, who represent a vulnerable population and may be exposed to drugs and environmental toxins, many of which are P-gp and BCRP substrates. Thus, alterations in regulated transport across the developing BBB may induce long-term changes in brain health and compromise pregnancy outcome. Furthermore, a large portion of neonatal adverse drug reactions are attributed to agents that target or access the nervous system, such as stimulants (e.g., caffeine), anesthetics (e.g., midazolam), analgesics (e.g., morphine) and antiretrovirals (e.g., Zidovudine); thus, understanding brain protection is key for the development of strategies to protect the fetal and neonatal brain.

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Funding

This work was funded by a Foundation grant from Canadian Institutes of Health Research (CIHR: FDN-148368) to S.G.M. M.E.E. was supported in part by a Queen Elizabeth II Graduate Scholarship in Science and Technology (QEII-GSST). E.B. is supported by the Higher Education Personnel Improvement Coordination (Coordenação de Aperfeiçoamento Pessoal de Nível Superior [CAPES]; finance code 001, CAPES-Print fellowship: 88887.370196/2019-00), The National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq]: 10578/2020-5) and the Research Support Foundation of Minas Gerais State (Fundação de Amparo à Pesquisa do Estado de Minas Gerais [FAPEMIG]: APQ-00338-18).  We thank Ms Phetcharawan Lye for the H & E images displayed on Fig. 2 A & B. This work was undertaken in compliance with REB policies at Sinai Health System (protocol n# 18-0057-E).

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Authors and Affiliations

  1. Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Medical Sciences Bldg. Rm. 3207. 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Margaret E. Eng, Enrrico Bloise & Stephen G. Matthews

  2. Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada

    Guinever E. Imperio, Enrrico Bloise & Stephen G. Matthews

  3. Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Enrrico Bloise

  4. Department of Obstetrics and Gynecology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

    Stephen G. Matthews

  5. Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

    Stephen G. Matthews

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  1. Margaret E. Eng
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  2. Guinever E. Imperio
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  3. Enrrico Bloise
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  4. Stephen G. Matthews
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Contributions

MEE: conceptualization, visualization—figures and tables, writing—original draft. GEI: conceptualization, writing—original draft. EB: conceptualization, writing—review and editing, supervision. SGM: conceptualization, writing—review and editing, supervision, project administration, funding acquisition.

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Correspondence to Stephen G. Matthews.

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Eng, M.E., Imperio, G.E., Bloise, E. et al. ATP-binding cassette (ABC) drug transporters in the developing blood–brain barrier: role in fetal brain protection. Cell. Mol. Life Sci. 79, 415 (2022). https://doi.org/10.1007/s00018-022-04432-w

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  • DOI: https://doi.org/10.1007/s00018-022-04432-w

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