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Astrocytes Increase the Functional Expression of P-Glycoprotein in an In Vitro Model of The Blood-Brain Barrier

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Abstract

Purpose. To investigate the influence of astrocytes on P-glycoprotein (Pgp) expression and intracellular accumulation of Pgp substrates, separate from their net transcellular transport across the blood-brain barrier (BBB).

Methods. An in vitroBBB model was used, comprising of brain capillary endothelial cells (BCEC) monolayers or BCEC co-cultured with astrocytes.

Results. BCEC+astrocyte co-cultures seemed to express a higher level of Pgp compared to BCEC monolayers. Inhibition of Pgp results in an increased intracellular accumulation of Pgp substrates in both BCEC monolayers and BCEC+astrocyte co-cultures, and increased the sensitivity for vinblastine mediated disruption of the in vitro BBB (called the vinblastine exclusion assay). BCEC monolayers were more sensitive to vinblastine mediated disruption compared to BCEC+astrocyte co-cultures. In the latter, but not in BCEC monolayers, an inhibitable polar transport of Pgp substrates was only found from the brain to the blood side of the filter.

Conclusions. Astrocytes increase the functional expression of Pgp in our in vitroBBB model. These results also illustrate that an important role for Pgp on the BBB is to protect the barrier against intracellular accumulation of cytotoxic BBB disrupting compounds.

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Authors and Affiliations

  1. Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    Pieter Jaap Gaillard, Inez Cornelia Johanna van der Sandt, Levina Helena Voorwinden, Dung Vu, Jette Lyngholm Nielsen, Albertus Gerrit de Boer & Douwe Durk Breimer

  2. Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, (LACDR), Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands

    Albertus Gerrit de Boer

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  1. Pieter Jaap Gaillard
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  2. Inez Cornelia Johanna van der Sandt
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  3. Levina Helena Voorwinden
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Gaillard, P.J., van der Sandt, I.C.J., Voorwinden, L.H. et al. Astrocytes Increase the Functional Expression of P-Glycoprotein in an In Vitro Model of The Blood-Brain Barrier. Pharm Res 17, 1198–1205 (2000). https://doi.org/10.1023/A:1026406528530

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