Dataset Information

Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier.

ABSTRACT:

Background and purpose

The respective impact and interplay between ABC (P-glycoprotein/P-gp/Abcb1a, BCRP/ABCG2, MRP/ABCC) and SLC transporter functions at the blood-brain barrier (BBB) and blood-retinal barriers (BRB) are incompletely understood.

Experimental approach

We measured the initial cerebral and retinal distribution of selected ABC substrates by in situ carotid perfusion using P-gp/Bcrp knockout mice and chemical ABC/SLC modulation strategies. P-gp, Bcrp, Mrp1 and Mrp4 were studied by confocal retina imaging.

Key results

Chemical or physical disruption of P-gp increased [(3) H]-verapamil transport by ~10-fold at the BBB and ~1.5-fold at the BRB. [(3) H]-Verapamil transport involved influx-mediated by an organic cation clonidine-sensitive/diphenhydramine-sensitive proton antiporter at both barriers; this effect was unmasked when P-gp was partially or fully inhibited/disrupted at the BBB. Studies of [(3) H]-mitoxantrone and [(3) H]-zidovudine transport suggested, respectively, that Bcrp efflux was less involved at the BRB than BBB, whereas Mrps were significantly and similarly involved at both barriers. Confocal imaging showed that P-gp and Bcrp were expressed in intra-retinal vessels (inner BRB/iBRB) but absent from the blood/basal membrane of cells of the retinal pigment epithelium (outer BRB/oBRB/RPE) where, in contrast, Mrp1 and Mrp4 were localized.

Conclusions and implications

P-gp, Bcrp, Mrp1 and Mrp4 are differentially expressed at the outer and inner BRB, resulting in an altered ability to limit substrate distribution at the retina as compared with the BBB. [(3) H]-Verapamil distribution is not P-gp-specific and involves a proton antiporter at both the BBB and BRB. However, this transport is concealed by P-gp at the BBB, but not at the BRB, where P-gp activity is reduced.

SUBMITTER: Chapy H

PROVIDER: S-EPMC4728421 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Publications

Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier.

Chapy Hélène H Saubaméa Bruno B Tournier Nicolas N Bourasset Fanchon F Behar-Cohen Francine F Declèves Xavier X Scherrmann Jean-Michel JM Cisternino Salvatore S

British journal of pharmacology 20160115 3

<h4>Background and purpose</h4>The respective impact and interplay between ABC (P-glycoprotein/P-gp/Abcb1a, BCRP/ABCG2, MRP/ABCC) and SLC transporter functions at the blood-brain barrier (BBB) and blood-retinal barriers (BRB) are incompletely understood.<h4>Experimental approach</h4>We measured the initial cerebral and retinal distribution of selected ABC substrates by in situ carotid perfusion using P-gp/Bcrp knockout mice and chemical ABC/SLC modulation strategies. P-gp, Bcrp, Mrp1 and Mrp4 we ...[more]

PMID: 26507673

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Dataset Information

Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier.

Similar Datasets

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