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Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat

Qaiser, MZ; Dolman, DEM; Begley, DJ; Abbott, NJ; Cazacu-Davidescu, M; Corol, DI; Fry, JP; (2017) Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat. Journal of Neurochemistry , 142 (5) pp. 672-685. 10.1111/jnc.14117. Green open access

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Abstract

Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found (3) H-PregS to enter more rapidly than (3) H-DHEAS and both to undergo extensive (>50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of (3) H-DHEAS and (3) H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the (3) H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory. This article is protected by copyright. All rights reserved.

Type: Article
Title: Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jnc.14117
Publisher version: http://doi.org/10.1111/jnc.14117
Language: English
Additional information: © 2017 The Authors Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Blood-brain barrier, dehydroepiandrosterone sulphate, neurosteroid, pregnenolone sulphate, steroid sulphatase
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1561336
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