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

Research output: Contribution to journalArticle

M. Zeeshan Qaiser, Diana E.M. Dolman, David J. Begley, N. Joan Abbott, Mihaela Cazacu-Davidescu, Delia I. Corol, Jonathan P. Fry

Original languageEnglish
Pages (from-to)672-685
Number of pages14
JournalJournal of Neurochemistry
Volume142
Issue number5
Early online date3 Aug 2017
DOIs
Publication statusPublished - 1 Sep 2017

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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 3H-PregS to enter more rapidly than 3H-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 3H-DHEAS and 3H-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 3H-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. (Figure presented.).

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