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Uptake and metabolism of sulphated steroids by the blood–brain barrier in the adult male rat
Author(s) -
Qaiser M. Zeeshan,
Dolman Diana E. M.,
Begley David J.,
Abbott N. Joan,
CazacuDavidescu Mihaela,
Corol Delia I.,
Fry Jonathan P.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14117
Subject(s) - pregnenolone , endocrinology , medicine , dehydroepiandrosterone , neuroactive steroid , androstenedione , steroid , steroid hormone , chemistry , blood–brain barrier , metabolism , efflux , steroid sulfatase , biology , hormone , biochemistry , central nervous system , androgen , receptor , gabaa receptor
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 GF 120918 and/or MK 571 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.