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- Title
Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat.
- Authors
Qaiser, M. Zeeshan; Dolman, Diana E. M.; Begley, David J.; Abbott, N. Joan; Cazacu‐Davidescu, Mihaela; Corol, Delia I.; Fry, Jonathan P.
- 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.
- Subjects
STEROID drugs; SULFATASES; DEHYDROEPIANDROSTERONE; NEURAL enhancement (Enhancement medicine); NEUROTECHNOLOGY (Bioengineering)
- Publication
Journal of Neurochemistry, 2017, Vol 142, Issue 5, p672
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.14117