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

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 Hsteroid 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.

Activation of Adrenal Steroidogenesis and an Improvement of Mood Balance in Postmenopausal Females after Spa Treatment Based on Physical Activity

“…However, in the earlier study, Wang et al [81] demonstrated the transport of peripherally applied pregnenolone sulfate across the BBB, which was approximately ten times slower when compared to the unconjugated pregnenolone. A recent study by Qaiser et al [82] also demonstrates an uptake of peripherally applied [ 3 H]-DHEAS and [ 3 H]-PregS, which is more rapid for the latter (less polar) conjugate. A consequent extensive (>50%) desulfation of both conjugates within 0.5 min of uptake was observed.…”

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

“…The sulphatase pathway in the CNS is relevant because (although recent studies are revisiting this paradigm; Qaiser et al, 2017 ), sulphated-steroids do not cross the blood-brain barrier. Therefore, sulphated neurosteroids like DHEA-S and P5-S need to be generated locally, and in line with this, their level in the CNS is independent from the level in the blood (Rajkowski et al, 1997 ) and varies throughout distinct brain regions (especially hippocampus and hypothalamus) (Jäntti et al, 2010 ).…”

Central intracrine DHEA synthesis in ageing-related neuroinflammation and neurodegeneration: therapeutic potential?

“…Although sulphated steroids such as DHEAS and pregnenolone sulphate may enter the brain through circulation via organic anion transporting peptides (OATP) transporting them both ways, it would appear that OATP transport of sulphated steroids favours movement out of the CNS, not in [ 155 ]. However, a recent study investigating the transport of DHEAS and PREGS through the blood brain barrier (BBB) of rats found that although PREGS entered the blood brain barrier more readily, DHEA was rapidly metabolised into androstenedione and androstenediol [ 156 ]. Further investigation found that the enzymes responsible for the rapid desulphatasion were mainly localised the BBB capillaries as opposed the brain parenchyma [ 156 ].…”

“…However, a recent study investigating the transport of DHEAS and PREGS through the blood brain barrier (BBB) of rats found that although PREGS entered the blood brain barrier more readily, DHEA was rapidly metabolised into androstenedione and androstenediol [ 156 ]. Further investigation found that the enzymes responsible for the rapid desulphatasion were mainly localised the BBB capillaries as opposed the brain parenchyma [ 156 ]. This argues that the DHEA in brain is likely from peripheral sources as opposed to de novo synthesis.…”