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

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

doi:10.1111/jnc.14117

M. Zeeshan Qaiser, Delia I. Corol + Show 5 more

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https://doi.org/10.1111/jnc.14117

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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.

Highlights

Neuroactive steroids have a variety of actions within the central nervous system (CNS), and include the so-called neurosteroids, synthesised within this tissue
When adjusted for perfusate flow rate, different brain regions show similar permeabilities for steroid sulphates The regional uptake of dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) after correction for vascular space is shown in Table 1 as the unidirectional transfer coefficients at 0.5 min, unidirectional transfer co-efficient (Kin)
For consistency with the method used for the reference data set, permeability–surface area product (PS) values for DHEAS and PregS were calculated from Kin values obtained for the slope of a plot of volume of distribution (Vd) against time from 0.25 to 0.5 min

Summary

Introduction

Neuroactive steroids have a variety of actions within the central nervous system (CNS), and include the so-called neurosteroids, synthesised within this tissue. The origin of DHEA and DHEAS in the brain remains an important question because the latter is the major circulating steroid in the adult primate, where it declines with age (Orentreich et al 1984; Campbell 2006) and is thought to act as a precursor for biologically active hormone in a variety of peripheral tissues, a form of intracrinology (see Labrie et al 1995; Reed et al 2005; Starka et al 2015) Both DHEAS and DHEA are known to have actions on the CNS. Many animal studies have shown administration of DHEA or DHEAS to enhance learning and memory (see Sujkovic et al 2012) and these effects have not consistently been repeated in human subjects (see Maninger et al 2009; Starka et al 2015), supplementation with DHEA(S) to ameliorate depression and improve cognitive function in elderly or demented subjects with lower DHEAS/cortisol ratios (Herbert 1998) remains a possibility (Grimley Evans et al 2006; Samaras et al 2013)

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