Neurosteroids in the mouse brain: Behavioral and pharmacological effects of a 3β-hydroxysteroid dehydrogenase inhibitor

Young, Jacques; Corpéchot, C.; Perché, Fabrice; Eychenne, Bernard; Haug, Marc; Baulieu, Étienne-Émile; Röbel, P

doi:10.1016/0039-128x(95)00220-k

Cited by 59 publications

(48 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results are in apparent contradiction to the reported high levels of PREG-S and DHEA-S measured in mammalian brain by RIA (19)(20)(21)(22) and the higher concentrations of PREG-S and DHEA-S in rodent brain than in blood (20)(21)(22). Moreover, PREG-S and DHEA-S were found to be still present in the brains of castrated and adrenalectomized male rats, whereas they disappeared from plasma.…”

contrasting

confidence: 83%

“…We show here that large amounts of PREG and DHEA are derivatized from lipoidal complexes by acylation derivatization reaction in the presence of triethylamine (TEA). The presence of these lipoidal derivatives of PREG and DHEA in rodent brain could explain the variations observed for PREG-S and DHEA-S measurements with direct (24)(25)(26)(27) and indirect (1,(19)(20)(21)(22) methods of analysis. The chemical identities of these lipoidal derivatives still need to be elucidated.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

Lière

Pianos

Eychenne

et al. 2004

Journal of Lipid Research

Self Cite

110

View full text Add to dashboard Cite

A new sample preparation method coupled to GC-MS analysis was developed and validated for quantification of sulfate esters of pregnenolone (PREG-S) and dehydroepiandrosterone (DHEA-S) in rat brain. Using a solid-phase extraction recycling protocol, the results show that little or no PREG-S and DHEA-S ( Ͻ 1 pmol/g) is present in rat and mouse brain. These data are in agreement with studies in which steroid sulfates were analyzed without deconjugation. We suggest that the discrepancies between analyses with and without deconjugation are caused by internal contamination of brain extract fractions, supposed to contain steroid sulfates, by lipoidal forms of PREG and DHEA (L-PREG and L-DHEA, respectively). These derivatives can be acylated very efficiently with heptafluorobutyric anhydride and triethylamine, and their levels in rodent brain ( ‫ف‬ 1 nmol/g) are much higher than those of their unconjugated counterparts. They are distinct from fatty acid esters, and preliminary data do not favor structures such as sulfolipids or sterol peroxides. Noncovalent interactions between steroids and proteolipidic elements, such as lipoproteins, could account for some experimental data. Given their abundance in rodent brain, the structural characterization and biological functions of L-PREG and L-DHEA in the central nervous system merit considerable attention. Four years ago, we developed and validated an analytical procedure for measuring trace amounts of neurosteroids in brain tissue by GC-MS (1). This method, which includes solid-phase extraction (SPE) and HPLC as fractionation and purification steps, is very suitable for quantifying simultaneously numerous neurosteroids in small individual regions of the central nervous system (CNS) (2) or peripheral nervous system (3) with high sensitivity and accuracy. Interest was primarily focused on pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their sulfated conjugates (PREG-S and DHEA-S, respectively) and on progesterone (PROG) and allopregnanolone (3 ␣ -hydroxy-5 ␣ -pregnan-20-one).Neurosteroids are synthesized by glial cells and neurons from cholesterol or from blood-borne precursors (4). In particular, PREG-S and DHEA-S are known to be neuroactive, and their major effects are the modulation of several neuronal membrane receptors, such as ␥ -aminobutyric acid (5, 6), N -methyl-d -aspartate (7), and σ receptors, by affecting neuronal excitability and behavior (8, 9). Notably, a physiologic function of PREG-S was suggested by the positive correlation between PREG-S levels in the hippocampus of aged rats and their spatial memory performance (10). However, some studies do not favor the concept that PREG-S and DHEA-S are actually neurosteroids. Indeed, contradictory results have been obtained concerning the presence and activity of the hydroxysteroid sulfotransferase, implied in the sulfation of free steroid.

show abstract

contrasting

confidence: 83%

mentioning

confidence: 99%

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

Lière

Pianos

Eychenne

et al. 2004

Journal of Lipid Research

Self Cite

110

View full text Add to dashboard Cite

show abstract

“…The endogenous concentrations of both DHEA and DHEAS were close to previously reported values for mouse (Young et al, 1996;Le Goascogne et al, 2000;Tagawa et al, 2006) and rat (Corpéchot et al 1981;Mathur et al, 1993;Ebner et al, 2006) brain. No other steroids have been reported in these tissues at concentrations likely to cross-react with the antibodies used in the present assays.…”

Section: Discussionsupporting

confidence: 88%

The steroid sulfatase inhibitor COUMATE attenuates rather than enhances access of dehydroepiandrosterone sulfate to the brain in the mouse

Nicolas¹,

Fry²

2007

Brain Research

View full text Add to dashboard Cite

Intraperitoneal injection of adult male mice with the neuroactive steroid dehydroepiandrosterone sulfate (DHEAS) at 1 and 40 mg/kg caused dose-dependent increases in the concentration of both this compound and its corresponding free steroid DHEA in brain within 1 h of injection.Pretreatment of these animals for 24 h with the steroid sulfatase inhibitor COUMATE at a dose (10 mg/kg, p.o.) shown previously to cause almost complete inhibition of this enzyme in liver and brain was expected to increase the amount of the DHEAS dose reaching the brain.Surprisingly however, the increases in brain concentrations of DHEAS and DHEA after injection of DHEAS i.p. were attenuated by pretreatment with COUMATE. The results suggest that the arylsulfamate based steroid sulfatase inhibitors such as COUMATE interfere with the influx of the DHEAS anion into the brain. Section: Regulatory Systems

show abstract

“…Using different in vivo paradigms, similar or lower doses of trilostane were shown to efficiently inhibit the enzyme 3 -hydroxysteroid dehydrogenase (Potts et al 1978, Young et al 1994, Phan et al 1999, Micevych et al 2003. A possible explanation was thus that the blockade of progesterone synthesis could lead to a shift of the biosynthesis equilibrium towards a greater synthesis of DHEA (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Finasteride suspended in 1·5% methylcellulose was administered for 5 days by daily gavage of 20 mg/kg. These doses of finasteride and trilostane have previously been shown to efficiently inhibit the 5 -reductase and 3 -hydroxysteroid dehydrogenase (3 -HSOD) enzymatic activities respectively (Potts et al 1978, Young et al 1994, Phan et al 1999, Micevych et al 2003. Experiments were carried out on the day following the last administration of either drug.…”

Section: Treatment With Inhibitors Of Progesterone Synthesis and Metamentioning

confidence: 99%

Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids

Robichaud¹,

Debonnel²

2004

Journal of Endocrinology

View full text Add to dashboard Cite

Important gender differences in mood disorders result in a greater susceptibility for women. Accumulating evidence suggests a reciprocal modulation between the 5-hydroxytryptamine (5-HT) system and neuroactive steroids. Previous data from our laboratory have shown that during pregnancy, the firing activity of 5-HT neurons increases in parallel with progesterone levels. This study was undertaken to evaluate the putative modulation of the 5-HT neuronal firing activity by different neurosteroids. Female rats received i.c.v. for 7 days a dose of 50 µg/kg per day of one of the following steroids: progesterone, pregnenolone, 5 -pregnane-3,20-dione (5 -DHP), 3 ,, 5 -pregnane-3 -ol,20-one and dehydroepiandrosterone (DHEA). 5 -DHP and DHEA were also administered for 14 and 21 days (50 µg/ kg per day, i.c.v.) as well as concomitantly with the selective sigma 1 ( 1 ) receptor antagonist NE-100. In vivo, extracellular unitary recording of 5-HT neurons performed in the dorsal raphe nucleus of these rats revealed that DHEA, 5 -DHP and 3 ,5 -THP significantly increased the firing activity of the 5-HT neurons. Interestingly, 5 -DHP and DHEA showed different timeframes for their effects with 5 -DHP having its greatest effect after 7 days to return to control values after 21 days, whereas DHEA demonstrated a sustained effect over the 21 day period. NE-100 prevented the effect of DHEA but not of 5 -DHP, thus indicating that its 1 receptors mediate the effect of DHEA but not that of 5 -DHP. In conclusion, our results offer a cellular basis for potential antidepressant effects of neurosteroids, which may prove important particularly for women with affective disorders.

show abstract

Neurosteroids in the mouse brain: Behavioral and pharmacological effects of a 3β-hydroxysteroid dehydrogenase inhibitor

Cited by 59 publications

References 11 publications

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

The steroid sulfatase inhibitor COUMATE attenuates rather than enhances access of dehydroepiandrosterone sulfate to the brain in the mouse

Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids

Contact Info

Product

Resources

About