Neuroactive steroids, their precursors, and polar conjugates during parturition and postpartum in maternal and umbilical blood: 1. identification and simultaneous determination of pregnanolone isomers

Hill, Martin; Pařı́zek, Antonı́n; Bičı́ková, Marie; Havlı́ková, Helena; Klak, Jan; Fait, T; Cibula, David; Hampl, Richard; Cegan, Alexander; Šulcová, J; Stárka, L.

doi:10.1016/s0960-0760(00)00192-8

Cited by 40 publications

(27 citation statements)

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“…As has been documented for 5a-PI, the steroids are metabolized to respective 3-oxo-derivatives (P5a/b), which are then transported to the maternal compartment via the placentawhere they are again converted into PI (Dombroski et al 1997). The levels of all PI in pregnancy are strikingly higher in comparison with the situation in non-pregnant women (Genazzani et al 1998, Hill et al 2000, Luisi et al 2000, Pearson Murphy et al 2001, Havlikova et al 2006.…”

Section: Introductionmentioning

confidence: 94%

“…The TMS derivatives of the steroids were prepared using the modified method of Hill et al (2000), with some of the modifications reported recently (Havlikova et al 2006). In summary, Sylon B (99% bis (trimethylsilyl)-trifluroacetamide (BTSFA)C1% trimethylchlorosilane (TMCS); 50 ml) was added to the dry residues from plasma, mixed briefly and heated at 90 8C for 45 min.…”

Section: Derivatizationmentioning

confidence: 99%

“…Some reports indicate that in addition to the brain's in situ synthesis, circulating PIs penetrate the blood-brain barrier (Bixo et al 1997, Corpechot et al 1997. Although several studies have brought information to light regarding the levels of PI in humans, only a small number have included data regarding the respective polar conjugates (Mickan & Zander 1979, Hill et al 2000, Havlikova et al 2006.…”

Section: Introductionmentioning

confidence: 99%

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Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

Kancheva

Hill

Cibula

et al. 2007

Journal of Endocrinology

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Pregnanolone isomers (PIs) and their polar conjugates (PICs) modulate ionotropic receptors such as g-aminobutyric acid or pregnane X receptors. Besides, brain synthesis, PI penetrates the blood-brain barrier. We evaluated the physiological importance of PI respecting the status of sex, menstrual cycle, and pregnancy. Accordingly, circulating levels of allopregnanolone (P3a5a), isopregnanolone (P3b5a), pregnanolone (P3a5b), epipregnanolone (P3b5b), their polar conjugates, and related steroids were measured in 15 men (M), 15 women in the follicular phase (F), 16 women in the luteal phase (L), and 30 women in the 36th week of gestation (P) using GC-MS. The steroid levels were similar in M and F, increased about thrice in L and escalated in P (38-410 times compared with F). The PICs were prevalent over the PIs (16-150 times). Higher ratios of 5a-PIC to 5a-PI found in P indicate the more intensive conjugation of 5a-PI during pregnancy. This mechanism probably provides for the elimination of neuroinhibitory P3a5a in the maternal compartment. Additionally, our result points to a limited sulfation capacity for neuroinhibitory P3a5b in P. In contrast to the situation in M, F, and L where the P3a5bC is the most abundant PIC, and P3a5b is present in minor quantities compared with the P3a5a, P3a5b may acquire physiological importance during pregnancy, contributing to the sustaining thereof. On the other hand, the declining formation of P3a5b may participate in the initiation of parturition, given the relative abundance of the steroid, its potency to suppress the activity of oxytocin-producing cells and its effectiveness in uterine relaxation.

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Section: Introductionmentioning

confidence: 94%

Section: Derivatizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

Kancheva

Hill

Cibula

et al. 2007

Journal of Endocrinology

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“…ALLO exerts multiple effects in CNS including anxiolysis (Wieland et al, 1991), antistress (Zimmerberg and Blaskey, 1998), antidepressant , and anticonvulsant activity (Frye, 1995), in addition to its neuroleptic-like activity . Accumulating evidence suggests that physiological fluctuations in brain concentrations of neuroactive steroids contribute towards the genesis, development and course of neurological and psychiatric or affective disorders (George et al, 1994;Bixo et al, 1997;Hill et al, 2000). For example, a variation of ALLO concentration across the menstrual cycle are probably involved in the cyclic mood changes observed with premenstrual tension syndrome (Wang et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Ugale

Hirani

Morelli

et al. 2004

Neuropsychopharmacol

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Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABA A receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 mg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 mg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3b-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3a-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABA A receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABA A receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO-mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.

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“…Fluctuations in the brain concentration of 3α,5α-THP and its precursor might contribute not only to the normal physiology but also to the genesis, development, and course of neurological and psychiatric disorders, particularly in women at the premenstrual phase, pregnancy, post-partum period and at the onset of menopause (Bixo et al 1997;Hill et al 2000). Dysequilibrium in the level of neurosteroids has been reported in affective disorders (George et al 1994).…”

Section: Introductionmentioning

confidence: 99%

The neurosteroid 3α-hydroxy-5α-pregnan-20-one affects dopamine-mediated behavior in rodents

2002

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Neuroactive steroids, their precursors, and polar conjugates during parturition and postpartum in maternal and umbilical blood: 1. identification and simultaneous determination of pregnanolone isomers

Cited by 40 publications

References 24 publications

Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

The neurosteroid 3α-hydroxy-5α-pregnan-20-one affects dopamine-mediated behavior in rodents

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