Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons

Irwin, Robert P.; Maragakis, Nicholas J.; Rogawski, Michael A.; Purdy, Robert H.; Farb, David H.; Paul, Steven M.

doi:10.1016/0304-3940(92)90327-4

Cited by 150 publications

(73 citation statements)

References 18 publications

(22 reference statements)

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“…DHEAS and PREGS are negative allosteric modulators of the ␥ -aminobutyric acid (GABA) A receptors (Majewska 1992), and positive modulators of N-methyl-D-aspartate (NMDA) receptor-mediated responses (Bowlby 1993;Irwin et al 1992Irwin et al , 1994. Evidence is mounting that DHEAS and PREGS act as agonists at central sigma receptors, especially sigma 1 sites, and exert facilitatory actions on NMDA-mediated glutamatergic and noradrenergic neurotransmission (Maurice and Lockhart 1997;Monnet et al 1995).…”

Section: Receptor Agonist ( ϩ )-N-allylnormetazocine (( ϩ )-mentioning

confidence: 99%

Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

Noda

Kamei

et al. 2000

Neuropsychopharmacology

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Mice exhibited a marked suppression of motility (conditioned fear stress) when placed in an environment in which they had previously received an electric footshock. This conditioned fear stress response was dose-dependently attenuated by neurosteroids such as dehydroepiandrosterone sulfate (DHEAS; 25 and 50 mg/kg, s.c.) and pregnenolone sulfate (PREGS; s.c.), and by a putative sigma 1 047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; s.c.) and allopregnanolone (5 and 20 mg/kg, s.c.) had no effect on this stress response. The attenuating effects of DHEAS (50 mg/kg, s.c.), PREGS (50 mg/kg, s.c.), and ( ϩ )- 047 (6 mg/kg, s.c.) were reversed by i.p.), a sigma 1 receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with ( ϩ )- 047 (3 mg/kg) Neurosteroids are synthesized in the brain, either de novo from cholesterol or from steroid hormone precursors, and accumulate in the nervous system to levels that are at least in part independent of steroidogenic gland secretion (Baulieu 1981). Neurosteroids, such as progesterone (PROG), pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their respective sulfate ester (PREGS or DHEAS), are involved in regulating the imbalance between excitation and inhibition in the CNS (Wu et al. 1991). The neurosteroids, allopregnanolone, allotetrahydrodeoxycorticosterone, PREGS, and DHEAS have been shown to possess antistress, anxiolytic, and antiamnesic properties in experimental animal models (Bitran et al. 1991;Brot et al. 1997;Maurice et al. , 1999Urani et al. 1998;Wieland et al. 1991). Recent evidence suggests that DHEAS and PREGS also play an important role in depression. Interestingly, decreased levels of DHEA, DHEAS, and PREGS have been associated with depression, cognitive dysfunction, aging, and other neurological conditions (Orentreich et al. 1984;Vallée et al. 1997), and DHEA improves the depression score in patients (Wolkowitz et al. 1997). However, the From the Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine (YN, HK, YK, TN, TN), Nagoya, Japan; and Department of Clinical Pharmacy, Faculty of Pharmacy, Meijo University (YK, TN, MN), Nagoya, Japan. receptor agonist, ( ϩ )-N-allylnormetazocine (( ϩ )-Address correspondence to: Dr. Toshitaka Nabeshima, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.Received October 18, 1999; revised February 2, 2000; accepted February 18, 2000. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 3 Neurosteroids and Sigma 1 Receptors 277 mechanism underlying the beneficial effects of neurosteroids is not yet known.Neurosteroids have been shown to affect the activity of neurotransmitter systems, which are involved in a variety of neuropsychiatric illnesses. DHEAS and PREGS are negative allosteric modulators of the ␥ -aminobutyric acid (GABA) A receptors (Majewska 1992), and positive modulators of N-methyl-D-aspartate (NMDA) receptor-mediated res...

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Section: Receptor Agonist ( ϩ )-N-allylnormetazocine (( ϩ )-mentioning

confidence: 99%

Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

Noda

Kamei

et al. 2000

Neuropsychopharmacology

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“…the steroids with a reduced A-ring including some of the neurosteroids, are very potent, rapid modulators of GABA-mediated responses. For details we recommend excellent, recent reviews on this subject (Baulieu and Robel, 1990;Lambert et al, 1987;Majewska, 1992;Paul and Purdy, 1992;Schumacher, 1990;McEwen, 1991;Simmonds, 1991). In short, endogenous and synthetic steroids with a reduced A-ring at the C-5 position and a hydroxyl group at the 3~-position act as allosteric agonists at the GABAa receptor; e.g.…”

Section: Immediate Actionsmentioning

confidence: 99%

“…The array of rapid cellular effects described for this class of steroids however is ever expanding. Recent reports include an increase of the NMDA receptor-mediated calcium influx in cultured hippocampal neurons by pregnenolone sulfate (Irwin et al, 1992) and a rapid depression of high threshold calcium currents in dissociated hippocampal neurons by most of the A-ring reduced steroid compounds (Ffrench-Mullen and Spence, 1991).…”

Section: Immediate Actionsmentioning

confidence: 99%

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

Joëls

Kloet

1994

Progress in Neurobiology

368

168

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“…GABA A R is an ionotropic receptor and a ligand-gated ion channel that increases the membrane conductance for Cl − ions upon activation, leading to hyperpolarization and reduced excitability of neurons (Majewska et al 1988). NMDAR is an ion channel protein that enables the flow of positively charged ions through the cell membrane when activated (Irwin et al 1992). Transcription of PRL induced by PS was unchanged following pretreatment with GABA A R and NMDAR inhibitors, indicating that PS may have different signaling pathways for the PRL regulation than its known signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Pregnenolone sulfate regulates prolactin production in the rat pituitary

Kang

Hong

Lee

et al. 2016

Journal of Endocrinology

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Pregnenolone sulfate (PS) is a neuroactive steroid hormone produced in the brain. In this study, the effects of PS on synthesis and secretion of rat pituitary prolactin (PRL) were examined. To accomplish this, GH3 rat pituitary adenoma cells were treated with PS, which showed significantly increased mRNA and protein levels of PRL compared with the control. The mechanism of action responsible for the effects of PS on PRL synthesis and secretion was investigated by pretreating cells with inhibitors of traditional PRLor the PS-related signaling pathway. PS-stimulated PRL transcription was significantly reduced by inhibitors of PKA, PKC and MAPK, but unchanged by GABAAR and NMDAR inhibitors. Western blotting analysis revealed that the total ERK1/2 level was upregulated in a time-dependent manner following PS treatment. An approximate 10% increase in GH3 cell proliferation was also observed in response to PS relative to the control. In the animal study, levels of PRL in the pituitary and in serum were elevated by PS. PS-stimulated PRL synthesis was also found to be associated with decreased expression of PRL target genes such as GNRH1, FSHB and LHB. These findings show that PS upregulates PRL synthesis and secretion in vivo and in vitro via MAPK signaling, suggesting that it has the potential for use as a therapeutic hormone to treat PRLrelated disorders such as hypoprolactinemia and low milk supply.

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Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons

Cited by 150 publications

References 18 publications

Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

Pregnenolone sulfate regulates prolactin production in the rat pituitary

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