Pregnenolone sulfate increases the convulsant potency of N-methyl-D-aspartate in mice

Maione, Sabatino; Berrino, Liberato; Vitagliano, S.; Leyva, Juan; Rossi, Francesco

doi:10.1016/0014-2999(92)90493-n

Cited by 60 publications

(20 citation statements)

References 6 publications

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“…Behavioral studies have shown that pregnenolone sulfate increases the convulsant potency of NMDA (Maione et al, 1992) and enhances memory retention in mice (Flood et al, 1992;Flood et al, 1995) and memory performance in the rat when injected directly into the nucleus basalis magnocellularis (Mayo et al, 1993). Pregnenolone sulfate also prevents NMDA receptor antagonist-induced deficits in a passive avoidance memory task (Mathis et al, 1994) and antagonizes dizocilpine-induced amnesia in rats (Cheney et al, 1995).…”

Section: Functions Of Pregnenolone/pregnenolone Sulfate In Vivomentioning

confidence: 99%

Neurosteroid regulation of central nervous system development

Mellon

2007

Pharmacology & Therapeutics

189

117

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Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABA A and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids -pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone.

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Section: Functions Of Pregnenolone/pregnenolone Sulfate In Vivomentioning

confidence: 99%

Neurosteroid regulation of central nervous system development

Mellon

2007

Pharmacology & Therapeutics

189

117

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“…In the nanomolar range, PREGS specifically enhanced the NMDA-gated currents in spinal cord neurons (40), intracellular Ca 2+ fluxes mediated through NMDA-receptor channels in cultured rat hippocampal neurons or chick hippocampal neurons (41,42), convulsant potency of NMDA in mice (43), and NMDA-induced phasic firing of vasopressin neurons in the rat supraoptic nucleus (44). DHEAS potentiated the intracellular Ca 2+ fluxes mediated through NMDA-receptor channels in mouse neocortical neuronal cultures (45).…”

Section: H]muscimol and [mentioning

confidence: 99%

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

2006

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Abstract. Steroids synthesized in the periphery or de novo in the brain, so called 'neurosteroids', exert both genomic and nongenomic actions on neurotransmission systems. Through rapid modulatory effects on neurotransmitter receptors, they influence inhibitory and excitatory neurotransmission. In particular, progesterone derivatives like 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) are positive allosteric modulators of the γ-aminobutyric acid type A (GABA A ) receptor and therefore act as inhibitory steroids, while pregnenolone sulphate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are negative modulators of the GABA A receptor and positive modulators of the N-methyl-D-aspartate (NMDA) receptor, therefore acting as excitatory neurosteroids. Some steroids also interact with atypical proteins, the sigma (σ) receptors. Recent studies particularly demonstrated that the σ 1 receptor contributes effectively to their pharmacological actions. The present article will review the data demonstrating that the σ 1 receptor binds neurosteroids in physiological conditions. The physiological relevance of this interaction will be analyzed and the impact on physiopathological outcomes in memory and drug addiction will be illustrated. We will particularly highlight, first, the importance of the σ 1 -receptor activation by PREGS and DHEAS which may contribute to their modulatory effect on calcium homeostasis and, second, the importance of the steroid tonus in the pharmacological development of selective σ 1 drugs.

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“…Pregnenolone and related molecules interact principally with ␥-aminobutyric acid receptors (10)(11)(12)(13)(14)(15)(16)(17), though modulation of N-methyl-D-aspartate (18)(19)(20)(21)(22)(23)(24), -opioid (24,25), and progesterone (26) receptors has also been suggested. However, it is so far unknown whether the documented in vivo effects are mediated directly by these steroids or by the products of their metabolism in brain and other tissues.…”

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confidence: 99%

Cyp7b, a novel brain cytochrome P450, catalyzes the synthesis of neurosteroids 7α-hydroxy dehydroepiandrosterone and 7α-hydroxy pregnenolone

Rose

Stapleton

Dott

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

204

161

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Steroids produced locally in brain (neurosteroids), including dehydroepiandrosterone (DHEA), inf luence cognition and behavior. We previously described a novel cytochrome P450, Cyp7b, strongly expressed in rat and mouse brain, particularly in hippocampus. Cyp7b is most similar to steroidogenic P450s and potentially could play a role in neurosteroid metabolism. To examine the catalytic activity of the enzyme mouse Cyp7b cDNA was introduced into a vaccinia virus vector. Extracts from cells infected with the recombinant showed NADPH-dependent conversion of DHEA (K m , 13.6 M) and pregnenolone (K m , 4.0 M) to slower migrating forms on thin layer chromatography. The expressed enzyme was less active against 25-hydroxycholesterol, 17␤-estradiol and 5␣-androstane-3␤,17␤-diol, with low to undetectable activity against progesterone, corticosterone, and testosterone. On gas chromatography and mass spectrometry of the Cyp7b metabolite of DHEA the retention time and fragmentation patterns were identical to those obtained with authentic 7␣-hydroxy DHEA. The reaction product also comigrated on thin layer chromatography with 7␣-hydroxy DHEA but not with 7␤-hydroxy DHEA; when [7␣-3 H]pregnenolone was incubated with Cyp7b extracts the extent of release of radioactivity into the medium suggested that hydroxylation was preferentially at the 7␣ position. Brain extracts also efficiently liberated tritium from [7␣-3 H]pregnenolone and converted DHEA to a product with a chromatographic mobility indistinguishable from 7␣-hydroxy DHEA. We conclude that Cyp7b is a 7␣-hydroxylase participating in the synthesis, in brain, of neurosteroids 7␣-hydroxy DHEA, and 7␣-hydroxy pregnenolone.

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Pregnenolone sulfate increases the convulsant potency of N-methyl-D-aspartate in mice

Cited by 60 publications

References 6 publications

Neurosteroid regulation of central nervous system development

Neurosteroid regulation of central nervous system development

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

Cyp7b, a novel brain cytochrome P450, catalyzes the synthesis of neurosteroids 7α-hydroxy dehydroepiandrosterone and 7α-hydroxy pregnenolone

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