Pregnenolone-sulfate: an endogenous antagonist of the γ-aminobutyric acid receptor complex in brain?

doi:10.1016/0006-8993(87)91394-1

Brain Research

Volume 404, Issues 1–2, 24 February 1987, Pages 355-360

https://doi.org/10.1016/0006-8993(87)91394-1 Get rights and content

Abstract

The interaction of the ‘neurosteroid’, pregnenolone-sulfate (PS), with the GABA/benzodiazepine/chloride ionophore receptor complex was investigated in rat brain subcellular preparations. At low micromolar concentrations PS competitively inhibited the binding of the convulsant[³⁵S]t-butylbicyclophosphorothionate (TBPS) and antagonized pentobarbital-stimulated [³H] flunitrazepam binding to synaptosomes. In addition, PS inhibited muscimol-stimulated³⁶Cl⁻uptake in brain synaptoneurosomes, indicating that PS has characteristics of a relatively potent antagonist of the chloride channel coupled to the GABA receptor. Together with our previous finding that A-ring reduced metabolites of progesterone and deoxycorticosterone also interact with the GABA receptor complex but as hypnotic barbiturates, these data suggest that the regulation of GABAergic neurotransmission by various neurosteroids may be an important mechanism for controlling neuronal excitability.

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This chapter describes current knowledge of endogenous neurosteroids, namely, their mechanism of action and therapeutic benefits in epilepsy, anxiety, and other neurological conditions. Neurosteroids are synthesized de novo within the nervous system and have rapid effects on neuronal excitability. A variety of neurosteroids are present in the brain including allopregnanolone (brexanolone), pregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol. Synthesized from cholesterol, neurosteroids interact with a wide variety of neurotransmitter receptors including GABA-A receptors, N-methyl-d-aspartate, and other neuronal receptors. Pregnane and androstane neurosteroids are positive allosteric modulators of GABA-A receptors and have therapeutic potential as anticonvulsant and anxiolytic agents. Neurosteroid sulfates are negative allosteric modulators at GABA-A receptors and can alter excitatory neurotransmission within the brain via glutamate receptors. Neurosteroids play a key role in regulation of seizure susceptibility, anxiety, and other neuropsychiatric conditions. Neurosteroid sulfates provide benefits such as attenuation of memory and psychiatric symptoms. Both sulfated steroids and neurosteroids play a key role in endogenous neuroprotective functions in the brain.
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This chapter describes current knowledge of endogenous neurosteroids, namely, their mechanism of action and therapeutic benefits in epilepsy, anxiety, and other neurological conditions. Neurosteroids are synthesized de novo within the nervous system and have rapid effects on neuronal excitability. A variety of neurosteroids are present in the brain including allopregnanolone (brexanolone), pregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol. Synthesized from cholesterol, neurosteroids interact with a wide variety of neurotransmitter receptors including GABA-A receptors, N-methyl-d-aspartate, and other neuronal receptors. Pregnane and androstane neurosteroids are positive allosteric modulators of GABA-A receptors and have therapeutic potential as anticonvulsant and anxiolytic agents. Neurosteroid sulfates are negative allosteric modulators at GABA-A receptors and can alter excitatory neurotransmission within the brain via glutamate receptors. Neurosteroids play a key role in regulation of seizure susceptibility, anxiety, and other neuropsychiatric conditions. Neurosteroid sulfates provide benefits such as attenuation of memory and psychiatric symptoms. Both sulfated steroids and neurosteroids play a key role in endogenous neuroprotective functions in the brain.
Neurosteroid regulation of GABA<inf>A</inf> receptors: A role in catamenial epilepsy
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The female reproductive hormones progesterone and estrogen regulate network excitability. Fluctuations in the circulating levels of these hormones during the menstrual cycle cause frequent seizures during certain phases of the cycle in women with epilepsy. This seizure exacerbation, called catamenial epilepsy, is a dominant form of drug-refractory epilepsy in women of reproductive age. Progesterone, through its neurosteroid derivative allopregnanolone, increases γ-aminobutyric acid type-A receptor (GABAR)-mediated inhibition in the brain and keeps seizures under control. Catamenial seizures are believed to be a neurosteroid withdrawal symptom, and it was hypothesized that exogenous administration of progesterone to maintain its levels high during luteal phase will treat catamenial seizures. However, in a multicenter, double-blind, phase III clinical trial, progesterone treatment did not suppress catamenial seizures. The expression of GABARs with reduced neurosteroid sensitivity in epileptic animals may explain the failure of the progesterone clinical trial. The expression of neurosteroid-sensitive δ subunit-containing GABARs is reduced, and the expression of α4γ2 subunit-containing GABARs is upregulated, which alters the inhibition of dentate granule cells in epilepsy. These changes reduce the endogenous neurosteroid control of seizures and contribute to catamenial seizures.
The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators
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Citation Excerpt :
Only the shortest construct, GluN2C-855KStop resulted in UBP684 having NAM activity at GluN2C; UBP684 activity in the longer constructs was similar to WT (Fig. 1E). The neurosteroid PS, an endogenous modulator of NMDARs, potentiates GluN2A- and GluN2B- containing receptors and inhibits GluN2C- and GluN2D-containing NMDARs [27–29]. As found for UBP684, deletion of the GluN2 CTD significantly altered PS PAM activity, but with qualitatively-distinct effects.
N-methyl-d-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR’s intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2′s M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation.
Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction
2018, Behavioural Brain Research
Pregnenolone sulfate (PregS), an endogenous neurosteroid, which negatively and positively modulates gamma amino butyric acid subunit A (GABA_A) and N-methyl D-aspartate (NMDA) receptors (R) respectively, among other potential neuroplastic changes on synaptic processes, has shown some beneficial effects on treating cognitive impairment associated with schizophrenia (CIAS) and negative symptoms. Lurasidone (Lur), an atypical antipsychotic drug (AAPD), and tandospirone (Tan), a 5-HT_1A R partial agonist, have also been reported to improve cognitive or negative symptoms, or both, in some schizophrenia patients.
We tested whether PregS, by itself, and in combination with Lur or Tan could rescue persistent deficits produced by subchronic treatment with the NMDAR antagonist, phencyclidine (PCP)-in episodic memory, executive functioning, and social behavior, using novel object recognition (NOR), operant reversal learning (ORL), and social interaction (SI) tasks, in male C57BL/6 J mice.
PregS (10, but not 3 mg/kg) significantly rescued subchronic PCP-induced NOR and SI deficits. Co-administration of sub-effective doses (SEDs) of PregS (3 mg/kg) + Lur (0.1 mg/kg) or Tan (0.03 mg/kg) rescued scPCP-induced NOR and SI deficits. Further, PregS (30, but not 10 mg/kg) rescued PCP-induced ORL deficit, as did the combination of SED PregS (10 mg/kg) +SED Lur (1 mg/kg) or Tan (1 mg/kg).
PregS was effective alone and as adjunctive treatment for treating two types of cognitive impairments and negative symptoms in this schizophrenia model. Further study of the mechanisms by which PregS alone and in combination with AAPDs and 5-HT_1A R partial agonists, rescues the deficits in cognition and SI in this preclinical model is indicated.

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^*: Present address: Department of Pharmacology, Box 3813, Duke University Medical Center, Durham, NC 27710, U.S.A.

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Abstract

Reference (20)

Excitatory effects of dehydroepiandrosterone, its sulfate and pregnenolone-sulfate, applied by iontophoresis and pressure on single neurones in the septo-optic area of guinea pig brain

Neurosci. Lett.

Pregnenolone and its sulfate in the rat brain

Brain Research

Glucocorticoids are modulators of GABA_A receptors in brain

Brain Research

Bicuculline and picrotoxin block γ-aminobutyric acid-gated Cl⁻ conductance by different mechanisms

Experientia

Action of some steroids on the central nervous system of the mouse: II

Pharmacol. Med. Chem.

Neurosteroids:3β-hydroxy-Δ₅-derivatives in the rodent brain

Amino acid pharmacology of mammalian central neurones grown in tissue culture

J. Physiol. (London)

New concepts of the mechanism of action of benzodiazepines

Life Sci.

Cortical inhibition and ψ-aminobutyric acid

Exp. Brain Res.

Regulation of GABA receptors by barbiturates and by related sedative, hypnotic and convulsant drugs

Cited by (320)

Neurosteroids and their receptors in ischemic stroke: From molecular mechanisms to therapeutic opportunities

Neurosteroids

Neurosteroids: Biosynthesis, Molecular Mechanisms, and Neurophysiological Functions in the Human Brain

Neurosteroid regulation of GABA<inf>A</inf> receptors: A role in catamenial epilepsy

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators

Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction

Pregnenolone-sulfate: an endogenous antagonist of the γ-aminobutyric acid receptor complex in brain?

Abstract

Neurosci. Lett.

Brain Research

Brain Research

Bicuculline and picrotoxin block γ-aminobutyric acid-gated Cl− conductance by different mechanisms

Experientia

Action of some steroids on the central nervous system of the mouse: II

Pharmacol. Med. Chem.

Neurosteroids:3β-hydroxy-Δ5-derivatives in the rodent brain

Amino acid pharmacology of mammalian central neurones grown in tissue culture

J. Physiol. (London)

New concepts of the mechanism of action of benzodiazepines

Life Sci.

Cortical inhibition and ψ-aminobutyric acid

Exp. Brain Res.

Regulation of GABA receptors by barbiturates and by related sedative, hypnotic and convulsant drugs

Bicuculline and picrotoxin block γ-aminobutyric acid-gated Cl⁻ conductance by different mechanisms

Neurosteroids:3β-hydroxy-Δ₅-derivatives in the rodent brain