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British Journal of Pharmacology Oct 2021Neurosteroids influence neuronal function and have multiple promising clinical applications. Direct modulation of postsynaptic neurotransmitter receptors by...
BACKGROUND AND PURPOSE
Neurosteroids influence neuronal function and have multiple promising clinical applications. Direct modulation of postsynaptic neurotransmitter receptors by neurosteroids is well characterized, but presynaptic effects remain poorly understood. Here, we report presynaptic glutamate release potentiation by neurosteroids pregnanolone and pregnanolone sulfate and compare their mechanisms of action to phorbol 12,13-dibutyrate (PDBu), a mimic of the second messenger DAG.
EXPERIMENTAL APPROACH
We use whole-cell patch-clamp electrophysiology and pharmacology in rat hippocampal microisland cultures and total internal reflection fluorescence (TIRF) microscopy in HEK293 cells expressing GFP-tagged vesicle priming protein Munc13-1, to explore the mechanisms of neurosteroid presynaptic modulation.
KEY RESULTS
Pregnanolone sulfate and pregnanolone potentiate glutamate release downstream of presynaptic Ca influx, resembling the action of a phorbol ester PDBu. PDBu partially occludes the effect of pregnanolone, but not of pregnanolone sulfate. Calphostin C, an inhibitor that disrupts DAG binding to its targets, reduces the effect PDBu and pregnanolone, but not of pregnanolone sulfate, suggesting that pregnanolone might interact with a well-known DAG/phorbol ester target Munc13-1. However, TIRF microscopy experiments found no evidence of pregnanolone-induced membrane translocation of GFP-tagged Munc13-1, suggesting that pregnanolone may regulate Munc13-1 indirectly or interact with other DAG targets.
CONCLUSION AND IMPLICATIONS
We describe a novel presynaptic effect of neurosteroids pregnanolone and pregnanolone sulfate to potentiate glutamate release downstream of presynaptic Ca influx. The mechanism of action of pregnanolone, but not of pregnanolone sulfate, partly overlaps with that of PDBu. Presynaptic effects of neurosteroids may contribute to their therapeutic potential in the treatment of disorders of the glutamate system.
Topics: Animals; Glutamic Acid; HEK293 Cells; Humans; Neurosteroids; Pregnanolone; Rats; Sulfates
PubMed: 33988248
DOI: 10.1111/bph.15529 -
Frontiers in Neuroendocrinology Oct 2020Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide... (Review)
Review
Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, emphasizing three key areas: biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be dealing with a two-edged sword: while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
Topics: Emotions; Female; Humans; Pregnanolone; Premenstrual Dysphoric Disorder; Progesterone
PubMed: 32730861
DOI: 10.1016/j.yfrne.2020.100856 -
American Journal of Health-system... Oct 2022
Topics: Humans; Pregnanolone; Anticonvulsants
PubMed: 36099427
DOI: 10.1093/ajhp/zxac219 -
Drugs Nov 2023Zuranolone (ZURZUVAE) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABA) receptor being developed by Sage... (Review)
Review
Zuranolone (ZURZUVAE) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABA) receptor being developed by Sage Therapeutics and Biogen for the treatment of mood disorders. In August 2023, zuranolone received its first approval in the USA for the treatment of adults with postpartum depression [pending scheduling by the US Drug Enforcement Administration (DEA)]. This article summarizes the milestones in the development of zuranolone leading to this first approval.
Topics: Adult; Female; Humans; Pregnanes; Pyrazoles; Depression, Postpartum; Pregnanolone
PubMed: 37882942
DOI: 10.1007/s40265-023-01953-x -
Lancet (London, England) Jul 2017Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABA) receptors, for the treatment of post-partum depression.
METHODS
For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547.
FINDINGS
This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference -12·2, 95% CI -20·77 to -3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia).
INTERPRETATION
In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress.
FUNDING
Sage Therapeutics, Inc.
Topics: Adult; Antidepressive Agents; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Infusions, Intravenous; Pregnanolone; Psychiatric Status Rating Scales; Treatment Outcome; Young Adult; beta-Cyclodextrins
PubMed: 28619476
DOI: 10.1016/S0140-6736(17)31264-3 -
ACS Chemical Neuroscience May 2023Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid...
Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid metabolism on neuroactive steroid signaling is not well understood. To begin to address this question, we set out to identify major metabolites of a neuroprotective synthetic steroid 20-oxo-5β-pregnan-3α-yl l-glutamyl 1-ester (pregnanolone glutamate, PAG) and characterize their effects on GABA and NMDA receptors (GABARs, NMDARs) and their influence on zebrafish behavior. Gas chromatography-mass spectrometry was used to assess concentrations of PAG and its metabolites in the hippocampal tissue of juvenile rats following intraperitoneal PAG injection. PAG is metabolized in the peripheral organs and nervous tissue to 20-oxo-17α-hydroxy-5β-pregnan-3α-yl l-glutamyl 1-ester (17-hydroxypregnanolone glutamate, 17-OH-PAG), 3α-hydroxy-5β-pregnan-20-one (pregnanolone, PA), and 3α,17α-dihydroxy-5β-pregnan-20-one (17-hydroxypregnanolone, 17-OH-PA). Patch-clamp electrophysiology experiments in cultured hippocampal neurons demonstrate that PA and 17-OH-PA are potent positive modulators of GABARs, while PAG and 17-OH-PA have a moderate inhibitory effect at NMDARs. PAG, 17-OH-PA, and PA diminished the locomotor activity of zebrafish larvae in a dose-dependent manner. Our results show that PAG and its metabolites are potent modulators of neurotransmitter receptors with behavioral consequences and indicate that neurosteroid-based ligands may have therapeutic potential.
Topics: Rats; Animals; Pregnanolone; Receptors, N-Methyl-D-Aspartate; Zebrafish; Glutamic Acid; Esters; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 37126803
DOI: 10.1021/acschemneuro.3c00131 -
Drugs Jun 2022Ganaxolone (ZTALMY; Marinus Pharmaceuticals) is a synthetic neuroactive steroid that acts as a positive allosteric modulator of the gamma-aminobutyric acid (GABA)... (Review)
Review
Ganaxolone (ZTALMY; Marinus Pharmaceuticals) is a synthetic neuroactive steroid that acts as a positive allosteric modulator of the gamma-aminobutyric acid (GABA) receptor complex. Ganaxolone received its first approval in March 2022 in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older. Approval was based on the results of a multinational phase III trial, in which ganaxolone was effective in reducing seizure frequency in children and adolescents with CDD. In the EU, a Marketing Authorization Application has been filed for ganaxolone in the treatment of seizures associated with CDD and an opinion from the Committee for Medicinal Products for Human Use is expected later this year. Oral ganaxolone is also currently undergoing phase III evaluation in the treatment of tuberous sclerosis complex-related epilepsy, while an intravenous formulation of ganaxolone is being evaluated in refractory status epilepticus. This article summarizes the milestones in the development of ganaxolone leading to this first approval for seizures associated with CDD.
Topics: Adolescent; Anticonvulsants; Child; Clinical Trials, Phase III as Topic; Drug Approval; Humans; Multicenter Studies as Topic; Pregnanolone; Seizures
PubMed: 35596878
DOI: 10.1007/s40265-022-01724-0 -
Physiological Research 2003The levels of four pregnanolone isomers and their polar conjugates and pregnenolone sulfate were measured in the plasma of 13 and 7 women at delivery with subarachnoidal... (Comparative Study)
Comparative Study
The levels of four pregnanolone isomers and their polar conjugates and pregnenolone sulfate were measured in the plasma of 13 and 7 women at delivery with subarachnoidal and epidural analgesia, respectively, and in corresponding samples of umbilical plasma using a simple quadrupole GC/MS system with electron impact ionization (pregnenolone isomers), RIA following HPLC separation (pregnenolone) and specific RIA (pregnanolone sulfate). The concentration of epipregnanolone (3beta-hydroxy-5beta-pregnan-20-one) in both maternal and umbilical plasma was much lower than that of other pregnanolone isomers. The levels of 3beta-hydroxy-pregnanolone isomers were significantly higher in the umbilical plasma than in the maternal, while the differences in 3alpha-hydroxy-isomers were insignificant. The differences in conjugates were insignificant with the exception of allopregnanolone, the levels of which were lower in umbilical plasma. In all the pregnanolone isomers, a significantly lower conjugated/unconjugated steroid ratio was found in the umbilical plasma than in the maternal plasma. In addition, time profiles of the steroids were measured around parturition and in the postpartum period in the maternal serum. Similarly, the levels of polar conjugates of all pregnanolone isomers were followed during parturition. Changes in concentrations of free steroids exhibited a similar pattern, with a fall primarily within the first hour after delivery. The decrease in conjugated steroids was shifted to the interval within the first hour and first day after delivery, and the changes were more pronounced. The time profiles of the conjugated/free steroid ratio exhibited a significant decrease within the first hour and the first day after delivery in all of the isomers investigated. A decrease was also observed in the ratio of 3alpha/3beta-isomers and 5alpha/5beta-isomers around parturition. The possible physiological consequences of the findings are indicated.
Topics: Female; Fetal Blood; Humans; Isomerism; Labor, Obstetric; Postpartum Period; Pregnancy; Pregnanolone
PubMed: 12678664
DOI: No ID Found -
Neurotherapeutics : the Journal of the... Jan 2007Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds... (Review)
Review
Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. GNX is an allosteric modulator of GABA(A) receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. GNX has been shown to be well tolerated in adults and children. In early phase II studies, GNX has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures.
Topics: Animals; Anticonvulsants; Brain; Clinical Trials as Topic; Epilepsy; Humans; Pregnanolone
PubMed: 17199022
DOI: 10.1016/j.nurt.2006.11.003 -
Revista de Neurologia May 2022Catamenial pattern epilepsy is defined as an increase in the frequency of seizures during a specific stage of the menstrual cycle compared to baseline. It has been... (Review)
Review
Catamenial pattern epilepsy is defined as an increase in the frequency of seizures during a specific stage of the menstrual cycle compared to baseline. It has been described that around a third of women with epilepsy have a catamenial pattern. The changes in the seizure pattern would be explained by the influence of catamenial fluctuations, of female gonadal hormones on neuronal excitability. Progesterone through its metabolite allopregnanolone plays a protective role by increasing GABAergic transmission; however, its effect on brain progesterone receptors can increase neuronal excitability. The effects of estrogens are complex, they tend to increase neuronal excitability, although their effects depend on their concentration and exposure time. Three catamenial patterns of seizure exacerbation have been proposed: the perimenstrual pattern, the periovulatory pattern, and the luteal pattern. The diagnostic approach is carried out through a systematic process of 4 steps: a) clinical history of the pattern of the menstrual cycle and epileptic seizures; b) diagnostic methods to characterize the menstrual cycle and the pattern of seizures; c) check diagnostic criteria; and d) categorize the catamenial pattern. The treatment options studied require a higher level of evidence, and there is no specific treatment. Optimization of conventional antiseizure treatment is recommended as the first therapeutic option. Other therapeutic options, such as non-hormonal and hormonal treatments, could be useful in case the first therapeutic option proves to be ineffective.
Topics: Epilepsy, Reflex; Female; Humans; Menstrual Cycle; Pregnanolone; Progesterone; Seizures
PubMed: 35484702
DOI: 10.33588/rn.7409.2022041