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Allopregnanolone

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https://www.readbyqxmd.com/read/28631553/administration-of-progesterone-throughout-pregnancy-increases-maternal-steroids-without-adverse-effect-on-mature-oligodendrocyte-immunostaining-in-the-guinea-pig
#1
Julia C Shaw, Hannah K Palliser, Kerrin Palazzi, Jonathan J Hirst
Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/28623385/juvenile-social-isolation-affects-maternal-care-in-rats-involvement-of-allopregnanolone
#2
Maria Giuseppina Pisu, Giorgia Boero, Francesca Biggio, Anna Garau, Daniela Corda, Mauro Congiu, Alessandra Concas, Patrizia Porcu, Mariangela Serra
RATIONALE: Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. Socially isolated virgin females showed a significant decrease in allopregnanolone levels, associated with increased anxiety-related behavior compared with group-housed rats. OBJECTIVES: The present study investigates whether post-weaning social isolation affects maternal behavior and assesses neuroactive steroid levels in adult female rats during pregnancy and postpartum...
June 16, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28619476/brexanolone-sage-547-injection-in-post-partum-depression-a-randomised-controlled-trial
#3
Stephen Kanes, Helen Colquhoun, Handan Gunduz-Bruce, Shane Raines, Ryan Arnold, Amy Schacterle, James Doherty, C Neill Epperson, Kristina M Deligiannidis, Robert Riesenberg, Ethan Hoffmann, David Rubinow, Jeffrey Jonas, Steven Paul, Samantha Meltzer-Brody
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 (GABAA) 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...
June 12, 2017: Lancet
https://www.readbyqxmd.com/read/28611376/allopregnanolone-mediates-the-exacerbation-of-tourette-like-responses-by-acute-stress-in-mouse-models
#4
Laura J Mosher, Sean C Godar, Marianela Nelson, Stephen C Fowler, Graziano Pinna, Marco Bortolato
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial confinement (SC), a moderate environmental stressor, increases tic-like responses and elicits TS-like sensorimotor gating deficits in the D1CT-7 mouse, one of the best-validated models of TS. Here, we hypothesized that these adverse effects may be mediated by neurosteroids, given their well-documented role in stress-response orchestration...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28589168/first-in-man-allopregnanolone-use-in-super-refractory-status-epilepticus
#5
Henrikas Vaitkevicius, Aatif M Husain, Eric S Rosenthal, Jonathan Rosand, Wendell Bobb, Kiran Reddy, Michael A Rogawski, Andrew J Cole
Super-refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120-h continuous infusion of allopregnanolone...
June 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28505538/synthesis-and-pharmacological-evaluation-of-neurosteroid-photoaffinity-ligands
#6
Pavel Y Savechenkov, David C Chiara, Rooma Desai, Alexander T Stern, Xiaojuan Zhou, Alexis M Ziemba, Andrea L Szabo, Yinghui Zhang, Jonathan B Cohen, Stuart A Forman, Keith W Miller, Karol S Bruzik
Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAAR), but the locations of their GABAAR binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAAR, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAAR responses, left-shifting the GABA concentration - response curve for human α1β3γ2 GABAARs expressed in Xenopus oocytes, and enhancing [(3)H]muscimol binding to α1β3γ2 GABAARs expressed in HEK293 cells...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28502262/effects-of-combined-iugr-and-prenatal-stress-on-the-development-of-the-hippocampus-in-a-fetal-guinea-pig-model
#7
A L Cumberland, H K Palliser, P Rani, D W Walker, J J Hirst
Intrauterine growth restriction (IUGR) and maternal stress during pregnancy are two compromises that negatively impact neurodevelopment and increase the risk of developing later life neuropsychiatric disorders such as schizophrenia, depression and behavioural disorders. Neurosteroids, particularly allopregnanolone, are important in protecting the developing brain and promoting many essential neurodevelopmental processes. Individually, IUGR and prenatal stress (PS) reduce myelination and neurogenesis within affected fetal brains, however less information is available on the combined effects of these two disorders on the term fetal brain...
May 15, 2017: Journal of Developmental Origins of Health and Disease
https://www.readbyqxmd.com/read/28499916/effects-of-neonatal-and-adolescent-neuroactive-steroid-manipulation-on-locomotor-activity-induced-by-ethanol-in-male-wistar-rats
#8
Iris Bartolomé, Anna Llidó, Sònia Darbra, Marc Pallarès
Neonatal neuroactive steroids levels are crucial for brain development. Alterations of neonatal neuroactive steroids levels induce anxiolytic-like effects and improve exploration in novel environments in adulthood. These behavioural traits, i.e. sensation/novelty seeking, anxiety or impulsivity, are associated with vulnerability to drug use and abuse. Adolescence is also recognized as a particularly critical developmental phase to contribute to vulnerable phenotype. However, the influence of neuroactive steroids during development in the vulnerability to drug addiction has been poorly studied...
May 10, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28476183/influence-of-endogenous-estradiol-progesterone-allopregnanolone-and-dehydroepiandrosterone-sulfate-on-brain-resting-state-functional-connectivity-across-the-menstrual-cycle
#9
Sabrina K Syan, Luciano Minuzzi, Dustin Costescu, Mara Smith, Olivia R Allega, Marg Coote, Geoffrey B C Hall, Benicio N Frey
OBJECTIVE: To [1] study brain resting state functional connectivity (Rs-FC) in a well-characterized sample of healthy women in the mid-follicular and late luteal phases of the menstrual cycle; and [2] examine the correlation between endogenous E2, P, allopregnanolone, and DHEAS and patterns of Rs-FC across the menstrual cycle. DESIGN: We studied the Rs-FC of the default mode network, salience network, meso-paralimbic network, fronto-parietal network, visual network, and sensorimotor network in the mid-follicular and late luteal phases...
May 2017: Fertility and Sterility
https://www.readbyqxmd.com/read/28471529/reduced-steroidogenesis-in-patients-with-pcdh19-female-limited-epilepsy
#10
Marina Trivisano, Chiara Lucchi, Cecilia Rustichelli, Alessandra Terracciano, Raffaella Cusmai, Grazia Maria Ubertini, Germana Giannone, Enrico Silvio Bertini, Federico Vigevano, Jozef Gecz, Giuseppe Biagini, Nicola Specchio
Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays...
June 2017: Epilepsia
https://www.readbyqxmd.com/read/28456011/neurosteroid-biosynthesis-downregulation-and-changes-in-gabaa-receptor-subunit-composition-a-biomarker-axis-in-stress-induced-cognitive-and-emotional-impairment
#11
REVIEW
Andrea Locci, Graziano Pinna
By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction...
April 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28428226/rapid-throughput-analysis-of-gabaa-receptor-subtype-modulators-and-blockers-using-disbac1-3-membrane-potential-red-dye
#12
Atefeh Mousavi Nik, Brandon Pressly, Vikrant Singh, Shane Antrobus, Susan Hulsizer, Michael A Rogawski, Heike Wulff, Isaac N Pessah
Fluorometric imaging plate reader membrane potential dye (FMP-Red-Dye) is a proprietary tool for basic discovery and high-throughput drug screening for G-protein-coupled receptors and ion channels. We optimized and validated this potentiometric probe to assay functional modulators of heterologous expressed GABAA receptor (GABAAR) isoforms (synaptic α1β3γ2, extrasynaptic α4β3δ, and β3 homopentomers). High-resolution mass spectrometry identified FMP-Red-Dye as 5,5'-(1-propen-1-yl-3-ylidene)bis[1,3-dimethyl-2-thio-barbituric acid]...
July 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28416442/allopregnanolone-decreases-interictal-spiking-and-fast-ripples-in-an-animal-model-of-mesial-temporal-lobe-epilepsy
#13
Maxime Lévesque, Rochelle Herrington, Leila Leclerc, Michael A Rogawski, Massimo Avoli
The objective of this study was to characterize the impact of allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, on interictal spikes and high-frequency oscillations (ripples: 80-200 Hz, fast ripples: 250-500 Hz) in the pilocarpine model of mesial temporal lobe epilepsy. Seven out of 25 Sprague-Dawley rats experiencing 1 h of pilocarpine-induced status epilepticus (SE) began treatment with allopregnanolone (9.6-12.8 mg/kg/day) on the following day...
April 15, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28416372/effects-of-bilobalide-ginkgolide-b-and-picrotoxinin-on-gabaa-receptor-modulation-by-structurally-diverse-positive-modulators
#14
Chiu Chin Ng, Rujee K Duke, Tina Hinton, Graham A R Johnston
Anxiolytics and anticonvulsants generally positively modulate the action of GABA, whereas many convulsants (including the chloride channel blocker picrotoxinin) negatively modulate the action of GABA on GABAA receptors. Like picrotoxinin, bilobalide and ginkgolide B, active constituents of Ginkgo biloba, have been shown to negatively modulate the action of GABA at α1β2γ2L GABAA receptors. However, unlike picrotoxinin, bilobalide and ginkgolide B are not known to cause convulsions. We have assessed the action of bilobalide, ginkgolide B and picrotoxinin on a range of GABAA modulators (etomidate, loreclezole, propofol, thiopentone sodium, diazepam, and allopregnanolone), using two-electrode voltage clamp electrophysiology at recombinant α1β2γ2L GABAA receptors expressed in Xenopus oocytes...
April 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28407365/role-of-allopregnanolone-biosynthesis-in-acute-stress-induced-anxiety-like-behaviors-in-mice
#15
Kazumi Yoshizawa, Ayano Okumura, Kozue Nakashima, Tomoyo Sato, Tatsuya Higashi
The neurosteroid allopregnanolone (3α, 5α-tetra-hydroprogesterone: ALLO) elicits anxiolytic, anticonvulsant, and hypnotic anesthetic effects in vivo similar to those induced by other positive allosteric modulators of the GABAA receptor. Endogenous ALLO has been shown to be rapidly elevated in the brain by acute stress paradigms, such as immobilization, in animal models. The present study was designed to ascertain the role of neurosteroid biosynthesis in the anxiety-like behavior induced by immobilization stress...
August 2017: Synapse
https://www.readbyqxmd.com/read/28383485/increased-regenerative-capacity-of-the-olfactory-epithelium-in-niemann-pick-disease-type-c1
#16
Anja Meyer, Andreas Wree, René Günther, Carsten Holzmann, Oliver Schmitt, Arndt Rolfs, Martin Witt
Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1(-/-) mutant mice compared with healthy controls (NPC1(+/+))...
April 6, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28381564/the-relationship-between-weight-gain-during-pregnancy-and-allopregnanolone-levels-a-longitudinal-study
#17
Anette Lundqvist, Herbert Sandström, Torbjörn Bäckström
OBJECTIVE: Excessive weight gain during pregnancy poses a risk for negative complications for mother and fetus. Hunger and satiety are regulated in the hypothalamus, where the gamma-amino-butyric acid system (GABA) plays an important role. Allopregnanolone, a progesterone metabolite, increases during pregnancy and is a potent GABA-A receptor modulating steroid. Allopregnanolone has been shown to induce overeating in rodents. The aim of this study was to investigate whether there is a relationship between weight gain and allopregnanolone concentrations during pregnancy in humans...
April 5, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/28374007/contribution-of-resting-conductance-gabaa-receptor-mediated-miniature-synaptic-currents-and-neurosteroid-to-chloride-homeostasis-in-central-neurons
#18
Tushar D Yelhekar, Michael Druzin, Staffan Johansson
Maintenance of a low intraneuronal Cl(-) concentration, [Cl(-)]i, is critical for inhibition in the CNS. Here, the contribution of passive, conductive Cl(-) flux to recovery of [Cl(-)]i after a high load was analyzed in mature central neurons from rat. A novel method for quantifying the resting Cl(-) conductance, important for [Cl(-)]i recovery, was developed and the possible contribution of GABAA and glycine receptors and of ClC-2 channels to this conductance was analyzed. The hypothesis that spontaneous, action potential-independent release of GABA is important for [Cl(-)]i recovery was tested...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28370307/open-label-proof-of-concept-study-of-brexanolone-in-the-treatment-of-severe-postpartum-depression
#19
Stephen J Kanes, Helen Colquhoun, James Doherty, Shane Raines, Ethan Hoffmann, David R Rubinow, Samantha Meltzer-Brody
OBJECTIVE: Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study...
March 2017: Human Psychopharmacology
https://www.readbyqxmd.com/read/28319848/treatment-of-premenstrual-dysphoric-disorder-with-the-gabaa-receptor-modulating-steroid-antagonist-sepranolone-uc1010-a-randomized-controlled-trial
#20
Marie Bixo, Karin Ekberg, Inger Sundström Poromaa, Angelica Lindén Hirschberg, Aino Fianu Jonasson, Lotta Andréen, Erika Timby, Marianne Wulff, Agneta Ehrenborg, Torbjörn Bäckström
CONTEXT: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. OBJECTIVE: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD)...
June 2017: Psychoneuroendocrinology
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