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Allopregnanolone

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https://www.readbyqxmd.com/read/28505538/synthesis-and-pharmacological-evaluation-of-neurosteroid-photoaffinity-ligands
#1
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
#2
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
#3
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 9, 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
#4
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
#5
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...
May 4, 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
#6
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
#7
Atefeh Mousavi Nik, Brandon Pressly, Vikrant Singh, Shane Antrobus, Susan Hulsizer, Michael A Rogawski, Heike Wulff, Isaac N Pessah
Fluorometric Imaging Plate Reader (FLIPR®) 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 DisSBAC1(3). GABAAR expressing cells equilibrated with FMP-Red-Dye exhibited depolarized equilibrium membrane (Em) potentials compared to GABAAR-null cells...
April 20, 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
#8
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
#9
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
#10
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...
April 13, 2017: Synapse
https://www.readbyqxmd.com/read/28383485/increased-regenerative-capacity-of-the-olfactory-epithelium-in-niemann-pick-disease-type-c1
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28278440/lower-allopregnanolone-during-pregnancy-predicts-postpartum-depression-an-exploratory-study
#16
Lauren M Osborne, Fiona Gispen, Abanti Sanyal, Gayane Yenokyan, Samantha Meilman, Jennifer L Payne
Current evidence is mixed on the role of progesterone and its metabolites in perinatal mood and anxiety disorders. We measured second and third trimester (T2 and T3) progesterone (PROG) and allopregnanolone (ALLO) levels by ELISA and postpartum depression (PPD) by clinician interview (DSM-IV criteria) in 60 pregnant women with a prior diagnosis of a mood disorder. Methods included multivariate and logistic regression with general linear mixed effect models. We found that, after adjustment, every additional ng/mL of T2 ALLO resulted in a 63% (95% CI 13% to 84%, p=0...
May 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28207286/lc-ms-ms-simultaneous-analysis-of-allopregnanolone-epiallopregnanolone-pregnanolone-dehydroepiandrosterone-and-dehydroepiandrosterone-3-sulfate-in-human-plasma
#17
Luana Lionetto, Fernando De Andrés, Matilde Capi, Martina Curto, Donata Sabato, Maurizio Simmaco, Paola Bossù, Eleonora Sacchinelli, Maria Donata Orfei, Federica Piras, Nerisa Banaj, Gianfranco Spalletta
AIM: Several neuropsychopharmacological properties have been attributed to the 3α-reduced pregnane steroids, allopregnanolone and pregnanolone, as well as to dehydroepiandrosterone sulfate because of their ability to modulate γ-aminobutyric acid (GABAA) receptors in the CNS. In order to understand better their role in several mechanisms in CNS, a new methodology is proposed to monitor these compounds in human plasma. Methodology & results: The analytes were first derivatized with 2-hydrazinopyridine and extracted from plasma using SPE...
March 2017: Bioanalysis
https://www.readbyqxmd.com/read/28192175/increased-anxiety-like-phenotype-in-female-guinea-pigs-following-reduced-neurosteroid-exposure-in-utero
#18
Angela L Cumberland, Hannah K Palliser, Gabrielle K Crombie, David W Walker, Jonathan J Hirst
Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders...
May 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28137424/pr-independent-neurosteroid-regulation-of-%C3%AE-2-gaba-a-receptors-in-the-hippocampus-subfields
#19
Doodipala Samba Reddy, Omkaram Gangisetty, Xin Wu
Progesterone (P) binding to the intracellular progesterone receptors (PRs) plays a key role in epilepsy via modulation of GABA-A receptor plasticity in the brain. This is thought to occur via conversion of P to neurosteroids such as allopregnanolone, an allosteric modulator of GABA-A receptors. In the female brain, the composition of GABA-A receptors is not static and undergoes dynamic spatial changes in response to fluctuations in P and neurosteroid levels. Synaptic α2-containing GABA-A receptors contribute to phasic neuronal excitability and seizure susceptibility...
March 15, 2017: Brain Research
https://www.readbyqxmd.com/read/28129443/anxiolytic-effects-of-hippocampal-neurosteroids-in-normal-and-neuropathic-rats-with-spared-nerve-injury
#20
Meng Zhang, Jia Liu, Meng-Meng Zhou, Honghai Wu, Yanning Hou, Yun-Feng Li, Yuxin Yin, Lemin Zheng, Jie Cai, Fei-Fei Liao, Feng-Yu Liu, Ming Yi, You Wan
Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of GABAA receptors, which play a vital role in modulating hippocampal functions. Chronic pain is accompanied by increased neurosteroid production in the spinal cord and thalamus. We hypothesize that hippocampal neurosteroids participate in pain or pain-associated emotions, which we tested with high-performance liquid chromatography/tandem mass spectrometry and pharmacological behavioral tests...
January 27, 2017: Journal of Neurochemistry
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