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Allopregnanolone

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https://www.readbyqxmd.com/read/28743598/decrease-in-endogenous-brain-allopregnanolone-induces-autism-spectrum-disorder-asd-like-behavior-in-mice-a-novel-animal-model-of-asd
#1
Ken Ebihara, Hironori Fujiwara, Suresh Awale, Dya Fita Dibwe, Ryota Araki, Takeshi Yabe, Kinzo Matsumto
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis...
July 22, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28740098/puerarin-ameliorated-the-behavioral-deficits-induced-by-chronic-stress-in-rats
#2
Zhi-Kun Qiu, Guan-Hua Zhang, De-Sheng Zhong, Jia-Li He, Xu Liu, Ji-Sheng Chen, Da-Nian Wei
The present study aimed to investigate the mechanisms underlying the antidepressant-like effects of puerarin via the chronic unpredictable stress (CUS) procedure in rats. Similar to Sertraline (Ser), Chronic treatment of puerarin (60 and 120 mg/kg, i.g) elicited the antidepressant-like effects by reversing the decreased sucrose preference in sucrose preference test (SPT), by blocking the increased latency to feed in novelty-suppressed feeding test (NSFT) and the increased immobility time in forced swimming test (FST) without affecting locomotor activity...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28715875/acute-orexigenic-effect-of-agmatine-involves-interaction-between-central-%C3%AE-2-adrenergic-and-gabaergic-receptors
#3
Brijesh Gulabrao Taksande, Omi Sharma, Manish Manohar Aglawe, Mayur Bhimrao Kale, Dinesh Yugraj Gawande, Milind Janraoji Umekar, Nandkishor Ramdas Kotagale
Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABAA receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABAA positive modulator, allopregnanolone or negative modulator of GABAA receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α2-adrenoceptors and the close association between α2-adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined...
July 13, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28707277/open-label-allopregnanolone-treatment-of-men-with-fragile-x-associated-tremor-ataxia-syndrome
#4
J Y Wang, A M Trivedi, N R Carrillo, J Yang, A Schneider, C Giulivi, P Adams, F Tassone, K Kim, S M Rivera, N Lubarr, C-Y Wu, R W Irwin, R D Brinton, J M Olichney, M A Rogawski, R J Hagerman
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks...
July 13, 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/28694181/allopregnanolone-involvement-in-feeding-regulation-overeating-and-obesity
#5
E Holmberg, J Sjöstedt, E Malinina, M Johansson, S Turkmen, G Ragagnin, A Lundqvist, M Löfgren, L Jaukkuri, M Bixo, T Bäckström
Obesity is strongly associated with ill health, primarily caused by consumption of excessive calories, and promoted (inter alia) by gamma-amino-butyric-acid (GABA) stimulating food intake by activating GABAA receptors (primarily with α3 and α2 subunits) in the hypothalamic arcuate nucleus and paraventricular nucleus. Allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS). As reviewed here, elevated allopregnanolone levels are associated with increases in food intake, preferences for energy-rich food, and obesity in humans and other mammals...
July 8, 2017: Frontiers in Neuroendocrinology
https://www.readbyqxmd.com/read/28667781/translocator-protein-18-kda-an-update-on-its-function-in-steroidogenesis
#6
REVIEW
Vassilios Papadopoulos, Jinjiang Fan, Barry Zirkin
Translocator protein (18 kDa), TSPO, is a ubiquitous mitochondrial protein. Studies of its responses to drug and endogenous ligands have shown TSPO to be involved either directly or indirectly in numerous biological functions, including mitochondrial cholesterol transport and steroid hormone biosynthesis, porphyrin transport and heme synthesis, apoptosis, cell proliferation, and anion transport. Localized to the outer mitochondrial membrane of steroidogenic cells, TSPO has been shown to associate with cytosolic and mitochondrial proteins as part of a large multiprotein complex involved in mitochondrial cholesterol transport, the rate-limiting step in steroidogenesis...
July 1, 2017: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28667510/a-randomized-controlled-trial-of-ganaxolone-in-posttraumatic-stress-disorder
#7
Ann M Rasmusson, Christine E Marx, Sonia Jain, Gail M Farfel, Julia Tsai, Xiaoying Sun, Thomas D Geracioti, Mark B Hamner, James Lohr, Richard Rosse, Lanier Summerall, Jennifer C Naylor, Cristine Cusin, Ariel J Lang, Rema Raman, Murray B Stein
Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks...
August 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28666923/allopregnanolone-levels-and-depressive-symptoms-during-pregnancy-in-relation-to-single-nucleotide-polymorphisms-in-the-allopregnanolone-synthesis-pathway
#8
Charlotte Hellgren, Erika Comasco, Alkistis Skalkidou, Inger Sundström-Poromaa
Allopregnanolone, a neurosteroid whose levels rise throughout gestation, putatively stabilizes antenatal mood. The present study aimed to investigate associations of plasma allopregnanolone to antenatal depressive symptoms, as well as to genetic and obstetric factors. Allopregnanolone plasma levels from 284 pregnant women were measured around gestational week 18. Haplotype tag single nucleotide polymorphisms in the aldo-keto reductase family 1, members C2 and C4 (AKR1C2, AKR1C4), and steroid 5 alpha-reductase 1 and 2 (SRD5A1, and SRD5A2) genes were genotyped in a larger sample of pregnant women (n=1351)...
July 20, 2017: Hormones and Behavior
https://www.readbyqxmd.com/read/28664280/ethanol-withdrawal-induced-dysregulation-of-neurosteroid-levels-in-plasma-cortex-and-hippocampus-in-genetic-animal-models-of-high-and-low-withdrawal
#9
Jeremiah P Jensen, Michelle A Nipper, Melinda L Helms, Matthew M Ford, John C Crabbe, David J Rossi, Deborah A Finn
RATIONALE: Endogenous γ-aminobutyric acidA receptor (GABAAR)-active neurosteroids (e.g., allopregnanolone) regulate central nervous system excitability and many physiological functions, so fluctuations are implicated in several neuropsychiatric disorders. Pertinently, evidence supports an inverse relationship between endogenous GABAAR-active neurosteroid levels and behavioral changes in excitability during ethanol withdrawal (WD). OBJECTIVES: The present studies determined mouse genotype differences in ten neurosteroid levels in plasma, cortex, and hippocampus over the time course of ethanol WD in the WD Seizure-Prone (WSP) and WD Seizure-Resistant (WSR) selected lines and in the DBA/2J (DBA) inbred strain...
June 29, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28655607/overexpression-of-the-18%C3%A2-kda-translocator-protein-tspo-in-the-hippocampal-dentate-gyrus-produced-anxiolytic-and-antidepressant-like-behavioural-effects
#10
Lei Li, Wei Wang, Li-Ming Zhang, Xiang-Yun Jiang, Shuzheng Sun, Li-Jun Sun, Ying Guo, Jie Gong, Youzhi Zhang, Henglin Wang, Yunfeng Li
The 18 kDa translocator protein (TSPO) is a five transmembrane domain protein that plays a crucial role in neurosteroid (e.g., allopregnanolone) synthesis by promoting the transport of cholesterol to the inner mitochondrial membrane. This protein is predominantly expressed in steroid-synthesizing tissues, including the central and peripheral nervous system, affecting stress-related disorders such as anxiety and depression. Recent studies have focused on the hippocampal dentate gyrus, which is very important for involvement of anxiety and depression...
June 24, 2017: Neuropharmacology
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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