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Allopregnanolone

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https://www.readbyqxmd.com/read/28319848/treatment-of-premenstrual-dysphoric-disorder-with-the-gabaa-receptor-modulating-steroid-antagonist-sepranolone-uc1010-a-randomized-controlled-trial
#1
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)...
March 1, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28278440/lower-allopregnanolone-during-pregnancy-predicts-postpartum-depression-an-exploratory-study
#2
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...
February 16, 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
#3
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
#4
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-mrna-in-the-hippocampus-subfields
#5
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...
January 27, 2017: Brain Research
https://www.readbyqxmd.com/read/28129443/anxiolytic-effects-of-hippocampal-neurosteroids-in-normal-and-neuropathic-rats-with-spared-nerve-injury
#6
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
https://www.readbyqxmd.com/read/28119080/allopregnanolone-promotes-proliferation-and-differential-gene-expression-in-human-glioblastoma-cells
#7
Carmen J Zamora-Sánchez, Valeria Hansberg-Pastor, Ivan Salido-Guadarrama, Mauricio Rodríguez-Dorantes, Ignacio Camacho-Arroyo
Allopregnanolone (3α-THP) is one of the main reduced progesterone (P4) metabolites that is recognized as a neuroprotective and myelinating agent. 3α-THP also induces proliferation of different neural cells. It has been shown that P4 favors the progression of glioblastomas (GBM), the most common and aggressive primary brain tumors. However, the role of 3α-THP in the growth of GBMs is unknown. Here, we studied the effects of 3α-THP on the number of cells, proliferation and gene expression in U87 cell line derived from a human GBM...
January 22, 2017: Steroids
https://www.readbyqxmd.com/read/28111749/progress-report-on-new-antiepileptic-drugs-a-summary-of-the-thirteenth-eilat-conference-on-new-antiepileptic-drugs-and-devices-eilat-xiii
#8
REVIEW
Meir Bialer, Svein I Johannessen, René H Levy, Emilio Perucca, Torbjörn Tomson, H Steve White
The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689)...
January 23, 2017: Epilepsia
https://www.readbyqxmd.com/read/28109985/the-synthetic-neuroactive-steroid-sge-516-reduces-status-epilepticus-and-neuronal-cell-death-in-a-rat-model-of-soman-intoxication
#9
Alison L Althaus, Hilary S McCarren, Aymen Alqazzaz, Cecelia Jackson, John H McDonough, Carl D Smith, Ethan Hoffman, Rebecca S Hammond, Albert J Robichaud, James J Doherty
Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines...
January 18, 2017: Epilepsy & Behavior: E&B
https://www.readbyqxmd.com/read/28104355/allopregnanolone-induces-state-dependent-fear-via-the-bed-nucleus-of-the-stria-terminalis
#10
Gillian M Acca, Abel S Mathew, Jingji Jin, Stephen Maren, Naomi Nagaya
Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST)...
January 16, 2017: Hormones and Behavior
https://www.readbyqxmd.com/read/28102853/skin-to-skin-contact-after-birth-and-the-natural-course-of-neurosteroid-levels-in-healthy-term-newborns
#11
K R McCallie, N W Gaikwad, M E Castillo Cuadrado, M Aleman, J E Madigan, D K Stevenson, V K Bhutani
OBJECTIVE: To determine the postnatal course of neurosteroid levels in relation to gender, mode of delivery and the extent of skin-to-skin (STS) contact during the first days of life in healthy term newborns. STUDY DESIGN: Prospective observational study of 39 neonates in which parents recorded total duration of STS in the first 2 days and nine neurosteroids (dehydroepiandrosterone-sulfate, progesterone, pregnenolone, pregnenolone-sulfate, allopregnanolone, isopregnanolone, epipregnanolone, pregnanolone and pregnanolone-sulfate) were assayed from blood samples at birth and at 1-2 days of age...
January 19, 2017: Journal of Perinatology: Official Journal of the California Perinatal Association
https://www.readbyqxmd.com/read/28102229/the-neurosteroidogenic-enzyme-5%C3%AE-reductase-mediates-psychotic-like-complications-of-sleep-deprivation
#12
Roberto Frau, Valentina Bini, Alessio Soggiu, Simona Scheggi, Alessandra Pardu, Silvia Fanni, Paola Roncada, Monica Puligheddu, Francesco Marrosu, Donatella Caruso, Paola Devoto, Marco Bortolato
Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive involvement of neuroactive steroids in psychopathology, we hypothesized that the behavioral complications of SD may be contributed by 5α-reductase (5αR), the rate-limiting enzyme in the conversion of progesterone into the neurosteroid allopregnanolone. We first tested whether rats exposed to SD may exhibit brain-regional alterations in 5αR isoenzymes and neuroactive steroid levels; then, we assessed whether the behavioral and neuroendocrine alterations induced by SD may be differentially modulated by the administration of the 5αR inhibitor finasteride, as well as progesterone and allopregnanolone...
January 19, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28072455/src-and-phospho-fak-kinases-are-activated-by-allopregnanolone-promoting-schwann-cells-motility-morphology-and-myelination
#13
Simona Melfi, Maria Magdalena Montt Guevara, Veronica Bonalume, Massimiliano Ruscica, Alessandra Colciago, Tommaso Simoncini, Valerio Magnaghi
Schwann cells' (SCs) development and maturation require coordinate and complementary interaction among several signals and intracellular pathways. Among factors controlling these processes, the signalling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) are relevant for SCs' fate, participating in regulation of SC adhesion, motility and migration. Recently, the progesterone metabolite allopregnanolone (ALLO) was proved to be synthesized by SCs, whereas it acts autocrinally on SC motility and proliferation, which are crucial processes for nerve development, maturation and regeneration...
January 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28068457/cellular-gabaergic-neuroactive-steroid-3%C3%AE-5%C3%AE-3-hydroxy-pregnan-20-one-3%C3%AE-5%C3%AE-thp-immunostaining-levels-are-increased-in-the-ventral-tegmental-area-of-human-alcohol-use-disorder-patients-a-postmortem-study
#14
Ahmet Sait Hasirci, Antoniette M Maldonado-Devincci, Matthew C Beattie, Todd K O'Buckley, A Leslie Morrow
BACKGROUND: The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP; allopregnanolone) enhances GABAergic activity and produces subjective effects similar to ethanol (EtOH). The effect of chronic alcohol exposure on 3α,5α-THP concentrations has been studied in mouse, rat, and monkey limbic brain areas. Chronic EtOH exposure produced divergent brain region and cell-specific changes in 3α,5α-THP concentrations in animal studies. However, 3α,5α-THP levels in similar human brain regions have never been examined in individuals diagnosed with alcohol use disorder (AUD)...
February 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28013353/changes-in-stress-stimulated-allopregnanolone-levels-induced-by-neonatal-estradiol-treatment-are-associated-with-enhanced-dopamine-release-in-adult-female-rats-reversal-by-progesterone-administration
#15
Patrizia Porcu, Valeria Lallai, Andrea Locci, Sandro Catzeddu, Valeria Serra, Maria Giuseppina Pisu, Mariangela Serra, Laura Dazzi, Alessandra Concas
BACKGROUND: Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. OBJECTIVE: We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood...
December 24, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/28009705/positive-allosteric-modulation-of-gabaa-receptors-attenuates-high-blood-pressure-in-schlager-hypertensive-mice
#16
Emily R Stevenson, Esther M C Johns, Francine Z Marques, Kristy L Jackson, Pamela J Davern, Roger G Evans, Geoffrey A Head
OBJECTIVE: Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors. METHODS: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5 mg/kg per day), or its vehicle, for a period of 2 weeks...
March 2017: Journal of Hypertension
https://www.readbyqxmd.com/read/27993636/anti-ptsd-like-effects-of-albiflorin-extracted-from-radix-paeoniae-alba
#17
Zhi-Kun Qiu, Jia-Li He, Xu Liu, Jia Zeng, Ji-Sheng Chen, Hong Nie
ETHNOPHARMACOLOGY RELEVANCE: Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that is characterized by symptoms of re-experiencing, avoidance and hyperarousal, as well as social and professional dysfunction at least one month after the exposure to a traumatic event. Biosynthesis of allopregnanolone has been suggested as one of the important contributors to PTSD. Albiflorin (AF) extracted from Radix paeoniae Alba had been shown to be effective in the therapy of depression...
December 16, 2016: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27979708/allopregnanolone-and-its-analog-br-297-rescue-neuronal-cells-from-oxidative-stress-induced-death-through-bioenergetic-improvement
#18
Imane Lejri, Amandine Grimm, Michel Miesch, Philippe Geoffroy, Anne Eckert, Ayikoe-Guy Mensah-Nyagan
Allopregnanolone (AP) is supposed to exert beneficial actions including anxiolysis, analgesia, neurogenesis and neuroprotection. However, although mitochondrial dysfunctions are evidenced in neurodegenerative diseases, AP actions against neurodegeneration-induced mitochondrial deficits have never been investigated. Also, the therapeutic exploitation of AP is limited by its difficulty to pass the liver and its rapid clearance after sulfation or glucuronidation of its 3-hydroxyl group. Therefore, the characterization of novel potent neuroprotective analogs of AP may be of great interest...
December 13, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27913096/a-sensitive-and-accurate-lc-ms-ms-assay-with-the-derivatization-of-1-amino-4-methylpiperazine-applied-to-serum-allopregnanolone-pregnenolone-and-androsterone-in-pre-and-postmenopausal-women
#19
Yuyong Ke, Renaud Gonthier, Fernand Labrie
The concentrations of allopregnanolone (Allopreg), pregnenolone (Preg) and androsterone (ADT) are very low in the circulation, especially in postmenopausal women, resulting in a considerable challenge for their accurate measurements in serum or plasma. In this report, a sensitive and reliable LC-MS/MS assay method has been developed using a simple sample preparation and the 1-Amino-4-methylpiperazine (AMP) derivatization procedure. A 5pg/ml (0.1pg on column) of low limit of quantitation has been achieved for Allopreg, Preg and ADT, with a sensitivity comparable to data obtained with the commercial reagent...
November 29, 2016: Steroids
https://www.readbyqxmd.com/read/27888513/decreased-allopregnanolone-levels-in-cerebrospinal-fluid-obtained-during-status-epilepticus
#20
Stefano Meletti, Chiara Lucchi, Giulia Monti, Giada Giovannini, Roberta Bedin, Tommaso Trenti, Cecilia Rustichelli, Giuseppe Biagini
Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders...
February 2017: Epilepsia
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