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Neurosteroid

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https://www.readbyqxmd.com/read/29301936/mapping-two-neurosteroid-modulatory-sites-in-the-prototypic-pentameric-ligand-gated-ion-channel-glic
#1
Wayland W L Cheng, Zi-Wei Chen, John R Bracamontes, Melissa M Budelier, Kathiresan Krishnan, Daniel J Shin, Cunde Wang, Xin Jiang, Douglas F Covey, Gustav Akk, Alex S Evers
Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand gated ion channels (pLGICs), and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand gated ion channel (GLIC), a prototypic pLGIC,...
January 4, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29283333/neurosteroids-and-ischemic-stroke-progesterone-a-promising-agent-in-reducing-the-brain-injury-in-ischemic-stroke
#2
REVIEW
Syed Suhail Andrabi, Suhel Parvez, Heena Tabassum
Progesterone (P4), a well-known neurosteroid, is produced by ovaries and placenta in females and by adrenal glands in both sexes. Progesterone is also synthesized by central nervous system (CNS) tissues to perform various vital neurological functions in the brain. Apart from performing crucial reproductive functions, it also plays a pivotal role in neurogenesis, regeneration, cognition, mood, inflammation, and myelination in the CNS. A substantial body of experimental evidence from animal models documents the neuroprotective role of P4 in various CNS injury models, including ischemic stroke...
2017: Journal of Environmental Pathology, Toxicology and Oncology
https://www.readbyqxmd.com/read/29281967/the-effects-of-vitamin-d-administration-on-brain-inflammatory-markers-in-high-fat-diet-induced-obese-rats
#3
Mahdieh Abbasalizad Farhangi, Mehran Mesgari-Abbasi, Ghazaleh Nameni, Ghazaleh Hajiluian, Parviz Shahabi
BACKGROUND: Obesity induced brain inflammation is associated with cognitive disorders. We aimed to investigate the influence of vitamin D on hypothalamus and hippocampus inflammatory response in high-fat diet induced obese rats. METHODS: In the beginning of the study, 40 rats were divided into two groups: control diet and high fat diet (HFD) for 16 weeks; then each group subdivided into two groups including: N, ND + vitamin D, HFD and HFD + vitamin D. Vitamin D supplementation was done for 5 weeks at 500 IU/kg dosage...
December 28, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/29274741/a-novel-therapeutic-approach-for-treatment-of-catamenial-epilepsy
#4
Suchitra Joshi, Huayu Sun, Karthik Rajasekaran, John Williamson, Edward Perez-Reyes, Jaideep Kapur
Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked...
December 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29273726/%C3%AE-subunit-containing-gabaa-receptors-modulate-respiratory-networks
#5
Gaspard Montandon, Haiying Wu, Hattie Liu, Michael T Vu, Beverley A Orser, Richard L Horner
Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAA receptors (δGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function in the preBötzinger Complex (preBötC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBötC δGABAARs in anesthetized rats and wild-type mice decreased breathing rate...
December 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29242992/dynamic-adaptation-in-neurosteroid-networks-in-response-to-alcohol
#6
Deborah A Finn, Vanessa A Jimenez
The term neurosteroid refers to rapid membrane actions of steroid hormones and their derivatives that can modulate physiological functions and behavior via their interactions with ligand-gated ion channels. This chapter will highlight recent advances pertaining to the modulatory effects of a select group of neurosteroids that are primarily potent positive allosteric modulators of γ-aminobutyric acidA receptors (GABAARs). Nanomolar concentrations of neurosteroids, which occur in vivo, potentiate phasic and tonic forms of GABAAR-mediated inhibition, indicating that both synaptic and extrasynaptic GABAARs possess sensitivity to neurosteroids and contribute to the overall ability of neurosteroids to modulate central nervous system excitability...
December 15, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29237239/sex-steroid-hormones-and-brain-function-pet-imaging-as-a-tool-for-research
#7
REVIEW
R Moraga-Amaro, A van Waarde, J Doorduin, E F J de Vries
Sex steroid hormones are major regulators of sexual characteristic among species. These hormones, however, are also produced in the brain. Steroidal hormone-mediated signaling via the corresponding hormone receptors can influence brain function at a cellular level and thus affect behavior and higher brain functions. Altered steroid hormone signaling has been associated with psychiatric disorders, such as anxiety and depression. Neurosteroids are also thought to have a neuroprotective effect in neurodegenerative diseases So far, the role of steroid hormone receptors in physiological and pathological conditions have mainly been investigated post-mortem on animal or human brain tissues...
December 13, 2017: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29223589/breakthroughs-in-neuroactive-steroid-drug-discovery
#8
REVIEW
Maria-Jesus Blanco, Daniel La, Quinn Coughlin, Caitlin A Newman, Andrew M Griffin, Boyd L Harrison, Francesco G Salituro
Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds...
December 2, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29210709/alphaxalone-binds-in-inner-transmembrane-%C3%AE-%C3%AE-interfaces-of-%C3%AE-1%C3%AE-3%C3%AE-2-%C3%AE-aminobutyric-acid-type-a-receptors
#9
Alexis M Ziemba, Andrea Szabo, David W Pierce, Marian Haburcak, Alex T Stern, Anahita Nourmahnad, Elizabeth S Halpin, Stuart A Forman
BACKGROUND: Neurosteroids like alphaxalone are potent anxiolytics, anticonvulsants, amnestics, and sedative-hypnotics, with effects linked to enhancement of γ-aminobutyric acid type A (GABAA) receptor gating in the central nervous system. Data locating neurosteroid binding sites on synaptic αβγ GABAA receptors are sparse and inconsistent. Some evidence points to outer transmembrane β-α interfacial pockets, near sites that bind the anesthetics etomidate and propofol. Other evidence suggests that steroids bind more intracellularly in β-α interfaces...
November 28, 2017: Anesthesiology
https://www.readbyqxmd.com/read/29197800/progesterone-suppresses-a%C3%AE-42-induced-neuroinflammation-by-enhancing-autophagy-in-astrocytes
#10
Yang Hong, Yunjiang Liu, Geng Zhang, Honghai Wu, Yanning Hou
Autophagy is an intracellular catabolic mechanism essential for recycling intracellular unfolding protein and eliminating toxic protein aggregates. Several studies have shown that deficient autophagy is implicated in the development of Alzheimer's disease (AD) progression. To date, rapidly emerging evidence suggests that neurosteroid progesterone (PG) may play an important role in ameliorating AD. However, the role of PG and its neuroprotective mechanism in regulating autophagy still require further investigation...
November 30, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29194818/rapid-non-genomic-modulation-by-neurosteroids-of-dendritic-spines-in-the-hippocampus-androgen-estrogen-and-corticosteroid
#11
REVIEW
Gen Murakami, Yasushi Hojo, Asami Kato, Yoshimasa Komatsuzaki, Shigeo Horie, Mika Soma, Jonghyuk Kim, Suguru Kawato
Memories are stored in synapses which consist of axon terminals and dendritic spines. Dendritic spines are postsynaptic structures of synapses and essential for synaptic plasticity and cognition. Therefore, extensive investigations about functions and structures of spines have been performed. Sex steroids and stress steroids have been shown to modulate hippocampal synapses. Although rapid modulatory action of sex steroids on synapses has been studied in hippocampal neurons over several decades, its essential molecular mechanisms have not been fully understood...
December 1, 2017: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29155210/transition-from-androgenic-to-neurosteroidal-action-of-5%C3%AE-androstane-3%C3%AE-17%C3%AE-diol-through-the-type-a-%C3%AE-aminobutyric-acid-receptor-in-prostate-cancer-progression
#12
Ding Xia, Doan V Lai, Weijuan Wu, Zachary D Webb, Qing Yang, Lichao Zhao, Zhongxin Yu, Jessica E Thorpe, Bryan C Disch, Michael A Ihnat, Muralidharan Jayaraman, Danny N Dhanasekaran, Kelly L Stratton, Michael S Cookson, Kar-Ming Fung, Hsueh-Kung Lin
Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration-resistant prostate cancer (CRPC). Several mechanisms including alternative intra-prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A γ-aminobutyric acid receptor (GABAAR), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells...
November 15, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29155148/functional-properties-and-mechanism-of-action-of-pptq-an-allosteric-agonist-and-low-nanomolar-positive-allosteric-modulator-at-gabaa-receptors
#13
Nawid Madjroh, Emma Rie Olander, Christoffer Bundgaard, Pella Cecilia Söderhielm, Anders A Jensen
The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αβ2γ2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus laevis oocytes by two-electrode voltage clamp electrophysiology...
January 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29142081/genetic-and-molecular-regulation-of-extrasynaptic-gaba-a-receptors-in-the-brain-therapeutic-insights-for-epilepsy
#14
Shu-Hui Chuang, Doodipala Samba Reddy
GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classical epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology...
November 15, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29079733/analgesic-effects-and-pharmacologic-mechanisms-of-the-gelsemium-alkaloid-koumine-on-a-rat-model-of-postoperative-pain
#15
Bo-Jun Xiong, Ying Xu, Gui-Lin Jin, Ming Liu, Jian Yang, Chang-Xi Yu
Postoperative pain (POP) of various durations is a common complication of surgical procedures. POP is caused by nerve damage and inflammatory responses that are difficult to treat. The neuroinflammation-glia-steroid network is known to be important in POP. It has been reported that the Gelsemium alkaloid koumine possesses analgesic, anti-inflammatory and neurosteroid modulating activities. This study was undertaken to test the analgesic effects of koumine against POP and explore the underlying pharmacologic mechanisms...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29074640/tspo-mutations-in-rats-and-a-human-polymorphism-impair-the-rate-of-steroid-synthesis
#16
David R Owen, Jinjiang Fan, Enrico Campioli, Sathvika Venugopal, Andrew Midzak, Edward Daly, Aline Harlay, Leeyah Issop, Vincenzo Libri, Dimitra Kalogiannopoulou, Eduardo Oliver, Enrique Gallego-Colon, Alessandro Colasanti, Les Huson, Ilan Rabiner, Puvan Suppiah, Charles Essagian, Paul M Matthews, Vassilios Papadopoulos
The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation and apoptosis.  TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation.  In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders...
October 26, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29070563/low-serum-%C3%AF-3-and-%C3%AF-6-polyunsaturated-fatty-acids-and-other-metabolites-are-associated-with-poor-linear-growth-in-young-children-from-rural-malawi
#17
Richard D Semba, Indi Trehan, Ximin Li, Norman Salem, Ruin Moaddel, M Isabel Ordiz, Kenneth M Maleta, Klaus Kraemer, Mark J Manary
Background: Stunting affects ∼25% of children <5 y of age and is associated with impaired cognitive and motor development and increased morbidity and mortality. The pathogenesis of stunting is poorly understood.Objective: The purpose of this study was to identify altered metabolic pathways associated with child stunting.Design: We measured 677 serum metabolites using liquid chromatography-tandem mass spectrometry in a cross-sectional study of 400 Malawian children aged 12-59 mo, of whom 62% were stunted...
December 2017: American Journal of Clinical Nutrition
https://www.readbyqxmd.com/read/29069423/testosterone-and-corticosterone-in-the-mesocorticolimbic-system-of-male-rats-effects-of-gonadectomy-and-caloric-restriction
#18
Daniel J Tobiansky, Anastasia M Korol, Chunqi Ma, Jordan E Hamden, Cecilia Jalabert, Ryan J Tomm, Kiran K Soma
Steroid hormones can modulate motivated behaviors through the mesocorticolimbic system. Gonadectomy (GDX) is a common method to determine how steroids influence the mesocorticolimbic system and caloric restriction (CR) is often used to invigorate motivated behaviors. The assumption is that the effect of these manipulations on brain steroid levels reflects circulating steroid levels. We now know that the brain regulates local steroid levels in a region-specific manner; however, previous studies have low spatial resolution...
October 20, 2017: Endocrinology
https://www.readbyqxmd.com/read/29066971/the-sigma-2-receptor-selective-agonist-siramesine-lu-28-179-decreases-cocaine-reinforced-pavlovian-learning-and-alters-glutamatergic-and-dopaminergic-input-to-the-striatum
#19
Anna M Klawonn, Anna Nilsson, Carl F Rådberg, Sarah H Lindström, Mia Ericson, Björn Granseth, David Engblom, Michael Fritz
Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29045302/neurosteroid-levels-in-patients-with-bipolar-disorder-and-a-history-of-cannabis-use-disorders
#20
Brittany L Mason, Erin Van Enkevort, Francesca Filbey, Christine E Marx, John Park, Alyson Nakamura, Prabha Sunderajan, E Sherwood Brown
PURPOSE/BACKGROUND: In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs). METHODS/PROCEDURES: Bipolar depressed participants were enrolled in a randomized placebo-controlled clinical trial to evaluate the efficacy of add-on pregnenolone for depression and before receiving pregnenolone or placebo...
December 2017: Journal of Clinical Psychopharmacology
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