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Doodipala Samba Reddy
Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus...
2018: Vitamins and Hormones
M G Carta, A Preti, H S Akiskal
Human population is increasing in immense cities with millions of inhabitants, in which life is expected to run 24 hours a day for seven days a week (24/7). Noise and light pollution are the most reported consequences, with a profound impact on sleep patterns and circadian biorhythms. Disruption of sleep and biorhythms has severe consequences on many metabolic pathways. Suppression of melatonin incretion at night and the subsequent effect on DNA methylation may increase the risk of prostate and breast cancer...
2018: Clinical Practice and Epidemiology in Mental Health: CP & EMH
Nicolas Diotel, Thierry D Charlier, Christian Lefebvre d'Hellencourt, David Couret, Vance L Trudeau, Joel C Nicolau, Olivier Meilhac, Olivier Kah, Elisabeth Pellegrini
Sex steroid hormones are synthesized from cholesterol and exert pleiotropic effects notably in the central nervous system. Pioneering studies from Baulieu and colleagues have suggested that steroids are also locally-synthesized in the brain. Such steroids, called neurosteroids, can rapidly modulate neuronal excitability and functions, brain plasticity, and behavior. Accumulating data obtained on a wide variety of species demonstrate that neurosteroidogenesis is an evolutionary conserved feature across fish, birds, and mammals...
2018: Frontiers in Neuroscience
Maja Johansson, Maria Månsson, Lars-Eric Lins, Bruce Scharschmidt, Magnus Doverskog, Torbjörn Bäckström
RATIONALE: GR3027 is a novel small molecule GABA-A receptor-modulating steroid antagonist, which in non-clinical studies has shown promise for treatment of human disorders due to allosteric over-activation of GABA-A receptors by neurosteroids, such as allopregnanolone. We here studied its safety, pharmacokinetics, and ability to inhibit allopregnanolone effects in humans. METHODS: Safety and pharmacokinetics were studied in healthy adult males receiving ascending single or multiple oral GR3027 vs...
February 28, 2018: Psychopharmacology
Meltem Weger, Nicolas Diotel, Benjamin D Weger, Tanja Beil, Andreas Zaucker, Helen L Eachus, James A Oakes, Jean Luc do Rego, Karl-Heinz Storbeck, Philipp Gut, Uwe Straehle, Sepand Rastegar, Ferenc Mueller, Nils Krone
The spatial and temporal expression of steroidogenic genes in zebrafish has not been fully characterized. Since zebrafish are increasingly employed in endocrine and stress research, a better characterization of steroidogenic pathways is required to target specific steps in the biosynthetic pathways in the future. Here, we have systematically defined the temporal and spatial expression of steroidogenic enzymes involved in glucocorticoid biosynthesis (cyp21a2, cyp11c1, cyp11a1, cyp11a2, cyp17a1, cyp17a2, hsd3b1, hsd3b2), as well as the mitochondrial electron-providing co-factors ferredoxin (fdx1, fdx1b) during zebrafish development...
February 27, 2018: Journal of Neuroendocrinology
Suchitra Joshi, Jaideep Kapur
The female reproductive hormones progesterone and estrogen regulate network excitability. Fluctuations in the circulating levels of these hormones during the menstrual cycle cause frequent seizures during certain phases of the cycle in women with epilepsy. This seizure exacerbation, called catamenial epilepsy, is a dominant form of drug-refractory epilepsy in women of reproductive age. Progesterone, through its neurosteroid derivative allopregnanolone, increases γ-aminobutyric acid type-A receptor (GABAR)-mediated inhibition in the brain and keeps seizures under control...
February 23, 2018: Brain Research
Xue-Ying He, Charles Isaacs, Song-Yu Yang
17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme...
2018: Journal of Alzheimer's Disease: JAD
Limei Zhang, Vito S Hernández, Jerome D Swinny, Anil K Verma, Torsten Giesecke, Andrew C Emery, Kerim Mutig, Luis M Garcia-Segura, Lee E Eiden
The lateral habenula (LHb) has a key role in integrating a variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types and neuronal circuits within the LHb coordinate physiological and motivational states. Here, we report a cell type in the medial division of the LHb (LHbM) in male rats that is distinguished by: (1) a molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) and estrogen receptor (Esr1/ERα) expression, at both mRNA and protein levels, as well as the mRNA for vesicular glutamate transporter Slc17a6/VGLUT2, which we term the GABAergic estrogen-receptive neuron (GERN); (2) its axonal projection patterns, identified by in vivo juxtacellular labeling, to both local LHb and to midbrain modulatory systems; and (3) its somatic expression of receptors for vasopressin, serotonin and dopamine, and mRNA for orexin receptor 2...
February 26, 2018: Translational Psychiatry
Ari L Mendell, Beryl Y T Chung, Carolyn E Creighton, Bettina E Kalisch, Craig D C Bailey, Neil J MacLusky
Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3α-hydroxy, 5α-reduced metabolites of these hormones. Two such metabolites are 5α-androstane-3α,17β-diol (3α-diol) and 5α-pregnan-3α-ol-20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA)A receptor (GABAA R) activity...
February 22, 2018: Brain Research
Sandra Seljeset, Damian P Bright, Philip Thomas, Trevor G Smart
γ-aminobutyric acid type A receptors (GABA A Rs) are important components of the central nervous system and they are functionally tasked with controlling neuronal excitability. These receptors are subject to post-translational modification and also to modulation by endogenous regulators, such as the neurosteroids. These modulators can either potentiate or inhibit GABA A R function. Whilst the former class of neurosteroids are considered to bind to and act from the transmembrane domain of the receptor, the domains that are important for the inhibitory neurosteroids remain less clear...
February 12, 2018: Neuropharmacology
HuaLin Cai, Xiang Zhou, George G Dougherty, Ravinder D Reddy, Gretchen L Haas, Debra M Montrose, Matcheri Keshavan, Jeffrey K Yao
Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naïve patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment...
February 7, 2018: Psychoneuroendocrinology
Richard W Olsen
gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABAA R) and Type B (GABABR) are the targets of the great majority of GABAergic drugs...
January 30, 2018: Neuropharmacology
Isaac V Cohen, Elizabeth T Cirulli, Matthew W Mitchell, Thomas J Jonsson, James Yu, Naisha Shah, Tim D Spector, Lining Guo, J Craig Venter, Amalio Telenti
BACKGROUND: Acetaminophen (paracetamol) is one of the most common medications used for management of pain in the world. There is lack of consensus about the mechanism of action, and concern about the possibility of adverse effects on reproductive health. METHODS: We first established the metabolome profile that characterizes use of acetaminophen, and we subsequently trained and tested a model that identified metabolomic differences across samples from 455 individuals with and without acetaminophen use...
February 1, 2018: EBioMedicine
Miguel Ortíz-Rentería, Rebeca Juárez-Contreras, Ricardo González-Ramírez, León D Islas, Félix Sierra-Ramírez, Itzel Llorente, Sidney A Simon, Marcia Hiriart, Tamara Rosenbaum, Sara L Morales-Lázaro
The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Martin Holtkamp
Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used...
January 24, 2018: Drugs
Vojtech Kapras, Vojtech Vyklicky, Milos Budesinsky, Ivana Cisarova, Ladislav Vyklicky, Hana Chodounska, Ullrich Jahn
A unique asymmetric total synthesis of the unnatural enantiomer of pregnanolone, as well as a study of its biological activity at the NMDA receptor, is reported. The asymmetry is introduced by a highly atom-economic organocatalytic Robinson annulation. A new method for the construction of the cyclopentane D-ring consisting of CuI-catalyzed conjugate addition and oxygenation followed by thermal cyclization employing the persistent radical effect was developed. ent-Pregnanolone sulfate is surprisingly only 2...
January 24, 2018: Organic Letters
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
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
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
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
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