Functional Properties of L-Glutamate Regulation in Anesthetized and Freely Moving Mice
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Synthesis of Conformationally Constrained Glutamate Analogues and Their Preliminary Evaluation As Glutamate Transport Inhibitors
University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2002 Synthesis of conformationally constrained glutamate analogues and their preliminary evaluation as glutamate transport inhibitors Travis Taylor Denton The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Denton, Travis Taylor, "Synthesis of conformationally constrained glutamate analogues and their preliminary evaluation as glutamate transport inhibitors" (2002). Graduate Student Theses, Dissertations, & Professional Papers. 9450. https://scholarworks.umt.edu/etd/9450 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. -
Characterization of a Domoic Acid Binding Site from Pacific Razor Clam
Aquatic Toxicology 69 (2004) 125–132 Characterization of a domoic acid binding site from Pacific razor clam Vera L. Trainer∗, Brian D. Bill NOAA Fisheries, Northwest Fisheries Science Center, Marine Biotoxin Program, 2725 Montlake Blvd. E., Seattle, WA 98112, USA Received 5 November 2003; received in revised form 27 April 2004; accepted 27 April 2004 Abstract The Pacific razor clam, Siliqua patula, is known to retain domoic acid, a water-soluble glutamate receptor agonist produced by diatoms of the genus Pseudo-nitzschia. The mechanism by which razor clams tolerate high levels of the toxin, domoic acid, in their tissues while still retaining normal nerve function is unknown. In our study, a domoic acid binding site was solubilized from razor clam siphon using a combination of Triton X-100 and digitonin. In a Scatchard analysis using [3H]kainic acid, the partially-purified membrane showed two distinct receptor sites, a high affinity, low capacity site with a KD (mean ± S.E.) of 28 ± 9.4 nM and a maximal binding capacity of 12 ± 3.8 pmol/mg protein and a low affinity, high capacity site with a mM affinity for radiolabeled kainic acid, the latter site which was lost upon solubilization. Competition experiments showed that the rank order potency for competitive ligands in displacing [3H]kainate binding from the membrane-bound receptors was quisqualate > ibotenate > iodowillardiine = AMPA = fluorowillardiine > domoate > kainate > l-glutamate. At high micromolar concentrations, NBQX, NMDA and ATPA showed little or no ability to displace [3H]kainate. In contrast, Scatchard analysis 3 using [ H]glutamate showed linearity, indicating the presence of a single binding site with a KD and Bmax of 500 ± 50 nM and 14 ± 0.8 pmol/mg protein, respectively. -
Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives
701xml UOPP_A_438055 October 9, 2009 12:27 UOPP #438055, VOL 41, ISS 6 Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives Javier I. Bardag´ı and Roberto A. Rossi QUERY SHEET This page lists questions we have about your paper. The numbers displayed at left can be found in the text of the paper for reference. In addition, please review your paper as a whole for correctness. There are no Editor Queries for this paper. TABLE OF CONTENTS LISTING The table of contents for the journal will list your paper exactly as it appears below: Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives Javier I. Bardag´ı and Roberto A. Rossi 701xml UOPP_A_438055 October 9, 2009 12:27 Organic Preparations and Procedures International, 41:1–36, 2009 Copyright © Taylor & Francis Group, LLC ISSN: 0030-4948 print DOI: 10.1080/00304940903378776 Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives Javier I. Bardag´ı and Roberto A. Rossi INFIQC, Departamento de Qu´ımica Organica,´ Facultad de Ciencias Qu´ımicas, Universidad Nacional de Cordoba,´ Ciudad Universitaria, 5000 Cordoba,´ ARGENTINA INTRODUCTION ................................................................................... 2 I. Uracils with Carbon-based Substituent ................................................. 3 1. C(Uracil)-C(sp3) Bonds............................................................................ 3 a. Perfluoroalkyl Compounds...................................................................12 2. C(Uracil)-C(sp2) Bonds...........................................................................13 -
(19) United States (12) Patent Application Publication (10) Pub
US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist. -
Poster Abstracts
POSTER ABSTRACTS Society of Toxicology (MASOT) www.masot.org Fall 2015 Scientific Meeting October 13th, 2015 Abstract 01 Tracking Inflammatory Macrophage Accumulation in the Lung during Ozone- induced Lung Injury in Mice M Francis, M Mandal, C. Sun, H Choi, JD Laskin, DL Laskin Rutgers University, Piscataway, NJ Ozone induced lung injury is associated with an accumulation of pro- and antiinflammatory macrophages (MP) in the lung which have been implicated in tissue injury and repair. In these studies, we used in vivo tracking techniques to investigate the origin of cell. Initially we generated bone marrow (BM) chimeric mice by adoptive transfer of BM cells from GFP+ mice into irradiated C57BL/6 mice. After 4 weeks, mice were exposed to air or ozone (0.8 ppm, 3 h). Macrophages were isolated from lungs 24- 72 h later, stained with fluorescent labeled antibodies, and analyzed by flow cytometry. Approximately 98% of BM cells were found to be GFP+ while only 5% were GFP+ in control lungs. Ozone exposure resulted in a marked increase in infiltrating mature GFP+CD11b+F4/80+ MP into the lung. Two populations, Ly6CHi proinflammatory and Ly6CLo antiinflammatory were identified. Proinflammatory GFP+Ly6CHi MP increased rapidly after ozone and remained elevated, increases in antiinflammatory GFP+Ly6CLo were transient. To assess potential mechanisms mediating the accumulation of these MP subpopulations in the lung, we used mice lacking Ccr2, a chemokine receptor involved in proinflammatory MP trafficking. Loss of Ccr2 resulted in decreased numbers of infiltrating CD11b+ MP in the lung. This was due to a selective reduction in proinflammatory Ly6CHi MP. -
Architecture Moléculaire Des Récepteurs NMDA : Arrangement Tétramérique Et Interfaces Entre Sous-Unités Morgane Riou
Architecture moléculaire des récepteurs NMDA : Arrangement tétramérique et interfaces entre sous-unités Morgane Riou To cite this version: Morgane Riou. Architecture moléculaire des récepteurs NMDA : Arrangement tétramérique et inter- faces entre sous-unités. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2014. Français. NNT : 2014PA066081. tel-01020863 HAL Id: tel-01020863 https://tel.archives-ouvertes.fr/tel-01020863 Submitted on 8 Jul 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THESE DE DOCTORAT De l’Université Pierre et Marie Curie - Paris VI Ecole Doctorale Cerveau Cognition Comportement ARCHITECTURE MOLECULAIRE DES RECEPTEURS NMDA : ARRANGEMENT TETRAMERIQUE ET INTERFACES ENTRE SOUS-UNITES Présentée par : Morgane RIOU Institut de Biologie de l' Ecole Normale Supérieure (IBENS) CNRS UMR8197, INSERM U1024 Ecole Normale Supérieure, 46 rue d’Ulm, 75005 Paris Direction Générale de l' Armement Soutenue le 28 février 2014 devant le jury composé de : Pr. Germain TRUGNAN Président Dr. David PERRAIS Rapporteur Dr. Pierre -
Systemic Administration of Mk-801 Protects Against ~=Met~Yl~~-Aspartate* and Quisqualate-Mediated Neurotoxicity in Perinatal Rats
Neatroscience Vol. 36, No. 3. pp. 589-599, 1990 0306-4522j90 $3.00 f 0.00 Printed in Great Britain Pergamon Press plc 0 1990 IBRO SYSTEMIC ADMINISTRATION OF MK-801 PROTECTS AGAINST ~=MET~YL~~-ASPARTATE* AND QUISQUALATE-MEDIATED NEUROTOXICITY IN PERINATAL RATS J. W. MCDONALD,* F. S. .%LvERS~IN,~$ II. Chmo~~,$ C. HmmN,$ R. CWEN~and M. V. JoHNsToN*~$$IIB *Neuroscience Training Program and Departments of TPediatrics and SNeurotogy, Medical SchooI, and &%nter for Human Growth and Development, University of Michigan, Ann Arbor, MI 48Io4, U.S.A. ~~~Fa~rnen~ of Neurology and Pediatrics, Johns Hopkins Un~~~~~ty Schoot of Medicine and the Kennedy Institute, Baltimore, MD 21205, U.S.A. Abstract-MK-801, a non-competitive antagonist of N-methy&aspartate-type glutamate receptors, was tested for its abiiity to antagonize excitotoxic actions of ~-methyl-~-as~~ate or quisqualic acid injected into the brains of seven-day-old rats, Stereotaxic injection of ~“me~yi-~aspa~ate (25 nmol/OS ai) or quisqualic acid (100 nmol/l.O ~1) into the corpus striatum under ether anesthesia consistently produced severe unilateral neuronal necrosis in the basal ganglia, dorsal hippocampus and overlying neocortex. The distribution of the damage corresponded to the topography of glutamate receptors in the vulnerable regions demonstrated by previous autoradiographic studies, ~-Methyl-~aspa~ate produced severe, mntluent neuronal destruction while quisquaiic acid typicatty caused more selective neuronaf necrosis. Intraperitoneal administration of MK-801 (0.1-1.0 mg/kg) 30 min before N-methyl-D-aspartate injection had a prominent dose-dependent neuroprotective effects as assessed morphometrically by comparison of bilateral striatal, hippocampal and cerebral hemisphere cross-sectional areas five days later. -
The Role of Diallyl Thiosulfinate Associated with Nuciferine And
Cai_Stesura Seveso 27/03/18 09:29 Pagina 59 DOI: 10.4081/aiua.2018.1.59 ORIGINAL PAPER The role of diallyl thiosulfinate associated with nuciferine and diosgenin in the treatment of premature ejaculation: A pilot study Tommaso Cai 1, Andrea Cocci 2, Giamartino Cito 2, Bruno Giammusso 3, Alessandro Zucchi 4, Francesco Chiancone 5, Maurizio Carrino 5, Francesco Mastroeni 6, Francesco Comerci 7, Giorgio Franco 8, Alessandro Palmieri 9 1 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy; 2 Department of Urology, University of Florence, Florence, Italy; 3 Department of Andrology, Policlinico Morgagni, Catania, Italy; 4 Department of Urology, University of Perugia, Perugia, Italy; 5 Department of Urology, Cardarelli Hospital, Naples, Italy; 6 Department of Urology, Azienda Ospedaliera Papardo, Messina, Italy 7 Urologist, Bologna, Italy; 8 Department of Urology, Sapienza University of Rome, Rome, Italy; 9 Department of Urology, University of Naples, Federico II, Naples, Italy. Summary Objective: To assess the efficacy and safety with prevalence rates of 20-30%, probably affecting of an association of diallyl thiosulfinate with every man at some point in his life (2, 3). It may result nuciferine and diosgenin in the treatment of a group of patients in unsatisfactory sexual intercourse for both partners, suffering from premature ejaculation (PE), primary or second- decreasing sexual self-confidence and self-esteem and ary to erectile dysfunction (ED). resulting in an overall reduction of quality of life (QoL) Materials and methods: From July 2015 to October 2016, 143 (4). Lifelong PE occurs within 30-60 seconds after vagi- patients (mean age 25.3; range 18-39) affected by PE complet- ed the study and were finally analyzed in this phase I study. -
Oncolytic Properties of Ampakines in Vitro DANIEL P
ANTICANCER RESEARCH 38 : 265-269 (2018) doi:10.21873/anticanres.12217 Oncolytic Properties of Ampakines In Vitro DANIEL P. RADIN, RICHARD PURCELL and ARNOLD S. LIPPA RespireRx Pharmaceuticals, Inc., Glen Rock, NJ, U.S.A. Abstract. Background/Aim: The 5-year survival rate of crucial for the consolidation of learning and memory (1, 2). glioblastoma (GBM) is ~10%, demonstrating that a new Over the past two decades, considerable strides have been therapeutic modality for this cancer is desperately needed. made in understanding AMPAR pharmacology, kinetics and Complicating the search for such a modality is that most large physiology by employing positive allosteric modulators molecules cannot pass through the blood brain barrier, so (PAMs) to delineate their function (3). For convenience, the molecules demonstrating efficacy in vitro may not be useful in term ampakines has been used to describe various classes of vivo because they never reach the brain. Recently, the selective drugs that act as PAM. serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) was Ampakines are further categorized as Class I ampakines, identified as an effective agent in targeting GBM in vitro and also known as high-impact ampakines, and Class II in vivo by agonizing AMPA-glutamate receptors (AMPARs), ampakines, also known as low-impact ampakines (3). Class eliciting massive calcium influx and mitochondrial calcium I or high-impact ampakines increase AMPAR agonist overload and apoptosis. Materials and Methods: In the current binding affinity by stabilizing the channel open confirmation study, we used a colorimetric cell viability assay to determine of the AMPAR, thereby offsetting desensitization, and if we could enhance the oncolytic effect of FLX in vitro by pre- enhancing AMPAergic steady-state currents up to 100-fold treating cells with an AMPAR-positive allosteric modulator (4). -
Comparative Thermodynamics of Partial Agonist Binding to An
COMPARATIVE THERMODYNAMICS OF PARTIAL AGONIST BINDING TO AN AMPA RECEPTOR BINDING DOMAIN A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Madeline Martínez May 2015 © 2015 Madeline Martínez ALL RIGHTS RESERVED Comparative Thermodynamics of Partial Agonist Binding to an AMPA Receptor Binding Domain Madeline Martínez, Ph.D. Cornell University 2015 AMPA receptors, ligand-gated cation channels endogenously activated by glutamate, mediate the majority of rapid excitatory synaptic transmission in the vertebrate central nervous system and are crucial for information processing within neural networks. Their involvement in a variety of neuropathologies and injured states makes them important therapeutic targets, and understanding the forces that drive the interactions between the ligands and protein binding sites is a key element in the development and optimization of potential drug candidates. Calorimetric studies yield quantitative data on the thermodynamic forces that drive binding reactions. This information can help elucidate mechanisms of binding and characterize ligand- induced conformational changes, as well as reduce the potential unwanted effects in drug candidates. The studies presented here characterize the thermodynamics of binding of a series of 5’substituted willardiine analogues, partial agonists to the GluA2 LBD under several conditions. The moiety substitutions (F, Cl, I, H, and NO2) explore a range of electronegativity, pKa, radii, and h-bonding capability. Competitive binding of these ligands to glutamate-bound GluA2 LBD at different pH conditions demonstrates the effects of charge in the enthalpic and entropic components of the Gibb’s free energy of binding. -
Preferred Drug List 4-Tier
Preferred Drug List 4-Tier 21NVHPN13628 Four-Tier Base Drug Benefit Guide Introduction As a member of a health plan that includes outpatient prescription drug coverage, you have access to a wide range of effective and affordable medications. The health plan utilizes a Preferred Drug List (PDL) (also known as a drug formulary) as a tool to guide providers to prescribe clinically sound yet cost-effective drugs. This list was established to give you access to the prescription drugs you need at a reasonable cost. Your out- of-pocket prescription cost is lower when you use preferred medications. Please refer to your Prescription Drug Benefit Rider or Evidence of Coverage for specific pharmacy benefit information. The PDL is a list of FDA-approved generic and brand name medications recommended for use by your health plan. The list is developed and maintained by a Pharmacy and Therapeutics (P&T) Committee comprised of actively practicing primary care and specialty physicians, pharmacists and other healthcare professionals. Patient needs, scientific data, drug effectiveness, availability of drug alternatives currently on the PDL and cost are all considerations in selecting "preferred" medications. Due to the number of drugs on the market and the continuous introduction of new drugs, the PDL is a dynamic and routinely updated document screened regularly to ensure that it remains a clinically sound tool for our providers. Reading the Drug Benefit Guide Benefits for Covered Drugs obtained at a Designated Plan Pharmacy are payable according to the applicable benefit tiers described below, subject to your obtaining any required Prior Authorization or meeting any applicable Step Therapy requirement. -
The Microbiota-Produced N-Formyl Peptide Fmlf Promotes Obesity-Induced Glucose
Page 1 of 230 Diabetes Title: The microbiota-produced N-formyl peptide fMLF promotes obesity-induced glucose intolerance Joshua Wollam1, Matthew Riopel1, Yong-Jiang Xu1,2, Andrew M. F. Johnson1, Jachelle M. Ofrecio1, Wei Ying1, Dalila El Ouarrat1, Luisa S. Chan3, Andrew W. Han3, Nadir A. Mahmood3, Caitlin N. Ryan3, Yun Sok Lee1, Jeramie D. Watrous1,2, Mahendra D. Chordia4, Dongfeng Pan4, Mohit Jain1,2, Jerrold M. Olefsky1 * Affiliations: 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. 2 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. 3 Second Genome, Inc., South San Francisco, California, USA. 4 Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. * Correspondence to: 858-534-2230, [email protected] Word Count: 4749 Figures: 6 Supplemental Figures: 11 Supplemental Tables: 5 1 Diabetes Publish Ahead of Print, published online April 22, 2019 Diabetes Page 2 of 230 ABSTRACT The composition of the gastrointestinal (GI) microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine (fMLF), are elevated in high fat diet (HFD)- induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon- like peptide-1 (GLP-1). Obese Fpr1-knockout (Fpr1-KO) mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota.