DOCSLIB.ORG

University of Cincinnati

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
University of Cincinnati ! "# $ % & % ' % !' ' "# ' '% $$(' Improving Therapeutics for Parkinson Disease A dissertation submitted to The Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in the Neuroscience Graduate Program and Physician Scientist Training Program at the University of Cincinnati College of Medicine by Jennifer A. O’Malley BS Case Western Reserve University 2002; BA Case Western Reserve University 2002 July 2009 Thesis Advisor/Chair: Dr. Kathy Steece-Collier, Ph.D. Committee Members: Dr. Caryl E. Sortwell, Ph.D. Dr. Michael Behbehani, Ph.D. Dr. John Bissler, M.D. Dr. Timothy Collier, Ph.D. Dr. David Richards, Ph.D. Dr. Kim Seroogy, Ph.D Abstract The following results are from studies designed with the overall goal of elucidating means for improving therapeutics for Parkinson’s disease. There is still much to be understood regarding the cellular and molecular mechanisms underlying the development of side effects to therapies for Parkinson’s disease such as levodopa- induced dyskinesias. Additionally, therapeutic intervention is further complicated when one considers the role of the functionally waning host environment, especially in the context of its responsivity to therapeutic agents. The work in this thesis was designed to focus on two aspects of Parkinson’s disease therapeutics, (1) improving graft efficacy by contributing additional information on how the host environment in regards to age impacts graft function in Parkinson’s disease, and (2) determining whether specific morphological changes of the nigral target neurons within the striatum impact development or severity of levodopa-induced dyskinesias. The first study demonstrates that while the aging striatum can, under specific conditions, support the survival of large numbers of grafted embryonic dopamine neurons, there is limited functional benefit even with robust cell survival. This realization is an important contribution to the field as it newly suggests the aged striatum is capable of supporting grafted dopamine neurons, but the limited efficacy of these grafts demonstrates the importance of the intricate balance between grafted cells and the aged host environment. The second study demonstrate that maintaining appropriate synaptic contacts that are presumably maintained when striatal medium spiny neuron cytoarchitecture is preserved, resulting in reduced drug-induced side-effects in parkinsonian rats. Future experiments are Page | xx needed to explore the specific requirements of the aging striatum for functional recovery and how to implement synaptic stability of medium spiny neurons in clinical practice to potentially decrease side-effects of dopamine replacement pharmacotherapy. Page | xxi The scientist is not a person who gives the right answers, he's one who asks the right questions. Claude Lévi-Strauss, Le Cru et le cuit, 1964 Page | iii Table of Contents ABBREVIATIONS XI LIST OF FIGURES AND TABLES XVI ABSTRACT XX DEDICATION XXII ACKNOWLEDGEMENTS XXIII CHAPTER 1: INTRODUCTION 1 1.1 HISTORY OF PARKINSON DISEASE 2 1.2 HISTOLOGICAL CHANGES IN PD 6 1.3 THE BASAL GANGLIA 11 1.3.1 NEUROANATOMY OF THE BASAL GANGLIA: 11 1.3.1.1 THE STRIATUM 14 1.3.1.2 THE SUBSTANTIA NIGRA AND VENTRAL TEGMENTAL AREA 18 1.3.1.3 THE SUB-THALAMIC NUCLEUS 18 1.3.1.4 THE GLOBUS PALLIDUS 19 1.3.1.5 THE PEDUNCULOPONTINE TEGMENTAL NUCLEUS 19 1.3.1.6 THE NUCLEUS ACCUMBENS 20 1.3.1.7 THE NUCLEUS BASALIS (BASAL NUCLEUS OF MEYNERT) 21 1.3.2 GENERAL CIRCUITRY IN THE NORMAL BASAL GANGLIA 21 Page | iv 1.4 BASAL GANGLIA CIRCUITRY IN THE PARKINSONIAN BRAIN 24 1.5 RISK FACTORS FOR PARKINSON DISEASE 28 1.6 THE ROLE OF AGE IN PARKINSON DISEASE 32 1.7 SYMPTOMS OF PARKINSON DISEASE 36 1.8 SYMPTOMATIC TREATMENT OF PARKINSON DISEASE 40 1.8.1 PHARMACOTHERAPY: 40 1.8.2 THERAPEUTIC SURGICAL OPTIONS 46 1.8.2.1 GENE THERAPY 46 1.8.2.2 PALLIDOTOMY 48 1.8.2.3 DEEP BRAIN STIMULATION 49 1.8.2.4 TRANSPLANTATION 53 1.8.2.4.1 PRECLINICAL ANIMAL STUDIES 53 1.8.2.4.2 TRANSPLANTATION: CLINICAL TRIALS 61 1.9 LEVODOPA- AND GRAFT-INDUCED DYSKINESIAS 67 1.10 POTENTIAL MECHANISMS UNDERLYING DYSKINESIA IN THE PARKINSONIAN STRIATUM 71 1.10.1 FACTORS UNDERLYING INDUCTION OF LIDS 72 1.10.2 THE AGING STRIATUM AND DYSKINESIAS 76 1.10.3 STRIATAL PLASTICITY AND DYSKINESIAS 77 1.10.3.1 SYNAPTIC PLASTICITY IN THE STRIATUM 77 1.10.3.2 CHANGES IN STRIATAL PLASTICITY WITH 6-OHDA DA-DEPLETION; POTENTIAL ROLE IN LIDS 79 1.10.4 DENDRITE MORPHOLOGY AND LIDS 80 Page | v 1.10.4.1 DENDRITIC SPINES 81 1.10.4.2 ROLE OF DENDRITIC MORPHOLOGY IN NEURONAL COMMUNICATION IN THE STRIATUM 85 1.10.4.3 ROLE OF DENDRITE AND SYNAPSE PATHOLOGY IN LIDS 88 1.11 CELLULAR TARGETS INVOLVED IN DEVELOPMENT AND MAINTENANCE OF DYSKINESIAS 89 1.11.1 PARALLELS BETWEEN DYSKINESIA INDUCTION & COCAINE SENSITIZATION 90 1.11.2 STRIATAL DOPAMINE RECEPTORS AND ASSOCIATED PATHWAYS 93 1.11.3 STRIATAL GLUTAMATERGIC RECEPTORS & ASSOCIATED PATHWAYS 96 1.11.4 THE ROLE OF SEROTONIN IN LIDS 99 1.12 MODELING PARKINSON’S DISEASE: THE RAT MODEL OF PD AND LIDS 101 CHAPTER 2; INTRODUCTION TO THE SPECIFIC AIMS 108 2.1 AIM 1: IMPROVING EFFICACY OF DA TERMINAL REPLACEMENT STRATEGIES: IMPACT OF AGE ON GRAFT FUNCTION 109 2.2 AIM 2: UNDERSTANDING MECHANISMS OF LEVODOPA-INDUCED DYSKINESIAS: THE ROLE OF STRIATAL PATHOLOGY ON LEVODOPA-INDUCED DYSKINESIAS 111 Page | vi CHAPTER 3; MATERIALS AND METHODS 113 3.1 AIM 1- IMPACT OF AGE ON GRAFT FUNCTION 114 3.1.1 BRIEF SUMMARY OF THE EXPERIMENTAL DESIGN 114 3.1.2 NIGROSTRIATAL DOPAMINE LESION 116 3.1.3 AMPHETAMINE-INDUCED ROTATIONAL ASYMMETRY 116 3.1.4 LATERAL FOREPAW STEP ADJUSTMENT TESTING 117 3.1.5 LEVODOPA PRIMING 117 3.1.6 PREPARATION OF TISSUE FOR TRANSPLANTATION 117 3.1.7 DOPAMINE NEURON TRANSPLANTATION 118 3.1.8 DYSKINESIA RATING 119 3.1.9 NECROPSY AND PREPARATION OF TISSUE 120 3.1.10 IMMUNOHISTOCHEMISTRY 121 3.1.11 STEREOLOGICAL QUANTIFICATION OF GRAFT CELL NUMBER 122 3.1.12 GRAFT VOLUME QUANTIFICATION 123 3.1.13 STRIATAL INTEGRITY 123 3.1.14 DENSITOMETRY ANALYSIS OF FOSB/ΔFOSB-IR CELLS 124 3.1.15 QUANTIFICATION OF NEURITE OUTGROWTH VIA DENSITOMETRY 125 3.1.16 QUANTIFICATION OF THIR FIBER DENSITY IN THE STRIATUM 128 3.1.17 STATISTICAL ANALYSIS 129 3.2 AIM 2- UNDERSTANDING MECHANISMS OF LEVODOPA-INDUCED DYSKINESIAS: THE ROLE OF STRIATAL PATHOLOGY ON LEVODOPA-INDUCED DYSKINESIAS 130 Page | vii 3.2.1 PILOT STUDY EXPERIMENTAL DESIGN 130 3.2.2 FOLLOW-UP STUDY DATA: EXPERIMENTAL DESIGN AND TIMELINE 133 3.2.3 EXPERIMENTAL SUBJECTS AND DOPAMINE DENERVATING LESION 136 3.2.4 NIMODIPINE ADMINISTRATION 136 3.2.5 LEVODOPA TREATMENT AND LID RATING 137 3.2.6 SENSORI-MOTOR INTEGRATION (VIBRISSAE) TEST 138 3.2.7 DENDRITIC SPINE DENSITY QUANTIFICATION USING A MODIFIED GOLGI- COX IMPREGNATION METHOD 139 3.2.8 IMMUNOHISTOCHEMISTRY 143 3.2.9 DENSITOMETRY ANALYSIS OF FOSB/DELTAFOSB-IR CELLS 144 3.2.10 AREA UNDER THE CURVE CALCULATIONS 145 3.2.11 MEDIAL TERMINAL NUCLEUS (MTN) GUIDED CONFIRMATION OF DA- DEPLETION 146 3.2.12 STATISTICAL ANALYSES 146 CHAPTER 4; EXPERIMENTAL RESULTS & DISCUSSION FOR SPECIFIC AIMS 148 4.1 AIM 1: IMPACT OF AGE ON GRAFT FUNCTION 149 4.1.1 RESULTS 149 4.1.2 GRAFTED CELL SURVIVAL AND TOTAL GRAFT VOLUME ACROSS AGES 151 4.1.3 CONFIRMATION OF NEURONAL INTEGRITY IN THE GRAFTED STRIATUM 154 Page | viii 4.1.4 NEURITE OUTGROWTH OF GRAFTS IN YOUNG, MIDDLE, AND AGED RATS 156 4.1.5 PRE- AND POST-GRAFT LIDS ACROSS AGES 170 4.1.6 EVALUATION OF PARKINSONIAN MOTOR BEHAVIORS; PRE- AND POST- GRAFT 175 4.1.7 FOSB/DELTAFOSB IMMUNOREACTIVITY IS REDUCED WITH GRAFTING ACROSS ALL AGES 177 4.1.8 DISCUSSION OF RESULTS FOR AIM 1 179 4.2 AIM 2: UNDERSTANDING MECHANISMS OF LEVODOPA-INDUCED DYSKINESIAS: THE ROLE OF STRIATAL PATHOLOGY ON LEVODOPA-INDUCED DYSKINESIAS 187 4.2.1 RESULTS 187 4.2.2 CONFIRMATION OF DENDRITIC SPINE LOSS WITH DA-DEPLETION, AND SPINE PRESERVATION WITH NIMODIPINE 188 4.2.3 IMPACT OF NIMODIPINE-MEDIATED SPINE PRESERVATION IN DA- DEPLETED RATS ON PARKINSONIAN MOTOR BEHAVIORS 194 4.2.4 ACUTELY ADMINISTERED NIMODIPINE DOES NOT ALTER THE EXPRESSION OF LIDS 200 4.2.5 PILOT STUDY DATA: IMPACT OF NIMODIPINE-MEDIATED SPINE PRESERVATION IN DA-DEPLETED RATS ON LIDS: 203 Page | ix 4.2.6 CONFIRMATION OF DA-DENERVATION AND IMPACT OF NIMODIPINE- MEDIATED SPINE PRESERVATION IN DA-DEPLETED RATS ON PARKINSONIAN MOTOR BEHAVIORS 208 4.2.7 FOLLOW-UP STUDY DATA: IMPACT OF NIMODIPINE-MEDIATED SPINE PRESERVATION IN DA-DEPLETED RATS ON LIDS 211 4.2.8 FOLLOW-UP STUDY DATA: IMPACT OF NIMODIPINE-MEDIATED SPINE PRESERVATION IN DA-DEPLETED RATS ON FOSB EXPRESSION 221 4.2.9 DISCUSSION FOR AIM 2 223 CHAPTER 5; DISCUSSION 229 5.1 SUMMARY OF THE RESULTS OF THE SPECIFIC AIMS 230 5.2 OPTIMIZING GRAFT EFFICACY 238 5.3 EFFICACY OF GRAFTING IN THE AGING PARKINSONIAN PATIENT 243 5.4 THOUGHTS ON HOW SPINE PRESERVATION MIGHT REDUCE LEVODOPA- INDUCED DYSKINESIAS 252 5.5 THE ROLE OF CALCIUM SIGNALING IN THE PARKINSONIAN STRIATUM; MODELING AN EXPLANATION FOR LIDS AND REDUCED GRAFT EFFICACY 259 5.6 FUTURE DIRECTIONS 268 CHAPTER 6; REFERENCES 270 Page | x Abbreviations 6-OHDA 6-hydroxydopamine A2A adenosine-2A AADC aromatic amino acid decarboxylase ACC anterior cingulate cortex ad autosomal dominant AMPA α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate ar autosomal recessive bFGF basic fibroblast growth factor C caudal CamKII calcium/calmodulin-dependent protein kinase II CB carotid body CeM central medial thalamic nuclei CL central lateral thalamic nuclei cm centimeter CNS central nervous system COMT catechol-0-methyl transferase Page | xi CREB cAMP response element binding D1R dopamine receptor 1 D2R dopamine receptor 2 DA Dopamine DARPP-32 dopamine and cAMP-regulated phospho-protein DBS deep brain stimulation dPL dorsal prelimbic cortices DR3 dopamine receptor 3 Erk1/ Erk2 extracellular signal-related kinase 1 / 2 FFD facial-forelimb dyskinesias FosB FBJ murine osteosarcoma viral oncogene homolog B GABA gamma-aminobutyric acid GID(s) graft-induced dyskinesias Glut glutamate GP globus pallidus GPe globus pallidus, externa GPi globus pallidus, interna HD Huntington’s disease Page | xii hESC (human) embyonic stem cell Hz Hertz i.m.
Load more

Recommended publications
  • 083 Toxicity of Ibotenic Acid and Muscimol Containing Mushrooms Reported to a Regional Poison Control Center from 2002-2016 Mich
    083 Toxicity of ibotenic acid and muscimol containing mushrooms reported to a regional poison control center from 2002-2016 Michael Moss 1,2 , Robert Hendrickson 1,2 1Oregon Health and Science University, Portland, OR, USA, 2Oregon Poison Center, Portland, OR, USA Background: Amanita muscaria (AM) and Amanita pantherina (AP) contain ibotenic acid and muscimol and may cause both excitatory and sedating symptoms. A "typical" syndrome of accidental ingestion with CNS depression in adults and CNS excitation in children and a paucity of GI symptoms or respiratory depression are based on relatively few reported cases with these mushrooms in North America. Research Question: What are the clinical effects of ibotenic acid/muscimol containing mushroom toxicity? Methods: Retrospective review of ingestions of ibotenic acid/muscimol containing mushrooms reported to a regional poison center from 2002-2016. Cases were included if identification was made by a mycologist or if AM was described as a red/orange mushroom with white spots. Results: Thirty-five cases met inclusion criteria. There were 24 cases of AM, 10 AP, and 1 A. aprica. Reason for ingestion included foraging (12), recreational (5), accidental (12), therapeutic (1), and self- harm (1). Of the accidental pediatric ingestions 4 (25%) were symptomatic. None of the children with a symptomatic ingestion of AM required admission. A 3-year old male who ingested AP developed vomiting, agitation, and lethargy. He was intubated and had a 3-day ICU stay. There were 25 symptomatic patients in total. All but one developed symptoms within 6 hours. Duration of symptoms was: <6 hours (6, 24%), 6-24 hours (15, 60%), >24 hours (1, 4%), and unreported (3, 12%).
    [Show full text]
  • Phytochem Referenzsubstanzen
    High pure reference substances Phytochem Hochreine Standardsubstanzen for research and quality für Forschung und management Referenzsubstanzen Qualitätssicherung Nummer Name Synonym CAS FW Formel Literatur 01.286. ABIETIC ACID Sylvic acid [514-10-3] 302.46 C20H30O2 01.030. L-ABRINE N-a-Methyl-L-tryptophan [526-31-8] 218.26 C12H14N2O2 Merck Index 11,5 01.031. (+)-ABSCISIC ACID [21293-29-8] 264.33 C15H20O4 Merck Index 11,6 01.032. (+/-)-ABSCISIC ACID ABA; Dormin [14375-45-2] 264.33 C15H20O4 Merck Index 11,6 01.002. ABSINTHIN Absinthiin, Absynthin [1362-42-1] 496,64 C30H40O6 Merck Index 12,8 01.033. ACACETIN 5,7-Dihydroxy-4'-methoxyflavone; Linarigenin [480-44-4] 284.28 C16H12O5 Merck Index 11,9 01.287. ACACETIN Apigenin-4´methylester [480-44-4] 284.28 C16H12O5 01.034. ACACETIN-7-NEOHESPERIDOSIDE Fortunellin [20633-93-6] 610.60 C28H32O14 01.035. ACACETIN-7-RUTINOSIDE Linarin [480-36-4] 592.57 C28H32O14 Merck Index 11,5376 01.036. 2-ACETAMIDO-2-DEOXY-1,3,4,6-TETRA-O- a-D-Glucosamine pentaacetate 389.37 C16H23NO10 ACETYL-a-D-GLUCOPYRANOSE 01.037. 2-ACETAMIDO-2-DEOXY-1,3,4,6-TETRA-O- b-D-Glucosamine pentaacetate [7772-79-4] 389.37 C16H23NO10 ACETYL-b-D-GLUCOPYRANOSE> 01.038. 2-ACETAMIDO-2-DEOXY-3,4,6-TRI-O-ACETYL- Acetochloro-a-D-glucosamine [3068-34-6] 365.77 C14H20ClNO8 a-D-GLUCOPYRANOSYLCHLORIDE - 1 - High pure reference substances Phytochem Hochreine Standardsubstanzen for research and quality für Forschung und management Referenzsubstanzen Qualitätssicherung Nummer Name Synonym CAS FW Formel Literatur 01.039.
    [Show full text]
  • Gabaergic Ventrolateral Pre‑Optic Nucleus Neurons Are Involved in the Mediation of the Anesthetic Hypnosis Induced by Propofol
    MOLECULAR MEDICINE REPORTS 16: 3179-3186, 2017 GABAergic ventrolateral pre‑optic nucleus neurons are involved in the mediation of the anesthetic hypnosis induced by propofol JIE YUAN1,2, ZHUXIN LUO2, YU ZHANG2, YI ZHANG1,2, YUAN WANG1,2, SONG CAO2,3, BAO FU2,4, HAO YANG2, LIN ZHANG2, WENJING ZHOU2 and TIAN YU2 1Department of Anesthesiology, Affiliated Hospital of Zunyi Medical College;2 Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical College; 3Department of Pain, Affiliated Hospital of Zunyi Medical College; 4Department of Intense Care Unit, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China Received February 9, 2017; Accepted July 13, 2017 DOI: 10.3892/mmr.2017.7035 Abstract. Intravenous anesthetics have been used clinically level, there are dozens of molecules known to be general to induce unconsciousness for seventeen decades, however the anesthetic targets, including a number of ion channels (2), mechanism of anesthetic-induced unconsciousness remains gap-junction channels (3), and G protein-coupled receptors (4). to be fully elucidated. It has previously been demonstrated It's remarkable that there is no single molecular target shared that anesthetics exert sedative effects by acting on endoge- by all general anesthetics (1). Therefore, effects of general nous sleep-arousal circuits. However, few studies focus on anesthetics must be comprehended in the context of network the ventrolateral pre-optic (VLPO) to locus coeruleus (LC) connectivity. sleep-arousal pathway. The present study aimed to investigate There are similarities between general anesthesia and if VLPO is involved in unconsciousness induced by propofol. natural sleep. Imaging studies have shown some paral- The present study additionally investigated if the inhibitory lels between the anesthetized brain and the brain during effect of propofol on LC neurons was mediated by activating deep non-rapid-eye-movement (NREM) sleep (5,6).
    [Show full text]
  • Pharmacological Studies on a Locust Neuromuscular Preparation
    J. Exp. Biol. (1974). 6i, 421-442 421 *&ith 2 figures in Great Britain PHARMACOLOGICAL STUDIES ON A LOCUST NEUROMUSCULAR PREPARATION BY A. N. CLEMENTS AND T. E. MAY Woodstock Research Centre, Shell Research Limited, Sittingbourne, Kent {Received 13 March 1974) SUMMARY 1. The structure-activity relationships of agonists of the locust excitatory neuromuscular synapse have been reinvestigated, paying particular attention to the purity of compounds, and to the characteristics and repeatability of the muscle response. The concentrations of compounds required to stimu- late contractions of the retractor unguis muscle equal in force to the neurally evoked contractions provided a measure of the relative potencies. 2. Seven amino acids were capable of stimulating twitch contractions, glutamic acid being the most active, the others being analogues or derivatives of glutamic or aspartic acid. Aspartic acid itself had no excitatory activity. 3. Excitatory activity requires possession of two acidic groups, separated by two or three carbon atoms, and an amino group a to a carboxyl. An L-configuration appears essential. The w-acidic group may be a carboxyl, sulphinyl or sulphonyl group. Substitution of any of the functional groups generally causes total loss of excitatory activity, but an exception is found in kainic acid in which the nitrogen atom forms part of a ring. 4. The investigation of a wide variety of compounds revealed neuro- muscular blocking activity among isoxazoles, hydroxylamines, indolealkyl- amines, /?-carbolines, phenazines and phenothiazines. No specific antagonist of the locust glutamate receptor was found, but synaptic blocking agents of moderately high activity are reported. INTRODUCTION The study of arthropod neuromuscular physiology has been impeded by the lack of an antagonist which can be used to block excitatory synaptic transmission by a specific postsynaptic effect.
    [Show full text]
  • Stimulation of Lateral Hypothalamic Kainate Receptors Selectively Elicits Feeding Behavior
    BRAIN RESEARCH 1184 (2007) 178– 185 available at www.sciencedirect.com www.elsevier.com/locate/brainres Research Report Stimulation of lateral hypothalamic kainate receptors selectively elicits feeding behavior Stacey R. Hettesa, Theodore W. Heyming, B. Glenn Stanleyb,c,⁎ aDepartment of Biology, Wofford College, Spartanburg, SC 29303, USA bDepartment of Psychology, University of California-Riverside, Riverside, CA 92521, USA cDepartment of Cell Biology and Neuroscience, University of California-Riverside, Riverside, CA 92521, USA ARTICLE INFO ABSTRACT Article history: Glutamate and its receptor agonists, NMDA, AMPA, and KA, elicit feeding when Accepted 24 September 2007 microinjected into the lateral hypothalamus (LH) of satiated rats. However, determining Available online 2 October 2007 the relative contributions of AMPA receptors (AMPARs) and KA receptors (KARs) to LH feeding mechanisms has been difficult due to a lack of receptor selective agonists and Keywords: antagonists. Furthermore, LH injection of KA produces behavioral hyperactivity, Lateral hypothalamus questioning a role for KARs in feeding selective stimulation. In the present study, we used Feeding the KAR agonist, (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid Kainate (ATPA), which selectively binds the GluR5 subunit of KARs, to stimulate feeding, Glutamate presumably via KAR activation. Using ATPA, we tested whether: (1) LH injection of ATPA ATPA elicits feeding, (2) prior treatment with the non-selective AMPA/KAR antagonist, CNQX, iGluR suppresses ATPA-elicited feeding, and (3) LH injection of ATPA elicits behavioral patterns specific for feeding. We found that injection of ATPA (0.1 and 1 nmol) elicited an intense feeding response (e.g., 4.8±1.6 g) that was blocked by LH pretreatment with CNQX, but was unaffected by pretreatment with the AMPAR selective antagonist, GYKI 52466.
    [Show full text]
  • Ibotenic Acid SAFETY DATA SHEET Section 2. Hazards Identification Section 3. Composition/Information on Ingredients
    SAFETY DATA SHEET Page: 1 of 5 Ibotenic Acid Revision: 04/17/2018 Supersedes Revision: 02/28/2014 according to Regulation (EC) No. 1907/2006 as amended by (EC) No. 1272/2008 Section 1. Identification of the Substance/Mixture and of the Company/Undertaking 1.1 Product Code: 14584 Product Name: Ibotenic Acid Synonyms: .alpha.-amino-2,3-dihydro-3-oxo-5-isoxazoleacetic acid; NSC 204850; 1.2 Relevant identified uses of the substance or mixture and uses advised against: Relevant identified uses: For research use only, not for human or veterinary use. 1.3 Details of the Supplier of the Safety Data Sheet: Company Name: Cayman Chemical Company 1180 E. Ellsworth Rd. Ann Arbor, MI 48108 Web site address: www.caymanchem.com Information: Cayman Chemical Company +1 (734)971-3335 1.4 Emergency telephone number: Emergency Contact: CHEMTREC Within USA and Canada: +1 (800)424-9300 CHEMTREC Outside USA and Canada: +1 (703)527-3887 Section 2. Hazards Identification 2.1 Classification of the Substance or Mixture: Acute Toxicity: Oral, Category 3 2.2 Label Elements: GHS Signal Word: Danger GHS Hazard Phrases: H301: Toxic if swallowed. GHS Precaution Phrases: P264: Wash {hands} thoroughly after handling. GHS Response Phrases: P301+310: IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. P330: Rinse mouth. GHS Storage and Disposal Phrases: Please refer to Section 7 for Storage and Section 13 for Disposal information. 2.3 Adverse Human Health Material may be irritating to the mucous membranes and upper respiratory tract. Effects and Symptoms: May be harmful by inhalation or skin absorption.
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Ibotenic Acid Item No. 14584 CAS Registry No.: 2552-55-8 Formal Name: α-amino-2,3-dihydro-3-oxo-5-isoxazoleacetic acid H H N O Synonym: NSC 204850 2 N MF: C5H6N2O4 FW: 158.1 O O Purity: ≥98% Supplied as: A solid OH Storage: -20°C Stability: ≥1 year Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Ibotenic acid is supplied as a solid. A stock solution may be made by dissolving the ibotenic acid in water. The solubility of ibotenic acid in water is approximately 10 mM. We do not recommend storing the aqueous solution for more than one day. Description Ibotenic acid is a neuroexcitatory amino acid originally isolated from Amanita species that functions as a NMDA and metabotropic glutamate receptor agonist.1 As a neurotoxin, ibotenic acid is often used to induce brain lesions in animals that model cognitive dysfunctions resulting from neurodegenerative diseases, traumatic brain injury, and stroke.2 References 1. Curtis, D.R., Lodge, D., and McLennan, H. The excitation and depression of spinal neurones by ibotenic acid. J. Physiol. 291, 19-28 (1979). 2. Tayebati, S.K. Animal models of cognitive dysfunction. Mech. Ageing Dev. 127(2), 100-108 (2005). WARNING CAYMAN CHEMICAL THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE. 1180 EAST ELLSWORTH RD SAFETY DATA ANN ARBOR, MI 48108 · USA This material should be considered hazardous until further information becomes available. Do not ingest, inhale, get in eyes, on skin, or on clothing.
    [Show full text]
  • Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Pharmacol Manuscript Author Rev. Author Manuscript Author manuscript; available in PMC 2016 April 05. Published in final edited form as: Pharmacol Rev. 2008 September ; 60(3): 358–403. doi:10.1124/pr.107.00107. Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection JEFFREY A. LIEBERMAN, FRANK P. BYMASTER, HERBERT Y. MELTZER, ARIEL Y. DEUTCH, GARY E. DUNCAN, CHRISTINE E. MARX, JUNE R. APRILLE, DONARD S. DWYER, XIN-MIN LI, SAHEBARAO P. MAHADIK, RONALD S. DUMAN, JOSEPH H. PORTER, JOSEPHINE S. MODICA-NAPOLITANO, SAMUEL S. NEWTON, and JOHN G. CSERNANSKY Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York (J.A.L.); Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana (F.P.B.); Division of Psychopharmacology, Vanderbilt University Medical Center, Psychiatric Hospital at Vanderbilt, Nashville, Tennessee (H.Y.M); Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (A.Y.D.); Departments of Psychiatry & Biology, University of North Carolina System–Chapel Hill, Chapel Hill, North Carolina (G.E.D.); Department of Psychiatry and Behavioral Sciences, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, North Carolina (C.E.M.); Department of Biology, Washington and Lee University, Lexington, Virginia (J.R.A.); Louisiana
    [Show full text]
  • Amanita Muscaria: Chemistry, Biology, Toxicology, and Ethnomycology
    Mycol. Res. 107 (2): 131–146 (February 2003). f The British Mycological Society 131 DOI: 10.1017/S0953756203007305 Printed in the United Kingdom. Review Amanita muscaria: chemistry, biology, toxicology, and ethnomycology Didier MICHELOT1* and Leda Maria MELENDEZ-HOWELL2 1 Muse´um National d’Histoire Naturelle, Institut Re´gulation et De´veloppement, Diversite´ Mole´culaire, Chimie et Biochimie des Substances Naturelles, USM 502 UMR 8041 C.N.R.S., 63 rue de Buffon, F-75005 Paris, France. 2 Syste´matique et Evolution, USM 602, 12, rue Buffon, F-75005 Paris, France. E-mail: [email protected] Received 12 July 2002; accepted 14 January 2003. The fly agaric is a remarkable mushroom in many respects; these are its bearing, history, chemical components and the poisoning that it provokes when consumed. The ‘pantherina’ poisoning syndrome is characterized by central nervous system dysfunction. The main species responsible are Amanita muscaria and A. pantherina (Amanitaceae); however, some other species of the genus have been suspected for similar actions. Ibotenic acid and muscimol are the active components, and probably, some other substances detected in the latter species participate in the psychotropic effects. The use of the mushroom started in ancient times and is connected with mysticism. Current knowledge on the chemistry, toxicology, and biology relating to this mushroom is reviewed, together with distinctive features concerning this unique species. INTRODUCTION 50 cm diam and bright red, orange, or even orange or yellow, apart from the white fleck. Many species of the The fly agaric, Amanita muscaria, and the panther, A. muscaria complex bear so-called crassospores (Tul- A.
    [Show full text]
  • Identification of Amino Acid Residues in Glur1 Responsible for Ligand
    The Journal of Neuroscience, May 1, 2001, 21(9):3052–3062 Identification of Amino Acid Residues in GluR1 Responsible for Ligand Binding and Desensitization T. G. Banke,3 J. R. Greenwood,2 J. K. Christensen,1 T. Liljefors,2 S. F. Traynelis,3 A. Schousboe,1 and Darryl S. Pickering1 Departments of 1Pharmacology and 2Medicinal Chemistry, NeuroScience PharmaBiotech Research Center,The Royal Danish School of Pharmacy, DK-2100 Copenhagen, Denmark, and 3Department of Pharmacology, Emory University, Atlanta, Georgia 30322 Although GluR1o and GluR3o are homologous at the amino acid Y716F mutation. A model is proposed of the AMPA receptor level, GluR3o desensitizes approximately threefold faster than binding site whereby a hydrogen-bonding matrix of water mol- GluR1o. By creating chimeras of GluR1o and GluR3o and point ecules plays an important role in determining both ligand affinity amino acid exchanges in their S2 regions, two residues were and receptor desensitization properties. Residues Y716 in identified to be critical for GluR1o desensitization: Y716 and the GluR1 and F728 in GluR3 differentially interact with this matrix R/G RNA-edited site, R757. With creation of the double-point to affect the binding affinity of some ligands, providing the mutant (Y716F, R757G)GluR1o , complete exchange of the de- possibility of developing subtype-selective compounds. sensitization rate of GluR1o to that of GluR3o was obtained. In Key words: AMPA receptor; desensitization; binding site; addition, both the potency and affinity of the subtype-selective GluR1; GluR2; GluR3; GluR4 agonist subtype-selectivity; mu- agonist bromohomoibotenic acid were exchanged by the tant receptors L-glutamate, the major excitatory neurotransmitter in the brain, excitotoxic death (Jensen et al., 1998, 1999).
    [Show full text]
  • 082 Muscimol and Ibotenic Acid Containing Mushrooms Exposures: US National Poison Data System 2001-2011 Michael Moss1,2, Robert
    082 Muscimol and ibotenic acid containing mushrooms exposures: US National Poison Data System 2001-2011 Michael Moss 1,2 , Robert Hendrickson 1,2 , Benjamin Hatten 3,4 1Oregon Health & Science University, Portland, OR, USA, 2Oregon Poison Center, Portland, OR, USA, 3University of Colorado School of Medicine, Aurora, CO, USA, 4Rocky Mountain Poison and Drug Center, Denver, CO, USA Background: There are several species of muscimol/ibotenic acid-containing mushrooms in the US including Amanita muscaria and Amanita pantherina . Data on exposure to these mushrooms is limited to case reports and small case series. Research Question: What are the demographics, distribution, frequency, and outcomes of exposure to muscimol/ibotenic acid-containing mushrooms in the U.S.? Methods: Retrospective review of NPDS muscimol-containing mushroom exposures from 2001-2011. Descriptive statistics were used to analyze the data. Results: There were 66 pediatric exposures(<6 years) and 414 cases >6 years, or of unknown age. Three deaths were reported and all were intentional adult exposures. Thirty-five cases resulted in a major effect with 26 of these cited as intentional ingestions. Observed effects were: none(14%), minor(20%), moderate(39%), major(7%), and unknown(20%). Other outcomes were: GI symptoms(29%), seizures(4%), and intubation(9%). Dispositions included: managed on-site(18%), treated and released(39%), admitted to the hospital(32%), and remainder unknown. Compared to A. pantherina , A. muscaria ingestions were less likely to require critical care (20% vs 28%), less likely to have major or moderate effects (30% vs 15%), and to be intentional (66% vs 44%). Pediatric exposures accounted for 13% of cases overall, but with regional variability(>70% of Alaskan cases were <6yo).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers Et Al
    US 20090076019A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers et al. (43) Pub. Date: Mar. 19, 2009 (54) METHODS FOR TREATING Publication Classification NEUROLOGICAL DISORDERS OR DAMAGE (51) Int. Cl. Inventors: Mike Tyers, Toronto (CA); Phedias A63/496 (2006.01) (75) CI2O 1/02 (2006.01) Diamandis, Toronto (CA); Peter B. A6II 3/445 (2006.01) Dirks, Toronto (CA) A63/64 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) HOWSON AND HOWSON A6IP 25/6 (2006.01) SUITE 210,501 OFFICE CENTER DRIVE A6IP 25/18 (2006.01) FT WASHINGTON, PA 19034 (US) (52) U.S. Cl. ...................... 514/252.13:435/29: 514/317; 514f613 (73) Assignees: Mount Sinai Hospital, Toronto (CA); HSC Research and Development Limited (57) ABSTRACT Partnership, Toronto (CA) A clonogenic neurosphere assay is described that carries out high throughput screens (HTS) to identify potent and/or (21) Appl. No.: 11/871,562 selective modulators of proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/ (22) Filed: Oct. 12, 2007 or self-renewing and multipotent neural stem cells (NSCs). Compositions comprising the identified modulators and Related U.S. Application Data methods of using the modulators and compositions, in par (60) Provisional application No. 60/851,615, filed on Oct. ticular to treat neurological disorders (e.g. brain or CNS can 13, 2006. cer) or damage are also disclosed. Neurosphere Stein Progenitor Differentiated eEE eEE t Prolifefatic Assay Patent Application Publication Mar. 19, 2009 Sheet 1 of 26 US 2009/0076019 A1 Figure 1 Neurosphere Progenitor O Defeitiated e CE M.
    [Show full text]