DOCSLIB.ORG

Neu2000, an NR2B-Selective, Moderate NMDA Receptor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Neu2000, an NR2B-Selective, Moderate NMDA Receptor Drug News & Perspectives 2010, 23(9): 549-556 THOMSON REUTERS LOOKING AHEAD Targeting both NMDA receptors and free NEU2000, AN NR2B-SELECTIVE, radicals may provide MODERATE NMDA RECEPTOR enhanced ANTAGONIST AND POTENT SPIN neuroprotection against TRAPPING MOLECULE FOR hypoxic-ischemic injury. STROKE confer substantial neuroprotection in ani- by Sung Ig Cho, Ui Jin Park, mal models of stroke have failed to show SUMMARY Jun-Mo Chung and Byoung Joo Gwag beneficial effects in clinical trials for stroke. Excess activation of ionotropic gluta- Free radicals mediate an additional route of mate receptors, primarily N-methyl-D- Stroke is a cerebrovascular injury caused by neuronal cell death after ischemia and aspartate (NMDA) receptors and free the interruption of blood flow to the brain reperfusion. Several antioxidants have radicals, evoke nerve cell death follow- due to thrombosis, embolic particles or advanced to clinical trials including edar- ing hypoxic-ischemic brain injury in var- blood vessel bursts. Stroke is the leading avone, a hydroxyl radical scavenger that has ious animal models. However, clinical cause of serious, long-term disability in shown beneficial effects in patients with trials in stroke patients using NMDA adults and the second leading cause of transient ischemia and which was approved receptor antagonists have failed to death in the U.S. and Europe (1). Rates of as a neuroprotective drug in Japan and show efficacy primarily due to the limit- stroke mortality and burden are more China. ed therapeutic time window for neuro- affected in low-income countries including protection and a narrow therapeutic NMDA receptor antagonists and antioxi- eastern Europe, northern Asia and central index. In comparison, antioxidants pro- dants are expected to confer neuroprotec- Africa (2). Ischemic stroke, a major type of longed the time window for neuropro- tion in human stroke if drug safety and the stroke caused by thrombosis and arterial tection in animal models of ischemic therapeutic time window are justified. As embolism, can cause neuronal death rapid- stroke and showed greater therapeutic NMDA receptor activation and free radicals ly in core areas, which is accompanied by potential in clinical trials for ischemic are expected to contribute to neuronal secondary death in the ischemic penumbra stroke. Excess activation of NMDA death through distinct signaling pathways subsequent to activation of multiple death receptors and free radicals mediate the at different points of time after hypoxic pathways. Tissue plasminogen activator, a two separate pathways of nerve cell ischemic injury, it is conceivable to reason thrombolytic agent approved in 1996 by the death in stroke and a safe and multi- that targeting both NMDA receptors and U.S. Food & Drug Administration, is used to functional drug that can block both free radicals may provide enhanced neuro- dissolve the clot and to improve neurologi- routes in the brain will likely provide a protection against hypoxic-ischemic injury cal outcome for acute ischemic stroke with- better therapeutic outcome in patients and increase the therapeutic time window, if in 3 hours after the onset of symptoms (3). with stroke. Derivatives of the lead safety is compromised. Mechanisms and interventional therapies structures of sulfasalazine and aspirin for ischemic neuronal death have been have led to the discovery of a new mol- THE ROLE OF NMDA RECEPTORS IN extensively investigated to establish a novel ecule, Neu2000, that has demonstrat- ISCHEMIC NEURONAL DEATH neuroprotection therapy with a greater ther- ed excellent neuroprotection against apeutic time window than that of throm- The excitatory neurotransmitter glutamate NMDA- and free radical-induced cell bolytic agents (4). Preclinical studies have is released and accumulates in ischemic death. Neu2000 is an NR2B-selective, provided extensive evidence that excess brain areas deprived of glucose and oxygen moderate NMDA receptor antagonist (Fig. 1). Abnormal accumulation of gluta- activation of N-methyl-D-aspartate (NMDA) with potent cell-permeable, spin trap- 2+ receptors mediates rapidly evolving neu- mate triggers influx and overload of Ca ping antioxidant action even at ronal death following ischemic insults. primarily through excess activation of the nanomolar concentrations. Nonclinical However, NMDA receptor antagonists that NMDA receptors. This increase in intracellu- and human phase I studies demonstrat- 2+ 2+ lar Ca ([Ca ]i) in neurons then triggers ed that Neu2000 can be translated to neuronal injury by activating cytotoxic pro- treat patients with stroke with better Correspondence: B.J. Gwag, [email protected] or teins such as nitric oxide synthase, calpain efficacy and therapeutic time window. [email protected] and endonuclease and by impairing mito- Copyright © 2010 Prous Science, S.A.U. or its licensors. All rights reserved. CCC: 0214-0934/2010. DOI: 10.1358/dnp.2010.23.9.1513493 549 NEU2000 FOR STROKE S.I. Cho et al. ROLE OF FREE RADICALS IN ISCHEMIC NEURONAL DEATH Ischemic injury produces free radicals through multiple pathways. Activation of 2 NMDA receptors causes the accumulation ↓ 2+ of [Ca ]i that triggers production of super- oxide and nitric oxide via the activation of xanthine oxidase, nitric oxide synthase and 2+ NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (14-16). Reoxygenation ↑ or reperfusion can give rise to superoxide and H2O2 by the oxidation of accumulated hypoxanthine and the uncoupling of elec- · ↑ ↑ 2 2 tron flow from mitochondria electron trans- port chain (Fig. 1) (4). During reperfusion, 2+ transient metal ions such as ferrous and fer- 2+ ↑ ric ions are uptaken and accumulate in vul- nerable cells, which results in •OH produc- · tion by the Fenton and the Haber–Weiss reactions (17-20). The therapeutic potential of antioxidants has been well documented in animal models of stroke with a longer therapeutic time window than NMDA recep- tor antagonists (21). Four antioxidants have advanced to clinical trials for acute Figure 1. Role of NMDA receptors and free radicals in ischemic injury. Interrupted blood flow to the brain ischemia. First, tirilazad, a lipid peroxidation causes deprivation of oxygen and glucose () that results in loss of ATP (), leading to membrane inhibitor, failed to show significant beneficial 2+ depolarization, Ca entry into the presynaptic terminal () and glutamate release from the synaptic effects in six randomized, controlled trials in vesicles into the synaptic cleft (). Accumulated glutamate causes influx and accumulation of Ca2+ patients with acute ischemic stroke. An through excess activation of postsynaptic NMDA receptors (NMDAR) ( ). Sustained Ca2+ overload for a few minutes can induce neuronal death. Following reperfusion of reoxygenation, cells are exposed to additional phase III study using a higher .– dosage of tirilazad was stopped with ques- excess oxygen molecules that can be converted to superoxide (O2 ) and hydrogen peroxide (H2O2) in .– mitochondria. O2 and H2O2 can be further converted to hydroxyl radicals (•OH) through the Fenton tions emerging in Europe regarding its safe- reaction and the Haber–Weiss reaction catalyzed by ferrous and ferric ions. Such toxic free radicals ty (22). Secondly, the administration of mediate slowly evolving secondary nerve cell death following ischemic injury. ebselen, a glutathione peroxidase mimic, to patients with acute ischemic stroke within 24 hours after stroke onset, improved out- come for 1 month but not after 3 months, in chondria and endoplasmic reticulum. receptor subtype 2B (NR2B)-selective man- Japan (23, 24). The modified Mathew Scale 2+ Neurons overloaded with Ca for even a few ners, respectively, showed no efficacy in and modified Barthel Index scores were also minutes can undergo neuronal death, sug- phase III trials for acute stroke therapy (9). improved in stroke patients subjected to gesting that NMDA receptors mediate rapid The lack of beneficial effects of NMDA early treatment with ebselen. In Japan, a and fulminant neuronal death following receptor antagonists in clinical trials is placebo-controlled, double-blind, random- ischemic injury (5, 6). Furthermore, NMDA largely attributable to the narrow therapeu- ized, multicenter trial of ebselen has been receptor antagonists prevent Ca2+ entry and tic time window and unwanted side effects initiated for patients with acute cortical overload in cultured neurons deprived of such as neuronal vacuolization and necrosis infarction but further clinical outcomes have glucose and oxygen and markedly attenuate primarily in the posterior cingulate and ret- not yet been reported. Thirdly, the phase III neuronal death induced by oxygen-glucose rosplenial cortex (10-12). Moreover, adminis- study of edaravone, a free radical scavenger, deprivation and in animals subjected to tration of potent NMDA receptor antago- was performed with 250 patients with acute ischemic stroke in Japan, which showed a transient cerebral ischemia (7, 8). nists can produce psychiatric adverse effects significant improvement in functional out- in humans as shown with selfotel, which In contrast to the neuroprotective effects come within 3 months, as evaluated by the verified in animal models of stroke, NMDA caused marked psychiatric and neurological modified Rankin scale (25). Edaravone was receptor antagonists have not improved side effects in human stroke patients at a approved for the treatment of acute stroke neurological outcomes in stroke patients subtherapeutic plasma
Load more

Recommended publications
  • WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 498/04 (2006.01) A61K 31/5365 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 519/00 (2006.01) A61P 25/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/IB20 17/050844 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (22) International Filing Date: KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, 15 February 2017 (15.02.2017) MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (25) Filing Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (26) Publication Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/298,657 23 February 2016 (23.02.2016) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, New York, New York 10017 (US).
    [Show full text]
  • Profil D'effets Indésirables Des Antagonistes R-NMDA
    Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase® Nhan-Taï Pierre Ly To cite this version: Nhan-Taï Pierre Ly. Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase®. Sciences pharmaceutiques. 2019. dumas- 03039996 HAL Id: dumas-03039996 https://dumas.ccsd.cnrs.fr/dumas-03039996 Submitted on 4 Dec 2020 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. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il n’a pas été réévalué depuis la date de soutenance. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D’autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact au SID de Grenoble : [email protected] LIENS LIENS Code
    [Show full text]
  • Interactions Between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke
    Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke Benoît Haelewyn, Ph.D.,* He´le` ne N. David, Ph.D.,† Nathalie Colloc’h, Ph.D., D.Sc.,‡ Denis G. Colomb, Jr., Ph.D.,§ Jean-Jacques Risso, Ph.D., D.Sc.,ʈ Jacques H. Abraini, Ph.D., D.Sc., Psy.D.# Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/115/5/1044/452771/0000542-201111000-00027.pdf by guest on 25 September 2021 ABSTRACT What We Already Know about This Topic • Whether nitrous oxide, like xenon, reduces of ischemic brain Background: Preclinical evidence in rodents has suggested damage in the setting of thrombolysis for thromboembolic that inert gases, such as xenon or nitrous oxide, may be prom- stroke is unknown. ising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has What This Article Tells Us That Is New shown that xenon interacts with tissue-type plasminogen ac- • In rats, when administrated during the ischemic period, nitrous tivator (tPA), a well-recognized approved therapy of acute oxide dose-dependently inhibited tPa-induced thrombolysis and subsequent reduction of ischemic brain damage. How- * Research Engineer and Head, Universite´ de Caen - Basse Nor- ever, in contrast to xenon, postischemic nitrous oxide in- mandie, Centre Universitaire de Ressources Biologiques, Caen, France. creased brain hemorrhage and barrier dysfunction. † Research Scientist, Universite´ Laval, Centre Hospitalier Universitaire Affilie´Hoˆtel-Dieu Le´vis, Le´vis, Que´bec, Canada; Universite´ Laval, Cen- tre de Recherche Universite´ Laval Robert-Giffard, Que´bec, Que´bec, Canada.
    [Show full text]
  • From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J
    REVIEW The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J. David Jentsch, Ph.D., and Robert H. Roth, Ph.D. Administration of noncompetitive NMDA/glutamate effects of these drugs are discussed, especially with regard to receptor antagonists, such as phencyclidine (PCP) and differing profiles following single-dose and long-term ketamine, to humans induces a broad range of exposure. The neurochemical effects of NMDA receptor schizophrenic-like symptomatology, findings that have antagonist administration are argued to support a contributed to a hypoglutamatergic hypothesis of neurobiological hypothesis of schizophrenia, which includes schizophrenia. Moreover, a history of experimental pathophysiology within several neurotransmitter systems, investigations of the effects of these drugs in animals manifested in behavioral pathology. Future directions for suggests that NMDA receptor antagonists may model some the application of NMDA receptor antagonist models of behavioral symptoms of schizophrenia in nonhuman schizophrenia to preclinical and pathophysiological research subjects. In this review, the usefulness of PCP are offered. [Neuropsychopharmacology 20:201–225, administration as a potential animal model of schizophrenia 1999] © 1999 American College of is considered. To support the contention that NMDA Neuropsychopharmacology. Published by Elsevier receptor antagonist administration represents a viable Science Inc. model of schizophrenia, the behavioral and neurobiological KEY WORDS: Ketamine; Phencyclidine; Psychotomimetic; widely from the administration of purportedly psychot- Memory; Catecholamine; Schizophrenia; Prefrontal cortex; omimetic drugs (Snyder 1988; Javitt and Zukin 1991; Cognition; Dopamine; Glutamate Jentsch et al. 1998a), to perinatal insults (Lipska et al. Biological psychiatric research has seen the develop- 1993; El-Khodor and Boksa 1997; Moore and Grace ment of many putative animal models of schizophrenia.
    [Show full text]
  • United States Patent (19) 11 Patent Number: 5,902,815 Olney Et Al
    USOO5902815A United States Patent (19) 11 Patent Number: 5,902,815 Olney et al. (45) Date of Patent: May 11, 1999 54 USE OF 5HT2A SEROTONIN AGONISTS TO Hougaku, H. et al., “Therapeutic effect of lisuride maleate on PREVENT ADVERSE EFFECTS OF NMDA post-stroke depression” Nippon Ronen Igakkai ZaSShi 31: RECEPTOR HYPOFUNCTION 52-9 (1994) (abstract). Kehne, J.H. et al., “Preclinical Characterization of the Poten 75 Inventors: John W. Olney, Ladue; Nuri B. tial of the Putative Atypical Antipsychotic MDL 100,907 as Farber, University City, both of Mo. a Potent 5-HT2A Antagonist with a Favorable CNS Saftey Profile.” The Journal of Pharmacology and Experimental 73 Assignee: Washington University, St. Louis, Mo. Therapuetics 277: 968–981 (1996). Maurel-Remy, S. et al., “Blockade of phencyclidine-induced 21 Appl. No.: 08/709,222 hyperlocomotion by clozapine and MDL 100,907 in rats reflects antagonism of 5-HT2A receptors' European Jour 22 Filed: Sep. 3, 1996 nal of Pharmacology 280: R9–R11 (1995). 51) Int. Cl. ........................ A61K 31/445; A61K 31/54; Olney, J.W., et al., “NMDAantagonist neurotoxicity: Mecha A61K 31/135 nism and prevention,” Science 254: 1515–1518 (1991). 52 U.S. Cl. .......................... 514/285; 514/315; 514/318; Olney, J.W., et al., “Glutamate receptor dysfunction and 514/646 schizophrenia.” Arch. Gen. Psychiatry 52:998-1007 (1995). 58 Field of Search ............................. 514/285; 314/315, Pulvirenti, L. et al., “Dopamine receptor agonists, partial 314/318, 646 agonists and psychostimulant addiction' Trends Pharmacol Sci 15: 374-9 (1994). 56) References Cited Robles, R.G. et al., “Natriuretic Effects of Dopamine Agonist Drugs in Models of Reduced Renal Mass” Journal of U.S.
    [Show full text]
  • A Radical Approach to Stroke Therapy
    Commentary A radical approach to stroke therapy James McCulloch* and Deborah Dewar Wellcome Surgical Institute and Hugh Fraser Neuroscience Laboratories, University of Glasgow, Glasgow G61 1QH, United Kingdom troke is a major cause of death and readily crosses the blood–brain barrier, (mitogen-activated protein kinases͞ Sdisability throughout the developed to augment endogenous brain ascorbic ERK1͞2). During ischemia, ERK1͞2 are world. Cerebrovascular disease ranks acid levels by up to 2 mM. However, in dephosphorylated, and there is a signif- third after cancer and heart disease as a the brain, ascorbic acid levels are heter- icant increase in ERK1͞2 phosphoryla- cause of death in the European Union ogeneous and highly compartmental- tion during reperfusion after forebrain and the U.S. The economic and social ized. In the rat, normal neuronal, glial, ischemia. Neurons and oligodendrocytes burdens of stroke are not consequences and cerebrospinal fluid levels of ascorbic at the margin of a focal ischemic lesion of mortality; they are imposed by the acid are Ϸ10 mM, 1 mM, and 0.5 mM, display increased MEK1͞2, indicating large majority of stroke patients who respectively (3). The antioxidant effects that this signaling pathway is activated survive but are physically and mentally of ascorbic acid at all of these sites within after ischemia and reperfusion in vivo disabled by stroke-induced brain dam- the brain could contribute to the efficacy (8). If MEK1͞2 is inhibited by the novel age. In the U.S., less than 2% of stroke of this agent in ischemia. Brain ascorbic agent, U0126, the extent of brain damage patients benefit from access to early acid levels are highly dynamic (although is reduced after either forebrain or focal thrombolysis, which removes the primary under rigorous homeostatic control), ischemia (2).
    [Show full text]
  • Chapter 1: Stroke and Neuroprotection 1 – 21
    DEVELOPMENT OF NOVEL THERAPEUTICS FOR STROKE: PRECLINICAL INVESTIGATIONS OF OSTEOPONTIN AND 3-IODOTHYRONAMINE By Kristian Paul Doyle A DISSERTATION Presented to the Department of Molecular Microbiology & Immunology at the Oregon Health & Science University in partial fulfillment of the requirements for the degree of Doctor of Philosophy 1 CONTENTS List of Figures v List of Tables ix Acknowledgements x Preface xi Abstract xii List of Abbreviations xv Chapter 1: Stroke and Neuroprotection 1 – 21 1.1 Introduction 2 1.2 Brief History of Stroke 2 1.3 Stroke Pathophysiology 4 1.4 Neuroprotection 17 1.5 Ischemic Preconditioning 19 1.6 Research Goal 21 Chapter 2: Osteopontin 22-86 2.1 An Introduction to OPN 23 2.2 The Structure of OPN 23 2.3 OPN, Integrins and Survival Signaling 25 2.4 OPN and Ischemic Injury 27 2.5 Preclinical Development of OPN 33 2.6 Optimizing Delivery 33 2 2.7 Improving the Potency of OPN 36 2.8 Identifying the Regions of OPN required for Neuroprotection 36 2.9 Hypothesis 37 2.10 Research Design 38 2.11 OPN has neuroprotective capability in vivo and in vitro 40 2.12 The mechanism of neuroprotection by OPN 51 2.13 OPN can be delivered to the brain by intranasal administration 56 2.14 Enhancing the neuroprotective capability of OPN 60 2.15 Peptides based on the N and C terminal fragment of thrombin cleaved OPN are neuroprotective 65 2.16 The C terminal peptide requires phosphorylation to be neuroprotective while the N terminal peptide does not require phosphorylation 70 2.17 Dose response and time window of NT 124-153 71 2.18
    [Show full text]
  • (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest Et A1
    US007964607B2 (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest et a1. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO[3,4-D]PYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460077 9/2004 WO 02085904 10/2002 (75) Inventors: Patrick Robert Verhoest, Old Lyme, CT WO 2004037176 5/2004 (US); Caroline ProulX-Lafrance, Ledyard, CT (US) OTHER PUBLICATIONS Wunder et a1, M01. PharmacoL, v01. 28, N0. 6, (2005), pp. 1776 (73) Assignee: P?zer Inc., New York, NY (U S) 1781. van der Staay et a1, Neuropharmacology, v01. 55 (2008), pp. 908 ( * ) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 USC 154(b) by 562 days. Primary Examiner * Susanna Moore (74) Attorney, Agent, or Firm * Jennifer A. Kispert; (21) Appl.No.: 12/118,062 Michael Herman (22) Filed: May 9, 2008 (57) ABSTRACT (65) Prior Publication Data The invention provides PDE9-inhibiting compounds of For US 2009/0030003 A1 Jan. 29, 2009 mula (I), Related US. Application Data (60) Provisional application No. 60/917,333, ?led on May 11, 2007. (51) Int. Cl. C07D 48 7/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01) (52) US. Cl. ................................... .. 514/262.1; 544/262 (58) Field of Classi?cation Search ................ .. 544/262; 5 1 4/2 62 .1 See application ?le for complete search history. and pharmaceutically acceptable salts thereof, Wherein R, R1, (56) References Cited R2 and R3 are as de?ned herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S.
    [Show full text]
  • Impact of Open Channel Blockers on the Surface Dynamics and Organization of NMDA Receptors Alexandra Fernandes
    Impact of open channel blockers on the surface dynamics and organization of NMDA receptors Alexandra Fernandes To cite this version: Alexandra Fernandes. Impact of open channel blockers on the surface dynamics and organization of NMDA receptors. Neurons and Cognition [q-bio.NC]. Université de Bordeaux, 2020. English. NNT : 2020BORD0181. tel-03177416 HAL Id: tel-03177416 https://tel.archives-ouvertes.fr/tel-03177416 Submitted on 23 Mar 2021 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. THÈSE PRÉSENTÉE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE BORDEAUX ÉCOLE DOCTORALE Sciences de la Vie et de la Santé SPÉCIALITÉ Neurosciences Par Alexandra FERNANDES Impact of open channel blockers on the surface dynamics and organization of NMDA receptors Sous la direction de Julien DUPUIS Soutenue le 10 Novembre 2020 Membres du jury : Mme SANS, Nathalie Directeur de recherche INSERM Président M. DE KONINCK, Paul Professeur, University of Laval Rapporteur Mme LÉVI, Sabine Directeur de recherche CNRS Rapporteur Mme CARVALHO, Ana Luísa Professeur, University of Coimbra Examinateur M. DUPUIS, Julien Chargé de recherche INSERM Directeur THÈSE PRÉSENTÉE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE BORDEAUX ÉCOLE DOCTORALE Sciences de la Vie et de la Santé SPÉCIALITÉ Neurosciences Par Alexandra FERNANDES Impact des bloqueurs de canal ouvert sur la dynamique et l’organisation de surface des récepteurs NMDA Sous la direction de Julien DUPUIS Soutenue le 10 Novembre 2020 Membres du jury : Mme SANS, Nathalie Directeur de recherche INSERM Président M.
    [Show full text]
  • NIDA Drug Supply Program Catalog, 25Th Edition
    RESEARCH RESOURCES DRUG SUPPLY PROGRAM CATALOG 25TH EDITION MAY 2016 CHEMISTRY AND PHARMACEUTICS BRANCH DIVISION OF THERAPEUTICS AND MEDICAL CONSEQUENCES NATIONAL INSTITUTE ON DRUG ABUSE NATIONAL INSTITUTES OF HEALTH DEPARTMENT OF HEALTH AND HUMAN SERVICES 6001 EXECUTIVE BOULEVARD ROCKVILLE, MARYLAND 20852 160524 On the cover: CPK rendering of nalfurafine. TABLE OF CONTENTS A. Introduction ................................................................................................1 B. NIDA Drug Supply Program (DSP) Ordering Guidelines ..........................3 C. Drug Request Checklist .............................................................................8 D. Sample DEA Order Form 222 ....................................................................9 E. Supply & Analysis of Standard Solutions of Δ9-THC ..............................10 F. Alternate Sources for Peptides ...............................................................11 G. Instructions for Analytical Services .........................................................12 H. X-Ray Diffraction Analysis of Compounds .............................................13 I. Nicotine Research Cigarettes Drug Supply Program .............................16 J. Ordering Guidelines for Nicotine Research Cigarettes (NRCs)..............18 K. Ordering Guidelines for Marijuana and Marijuana Cigarettes ................21 L. Important Addresses, Telephone & Fax Numbers ..................................24 M. Available Drugs, Compounds, and Dosage Forms ..............................25
    [Show full text]
  • Marrakesh Agreement Establishing the World Trade Organization
    No. 31874 Multilateral Marrakesh Agreement establishing the World Trade Organ ization (with final act, annexes and protocol). Concluded at Marrakesh on 15 April 1994 Authentic texts: English, French and Spanish. Registered by the Director-General of the World Trade Organization, acting on behalf of the Parties, on 1 June 1995. Multilat ral Accord de Marrakech instituant l©Organisation mondiale du commerce (avec acte final, annexes et protocole). Conclu Marrakech le 15 avril 1994 Textes authentiques : anglais, français et espagnol. Enregistré par le Directeur général de l'Organisation mondiale du com merce, agissant au nom des Parties, le 1er juin 1995. Vol. 1867, 1-31874 4_________United Nations — Treaty Series • Nations Unies — Recueil des Traités 1995 Table of contents Table des matières Indice [Volume 1867] FINAL ACT EMBODYING THE RESULTS OF THE URUGUAY ROUND OF MULTILATERAL TRADE NEGOTIATIONS ACTE FINAL REPRENANT LES RESULTATS DES NEGOCIATIONS COMMERCIALES MULTILATERALES DU CYCLE D©URUGUAY ACTA FINAL EN QUE SE INCORPOR N LOS RESULTADOS DE LA RONDA URUGUAY DE NEGOCIACIONES COMERCIALES MULTILATERALES SIGNATURES - SIGNATURES - FIRMAS MINISTERIAL DECISIONS, DECLARATIONS AND UNDERSTANDING DECISIONS, DECLARATIONS ET MEMORANDUM D©ACCORD MINISTERIELS DECISIONES, DECLARACIONES Y ENTEND MIENTO MINISTERIALES MARRAKESH AGREEMENT ESTABLISHING THE WORLD TRADE ORGANIZATION ACCORD DE MARRAKECH INSTITUANT L©ORGANISATION MONDIALE DU COMMERCE ACUERDO DE MARRAKECH POR EL QUE SE ESTABLECE LA ORGANIZACI N MUND1AL DEL COMERCIO ANNEX 1 ANNEXE 1 ANEXO 1 ANNEX
    [Show full text]
  • Understanding History, and Not Repeating It. Neuroprotection For
    Clinical Neurology and Neurosurgery 129 (2015) 1–9 Contents lists available at ScienceDirect Clinical Neurology and Neurosurgery jo urnal homepage: www.elsevier.com/locate/clineuro Review Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: From review to preview a a b b,c a,b,c,d,∗ Stephen Grupke , Jason Hall , Michael Dobbs , Gregory J. Bix , Justin F. Fraser a Department of Neurosurgery, University of Kentucky, Lexington, USA b Department of Neurology, University of Kentucky, Lexington, USA c Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA d Department of Radiology, University of Kentucky, Lexington, USA a r t i c l e i n f o a b s t r a c t Article history: Background: Neuroprotection for ischemic stroke is a growing field, built upon the elucidation of the Received 17 April 2014 biochemical pathways of ischemia first studied in the 1970s. Beginning in the early 1990s, means by Received in revised form 7 November 2014 which to pharmacologically intervene and counteract these pathways have been sought, though with Accepted 13 November 2014 little clinical success. Through a comprehensive review of translations from laboratory to clinic, we aim Available online 3 December 2014 to evaluate individual mechanisms of action, while highlighting potential barriers to success that will guide future research. Keywords: Methods: The MEDLINE database and The Internet Stroke Center clinical trials registry were queried Acute stroke Angiography for trials involving the use of neuroprotective agents in acute ischemic stroke in human subjects. For the purpose of the review, neuroprotective agents refer to medications used to preserve or protect the Brain ischemia Drug trials potentially ischemic tissue after an acute stroke, excluding treatments designed to re-establish perfusion.
    [Show full text]