molecular and cellular biology of neuroprotection in the cns - christian alzheimer

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molecular and cellular biology of neuroprotection in the cns - christian alzheimer

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Christian Alzheimer Molecular and Cellular Biology of Neuroprotection in the CNS Molecular and Cellular Biology of Neuroprotection in the CNS Molecular and Cellular Biology of Neuroprotection in the CNS Edited by Christian Alzheimer Institute of Physiology University of Kiel Kiel, Germany Kluwer Academic / Plenum Publishers New York, Boston, Dordrecht, London, Moscow Molecular and Cellular Biology of Neuroprotection in the CNS Edited by Christian Alzheimer ISBN 0-306-47414-X AEMB volume number: 513 ©2002 Kluwer Academic / Plenum Publishers and Landes Bioscience Kluwer Academic / Plenum Publishers 233 Spring Street, New York, NY 10013 http://www.wkap.nl Landes Bioscience 810 S. Church Street, Georgetown, TX 78626 http://www.landesbioscience.com; http://www.eurekah.com Landes tracking number: 1-58706-104-X 10 987654321 A C.I.P. record for this book is available from the Library of Congress. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher. Printed in the United States of America. Library of Congress Cataloging-in-Publication Data CIP applied for but not received at time of publication. v PREFACE The adult mammalian brain is not well equipped for self-repair. Although neuronal loss reinstalls parts of the molecular machinery that is essential for neuronal development, other factors and processes actively impede regeneration of the damaged brain. Many therapeutic efforts thus aim to promote or inhibit these endogenous pathways. In addition, more radical approaches appear on the horizon, such as replacement of lost neurons with grafted tissue. Neurorepair, however, is not the topic of this book. Here, we go one step back in the sequence of events that lead eventually to the demise of a neuronal population. This book focuses on the precious period when an initial damaging event evolves into a vast loss of neurons. The time frame might be hours to days in acute brain injury or months to years in chronic neurodegenerative diseases. Given the limited capacity of regeneration, protecting neurons that are on the brink of death is a major challenge for basic and clinical neuroscience, with implications for a broad spectrum of neurological and psychiatric diseases, ranging from stroke and brain trauma to Parkinson´s and Alzheimer´s disease. In recent years, rapid progress has been made in unravelling many of the cellular and molecular players in neuronal death and survival. However, as the field develops into more and more specialized branches, the notion of common pathogenic pathways of neuronal loss might get buried under the wealth of novel data. Thus it seems a timely endeavor to provide an overview on the most exciting recent developments in neuroprotective signaling and experimental neuroprotection. This book brings together experts from cellular and molecular neurobiology, neurophysiology, neuroanatomy, neuropharmacology, neuroimmunology and neurology. It is my hope that the book serves as a reference text for both basic neuroscientists and clinicians, offering a fresh look at many (certainly not all) of the highly intertwined processes that determine the fate of CNS neurons in the face of acute or chronic insults. The book is written mostly from the viewpoint of the basic scientist who works at the cellular and molecular level, but who also develops and tests new hypotheses using animal models of acute and chronic brain injury. Although many of the new findings hold promise for therapeutic interventions, their translation into clinically relevant neuroprotective strategies is still in its infancy. If this book helps to bridge this gap, it will certainly be worth the effort. vi I thank my publisher, Ron Landes, for his support and the opportunity to put this volume together. It was a pleasure working with Cynthia Dworaczyk, who coordinated the production of this book in a most skillful fashion. Finally, I am greatly indebted to the authors for their time and their valuable contributions. Christian Alzheimer Munich, February 2002 vii PARTICIPANTS Dr. Christian Alzheimer Institute of Physiology University of Munich Pettenkoferstrasse 12 D-80336 Munich Germany Present Address: Institute of Physiology University of Kiel Olshausenstrasse 40 D-24098 Kiel Germany Dr. Guiseppe Battaglia Istituto Neurologico Mediterraneo Neuromed 86077 Pozzilli Italy Dr. Christian Behl Max Planck Institute of Psychiatry Kraepelinstrasse 2-10 80804 Munich Germany Dr. Martin Berry King´s College GKT School of Biomedical Research, Neuronal Damage and Repair Centre for Neuroscience, Hodgkin Building Guy´s Campus—London Bridge London SE1 1UL UK Dr. Ulrike Blömer Department of Neurosurgery University of Kiel Weimarer Str. 8 D-24106 Kiel Germany Dr. Valeria Bruno Istituto Neurologico Mediterraneo Neuromed 86077 Pozzilli Italy Dr. Samantha L. Budd Astra Zeneca Södertälje Bioscience 14157 Huddinge Sweden Dr. Georg Dechant Max-Planck-Institute of Neurobiology Am Klopferspitz 18a D-82152 Martinsried Germany Dr. Ulrich Dirnagl Department of Neurology Experimental Neurology Charité D-10098 Berlin Germany viii Participants Dr. Matthias Endres Department of Neurology Experimental Neurology Charité D-10098 Berlin Germany Dr. Peter J. Flor Nervous System Research Novartis Pharma AG CH-4002 Basel Switzerland Dr. Gwenn Garden Department of Neurology UW School of Medicine Seattle, WA 98195 U.S.A. Dr. Arnold Ganser Department of Hematology and Oncology Medical School Hannover Carl-Neuberg-Strasse 1 D-30625 Hannover Germany Dr. Fabrizio Gasparini Nervous System Research Novartis Pharma AG CH-4002 Basel Switzerland Dr. Saadi Ghatan Department of Neurological Surgery UW School of Medicine Seattle, WA 98195 U.S.A. Dr. Thomas Gillessen Max-Planck-Institute of Psychiatry Kraepelinstrasse 2 - 10 D-80804 Munich Germany Dr. Joseph T. Ho Department of Neurological Surgery UW School of Medicine Seattle, WA 98195 U.S.A. Dr. Yoshito Kinoshita Department of Neurological Surgery UW School of Medicine Seattle, WA 98195 U.S.A. Dr. Kerstin Krieglstein Department of Anatomy and Neuroanatomy University of Göttingen Kreuzbergring 36 D-37075 Göttingen Germany Dr. Sebastian Jander Department of Neurology University of Düsseldorf Moorenstrasse 5 D-40225 Düsseldorf Germany Dr. Mark D. Johnson Department of Neurological Surgery UW School of Medicine Seattle, WA 98195 U.S.A. Dr. Stuart A. Lipton The Burnham Institute 10901 North Torrey Pines Road La Jolla, California 92037 U.S.A. ix Participants Dr. Ann Logan Molecular Neuroscience Department of Medicine Wolfson Research Laboratories Queen Elizabeth Hospital Edgbaston, Birmingham B15 2TH United Kingdom Dr. Hugo Marti Institute of Physiology University of Zürich Winterthurerstrasse 190 CH-8057 Zürich Switzerland Dr. Richard S. Morrison Department of Neurological Surgery UW School of Medicine Seattle, Washington 98195-6470 U.S.A. Dr. Ferdinando Nicoletti Istituto Neurologico Mediterraneo Neuromed 86077 Pozzilli and Department of Human Physiology and Pharmacology University “La Sapienza” Rome Italy Dr. Harald Neumann Neuroimmunology European Neuroscience Institute Waldweg 33 D-37073 Göttingen Germany Dr. William M. Pardridge Department of Medicine UCLA School of Medicine Los Angeles, California 90095-1682 U.S.A. Dr. Rod J. Sayer Department of Physiology University of Otago P.O. Box 913 Dunedin New Zealand Dr. Michaela Scherr Department of Hematology and Oncology Medical School Hannover Carl-Neuberg-Strasse 1 D-30625 Hannover Germany Dr. Michael Schroeter Department of Neurology University of Düsseldorf Moorenstrasse 5 D-40225 Düsseldorf Germany Dr. Guido Stoll Department of Neurology University of Würzburg Josef-Schneider-Strasse 11 D-97080 Würzburg Germany Dr. Trevor W. Stone Division of Neuroscience and Biomedical Systems West Medical Building University of Glasgow Glasgow G12 8QQ Scotland x Participants Dr. Davide Trotti Department of Neurology Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital, Harvard Medical School Charlestown, MA 02129 U.S.A. Dr. Klaus Unsicker Institute of Anatomy and Cell Biology University of Heidelberg Im Neuenheimer Feld 307 D-69120 Heidelberg Germany Dr. Sabine Werner Institute of Cell Biology ETH Hönggerberg CH-8093 Zurich Switzerland Dr. Midori A. Yenari Department of Neurosurgery Stanford University 1201 Welch Road MSLS Building P304 Stanford, California 94305-5487 U.S.A. [...]... receptors requires binding of a coagonist to the so-called glycine-binding site of the NMDA receptor Very recently, the amino acid D-serine has been suggested to be an endogenous ligand for the glycine-binding site.129 This is supported by the findings that (1) D-serine has a high potency to potentiate NMDAR-mediated neurotransmission, (2) D-serine is colocalized with NMDARs in the forebrain and (3) enzymatic... swelling following the influx of Na+, Cl- and H2O can result in plasma membrane rupture and further release of cytoplasmic glutamate into the extracellular space In summary, hypoxia/ischemia results in a secondary net increase in the extracellular glutamate concentration.7 7-7 9 As in the other above-mentioned acute CNS insults, this increase in extracellular glutamate results in excitotoxic damage.8 0-8 3... several Ca2+-activated proteases, the activity of the Ca2+-dependent cysteine protease calpain is increased following glutamate receptor-mediated Ca2+ loading 17 4-1 77 Calpain activation results in proteolysis of structural proteins and degradation of the neuronal cytoskeleton.177 Furthermore, calpain may direct the mode of cell death to necrosis by preventing the cytochrome c-mediated activation of caspases... Unsicker and Kerstin Krieglstein Abstract 353 Introduction 353 TGF-βs: A Brief Overview of Their Molecular Biology, Biochemistry β and Signaling 354 Expression of TGF-βs and TβRs in the Nervous System 358 β β TGF-βs and the Regulation of Proliferation, Survival β and Differentiation of Neurons 360 Regulation of Neuron Survival and Maintenance... Activation of different ionotropic receptor types is linked to excitotoxic cell damage through the underlying ion currents Depending on the predominance of either Na+ or Ca2+ influx, two different components of excitotoxicity have been suggested Na + ion influx mediated by activation of NMDA-type and non-NMDA-type glutamate receptors is followed by secondary influx of Cl- and H2O and results in swelling of. .. distributed in different types of CNS neurons and shape the late component of glutamatergic EPSCs Second, the opening of the ligand-gated cation channel does not only depend on binding of agonist but is voltage-dependent, since the channel is blocked by Mg2+ions at resting membrane potentials and a depolarization of the plasma membrane is required to relieve the Mg2+-dependent block Third, activation of NMDA... through the reaction of NO with superoxide anions (O 2-) to form peroxynitrite (ONOO-).184 Other classes of enzymes are also thought to be involved in the Ca2+-mediated cell death but in less direct ways Calcineurin is a Ca2+/calmodulin-activated phosphatase which can dephosphorylate nNOS, thereby increasing its activity185 and potentially increasing excitotoxic damage Calcineurin has been convincingly... these amino acids are (1) constituents of intermediary metabolism and are (2) located in the brain ubiquitously in high concentrations rendered them unlikely candidates as neurotransmitters These findings fueled a sustained debate about their physiological role as neurotransmitters in the 1970s Today, L-glutamate is accepted as the predominant fast excitatory neurotransmitter in the vertebrate brain... subfields and the extent of damage is in the order CA1 > CA4 > CA3 > CA2, thus indicating different susceptibility to SE-induced cell death.12,50 In animal models of epilepsy using chemoconvulsant-induced or electrical stimulation-induced SE, similar patterns of brain damage were observed.5 1-5 4 Experiments aimed at the observation of ultrastructural changes have demonstrated that certain features of cell... death following oral intake of glutamate or aspartate in brain regions devoid of the blood-brain barrier in mice and nonhuman primates (Fig 1). 4-9 Thus, L-glutamate is the primary excitatory transmitter in the mammalian CNS but is cytotoxic under certain conditions This relation between the physiological function as excitatory amino acid (EAA) and the pathological effect is reflected by the term “excitotoxicity” . Christian Alzheimer Molecular and Cellular Biology of Neuroprotection in the CNS Molecular and Cellular Biology of Neuroprotection in the CNS Molecular and Cellular Biology of Neuroprotection. that determine the fate of CNS neurons in the face of acute or chronic insults. The book is written mostly from the viewpoint of the basic scientist who works at the cellular and molecular level,. develops and tests new hypotheses using animal models of acute and chronic brain injury. Although many of the new findings hold promise for therapeutic interventions, their translation into clinically relevant

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  • Molecular and Cellular Biology of Neuroprotection in the CNS

    • Cover

    • PREFACE

    • PARTICIPANTS

    • CONTENTS

    • I. NEURONAL CELL DEATH-Overview of Basic Mechanisms

      • 1. EXCITATORY AMINO ACID NEUROTOXICITY

        • Clinical Relevance of Excitatory Amino Acid Neurotoxicity

        • Traumatic Brain Injury

        • Neurodegenerative Diseases

        • Implication of Distinct Glutamate Receptor Classes in Excitotoxicity

        • Ionic Dependence of Excitotoxic Cell Damage

        • Mitochondrial Dysfunction

        • in Excitotoxicity

        • Role of Nitric oxide and other Reactive Nitrogen Species in Excitotoxicity

        • Excitotoxicity, Calcium Loading and Apoptosis

        • Key Signaling Players in Neuronal Apoptosis

        • Conclusions

        • 2. NEURONAL SURVIVAL AND CELL DEATH SIGNALING PATHWAYS

          • Death receptor-Mediated Neuronal Apoptosis

          • Signal Transduction Pathways

          • Nuclear Signaling Pathways

          • p53-Mediated Cell Death Signaling Pathways

          • Bcl-2 Family Members and Mitochondrial Integrity

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