Molecular and Cellular Biology of Neuroprotection in the CN S Christian Alzheimer
AEMB volume number. 513
I. NEURONAL CELL DEATH OVERVIEW OF BASIC MECHANISMS 1 1. EXCITATORY AMINO ACID NEUROTOXICITY 3 Thomas Gillessen, Samantha L. Budd and Stuart A. Lipton Historical Perspective»»..»» 3 Clinical Relevance of Excitatory Amino Acid Neurotoxicity 5 Epilepsy»»..»..»»»»»»..»».»...»..»»..» 5 Traumatic Brain Injury»» 7 Hypoxia/Ischemia»..»..»» 7 Neu rodegenerative Diseases»..»»..»»..»» 9 Intoxication with Exogenous Excitatory Amino Acids»»....» 9 Implication of Distinct Glutamate Receptor Classes in Excitotoxicity»..»..1 0 Ionic Dependence of Excitotoxic Cell Damage»»» 1 2 Mitochondrial Dysfunction.»»..»..»»»»»» 1 4 The Role of Reactive Oxygen Specie s in Excitotoxicity.»»»..»»»..»..»»..»»..»»»».. 1 6 Role of Nitric oxide and other Reactive Nitrogen Species in Excitotoxicity». 1 9 Excitotoxicity, Calcium Loading and Apoptosis»..»..»..»....»»..»..»..»».»..»»»..»..»..» 2 1 Key Signaling Players in Neuronal Apoptosis.»..»..»»»»»..»»»..22 Conclusions.»»..»»..»..»..»»»»..»..».»»»..»..»..»»..».»».25 2. NEURONAL SURVIVAL AND CELL DEAT H SIGNALING PATHWAYS 41 Richard S. Morrison, Yoshito Kinoshita, Mark D. Johnson, Saadi Ghatan, Joseph T. Ho and Gwenn Garden Abstract»..»..»..»..»»»»..»»»..»...41 Introduction.»..»..»»»»..»»»..»»..»..»..»..»..»..»41 Death receptor-mediated Neuronal Apoptosis»..»»....»..»..»»»»..»..»42 Signal Transduction Pathways...»»..»..»»..»»»»..»»..»»....»»»..4 8 Nuclear Signaling Pathways».».»»..»..»»»»..»...»»..»»..53 p53-mediated Cell Death Signaling Pathways»..»..»»»..»..»..». 5 6 Bcl-2 Family Members and Mitochondrial Integrity»»..»»..»..»..»..» 60 Proteolytic Enzymes»..»..»».».»»»»»..»..»»...64
Calpains» 66 Abbreviations»»..»..»» 66 3. DETRIMENTAL AND BENEFICIAL EFFECTS OF INJURY INDUCED INFLAMMATION AND CYTOKINE EXPRESSION IN THE NERVOUS SYSTEM 8 7 Guido Stoll, Sebastian Jander and Michael Schroete r Abstract» 87 Introduction»....»» 88 Glial Cell Populations in the Central Nervous System»..»»..» 88 Entry of Inflammatory Cells into the CNS : The Blood-Brain-Barrie r and Immunological Cell adhesion Molecules»» 89 Inflammation and CNS Injury»..»» 90 Beneficial Effects of Neuroinflammation» 99 Acknowledgement»..».»..».»..» 104 4. CELLULAR AND MOLECULAR DETERMINANT S OF GLIAL SCAR FORMATION 115 Ann Logan and Martin Berry Introduction»»»»»..»..» 11 5 Development of the Scar»»..»» 118 Axon Regeneration and Scarring»»»»..» 122 Cytokines and Scarring»..»»»..»».» 124 Trophic Regulation of the Scar»..»»..» 133 Protease Regulation of Scarring...»....»»»..»...».» 134 Therapeutic Modulation of the Scar»..»»».»...»..»»..» 135 Conclusions.»..»..»..»»»»..»»»» 13 7 II. ION CHANNELS, RECEPTORS AND SIGNALING PATHWAYS 159 5. Na* CHANNELS AND Cat+ CHANNELS OF THE CEL L MEMBRANE AS TARGET S OF NEUROPROTECTIVE SUBSTANCES» 161 Christian Alzheimer Introduction»»»»»..»..»»..»..»..»»..»» 16 1 Na* Channels.»..»..»...»»..»..»..»..»...»....»...».»..»»»»..»»»»..»..».162 Na* Channel Blockers as Neuroprotective Agents.»..»..»..»»»»»»».16 8 Ca" Channels.»..»»..»..»..»»...»..»..»..»»..»....»..»»..»..»..»..»..»» 17 3 Acknowledgements.»»»»...»»»» 177
6. INTRACELLULAR Ca t+ HANDLING 183 Rod J. Sayer Abstract»..» 18 3 Introduction.......» 183 Cytosolic Caz+ Buffering»» 184 Caz+ Buffering and Neuroprotection.»»..».... 18 5 The Endoplasmic Reticulum Ca z * Store 18 7 The Endoplasmic Reticulum and Neuroprotection 188 Mitochondria and Ca z' Homeostasis 189 Mitochondria, Neurotoxicity and Neuroprotection» 190 Future Challenges»» 19 1 7. NEUROPROTECTIVE ACTIVITY OF METABOTROPI C GLUTAMATE RECEPTOR LIGANDS 19 7 Peter J. Flor, Giuseppe Battaglia, Ferdinando Nicoletti, Fabrizio Gasparini and Valeria Brun o Abstract» 197 Introduction..»......»»» 198 Chemical Structures and Receptor Profil e of Neuroprotective mglur Ligands.»..»» 199 Physico-Chemical and Pharmacokinetic Properties of Neuroprotectiv e mglur Ligands»»..»..»....»»..».... 20 2 Group-1 mglurs as Targets for Neuroprotective Drugs»»..20 4 Neuroprotection mediated by Group-II mglurs»»..» 20 7 Role of Group-III mglurs in Neuroprotection»..» 21 1 Conclusions and Outlook»..» 21 4 8. A ROLE FOR GLUTAMATE TRANSPORTERS IN NEURODEGENERATIVE DISEASES 22 5 Davide Trotti Introduction...»..».».......»..»»»»..».. 22 5 The Na*/K*-Dependent High Affinity Glutamate Transporters.....» 22 6 Localization of Glutamate Transporters....»............»..»»..»»..227 Functional Properties, Stoichiometry and Kinetic s of the Glutamate Transporters..................».»..»..»..»..»»..»» 22 7 Glutamate Transporter Topology..»..»..».....»... 23 0 Role of Glutamate Transporters in the Excitatory Neurotransmission.»..»..»..23 0 Regulation of Glutamate Transporters....»....»»........».....»»....»...234 Glutamate Transporters in Disease States..»»»».........23 6 Concluding Remarks...»..»......»....»»...»»»»..»» 242
9. PURINES AND NEUROPROTECTION 249 Trevor W. Ston e Abstract.»..»» 24 9 Adenosine..».»»» 25 0 Adenosine Receptors 250 A2A Receptors»»..» 257 Abbreviations»..»» 270 10. HEAT SHOCK PROTEINS AND NEUROPROTECTION 28 1 Midori A. Yenari Abstract»»» 28 1 Introduction»..» 281 Where and When is Hsp70 Expressed?»..»» 283 Correlative Evidence for a Neuroprotective Role 285 Neuroprotection with Hsp70 Overexpression» 286 Potential Mechanisms of Protection» 291 Conclusion.» 295 Acknowledgments» 295 III. NEUROTROPHIC FACTORS AS NEUROPROTECTIVE AGENTS 30 1 11. NEUROTROPHINS 303 Georg Dechant and Harald Neumann Summary.»..»»..»..»»..»..»»...».».»» 303 From Neurotrophin Physiology to Therapy.»..»..»...»»»....»» 303 Structure and Physiological Functions of Neurotrophins and Their Receptors 304 Neurotrophins in Animal Models of Pathological Situation s and Clinical Trials.....»..»..»»..»»»..»»..»» 314 Non-Neuroprotective and Side Effects of Neurotrophins»..» 319 Potential Improvements of Neurotrophin Therapy..».»..»»..»»..» 320 Acknowledgments.»»..»..»»»»»»»..»»..»..»» 324 12. FIBROBLAST GROWTH FACTOR S AND NEUROPROTECTION» 33 5 Christian Alzheimer and Sabine Werne r Introduction Fibr oblast Growth Factors (FGFs) and FGF Receptors»..»» 335 Distribution of FGFs in Adult Brain»»»..»»..»» 336 FGFs and Neuronal Development»...»..»»»..»»....»..»..»..»..»..» 337 Upregulation of FGFs after Brain Injury.»»..»»..»..»»»..»» 338 Neu roprotective Effects of FGF2»»»..»»..»»»»..» 33 9 FGFs and Glia.»..»»»..»»..»..»»»»..» 340
Neuroprotective Mechanisms of FGF2 34 1 Summary and Conclusions»» 343 Acknowledgements» 345 13. TGF-ßS AND THEIR ROLES IN THE REGULATIO N OF NEURON SURVIVAL 353 Klaus Unsicker and Kerstin Krieglstein Abstract» 35 3 Introduction.. 35 3 TGF-ßs: A Brief Overview of Their Molecular Biology, Biochemistry and Signaling»»..» 35 4 Expression of TGF-ßs and TI3Rs in the Nervous System.»....» 358 TGF-13s and the Regulation of Proliferation, Survival and Differentiation of Neurons» 360 Regulation of Neuron Survival and Maintenance by Member s of the TGF-D Superfamily Other Than TGF-ßs Proper»..» 364 Conclusions»»» 366 Acknowledgements.» 366 14. VASCULAR ENDOTHELIAL GROWTH FACTOR 375 Hugo H. Marti The Members of the VEGF Family»..»..»..»....»».. 375 Regulation of VEGF and VEGF Receptor Expression...»..» 378 Pleiotropic Action of VEGF in the CNS»»»..»......» 380 Intracellular Signaling Events»..»»..»..»..».. 387 Conclusion»..»..»».».»».. 38 7 Acknowledgments».....»..»»»..»»».. 38 8 IV. ADVANCES IN DRUG DELIVERY TO CNS NEURONS»..395 15. BLOOD-BRAIN BARRIER DRUG TARGETING ENABLE S NEUROPROTECTION IN BRAIN ISCHEMIA FOLLOWIN G DELAYED INTRAVENOUS ADMINISTRATION OF NEUROTROPHINS 397 William M. Pardridge Abstract...»»..»..»....»»..»..»»..»..»..»»..»...397 Blood-Brain Barrier, Neurotrophins and Neurologica l Chimeric Peptide Technology»»»»..»..»»»....»..»...»..».»..»....»..»»»..».. 401 Targeting Chimeric Neurotrophic Factors to the Brain»..»..»..»»....»..»...406 Targeting Gene Therapeutics to the Brain.»»...»..»..»»».».»....»»..». 423 Drug Targeting to the Human Brain»....»....»»»..42 6 Acknowledgments...».».....»»».»»».»...»..»..»...»....»....»»..». 427
16. INVASIVE DRUG DELIVERY 43 1 Ulrike Blbmer, Arnold Ganser and Michaela Scherr Abstract»».43 1 Vectors in Gene Therapy.»» 43 2 Direct DNA Delivery and Synthetic Nonviral Vectors 433 Viral Vectors and Gene Delivery» 43 4 Herpes Simplex Viral Vectors 43 5 Adenoviral Vectors 43 6 Adeno-Associated Viral Vector (AAV)» 43 7 Retrovirus 43 7 Biology ofretroviruses.»..»»» 438 Moloney Murine Leukemia Virus and Lenitvirus Based Vectors» 44 0 Retroviral Gene Transfer Ex Vivo.» 44 1 Retroviral Gene Transfer In Vivo.» 443 Retroviral Vector Safety» 444 Conclusion» 445 V. NEUROPROTECTIVE STRATEGIES IN ANIMAL AND IN VITRO MODELS OF NEURONAL DAMAGE....453 17. ISCHEMIA AND STROKE 455 Matthias Endres and Ulrich Dirnag l Abstract»..»»»..»..»»..»..»»..»» 45 5 Epidemiological Data»..»..»..»..»»..» 45 5 Introduction....»..»..»»»..»»»»..» 45 5 Global vs. Focal Ischemia.»»..»»»»..»..»»»»»45 6 Animal Models of Cerebral ischemia»»..»...».»»»..»..»»..» 45 6 In vitro Models of Cerebral ischemia»..»..»..»..»..»..»...».»..»..»..» 458 Importance of Physiologic Parameters for Stroke Outcome» 458 Pathophysiological Cascades Following Cerebral ischemia»..»..» 459 Glutamate Receptors and Excitotoxicity.»»..»..»»»»..»».» 462 Tissue Acidosis.»»»»»..»..»..»»..»»..»».» 464 Protein Synthesis and Early Gene Expression»...»»..» 464 Molecular Mechanisms.»..»»..»»»»...»...».»..»»..»..» 466 Experimental Evidence for Caspase-Mediated Cell Death Following Cerebral Ischemia.»..»...»..»..»..»..»..»»»»»»»».. 467 Caspase Inhibition Protects From Cerebral ischemia.»..»..»..»..»»..»..»..»..»..»..467 Conclusion ----»..»...»....»..»..»»»»»..». 468 18. NEUROPROTECTIVE STRATEGIES IN ALZHEIMER'S DISEASE 47 5 Christian Behl Introduction»....»»»...».»..»..»»..»»..»..»..»»..» 475 What is the Cause of AD?»...»»».».»»»» 476 AD Genetics and Biochemistry»»..»..»..»»»...479
Neurotoxicology of Aß 482 AD Risk Factors»»..»» 484 Mouse Models of AD»..» 485 Clinical AD Therapy 486 Experimental AD Therapies» 487 AD Prevention» 489 Final Remarks» 492 INDEX 497