Elsevier S & T

CNS Regeneration: Basic Science and Clinical Advances

Kordower, Jeffrey; Tuszynski, Mark H.

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Table of contents
  • Table of Contentsv
  • Introductionxvii
  • List of Contributorsxix
  • PART I Responses to Injuryxxiii
  • Chapter 1 Intrinsic Determinants of Axon Regeneration1
  • Introduction2
  • Axon Regeneration in the PNS3
  • DRG Neurons and the Conditioning Effect3
  • Growth-promoting Signals5
  • Role of Monocytes8
  • Signaling Cascades9
  • Transcriptional Changes11
  • Growth-associated Genes14
  • Summary15
  • Axon Regeneration in the CNS15
  • The Optic Nerve as a Model System15
  • Optic Nerve Regeneration in Lower Vertebrates15
  • Injury Response in Mammalian RGCs16
  • Trophic Factors Enhance Cell Survival After Axotomy17
  • Role of Microglia18
  • Axon Regeneration After Optic Nerve Injury19
  • Axon Regeneration Through the Optic Nerve21
  • Changes in Gene Expression Associated with Optic Nerve Regeneration22
  • Similar Changes in Gene Expression Underlie Regeneration in the CNS and PNS23
  • Intracellular Signaling Pathways24
  • Further Enhancement of Axon Regeneration Requires Combinatorial Therapies25
  • The Cell Body Response in Other CNS Neurons26
  • Conclusions27
  • Acknowledgements27
  • References27
  • Chapter 2 Axonal Responses to Injury41
  • Communication of Injury Information by Retrograde Signaling from Injured Axons to the Cell Body42
  • Rapid Signaling – the Electrophysiological Response42
  • Signaling Coordinated by Molecular Motors43
  • The Cell Body Response to Axonal Injury – Mobilizing Growth Programs47
  • Axonal Regeneration – How Do Axons Re-grow?47
  • Axonal Maintenance and Segment Fusion as an Alternative to Re-growth?50
  • Summary52
  • Acknowledgements53
  • References53
  • Chapter 3 Glial Cells, Inflammation, and CNS Trauma Modulation of the Inflammatory Environment After59
  • Introduction60
  • Are Adult CNS Axons Capable of Robust Regeneration?61
  • Do Glial Cells Contribute to CNS Regenerative Failure?64
  • Oligodendrocytes and Myelin64
  • Astrocytes and the Glial Scar67
  • The Function of Inhibitory Molecules74
  • What Causes Astrocyte Gliosis and Increases in Inhibitory Molecules?76
  • Triggers of Astrocyte Gliosis76
  • Triggers for Inhibitory Molecules77
  • What is the Role of Inflammation in CNS Injury?78
  • Macrophages and Microglia78
  • Macrophages, Microglia, and Inhibitory Molecules80
  • Can Glial Responses be Modified to Enhance Regeneration?81
  • References82
  • PART II Stem Cells and Trophic Factors in CNS Repaira
  • Chapter 4 Neurotrophic Factors95
  • Introduction95
  • The Classic Neurotrophin Family99
  • Neurotrophin Roles in the PNS102
  • Neurotrophin Roles in the CNS103
  • Cellular Targets and Effects of the Classic Neurotrophins in the Injured Nervous System106
  • GDNF Family of LigandsŽ Neurotrophic Factors109
  • Other Members of the TGFB-superfamily116
  • The Cytokine Growth Factors117
  • The Insulin-like Growth Factors119
  • Hematopoietic Cytokines122
  • Fibroblast Growth Factors123
  • Growth Factor Analogs125
  • Summary of Growth Factor Effects and Potential Uses126
  • Considerations and Future Directions126
  • Acknowledgments128
  • References128
  • Chapter 5 Stem Cell Therapy for Brain Tumors145
  • Neural Stem Cells147
  • Exogenous and Endogenous NSCs Respond to Gliomas148
  • Mechanisms for NSC Homing to Gliomas148
  • Exploiting NSCs as Vehicles for Delivering Toxic Payloads150
  • Horizon154
  • References155
  • Chapter 6 Stem Cell Therapies for Parkinson’s Disease161
  • Transplanting Dopamine Neurons in Parkinson’s Disease162
  • Imaging and Current Treatment Options163
  • Imaging163
  • Neurotransmitter Pharmacology164
  • Deep Brain Stimulation166
  • Neurotrophic Factors and Gene Therapy167
  • Ex Vivo and In Vivo Stem Cells in PD169
  • Making Dopamine Neurons in the Laboratory169
  • The Identity of Midbrain DA Neurons170
  • Endogenous Stem Cells171
  • References173
  • Chapter 7 Adult Neural Progenitor Cells in CNS Function and Disease181
  • Introduction182
  • Biology of Neural Stem Cells183
  • Neurogenesis in the Adult Brain185
  • Maturation of Newborn Neurons in the Adult Hippocampus189
  • Maturation of Newborn Neurons in the Adult Olfactory Bulb189
  • Regulation of Neurogenesis189
  • Functional Significance of Hippocampal Neurogenesis190
  • Functional Significance of OB Neurogenesis192
  • Adult Neurogenesis and Disease192
  • Altered Neurogenesis as a Potential Cause of Disease192
  • NPCs as a Potential Treatment Source for Neurological Disease193
  • Conclusions194
  • Acknowledgments195
  • References195
  • Chapter 8 Neurotrophic Factors in Alzheimer’s Disease201
  • Introduction201
  • Rationale for Growth Factor Approaches202
  • Nerve Growth Factor and Basal Forebrain Cholinergic Neurons203
  • Nerve Growth Factor and Alzheimer’s Disease205
  • Preclinical Studies of Ex Vivo NGF Gene Therapy207
  • A Phase 1 Human Trial of Ex Vivo NGF Gene Therapy for AD209
  • In Vivo Adeno-associated Virus-NGF Gene Delivery for AD213
  • Other Means of NGF Delivery to the CNS215
  • Other Growth Factors for AD215
  • Conclusions216
  • Acknowledgements216
  • References216
  • PART III Novel Therapies for Parkinson’s and Huntington’s Diseased
  • Chapter 9 Direct Delivery of GDNF into the Non-Human Primate and Human Parkinsonian Brain: Success a223
  • Introduction224
  • Effects of GDNF in Non-human Primates225
  • The MPTP-lesioned Rhesus Monkey Model of Parkinson’s Disease226
  • Acute Delivery of GDNF227
  • Chronic Delivery of GDNF Using Computer-controlled Programmable Pumps230
  • Direct Brain Delivery of GDNF in Human Parkinsonian Subjects233
  • Ventricular Delivery233
  • Chronic Delivery of GDNF Using Computer-controlled Programmable Pumps234
  • Point Source Concentration of GDNF May Explain Failure of Phase-2 Clinical Trial238
  • Concerns Over Two Safety Issues Derail all GDNF Trials239
  • Future Directions240
  • Summary241
  • Acknowledgments242
  • References242
  • Chapter 10 Stimulating and Ablative Treatment for Parkinson’s Disease245
  • Introduction246
  • Pathophysiology247
  • Patient Selection249
  • Ablative Procedures250
  • Pallidotomy253
  • Thalamotomy255
  • Subthalamotomy255
  • Deep Brain Stimulation256
  • Pallidal Stimulation256
  • Subthalamic Stimulation258
  • Thalamic Stimulation260
  • Conclusion261
  • References262
  • Chapter 11 Gene and Cellular Transplantation Therapies for Huntington’s Disease267
  • Introduction268
  • Cell Death Mechanisms268
  • Animal Models270
  • Therapies272
  • Gene Therapy272
  • Cell Transplantation Therapy283
  • References288
  • PART IV Novel Therapies for Alzheimer’s Diseaseg
  • Chapter 12 Anti-amyloid-β Immunotherapy as a Treatment for Alzheimer’s Disease295
  • Introduction296
  • Active Immunization298
  • Passive Immunization299
  • Mechanisms of Plaque Reduction Following Immunization302
  • Pathologic Consequences of Aβ Immunization304
  • Behavioral Consequences of Aβ Immunization306
  • Negative Consequences of Immunization309
  • Aβ Immunization Trials in Humans310
  • Future Goals312
  • References313
  • PART V Novel Therapies for Spinal Cord Injury and White Matter Demyelinatione
  • Chapter 13 Axonal Plasticity and Regeneration in the Injured Spinal Cord319
  • Introduction319
  • CNS Regeneration Failure vs. PNS Regeneration Success320
  • Individual Approaches to Enhancing Spinal Cord Plasticity and Regeneration321
  • Growth Factors321
  • Pharmacological Enhancement of Axonal Growth: cAMP and Inosine326
  • Degrading the Extracellular Matrix326
  • Neutralizing Myelin and Inactivating Rho327
  • Combinatorial Therapies Support Axonal Bridging Beyond Spinal Cord Lesion Sites328
  • Conclusion331
  • Acknowledgments331
  • References331
  • Chapter 14 Modifying the Extracellular Matrix as a Treatment to Improve Functional Recovery after Sp337
  • The CNS Extracellular Matrix338
  • The Extracellular Matrix in Axon Regeneration340
  • The Extracellular Matrix in Plasticity341
  • Physiological Modification of the Extracellular Matrix343
  • Treatments to Modify the Extracellular Matrix343
  • Matrix Modification and Axon Regeneration344
  • Matrix Modification and Plasticity346
  • How Might Modification of the Extracellular Matrix Form Part of a Treatment for Spinal Cord Injury?349
  • Future Perspectives350
  • References350
  • Chapter 15 Myelin Neutralization for Spinal Cord Injury and Stroke355
  • Introduction355
  • Myelin-associated Inhibitors of Neurite Outgrowth357
  • Nogo-A357
  • MAG358
  • OMgp358
  • Ephrin-B3358
  • Receptor Complexes Involved in Neurite Outgrowth Inhibition359
  • Downstream Effectors360
  • RhoA360
  • Calcium and Protein Kinase C361
  • Blocking the Neurite Outgrowth Inhibitory Activity of Myelin In Vivo361
  • Antibody Neutralization of Nogo-A361
  • Inhibition of NgR and Lingo-1 with Biological Antagonists364
  • Inhibition of RhoA with C3 Transferase365
  • PKC Inhibitors365
  • Conclusion366
  • References367
  • Chapter 16 Strategies to Inhibit Signaling Through Nogo Receptor 1 for Spinal Cord Injury and Stroke373
  • Introduction374
  • Nogo Receptor 1: Its Co-receptors, Ligands, and Signalling Pathways375
  • Strategies to Block Signaling Through Nogo Receptor 1376
  • Recombinant Proteins377
  • Antibodies377
  • Peptide/Small Molecule Inhibitors378
  • Other Strategies380
  • Nogo Receptor Inhibition Promotes Axonal Sprouting and Functional Recovery in Rodent Models of Spina380
  • Nogo Receptor Inhibition Promotes Axonal Plasticity and Functional Recovery in Rodent Models of Stro384
  • Clinical Development of Nogo Receptor Inhibitors384
  • Acknowledgements384
  • References385
  • Chapter 17 Cyclic AMP Modulation of Axonal Regeneration Following Spinal Cord Injury389
  • The Role of the CNS Environment in Regenerative Failure390
  • Historical Perspectives390
  • Myelin Inhibitors – Structures and Signaling391
  • The Conditioning Lesion Effect and cAMP395
  • Reversal of Myelin Inhibition In Vitro Through Elevation of cAMP397
  • Elevation of cAMP in Models of Spinal Cord Injury399
  • Downstream Effectors of cAMP in Spinal Cord Injury405
  • Conclusions407
  • References407
  • Chapter 18 Multiple Sclerosis: Remyelination413
  • Introduction413
  • Conduction Abnormalities in Demyelinated Axons414
  • Endogenous Myelin Repair and Potential Stimulation of Endogenous Progenitors416
  • Remyelination as a Cell Therapy Approach to Improve Conduction in MS417
  • Remyelination by Endogenous Cells and Conduction Improvement417
  • Remyelination of Axons by Cellular Transplants418
  • Transplantation of Peripheral Myelin-forming Cells for Remyelination of Adult CNS Axons421
  • Nodal Reconstruction of Remyelinated Spinal Cord Axons425
  • Neuroprotection of Corticospinal Tract Neurons by OEC Transplantation428
  • Clinical Studies Using OECs in Spinal Cord Injury428
  • Concluding Remarks430
  • References430
  • PART VI Design of Clinical Trialsk
  • Chapter 19 Clinical Trials in Rehabilitation With Neural Repair437
  • Introduction437
  • Confounders in the Translation of Pre-clinical Trials438
  • Clinical Trial Designs442
  • Aims445
  • Methods446
  • Entry Criteria446
  • Design446
  • Interventions447
  • Outcome Measures448
  • Adverse Effects452
  • Data Analysis452
  • Ethical Concerns in Clinical Trials of Repair452
  • Embryonic Stem Cells452
  • Sham Surgery453
  • Participation in Clinical Trials454
  • References455
  • Index457
  • Color Plates475
Book details
  • Vendor Elsevier S & T
  • SKU 9780123739940
  • ISBN-13 9780080556987
  • Author Kordower, Jeffrey; Tuszynski, Mark H.
  • Edition 2nd
  • Category Medical
  • Subject Neuroscience

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This second edition updates the burgeoning field of regeneration in the Central Nervous System (CNS) from molecular, systems, and disease-based perspective. While the book covers numerous areas in detail, special emphasis is given to discussions of movement disorders such as Parkinson’s disease, Alzheimer’s disease, and spinal cord injury.

* Incorporates information gained from cutting-edge photomicroscopy techniques
* Includes current information on clinical trials
* Presents chapters on stem cells and other novel treatments for diseases of the CNS