Neurotrophic Factors

Neurotrophic Factors

by Franz Hefti (Editor)

Paperback(Softcover reprint of the original 1st ed. 1999)

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Product Details

ISBN-13: 9783642641824
Publisher: Springer Berlin Heidelberg
Publication date: 09/22/2011
Series: Handbook of Experimental Pharmacology , #134
Edition description: Softcover reprint of the original 1st ed. 1999
Pages: 325
Product dimensions: 6.10(w) x 9.25(h) x 0.03(d)

Table of Contents

1 Biological Roles of Neurotrophins.- A. Introduction.- B. Neurotrophins in Different Species.- C. Trophic Roles of Neurotrophins in the Peripheral Nervous System.- I. Sensory Neurons.- 1. Nerve Growth Factor.- 2. Brain-Derived Neurotrophic Factor.- 3. Neurotrophin-3.- 4. Neurotrophin-4/5.- II. Sympathetic Neurons.- D. Trophic Roles of Neurotrophins in the Central Nervous System.- I. Prevention of Cell Death.- II. Other Trophic Actions.- 1. Regulation of Gene Expression.- 2. Functional and Morphological Effects on the Developing Cortex and Motoneurons.- E. Synaptic Transmission.- F. Modulation of Transcription of Neurotrophin Genes.- G. Regressive Events and Neurotrophins.- H. Conclusions and Perspectives.- References.- 2 Molecular Anatomy of Neurotrophic Factors.- A. Multi-Component Receptors, Specificity and Cross-Talk.- B. Insights into Neurotrophic-Factor Function from Structural Analyses.- C. Electrostatic Forces and the Interaction of Neurotrophic Factors with Their Receptors.- D. Site-Directed Mutagenesis and Structure-Activity Relationships.- E. Ligands with Altered Receptor-Binding Specificity Offer New Insights into Neurotrophic Factor Function.- F. Conclusions.- References.- 3 Neurotrophin Treatment of Peripheral Sensory Neuropathies.- Abbreviations.- A. Introduction.- B. Organization of the Peripheral Nervous System.- I. Sensory Neurons.- II. Sympathetic Neurons.- III. Parasympathetic Neurons.- C. Role of NGF in PNS Development.- D. Role of NGF in the Adult PNS.- E. NGF Receptors.- I. Expression in Normal Nerves.- II. Expression in Injured Nerves.- III. Alterations in NGF and NGF-Receptor Expression in Human Diabetic Neuropathy.- F. The Role of Neurotrophins in the Pathogenesis of Peripheral Sensory Neuropathies.- I. Pharmacology of Neurotrophins in Chemotherapeutic-Induced (Toxic) Peripheral Sensory Neuropathies.- II. Pharmacology of NGF in Experimental Diabetic Neuropathy.- 1. Therapeutic Effects of NGF in Experimental Diabetic Neuropathy.- III. Summary.- G. Clinical Peripheral Sensory Neuropathies: Diabetic Polyneuropathy.- I. Epidemiology of Diabetic Neuropathy.- II. Current Treatment of Peripheral Sensory Neuropathies.- H. Trial Design Considerations for the Study of Peripheral Sensory Neuropathies.- I. Selection of Study Endpoints.- II. Study Endpoints for Evaluation of Efficacy of rhNGF.- I. Clinical Studies of Nerve Growth Factor.- I. Safety, Pharmacokinetics and Pharmacodynamic Effects of rhNGF.- II. Preliminary Evidence of Efficacy of rhNGF in the Treatment of Peripheral Sensory Neuropathies.- J. Interpretation of Clinical-Trial Results.- K. Conclusions.- References.- 4 Neurotrophic Factors and Amyotrophic Lateral Sclerosis.- A. Introduction.- I. Developmental Cell Death of Motoneurons.- II. Pathological Cell Death of Motoneurons and Human Motoneuron Disease.- III. Why Should Neurotrophic Factors Interfere with the Pathogenic Mechanisms in Sporadic ALS?.- IV. Ciliary Neurotrophic Factor (CNTF) and Related Molecules.- 1. The CNTF Receptor Complex: Actions of Leukemia Inhibitory Factor, Oncostatin M and Cardiotrophin-1 Are Mediated Through Shared Receptor Subunits.- 2. The Function of Endogenous CNTF and Related Factors for Motoneurons.- 3. Pharmacological Effects of CNTF on Lesioned Motoneurons.- 4. Effects of CNTF and Other Neurotrophic Factors in Murine Animal Models for Motoneuron Disease.- 5. Pharmacological Effects of Systemically Applied CNTF.- V. The Effects of Neurotrophins on Motoneurons.- 1. Nerve Growth Factor.- 2. The Effects of Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotrophin-4/5 (NT-4/5) on Motoneurons.- 3. Physiological Functions of Neurotrophins for Motoneurons, As Revealed by Gene Targeting.- 4. Pharmacological Potential of Neurotrophins for Treatment of Amyotrophic Lateral Sclerosis.- VI. Glial-Derived Neurotrophic Factor.- 1. Specificity of GDNF for Motoneurons and Neuronal Populations in the Peripheral Nervous System.- 2. Physiological Function of GDNF: Evidence from Gene Knockout Studies.- 3. The Pharmacological Potential of GDNF for Treatment of Human Motoneuron Disease.- VII. Insulin-Like Growth Factors (IGF).- 1. Specific Function of IGF-I on Developing and Postnatal Motoneurons.- 2. Pharmacokinetics of IGF-I.- 3. Effects of IGF-I in Animal Models of Motoneuron Degeneration.- VIII. Future Perspectives: Are Newest Clinical Trials in ALS Patients with Neurotrophic Factors Meaningful?.- 1. Strategies to Increase the Availability of Pharmacologically Applied Neurotrophic Factors to Degenerating Motoneurons.- 2. Development of Modified Factors with Increased Specificity and Improved Pharmacokinetic Properties.- 3. Combinations of Neurotrophic Factors: The Better Strategy?.- References.- 5 Neuropharmacology of Insulin-Like Growth Factors.- Abbreviations.- A. Introduction.- B. Background.- I. IGF Genes and Transcripts.- 1. IGF-I.- 2. IGF-II.- II. IGF Receptors.- 1. Type-I Receptors.- 2. Type-II Receptors.- III. IGF Binding Proteins.- C. Neurotrophic Relationships.- I. Peripheral Nervous System.- II. Central Nervous System.- D. Neurological Disorders Targeted for IGF Therapy.- I. Diabetic Neuropathy.- 1. Pathophysiology.- 2. Experimental Observations in Non-Primates.- a) IGF Activity in Experimental IDDM.- b) IGF Activity in Experimental NIDDM.- c) IGF Treatment Prevents Neuropathy.- d) Relationship of Disturbances in IGF Axis to Hyperglycemia, Hyperinsulinemia and Weight Loss.- 3. IGF Activity in Primates.- a) Diabetic Monkeys.- b) Clinical Diabetes.- II. Chemotherapy-Induced Neuropathy.- III. Amyotrophic Lateral Sclerosis (ALS).- IV. Stroke.- V. Alzheimer’s Disease.- VI. Myotonic Dystrophy.- E. Pharmacological Considerations.- I. Routes of Administration.- II. Volume of Distribution and Daily Production.- III. Bound and Free IGF Pools.- IV. Elimination Half-Time.- V. Clinical Effects of Recombinant Human IGF-I.- 1. Normal Subjects.- 2. Patient Populations.- VI. Effects of Recombinant Human IGF-II.- F. Concluding Comments.- References.- 6 Neurotrophic Factors in Peripheral Nerve Injury and Regeneration.- A. Introduction.- B. Causes of Peripheral Nerve Damage.- C. Symptoms and Pathophysiology of Peripheral-Nerve Damage.- I. Sensory Neuropathies.- II. Motor Neuronopathies.- D. Current Approaches to Therapy.- I. Sensory Neuropathies.- 1. Surgery.- 2. Analgesic Drugs.- II. Motor Neuronopathies.- E. Methods for the Study of Peripheral Nerve Damage in Laboratory Animals.- I. Mechanical Injury.- II. Neurotoxins.- III. Diabetes.- IV. Hereditary Motor Neuronopathies in Mice.- F. Endpoints Used to Assess Peripheral Nerve Regeneration In Vivo.- I. Quantitative Morphometric Analysis.- II. Functional Assays of Nerve Regeneration Distance.- III. Assessing the Functional Innervation of Target Tissues.- G. Beneficial Effects of Neurotrophic Agents in Animal Models of Neuropathy.- I. Mechanical Nerve Injury.- II. Neurotoxins.- III. Diabetes.- IV. Motor Neuronopathy in Mice.- H. Drug-Development Issues.- I. Clinical Experience with Neurotrophic Factors.- J. Conclusions and Future Directions.- References.- 7 Nerve Growth Factor Treatment for Alzheimer’s Disease: The Experience of the First Attempt at Intracerebral Neurotrophic Factor Therapy.- A. Introduction.- B. Nerve Growth Factor as a Therapeutic Agent to Counteract Cholinergic Neuron Degeneration.- I. Cholinergic Neuron Atrophy in Alzheimer’s Disease (AD).- II. Role of NGF in Cholinergic Neuron Development and Adult Function.- III. Pharmacological Effects of NGF in Animals with Experimental Cholinergic Deficits.- IV. Human Studies with NGF: Efficacy and Possible Adverse Effects.- V. Alternative Administration Strategies and Small-Molecule Mimetics.- C. Neurotrophic Factors for Non-Cholinergic Neurons Affected by the Disease.- D. Relationship to Alzheimer’s Disease Pathology.- E. Conclusions.- References.- 8 Neurotrophic Roles of GDNF and Related Factors.- A. Introduction.- B. Molecular Structure of GDNF and Related Molecules.- I. Glial Cell Line-Derived Neurotrophic Factor.- II. Neurturin.- 1. Persephin.- C. Receptors and Signal Transduction of GDNF and Neurturin.- I. Ret.- 1. Molecular Structure and Signaling Pathways.- 2. Ret As a Functional Receptor for GDNF and Neurturin.- II. Additional Components of the Ret-Receptor Complex: ?1-and ?2-receptors.- 1. The GFR-al Receptor.- 2. The Neurturin-/TrnR2-/RTL2/GFR-?2-Receptor.- D. Distribution of GDNF, Neurturin and Their Receptors.- I. GDNF and Neurturin in the Nervous System.- II. GDNF and Neurturin in Non-Neural Tissues.- III. Expression of Ret, GFR-?1 and GFR-?2 in the Developing and Adult Nervous System.- IV. Expression of GDNF and its Receptors in the Lesioned Nervous System.- V. Expression of Ret, GFR-?1 and GFR-?2 Outside the Nervous System: Involvement of Ret in Neuroendocrine and Gastrointestinal Disorders.- E. Functions of GNDF and Neurturin in the Nervous System As Revealed In Vitro and In Vivo.- I. Glial Cell Line-Derived Neurotrophic Factor.- 1. GDNF and the Nigrostriatal Dopaminergic System.- a) Cultured Mesencephalic Cells.- b) Animal Models of Parkinsonism.- c) Effects in Unlesioned Animals.- 2. Other CNS Aminergic Neurons.- 3. GDNF and Intrinsic Striatal Neurons.- 4. Spinal Cord and Brainstem Motoneurons.- 5. Cerebellar Neurons.- 6. Sensory Neurons.- 7. Autonomic Neurons.- 8. Neural Crest.- 9. GDNF in CNS Lesion Models Other Than Parkinsonism.- II. Neurturin.- F. Developmental Roles of GDNF, Neurturin and Their Receptors As Revealed by Gene Targeting.- I. Glial Cell Line-Derived Neurotrophic Factor.- II. Ret.- III. Neurturin.- G. Perspectives.- I. Clinical Relevance.- II. Neurobiological Relevance.- References.- 9 Role of Neurotrophic Factors in Cerebral Ischemia.- A. Neurotrophic Factors, Their Receptors and Their Expression in the Central Nervous System (CNS).- I. Neurotrophic Factors Support Survival and Functionality of Neurons.- II. Neurotrophic-Factor Families.- 1. Neurotrophins.- 2. Glial-Derived Neurotrophic Factor (GDNF) and Transforming Growth Factors (TGFs).- 3. Ciliary Neurotrophic factor (CNTF), Fibroblast Growth Factors (FGFs), Insulin-Like Growth Factors (IGFs) and Other Factors.- III. Afferent Activity Regulates Neurotrophic Factor Expression.- B. Hypoxic-Ischemic Injury Regulates the Expression of Neurotrophic Factors and Their Receptors in the Central Nervous System.- I. Global Hypoxic-Ischemic Injury.- 1. Neurotrophins.- 2. Basic Fibroblast Growth Factor.- 3. IGFs, TGF-b and Other Factors.- II. Focal Hypoxic-Ischemic Injury.- 1. Neurotrophins.- 2. Basic Fibroblast Growth Factor.- 3. Other Factors.- C. Specific Growth Factors Can Attenuate Morphological and Functional Damage Caused by Hypoxic-Ischemic Brain Injury.- I. Global Ischemic Injury.- 1. Neurotrophins.- 2. Basic Fibroblast Growth Factor.- 3. TGF-b, IGF-I and Other Factors.- II. Focal Ischemic Injury.- 1. Neuroprotective Effects of Neurotrophins.- 2. Neuroprotective Effects of bFGF.- 3. Neuroprotective effects of IGF-I, TGF-? and Other Growth Factors.- 4. Protection Via Neurotrophic-Factor Induction.- D. Therapeutic Potential of Neurotrophic Factors in Hypoxic-Ischemic Brain Injury.- References.- 10 Strategies for Administering Neurotrophic Faetors to the Central Nervous System.- Abbreviations.- A. Introduction.- I. Characteristics of Neurotrophic Factors (NFs).- II. Rationale for Using NFs in Clinical Paradigms.- B. Administration of NFs to the Central Nervous System.- I. Delivery Issues.- C. Delivery Methods.- I. Delivery of NFs Using Mechanical-Release Devices.- 1. Systemic Delivery.- 2. Pumps.- 3. Slow Polymer-Release System.- II. Delivery of NFs Using Gene Therapy Approaches.- 1. In Vivo Gene Therapy.- a) Viral Vectors.- b) Adenoviral Vectors.- c) Adeno-Associated Viral Vectors.- d) Retroviral Vectors.- 2. Ex Vivo Gene Therapy.- a) Cell Grafting.- b) Encapsulation of Engineered Cell Lines.- D. Conclusion.- References.- 11 Neurotrophic Factor Mimetics.- A. Introduction.- B. Direct and Indirect Receptor Ligands.- I. Peptide Mimetics.- II. K-252a and Related Compounds that Modulate Trk Receptor Signalling.- III. Immunophilin Ligands.- IV. Others.- C. Regulators of Neurotrophic Factor Synthesis or Release.- I. Hormonal Regulation of Neurotrophin or Neurotrophin Receptor Expression.- II. Compounds Regulating Neurotrophin Synthesis.- D. Examples of Growth Hormone Secretagogues.- I. Discovery of L-692,429 and MK-0677.- II. The MK-0677 Receptor.- III. Clinical Use.- E. Conclusions.- References.

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