Dominguez Neurodegenerative Diseases

1. Auflage 2010
ISBN: 978-3-642-16758-4
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 6, 196 Seiten

Reihe: Topics in Medicinal Chemistry

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach.- Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer's Disease.- Glutamate and Neurodegenerative Disease.- Modulation of the Kynurenine Pathway for the Potential Treatment of Neurodegenerative Diseases.- Spinal Muscular Atrophy: Current Therapeutic Strategies

Autoren/Hrsg.

Dominguez, Celia

Inhaltsverzeichnis

1;Topics in Medicinal ChemistryAlso Available Electronically;8
1.1;Aims and Scope;8
2;Preface to the Series;10
3;Foreword to Volume 6;12
4;Contents;18
5;The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach;20
5.1;1 Neurodegeneration;22
5.2;2 Overview of Histone Deacetylases;23
5.2.1;2.1 Classification;23
5.2.2;2.2 Structural Aspects of Zinc-Dependent Histone Deacetylases;27
5.2.3;2.3 General Overview of Known Class I, II, and IV HDAC Inhibitors;28
5.2.3.1;2.3.1 Introduction;28
5.2.3.2;2.3.2 Hydroxamic Acids;29
5.2.3.3;2.3.3 Ortho-N-Acyl-Phenylene Diamines;30
5.2.3.4;2.3.4 Ortho-N-Acyl-Phenolamines;30
5.2.3.5;2.3.5 Macrocyclic Natural Products;31
5.2.3.6;2.3.6 Ketones and Trifluoromethyl Ketones;32
5.2.3.7;2.3.7 Carboxylic Acids;33
5.2.3.8;2.3.8 Selectivity Determination;34
5.2.4;2.4 The Sirtuins (Class III HDACs);35
5.2.4.1;2.4.1 Structure, Mechanism, and Function of Sirtuins;35
5.2.4.2;2.4.2 Sirtuin Inhibitors;36
5.2.4.3;2.4.3 Sirtuin Activators;38
5.3;3 Potential Treatment of Neurodegenerative Disorders with HDAC Inhibitors;40
5.3.1;3.1 Introduction;40
5.3.2;3.2 HDACs, Chromatin Remodeling, and Control of the Epigenome;40
5.3.3;3.3 Control and Dysregulation of Gene Transcription in Neurodegeneration;41
5.3.4;3.4 Sequestration of HATs and Transcriptional Factors in Neurodegeneration;42
5.3.5;3.5 HDAC Inhibitors Ameliorate Transcriptional Dysregulation;44
5.4;4 Effect of HDAC Inhibitors on Reversing Protein Accumulation in Neurodegeneration;47
5.4.1;4.1 The Role of the Ubiquitin-Proteosome System and Autophagy Pathways;47
5.4.2;4.2 Regulation of Protein Turnover by HATS and HDACs;48
5.4.3;4.3 Effect of SUMO E3 Ligase Activity of Class IIa HDACs;49
5.4.4;4.4 HDAC6: A Master Regulator of Cell Response to Cytotoxic Insults;50
5.4.5;4.5 HDACs and Sirtuins Regulate Autophagy Pathways;52
5.5;5 Neuroprotection Through HDAC Inhibition;53
5.5.1;5.1 Introduction;53
5.5.2;5.2 Neuroprotection by Sirtuins;54
5.6;6 Treating Cognitive Impairment and Depression with HDAC Inhibitors;56
5.6.1;6.1 Introduction;56
5.6.2;6.2 Procognitive Effects of HDAC Inhibition;56
5.6.3;6.3 Antidepressant Effects of HDAC Inhibition;60
5.7;7 Conclusion;60
5.8;References;61
6;Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer´s Disease;76
6.1;1 Introduction;77
6.2;2 AD as a Disease of Synaptic Dysfunction;79
6.2.1;2.1 Synapse Loss in AD;79
6.2.2;2.2 Abeta and Synapse Function;80
6.2.3;2.3 Synapse Loss as Both Cause and Effect in AD;80
6.3;3 Cyclic Nucleotides and Synaptic Plasticity;82
6.3.1;3.1 c83
6.3.2;3.2 cGMP;84
6.4;4 The Phosphodiesterases;84
6.4.1;4.1 Enzyme Structure and Function;84
6.4.2;4.2 Compartmentalization of PDE Signaling;86
6.4.3;4.3 PDE4;87
6.4.4;4.4 PDE7 and PDE8B;90
6.4.5;4.5 PDE5A;92
6.4.6;4.6 PDE9A;93
6.4.7;4.7 PDE2A;97
6.5;5 Perspective;101
6.6;References;103
7;Glutamate and Neurodegenerative Disease;110
7.1;1 Introduction;111
7.2;2 NMDA Receptors;113
7.2.1;2.1 NMDA Receptor Biology;113
7.2.2;2.2 NMDA Receptor Modulators;117
7.3;3 AMPA Receptors;119
7.3.1;3.1 AMPA and Kainate Receptor Biology;119
7.3.2;3.2 AMPA Receptor Modulators;123
7.4;4 Metabotropic Glutamate Receptors;127
7.4.1;4.1 Metabotropic Glutamate Receptor Biology;127
7.4.2;4.2 Metabotropic Glutamate Receptor Modulators;130
7.4.2.1;4.2.1 mGluR1;131
7.4.2.2;4.2.2 mGluR2 and 3;133
7.4.2.3;4.2.3 mGluR4;136
7.4.2.4;4.2.4 mGluR5;137
7.4.2.5;4.2.5 mGluR 6, 7, and 8;142
7.5;5 Glutamate Transporters;143
7.5.1;5.1 Glutamate Transporter Biology and the Role of Astrocytes;143
7.5.2;5.2 Glutamate Transporter Modulators;146
7.6;6 Conclusion;147
7.7;References;147
8;Modulation of the Kynurenine Pathway for the Potential Treatment of Neurodegenerative Diseases;167
8.1;1 Introduction;168
8.2;2 Tryptophan Metabolism and the Kynurenine Pathway;168
8.3;3 Introduction of KP Enzymes and Key Metabolites;169
8.4;4 Physiological and Pathological Features of KP Pathway;170
8.4.1;4.1 Physiological Role;170
8.4.2;4.2 Kynurenines and CNS Dysfunction;171
8.4.3;4.3 Kynurenine Pathway and Disease;173
8.5;5 Enzymes in the KP as Drug Targets and Their Inhibitors;173
8.5.1;5.1 Indoleamine 2,3-Dioxygenase;174
8.5.2;5.2 KAT II Inhibitors;176
8.5.3;5.3 Kynureninase Inhibitors;177
8.5.4;5.4 3-Hydroxyanthranilic Acid Oxygenase Inhibitors;178
8.5.5;5.5 KMO Inhibitors;178
8.5.6;5.6 KMO Inhibition and Stroke/Ischemia;181
8.5.7;5.7 KMO Inhibition and Huntington´s Disease;182
8.5.7.1;5.7.1 Optimization of KMO Inhibitors for the Potential Treatment of HD;183
8.6;6 Perspective and Future Challenges;187
8.7;References;189
9;Spinal Muscular Atrophy: Current Therapeutic Strategies;195
9.1;1 Introduction;196
9.2;2 SMA Genetics;196
9.3;3 SMA Diagnosis and Categorization;197
9.4;4 Current Treatments;197
9.4.1;4.1 Preclinical Evaluation;197
9.4.1.1;4.1.1 In Vitro and Ex Vivo Assays;197
9.4.1.2;4.1.2 In Vivo Models;198
9.4.2;4.2 Supportive Treatments;199
9.4.3;4.3 Investigational Therapies;199
9.4.3.1;4.3.1 Biological Strategies for the Treatment of SMA;199
9.4.3.2;4.3.2 Small Molecule Agents;200
9.4.3.2.1;HDAC Inhibitors;201
9.4.3.2.2;Antibiotics and Their Derivatives;203
9.4.3.2.3;Agents that Inhibit the Decapping Scavenger Enzyme;204
9.4.3.2.4;Natural Polyphenols;205
9.4.3.2.5;Other Chemical Agents;205
9.5;5 Target Product Profile for an SMA Therapeutic;206
9.6;6 Conclusions;206
9.7;References;207
10;Index;210