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 cAMP;83 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 Ro