Neurodegeneration

D Bozyczko-Coyne and M Williams, Worldwide Discovery Research, Cephalon, Inc., West Chester, PA, USA

© 2007 Elsevier Ltd. All Rights Reserved.

6.08.1 Overview 194

6.08.2 Alzheimer's Disease 196

6.08.2.1 Disease State/Diagnosis 196

6.08.2.2 Disease Basis 197

6.08.2.2.1 The cholinergic hypothesis 198

6.08.2.2.2 The amyloid hypothesis 198

6.08.2.2.3 The tau hypothesis 198

6.08.2.2.4 The inflammatory cascade hypothesis 198

6.08.2.2.5 Genetic risk factors 198

6.08.2.3 Experimental Disease Models 199

6.08.2.3.1 Pharmacological and lesion models 199

6.08.2.3.2 Natural models 201

6.08.2.3.3 Genetic models 201

6.08.2.4 Clinical Trial Issues 201

6.08.2.5 Current Treatment 202

6.08.2.5.1 Cholinesterase inhibitors 202

6.08.2.5.2 N-Methyl-D-aspartate (NMDA) receptor antagonists 203

6.08.2.6 Unmet Medical Needs 203

6.08.2.7 New Research Areas 203

6.08.2.7.1 Muscarinic acetylcholine receptors (mAChRs) 204

6.08.2.7.2 Nicotinic acetylcholine receptors (nAChRs) 205

6.08.2.7.3 Histamine receptor antagonists 205

6.08.2.7.4 g-Amino-butyric acid receptor antagonists 206

6.08.2.7.5 5-Hydroxytryptamine (5HT)-receptor agonists 207

6.08.2.7.6 Thyrotropin-releasing hormone agonists 207

6.08.2.7.7 Hormone replacement therapy (HRT) - gonadatropin-releasing hormone (GnRH) agonists (estrogen) 207

6.08.2.7.8 Prolyl endopeptidase inhibitors 207

6.08.2.7.9 Secretase inhibitors 207

6.08.2.7.10 ß-Amyloid aggregation blockers 209

6.08.2.7.11 Tau kinase inhibitors 209

6.08.2.7.12 Anti-inflammatory compounds 211

6.08.2.7.13 Statins 211

6.08.2.7.14 Neuroprotectants 211

6.08.3 Parkinson's Disease 212

6.08.3.1 Disease State/Diagnosis 212

6.08.3.2 Disease Basis 212

6.08.3.3 Experimental Disease Models 212

6.08.3.3.1 Neurotoxin models 212

6.08.3.3.2 Genetic models 213

6.08.3.4 Clinical Trial Issues 213

6.08.3.5 Current Treatment 214

6.08.3.5.1 Dopamine replacement 215

6.08.3.5.2 Dopamine receptor agonists 215

6.08.3.5.3 Dopamine metabolism inhibitors 215

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