A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease

• Published in: PloS one 2011-12, Vol.6 (12), p.e27865
• Main Authors: Chen, Qi, Prior, Marguerite, Dargusch, Richard, Roberts, Amanda, Riek, Roland, Eichmann, Cédric, Chiruta, Chandramouli, Akaishi, Tatsuhiro, Abe, Kazuho, Maher, Pamela, Schubert, David
• Format: Article
• Language: English
• Subjects: Advertising executives; Age; Aging; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Anti-Alzheimer's disease agents; Behavior, Animal - drug effects; Biology; Brain research; Brain-Derived Neurotrophic Factor - metabolism; Cell culture; Chemistry; Cognition & reasoning; Cognition - drug effects; Cognitive ability; Curcumin - analogs & derivatives; Curcumin - chemistry; Curcumin - pharmacology; Disease Models, Animal; Drug discovery; Drug therapy; Genetic engineering; Heat-Shock Proteins - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Humans; Immunohistochemistry; Inflammation - pathology; Laboratories; Long-Term Potentiation - drug effects; Medicine; Memory; Memory - drug effects; Metabolism; Mice; Nerve Growth Factors - pharmacology; Neurobiology; Neurodegenerative diseases; Neurological diseases; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurosciences; Oxidants - metabolism; Oxidative stress; Oxidative Stress - drug effects; Pharmaceutical sciences; Phosphorylation - drug effects; Physiological aspects; Proteins; Pyrazoles - chemistry; Pyrazoles - pharmacology; R&D; Rats; Research & development; Risk factors; Rodents; Solubility - drug effects; Structure-Activity Relationship; Synapses - drug effects; Synapses - metabolism; Transgenic animals; Trends; Up-Regulation - drug effects; β-Amyloid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027865

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.