Development of Precision Small-Molecule Proneurotrophic Therapies for Neurodegenerative Diseases

Age-related neurodegenerative diseases, such as Alzheimer's disease, will represent one of the largest future burdens on worldwide healthcare systems due to the increasing proportion of elderly in our society. As deficiencies in neurotrophins are implicated in the pathogenesis of many age-relat...

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Bibliographic Details
Published in:	Vitamins and hormones Vol. 104; pp. 263 - 311
Main Authors:	Janssens, J, Lu, D, Ni, B, Chadwick, W, Siddiqui, S, Azmi, A, Etienne, H, Jushaj, A, van Gastel, J, Martin, B, Maudsley, S
Format:	Journal Article
Language:	English
Published:	United States 2017
Subjects:	Animals Central Nervous System - drug effects Central Nervous System - growth & development Central Nervous System - metabolism Cognitive Dysfunction - drug therapy Cognitive Dysfunction - metabolism Cognitive Dysfunction - prevention & control Dimerization Drug Design Drugs, Investigational - chemistry Drugs, Investigational - therapeutic use Humans Ligands Molecular Targeted Therapy Nerve Growth Factors - chemistry Nerve Growth Factors - metabolism Nerve Growth Factors - therapeutic use Neurodegenerative Diseases - drug therapy Neurodegenerative Diseases - metabolism Neuronal Plasticity - drug effects Neurons - drug effects Neurons - metabolism Neuroprotection - drug effects Neuroprotective Agents - chemistry Neuroprotective Agents - metabolism Neuroprotective Agents - therapeutic use Nootropic Agents - chemistry Nootropic Agents - metabolism Nootropic Agents - therapeutic use Protein Precursors - chemistry Protein Precursors - metabolism Protein Precursors - therapeutic use Receptors, Nerve Growth Factor - agonists Receptors, Nerve Growth Factor - metabolism Signal Transduction - drug effects Neurotrophin Tyrosine kinase Neurodegeneration Precision Receptor Aging Dementia
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Summary:	Age-related neurodegenerative diseases, such as Alzheimer's disease, will represent one of the largest future burdens on worldwide healthcare systems due to the increasing proportion of elderly in our society. As deficiencies in neurotrophins are implicated in the pathogenesis of many age-related neurodegenerative disorders, it is reasonable to consider that global neurotrophin resistance may also become a major healthcare threat. Central nervous system networks are effectively maintained through aging by neuroprotective and neuroplasticity signaling mechanisms which are predominantly controlled by neurotrophin receptor signaling. Neurotrophin receptors are single pass receptor tyrosine kinases that form dimeric structures upon ligand binding to initiate cellular signaling events that control many protective and plasticity-related pathways. Declining functionality of the neurotrophin ligand-receptor system is considered one of the hallmarks of neuropathological aging. Therefore, it is imperative to develop effective therapeutic strategies to contend with this significant issue. While the therapeutic applications of cognate ligands for neurotrophin receptors are limited, the development of nonpeptidergic, small-molecule ligands can overcome these limitations, and productively regulate this important receptor system with beneficial effects. Using our advanced knowledge of the high-dimensionality complexity of receptor systems, the future generation of precision medicines targeting these systems will be an attainable goal.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1
ISSN:	0083-6729
DOI:	10.1016/bs.vh.2016.10.006