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Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm

Authors :
Sylvia Josephy-Hernandez
Sean Jmaeff
Iulia Pirvulescu
Tahar Aboulkassim
H. Uri Saragovi
Source :
Neurobiology of Disease, Vol 97, Iss , Pp 139-155 (2017)
Publication Year :
2017
Publisher :
Elsevier, 2017.

Abstract

Neurodegenerative disorders are prevalent, complex and devastating conditions, with very limited treatment options currently available. While they manifest in many forms, there are commonalities that link them together. In this review, we will focus on neurotrophins – a family of related factors involved in neuronal development and maintenance. Neurodegenerative diseases often present with a neurotrophin imbalance, in which there may be decreases in trophic signaling through Trk receptors for example, and/or increases in pro-apoptotic activity through p75. Clinical trials with neurotrophins have continuously failed due to their poor pharmacological properties as well as the unavoidable activation of p75. Thus, there is a need for drugs without such setbacks. Small molecule neurotrophin mimetics are favorable options since they can selectively activate Trks or inactivate p75. In this review, we will initially present a brief outline of how these molecules are synthesized and their mechanisms of action; followed by an update in the current state of neurotrophins and small molecules in major neurodegenerative diseases. Although there has been significant progress in the development of potential therapeutics, more studies are needed to establish clear mechanisms of action and target specificity in order to transition from animal models to the assessment of safety and use in humans.

Details

Language :
English
ISSN :
1095953X
Volume :
97
Issue :
139-155
Database :
Directory of Open Access Journals
Journal :
Neurobiology of Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.b50bcef604e546adbdf4048778c5578f
Document Type :
article
Full Text :
https://doi.org/10.1016/j.nbd.2016.08.004