Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice.
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| Abstract |
In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB receptor has proven to be difficult. By using a peptidomimetic approach, we developed a highly potent and selective TrkB inhibitor, cyclotraxin-B, capable of altering TrkB-dependent molecular and physiological processes such as synaptic plasticity, neuronal differentiation and BDNF-induced neurotoxicity. Cyclotraxin-B allosterically alters the conformation of TrkB, which leads to the inhibition of both BDNF-dependent and -independent (basal) activities. Finally, systemic administration of cyclotraxin-B to mice results in TrkB inhibition in the brain with specific anxiolytic-like behavioral effects and no antidepressant-like activity. This study demonstrates that cyclotraxin-B might not only be a powerful tool to investigate the role of BDNF and TrkB in physiology and pathology, but also represents a lead compound for the development of new therapeutic strategies to treat brain disorders.
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| Authors | Maxime Cazorla, Anne Jouvenceau, Christiane Rose, Jean-Philippe Guilloux, Catherine Pilon, Alex Dranovsky, Joël Prémont |
| Journal | PloS one (PLoS One) Vol. 5 Issue 3 Pg. e9777 (Mar 19 2010) ISSN: 1932-6203 [Electronic] United States |
| PMID | 20333308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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