Details

Autor(en) / Beteiligte

• Cazorla, Maxime
• Jouvenceau, Anne
• Rose, Christiane
• Guilloux, Jean-Philippe
• Pilon, Catherine
• Dranovsky, Alex
• Prémont, Joël
• Kato, Tadafumi

Titel

Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice

Ist Teil von

• PloS one, 2010-03, Vol.5 (3), p.e9777

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.