Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice
Maxime Cazorla, Joël Prémont, Andre Mann, Nicolas Girard, Christoph Kellendonk, Didier Rognan
Maxime Cazorla, Joël Prémont, Andre Mann, Nicolas Girard, Christoph Kellendonk, Didier Rognan
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Research Article Neuroscience

Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

Abstract

The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of structure-based in silico screening and high-capacity functional assays in recombinant and neuronal cells, we identified a low–molecular weight TrkB ligand (ANA-12) that prevented activation of the receptor by BDNF with a high potency. ANA-12 showed direct and selective binding to TrkB and inhibited processes downstream of TrkB without altering TrkA and TrkC functions. KIRA-ELISA analysis demonstrated that systemic administration of ANA-12 to adult mice decreased TrkB activity in the brain without affecting neuronal survival. Mice administered ANA-12 demonstrated reduced anxiety- and depression-related behaviors on a variety of tests predictive of anxiolytic and antidepressant properties in humans. This study demonstrates that structure-based virtual screening strategy can be an efficient method for discovering potent TrkB-selective ligands that are active in vivo. We further propose that ANA-12 may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders.

Authors

Maxime Cazorla, Joël Prémont, Andre Mann, Nicolas Girard, Christoph Kellendonk, Didier Rognan

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Figure 7

ANA-12 demonstrates anxiolytic-like properties.

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ANA-12 demonstrates anxiolytic-like properties. (A) Exploratory behavior...
(A) Exploratory behavior in the elevated plus maze. The number of entries and the time spent in the different arms of the maze are presented. The increased ratio of entries and time in the open arms versus total observed for ANA-12–treated animals is representative of decreased anxiety. (B) Behavioral measures of saline-treated and ANA-12–treated mice in the novelty-suppressed feeding test. The latency to reach the illuminated center and to eat the food was dramatically decreased in animals that received ANA-12, while the home cage food consumption was not different between both groups. (C) Exploratory behavior in the novel open field of saline-treated and ANA-12–treated mice. Ambulatory distance was measured during 60 minutes and was not different between the 2 groups. Inset shows the total ambulatory distance acquired during the 60-minute session. The total distance covered during the first 10 minutes of the task is also shown. *P < 0.05; **P < 0.01; ***P < 0.005; §P < 0.001, compared with saline. Data are presented as mean ± SEM.