Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice
Maxime Cazorla, … , Christoph Kellendonk, Didier Rognan
Maxime Cazorla, … , Christoph Kellendonk, Didier Rognan
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):1846-1857. https://doi.org/10.1172/JCI43992.
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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 6

Injection of ANA-12 i.p. inhibits TrkB receptors in the brain.

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Injection of ANA-12 i.p. inhibits TrkB receptors in the brain. (A) ANA-1...
(A) ANA-12 stability in mouse serum. ANA-12 was incubated in serum of mice for 15, 30, 45, and 60 minutes at 37°C. Data represent mean ± SEM of 2 experiments. (B) ANA-12 bioavailability in mouse brain, 30 minutes, 1, 2, 4, and 6 hours after a single i.p. injection. Data represent mean ± SEM of 3 animals/group. (C) Pharmacokinetics of TrkB inhibition in the brain following i.p. injection of saline or ANA-12 (0.5 mg/kg) into adult mice. The level of phospho- and total TrkB in the whole brain of saline-treated and ANA-12–treated mice was detected using KIRA-ELISA assays 2 and 4 hours after injection. Values are expressed as a percentage of the signal obtained for saline-treated animals for the 2 time points (data presented for the saline-treated group are those obtained at 2 hours but were similar at 4 hours). Data represent mean ± SEM of 8 animals/group assessed in 2 different assays. ***P < 0.0001 compared with saline. (D) Pharmacokinetics of TrkB inhibition in different brain regions. Data represent mean ± SEM of 8 animals/group assessed in 2 different assays. Two-way ANOVA analyses of the data indicated a significant effect of treatment over time (P < 0.0001) and between structures (P < 0.0001). Post-hoc analysis showed significant effect in (a) striatum (P < 0.001) and cortex (P < 0.01) at 2 hours and in (b) all structures (P < 0.001) at 4 hours, compared with saline. At 2 hours (c), significant differences existed for striatum compared with cortex (P < 0.01) and hippocampus (P < 0.001), while at 4 hours (d), differences were significant between striatum and cortex (P < 0.01) and hippocampus (P < 0.05). For better clarity, the graph is magnified.