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

Neurobiology and Molecular Pharmacology, Centre de Psychiatrie et Neurosciences, UMR-894 INSERM/Université Paris Descartes, Paris, France.
The Journal of clinical investigation (Impact Factor: 13.77). 05/2011; 121(5):1846-57. DOI: 10.1172/JCI43992
Source: PubMed

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.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nociceptors and neurons in the central nervous system (CNS) that receive nociceptive input show remarkable plasticity in response to injury. This plasticity is thought to underlie the development of chronic pain states. Hence, further understanding of the molecular mechanisms driving and maintaining this plasticity has the potential to lead to novel therapeutic approaches for the treatment of chronic pain states. An important concept in pain plasticity is the presence and persistence of "hyperalgesic priming." This priming arises from an initial injury and results in a remarkable susceptibility to normally subthreshold noxious inputs causing a prolonged pain state in primed animals. Here we describe our current understanding of how this priming is manifested through changes in signaling in the primary nociceptor as well as through memory like alterations at CNS synapses. Moreover, we discuss how commonly utilized analgesics, such as opioids, enhance priming therefore potentially contributing to the development of persistent pain states. Finally we highlight where these priming models draw parallels to common human chronic pain conditions. Collectively, these advances in our understanding of pain plasticity reveal a variety of targets for therapeutic intervention with the potential to reverse rather than palliate chronic pain states.
    Handbook of experimental pharmacology 01/2015; 227:15-37. DOI:10.1007/978-3-662-46450-2_2
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Author Summary Visceral leishmaniasis (VL), a globally important parasitic disease responsible for over 40,000 deaths p.a., results in pronounced changes in splenic organisation associated with impaired immune function and persistent parasite infection. We have previously shown that receptor tyrosine kinase (RTKi) inhibitors can restore splenic architecture and improve immunocompetence, and that mononuclear phagocytes (MPs) are involved in this process. Here, we provide evidence that neurotrophin receptor Ntrk2 (also known as TrkB) plays a role in the pathologic remodeling of the spleen that accompanies experimental Leishmania donovani-infection. We show that following infection of mice with L.donovani, Ntrk2 is expressed on splenic endothelial cells that are closely associated with F4/80hiCD11bloCD11c+ macrophages expressing Ntrk2 ligands. Administration of the Ntrk2 antagonist ANA-12 to infected mice significantly inhibited compartment-specific vascular remodeling of the spleen. This study expands our understanding of the pathogenesis of experimental VL and also demonstrates the potential of Ntrk2/Bdnf as targets for treatment of infection-induced vascular remodeling.
    PLoS Pathogens 02/2015; 11(2):e1004681. DOI:10.1371/journal.ppat.1004681 · 8.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The monoamine hypothesis has been the prevailing hypothesis of depression over the last several decades. It states that depression is associated with reduced monoamine function. Hence efforts to increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters has been a central theme in depression research since the 1960s. The selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are currently first line treatment options for major depressive disorder (MDD). One of the recent trends in antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic receptors and additional transporters (e.g. with multimodal drugs and triple re-uptake inhibitors) or by adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses of depression have been brought forward in pre-clinical and clinical research based on biological hallmarks of the disease and efficacy of pharmacological interventions. A central strategy has been to target glutamate receptors (for example, with intravenous infusions of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine). Other strategies have been based on modulation of cholinergic and γ-aminobutyric acid (GABA)ergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal(HPA)-axis, the reward system and neuroinflammation. Here we review the pharmacological profiles of compounds that derived from these strategies and have been recently tested in clinical trials with published results. In addition, we discuss putative treatments for depression that are being investigated at the preclinical level and outline future directions for antidepressant research. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 03/2015; 167. DOI:10.1016/j.bcp.2015.03.011 · 4.65 Impact Factor

Full-text (2 Sources)

Available from
May 28, 2014