The Help Fight Childhood Cancer project researchers have published a paper on serendipitous results they found from the drug candidate search run on World Community Grid. The project originally searched for candidate compounds that targeted specific proteins to help cure a childhood brain cancer called neuroblastoma. Some of the targeted proteins are also involved in several psychological disorders. They have found that some of the identified compounds show an antidepressant capability. Furthermore, additional research might lead to potential treatments for Huntington’s disease and Alzheimer’s disease. The paper was published in the journal Neurochemistry International.
Paper title: Effects of novel small compounds targeting TrkB on neuronal cell survival and depression-like behavior
Authors: Mayu Fukuda, Atsushi Takotori, Yohko Nakamura, Akiko Suganami, Tyuji Hoshino, Yutaka Tamura, Akira Nakagawara
Brain-derived neurotrophic factor (BDNF) and its high affinity receptor tyrosine kinase receptor B (TrkB) are involved in neuronal survival, maintenance, differentiation and synaptic plasticity. Deficiency of BDNF was reported to be associated with psychological disorders such as depression. Hence we examined proliferative effect of 11 candidate TrkB agonistic compounds in TrkB-expressing SH-SY5Y cells, via a hypothesis that some candidate compounds identified in our previous in silico screening for a small molecule targeting the BDNF binding domain of TrkB should activate TrkB signaling. In the present study, two promising compounds, 48 and 56, were identified and subsequently assessed for their ability to induce TrkB phosphorylation in vitro and in vivo. Likewise those seen in BDNF, the compounds mediated TrkB phosphorylation was blocked by the Trk inhibitor, K252a. Since BDNF-TrkB signaling deficiency is associated with the pathogenesis of depression and reactivation of this signaling by antidepressants is a cause of the pathogenic state recovery, the compounds were subjected to the assessment for forced swim test, which is a mouse model of depression. We found that compound 48 significantly reduced mouse immobility time compared with the control vehicle injection, suggesting the confirmation of hypothetical antidepressant-like efficacy of 48 compound in vivo. Thus, our present study demonstrated that compound 48, selected through in silico screening, is a novel activator of TrkB signaling and a potential antidepressant molecule.
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