title: Effects of novel small compounds targeting TrkB on neuronal cell survival and depression-like behavior.
abstract: 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.
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan; Department of Molecular Biology and Oncology, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-8670, Japan. Electronic address: mfukuda@chiba-cc.jp.
authors.forename: Mayu
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan; Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan. Electronic address: atakatori@chiba-cc.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takatori
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan; Division of Cancer Prevention and Epidemiology, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. Electronic address: ynakamur@chiba-cc.jp.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. Electronic address: a.suganami@restaff.chiba-u.jp.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suganami
authors.affiliation: Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: hoshino@chiba-u.jp.
authors.forename: Tyuji
authors.initials: T
authors.lastname: Hoshino
authors.affiliation: Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. Electronic address: yutaka_tamura@faculty.chiba-u.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Saga-ken Medical Center Koseikan, Saga 840-8571, Japan. Electronic address: nakagawara-a@koseikan.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020813:Receptor, trkB / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D020813:Receptor, trkB
keywords: Anti-depressant; BDNF; Forced swim test; TrkB