Year: 2016
Type: dissertation
Abstract: Brain-derived neurotrophic factor (BDNF) and its high affinity receptor tyrosine kinase receptor B (TrkB) are involved in maintaining neuronal survival, differentiation, and synaptic plasticity.In our previous study, in silico screening to identify compounds targeting the BDNF binding domain of TrkB led to a hypothesis that the candidate compounds activate TrkB signaling.To test this hypothesis in the present study, we first examined the selected compounds for their proliferative effects in TrkB-expressing SH-SY5Y cells.The two positive compounds, 48 and 56, were then assessed for their ability to induce TrkB phosphorylation in vitro and in vivo.The elevated phosphorylation of TrkB by the compounds was blocked by the Trk inhibitor, K252a.Because dysfunction of BDNF-TrkB signaling is associated with the pathogenesis of depression, we conducted a forced swim test to confirm the efficacy of the compounds in a mouse model of depression.We found that compound 48 significantly reduced mouse immobility time compared with that following a vehicle injection, suggesting an antidepressant-like effect of the 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 agent.
Author: FUKUDA, Mayu
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Identification of novel candidate chemical compounds targeting TrkB to induce apoptosis in neuroblastoma, Generation of the MYCN/NCYM mouse model and the drug discovery for human neuroblastoma, Molecular mechanism by which NLRR1, a therapeutic target in neuroblastoma, selectively enhances growth signals, G8641311604
OpenAlex ID: W7144864147