PUBLICATION
A novel orexin antagonist from a natural plant was discovered using zebrafish behavioural analysis
- Authors
- Yamanaka, M., Iwata, H., Masuda, K., Araki, M., Okuno, Y., Okamura, M., Koiwa, J., Tanaka, T.
- ID
- ZDB-PUB-200521-11
- Date
- 2020
- Source
- European review for medical and pharmacological sciences 24: 5127-5139 (Journal)
- Registered Authors
- Tanaka, Toshio
- Keywords
- none
- Datasets
- GEO:GSE129812
- MeSH Terms
-
- Animals
- Azepines/chemistry
- Azepines/pharmacology*
- Behavior, Animal/drug effects*
- Biological Products/chemistry
- Biological Products/pharmacology*
- HEK293 Cells
- Humans
- Molecular Docking Simulation
- Orexin Receptor Antagonists/chemistry
- Orexin Receptor Antagonists/pharmacology*
- Orexin Receptors/metabolism
- Plants/chemistry*
- Triazoles/chemistry
- Triazoles/pharmacology*
- Zebrafish*
- PubMed
- 32432777 Full text @ Eur Rev Med Pharmacol Sci
Citation
Yamanaka, M., Iwata, H., Masuda, K., Araki, M., Okuno, Y., Okamura, M., Koiwa, J., Tanaka, T. (2020) A novel orexin antagonist from a natural plant was discovered using zebrafish behavioural analysis. European review for medical and pharmacological sciences. 24:5127-5139.
Abstract
Objective Phenotypic screening is one of the most practical approaches to the identification of mediators of behaviour, since it is difficult to model brain function in vitro, at a cellular level. We used a zebrafish (Danio rerio) behavioural assay to discover novel, natural, neuroactive compounds.
Materials and methods A zebrafish behavioural assay was performed for seven natural compounds, obtained from plants. The behavioural profiles were compared to those of known psychoactive drugs. We characterised a natural compound exhibiting a behaviour profile similar to that of suvorexant, using in silico, in vitro and microarray expression analysis.
Results The behavioural analysis performed in this study classified central nervous system drugs according to their mechanism. Zebrafish treated with a natural compound, 8b-(4'-Hydroxytigloyloxy) costunolide (8b), showed behaviour profiles similar to those of zebrafish treated with suvorexant, a known orexin antagonist. This behavioural assay was validated using in silico and in vitro assays, which revealed that the new compound was a dual orexin receptor antagonist. In addition, transcriptome analysis suggested that 8b might regulate the nuclear factor-κB (NF-κB) related pathway.
Conclusions We conclude that zebrafish phenotypic screening, combined with in silico assays and gene expression profiling, is a useful strategy to discover and characterize novel therapeutic compounds, including natural products.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping