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2020/05/25

A novel orexin antagonist from a natural plant was discovered using zebrafish behavioural analysis

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.