PUBLICATION
Multidimensional chemobehavior analysis of flavonoids and neuroactive compounds in zebrafish
- Authors
- Bugel, S.M., Tanguay, R.L.
- ID
- ZDB-PUB-180303-12
- Date
- 2018
- Source
- Toxicology and applied pharmacology 344: 23-34 (Journal)
- Registered Authors
- Tanguay, Robyn L.
- Keywords
- Behavior, Flavonoids, GABA receptor, Locomotion, Neurotoxicity, Zebrafish
- MeSH Terms
-
- Animals
- Dose-Response Relationship, Drug
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/physiology
- Flavonoids/chemistry*
- Flavonoids/pharmacology*
- GABA Modulators/chemistry*
- GABA Modulators/pharmacology*
- Locomotion/drug effects
- Locomotion/physiology*
- Neurotransmitter Agents/chemistry
- Neurotransmitter Agents/pharmacology
- Receptors, GABA-A/physiology
- Zebrafish
- PubMed
- 29499247 Full text @ Tox. App. Pharmacol.
- CTD
- 29499247
Citation
Bugel, S.M., Tanguay, R.L. (2018) Multidimensional chemobehavior analysis of flavonoids and neuroactive compounds in zebrafish. Toxicology and applied pharmacology. 344:23-34.
Abstract
The comparative analysis of complex behavioral phenotypes is valuable as a reductionist tool for both drug discovery and defining chemical bioactivity. Flavonoids are a diverse class of chemicals that elicit robust neuroactive and hormonal actions, though bioactivity information is limited for many, particularly for neurobehavioral endpoints. Here, we used a zebrafish larval chemomotor response (LCR) bioassay to comparatively evaluate a suite of 24 flavonoids, and in addition a panel of 30 model neuroactive compounds representing diverse modes of action (e.g. caffeine, chlorpyrifos, methamphetamine, nicotine, picrotoxin). Naïve larval zebrafish were exposed to concentration ranges of each compound at 120 hour post-fertilization (hpf) and locomotor activity measured for 5 h. The model neuroactive compounds were largely behaviorally bioactive (20 of 30) with most effects phenotypic of their known modes of action. Flavonoids rapidly and broadly elicited hyperactive locomotor effects (22 of 24). Multidimensional analyses compared responses over time and identified three distinct bioactive groups of flavonoids based on efficacy and potency. Using GABAergics to modulate hyperactive responses, two flavonoids, (S)-equol and kaempferol were tested for GABAA receptor antagonism, as well as a known GABAA receptor antagonist, picrotoxin. Pharmacological intervention with positive allosteric modulators of the GABAA receptor, alfaxalone and chlormethiazole, ameliorated the hyperactive response to picrotoxin, but not for (S)-equol or kaempferol. Taken together, these studies demonstrate that flavonoids are differentially bioactive and that the chemobehavioral effects likely do not involve a GABAA receptor mediated mode of action. Overall, the integrative zebrafish platform provides a useful framework for comparatively evaluating high-content chemobehavioral data for sets of structurally- and mechanistically-related flavonoids and neuroactive compounds.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping