TitleMultidimensional chemobehavior analysis of flavonoids and neuroactive compounds in zebrafish.
Publication TypeJournal Article
Year of Publication2018
AuthorsBugel, SM, Tanguay, RL
JournalToxicol Appl Pharmacol
Date Published2018 04 01
KeywordsAnimals, Dose-Response Relationship, Drug, Embryo, Nonmammalian, Flavonoids, GABA Modulators, Locomotion, Neurotransmitter Agents, Receptors, GABA-A, Zebrafish

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 GABA receptor antagonism, as well as a known GABA receptor antagonist, picrotoxin. Pharmacological intervention with positive allosteric modulators of the GABA 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 GABA 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.

Alternate JournalToxicol. Appl. Pharmacol.
PubMed ID29499247
PubMed Central IDPMC5912343
Grant ListK99 ES025280 / ES / NIEHS NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States