Toxicity of Uliginosin B in Caenorhabditis elegans Involves P-Glycoprotein and Dopaminergic System

Uliginosin B, a dimeric acylphloroglucinol that occurs in several Hypericum species native to South America, has antidepressant-like effects in rodent models and inhibits monoamines uptake, especially dopamine, which makes this phloroglucinol a promising candidate to develop new antidepressant drugs. However, toxicity studies on this compound are still scarce. In this sense, the objective of current study was to evaluate uliginosin B toxicity using Caenorhabditis elegans as an alternative model to mammals. The interaction with P-glycoprotein and with the dopaminergic system was evaluated using NL131 (pgp-3(pk18) X) and BY200 (dat-1p::green fluorescent protein;rol-6) strains, respectively. Uliginosin B concentrations ranged from 1 to 20 µM. The value of LC₅₀ determined in the N2 strain (wild) was 14 µM. However, uliginosin B did not impair body development, production of reactive oxygen species, and reproduction in surviving worms. These results indicate no reproductive toxicity and suggest that adaptive resistance mechanisms to acute toxic effects of uliginosin B have taken place. In addition, uliginosin B did not affect NL 131 survival, indicating that P-glycoprotein is relevant for its toxicity. In swimming-induced paralysis assay, worms (BY200) treated with uliginosin B at 10 and 20 µM plus dopamine (50 mM) took longer to decelerate. In addition, uliginosin B (20 µM) caused morphological changes in GFP-tagged dopaminergic neurons. In conclusion, uliginosin B displayed acute toxicity against C. elegans wild type, which seems to be subject to adaptive mechanisms and dependent on glycoprotein P functioning. The dopaminergic system also appears to be a toxicity target of this compound.