BEHAVIORAL AND MOLECULAR BASES OF THE ANTHELMINTIC ACTIVITY OF ESSENTIAL OILS EXPLORED IN THE NEMATODE CAENORHABDITIS ELEGANS

HERNANDO, G.; TURANI, O.; BOUZAT, C.

Buenos Aires

Congreso; Reunión Conjunta SAIC. SAI. AAFE. NANOMED-AR; 2021

SAIC. SAI. AAFE. NANOMED-AR

Control of helminth infections in both human and veterinary medicine currently relies mainly on chemotherapy, but acquisition ofresistance is an increasing problem that leads to the urgent needof discovery of novel drugs. C. elegans has demonstrated to be amodel system for the discovery of new anthelmintics and for characterizing their mechanisms of action and resistance. Essential oils(EOs) are natural products produced by aromatic plants. We perform paralysis assays of wild-type and mutant C. elegans strain toidentify EOs with potential anthelmintic activities, reveal the activecomponents, their target sites, and mechanisms of action. We foundthat EOs belonging to different orders produce rapid paralysis ofC. elegans with EC50 values between 0.02-2 % EOs. All EOs tested also inhibited egg hatching, a property related to anthelmintic ability. Thus, EOs mediate both rapid and long-term anthelminticeffects. We examined anthelmintic properties of terpenoids and phenylpropenes and determined that all compounds tested produce both paralysis and egg-hatching inhibition. By testing mutant worms, we identified the muscle L-AChR and GABA receptors as EOs andtrans-cinnamaldehyde (TC, phenylpropene) targets. Thus, by modulating two receptors with key roles in worm motility, these EOs emerge as novel sources of anthelmintic compounds. To unequivocally confirm that these receptors are targets of TC and to describethe mechanism by which they affect these receptors, we performed whole-cell and single-channel recordings from C. elegans muscle cells. Electrophysiological recordings at the single-channel level revealed that TC reduces L-AChR channel activity without affecting channel properties. The results are compatible with the action of these drugs as allosteric inhibitors. It is hoped that this work can update the recent progress on natural nematicide discoveries and provide new ideas for the design and mechanism of action studies of anthelmintics