Multitarget compounds from essential oils as novel anthelmintic drugs

HERNANDO, G.S.; TURANI, O.; RODRÍGUEZ ARAUJO, N.; BOUZAT, C.B.

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Sociedad Argentina de Investigación Clinica, Sociedad Argentina de Inmunología y Sociedad Argentina de Fisiología

Essential oils (EOs) have a long history in traditional medicine all over the world. In this work we evaluated the anthelmintic potential of different EOs and their main constituents and deciphered the molecular bases of their activity. We use the nematode Caenorhabditis elegans as a model for anthelmintic drug discovery. We combined behavioral assays of wild-type and mutant worms with electrophysiological recordings from cultured cells to identify EOs with potential anthelmintic activity and to reveal the active components, their target sites, and mechanisms of action. We found that six different EOs produced rapid paralysis of worms with different potencies, showing EC50 values between 0.02-2%. All EOs also inhibited egg at similar concentrations than for adult stage, indicating that they can mediate both rapid and long-term anthelmintic effects. For the identification of EOs drug targets, we focused on ligand-gated ion channels (LGIC) involved in worm locomotion and behavior. By testing mutant worms, we identified the muscle GABA receptor and two nicotinic receptors, L-AChR and N-AChR, as targets of EOs and of a main component, trans-cinnamaldehyde (TC). Worms lacking glutamate-activated chloride channels (GLuClR) were partially resistant to TC whereas those lacking a serotonin-activated chloride channel (MOD-1) behaved as the wild-type. To confirm that the receptors are targets of TC, we performed whole-cell and/or single-channel recordings from C. elegans muscle cells and/or mammalian cells heterologously expressing worm receptors. We found that TC significantly reduced muscle L-AChR channel activity (⁓55% at 100 μM), inhibited GluClR currents elicited by glutamate, and did not affect MOD-1 function. The analysis indicated that TC acts as an allosteric inhibitor of several LGICs that are conserved in nematodes. By modulating receptors with key roles in worm motility, EOs emerge as sources of multitarget compounds with high potential for anthelmintic therapies.