Multitarget compounds from essential oils as novel anthelmintic drugs

Abstract

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 re- veal the active components, their target sites, and mech- anisms of action. We found that six different EOs pro- duced rapid paralysis of worms with different potencies, showing EC50 values between 0.02-2%. All EOs also in- hibited 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 tar- gets of EOs and of a main component, trans-cinnamalde- hyde (TC). Worms lacking glutamate-activated chloride channels (GLuClR) were partially resistant to TC where- as 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), in- hibited 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