Inhibition of Caenorhabditis elegans neuromuscular activity by terpenoids: evaluation at the behavioral and molecular levels

HERNANDO GUILLERMINA; TURANI ORNELLA; BOUZAT CECILIA

MONTEVIDEO

Workshop; Expanding C. elegans research: First Latin American Worm Meeting; 2017

Institut Pasteur

There is an urgent need to develop novel anthelmintic agents in view of the increasing threat to live-stock and humans from anthelmintic-resistant strains of parasites. Medicinal plants provide an alternative source of potential anthelmintic compounds. The muscle levamisole-sensitive acetylcholine receptor (L-AChR) and the GABA-A receptor (UNC-49R) are involved in Caenorhabditis elegans muscle contraction and are targets of widely used anthelmintic drugs. By using plant extracts, we identified three terpenoids -thymol, carvacrol and eugenol- that have the capability to paralyze C. elegans. Behavioral assays in C. elegans strains lacking Cys-loop receptors revealed that L-AChR and GABA-A receptors are involved in the terpenoid-induced paralysis. By using a primary culture of C. elegans L1 muscle cells we explored their actions at the macroscopic current and single-channel levels. Thymol is not capable of eliciting macroscopic currents but it significantly inhibits ACh- and GABA-elicited responses. Single-channel activity of L-AChRs elicited by ACh is affected by the presence of terpenoids. All compounds produce a dramatic reduction in the frequency of opening events activated by ACh without affecting the channel properties. The analysis suggests that inhibition of receptor activity by terpenoids is mediated by increased desensitization or slow open-channel blockade. Thus, by acting at the neuromuscular junction, these terpenoids are novel anthelmintic candidates. Moreover, we showed that thymol potentiates the paralyzing actions of established anthelmintic agents, indicating that it could be used in combination with these drugs as a strategy to reduce acquisition of resistance.