Abstract
The anthelmintic treatment of nematode infections remains the pillar of worm control in both human and veterinary medicine. Since control is threatened by the appearance of drug resistant nematodes, there is a need to develop novel compounds, among which phytochemicals constitute potential anthelmintic agents. Caenorhabditis elegans has been pivotal in anthelmintic drug discovery and in revealing mechanisms of drug action and resistance. By using C. elegans, we here revealed the anthelmintic actions of three plant terpenoids -thymol, carvacrol and eugenol- at the behavioral level. Terpenoids produce a rapid paralysis of worms with a potency rank order carvacrol > thymol > eugenol. In addition to their paralyzing activity, they also inhibit egg hatching, which would, in turn, lead to a broader anthelmintic spectrum of activity. To identify drug targets, we performed an in vivo screening of selected strains carrying mutations in receptors involved in worm locomotion for determining resistance to the paralyzing effect of terpenoids. The assays revealed that two Cys-loop receptors with key roles in worm locomotion -Levamisole sensitive nicotinic receptor (L-AChR) and GABA(A) (UNC-49) receptor- are involved in the paralyzing effects of terpenoids. To decipher the mechanism by which terpenoids affect these receptors, we performed electrophysiological studies using a primary culture of C. elegans L1 muscle cells. Whole cell recordings from L1 cells demonstrated that terpenoids decrease macroscopic responses of L-AChR and UNC-49 receptor to their endogenous agonists, thus acting as inhibitors. Single-channel recordings from L-AChR revealed that terpenoids decrease the frequency of opening events, probably by acting as negative allosteric modulators. The fact that terpenoids act at different receptors may have important advantages regarding efficacy and development of resistance. Thus, our findings give support to the use of terpenoids as either an alternative or a complementary anthelmintic strategy to overcome the ever-increasing resistance of parasites to classical anthelmintic drugs.
Highlights
Parasitic nematodes cause extensive morbidity and mortality in humans and animals and have major economic impact worldwide due to considerable losses in livestock and food crops [1]
We found that three terpenoid compounds present in essential oil of plants–thymol, carvacrol and eugenol–produce rapid paralysis of C. elegans and inhibit egg hatching, mediating both rapid and long-term anthelmintic effects
By testing mutant worms that lack receptor proteins essential for locomotion we identified two different muscle receptors, nicotinic and GABA receptors, as terpenoid targets of the paralyzing effects
Summary
Parasitic nematodes cause extensive morbidity and mortality in humans and animals and have major economic impact worldwide due to considerable losses in livestock and food crops [1]. Humans themselves are host to different roundworm species, some of which are causative agents in core neglected tropical diseases, such as trichuriasis, ascariasis, hookworm disease, lymphatic filariasis, onchocerciasis, and dracunculiasis [2,3] These human diseases affect billions of people [4]. Gastrointestinal nematodes, such as Haemonchus contortus and Ascaris suum, are one of the main causes of losses in animal productivity worldwide. There is an urgent need for concerted efforts to develop novel anthelmintic agents
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