Monoterpenes As Modulators Of Cys-Loop Receptors: Insights Into Anthelmintic Activity In Caenorhabditis Elegans

Abstract

Growing resistance to conventional anthelmintics, coupled with the limited development of new compounds, has intensified the search for alternative therapeutic strategies. Among these, combination therapy—incorporating commercial drugs, new agents, or natural products— emerges as a promising approach to broaden treatment efficacy. Monoterpenes from essential oils are particularly attractive due to their reported anthelmintic activity. Here, we evaluated the effects of geraniol and citronellol on Caenorhabditis elegans, both individually and in combination with commercial anthelmintics. C. elegans is a well-established model system for anthelmintic drug discovery. Combining bioactive phytochemicals with synthetic drugs has been proposed as a strategy to enhance nematode control in both human and veterinary medicine. Behavioral assays showed that both terpenes significantly inhibited pharyngeal pumping in wild-type worms. In glutamate-gated chloride channel (GluCl)-defi- cient mutants, inhibition was reduced, suggesting GluCl channels asrelevant targets. In contrast, ACR-23 (betaine-gated cation channel) and MOD-1 (serotonin-gated chloride channel) mutants did not differ from wild-type. Paralysis assays were performed by exposing syn- chronized adult’s worms to 0.600–0.750 mM geraniol or citronellol, respectively. Both compounds exhibited clear anthelmintic activity in a concentration-dependent manner. Combinations with anthelmint- ics were evaluated using the Chou–Talalay combination index. In addition, body length was measured and Cys-loop receptor mutant strains were employed to identify potential molecular targets. The results position Cys-loop receptors, particularly GluCl, as relevant molecular targets and highlight geraniol and citronellol as modula- tors of these channels, supporting their potential use in combined therapeutic strategies for helminth control in human and veterinary health