title: Interactions of anthelmintic drugs in Caenorhabditis elegans neuro-muscular ion channel mutants.
abstract: Due to the increasing development of anthelmintic resistance in nematodes worldwide, it is important to search for anthelmintic compounds with new modes of action and also to investigate the possibility to combine compounds with possible synergistic effects. There might also be the chance to take advantage of the fact that nematode populations which have developed resistance against one anthelmintic class might respond hypersusceptibly to another drug class. The aim of this study was to investigate responses of Caenorhabditis elegans populations with mutations in neuro-muscular ion channels to different anthelmintic classes. Furthermore, potential synergistic effects between two anthelmintic compounds from different classes, i.e. emodepside and tribendimidine, were studied. Although there was neither a synergistic nor an antagonistic effect between emodepside and tribendimidine, other types of interactions could be identified. The C. elegans GABAA-receptor (GABAA-R) unc-49 mutants, showing decreased emodepside susceptibility, were more susceptible to tribendimidine than wild-type C. elegans. In contrast, the reverse phenomenon - hypersusceptibility to emodepside in tribendimidine resistant acetylcholine-receptor (AChR) loss of function mutants - was not observed. Moreover, the slo-1 mutant strain (completely emodepside resistant) also showed hypersusceptibility to piperazine. Interestingly, neither the GABAA-R unc-49 mutants nor the AChR mutants showed decreased susceptibility against piperazine, although there were some studies that indicated an involvement of GABAA-R or AChR in the piperazine mode of action. In conclusion, the present study provides evidence suggesting that interactions between commercially available anthelmintic drugs with different modes of action might be a relatively common phenomenon but this has to be carefully worked out for each anthelmintic and each anthelmintic drug combination. Moreover, results obtained in C. elegans will have to be confirmed using parasitic nematodes in the future.
authors.affiliation: Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Miltsch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krücken
authors.forename: Janina
authors.initials: J
authors.lastname: Demeler
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ramünke
authors.forename: Achim
authors.initials: A
authors.lastname: Harder
authors.forename: Georg
authors.initials: G
authors.lastname: von Samson-Himmelstjerna
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D047630:Depsipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D005838:Genotype; D015801:Helminth Proteins / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010655:Phenylenediamines / Q000494:pharmacology; D000077489:Piperazine; D010879:Piperazines / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism
chemical_list: D000871:Anthelmintics; D047630:Depsipeptides; D015801:Helminth Proteins; D007473:Ion Channels; D010655:Phenylenediamines; D010879:Piperazines; D011950:Receptors, Cholinergic; C056017:tribendimidine; D000077489:Piperazine; C468987:emodepside