Activity of novel nicotinic anthelmintics in cut preparations of Caenorhabditis elegans Elizabeth Ruiz-Lancheros, Charles Viau, Tita N. Walter, Abdel Francis, Timothy G. Geary ⇑ Institute of Parasitology, McGill University, Macdonald Campus, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, Canada H9X 3V9 article info Article history: Received 13 September 2010 Received in revised form 23 November 2010 Accepted 25 November 2010 Available online 30 December 2010 Keywords: Anthelmintic Caenorhabditis elegans Cholinergic Monepantel Derquantel Levamisole Pyrantel abstract The free-living nematode Caenorhabditis elegans is a useful model for studying the pharmacology of anthelmintics. Currently approved anthelmintics have various mechanisms of action, including activity at nematode nicotinic acetylcholine receptors (nAChRs). Classical anthelmintic agonists of these recep- tors (nicotine, levamisole, pyrantel and bephenium) caused intact specimens of C. elegans to undergo con- tracted paralysis. The nAChR antagonist mecamylamine paralysed intact worms and blocked the actions of the agonists. The time to onset of effects of these drugs was enhanced when worms bisected between the mid- and anterior-portions were tested. The novel anthelmintic nAChR antagonist derquantel (2-des- oxoparaherquamide, 2-DOPH) was weakly active in intact specimens of C. elegans at concentrations of 50 lM over several days. No antagonism of the nAChR agonists was observed with this drug in intact worms. However, derquantel had direct and marked effects on motility in cut worms and blocked the effects of nAChR agonists in this preparation. A representative of the new amino-acetonitrile derivative (AAD) class of nAChR agonists was not antagonised by derquantel in cut C. elegans, suggesting that these two anthelmintics may not demonstrate unfavourable drug–drug interactions at the receptor level if used to treat livestock infected with parasitic nematodes. The permeability properties of the C. elegans cuticle may be more restrictive than those of adult parasites, calling into question primary anthelmintic screen- ing strategies that rely on this model organism. Ó 2011 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. 1. Introduction Several classes of anthelmintics are in use in veterinary and hu- man medicine for control of nematodiases (see Lacey, 1988; Martin et al., 1997; Holden-Dye and Walker, 2007 for a review), including the c-aminobutyric acid (GABA) agonist piperazine, inhibitors of tubulin polymerisation in the benzimidazole class, macrocyclic lac- tones, which open glutamate-gated Cl  channels, emodepside, a cyclodepsipeptide thought to open a potassium channel, diethyl- carbamazine, nitazoxanide, neither with a known mechanism of action, and agonists of nicotinic acetylcholine receptors (nAChRs) including pyrantel, levamisole and monepantel, a new drug in the amino-acetonitrile derivatives (AAD) class (Kaminsky et al., 2008). As with all chemotherapeutic agents, resistance to anthelmintics is a continuing concern (Gilleard and Beech, 2007). Derquantel (2-desoxoparaherquamide; 2-DOPH), a novel nAChR antagonist (Lee et al., 2002), is effective against nematodes which are resistant to other anthelmintics (Zinser et al., 2002). This compound is of interest compared with its parent compound, paraherquamide, in part because of its apparently lower toxicity in some mammalian species (Lee et al., 2002). Much can be learnt about anthelmintics in experiments using the free-living nematode Caenorhabditis elegans (Holden-Dye and Walker, 2007). This worm can be easily maintained in culture in the laboratory, especially compared with parasitic worms, which have complex life-cycles. It also has a sequenced genome and an impres- sive molecular toolkit for functional genomics experiments, and ge- netic screens can be easily carried out in it to decipher mechanisms of action (Holden-Dye and Walker, 2007; Kaminsky et al., 2008). However, it is not a perfect model for parasitic species (Geary and Thompson, 2001; Holden-Dye and Walker, 2007). Only about 70– 80% of genes in parasitic nematodes have obvious homologues in C. elegans (Geary and Thompson, 2001; Ghedin et al., 2007) and their intermediary metabolisms differ in some respects (Geary and Thompson, 2001). C. elegans lives in the soil and is more adapted to deal with stresses and xenobiotics common to soil environments than are adult stages of parasitic nematodes, which are adapted for existence in different compartments within a host and are the pri- mary targets for anthelmintic chemotherapy (Geary and Thompson, 2001). It can be argued that C. elegans is better equipped to deal with xenobiotic insults found in its environment (potential drugs) than are adult stages of parasitic species in this phylum; free-living larval stages of trichostrongylid nematodes, which also exist in external 0020-7519/$36.00 Ó 2011 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijpara.2010.11.009 ⇑ Corresponding author. Tel.: +1 514 398 7722; fax: +1 514 398 7857. E-mail address: timothy.g.geary@mcgill.ca (T.G. Geary). International Journal for Parasitology 41 (2011) 455–461 Contents lists available at ScienceDirect International Journal for Parasitology journal homepage: www.elsevier.com/locate/ijpara