Effects of monepantel on nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum

Abstract

Zolvix ® is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel has been demonstrated to act on deg-3/des-2 containing nAChRs in several nematodes as a positive allosteric modulator. The drug produces hypercontraction of nematode muscle. We investigated the effects of monepantel on muscle strips isolated form adult Ascaris suum. The drug did not significantly increase baseline tension when applied on its own. Contractions induced by acetylcholine and several cholininomimetic anthelmintics where antagonized by monepantel. Further investigation revealed that the antagonism was non-competitive in nature. We also investigated the effect of monepantel on nAChRs from O. dentatum heterologously expressed in Xenopus laevis oocytes. We investigated the effects of monepantel on OD3, a levamisole preferring nAChR subtype, OD4, a pyrantel preferring subtype and ACR-16 a nicotine preferring subtype. For each subtype tested monepantel applied in isolation produced no measureable currents, nor did it produce currents in the presence of choline. When monepantel was continuously applied it reduced the amplitude of acetylcholine induced currents in a concentration dependent manner for the three nAChR subtypes tested. In all three cases monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 was particularly sensitive to monepantel inhibition. Our findings suggest that the mode of action of monepantel is more complex than previously described.