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- Title
Tribendimidine: Mode of Action and nAChR Subtype Selectivity in Ascaris and Oesophagostomum.
- Authors
Robertson, Alan P.; Puttachary, Sreekanth; Buxton, Samuel K.; Martin, Richard J.
- Abstract
The cholinergic class of anthelmintic drugs is used for the control of parasitic nematodes. One of this class of drugs, tribendimidine (a symmetrical diamidine derivative, of amidantel), was developed in China for use in humans in the mid-1980s. It has a broader-spectrum anthelmintic action against soil-transmitted helminthiasis than other cholinergic anthelmintics, and is effective against hookworm, pinworms, roundworms, and Strongyloides and flatworm of humans. Although molecular studies on C. elegans suggest that tribendimidine is a cholinergic agonist that is selective for the same nematode muscle nAChR as levamisole, no direct electrophysiological observations in nematode parasites have been made to test this hypothesis. Also the hypothesis that levamisole and tribendimine act on the same receptor, does not explain why tribendimidine is effective against some nematode parasites when levamisole is not. Here we examine the effects of tribendimidine on the electrophysiology and contraction of Ascaris suum body muscle and show that tribendimidine produces depolarization antagonized by the nicotinic antagonist mecamylamine, and that tribendimidine is an agonist of muscle nAChRs of parasitic nematodes. Further pharmacological characterization of the nAChRs activated by tribendimidine in our Ascaris muscle contraction assay shows that tribendimidine is not selective for the same receptor subtypes as levamisole, and that tribendimidine is more selective for the B-subtype than the L-subtype of nAChR. In addition, larval migration inhibition assays with levamisole-resistant Oesophagostomum dentatum isolates show that tribendimidine is as active on a levamisole-resistant isolate as on a levamisole-sensitive isolate, suggesting that the selectivity for levamisole and tribendimidine is not the same. It is concluded that tribendimidine can activate a different population of nematode parasite nAChRs than levamisole, and is more like bephenium. The different nAChR subtype selectivity of tribendimidine may explain why the spectrum of action of tribendimidine is different to that of other cholinergic anthelmintics like levamisole. Author Summary: Nematode parasites are a plague on the human condition in many developing countries with limited health care and sanitation. The morbidity produced by these parasites limits human health, development and prosperity. Nematode parasites also adversely affect animal welfare and production. Vaccines are not effective, so anthelmintic drugs are necessary for prophylaxis and treatment. Most anthelmintics belong to one of three classes: the macrocyclic lactones (ivermectin, moxidectin); the nicotinic anthelmintics (levamisole, pyrantel, derquantel) or; the benzimidazoles (albendazole, mebendazole). With the limited number of drugs available, there is real concern about the development of resistance. Tribendimidine was developed in China in the mid-1980s as a broad spectrum anthelmintic against soil-transmitted nematodes. Its mode of action has been investigated molecularly in C. elegans and on expressed nAChRs but, its mode of action has not been investigated directly in parasitic nematodes. Here we describe its effects on muscle contraction and electrophysiology in the pig nematode parasite, A. suum, which is very similar or the same as the human parasite, A. lumbricoides. Here we show that tribendimidine is a B-subtype selective nicotinic anthelmintic agonist that activates muscle nAChRs that are pharmacologically different from other cholinergic anthelmintics. It is concluded that tribendimidine could be effective against nematode parasites resistant to another cholinergic anthelmintic.
- Subjects
CHINA; ASCARIS; HELMINTHS; ASCARIS suum; ANIMAL welfare; FISH parasites; NICOTINIC agonists; CAENORHABDITIS elegans
- Publication
PLoS Neglected Tropical Diseases, 2015, Vol 9, Issue 2, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0003495