The Experts below are selected from a list of 40542 Experts worldwide ranked by ideXlab platform
D M Leathwick - One of the best experts on this subject based on the ideXlab platform.
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the role of combination Anthelmintic formulations in the sustainable control of sheep nematodes
Veterinary Parasitology, 2012Co-Authors: David Bartram, Ma Taylor, D M Leathwick, Thomas Geurden, Steven J MaederAbstract:Combinations of Anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (1) to enable the effective control of nematodes in the presence of single or multiple drug resistance, and (2) to slow the development of resistance to the component Anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow the development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the Anthelmintics in the combination. Combinations slow the development of a resistant parasite population by reducing the number of resistant genotypes which survive treatment, because multiple alleles conferring resistance to all the component Anthelmintic classes must be present in the same parasite for survival. Individuals carrying multiple resistance alleles are rarer than those carrying single resistance alleles. This enhanced efficacy leads to greater dilution of resistant genotypes by the unselected parasites in refugia, thus reducing the proportion of resistant parasites available to reproduce with other resistant adults that have survived treatment. Concerns over the use of Anthelmintic combinations include the potential to select for resistance to multiple Anthelmintic classes concurrently if there are insufficient parasites in refugia; the potential for shared mechanisms of resistance between chemical classes; and the pre-existing frequency of resistance alleles may be too high on some farms to warrant the introduction of certain combinations. In conclusion, Anthelmintic combinations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable Anthelmintic use.
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modelling the benefits of a new class of Anthelmintic in combination
Veterinary Parasitology, 2012Co-Authors: D M LeathwickAbstract:Since 2009 two new classes of Anthelmintics have been registered for use in sheep in New Zealand. This raises challenging questions about how such new actives should be used, not only to minimise the development of resistance to them, thereby ensuring their availability as effective treatments for as long as possible, but also to minimise the further development of resistance to the other Anthelmintic classes. One strategy which appears to offer considerable potential for slowing the development of resistance is the use of combinations of different Anthelmintic classes, although this approach remains contentious in some countries. The potential benefit of using Anthelmintics in combination is particularly relevant to two recently released Anthelmintic compounds because one, monepantel, is presently only available as a single active product while the other, derquantel, is only available in combination with abamectin. A simulation modelling approach was used to investigate the potential benefits of using Anthelmintics in combination. The rate at which resistance develops to a new 'active' when used alone was compared to an equivalent compound used in combination with a second compound from an alternative class (in this case, abamectin), when various levels of resistance occur to the second active. In addition, the potential of a new active to reduce further development of resistance to the second compound in the combination was evaluated. Finally, the use of combinations as compared to sequential or rotational use patterns, in the presence of side resistance between two actives was investigated. The modelling simulations suggest a significant advantage to both compounds when they are used in combination, especially if both initially have high efficacy. The development of resistance to the new active was delayed, although to a lesser extent, even when the efficacy of the second active in the combination was only 50%. Under a 'low-refugia' management environment resistance to all actives developed more rapidly, and the advantage of using actives in combination was reduced. When used in conjunction with other resistance management strategies, a combination containing a new active prevented further development of resistance to the older class. Using actives in combination was superior to using them individually either sequentially or in rotation, even in the presence of side-resistance between the two Anthelmintic classes.
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Anthelmintic resistance in nematode parasites of cattle a global issue
Trends in Parasitology, 2011Co-Authors: I A Sutherland, D M LeathwickAbstract:Acceptable performance of grazing cattle frequently depends on the availability of effective broad-spectrum Anthelmintics to remove, or prevent infection with, gastrointestinal nematodes. This control is increasingly threatened by populations of nematodes resistant to the most commonly used Anthelmintics. Although this appears to have developed more slowly than in nematodes infecting small ruminants, the number of reports in the literature over the past five years suggests a rapidly escalating problem. This review discusses this literature, several issues unique to cattle parasitism and Anthelmintics, and how previous research in small ruminants can improve the management of Anthelmintic resistance in cattle.
Steven J Maeder - One of the best experts on this subject based on the ideXlab platform.
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world association for the advancement of veterinary parasitology w a a v p guideline Anthelmintic combination products targeting nematode infections of ruminants and horses
Veterinary Parasitology, 2012Co-Authors: Timothy G. Geary, Peter Holdsworth, Steven J Maeder, W E Pomroy, Barry C. Hosking, P. J. Skuce, Georg Von Samsonhimmelstjerna, Jozef VercruysseAbstract:Increasing threats from Anthelmintic resistant nematode populations warrant and motivate a reappraisal of chemotherapeutic strategies for nematode control in ruminant livestock and horses. The objective of this paper is to present a guideline for the evaluation of products containing two or more constituent Anthelmintic actives in a single dosage form for the treatment of nematode infections in these animals. At present, regulatory policies on the approval of such products vary across jurisdictions, and this World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) guideline should enable the harmonization of the requirements. This guideline makes clear recommendations on the minimal standards needed, but stresses that registration dossiers for combination Anthelmintic products submitted for approval must conform to the standards and practices already established in existing guidelines for Anthelmintics.
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the role of combination Anthelmintic formulations in the sustainable control of sheep nematodes
Veterinary Parasitology, 2012Co-Authors: David Bartram, Ma Taylor, D M Leathwick, Thomas Geurden, Steven J MaederAbstract:Combinations of Anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (1) to enable the effective control of nematodes in the presence of single or multiple drug resistance, and (2) to slow the development of resistance to the component Anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow the development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the Anthelmintics in the combination. Combinations slow the development of a resistant parasite population by reducing the number of resistant genotypes which survive treatment, because multiple alleles conferring resistance to all the component Anthelmintic classes must be present in the same parasite for survival. Individuals carrying multiple resistance alleles are rarer than those carrying single resistance alleles. This enhanced efficacy leads to greater dilution of resistant genotypes by the unselected parasites in refugia, thus reducing the proportion of resistant parasites available to reproduce with other resistant adults that have survived treatment. Concerns over the use of Anthelmintic combinations include the potential to select for resistance to multiple Anthelmintic classes concurrently if there are insufficient parasites in refugia; the potential for shared mechanisms of resistance between chemical classes; and the pre-existing frequency of resistance alleles may be too high on some farms to warrant the introduction of certain combinations. In conclusion, Anthelmintic combinations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable Anthelmintic use.
J A Van Wyk - One of the best experts on this subject based on the ideXlab platform.
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The role of targeted selective treatments in the development of refugia-based approaches to the control of gastrointestinal nematodes of small ruminants
Veterinary Parasitology, 2009Co-Authors: F. Kenyon, G C Coles, J A Van Wyk, Jacques Cabaret, M. Várady, A.w. Greer, G. Cringoli, E. Papadopoulos, B. Berrag, E. ThomasAbstract:Anthelmintic resistance is recognised as a major problem affecting small ruminant production worldwide and now threatens the sustainability of many of these systems. One method that has been proposed to prolong the efficacy of our current Anthelmintics is the maintenance of a parasite population in refugia (unexposed to a drug) which will maintain the genes for susceptibility within the parasite population. Management strategies that employ refugia-based methods include targeted or strategically timed whole flock treatments, targeted selective treatments (TST), whereby only a proportion of the flock is treated at any one time, and the dilution of resistant with susceptible parasites. The ability to effectively target Anthelmintic use relies on the identification of those animals that will most benefit from treatment. This review explains the concept of refugia, describes the role of refugia-based approaches to the management of Anthelmintic resistance and reviews the markers that have been studied as indicators for TSTs as well as the implementation of refugia-based strategies. Recent results suggest that targeting Anthelmintic treatment on the basis of anaemia, milk production and liveweight gain may offer a means of reducing Anthelmintic usage whilst still maintaining animal performance.
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Anthelmintic resistance in south africa surveys indicate an extremely serious situation in sheep and goat farming
Onderstepoort Journal of Veterinary Research, 1999Co-Authors: M O Stenson, J S Van Der Merwe, R J Vorster, P G Viljoen, J A Van WykAbstract:VANWYK, J.A., STENSON, M.O , VAN DER MERWE J.S. , VORSTER, R.J. & VILJOEN, P.G. 1999. Anthelmintic resistance in South Africa: Surveys indicate an extremely serious situation in sheep farm ing. Onderstepoort Journal of Veterinary Research, 66:273-284 Surveys to determine the prevalence and degree of resistance of Haemonchus spp. of sheep and goats to the available Anthelmintics in South Africa indicate that small ruminant production is enter ing a crisis situation . Three surveys employing the faecal egg count reduction (FECR) test to determine resistance were conducted in some of the main sheep-producing areas in the summer rainfall region of South Africa , where H. contortus is the principal worm species in sheep. After analyzing the data recorded in the surveys by six different methods, including the RESO test at two different levels of confidence, the results obtained in the least stringent one (geometric mean reduction of the worm egg counts of drenched, vs untreated group of sheep) are reported in this paper, so that if any bias was obtained it would be in the favour of the Anthelmintic. In Mpumalanga and KwaZulu-Natal there was Anthelmintic resistance in Haemonchus spp. on all the 52 farms surveyed. Sixteen percent of the strains of H. contortus were < 60 % susceptible to three of the four Anthelmintics tested, and 8 % of the strains were < 40 % susceptible to all four of the Anthelmintics. FECR tests of sheep in six localities in the Lebowa district of Northern Province indi cated that even in previously disadvantaged communities where Anthelmintic treatment is less inten sive, Anthelmintic resistance is developing, and is possibly at the level at which the situation on com mercial sheep and goat farms in South Africa was 25 years ago. From the data it appears that the level of Anthelmintic resistance of H. contortus in South Africa is possibly the highest that has so far been recorded in the world and that strains of it are emerging that may soon not be controllable by treatment with any of the existing Anthelmintics. Farmers in the sum mer rainfall region , if not the whole country, must be alerted to the immediate need for testing the parasite burdens of their sheep for susceptibility to preparations in all four groups of Anthelmintic compounds currently available. Alternative methods of integrated worm control , including biological , must be sought and implemented with urgency, to reduce further selection for resistance and to in duce reversion of the re sistance that has already developed.
Jacques Cabaret - One of the best experts on this subject based on the ideXlab platform.
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Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine-and Derquantel-Sensitive nAChRs
PLoS Pathogens, 2014Co-Authors: Samuel Buxton, Alan P. Robertson, Jacques Cabaret, Melanie Abongwa, Elise Courtot, Cédric Neveu, Claude Charvet, Jacques Cortet, Nicolas Peineau, Richard J MartinAbstract:Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important classical Anthelmintics like levamisole and pyrantel, as well as novel Anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic Anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic Anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. Author Summary Parasitic nematode infections of humans and animals are world-wide. In humans, they cause disease and perpetuate a cycle of poverty. In animals, the parasites cause welfare problems and production loss. In developing countries, the debilitating effect of nematode parasites in school children limits their education, and in adults reduces productivity. These two factors, along with the production loss associated with nematode infections of animals that affects human nutrition, sustain poverty. Treatment and prophylaxis of these parasites requires the use of Anthelmintic drugs. Here, we employ the Xenopus oocyte expression system to investigate the diversity of Anthelmintic receptors in the parasitic nematode Oesophagostomum dentatum. We demonstrate effects of the novel' Anthelmintics tribendimidine and derquantel on these reconstituted receptors, revealing, for the first time, the subunits that make up a tribendimidine- and derquantel-sensitive receptor from a parasitic nematode. We show that the receptor structure and pharmacology can be plastic, and depends on subunit composition and stoichiometry. The factors that affect the diversity of the receptor may contribute to Anthelmintic resistance. Our results demonstrate the presence of acetylcholine receptor subtypes that may serve as Anthelmintic targets and suggest that pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms.
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The evaluation of Anthelmintic resistance: how good are we ?
2012Co-Authors: Jacques CabaretAbstract:The evaluation of Anthelmintic resistance is still based on faecal egg count reduction test (FECRT) since molecular mode of action remains unclear or unknown for most Anthelmintics. The evaluation based on FECRT is greatly depending on the level of infection, the intensity of resistance, the number o and the procedure of sampling. The mode of calculation of efficacy of Anthelmintics can be based on several statisticl procedures that may affect the evaluation of efficacy. There is a real need for establishing a guide for evaluating in practice resistance of nematodes to Anthelmintics.
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Contrasting views of animal healthcare providers on worm control practices for sheep and goats in an arid environment
Parasite, 2012Co-Authors: Hafiz Abubaker Saddiqi, Abdul Jabbar, W. Babar, M. Sarwar, Z. Iqbal, Jacques CabaretAbstract:A questionnaire survey was conducted to determine the worm control practices and Anthelmintic usage of 150 key respondents involved in sheep and goat production in the arid Thal area of Pakistan. The information was collected by visiting farms, and interviewing the key respondents which included veterinary officers (n = 15), veterinary assistants (n = 51), traditional practitioners (n = 24), and small and large scale sheep/goat farm herders and owners (n = 60). Among all interviewed animal healthcare providers, the veterinary officers had the highest level of awareness of parasitic infection and advocated the use of modern available Anthelmintics according to the predefined schedule. The farmers on the other hand, had the lowest level of knowledge about parasitic infections. They used modern Anthelmintics at low frequencies (every six months) following an unusual practice of diluting the medicine. Veterinary assistants had a medium level of awareness about the parasitic infections using Anthelmintic treatments when they deemed necessary rather than following a predefined treatment schedule. Traditional practitioners were also aware of parasitic infections and used traditional Anthelmintics or a combination of the traditional and modern Anthelmintics. The animal health providers had a different awareness and knowledge of parasitic infections which resulted in contrasting proposals for its' control. The farmers used worm control measures in accordance with their own views and those of animal healthcare advisors, combining modern and traditional treatments. This study provides the first insight into the differing views of those animal healthcare providers who form the basis for effective parasitic control within the sheep and goat industry of an arid region
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The role of targeted selective treatments in the development of refugia-based approaches to the control of gastrointestinal nematodes of small ruminants
Veterinary Parasitology, 2009Co-Authors: F. Kenyon, G C Coles, J A Van Wyk, Jacques Cabaret, M. Várady, A.w. Greer, G. Cringoli, E. Papadopoulos, B. Berrag, E. ThomasAbstract:Anthelmintic resistance is recognised as a major problem affecting small ruminant production worldwide and now threatens the sustainability of many of these systems. One method that has been proposed to prolong the efficacy of our current Anthelmintics is the maintenance of a parasite population in refugia (unexposed to a drug) which will maintain the genes for susceptibility within the parasite population. Management strategies that employ refugia-based methods include targeted or strategically timed whole flock treatments, targeted selective treatments (TST), whereby only a proportion of the flock is treated at any one time, and the dilution of resistant with susceptible parasites. The ability to effectively target Anthelmintic use relies on the identification of those animals that will most benefit from treatment. This review explains the concept of refugia, describes the role of refugia-based approaches to the management of Anthelmintic resistance and reviews the markers that have been studied as indicators for TSTs as well as the implementation of refugia-based strategies. Recent results suggest that targeting Anthelmintic treatment on the basis of anaemia, milk production and liveweight gain may offer a means of reducing Anthelmintic usage whilst still maintaining animal performance.
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In vitro screening of six Anthelmintic plant products against larval Haemonchus contortus with a modified methyl-thiazolyl-tetrazolium reduction assay
Journal of Ethnopharmacology, 2006Co-Authors: P Hordegen, Jacques Cabaret, H Hertzberg, W Langhans, V MaurerAbstract:Because of the increasing Anthelmintic resistance and the impact of conventional Anthelmintics on the environment, it is important to look for alternative strategies against gastrointestinal nematodes. Phytotherapy could be one of the major options to control these pathologies. Extracts or ingredients of six different plant species were tested against exsheathed infective larvae of Haemonchus contortus using a modified methyl-thiazolyl-tetrazolium (MTT) reduction assay. Pyrantel tartrate was used as reference Anthelmintic. Bromelain, the enzyme complex of the stem of Ananas comosus (Bromeliaceae), the ethanolic extracts of seeds of Azadirachta indica (Meliaceae), Caesalpinia crista (Caesalpiniaceae) and Vernonia Anthelmintica (Asteraceae), and the ethanolic extracts of the whole plant of Fumaria parviflora (Papaveraceae) and of the fruit of Embelia ribes (Myrsinaceae) showed an Anthelmintic efficacy of up to 93%, relative to pyrantel tartrate. Based on these results obtained with larval Haemonchus contortus, the modified MTT reduction assay could be a possible method for testing plant products with Anthelmintic properties.
Richard J Martin - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological profile of [i]Ascaris suum[/i] ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in [i]Ascaris[/i] tissues
British Journal of Pharmacology, 2016Co-Authors: Melanie Abongwa, Alan P. Robertson, Samuel K Buxton, Elise Courtot, Claude L. Charvet, Cédric Neveu, Ciaran J Mccoy, Saurabh Verma, Richard J MartinAbstract:Control of nematode parasite infections relies largely on anthelminthic drugs, several of which act on nicotinic acetylcholine receptors (nAChRs) and there are concerns about the development of resistance. There is an urgent need for development of new resistance-busting drugs and novel Anthelmintic drug targets. We describe the functional expression and pharmacological characterization of the homomeric nAChR, ACR-16, from a nematode parasite.[br/] Using RT-PCR, molecular cloning, and two-electrode voltage-clamp electrophysiology, we localized acr-16 mRNA in Ascaris suum, then cloned and expressed acr-16 cRNA in Xenopus oocytes. Sensitivity of the receptor to cholinergic Anthelmintics and a range of nicotinic agonists was then tested.[br/] Amino acid sequence comparison with vertebrate nAChR subunits revealed ACR-16 to be most closely related to α7 receptors, but with some striking distinctions. acr-16 mRNA was recovered from A. suum somatic muscle, pharynx, ovijector, head and intestine. In electrophysiological experiments, we observed that existing cholinergic Anthelmintic agonists (morantel, levamisole, methyridine, thenium, bephenium, tribendimidine & pyrantel) did not activate Asu-ACR-16 (except for small currents to oxantel). Other nAChR agonists: nicotine, acetylcholine, cytisine, 3-bromocytisine and epibatidine produced robust current responses which desensitized at a rate that varied with the agonists. Unlike α7, Asu-ACR-16 was insensitive to α-bungarotoxin, and did not respond to genistein or other α7 positive allosteric modulators. Asu-ACR-16 had a lower calcium permeability than α7 receptors.[br/] We suggest that ACR-16 has diverse tissue-dependent functions in nematode parasites and is a suitable drug target for development of novel Anthelmintic compounds.
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Recent advances in candidate-gene and whole-genome approaches to the discovery of Anthelmintic resistance markers and the description of drug/receptor interactions
International Journal for Parasitology, 2014Co-Authors: Andrew C. Kotze, P. J. Skuce, Richard J Martin, Peter W. Hunt, Georg Von Samson-himmelstjerna, Heinz Sager, Jürgen Krücken, Jane Hodgkinson, Anne Lespine, Aaron R. JexAbstract:Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS) provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of Anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how Anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of Anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate-gene and whole-genome approaches to understanding Anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of Anthelmintic resistance.
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Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine-and Derquantel-Sensitive nAChRs
PLoS Pathogens, 2014Co-Authors: Samuel Buxton, Alan P. Robertson, Jacques Cabaret, Melanie Abongwa, Elise Courtot, Cédric Neveu, Claude Charvet, Jacques Cortet, Nicolas Peineau, Richard J MartinAbstract:Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important classical Anthelmintics like levamisole and pyrantel, as well as novel Anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic Anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic Anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. Author Summary Parasitic nematode infections of humans and animals are world-wide. In humans, they cause disease and perpetuate a cycle of poverty. In animals, the parasites cause welfare problems and production loss. In developing countries, the debilitating effect of nematode parasites in school children limits their education, and in adults reduces productivity. These two factors, along with the production loss associated with nematode infections of animals that affects human nutrition, sustain poverty. Treatment and prophylaxis of these parasites requires the use of Anthelmintic drugs. Here, we employ the Xenopus oocyte expression system to investigate the diversity of Anthelmintic receptors in the parasitic nematode Oesophagostomum dentatum. We demonstrate effects of the novel' Anthelmintics tribendimidine and derquantel on these reconstituted receptors, revealing, for the first time, the subunits that make up a tribendimidine- and derquantel-sensitive receptor from a parasitic nematode. We show that the receptor structure and pharmacology can be plastic, and depends on subunit composition and stoichiometry. The factors that affect the diversity of the receptor may contribute to Anthelmintic resistance. Our results demonstrate the presence of acetylcholine receptor subtypes that may serve as Anthelmintic targets and suggest that pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms.
