Skip to main content Accessibility help
×
Home

Article contents

Mode of action of levamisole and pyrantel, anthelmintic resistance, E153 and Q57

Published online by Cambridge University Press:  03 July 2007


R. J. MARTIN
Affiliation:
Department of Biomedical Sciences, Iowa State University, Ames, IA, 50011, USA.
A. P. ROBERTSON
Affiliation:
Department of Biomedical Sciences, Iowa State University, Ames, IA, 50011, USA.
Corresponding
E-mail address:

Summary

Here we review molecular information related to resistance to the cholinergic anthelmintics in nematodes. The amount of molecular information available varies between the nematode species, with the best understood so far being C. elegans. More information is becoming available for some other parasitic species. The cholinergic anthelmintics act on nematode nicotinic acetylcholine receptors located on somatic muscle cells. Recent findings demonstrate the presence of multiple types of the nicotinic receptors in several nematodes and the numerous genes required to form these multimeric proteins. Not only are the receptors the product of several genes but they are subject to modulation by several other proteins. Mutations altering these modulatory proteins could alter sensitivity to the cholinergic anthelmitics and thus lead to resistance. We also discuss the possibility that resistance to the cholinergic anthelmintics is not necessarily the result of a single mutation but may well be polygenic in nature. Additionally, the mutations resulting in resistance may vary between different species or between resistant isolates of the same species. A list of candidate genes to examine for SNPs is presented.


Type
Research Article
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below.

References

Aceves, J., Erlij, D. and Martinez-Maranon, R. (1970). The mechanism of the paralysing action of tetramisole on Ascaris somatic muscle. British Journal of Pharmacology 38, 602607.CrossRefGoogle ScholarPubMed
Albonico, M., Bickle, Q., Haji, H. J., Ramsan, M., Khatib, K. J., Montresor, A., Savioli, L. and Taylor, M. (2002). Evaluation of the efficacy of pyrantel-oxantel for the treatment of soil-transmitted nematode infections. Transactions of the Royal Society of Tropical Medicine and Hygiene 96, 685690.CrossRefGoogle ScholarPubMed
Albonico, M., Crompton, D. W. and Savioli, L. (1999). Control strategies for human intestinal nematode infections. Advances in Parasitology 42, 277341.CrossRefGoogle ScholarPubMed
Aubry, M. L., Cowell, P., Davey, M. J. and Shevde, S. (1970). Aspects of the pharmacology of a new anthelmintic: pyrantel. British Journal of Pharmacology 38, 332344.CrossRefGoogle ScholarPubMed
Bartos, M., Rayes, D. and Bouzat, C. (2006). Molecular determinants of pyrantel selectivity in nicotinic receptors. Molecular Pharmacology 70, 13071318.CrossRefGoogle ScholarPubMed
Benian, G. M., L'Hernault, S. W. and Morris, M. E. (1993). Additional sequence complexity in the muscle gene, unc-22, and its encoded protein, twitchin, of Caenorhabditis elegans. Genetics 134, 10971104.Google ScholarPubMed
Bjorn, H., Roepstorff, A., Waller, P. J. and Nansen, P. (1990). Resistance to levamisole and cross-resistance between pyrantel and levamisole in Oesophagostomum quadrispinulatum and Oesophagostomum dentatum of pigs. Veterinary Parasitology 37, 2130.CrossRefGoogle ScholarPubMed
Blaxter, M. L., De, L. P., Garey, J. R., Liu, L. X., Scheldeman, P., Vierstraete, A., Vanfleteren, J. R., Mackey, L. Y., Dorris, M., Frisse, L. M., Vida, J. T. and Thomas, W. K. (1998). A molecular evolutionary framework for the phylum Nematoda. Nature 392, 7175.CrossRefGoogle ScholarPubMed
Brejc, K., van Dijk, W. J., Klaassen, R. V., Schuurmans, M., van Der, O. J., Smit, A. B. and Sixma, T. K. (2001). Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269276.CrossRefGoogle ScholarPubMed
Brown, L. A., Jones, A. K., Buckingham, S. D., Mee, C. J. and Sattelle, D. B. (2006). Contributions from Caenorhabditis elegans functional genetics to antiparasitic drug target identification and validation: nicotinic acetylcholine receptors, a case study. International Journal for Parasitology 36, 617624.CrossRefGoogle ScholarPubMed
Changeux, J. P., Benoit, P., Bessis, A., Cartaud, J., Devillers-Thiery, A., Fontaine, B., Galzi, J. L., Klarsfeld, A., Laufer, R., Mulle, C., et al. (1990). The acetylcholine receptor: functional architecture and regulation. Advances in Second Messenger and Phosphoprotein Research 24, 1519.Google ScholarPubMed
Corringer, P. J., Bertrand, S., Bohler, S., Edelstein, S. J., Changeux, J. P. and Bertrand, D. (1998). Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors. Journal of Neuroscience 18, 648657.CrossRefGoogle ScholarPubMed
Culetto, E., Baylis, H. A., Richmond, J. E., Jones, A. K., Fleming, J. T., Squire, M. D., Lewis, J. A. and Sattelle, D. B. (2004). The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. Journal of Biological Chemistry 279, 4247642483.CrossRefGoogle ScholarPubMed
Evans, A. M. and Martin, R. J. (1996). Activation and cooperative multi-ion block of single nicotinic-acetylcholine channel currents of Ascaris muscle by the tetrahydropyrimidine anthelmintic, morantel. British Journal of Pharmacology 118, 11271140.CrossRefGoogle ScholarPubMed
Fleming, J. T., Squire, M. D., Barnes, T. M., Tornoe, C., Matsuda, K., Ahnn, J., Fire, A., Sulston, J. E., Barnard, E. A., Sattelle, D. B. and Lewis, J. A. (1997). Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits. Journal of Neuroscience 17, 58435857.CrossRefGoogle ScholarPubMed
Gally, C., Eimer, S., Richmond, J. E. and Bessereau, J. L. (2004). A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans. Nature 431, 578582.CrossRefGoogle ScholarPubMed
Ghedin, E., Wang, S., Foster, J. M. and Slatko, B. E. (2004). First sequenced genome of a parasitic nematode. Trends in Parasitology 20, 151153.CrossRefGoogle ScholarPubMed
Gottschalk, A., Almedom, R. B., Schedletzky, T., Anderson, S. D., Yates, J. R. III and Schafer, W. R. (2005). Identification and characterization of novel nicotinic receptor-associated proteins in Caenorhabditis elegans. EMBO Journal 24, 25662578.CrossRefGoogle ScholarPubMed
Hoekstra, R., Visser, A., Wiley, L. J., Weiss, A. S., Sangster, N. C. and Roos, M. H. (1997). Characterization of an acetylcholine receptor gene of Haemonchus contortus in relation to levamisole resistance. Molecular and Biochemical Parasitology 84, 179187.CrossRefGoogle ScholarPubMed
Jones, A. K., Buckingham, S. D. and Sattelle, D. B. (2005). Chemistry-to-gene screens in Caenorhabditis elegans. Nature Reviews Drug Discovery 4, 321330.CrossRefGoogle ScholarPubMed
Jones, A. K. and Sattelle, D. B. (2004). Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. Bioessays 26, 3949.CrossRefGoogle ScholarPubMed
Kagawa, H., Takuwa, K. and Sakube, Y. (1997). Mutations and expressions of the tropomyosin gene and the troponin C gene of Caenorhabditis elegans. Cell Structure and Function 22, 213218.CrossRefGoogle ScholarPubMed
Levandoski, M. M., Robertson, A. P., Kuiper, S., Qian, H. and Martin, R. J. (2005). Single-channel properties of N- and L-subtypes of acetylcholine receptor in Ascaris suum. International Journal for Parasitology 35, 925934.CrossRefGoogle ScholarPubMed
Lewis, J. A., Elmer, J. S., Skimming, J., McLafferty, S., Fleming, J. and McGee, T. (1987). Cholinergic receptor mutants of the nematode Caenorhabditis elegans. Journal of Neuroscience 7, 30593071.CrossRefGoogle ScholarPubMed
Lewis, J. A., Wu, C. H., Berg, H. and Levine, J. H. (1980). The genetics of levamisole resistance in the nematode Caenorhabditis elegans. Genetics 95, 905928.Google ScholarPubMed
Martin, R. J. (1982). Electrophysiological effects of piperazine and diethylcarbamazine on Ascaris suum somatic muscle. British Journal of Pharmacology 77, 255265.CrossRefGoogle ScholarPubMed
Martin, R. J., Clark, C. L., Trailovic, S. M. and Robertson, A. P. (2004). Oxantel is an N-type (methyridine and nicotine) agonist not an L-type (levamisole and pyrantel) agonist: classification of cholinergic anthelmintics in Ascaris. International Journal for Parasitology 34, 10831090.CrossRefGoogle Scholar
Martin, R. J., Murray, I., Robertson, A. P., Bjorn, H. and Sangster, N. (1998). Anthelmintics and ion-channels: after a puncture, use a patch. International Journal for Parasitology 28, 849862.CrossRefGoogle Scholar
Mitreva, M., Blaxter, M. L., Bird, D. M. and McCarter, J. P. (2005). Comparative genomics of nematodes. Trends in Genetics 21, 573581.CrossRefGoogle ScholarPubMed
Pennington, A. J. and Martin, R. J. (1990). A patch-clamp study of acetylcholine-activated ion channels in Ascaris suum muscle. Journal of Experimental Biology 154, 201221.Google ScholarPubMed
Qian, H., Martin, R. J. and Robertson, A. P. (2006). Pharmacology of N-, L-, and B-subtypes of nematode nAChR resolved at the single-channel level in Ascaris suum. FASEB Journal 14, 26062608.CrossRefGoogle Scholar
Rayes, D., De Rosa, M. J., Bartos, M. and Bouzat, C. (2004). Molecular basis of the differential sensitivity of nematode and mammalian muscle to the anthelmintic agent levamisole. Journal of Biological Chemistry 279, 3637236381.CrossRefGoogle ScholarPubMed
Richmond, J. E. and Jorgensen, E. M. (1999). One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction. Nature Neuroscience 2, 791797.CrossRefGoogle ScholarPubMed
Robertson, A. P., Bjorn, H. E. and Martin, R. J. (1999). Resistance to levamisole resolved at the single-channel level. FASEB Journal 13, 749760.CrossRefGoogle ScholarPubMed
Robertson, A. P., Clark, C. L., Burns, T. A., Thompson, D. P., Geary, T. G., Trailovic, S. M. and Martin, R. J. (2002). Paraherquamide and 2-deoxy-paraherquamide distinguish cholinergic receptor subtypes in Ascaris muscle. Journal of Pharmacology and Experimental Therapeutics 302, 853860.CrossRefGoogle ScholarPubMed
Robertson, S. J. and Martin, R. J. (1993). Levamisole-activated single-channel currents from muscle of the nematode parasite Ascaris suum. British Journal of Pharmacology 108, 170178.CrossRefGoogle ScholarPubMed
Roos, M. H., Kwa, M. S., Veenstra, J. G., Kooyman, F. N. and Boersema, J. H. (1993). Molecular aspects of drug resistance in parasitic helminths. Pharmacology and Therapeutics 60, 331336.CrossRefGoogle ScholarPubMed
Sangster, N. C. and Dobson, R. J. (2002). Anthelmintic resistance. In The Biology of Nematodes (ed. Lee, D. L.), pp. 531567. Taylor and Francis, London and New York.CrossRefGoogle Scholar
Touroutine, D., Fox, R. M., Von Stetina, S. E., Burdina, A., Miller, D. M. III and Richmond, J. E. (2005). acr-16 encodes an essential subunit of the levamisole-resistant nicotinic receptor at the Caenorhabditis elegans neuromuscular junction. Journal of Biological Chemistry 280, 2701327021.CrossRefGoogle ScholarPubMed
Towers, P. R., Edwards, B., Richmond, J. E. and Sattelle, D. B. (2005). The Caenorhabditis elegans lev-8 gene encodes a novel type of nicotinic acetylcholine receptor alpha subunit. Journal of Neurochemistry 93, 19.CrossRefGoogle ScholarPubMed
Trailovic, S. M., Clark, C. L., Robertson, A. P. and Martin, R. J. (2005). Brief application of AF2 produces long lasting potentiation of nAChR responses in Ascaris suum. Molecular and Biochemical Parasitology 139, 5164.CrossRefGoogle ScholarPubMed
Trailovic, S. M., Robertson, A. P., Clark, C. L. and Martin, R. J. (2002). Levamisole receptor phosphorylation: effects of kinase antagonists on membrane potential responses in Ascaris suum suggest that CaM kinase and tyrosine kinase regulate sensitivity to levamisole. Journal of Experimental Biology 205, 39793988.Google ScholarPubMed
von Samson-Himmelstjerna, G., Buschbaum, S., Wirtherle, N., Pape, M. and Schnieder, T. (2003). TaqMan minor groove binder real-time PCR analysis of beta -tubulin codon 200 polymorphism in small strongyles (Cyathostomin) indicates that the TAC allele is only moderately selected in benzimidazole-resistant populations. Parasitology 127, 489496.CrossRefGoogle ScholarPubMed
Wiley, L. J., Weiss, A. S., Sangster, N. C. and Li, Q. (1996). Cloning and sequence analysis of the candidate nicotinic acetylcholine receptor alpha subunit gene tar-1 from Trichostrongylus colubriformis. Gene 182, 97100.CrossRefGoogle ScholarPubMed
World Health Organization (2000). The use of essential drugs. Ninth report of the WHO expert committee (including the revised Model list of essential drugs). WHO technical report series No. 895. World Health Organization, Geneva.Google Scholar
Zinser, E. W., Wolf, M. L., Alexander-Bowman, S. J., Thomas, E. M., Davis, J. P., Groppi, V. E., Lee, B. H., Thompson, D. P. and Geary, T. G. (2002). Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammals. Journal of Veterinary Pharmacology and Therapeutics 25, 241250.CrossRefGoogle ScholarPubMed

Full text views

Full text views reflects PDF downloads, PDFs sent to Google Drive, Dropbox and Kindle and HTML full text views.

Total number of HTML views: 13
Total number of PDF views: 183 *
View data table for this chart

* Views captured on Cambridge Core between September 2016 - 30th November 2020. This data will be updated every 24 hours.

Hostname: page-component-6d4bddd689-22mf8 Total loading time: 1.184 Render date: 2020-11-30T19:38:57.371Z Query parameters: { "hasAccess": "0", "openAccess": "0", "isLogged": "0", "lang": "en" } Feature Flags last update: Mon Nov 30 2020 18:40:00 GMT+0000 (Coordinated Universal Time) Feature Flags: { "metrics": true, "metricsAbstractViews": false, "peerReview": true, "crossMark": true, "comments": true, "relatedCommentaries": true, "subject": true, "clr": false, "languageSwitch": true }

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Mode of action of levamisole and pyrantel, anthelmintic resistance, E153 and Q57
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Mode of action of levamisole and pyrantel, anthelmintic resistance, E153 and Q57
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Mode of action of levamisole and pyrantel, anthelmintic resistance, E153 and Q57
Available formats
×
×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *