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International journal for parasitology. Drugs and drug resistance2018; 8(3); 540-549; doi: 10.1016/j.ijpddr.2018.11.003

Nicotine-sensitive acetylcholine receptors are relevant pharmacological targets for the control of multidrug resistant parasitic nematodes.

Abstract: The control of parasitic nematodes impacting animal health relies on the use of broad spectrum anthelmintics. However, intensive use of these drugs has led to the selection of resistant parasites in livestock industry. In that respect, there is currently an urgent need for novel compounds able to control resistant parasites. Nicotine has also historically been used as a de-wormer but was removed from the market when modern anthelmintics became available. The pharmacological target of nicotine has been identified in nematodes as acetylcholine-gated ion channels. Nicotinic-sensitive acetylcholine receptors (N-AChRs) therefore represent validated pharmacological targets that remain largely under-exploited. In the present study, using an automated larval migration assay (ALMA), we report that nicotinic derivatives efficiently paralyzed a multiple (benzimidazoles/levamisole/pyrantel/ivermectin) resistant field isolate of H. contortus. Using C. elegans as a model we confirmed that N-AChRs are preferential targets for nornicotine and anabasine. Functional expression of the homomeric N-AChR from C. elegans and the distantly related horse parasite Parascaris equorum in Xenopus oocytes highlighted some striking differences in their respective pharmacological properties towards nicotine derivative sensitivity. This work validates the exploitation of the nicotine receptors of parasitic nematodes as targets for the development of resistance-breaking compounds.
Publication Date: 2018-11-20 PubMed ID: 30502120PubMed Central: PMC6287576DOI: 10.1016/j.ijpddr.2018.11.003Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article focuses on the utilization of nicotine-sensitive acetylcholine receptors as a potential new target for controlling multidrug-resistant parasitic nematodes, commonly found in livestock. The study primarily investigates the use of nicotine derivatives to effectively manage a resistant species of these parasitic nematodes.

Background

  • The research was conducted in response to the increasing resistance of parasitic nematodes to conventional anthelmintic drugs. These drugs are vital to managing the health of livestock animals by controlling these parasitic worms.
  • Interestingly, nicotine was once used as a de-wormer before the advent of modern anthelmintics. Recent studies have re-established nicotine’s potential in terms of its pharmacological targets, specifically, acetylcholine-gated ion channels within the nematodes.

Methodology & Findings

  • The researchers employed an automated larval migration assay (ALMA) to investigate the effects of nicotinic derivatives on a resistant species of H. contortus.
  • The outcomes illustrate that the nicotinic derivatives significantly paralyzed the H. contortus specimen replying on the multiple drugs such as benzimidazoles, levamisole, pyrantel, ivermectin for resistance.
  • The research further validated the results by utilizing C. elegans (a model organism) and was able to confirm that Nicotinic-sensitive acetylcholine receptors (N-AChRs) are particularly susceptible to nornicotine and anabasine.
  • To support these findings, they conducted a functional expression investigation of a homomeric N-AChRs in a horse parasite. This investigation revealed considerable differences in the response to nicotine derivatives between the horse parasite and the C. elegans.

Implications & Conclusions

  • The study highlights the potential of exploiting nicotine receptors in the management of resistant parasitic nematodes.
  • This research reiterates the need for novel compounds, such as nicotine derivatives, to control resistant parasites in livestock and therefore promotes the novel exploitation of nicotine receptors for such drug developments.

Cite This Article

APA
Charvet CL, Guégnard F, Courtot E, Cortet J, Neveu C. (2018). Nicotine-sensitive acetylcholine receptors are relevant pharmacological targets for the control of multidrug resistant parasitic nematodes. Int J Parasitol Drugs Drug Resist, 8(3), 540-549. https://doi.org/10.1016/j.ijpddr.2018.11.003

Publication

ISSN: 2211-3207
NlmUniqueID: 101576715
Country: Netherlands
Language: English
Volume: 8
Issue: 3
Pages: 540-549
PII: S2211-3207(18)30131-3

Researcher Affiliations

Charvet, Claude L
  • ISP, INRA, Université Tours, UMR1282, 37380, Nouzilly, France.
Guégnard, Fabrice
  • ISP, INRA, Université Tours, UMR1282, 37380, Nouzilly, France.
Courtot, Elise
  • ISP, INRA, Université Tours, UMR1282, 37380, Nouzilly, France.
Cortet, Jacques
  • ISP, INRA, Université Tours, UMR1282, 37380, Nouzilly, France.
Neveu, Cedric
  • ISP, INRA, Université Tours, UMR1282, 37380, Nouzilly, France. Electronic address: cedric.neveu@inra.fr.

MeSH Terms

  • Animals
  • Anthelmintics / pharmacology
  • Antinematodal Agents / pharmacology
  • Ascaridoidea / drug effects
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / metabolism
  • Drug Delivery Systems
  • Drug Resistance, Multiple
  • Haemonchus / drug effects
  • Haemonchus / physiology
  • Helminth Proteins / drug effects
  • Helminth Proteins / metabolism
  • Horses / parasitology
  • Larva / drug effects
  • Larva / physiology
  • Levamisole / pharmacology
  • Livestock / parasitology
  • Nematoda / drug effects
  • Nematode Infections / drug therapy
  • Nematode Infections / parasitology
  • Nicotine / chemistry
  • Nicotine / pharmacology
  • Protein Subunits / metabolism
  • Receptors, Nicotinic / drug effects
  • Sheep
  • Xenopus laevis

Grant Funding

  • P40 OD010440 / NIH HHS

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Citations

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