| Autor: |
Guégnard, Fabrice, Cortet, Jacques, Charvet, Claude, Neveu, Cédric |
| Přispěvatelé: |
Courtot, Elise |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Abstract book-27. WAAVP . 2019; 27. Conference of the World Association for the Advancement of Veterinary Parasitology, Madison, USA, 2019-07-07-2019-07-11, 117-118 |
| Popis: |
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 until modern anthelmintics were marketed. 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 than remain largely under-exploited. In the present study, we developed an automated larval migration assay (ALMA) and showed that nicotinic derivatives (anabasine/nornicotine) efficiently paralyzed a multiple (benzimidazoles/levamisole/ pyrantel/ivermectin) resistant field isolate of Haemonchus contortus. Additionally, using Caenorhabditis elegans as a model, we confirmed that the N-AChRs subtype contributes to the anthelmintic effect of nicotinic analogs. Interestingly, the 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. Noteworthy, nicotine and anabasine were more potent than ACh in activating the P. equorum N-AChR as revealed by their respective EC50 values (2.9 ± 0.5 μM and 1.7 ± 0.1 μM versus 6.4 ± 1.1 μM, respectively), unlike nornicotine (34.9 ± 7.2 μM) whereas the potency series for the C. elegans N-AChR was Nic > ACh = Ana > Nor. Taken together these results validate the exploitation of the N-AChRs of parasitic nematodes as targets for the development of resistance-breaking compounds. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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