The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls)
Abstract Background The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this...
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ftdoajarticles:oai:doaj.org/article:d7d9b83ff9b54087a593af2f39481b73 2023-05-15T15:51:11+02:00 The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) Lucien Rufener Vanessa Danelli Daniel Bertrand Heinz Sager 2017-11-01T00:00:00Z https://doi.org/10.1186/s13071-017-2470-4 https://doaj.org/article/d7d9b83ff9b54087a593af2f39481b73 EN eng BMC http://link.springer.com/article/10.1186/s13071-017-2470-4 https://doaj.org/toc/1756-3305 doi:10.1186/s13071-017-2470-4 1756-3305 https://doaj.org/article/d7d9b83ff9b54087a593af2f39481b73 Parasites & Vectors, Vol 10, Iss 1, Pp 1-15 (2017) Lotilaner γ-aminobutyric acid-gated chloride channels GABACl Isoxazoline Invertebrates Non-competitive antagonist Infectious and parasitic diseases RC109-216 article 2017 ftdoajarticles https://doi.org/10.1186/s13071-017-2470-4 2022-12-31T08:17:57Z Abstract Background The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this chemical class, is currently evaluated for its excellent ectoparasiticide properties. Methods In this study, we investigated the molecular mode of action and pharmacology of lotilaner. We report the successful gene identification, cDNA cloning and functional expression in Xenopus oocytes of Drosohpila melanogaster (wild type and dieldrin/fipronil-resistant forms), Lepeophtheirus salmonis (an ectoparasite copepod crustacean of salmon), Rhipicephalus microplus and Canis lupus familiaris GABACls. Automated Xenopus oocyte two-electrode voltage clamp electrophysiology was used to assess GABACls functionality and to compare ion channel inhibition by lotilaner with that of established insecticides addressing GABACls as targets. Results In these assays, we demonstrated that lotilaner is a potent non-competitive antagonist of insects (fly) GABACls. No cross-resistance with dieldrin or fipronil resistance mutations was detected, suggesting that lotilaner might bind to a site at least partly different from the one bound by known GABACl blockers. Using co-application experiments, we observed that lotilaner antagonism differs significantly from the classical open channel blocker fipronil. We finally confirmed for the first time that isoxazoline compounds are not only powerful antagonists of GABACls of acari (ticks) but also of crustaceans (sea lice), while no activity on a dog GABAA receptor was observed up to a concentration of 10 μM. Conclusions Together, these results demonstrate that lotilaner is a non-competitive antagonist specific to invertebrate’s γ-aminobutyric acid-gated chloride channels (GABACls). They contribute to our understanding of the mode of action of this new ectoparasiticide compound. Article in Journal/Newspaper Canis lupus Directory of Open Access Journals: DOAJ Articles Parasites & Vectors 10 1 |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Lotilaner γ-aminobutyric acid-gated chloride channels GABACl Isoxazoline Invertebrates Non-competitive antagonist Infectious and parasitic diseases RC109-216 |
spellingShingle |
Lotilaner γ-aminobutyric acid-gated chloride channels GABACl Isoxazoline Invertebrates Non-competitive antagonist Infectious and parasitic diseases RC109-216 Lucien Rufener Vanessa Danelli Daniel Bertrand Heinz Sager The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) |
topic_facet |
Lotilaner γ-aminobutyric acid-gated chloride channels GABACl Isoxazoline Invertebrates Non-competitive antagonist Infectious and parasitic diseases RC109-216 |
description |
Abstract Background The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this chemical class, is currently evaluated for its excellent ectoparasiticide properties. Methods In this study, we investigated the molecular mode of action and pharmacology of lotilaner. We report the successful gene identification, cDNA cloning and functional expression in Xenopus oocytes of Drosohpila melanogaster (wild type and dieldrin/fipronil-resistant forms), Lepeophtheirus salmonis (an ectoparasite copepod crustacean of salmon), Rhipicephalus microplus and Canis lupus familiaris GABACls. Automated Xenopus oocyte two-electrode voltage clamp electrophysiology was used to assess GABACls functionality and to compare ion channel inhibition by lotilaner with that of established insecticides addressing GABACls as targets. Results In these assays, we demonstrated that lotilaner is a potent non-competitive antagonist of insects (fly) GABACls. No cross-resistance with dieldrin or fipronil resistance mutations was detected, suggesting that lotilaner might bind to a site at least partly different from the one bound by known GABACl blockers. Using co-application experiments, we observed that lotilaner antagonism differs significantly from the classical open channel blocker fipronil. We finally confirmed for the first time that isoxazoline compounds are not only powerful antagonists of GABACls of acari (ticks) but also of crustaceans (sea lice), while no activity on a dog GABAA receptor was observed up to a concentration of 10 μM. Conclusions Together, these results demonstrate that lotilaner is a non-competitive antagonist specific to invertebrate’s γ-aminobutyric acid-gated chloride channels (GABACls). They contribute to our understanding of the mode of action of this new ectoparasiticide compound. |
format |
Article in Journal/Newspaper |
author |
Lucien Rufener Vanessa Danelli Daniel Bertrand Heinz Sager |
author_facet |
Lucien Rufener Vanessa Danelli Daniel Bertrand Heinz Sager |
author_sort |
Lucien Rufener |
title |
The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) |
title_short |
The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) |
title_full |
The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) |
title_fullStr |
The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) |
title_full_unstemmed |
The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls) |
title_sort |
novel isoxazoline ectoparasiticide lotilaner (credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (gabacls) |
publisher |
BMC |
publishDate |
2017 |
url |
https://doi.org/10.1186/s13071-017-2470-4 https://doaj.org/article/d7d9b83ff9b54087a593af2f39481b73 |
genre |
Canis lupus |
genre_facet |
Canis lupus |
op_source |
Parasites & Vectors, Vol 10, Iss 1, Pp 1-15 (2017) |
op_relation |
http://link.springer.com/article/10.1186/s13071-017-2470-4 https://doaj.org/toc/1756-3305 doi:10.1186/s13071-017-2470-4 1756-3305 https://doaj.org/article/d7d9b83ff9b54087a593af2f39481b73 |
op_doi |
https://doi.org/10.1186/s13071-017-2470-4 |
container_title |
Parasites & Vectors |
container_volume |
10 |
container_issue |
1 |
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1766386255842508800 |