The novel isoxazoline ectoparasiticide lotilaner (Credelio): a non-competitive antagonist specific to invertebrates gamma-aminobutyric acid-gated chloride channels (GABACls).

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Rufener L, Danelli V, Bertrand D, Sager H

The novel isoxazoline ectoparasiticide lotilaner (Credelio): a non-competitive antagonist specific to invertebrates gamma-aminobutyric acid-gated chloride channels (GABACls).

Parasit Vectors. 2017 Nov 1;10(1):530. doi: 10.1186/s13071-017-2470-4.

PubMed ID
29089046 [ View in PubMed
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Abstract

BACKGROUND: The isoxazolines are a novel class of parasiticides that are potent inhibitors of gamma-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 GABA(A) receptor was observed up to a concentration of 10 muM. CONCLUSIONS: Together, these results demonstrate that lotilaner is a non-competitive antagonist specific to invertebrate's gamma-aminobutyric acid-gated chloride channels (GABACls). They contribute to our understanding of the mode of action of this new ectoparasiticide compound.

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