Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes
Abstract Background Isoxazolines, including sarolaner, lotilaner, afoxolaner and fluralaner, are a class of ectoparasiticides that target gamma-aminobutyric acid receptors (GABARs) in insects and acari. However, their potential action on mammalian GABARs has not been extensively compared. Methods Th...
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| Language: | English |
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BMC
2025-06-01
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| Series: | Parasites & Vectors |
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| Online Access: | https://doi.org/10.1186/s13071-025-06847-3 |
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| author | Heinz Sager Anouk Sarr Emmanuelle Kuntz Lucien Rufener |
| author_facet | Heinz Sager Anouk Sarr Emmanuelle Kuntz Lucien Rufener |
| author_sort | Heinz Sager |
| collection | DOAJ |
| description | Abstract Background Isoxazolines, including sarolaner, lotilaner, afoxolaner and fluralaner, are a class of ectoparasiticides that target gamma-aminobutyric acid receptors (GABARs) in insects and acari. However, their potential action on mammalian GABARs has not been extensively compared. Methods This study investigated the inhibitory effects of these isoxazolines on human and canine GABARs expressed in Xenopus oocytes. Eleven functional GABAR subunit combinations from human and canine isoforms were successfully cloned and expressed. Two-electrode voltage-clamp measurements were performed to determine the inhibitory effects of the isoxazolines. Results Sarolaner, afoxolaner and fluralaner exhibited partial to high inhibition of human and canine GABARs, with fluralaner showing the lowest half-maximal inhibitory concentration (IC50) values (1.9–13 µM). In contrast, lotilaner had little or no inhibitory effect, with IC50 values > 30 µM for both human and canine GABARs. Conclusions While neurological adverse events have been reported in dogs, particularly in breeds with the multidrug resistance 1 (MDR1) gene mutation, this study suggests that direct inhibition of canine GABARs may not be the primary cause. However, the interpretation of these results represents a challenge, and a direct correlation with documented cases of adverse events remains difficult. Further research is needed to understand the exposure of mammalian GABARs to isoxazolines and the analog-specific safety risks associated with the observed in vitro receptor activities. Graphical Abstract |
| format | Article |
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| institution | OA Journals |
| issn | 1756-3305 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Parasites & Vectors |
| spelling | doaj-art-2bc3a8a0b14d4ddc80b8345e1279fc6c2025-08-20T02:31:03ZengBMCParasites & Vectors1756-33052025-06-011811810.1186/s13071-025-06847-3Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytesHeinz Sager0Anouk Sarr1Emmanuelle Kuntz2Lucien Rufener3Elanco Animal HealthInvenesis SàrlElanco Animal HealthInvenesis SàrlAbstract Background Isoxazolines, including sarolaner, lotilaner, afoxolaner and fluralaner, are a class of ectoparasiticides that target gamma-aminobutyric acid receptors (GABARs) in insects and acari. However, their potential action on mammalian GABARs has not been extensively compared. Methods This study investigated the inhibitory effects of these isoxazolines on human and canine GABARs expressed in Xenopus oocytes. Eleven functional GABAR subunit combinations from human and canine isoforms were successfully cloned and expressed. Two-electrode voltage-clamp measurements were performed to determine the inhibitory effects of the isoxazolines. Results Sarolaner, afoxolaner and fluralaner exhibited partial to high inhibition of human and canine GABARs, with fluralaner showing the lowest half-maximal inhibitory concentration (IC50) values (1.9–13 µM). In contrast, lotilaner had little or no inhibitory effect, with IC50 values > 30 µM for both human and canine GABARs. Conclusions While neurological adverse events have been reported in dogs, particularly in breeds with the multidrug resistance 1 (MDR1) gene mutation, this study suggests that direct inhibition of canine GABARs may not be the primary cause. However, the interpretation of these results represents a challenge, and a direct correlation with documented cases of adverse events remains difficult. Further research is needed to understand the exposure of mammalian GABARs to isoxazolines and the analog-specific safety risks associated with the observed in vitro receptor activities. Graphical Abstracthttps://doi.org/10.1186/s13071-025-06847-3IsoxazolineLotilanerFluralanerSarolanerAfoxolanerGABAR |
| spellingShingle | Heinz Sager Anouk Sarr Emmanuelle Kuntz Lucien Rufener Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes Parasites & Vectors Isoxazoline Lotilaner Fluralaner Sarolaner Afoxolaner GABAR |
| title | Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes |
| title_full | Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes |
| title_fullStr | Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes |
| title_full_unstemmed | Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes |
| title_short | Comparative analysis of isoxazoline activity on human and canine GABA receptors expressed in Xenopus oocytes |
| title_sort | comparative analysis of isoxazoline activity on human and canine gaba receptors expressed in xenopus oocytes |
| topic | Isoxazoline Lotilaner Fluralaner Sarolaner Afoxolaner GABAR |
| url | https://doi.org/10.1186/s13071-025-06847-3 |
| work_keys_str_mv | AT heinzsager comparativeanalysisofisoxazolineactivityonhumanandcaninegabareceptorsexpressedinxenopusoocytes AT anouksarr comparativeanalysisofisoxazolineactivityonhumanandcaninegabareceptorsexpressedinxenopusoocytes AT emmanuellekuntz comparativeanalysisofisoxazolineactivityonhumanandcaninegabareceptorsexpressedinxenopusoocytes AT lucienrufener comparativeanalysisofisoxazolineactivityonhumanandcaninegabareceptorsexpressedinxenopusoocytes |