Glutamate-gated chloride channels and the mode of action of the abamectin/milbemycin anthelmintics

Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Parasitology (Impact Factor: 2.56). 02/2005; 131 Suppl(Suppl.):S85-95. DOI: 10.1017/S0031182005008218
Source: PubMed

ABSTRACT The macrocyclic lactones are the biggest selling and arguably most effective anthelmintics currently available. They are good substrates for the P-glycoproteins, which might explain their selective toxicity for parasites over their vertebrate hosts. Changes in the expression of these pumps have been implicated in resistance to the macrocyclic lactones, but it is clear that they exert their anthelmintic effects by binding to glutamate-gated chloride channels expressed on nematode neurones and pharyngeal muscle cells. This effect is quite distinct from the channel opening induced by glutamate, the endogenous transmitter acting at these receptors, which produces rapidly opening and desensitising channels. Ivermectin-activated channels open very slowly but essentially irreversibly, leading to a very long-lasting hyperpolarisation or depolarisation of the neurone or muscle cell and therefore blocking further function. Molecular and genetic studies have shown that there are multiple GluCl isoforms in both free-living and parasitic nematodes: the exact genetic make-up and functions of the GluCl may vary between species. The known expression patterns of the GluCl explain most of the observed biological effects of treatment with the macrocyclic lactones, though the reason for the long-lasting inhibition of larval production in filarial species is still poorly understood.

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Available from: Adrian J Wolstenholme, Sep 28, 2015
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    • "In gastro-intestinal parasites and insects, the best-studied members of this family are the glutamate-gated chloride channels (GluCls), which are widely expressed in the nervous system and on pharyngeal muscle (Wolstenholme, 2012). The MLs cause an essentially irreversible activation of these receptors, which has several deleterious consequences for the parasite, including paralysis together with inhibition of feeding and of egg-production (Wolstenholme and Rogers, 2005). In D. immitis, infertility caused by MLs has been attributed to effects on the male parasites (Lok et al. 1995). "
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    ABSTRACT: Prevention of heartworm disease caused by Dirofilaria immitis in domestic dogs and cats relies on a single drug class, the macrocyclic lactones (MLs). Recently, it has been demonstrated that ML-resistant D. immitis are circulating in the Mississippi Delta region of the USA, but the prevalence and impact of these resistant parasites remains unknown. We review published studies that demonstrated resistance in D.immitis , along with our current understanding of its mechanisms. Efforts to develop in vitro tests for resistance have not yet yielded a suitable assay, so testing infected animals for microfilariae that persist in the face of ML treatment may be the best current option. Since the vast majority of D. immitis populations continue to be drug-sensitive, protected dogs are likely to be infected with only a few parasites and experience relatively mild disease. In cats, infection with small numbers of worms can cause severe disease and so the clinical consequences of drug resistance may be more severe. Since melarsomine dihydrochloride, the drug used to remove adult worms, is not an ML, the ML-resistance should have no impact on our ability to treat diseased animals. A large refugium of heartworms that are not exposed to drugs exists in unprotected dogs and in wild canids, which may limit the development and spread of resistance alleles.
    Parasitology 06/2015; 142(10):1-11. DOI:10.1017/S003118201500061X · 2.56 Impact Factor
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    • "Insecticides that act on GluCls include abamectin, ivermectin, fipronil and the indole diterpenoid compound nodulisporic acid. A particular mutation in the α-subunit of GluCls causes the substitution of one amino acid, resulting in reduced sensitivity of the mutant channel to insecticide and thereby causing insecticide resistance [52]. A total of 7 GluCls sequences were identified from the CSM transcriptome (Table S8), but most of insects, such as D. melanogaster, T. castaneum and A. mellifera, only have one glutamate-gated chloride channel subunit. "
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    ABSTRACT: The carmine spider mite (CSM), Tetranychus cinnabarinus, is an important pest mite in agriculture, because it can develop insecticide resistance easily. To gain valuable gene information and molecular basis for the future insecticide resistance study of CSM, the first transcriptome analysis of CSM was conducted. A total of 45,016 contigs and 25,519 unigenes were generated from the de novo transcriptome assembly, and 15,167 unigenes were annotated via BLAST querying against current databases, including nr, SwissProt, the Clusters of Orthologous Groups (COGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). Aligning the transcript to Tetranychus urticae genome, the 19255 (75.45%) of the transcripts had significant (e-value <10-5) matches to T. urticae DNA genome, 19111 sequences matched to T. urticae proteome with an average protein length coverage of 42.55%. Core Eukaryotic Genes Mapping Approach (CEGMA) analysis identified 435 core eukaryotic genes (CEGs) in the CSM dataset corresponding to 95% coverage. Ten gene categories that relate to insecticide resistance in arthropod were generated from CSM transcriptome, including 53 P450-, 22 GSTs-, 23 CarEs-, 1 AChE-, 7 GluCls-, 9 nAChRs-, 8 GABA receptor-, 1 sodium channel-, 6 ATPase- and 12 Cyt b genes. We developed significant molecular resources for T. cinnabarinus putatively involved in insecticide resistance. The transcriptome assembly analysis will significantly facilitate our study on the mechanism of adapting environmental stress (including insecticide) in CSM at the molecular level, and will be very important for developing new control strategies against this pest mite.
    PLoS ONE 05/2014; 9(5):e94779. DOI:10.1371/journal.pone.0094779 · 3.23 Impact Factor
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    • "Avermectins exert their anthelmintic effects by binding to glutamategated chloride channels that are expressed on nematode neurons and pharyngeal muscle cells. Ivermectin, the first synthesized avermectin, is able to activate channel opening very slowly, but the opening is essentially irreversibly, leading to a very long-lasting hyperpolarization or depolarization of the neuron or muscle cell and blocking further function (Wolstenholme & Rogers, 2005). In vertebrates, macrocyclic lactones can produce γ-aminobutyric acid (GABA)-mimetic effects by acting as agonists at GABA A receptors and stimulating GABA release (Dawson et al., 2000; de Souza Spinosa et al., 2000; Shoop et al., 1995; Yang, 2012). "
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    ABSTRACT: Ivermectin (IVM) is an antiparasitic drug that is widely used in domestic animals. In mammals, IVM act as a γ-aminobutyric acid (GABA) receptor agonist. This neurotransmitter plays an important role in the regulation of female sexual behavior. The present study investigated the effects of therapeutic (0.2mg/kg) and high (1.0mg/kg) IVM doses on female sexual behavior in physiological and pharmacological conditions. Female rats in estrus or treated with estradiol valerate to induce sexual behavior 24h before the experiments were employed. Ivermectin was administered 15min before the sexual observations. The number of lordosis events in 10 mounts was recorded to calculate the lordosis quotient. The intensity of lordosis (0 [no lordosis], 1 [low lordosis], 2 [normal lordosis], and 3 [exaggerated lordosis]) was scored. In estrus and hormonal treated female both IVM doses decreased the intensity of the lordosis reflex and the percentage of females that presented high levels of lordosis (exaggerated lordosis). However, the number of females that presented lordosis was unaltered. We conclude that in both hormonal conditions IVM 0.2mg/kg treatment reduced female sexual behavior and the execution of the lordosis reflex. The present results may be useful for avoiding the side effects of this drug in veterinary practice.
    Neurotoxicology and Teratology 05/2014; 43. DOI:10.1016/ · 2.76 Impact Factor
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