Inhibition of P-glycoprotein enhances sensitivity of Caenorhabditis elegans to ivermectin

Ardelli, Bernadette F.; Prichard, Roger K.

doi:10.1016/j.vetpar.2012.09.021

Cited by 79 publications

(110 citation statements)

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“…Particularly, Pgp14 and Pgp6 were the most highly overexpressed genes in both IVM-and MOX-selected strains. Interestingly, Pgp14 is the most important Pgp involved in IVM susceptibility in C. elegans (14), while Pgp6 plays a great role in protecting C. elegans from MOX toxicity (9,57). Since PGP6 is expressed in the amphids, its overexpression could help protect the nematodes from the effects of ML on extrapharyngeal neurons associated with the amphids.…”

Section: Discussionmentioning

confidence: 99%

“…Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8)(9)(10)(11)(12)(13), and they are involved in the tolerance of Caenorhabditis elegans (9,(14)(15)(16) and parasitic nematodes such as Haemonchus contortus or Cooperia oncophora (13,(17)(18)(19)(20) to MLs. In addition, mutation of the dyf-7 gene was associated with an IVM resistance phenotype in C. elegans and in H. contortus, leading to an abnormal dendritic morphology of amphid sensory neurons, as revealed by a dye-filling-defective phenotype (21).…”

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confidence: 99%

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Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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show abstract

“…Strains that showed resistance to ivermectin also showed resistance to moxidectin, levamisole, and pyrantel, but not to albendazole. Inactivation of pgp-1, -5, -6, -12, and -13 all produced enhanced sensitivity to ivermectin (Ardelli and Prichard, 2013). These genes are primarily expressed in the intestine, pharynx and amphids.…”

Section: Anthelmintic Drugs and Nematicides: Studies In Caenorhabditimentioning

confidence: 99%

“…elegans has been used to study ivermectin resistance, which may involve changes in P-glycoprotein (members of the ABC transporter superfamily, for review see Ardelli, 2013) activity. Increased expression of pgp genes resulted in increased resistance to ivermectin (James and Davey, 2009), while loss-of-function of individual Pglycoproteins resulted in enhanced susceptibility to ivermectin (Ardelli and Prichard, 2013;Janssen et al, 2013). In their study, James and Davey (2009) exposed C. elegans to increasing concentrations of ivermectin.…”

Section: Anthelmintic Drugs and Nematicides: Studies In Caenorhabditimentioning

confidence: 99%

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Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans

Holden‐Dye

Walker²

2014

WormBook

136

129

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Response of G Protein-Coupled Receptors and Ion Channels to Toxicants at Environmentally Relevant Concentrations

Wang

2022

Toxicology at Environmentally Relevant Concentrations in Caenorhabditis Elegans

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Inhibition of P-glycoprotein enhances sensitivity of Caenorhabditis elegans to ivermectin

Cited by 79 publications

References 48 publications

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans

Response of G Protein-Coupled Receptors and Ion Channels to Toxicants at Environmentally Relevant Concentrations

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