Changes in the acetylcholinesterase activity of the nematode Nippostrongylus brasiliensis following treatment with benzimidazoles in vivo

Rapson, E. B.; Lee, Donald L.; Watts, Stuart D.M.

doi:10.1016/0166-6851(81)90024-4

Cited by 11 publications

(5 citation statements)

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“…of acetylcholinesterase (AChE) from Nippostrongylus brasiliensis, provide insight on the downstream effect of accumulation of these granules. While BZs induce accumulation of AChE in the organism, there is a rapid and marked suppression of AChE secreted to media [32,48]. Consistent results have been reported for AChE secretion by Heligmosomoides polygyrus adults [33] and total protein released by Brugia malayi microfilariae [22].…”

Section: Open Accesssupporting

confidence: 79%

“…Whether this effect triggers parasite clearance remains unproven. However, an important aspect of the N. brasiliensis work is the correlation between the accumulation of AChE (due to inhibition of protein secretion) and the dynamics of worm expulsion in vivo [48], indicating that this is plausible, at least for gastrointestinal (GI) nematodes.…”

Section: Open Accessmentioning

confidence: 99%

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When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions

Moreno

Geary

Tritten

2021

Trends in Parasitology

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Helminth secretomes comprise many potential immunomodulators. The molecular and functional diversity of these entities and their importance at the host-parasite interface have been increasingly recognized. It is now common to hypothesize that parasite-derived molecules (PDMs) are essential mediators used by parasites to establish and remain in their hosts. Suppression of PDM release has been reported for two anthelmintic drug classes, the benzimidazoles and macrocyclic lactones, the mechanisms of action of which remain incompletely resolved. We propose that bringing together recent insights from different streams of parasitology research, for example, immunoparasitology and pharmacology, will stimulate the development of new ways to alter the host-parasite interface in the search for novel anthelmintic strategies. Altering the Host-Parasite Interface as a Strategy for Helminth Control Mammals, including humans, have been selected through evolution for resistance to almost all parasites. Nonetheless, certain species of parasites have evolved the ability to infect selected host species (permissive hosts) by overcoming or manipulating the normally highly effective host immune system. Understanding how parasite species colonize permissive hostswhile being excluded from nonpermissive hostshas been a long-standing challenge in parasitology research, but recent advances in our ability to decipher the language of the host-parasite interface have begun to illuminate key factors that determine the outcome of this interaction [1]. The intriguing possibility of rationally converting permissive into nonpermissive hosts as a therapeutic strategy warrants more research into the composition of parasite secretomes (see Glossary), identification of the molecules that enable them to establish in the host, and the mechanisms by which these molecules are released to the host milieu. Helminths are complex metazoan organisms that belong to different taxonomic families, many members of which have adopted a parasitic lifestyle. The pathologies they cause in humans and animals, and their deleterious impact on crop production, represent threats to socioeconomic development [2-5]. In addition, progression of drug resistance has been rapid, especially among livestock parasites [5,6]. Expansion of the toolkit for helminth control is urgently needed, as is the acquisition of a deeper understanding of the mechanisms behind current anthelmintic therapies, which might, in turn, inspire new approaches to therapeutic intervention. Focusing on nematodes, we present scenarios in which anthelmintic therapy seems to alter host-parasite crosstalk via the suppression of parasite excretion/secretion processes. We further propose that current anthelmintic screening approaches, from empirical to rational, should be expanded to incorporate these processes as an important source of drug targets. The literature suggests that these basic principles apply to helminths beyond the phylum Nematoda.

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Section: Open Accesssupporting

confidence: 79%

Section: Open Accessmentioning

confidence: 99%

When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions

Moreno

Geary

Tritten

2021

Trends in Parasitology

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“…in Ascaris suum and Syngamus tracheae, Borgers, De Nollin, De Brabander & Thienpont (1975); Kohler & Bachman (1980)) and other tissues; benzimidazole resistance may be due to alterations in parasite tubulin and the kinetics of drug binding rather than any surface-mediated event (Lacey & Pritchard, 1986). The proposed mode of action of BZ drugs and ancillary phenomena, such as the induction of increased acetylcholinesterase activity (Rapson, Lee & Watts, 1981;Rapson, Chilwan & Jenkins, 1986), suggest that the parasite surface is unlikely to be involved in parasite -drug interactions.…”

Section: Nematodesmentioning

confidence: 99%

The interactions between drugs and the parasite surface

Chappell

1988

Parasitology

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SUMMARYThe interrelationships between drugs and parasite surfaces are considered under the headings of (a) effects on membrane transport, (b) drug uptake mechanisms and (c) effects on surface morphology and function: praziquantel is discussed under a separate heading. The range of chemotherapeutic compounds that cause permeability changes and concomitant morphological disruption is discussed in terms of mode of drug action. Interpretation of the available data renders it difficult to identify the primary mode of action in the drugs considered. Drug uptake mechanisms are known for relatively few compounds; drug resistance as a function of drug acquisition is discussed. The role of the parasite surface as a specific drug target is argued.

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“…benzimidazole-based drugs have been observed by other workers. Rapson et al (1981) found that treatment of rats with either oxfendazole or mebendazole caused a marked accumulation of acetylcholinesterase in the parasitic nematode Nippostrongylus brasiliensis. It appeared that this was the result of inhibition of the excretion of the enzyme to the exterior of the worms.…”

Section: Discussionmentioning

confidence: 98%

The genetics, ultrastructure, and tubulin polypeptides of mebendazole-resistant mutants of Caenorhabditis elegans

Woods¹,

Malone²,

Spence³

et al. 1989

Can. J. Zool.

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1989. The genetics, ultrastructure, and tubulin polypeptides of mebendazole-resistant mutants of Caenorhabditis elegans. Can. J. Zool. 67: 2422 -2431. Mebendazole-resistant mutants of Caenorhabditis elegans were isolated following mutagenesis of the wild-type strain, N2, with ethylmethane sulphonate. The mutants define a single autosomal gene and are allelic to ben-1. They grow, move, and reproduce normally in the presence of mebendazole and are cross-resistant to albendazole, cambendazole, fenbendazole, methylbenzimidazole carbamate, and thiabendazole. Accumulations of membrane-bound, electron-dense material associated with the nervous tissue and associated cells are seen in electron micrographs of L3, LA, and adult stages of N2 grown in the presence of mebendazole, but are not found in the mutants. The electron-dense material appears to be associated with the accessory cells of the neuropil rather than with the neurons. The tubulins from wild type, N2, and the mutants were characterised by two-dimensional electrophoresis followed by silver staining and Western blotting with monoclonal antibodies to a -and P-tubulin. A single isotype of a-tubulin is apparent in both N2 and the mutants. One major and three minor P-tubulin isotypes, bt-1 to bt-3, can be discerned in N2; the minor isotype bt-2 is absent in all the mutants. These findings suggest that the isotype bt-2 is the primary site of action of benzimidazole-based drugs in C. elegans.

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Changes in the acetylcholinesterase activity of the nematode Nippostrongylus brasiliensis following treatment with benzimidazoles in vivo

Cited by 11 publications

References 11 publications

When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions

When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions

The interactions between drugs and the parasite surface

The genetics, ultrastructure, and tubulin polypeptides of mebendazole-resistant mutants of Caenorhabditis elegans

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