Drug resistance and neurotransmitter receptors of nematodes: recent studies on the mode of action of levamisole

Abstract

Here we review recent studies on the mode of action of the cholinergic anthelmintics (levamisole, pyrantel etc.). We also include material from studies on the free living nematode Caenorhabditis elegans. The initial notion that these drugs act on a single receptor population, while attractive, has proven to be an oversimplification. In both free living and parasitic nematodes there are multiple types of nicotinic acetylcholine receptor (nAChR) on the somatic musculature. Each type has different (sometimes subtly so) pharmacological properties. The implications of these findings are: (1) combinations of anthelmintic that preferentially activate a broad range of nAChR types would be predicted to be more effective; (2) in resistant isolates of parasite where a subtype has been lost, other cholinergic anthelmintics may remain effective. Not only are there multiple types of nAChR, but relatively recent research has shown these receptors can be modulated; it is possible to increase the response of a parasite to a fixed concentration of drug by altering the receptor properties (e.g. phosphorylation state). These findings offer a potential means of increasing efficacy of existing compounds as an alternative to the costly and time consuming development of new anthelmintic agents.

Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans

“…Its mode of action has primarily been studied in A. suum where it acts as a weak GABA-mimetic and causes a flaccid, reversible paralysis of body wall muscle. Single channel recordings provide evidence that it is a low efficacy, partial agonist at GABA-gated chloride channels (Martin, 1985). Recently the action of piperazine has been investigated in C. elegans by comparing its action on wild type and mutants for unc-49, a gene which encodes C. elegans GABA A -like receptor subunits expressed at the body wall Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans neuromuscular junction (Miltsch et al, 2013).…”

“…These authors also found evidence that pyrantel and acetylcholine compete for the same receptor. Their precise mode of action has been carefully studied at the single-channel level on the body wall muscle preparation of A. suum (for review see Martin et al, 2005). Pharmacological analysis has provided evidence for subtypes of nACh receptor (Qian et al, 2006), an N-type (preferentially activated by nicotine), a B-type (preferentially activated by bephenium), and an L-type (preferentially activated by levamisole and associated with levamisole resistance).…”

“…These authors review the value of the C. elegans levamisole receptor as a model for parasitic nematodes and note that while C. elegans has levamisole-activated channels ranging from 26-36 pS, those in A. suum range from 18-53 pS (Qian et al, 2006;Levandoski et al, 2005). The reader is referred to an in-depth review relating levamisole research using C. elegans to research using parasitic nematodes by Martin et al (2012b). Another review compares the nAChRs of C. elegans with those of parasitic nematodes (Holden-Dye et al, 2013).…”

Functional genomics in Brugia malayi reveal diverse muscle nAChRs and differences between cholinergic anthelmintics

“…Their neuromuscular systems are unlike those of vertebrates because nematode muscles send processes to the motor neurons to form synapses, rather than the other way around. Membrane ion-channels, which regulate nematode neuromuscular systems, are target sites of major classes of anthelmintic drugs, including the cholinergic anthelmintics levamisole, pyrantel, and derquantel (10)(11)(12)(13)(14)(15)(16)(17). Here, we have combined a number of techniques for the study of muscle pentameric acetylcholine receptor channels (nAChRs) of the filarial nematode parasite, Brugia malayi.…”

Breaking-Out Bad: A Case of Levamisole-Induced Vasculitis

“…6 LIV is associated with several characteristic clinical, pathological, and serological findings. There is a 4:1 female predominance of clinical manifestations.…”