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

• Published in: Parasitology Vol. 131; no. S1; pp. S71 - S84
• Main Authors: MARTIN, R. J., VERMA, S., LEVANDOSKI, M., CLARK, C. L., QIAN, H., STEWART, M., ROBERTSON, A. P.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.01.2005
• Subjects: acetylcholine; Adenosine Triphosphate - metabolism; animal parasitic nematodes; Animals; anthelmintics; Antinematodal Agents - metabolism; Antinematodal Agents - pharmacology; Antiparasitic agents; Binding sites; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - enzymology; Caenorhabditis elegans - physiology; Cells; cholinergic anthelmintics; Cyclic AMP-Dependent Protein Kinases - metabolism; Drug resistance; Drug Resistance - physiology; Kinases; Larva - physiology; levamisole; Levamisole - metabolism; Levamisole - pharmacology; literature reviews; mechanism of action; Membrane Potentials - physiology; Mode of action; nAChR; Nematoda; Nematoda - drug effects; Nematoda - enzymology; Nematoda - metabolism; Nematoda - physiology; Nematodes; Neuropeptides - drug effects; Neuropeptides - physiology; neurotransmitters; nicotinic acetylcholine receptors; Parasites; Parasitology; Patch-Clamp Techniques - veterinary; Phosphoric Monoester Hydrolases - metabolism; Phosphotransferases - metabolism; Proteins; receptor modulation; receptor subtype; receptor subtypes; receptors; Receptors, Cholinergic - chemistry; Receptors, Cholinergic - classification; Receptors, Cholinergic - genetics; Receptors, Cholinergic - metabolism; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; resistance; receptor modulation; levamisole; receptor subtype; nAChR; resistance
• ISSN: 0031-1820; 1469-8161
• DOI: 10.1017/S0031182005008668

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.