Comparative neuromuscular blocking actions of levamisole and pyrantel-type anthelmintics on rat and gastrointestinal nematode somatic muscle

Atchison, William D.; Geary, Timothy G.; Manning, Benjamin; VandeWaa, Elizabeth A.; Thompson, David P.

doi:10.1016/0041-008x(92)90289-5

Cited by 26 publications

(24 citation statements)

References 17 publications

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“…Therefore, it seems likely that both the position and the type of amino acid are important in making AChRs highly sensitive to anthelmintics. potential have shown that the spastic contraction evoked by levamisole is quantitatively similar to that evoked by ACh in the muscle of H. contortus, which is 10 -100 times more sensitive to the acute action of levamisole than the rat muscle (2).…”

Section: Achrs By Levamisolementioning

confidence: 85%

“…The efficacy of these drugs is based on their ability to act as full agonists of AChRs in nematodes (1). Contractility and membrane potential measurements have shown that the nematode axial muscle is 10 -100 times more sensitive to the acute action of pyrantel and levamisole than the rat muscle (2). The molecular bases of this selectivity have not been yet elucidated.…”

mentioning

confidence: 99%

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Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Rayes

Rosa

Bartos

et al. 2004

Journal of Biological Chemistry

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Levamisole is an anthelmintic agent that exerts its therapeutic effect by acting as a full agonist of the nicotinic receptor (AChR) of nematode muscle. Its action at the mammalian muscle AChR has not been elucidated to date despite its wide use as an anthelmintic in humans and cattle. By single channel and macroscopic current recordings, we investigated the interaction of levamisole with the mammalian muscle AChR. Levamisole activates mammalian AChRs. However, single channel openings are briefer than those activated by acetylcholine (ACh) and do not appear in clusters at high concentrations. The peak current induced by levamisole is about 3% that activated by ACh. Thus, the anthelmintic acts as a weak agonist of the mammalian AChR. Levamisole also produces open channel blockade of the AChR. The apparent affinity for block (190 M at ؊70 mV) is similar to that of the nematode AChR, suggesting that differences in channel activation kinetics govern the different sensitivity of nematode and mammalian muscle to anthelmintics. To identify the structural basis of this different sensitivity, we performed mutagenesis targeting residues in the ␣ subunit that differ between vertebrates and nematodes. The replacement of the conserved ␣Gly-153 with the homologous glutamic acid of nematode AChR significantly increases the efficacy of levamisole to activate channels. Channel activity takes place in clusters having two different kinetic modes. The kinetics of the high open probability mode are almost identical when the agonist is ACh or levamisole. It is concluded that ␣Gly-153 is involved in the low efficacy of levamisole to activate mammalian muscle AChRs.At the neuromuscular junction, acetylcholine (ACh) 1 mediates fast neurotransmission by activating nicotinic receptors (AChRs). AChRs in nematode muscle are targets for anthelmintic chemotherapy. Levamisole and pyrantel are two widely used anthelmintic drugs. By binding to the AChR they lead to a depolarization of the somatic muscle of nematodes. The efficacy of these drugs is based on their ability to act as full agonists of AChRs in nematodes (1). Contractility and membrane potential measurements have shown that the nematode axial muscle is 10 -100 times more sensitive to the acute action of pyrantel and levamisole than the rat muscle (2). The molecular bases of this selectivity have not been yet elucidated. The kinetics of activation of nematode AChRs by levamisole has been studied in several preparations from parasite muscle (1, 3), but its action on mammalian muscle AChRs has not been described to date. The effects of levamisole on human neuronal ␣ 3 ␤ 2 and ␣ 3 ␤ 4 AChRs have been studied recently (4) with the voltage clamp method. It was shown that levamisole behaves as a weak partial agonist, an allosteric modulator, and an open channel blocker of neuronal AChRs (4).ACh is responsible for neuromuscular transmission in nematodes (1). In Caenorhabditis elegans muscle, levamisoleactivated AChRs are composed of the unc-38 subunit, which encodes an ␣ subunit, and lev-1 and...

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Section: Achrs By Levamisolementioning

confidence: 85%

mentioning

confidence: 99%

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Rayes

Rosa

Bartos

et al. 2004

Journal of Biological Chemistry

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“…Levamisole was shown to be the effective compound while dexamisole has no anthelmintic properties (Bullock et al 1968). The action of tetramisole and levamisole consists in a paralysis of the nematodes (Thienpont et al 1966;Aceves et al 1970;Atchison et al 1992). Nematode paralysis results from a maintained depolarization of their muscle cells (Aceves et al 1970;Harrow and Gration 1985;Atchison et al 1992).…”

Section: Tetramisole Levamisole and Acetylcholine Receptorsmentioning

confidence: 99%

“…The action of tetramisole and levamisole consists in a paralysis of the nematodes (Thienpont et al 1966;Aceves et al 1970;Atchison et al 1992). Nematode paralysis results from a maintained depolarization of their muscle cells (Aceves et al 1970;Harrow and Gration 1985;Atchison et al 1992). Muscle cell depolarization is the consequence of levamisole acting as an agonist on neuromuscular acetylcholine (ACh) receptors of the nematode (Lewis et al 1980;Harrow and Gration 1985;Robertson and Martin 1993).…”

Section: Tetramisole Levamisole and Acetylcholine Receptorsmentioning

confidence: 99%

Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex

Nowak

Rosay

Czégé

et al. 2015

Subcellular Biochemistry

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Tissue non-specific alkaline phosphatase (TNAP) may be involved in the synthesis of GABA and adenosine, which are the main inhibitory neurotransmitters in cortex. We explored this putative TNAP function through electrophysiological recording (local field potential ) in slices of mouse somatosensory cortex maintained in vitro. We used tetramisole, a well documented TNAP inhibitor, to block TNAP activity. We expected that inhibiting TNAP with tetramisole would lead to an increase of neuronal response amplitude, owing to a diminished availability of GABA and/or adenosine. Instead, we found that tetramisole reduced neuronal response amplitude in a dose-dependent manner. Tetramisole also decreased axonal conduction velocity. Levamisole had identical effects. Several control experiments demonstrated that these actions of tetramisole were independent from this compound acting on TNAP. In particular, tetramisole effects were not stereo-specific and they were not mimicked by another inhibitor of TNAP, MLS-0038949. The decrease of axonal conduction velocity and preliminary intracellular data suggest that tetramisole blocks voltage-dependent sodium channels. Our results imply that levamisole or tetramisole should not be used with the sole purpose of inhibiting TNAP in living excitable cells as it will also block all processes that are activity-dependent. Our data and a review of the literature indicate that tetramisole may have at least four different targets in the nervous system. We discuss these results with respect to the neurological side effects that were observed when levamisole and tetramisole were used for medical purposes, and that may recur nowadays due to the recent use of levamisole and tetramisole as cocaine adulterants.

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“…In vivo animal assays are undoubtedly the best way to test parasitic worms in their natural growth environment. 5,15,16 These assays, however, require large quantities of the compounds, huge spaces to house the animals, long wait times, and thus higher research costs. Tests on smaller rodents such as mice and chicken are pragmatic but require about 100 mg of the chemical and are impractical for any large-scale random experiments with multiple chemicals.…”

Section: Introductionmentioning

confidence: 99%

Microfluidics-enabled method to identify modes of Caenorhabditis elegans paralysis in four anthelmintics

2013

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The discovery of new drugs is often propelled by the increasing resistance of parasites to existing drugs and the availability of better technology platforms. The area of microfluidics has provided devices for faster screening of compounds, controlled sampling/sorting of whole animals, and automated behavioral pattern recognition. In most microfluidic devices, drug effects on small animals (e.g., Caenorhabditis elegans) are quantified by an end-point, dose response curve representing a single parameter (such as worm velocity or stroke frequency). Here, we present a multi-parameter extraction method to characterize modes of paralysis in C. elegans over an extended time period. A microfluidic device with real-time imaging is used to expose C. elegans to four anthelmintic drugs (i.e., pyrantel, levamisole, tribendimidine, and methyridine). We quantified worm behavior with parameters such as curls per second, types of paralyzation, mode frequency, and number/duration of active/immobilization periods. Each drug was chosen at EC 75 where 75% of the worm population is responsive to the drug. At equipotent concentrations, we observed differences in the manner with which worms paralyzed in drug environments. Our study highlights the need for assaying drug effects on small animal models with multiple parameters quantified at regular time points over an extended period to adequately capture the resistance and adaptability in chemical environments. V C 2013 AIP Publishing LLC. [http://dx

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Comparative neuromuscular blocking actions of levamisole and pyrantel-type anthelmintics on rat and gastrointestinal nematode somatic muscle

Cited by 26 publications

References 17 publications

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex

Microfluidics-enabled method to identify modes of Caenorhabditis elegans paralysis in four anthelmintics

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