Abstract
Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM derquantel alone and in combination with 0.3 μM abamectin. We found that derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.
Highlights
Gastro-intestinal nematode parasite infections of both humans and animals are a global public health problem
Other more recent drugs include the amino-acetonitrile derivatives which act on ligand-gated ion channels (LGICs) receptors comprised of DEG-3/DES-2 nicotinic acetylcholine receptor (nAChR) subunits [14]; and the cyclooctadepsipeptide whose mode of action is understood to be on SLO-1 potassium channels [15, 16] and latrophilin receptors [17]
Representative traces produced in response to different concentrations of acetylcholine and pyrantel are shown in Fig 2A and 2B respectively
Summary
Gastro-intestinal nematode parasite infections of both humans and animals are a global public health problem. These infections cause livestock production losses, morbidity, and if left uncontrolled, may result in death [1]. In the absence of effective sanitation and vaccines, control of nematode parasite infections is achieved by the use of anthelmintic drugs, many of which act on ligand-gated ion channels (LGICs) [2,3,4]. There are a limited number of anthelmintics which are currently approved for use [2] Those that act on nAChRs include: imidazothiazoles (levamisole) [7], tetrahydropyrimidine derivatives (pyrantel, oxantel, morantel) [8], spiroindoles (derquantel) [9], and tribendimidine [10]. Other more recent drugs include the amino-acetonitrile derivatives (monepantel) which act on LGICs receptors comprised of DEG-3/DES-2 nAChR subunits [14]; and the cyclooctadepsipeptide (emodepside) whose mode of action is understood to be on SLO-1 potassium channels [15, 16] and latrophilin receptors [17]
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