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The Conqueror Worm: recent advances with cholinergic anthelmintics and techniques excite research for better therapeutic drugs.
Martin RJ
,
Puttachary S
,
Buxton SK
,
Verma S
,
Robertson AP
.
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The following account is based on a review lecture given recently at the British Society of Parasitology. We point out that nematode parasites cause very widespread infections of humans, particularly in economically underdeveloped areas where sanitation and hygiene are not adequate. In the absence of adequate clean water and effective vaccines, control and prophylaxis relies on anthelmintic drugs. Widespread use of anthelmintics to control nematode parasites of animals has given rise to the development of resistance and so there is a concern that similar problems will occur in humans if mass drug administration is continued. Recent research on the cholinergic anthelmintic drugs has renewed enthusiasm for the further development of cholinergic anthelmintics. Here we illustrate the use of three parasite nematode models, Ascaris suum, Oesophagostomum dentatum and Brugia malayi, microfluidic techniques and the Xenopus oocyte expression system for testing and examining the effects of cholinergic anthelmintics. We also show how the combination of derquantel, the selective nematode cholinergic antagonist and abamectin produce increased inhibition of the nicotinic acetylcholine receptors on the nematode body muscle. We are optimistic that new compounds and combinations of compounds can limit the effects of drug resistance, allowing anthelmintics to be continued to be used for effective treatment of human and animal helminth parasites.
Fig. 1. Edgar Allan Poe, the author of the poem The Conqueror Worm, which was first published in 1843. Daguerreotype of Poe by William S. Hartshorn (1848), Library of Congress, Prints and Photographs Division [#91796062].
Fig. 2. (colour online) Ascaris, Brugia and Oesophagostomum adult worms: (A) Ascaris suum, a single worm and scale bar (inset) and active swimming worms; (B) Brugia malayi, a single motile worm; (C) Oesophagostomum dentatum, female (top), male (bottom).
Fig. 3. (colour online) Microfluidic chamber with drug well and micro-channels. The L3 larvae of nematode parasites or adult Caenorhabditis elegans are placed in the input–output port (worm inlet 1/0 port) via syringe and catheter. They can be driven into the drug well and held under a voltage field, and released at a defined time by reversing the voltage. The escape and behaviour of the larvae/worms following entry into the drug field is tested at different drug concentrations. The swimming of the larvae/worms in the channels is described by a sinusoidal wave with measurement of frequency (N), wavelength (λ), amplitude (a) and velocity (v).
Fig. 4. (colour online) Expression of different parasite nAChRs using Xenopus oocyte expression reveals the effect of subunit combinations on anthelmintic sensitivity. Antagonism of derquantel depends on nAChR subtype, demonstrated using two of the four different expressed O. dentatum subunits that can occur. (A) Expression of Ode-UNC-63:Ode-UNC-29:Ode-UNC-38:Ode-ACR-8 in Xenopus oocytes produces receptors that, under voltage clamp, produce currents to acetylcholine, levamisole, tribendimidine, pyrantel, bephenium, thenium and nicotine, with the biggest current to levamisole. This receptor is competitively antagonized by derquantel (plot). (B) Expression of Ode-UNC-63:Ode-UNC-29:Ode-UNC-38 in Xenopus oocytes produces receptors that, under voltage clamp, produce currents to acetylcholine, levamisole, tribendimidine, pyrantel, bephenium, thenium and nicotine, with the biggest current to pyrantel. This receptor is non-competitively antagonized by derquantel (plot).
Fig. 5. (colour online) Photograph of an Ascaris body muscle flap being tested with levamisole under isometric contraction. The trace shows the contraction effect of levamisole applied in cumulative doses.
Fig. 6. (colour online) (A) Isometric contraction of Ascaris suum muscle strips produced by application of increasing concentrations of acetylcholine and antagonism by 1 μM derquantel, 1 μM derquantel + 0.3 μM abamectin and wash. Note that derquantel decreases the responses to acetylcholine and that the addition of abamectin increases the inhibition. (B) The concentration-depolarizing–response plot of acetylcholine, showing mean ± standard error (SE) bars. Control (n = 11, filled circles); in the presence of 1 μM derquantel (n = 11); 1 μM derquantel + 0.3 μM abamectin. The predicted additive effect is shown by the dashed line. The derquantel–abamectin combination is statistically (P < 0.05) more inhibitory than additive at concentrations > 10 μM acetylcholine.
Fig. 7. (colour online) Nomarski photomicrograph of a Brugia malayi muscle flap dissection with a diagram of a patch-pipette placed for whole-cell current clamp recording of the nicotinic receptors. Scale bar 10 μm. (B) Bar chart (mean ± SE) of normalized currents produced by the nAChR agonists/anthelmintics (30 μM) on B. malayi muscles in whole-cell patch-clamp. All current responses were normalized to ACh currents (*P < 0.05, paired t-test). Displayed above the bars are sample whole-cell current traces. Scale bar, horizontal 30 s, vertical 700 pA. (C) Plot of motility versus time (min) of adult female B. malayi in the absence and presence of 30 μM levamisole. Four worms/treatment were used for the assay. Comparisons of motility were made between control and treated worms at each time point, **P < 0.01, ***P < 0.001.
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