Amliwala, K., Willson, J., Holden-Dye, L., Harder, A. and Walker, R.J.
Effect of the anthelmintic emodepside on locomotion in C-elegans, and on the somatic muscle of A-suum.
Journal of Physiology, 543, (S222), .
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Emodepside is an anthelmintic with a distinct mode of action which may involve a latrophilin receptor (Bernt et al. 1998). Here we report preliminary studies using the nematode Caenorhabditis elegans for behaviour and Ascaris suum for physiology, with the aim of identifying the genetic basis of emodepside action.
The effect of emodepside on a synchronized population of C. elegans (N2 Bristol strain) was determined. Approximately 100 eggs were placed on agar plates containing E. coli (OP50) and either emodepside (100 pMÐ90 nM) or vehicle control (1 % ethanol). The developmental progress of the worm was monitored for 5 days. The effect of emodepside on locomotion was determined by counting body bends/min. Emodepside had no observable effect on larval stages of C. elegans at any of the concentrations tested. However, in mature fertile adults there was a concentration-dependent effect on locomotion. The threshold for this effect was observed at 4.5 nM (13 ± 2 compared with control 25 ± 1 body bends/min, n = 4), and at 90 nM locomotion was dramatically decreased (P < 0.0001, Student's unpaired t test) to 1.3 ± 0.3 body bends/min (means ± S.E.M.). This suggests emodepside interacts with a target that is expressed, or is functionally important, in the adults only. Furthermore, this target is involved in motor control.
To determine whether the effect of emodepside may be mediated pre- or postsynaptic to the neuromuscular junction, we performed physiological experiments on an in vitro preparation of A. suum body wall muscle as described by Trim et al. (1997). The effect of drugs on muscle tension was compared for muscle strips with or without nerve cord. The excitatory neuromuscular junction transmitter acetylcholine, ACh (30 µM), elicited a rapid and reversible contraction in both preparations. Emodepside (10 µM) inhibited this contraction in muscle with nerve cord but not in denervated muscle (39 ± 6 % inhibition with nerve cord, n = 7; 0.5 ± 6 % inhibition in denervated muscle, n = 6; means ± S.E.M.).
These data show that emodepside has an inhibitory action on locomotion and that its action in the nematode motor nervous system is likely to be presynaptic to the neuromuscular junction. We are currently investigating the role of C. elegans candidate latrophilin-like receptors in the mode of action of emodepside.
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