TY  - JOUR
AU  - Abongwa, Melanie
AU  - Marjanović, Đorđe
AU  - Tipton, James G.
AU  - Zheng, Fudan
AU  - Martin, Richard J.
AU  - Trailović, Saša
AU  - Robertson, Alan P.
PY  - 2018
UR  - https://vet-erinar.vet.bg.ac.rs/handle/123456789/1622
AB  - Zolvix (R) is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs) in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes. Using two-electrode voltagec-lamp electrophysiology, we studied the effects of monepantel on a nicotine preferring homomeric nAChR subtype from A. suum comprising of ACR-16; a pyrantel/tribendimidine preferring heteromeric subtype from O. dentatum comprising UNC-29, UNC-38 and UNC-63 subunits; and a levamisole preferring subtype (O. dentatum) comprising UNC-29, UNC-38, UNC-63 and ACR-8 subunits. For each subtype tested, monepantel applied in isolation produced no measurable currents thereby ruling out an agonist action. When monepantel was continuously applied, it reduced the amplitude of acetylcholine induced currents in a concentration-dependent manner. In all three subtypes, monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 from A. suum was particularly sensitive to monepantel inhibition (IC50 values: 1.6 +/- 3.1 nM and 0.2 +/- 2.3 mu M). We also investigated the effects of monepantel on muscle flaps isolated from adult A. suum. The drug did not significantly increase baseline tension when applied on its own. As with acetylcholine induced currents in the heterologously expressed receptors, contractions induced by acetylcholine were antagonized by monepantel. Further investigation revealed that the inhibition was a mixture of competitive and non-competitive antagonism. Our findings suggest that monepantel is active on multiple nAChR subtypes.
PB  - Elsevier Sci Ltd, Oxford
T2  - International Journal for Parasitology-Drugs and Drug Resistance
T1  - Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum
VL  - 8
IS  - 1
SP  - 36
EP  - 42
DO  - 10.1016/j.ijpddr.2017.12.001
ER  - 

@article{
author = "Abongwa, Melanie and Marjanović, Đorđe and Tipton, James G. and Zheng, Fudan and Martin, Richard J. and Trailović, Saša and Robertson, Alan P.",
year = "2018",
abstract = "Zolvix (R) is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs) in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes. Using two-electrode voltagec-lamp electrophysiology, we studied the effects of monepantel on a nicotine preferring homomeric nAChR subtype from A. suum comprising of ACR-16; a pyrantel/tribendimidine preferring heteromeric subtype from O. dentatum comprising UNC-29, UNC-38 and UNC-63 subunits; and a levamisole preferring subtype (O. dentatum) comprising UNC-29, UNC-38, UNC-63 and ACR-8 subunits. For each subtype tested, monepantel applied in isolation produced no measurable currents thereby ruling out an agonist action. When monepantel was continuously applied, it reduced the amplitude of acetylcholine induced currents in a concentration-dependent manner. In all three subtypes, monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 from A. suum was particularly sensitive to monepantel inhibition (IC50 values: 1.6 +/- 3.1 nM and 0.2 +/- 2.3 mu M). We also investigated the effects of monepantel on muscle flaps isolated from adult A. suum. The drug did not significantly increase baseline tension when applied on its own. As with acetylcholine induced currents in the heterologously expressed receptors, contractions induced by acetylcholine were antagonized by monepantel. Further investigation revealed that the inhibition was a mixture of competitive and non-competitive antagonism. Our findings suggest that monepantel is active on multiple nAChR subtypes.",
publisher = "Elsevier Sci Ltd, Oxford",
journal = "International Journal for Parasitology-Drugs and Drug Resistance",
title = "Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum",
volume = "8",
number = "1",
pages = "36-42",
doi = "10.1016/j.ijpddr.2017.12.001"
}

Abongwa, M., Marjanović, Đ., Tipton, J. G., Zheng, F., Martin, R. J., Trailović, S.,& Robertson, A. P.. (2018). Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum. in International Journal for Parasitology-Drugs and Drug Resistance
Elsevier Sci Ltd, Oxford., 8(1), 36-42.
https://doi.org/10.1016/j.ijpddr.2017.12.001

Abongwa M, Marjanović Đ, Tipton JG, Zheng F, Martin RJ, Trailović S, Robertson AP. Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum. in International Journal for Parasitology-Drugs and Drug Resistance. 2018;8(1):36-42.
doi:10.1016/j.ijpddr.2017.12.001 .

Abongwa, Melanie, Marjanović, Đorđe, Tipton, James G., Zheng, Fudan, Martin, Richard J., Trailović, Saša, Robertson, Alan P., "Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum" in International Journal for Parasitology-Drugs and Drug Resistance, 8, no. 1 (2018):36-42,
https://doi.org/10.1016/j.ijpddr.2017.12.001 . .