Carvacrol acts as a potent selective antagonist of different types of nicotinic acetylcholine receptors and enhances the effect of monepantel in the parasitic nematode Ascaris suum.

Autor: Marjanović DS; Faculty of Veterinary Medicine, University of Belgrade, Bulevar oslobodjenja 18, 11000 Belgrade, Serbia. Electronic address: drdjolevet@yahoo.com., Zdravković N; Faculty of Veterinary Medicine, University of Belgrade, Bulevar oslobodjenja 18, 11000 Belgrade, Serbia. Electronic address: nemanja.zdravkovich@gmail.com., Milovanović M; Faculty of Veterinary Medicine, University of Belgrade, Bulevar oslobodjenja 18, 11000 Belgrade, Serbia. Electronic address: miram@vet.bg.ac.rs., Trailović JN; Faculty of Veterinary Medicine, University of Belgrade, Bulevar oslobodjenja 18, 11000 Belgrade, Serbia. Electronic address: tjelena@vet.bg.ac.rs., Robertson AP; College of Veterinary Medicine, Iowa State University, Ames, IA, 50011, USA. Electronic address: alanr@iastate.edu., Todorović Z; Faculty of Medicine, University of Belgrade, Doktora Subotića 8, 11000 Belgrade, Serbia. Electronic address: zoran.todorovic@med.bg.ac.rs., Trailović SM; Faculty of Veterinary Medicine, University of Belgrade, Bulevar oslobodjenja 18, 11000 Belgrade, Serbia. Electronic address: sasa@vet.bg.ac.rs.
Jazyk: angličtina
Zdroj: Veterinary parasitology [Vet Parasitol] 2020 Feb; Vol. 278, pp. 109031. Date of Electronic Publication: 2020 Jan 20.
DOI: 10.1016/j.vetpar.2020.109031
Abstrakt: The neuromuscular system of parasitic nematodes has proven to be an efficient pharmacological target for antihelmintics. Some of the most frequently used antiparasitic drugs are agonists or antagonists of nicotinic acetylcholine receptors (nAChRs). The antinematodal mechanism of action of carvacrol involves the inhibition of parasite muscle contraction. We have examined the interaction of carvacrol with antinematodal drugs that are agonists of different subtypes of nAChRs and monepantel, which is a non-competitive antagonist of this receptor in A. suum. Additionally, we investigated the effect of carvacrol on the muscle type of nAChRs in the mammalian host. As orthosteric agonists of nAChR, pyrantel, morantel and befinijum lead to dose-dependent contractions of the neuromuscular preparation of Ascaris suum. Carvacrol 100 μM decreased the E max of pyrantel, morantel and bephenium by 29%, 39% and 12 %, 39 % and 12 % respectively. The EC 50 ratio was 3.43, 2.95 and 2.47 for pyrantel, morantel and bephinium, respectively. Carvacrol 300 u μM reduces the E max of pyrantel, morantel and bephenium by 71%, 80% and 75 %, 80 % and 75 % respectively. The EC 50 ratio for pyrantel, morantel and bephenium was 3.88, 3.19 and 4.83 respectively. Furthermore, carvacrol enhances the inhibitory effect of monepantel on A. suum contractions, which may have an effective clinical application. On the other hand, tested concentrations of carvacrol did not significantly affect the EFS-induced contractions of the rat diaphragm, indicating a lack of interaction with the postsynaptic nAChR at the muscle end plate in mammals, but the highest concentration (300 μM) caused a clear tetanic fade. Carvacrol exhibited a time and dose-dependent effect on the Rota-rod performances of rats with a high value of the ED 50 (421.6 mg/kg). In our research, carvacrol dominantly exhibited characteristics of a non-competitive antagonist of nAChR in A. suum, and enhances the inhibitory effect of monepantel. The combination of monepantel and carvacrol may be clinically very effective, and the carvacrol molecule itself can be used as a promising platform for the development of new anthelmintic drugs.
Competing Interests: Declaration of Competing Interest The authors have declared that no competing interests exist.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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