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
Samo za registrovane korisnike
2020
Autori
Marjanović, ĐorđeZdravković, Nemanja
Milovanović, Mirjana
Nedeljković-Trailović, Jelena
Robertson, Alan P.
Todorović, Zoran
Trailović, Saša
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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 mu M decreased the E-max of pyrantel, morantel and bephenium by 29%, 39% and 12 %, 39 % and 12 % respectively. The EC50 ratio was 3.43, 2.95 and 2.47 for pyrantel, mor...antel and bephinium, respectively. Carvacrol 300 u mu M reduces the E-max of pyrantel, morantel and bephenium by 71%, 80% and 75 %, 80 % and 75 % respectively. The EC50 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. mum 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 mu M) 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 ED50 (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.
Ključne reči:
Carvacrol / Monepantel / A. suum / nAChRIzvor:
Veterinary Parasitology, 2020, 278, UNSP 109031-Izdavač:
- Elsevier, Amsterdam
Finansiranje / projekti:
Napomena:
- Peer-reviewed manuscript: http://vet-erinar.vet.bg.ac.rs/handle/123456789/1841
DOI: 10.1016/j.vetpar.2020.109031
ISSN: 0304-4017
PubMed: 32032866
WoS: 000517852700012
Scopus: 2-s2.0-85078737583
Kolekcije
Institucija/grupa
Fakultet veterinarske medicineTY - JOUR AU - Marjanović, Đorđe AU - Zdravković, Nemanja AU - Milovanović, Mirjana AU - Nedeljković-Trailović, Jelena AU - Robertson, Alan P. AU - Todorović, Zoran AU - Trailović, Saša PY - 2020 UR - https://vet-erinar.vet.bg.ac.rs/handle/123456789/1807 AB - 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 mu M decreased the E-max of pyrantel, morantel and bephenium by 29%, 39% and 12 %, 39 % and 12 % respectively. The EC50 ratio was 3.43, 2.95 and 2.47 for pyrantel, morantel and bephinium, respectively. Carvacrol 300 u mu M reduces the E-max of pyrantel, morantel and bephenium by 71%, 80% and 75 %, 80 % and 75 % respectively. The EC50 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. mum 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 mu M) 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 ED50 (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. PB - Elsevier, Amsterdam T2 - Veterinary Parasitology T1 - 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 VL - 278 SP - UNSP 109031 DO - 10.1016/j.vetpar.2020.109031 ER -
@article{ author = "Marjanović, Đorđe and Zdravković, Nemanja and Milovanović, Mirjana and Nedeljković-Trailović, Jelena and Robertson, Alan P. and Todorović, Zoran and Trailović, Saša", year = "2020", abstract = "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 mu M decreased the E-max of pyrantel, morantel and bephenium by 29%, 39% and 12 %, 39 % and 12 % respectively. The EC50 ratio was 3.43, 2.95 and 2.47 for pyrantel, morantel and bephinium, respectively. Carvacrol 300 u mu M reduces the E-max of pyrantel, morantel and bephenium by 71%, 80% and 75 %, 80 % and 75 % respectively. The EC50 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. mum 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 mu M) 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 ED50 (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.", publisher = "Elsevier, Amsterdam", journal = "Veterinary Parasitology", title = "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", volume = "278", pages = "UNSP 109031", doi = "10.1016/j.vetpar.2020.109031" }
Marjanović, Đ., Zdravković, N., Milovanović, M., Nedeljković-Trailović, J., Robertson, A. P., Todorović, Z.,& Trailović, S.. (2020). 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. in Veterinary Parasitology Elsevier, Amsterdam., 278, UNSP 109031. https://doi.org/10.1016/j.vetpar.2020.109031
Marjanović Đ, Zdravković N, Milovanović M, Nedeljković-Trailović J, Robertson AP, Todorović Z, Trailović S. 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. in Veterinary Parasitology. 2020;278:UNSP 109031. doi:10.1016/j.vetpar.2020.109031 .
Marjanović, Đorđe, Zdravković, Nemanja, Milovanović, Mirjana, Nedeljković-Trailović, Jelena, Robertson, Alan P., Todorović, Zoran, Trailović, Saša, "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" in Veterinary Parasitology, 278 (2020):UNSP 109031, https://doi.org/10.1016/j.vetpar.2020.109031 . .