Faculty of Veterinary Medicine, University of Belgrade, Bulevar oslobodjenja 18, 11000 Belgrade, Serbia.
College of Veterinary Medicine, Iowa State University, Ames, IA, 50011, USA.
Vet Parasitol. 2020 Feb;278:109031. doi: 10.1016/j.vetpar.2020.109031. Epub 2020 Jan 20.
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 of pyrantel, morantel and bephenium by 29%, 39% and 12 %, 39 % and 12 % respectively. The EC ratio was 3.43, 2.95 and 2.47 for pyrantel, morantel and bephinium, respectively. Carvacrol 300 u μM reduces the E of pyrantel, morantel and bephenium by 71%, 80% and 75 %, 80 % and 75 % respectively. The EC 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 (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.
寄生虫线虫的神经肌肉系统已被证明是抗蠕虫药物的有效药理靶点。一些最常用的驱虫药物是烟碱型乙酰胆碱受体（nAChR）的激动剂或拮抗剂。香芹酚抗线虫的作用机制涉及抑制寄生虫肌肉收缩。我们研究了香芹酚与作为不同亚型 nAChR 激动剂的驱虫药物以及莫能菌素的相互作用，莫能菌素是猪蛔虫中该受体的非竞争性拮抗剂。此外，我们还研究了香芹酚对哺乳动物宿主肌肉型 nAChR 的影响。作为 nAChR 的变构激动剂，噻嘧啶、左咪唑和苯并咪唑导致猪蛔虫的神经肌肉制剂产生剂量依赖性收缩。100 μM 的香芹酚使噻嘧啶、左咪唑和苯并咪唑的 E 降低了 29%、39%和 12%、39%和 12%。噻嘧啶、左咪唑和苯并咪唑的 EC 比值分别为 3.43、2.95 和 2.47。300 μM 的香芹酚使噻嘧啶、左咪唑和苯并咪唑的 E 降低了 71%、80%和 75%、80%和 75%。噻嘧啶、左咪唑和苯并咪唑的 EC 比值分别为 3.88、3.19 和 4.83。此外，香芹酚增强了莫能菌素对猪蛔虫收缩的抑制作用，这可能具有有效的临床应用。另一方面，测试浓度的香芹酚对大鼠膈神经诱导的收缩没有显著影响，这表明在哺乳动物中，香芹酚与肌肉终板的突触后 nAChR 没有相互作用，但最高浓度（300 μM）引起明显的强直性褪色。香芹酚对大鼠的转棒性能表现出时间和剂量依赖性的影响，其 ED 值很高（421.6 mg/kg）。在我们的研究中，香芹酚在猪蛔虫中主要表现为 nAChR 的非竞争性拮抗剂的特征，并增强了莫能菌素的抑制作用。莫能菌素和香芹酚的联合使用可能在临床上非常有效，香芹酚分子本身可以作为开发新驱虫药物的有前途的平台。
