Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms.
Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms.
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DOI：
10.1371/journal.pone.0146854
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Martin RJ
中科院分区：
文献类型：
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作者：
Abongwa M;Buxton SK;Robertson AP;Martin RJ
线虫寄生虫可以用药物控制，但经常使用药物引起了对耐药性发展的担忧。药物组合可能比单一药物更有效，并延迟耐药性的发生。已发现烟碱拮抗剂derquantel和大环内酯abamectin的组合对胃肠道线虫寄生虫具有协同驱虫作用。我们已经观察到，在以前的收缩和电生理实验中，derquantel是一种有效的选择性拮抗剂线虫寄生虫肌肉烟碱受体，阿维菌素是一种抑制剂相同的烟碱受体。为了进一步探索这些抑制作用，我们在电压钳下在非洲爪蟾卵母细胞中表达结节蠕虫Oesophagostomum dentatum（Ode-29：Ode-63：Ode-38）的肌肉烟碱受体，并测试了阿维菌素对噻嘧啶和乙酰胆碱反应的影响。0.03 μM阿维菌素以非竞争性方式拮抗受体（Rmax降低，EC 50无变化）。当阿维菌素增加到0.1 μM时，这种拮抗作用增加。然而，当我们将阿维菌素的浓度进一步增加到0.3 μM、1 μM或10 μM时，我们发现拮抗作用降低并且小于0.1 μM阿维菌素。阿维菌素的双相效应表明阿维菌素作用于两个变构位点：一个高亲和力负变构（NAM）位点引起拮抗作用，另一个低亲和力正变构（PAM）位点引起拮抗作用降低。我们还测试了0.1 μM的derquantel单独使用以及与0.3 μM的阿维菌素联合使用的效果。我们发现，这些受体的derquantel，像阿维菌素，作为一个非竞争性拮抗剂，derquantel和阿维菌素的组合产生更大的抑制。这些观察结果证实了阿维菌素对线虫烟碱受体的拮抗作用，除了GluCl的影响，并说明了更复杂的大环内酯的影响，可以与其他驱虫剂的组合开发。
Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM derquantel alone and in combination with 0.3 μM abamectin. We found that derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.