The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel
The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel
复制标题
DOI：
10.1016/j.taap.2017.10.012
复制
发表时间：
2017-12-01
影响因子：
3.8
通讯作者：
Babes, Alexandru
中科院分区：
文献类型：
--
作者：
Babes, Ramona-Madalina;Selescu, Tudor;Babes, Alexandru
吡喹酮是治疗血吸虫病的最有效的驱虫药，血吸虫病是一种由曼氏血吸虫引起的传染病。虽然已知吡喹酮会触发钙流入裂口线虫，随后导致蠕虫痉挛性麻痹和体表破坏，但尚未完全了解药物的作用机制。尽管吡喹酮的耐受性相对较好，但据报道它会引起轻微的副作用，包括恶心、腹痛和头痛。近年来，在沙门氏菌中发现了大量的瞬时受体电位（TRP）通道基因。为了研究吡喹酮对TRP melastatin type 8（TRPM 8）、TRP vanilloid type 1（TRPV 1）和TRP ankyrin type 1（TRPA 1）三种哺乳动物TRP通道的影响，我们采用了mansoni方法。采用钙荧光显微镜和膜片钳技术，我们记录了吡喹酮对表达重组TRPM8，TRPV1或TRPA1的HEK293T细胞，以及对培养的野生型和TRPM8无效突变小鼠背根神经节（DRG）神经元的影响。我们发现吡喹酮是哺乳动物和鸟类感冒和薄荷醇受体TRPM8的相对有效和选择性的部分激动剂。临床相关浓度的吡喹酮对培养的DRG神经元的激活主要由TRPM 8介导。我们的研究结果可能为更好地了解吡喹酮的作用机制及其不良反应提供线索。
Praziquantel is the most effective anthelminthic drug for the treatment of schistosomiasis, an infectious disease caused by the platyhelminth Schistosoma mansoni. While praziquantel is known to trigger calcium influx into schisostomes, followed by spastic paralysis of the worms and tegumental disruption, the mechanism of action of the drug is not completely understood. Although relatively well tolerated, praziquantel has been reported to cause mild adverse effects, including nausea, abdominal pain and headaches. As a number of putative Transient Receptor Potential (TRP) channel genes have recently been predicted in S. mansoni, we sought to investigate the effect of praziquantel on three mammalian TRP channels, TRP melastatin type 8 (TRPM8), TRP vanilloid type 1 (TRPV1) and TRP ankyrin type 1 (TRPA1). Using calcium microfluorimetry and the patch clamp technique, we recorded the effect of praziquantel on HEK293T cells expressing recombinant TRPM8, TRPV1 or TRPA1, as well as on cultured dorsal root ganglion (DRG) neurons from wild type and TRPM8 null mutant mice. We discovered that praziquantel is a relatively potent and selective partial agonist of the mammalian and avian cold and menthol receptor TRPM8. The activation of cultured DRG neurons by clinically relevant concentrations of praziquantel is predominantly mediated by TRPM8. Our results may provide clues to a better understanding of praziquantel's mechanism of action and its adverse effects.