The anti-schistosomal drug praziquantel is an adenosine antagonist
The anti-schistosomal drug praziquantel is an adenosine antagonist
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DOI：
10.1017/s0031182007002600
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发表时间：
2007-08-01
期刊：
影响因子：
2.4
通讯作者：
Valle, C.
中科院分区：
文献类型：
--
作者：
Angelucci, F.;Basso, A.;Valle, C.
吡喹酮（PZQ）是抗血吸虫病的首选药物，其作用机制仍不清楚。由于血吸虫暴露于该药物与钙流入和肌肉收缩有关，因此钙通道被建议作为靶标，尽管 PZQ 与其亚基的直接组合从未得到证实。我们报告了 PZQ 迄今为止未知的作用，即抑制核苷摄取，正如使用放射性同位素标记的腺苷和尿苷在活体蠕虫中观察到的那样。这种效应在血吸虫中清晰可见，但在培养的哺乳动物细胞中不存在。此外，它是仅在药物的活性左-R(-)立体异构体中观察到的特定药理作用，并且是至少一种具有抗血吸虫活性的苯二氮卓类药物所共有的。鉴于血吸虫不能从头合成嘌呤核苷，这种新奇的效应具有重要意义。讨论了这种新作用与 PZQ 对钙通道的已知作用之间可能的关系，因为已知腺苷可与特定受体结合并充当哺乳动物细胞中钙释放的间接拮抗剂。如果钙通道在血吸虫中也与腺苷受体相关，就像在哺乳动物中一样，这将支持 PZQ 诱导的钙流入可能与腺苷受体阻断相关的假设。
The mechanism of action of praziquantel (PZQ), the drug of choice against schistosomiasis, is still unclear. Since exposure of schistosomes to the drug is associated with calcium influx and muscular contraction, calcium channels have been suggested as the target, although direct combination of PZQ with their subunits was never demonstrated. We report a hitherto unknown effect of PZQ, namely the inhibition of nucleoside uptake, as observed in living worms using radioisotope labelled adenosine and uridine. This effect is clearly seen in schistosomes but is absent in mammalian cells in culture. Moreover it is a specific pharmacological effect seen exclusively with the active levo-R(-)stereo isomer of the drug, and is shared by at least one benzodiazepine having antischistosomal activity. This novel effect acquires significance given that schistosomes cannot synthesize purine nucleosides de novo. A possible relationship between this novel effect and the known action of PZQ on calcium channels is discussed, since adenosine is known to bind to specific receptors and to behave as an indirect antagonist of calcium release in mammalian cells. If calcium channels were correlated with adenosine receptors also in schistosomes, as they are in mammals, this would support the hypothesis that PZQ-induced calcium influx may be correlated to adenosine receptor blockade.