The Antiemetic 5-HT3 Receptor Antagonist Palonosetron Inhibits Substance P-Mediated Responses In Vitro and In Vivo
The Antiemetic 5-HT3 Receptor Antagonist Palonosetron Inhibits Substance P-Mediated Responses In Vitro and In Vivo
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DOI：
10.1124/jpet.110.166181
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发表时间：
2010-11-01
影响因子：
3.5
通讯作者：
Slusher, Barbara S.
中科院分区：
文献类型：
--
作者：
Rojas, Camilo;Li, Ying;Slusher, Barbara S.
帕洛诺司琼是唯一一种被批准用于治疗中度致吐化疗中延迟化疗诱导的恶心和呕吐（CINV）的5-HT 3受体拮抗剂。越来越多的证据表明，P物质（SP），优先作用于神经激肽-1（NK-1）受体的内源性配体，而不是5-羟色胺（5-HT），是延迟性呕吐的主要介质。然而，帕洛诺司琼不与NK-1受体结合。最近的数据显示NK-1和5-HT（3）受体信号通路之间存在串扰;我们假设，如果帕洛诺司琼差异性地抑制NK-1/5-HT 3串扰，则有助于解释其在延迟性呕吐中的疗效。因此，我们评估了帕洛诺司琼，格拉司琼，昂丹司琼对SP诱导的反应在体外和体内的效果。NG 108 -15细胞与帕洛诺司琼，格拉司琼，或昂丹司琼预孵育;拮抗剂被删除，并测定对SP诱导的钙释放的5-羟色胺增强的影响。在没有拮抗剂的情况下，5-羟色胺增强SP诱导的钙离子释放。与帕洛诺司琼预孵育后，而不是昂丹司琼或格拉司琼，5-羟色胺增强的SP反应被抑制。用顺铂和帕洛诺司琼、格拉司琼或昂丹司琼处理大鼠。在不同的时间给药后，单神经元记录从结状神经节刺激后收集SP;结状神经节神经元对SP的反应增强时，动物用顺铂预处理。帕洛诺司琼剂量依赖性地抑制顺铂诱导的SP增强，而昂丹司琼或格拉司琼则无此作用。结果与先前的数据一致，显示帕洛诺司琼与较老的5-HT 3受体拮抗剂相比表现出不同的药理学，并提供了帕洛诺司琼在临床延迟CINV中观察到的疗效的基本原理。
Palonosetron is the only 5-HT3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT3 crosstalk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT3 receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.