Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation
Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation
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DOI：
10.1016/j.pbb.2015.02.010
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发表时间：
2015-04-01
影响因子：
3.6
通讯作者：
Mercadante, Frank
中科院分区：
文献类型：
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作者：
Darmani, Nissar A.;Zhong, Weixia;Mercadante, Frank
为了更好地了解5-HT 3的止吐作用，（帕洛诺司琼）-和速激肽NK 1（奈妥匹坦）-受体拮抗剂，单独或组合，我们评估帕洛诺司琼和/或奈妥匹坦预处理对顺铂诱发的呕吐和脑干激酶如细胞外信号调节蛋白激酶1和2（ERK 1/2）磷酸化的变化的影响，蛋白激酶C α/β（PKC α/β）和蛋白激酶A（PICA）在最小的鼩。我们的结果表明，顺铂（10 mg/kg，i. p.）在至少40小时内引起呕吐，在注射后1 - 2小时和32 - 34小时分别出现早期和延迟期的高峰。在早期阶段（顺铂后0 - 16小时），帕洛诺司琼（0.1mg/kg，s.c.）显着保护鼩从呕吐与几乎完全抑制呕吐频率。帕洛诺司琼也显著保护了延迟期（顺铂后27 - 40小时）的呕吐，但平均呕吐频率的降低没有达到显著性。另一方面，奈妥匹坦（5 mg/kg，i. p.）完全消除了延迟期的呕吐，并倾向于抑制急性期的平均呕吐频率。在两个阶段，联合治疗几乎完全保护了鼩 鼱免于呕吐。除顺铂给药后40 h外，脑干pERK 1/2水平在所有时间点均显著升高。PICA磷酸化在整个延迟期趋于升高，但仅在33 h时显著升高。脑干pPK α/β水平在急性期增强，在2 h时显著升高。帕洛诺司琼、奈妥匹坦及其联合用药对急性期pERK 1/2水平升高无影响，但联合用药在顺铂治疗后33 h逆转了ERK 1/2磷酸化。此外，只有联合方案阻止了急性期观察到的顺铂诱导的PKC α/β磷酸化。另一方面，帕洛诺司琼和奈妥匹坦，无论是单独或组合，有效地降低诱导的pPKA水平升高在延迟相。这些对5-HT 3-和NK 1-受体下游顺铂相关呕吐信号的影响有助于我们更好地理解顺铂诱导呕吐的细胞内基础。(C)© 2015 Elsevier Inc版权所有。
To better understand the anti-emetic profile of the 5-HT3 (palonosetron)- and the tachykinin NK1 (netupitant) -receptor antagonists, either alone or in combination, we evaluated the effects of palonosetron and/or netupitant pretreatment on cisplatin-evoked vomiting and changes in the phosphorylation of brainstem kinases such as the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), protein kinase C alpha/beta (PKC alpha/beta), and protein kinase A (PICA) in the least shrew. Our results demonstrate that cisplatin (10 mg/kg, i.p.) causes emesis in the least shrew over 40 h with respective peak early- and delayed-phases occurring at 1 - 2 and 32 - 34 h post-injection. During the early phase (0 - 16 h post cisplatin), palonosetron (0.1 mg/kg, s.c.) significantly protected shrews from vomiting with a near complete suppression of vomit frequency. Palonosetron also significantly protected shrews from vomiting during the delayed phase (27 - 40 h post cisplatin), but the reduction in mean vomit frequency failed to achieve significance. On the other hand, netupitant (5 mg/kg, i.p.) totally abolished vomiting during the delayed phase, and tended to suppress the mean vomit frequency during the acute phase. The combined treatment protected shrews almost completely from vomiting during both phases. Brainstem pERK1/2 levels were significantly elevated at all time-points except at 40 h post-cisplatin administration. PICA phosphorylation tended to be elevated throughout the delayed phase, but a significant increase only occurred at 33 h. Brainstem pPK alpha/beta levels were enhanced during acute-phase with a significant elevation at 2 h. Palonosetron, netupitant or their combination had no effect on elevated pERK1/2 levels during acute phase, but the combination reversed ERK1/2 phosphorylation at 33 h post-cisplatin treatment. In addition, only the combined regimen prevented the cisplatin-induced PKC alpha/beta phosphorsdation observed at the acute phase. On the other hand, palonosetron and netupitant, either alone or in combination, were effective in reducing the induced elevated pPKA levels during the delayed phase. These effects on cisplatin-related emetic signals downstream of 5-HT3- and NK1-receptors help us to better understand the intracellular basis of cisplatin-induced vomiting. (C) 2015 Elsevier Inc All rights reserved.