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

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.