title: 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.
abstract: 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 (PKCα/β), and protein kinase A (PKA) in the least shrew. Our results demonstrate that cisplatin (10mg/kg, i.p.) causes emesis in the least shrew over 40h with respective peak early- and delayed-phases occurring at 1 - 2 and 32 - 34h post-injection. During the early phase (0 - 16h post cisplatin), palonosetron (0.1mg/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 - 40h post cisplatin), but the reduction in mean vomit frequency failed to achieve significance. On the other hand, netupitant (5mg/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 40h post-cisplatin administration. PKA phosphorylation tended to be elevated throughout the delayed phase, but a significant increase only occurred at 33h. Brainstem pPKCα/β levels were enhanced during acute-phase with a significant elevation at 2h. Palonosetron, netupitant or their combination had no effect on elevated pERK1/2 levels during acute phase, but the combination reversed ERK1/2 phosphorylation at 33h post-cisplatin treatment. In addition, only the combined regimen prevented the cisplatin-induced PKCα/β phosphorylation 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.
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA. Electronic address: ndarmani@westernu.edu.
authors: Nissar A
authors: NA
authors: Darmani
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
authors: Weixia
authors: W
authors: Zhong
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
authors: Seetha
authors: S
authors: Chebolu
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
authors: Frank
authors: F
authors: Mercadante
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007546:Isoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000077924:Palonosetron; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011812:Quinuclidines / Q000008:administration & dosage / Q000627:therapeutic use*; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D012788:Shrews; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy*; D010879:Piperazines; D044482:Benzeneacetamides
chemical_list: D000932:Antiemetics; D002945:Cisplatin; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D007546:Isoquinolines; D064729:Neurokinin-1 Receptor Antagonists; D000077924:Palonosetron; D011493:Protein Kinase C; D011725:Pyridines; D011812:Quinuclidines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides
keywords: 5-HT(3) receptor; Cisplatin; ERK1/2; Emesis; NK(1) receptor; PKA