Prevention of cisplatin-induced nausea and vomiting by seabuckthorn (Hippophae rhamnoides L.) seed oil: Insights at the level of orexin-A in rats

Document Type : Original Article


1 Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China

2 Key Laboratory of Pharmaceutical Research for Metabolic Diseases, Qingdao University of Science and Technology, Qingdao, China

3 Qingdao Jimo People’s hospital, Qingdao, China


Objective(s): Nausea and vomiting are perennial problems in cancer patients undergoing chemotherapy. Orexin-A (OXA) has been shown to regulate feeding and gastric motility. Seabuckthorn (Hippophae rhamnoides L.) seed oil (SSO) has been proved to promote digestion and bowel movements. We investigated whether SSO alleviated cisplatin-induced vomiting and its possible mechanism involved in OXA.
Materials and Methods: Rats were randomly divided into normal control group (NCG), cisplatin group (CG), SSO low-dose group (SLG), SSO middle-dose group (SMG) SSO high-dose group (SHG), and ondansetron group (OG). Rats were pretreated respectively with SSO (0.850, 1.675, and 3.350 g/kg·BW) and ondansetron (2 mg/kg·BW) in SLG, SMG, SHG, and OG for 6 days, and the same volume of saline in NCG and CG groups. On the 6th day, cisplatin (6 mg/kg, IP) was administered in all groups except NCG. The cumulative food and kaolin intake, gastric emptying, plasma OXA level, OX1R mRNA and protein expression in the hypothalamus and brainstem, and OXA expression in the lateral hypothalamic area (LHA) were observed, and the HPLC method was used to analyze the composition of SSO.  
Results: Kaolin intake in cisplatin-induced vomiting rats was significantly reduced (p <0.05) and gastric emptying delayed by cisplatin was improved (p <0.05-0.01) by pretreatment with SSO. Plasma OXA concentration, OX1R expression in the hypothalamus and brainstem increased significantly (p <0.05–0.01). Furthermore, OXA expression in LHA also increased significantly (p <0.05).
Conclusion: SSO prevents cisplatin-induced vomiting in rats, which is possibly involved in increasing peripheral and central OXA and the expression of OX1R in the hypothalamus and brainstem.


1. Grunberg SM, Osoba D, Hesketh PJ, Gralla RJ, Borjeson S, Rapoport BL, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity—an update. Support Care Cancer 2005;13:80-84.
2. Hesketh PJ, Belle SV, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003;39:1074-1080.
3. Sun S, Xu L, Sun X, Guo F, Gong Y, Gao S. Orexin-A affects gastric distention sensitive neurons in the hippocampus and gastric motility and regulation by the perifornical area in rats. Neurosci Res 2016;110:59-67.
4. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998;92:573-585.
5. De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998;95:322-327.
6. Matsuki T, Sakurai T. Orexins and orexin receptors: from molecules to integrative physiology. Results Probl Cell Differ 2008;46:27-55.
7. Grabauskas G, Moises HC. Gastrointestinal-projecting neurones in the dorsal motor nucleus of the vagus exhibit direct and viscerotopically organized sensitivity to orexin. J Physiol 2003;549:37-56.
8. Kobashi M, Furudono Y, Matsuo R, Yamamoto T. Central orexin facilitates gastric relaxation and contractility in rats. Neurosci Lett 2002;332:171-174.
9. Hao H, Luan X, Guo F, Sun X, Gong Y, Xu L. Lateral hypothalamic area orexin-A influence the firing activity of gastric distension-sensitive neurons and gastric motility in rats. Neuropeptides 2016;57:45-52.
10. Upadhyay NK, Kumar R, Mandotra SK, Meena RN, Siddiqui MS, Sawhney RC, et al. Safety and healing efficacy of Sea buckthorn (Hippophae rhamnoides L.) seed oil on burn wounds in rats. Food Chem Toxicol. 2009;47:1146-1153.
11. Basu M, Prasad R, Jayamurthy P, Pal K, Arumughan C, Sawhney RC. Antiatherogenic effects of seabuckthorn (Hippophaea rhamnoides) seed oil. Phytomedicine 2007;14:770-777.
12. Shi J, Wang L, Lu Y, Ji Y, Wang Y, Dong K, et al. Protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury. J Radiat Res 2017;58:24-32.
13. Saito R, Takano Y. Easy method for emesis using rats. Nihon Yakurigaku Zasshi 2006;127:461-466.
14. Cao SG, Wu H, Cai ZZ. Dose-dependent effect of ghrelin on gastric emptying in rats and the related mechanism of action. Kaohsiung J Med Sci 2016;32:113117.
15. De Jonghe BC, Horn CC. Chemotherapy-induced pica and anorexia are reduced by common hepatic branch vagotomy in the rat. Am J Physiol Regul Integr Comp Physiol 2008;294:R756-65.
16. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 2008.
17. Arimboor R, Venugopalan V, Sarinkumar K, Arumughan C, Swahney RC. Integrated processing of fresh Indian sea buckthorn (Hippophae rhamnoides) berries and chemical evaluation of products. J Sci Food Agr 2006;86:2345-2353.
18. Guliyev V, Gul M, Yildirim A. Hippophae rhamnoides L.: chromatographic methods to determine chemical composition, use in traditional medicine and pharmacological effects. J Chromatogr B Analyt Technol Biomed Life Sci, 2004;812:291-307.
19. van Lieshout EM, Peters WH, Jansen JB. Effects of oltipraz, alpha-tocopherol, beta-carotene and phenethylisothiocyanate on rat oesophageal, gastric, colonic and hepatic glutathione, glutathione S-transferase and peroxidase. Carcinogenesis. 1996;17:1439-1445.
20. da Silva Porto PA, Laranjinha JA, de Freitas VA. Antioxidant protection of low density lipoprotein by procyanidins: structure/activity relationships. Biochem Pharmacol 2003;66:947-954.
21. Bagchi D, Bagchi M, Stohs SJ, Ray SD, Sen CK, Preuss HG. Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci 2002;957:260-270.
22. Xing J, Yang B, Dong Y, Wang B, Wang J, Kallio HP. Effects of sea buckthorn (Hippophaë rhamnoides L.) seed and pulp oils on experimental models of gastric ulcer in rats. Fitoterapia 2002;73:644-650.
23. Dogra R, Tyagi SP, Kumar A. Efficacy of Seabuckthorn (Hippophae rhamnoides) oil vis-a-vis other standard drugs for management of gastric ulceration and erosions in dogs. Vet Med Int 2013;2013:176848.  
24. Palatty PL, Haniadka R, Valder B, Arora R, Baliga MS. Ginger in the prevention of nausea and vomiting: A review. Crit Rev Food Sci Nutr 2013;53:659-669.
25. Matsuki N, Torii Y, Saito H. Effects of iron and deferoxamine on cisplatininduced emesis: Further evidence for the role of free radicals. Eur J Pharmacol 1993;248:329-331.
26. Badary OA, Awad AS, Sherief MA, Hamada FMA. In vitro and in vivo effects of ferulic acid on gastrointestinal motility: inhibition of cisplatin-induced delay in gastric emptying in rats. World J Gastroenterol 2006;12:5363–5367.
27. Marx W, Ried K, Mccarthy AL, Vitetta L, Sali A, McKavanagh D, et al. GingerMechanism of action in chemotherapy-induced nausea and vomiting: A review. Crit Rev Food Sci Nutr 2017;57:141-146.
28. Abdel-Aziz H, Windeck T, Ploch M, Verspohl EJ. Mode of action of gingerols and shogaols on 5-HT3 receptors: Binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. Eur J Pharmacol 2006;530:136-143.
29. Qian W, Cai X, Wang Y, Zhang X, Zhao H, Qian Q, et al. Effect of gingerol on cisplatin-induced pica analogous to emesis via modulating expressions of dopamine 2 receptor, dopamine transporter and tyrosine hydroxylase in the vomiting model of rats. Yonago Acta Med 2016;59:100-110.
30. Baccari M. Orexins and gastrointestinal functions. Curr Protein Pept Sci 2010;11:148-155.
31. Kobashi M, Furudono Y, Matsuo R, Yamamoto T. Central orexin facilitates gastric relaxation and contractility in rats. Neurosci Lett 2002;332:171-174.
32. Yamamoto K, Asano K, Tasaka A, Ogura Y, Kim S, Ito Y, et al. Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats. Br J Pharmacol 2014;171:2888-2899.
33. Guo F, Xu L, Gao S, Sun X, Zhang N, Gong Y. Effect of orexin-A in the arcuate nucleus on cisplatin-induced gastric side effects in rats. Neurosci Res 2019;143:53-60.