W1364 Role of Hypothalamic Ghs-R1a on Appetite Loss During Chemotherapy

Background/Aim: Because ghrelin is a strong orexigenic peptide, targeted depletion of the ghrelin receptor is expected to have a significant effect on feeding behavior. Although recent loss-of-function studies using GHS-R1a knockout animals have raised questions regarding the physiological significance of ghrelin on feeding, the roles of central GHS-R1a in anorexia models have not been investigated. To clarify that the gut-brain axis is associated with the regulation of appetite and the hypothalamic ghrelin signal, we investigated hypothalamic GHS-R1a gene expression and studied chemotherapy-induced dyspepsia in rats. Methods: We first examined the effects of an intracerebroventricular (ICV) injection of exogenous ghrelin on food intake with or without cisplatin treatment, as well as those of 48-h fasting and cisplatin or a 5-HT receptor agonist treatment on hypothalamic GHS-R1a mRNA expression. To identify the mechanism of the cisplatin-induced decrease in hypothalamic GHSR1a mRNA expression, we evaluated the effects of SB242084, a 5-HT2C receptor antagonist, and Rikkunshito (RKT), a ghrelin receptor activator (Endocrinology, 151, 2009) on hypothalamic GHS-R1a gene expression, as well as the effect of coadministration of a GHS-R1a antagonist on decreased food intake. Results: Compared to vehicle controls, ICV ghrelininjected rats (2 nmol/head) that were treated with cisplatin failed to reduce the decrease in food intake. Hypothalamic GHS-R1a gene expression was significantly enhanced during the 48-h fasting but was reduced after treatment with cisplatin or mCPP, a 5-HT2C receptor agonist (saline; 1.0 ± 0.08 vs. mCPP; 0.77 ± 0.06 relative mRNA, p = 0.0157, Steel's test), but not with 1B/2B receptor agonist treatment. The induced decrease was reversed by a 5HT2C receptor antagonist (cisplatin plus saline; 0.83 ± 0.06, and vs. relative mRNA level in cisplatin plus SB242084HCl, 1.2 ± 0.06, p = 0.026) or RKT (0.71 ± 0.06; cisplatin plus 500 mg/kg, 1.12 ± 0.09, p = 0.009; cisplatin plus 1000 mg/kg, 1.06 ± 0.09, p = 0.03), but not by granisetron or ondansetron, which are 5-HT3 receptor antagonists. The suppressive effect of cisplatin and mCPP on the decrease in food intake was abolished by coadministration of the GHS-R1a antagonist. Conclusion: Cisplatin-induced anorexia may worsen because of decreased hypothalamic GHS-R1a gene expression. Activation of the cerebral 5-HT2C receptor partially contributed to the decrease in GHS-R1a gene expression after cisplatin treatment.