Rikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexia via hypothalamic ghrelin interaction

Circulating ghrelin concentration regulates appetite behavior, but no study thus far has focused on the role of central ghrelin in anorexia after chemotherapy. To clarify the action mechanisms of rikkunshito (RKT), a traditional Japanese medicine, on cisplatin-induced anorexia, we attempted to elucidate its effect on hypothalamic ghrelin receptor expression in cisplatin-induced anorexia. We first examined the effects of an intracerebroventricular (ICV) injection of exogenous ghrelin on food intake with or without cisplatin treatment, and the effects of cisplatin or m-chlorophenylpiperazine (mCPP), a 5-HT2C receptor agonist, on hypothalamic growth hormone secretagogue receptor 1a (GHS-R1a) mRNA expression. To identify the mechanism of cisplatin-induced decrease in hypothalamic GHS-R1a mRNA expression, we evaluated the effects of SB242084HCl, a 5-HT2C receptor antagonist, and RKT on hypothalamic GHS-R1a gene expression, along with the effect of coadministration of a GHS-R1a antagonist on decreased food intake. Compared to vehicle controls, an ICV-injected rat ghrelin failed to inhibit the decrease in food intake in cisplatin-treated rats. Hypothalamic GHS-R1a gene expression was significantly reduced after cisplatin or mCPP treatment, and the induced decrease was reversed by SB242084HCl or RKT, but not granisetron or ondansetron, both of which are 5-HT3 receptor antagonists. Their suppressive effect on the decrease in food intake was abolished by coadministration of the GHS-R1a antagonist. Administration of RKT or SB242084HCl reversed the decrease in food intake induced by mCPP injection. The improvement by RKT on decreased food intake after cisplatin treatment was partly mediated by hesperidin and isoliquiritigenin, components of RKT. Cisplatin-induced anorexia may worsen because of decreased hypothalamic GHS-R1a gene expression. A 5-HT2C receptor antagonist and RKT suppressed cisplatin-induced anorexia by inhibiting reduction of GHS-R1a signal transduction in the hypothalamus.