Japanese Herbal Medicine Suppresses Cisplatin-induced Anorexia(Symposium/Brain-gut Interaction in the Pathophysiology of Functional Dyspepsia)

Abstract

Chemotherapy with an anticancer agent generally causes gastrointestinal tract disorders such as vomiting and anorexia, but the mechanism remains unclear. Rikkunshito, a kampo preparation, is known to alleviate such adverse reactions. In this study, we attempted to clarify the mechanism. We investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists and vagotomy as well as the decrease-suppressing effects of Rikkunshito and 5-HT antagonists. In addition, binding affinities of Rikkunshito components were determined in receptor-binding assays using 5-HT_<2B> and 5-HT_<2C> receptors. Cisplatin, 5-HT, BW723C86 (5-HT_<2B> receptor agonist), and m-chlorophenylpiperazine HCl (5-HT_<2C> agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT_3 and 5-HT_4 agonists had no effect. In contrast, 5-HT_<2B> and 5-HT_<2C> antagonists suppressed the cisplatin-induced decrease of plasma acylated-ghrelin level and food intake. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylatedghrelin level, which was further decreased by cisplatin. Rikkunshito suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of Rikkunshito was blocked by a ghrelin antagonist. Components of Rikkunshito, 3,3',4',5,6,7,8-heptamethoxyflavone, hesperidin, and isoliquiritigenin showed a 5-HT_<2B>-antagonistic effect in vitro, and oraladministration of Rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level. The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT_<2B/2C> receptors and suppressed by flavonoids in Rikkunshito.