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Rikkunshito, an Herbal Medicine, Suppresses Cisplatin-Induced Anorexia in Rats Via 5-HT2 Receptor Antagonism

      Background & Aims: 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. Methods: 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-HT2B and 5-HT2C receptors. Results: Cisplatin, 5-HT, BW723C86 (5-HT2B–receptor agonist), and m-chlorophenylpiperazine HCl (5-HT2C agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT3 and 5-HT4 agonists had no effect. In contrast, 5-HT2B and 5-HT2C 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 acylated-ghrelin level, which was decreased further 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 iso-liquiritigenin showed a 5-HT2B-antagonistic effect in vitro, and oral administration of rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level. Conclusions: The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.

      Abbreviations used in this paper:

      CPB (1-(3-chlorophenyl) biguanide HCl), GHRP-6 ([D-Lys3]–ghrelin receptor antagonist), HMF (3,3′,4′,5,6,7,8-heptamethoxyflavone), 5-HT (serotonin), Ki (inhibition constant 5-HT2B/2C–receptor binding-inhibitory activities), mCPP (m-chlorophenyl piperazine HCl), CD (hydroxypropyl-β-cyclodextrin)
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