Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism.
OBJECTIVE
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.
Takeda
Hiroshi
H
Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan. h_takeda@med.hokudai.ac.jp
Sadakane
Chiharu
C
Hattori
Tomohisa
T
Katsurada
Takehiko
T
Ohkawara
Tatsuya
T
Nagai
Koichi
K
Asaka
Masahiro
M
D000215:Acylation; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000970:Antineoplastic Agents; D001835:Body Weight / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology; D002945:Cisplatin; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004435:Eating / Q000187:drug effects; D047309:Flavones / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D054439:Ghrelin / Q000097:blood / Q000378:metabolism; D006569:Hesperidin / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects* / Q000294:innervation; D013876:Thiophenes / Q000494:pharmacology; D014628:Vagotomy
C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; C501187:5,6,2',3',5',6'-hexamethoxyflavone; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D000970:Antineoplastic Agents; D047188:Chalcones; D018492:Dopamine Antagonists; D004365:Drugs, Chinese Herbal; D047309:Flavones; C520836:GHRP-6, Lys(3)-; D005765:Gastrointestinal Agents; D054439:Ghrelin; D007211:Indoles; D009842:Oligopeptides; D010879:Piperazines; D011804:Quinolines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D054440:Receptors, Ghrelin; C118948:SB 215505; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; C084136:liu-jun-zi-tang; D012701:Serotonin; C040920:isoliquiritigenin; D006569:Hesperidin; D002945:Cisplatin; C015068:1-(3-chlorophenyl)piperazine