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Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism.

AbstractBACKGROUND & 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.
AuthorsHiroshi Takeda, Chiharu Sadakane, Tomohisa Hattori, Takehiko Katsurada, Tatsuya Ohkawara, Koichi Nagai, Masahiro Asaka
JournalGastroenterology (Gastroenterology) Vol. 134 Issue 7 Pg. 2004-13 (Jun 2008) ISSN: 1528-0012 [Electronic] United States
PMID18439428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine
  • 5,6,2',3',5',6'-hexamethoxyflavone
  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Aminopyridines
  • Antineoplastic Agents
  • Chalcones
  • Dopamine Antagonists
  • Drugs, Chinese Herbal
  • Flavones
  • GHRP-6, Lys(3)-
  • Gastrointestinal Agents
  • Ghrelin
  • Indoles
  • Oligopeptides
  • Piperazines
  • Quinolines
  • Receptor, Serotonin, 5-HT2B
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Ghrelin
  • SB 215505
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Receptor Agonists
  • Thiophenes
  • liu-jun-zi-tang
  • Serotonin
  • isoliquiritigenin
  • Hesperidin
  • Cisplatin
  • 1-(3-chlorophenyl)piperazine
Topics
  • Acylation
  • Aminopyridines (pharmacology)
  • Animals
  • Anorexia (chemically induced, metabolism, physiopathology, prevention & control)
  • Antineoplastic Agents
  • Body Weight (drug effects)
  • Chalcones (pharmacology)
  • Cisplatin
  • Disease Models, Animal
  • Dopamine Antagonists (metabolism, pharmacology, therapeutic use)
  • Dose-Response Relationship, Drug
  • Drugs, Chinese Herbal (metabolism, pharmacology, therapeutic use)
  • Eating (drug effects)
  • Flavones (pharmacology)
  • Gastric Mucosa (metabolism)
  • Gastrointestinal Agents (metabolism, pharmacology, therapeutic use)
  • Ghrelin (blood, metabolism)
  • Hesperidin (pharmacology)
  • Indoles (pharmacology)
  • Male
  • Oligopeptides (pharmacology)
  • Piperazines (pharmacology)
  • Protein Binding
  • Quinolines (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2B (metabolism)
  • Receptor, Serotonin, 5-HT2C (metabolism)
  • Receptors, Ghrelin (drug effects, metabolism)
  • Serotonin (metabolism)
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Receptor Agonists (pharmacology)
  • Stomach (drug effects, innervation)
  • Thiophenes (pharmacology)
  • Vagotomy

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