FDに対する漢方薬の効果と脳腸相関 : セロトニン・グレリンの役割(シンポジウム:機能性胃腸症(Functional Dyspepsia)の病態を巡る脳腸相関,2008年,第49回日本心身医学会総会(札幌))  [in Japanese] Japanese Herbal Medicine Suppresses Cisplatin-induced Anorexia(Symposium/Brain-gut Interaction in the Pathophysiology of Functional Dyspepsia)  [in Japanese]

従来,functional dyspepsia(FD)の病態において消化管の機能異常が重視されてきたが,最近では脳-腸相関の関与が注目されている.六君子湯はFDに対する臨床効果が最も確立している漢方薬であり,特に食欲改善効果が顕著である.胃で産生される摂食ホルモンであるグレリンは,摂食調節に加えて,消化管運動,胃酸分泌にも関与することが示されており,脳-胃相関において重要な役割を果たしている.そこで今回,ラットにcisplatin(CDDP)を投与して食欲不振モデルを作製し,六君子湯の作用メカニズム,特にグレリンに対する影響を検討した.その結果,CDDPはおもにセロトニン5-HT_<2B>受容体を刺激して血漿アシルグレリンおよび摂餌量を低下させること,六君子湯は血漿アシルグレリンの増加を介してCDDPによる食欲不振を改善させ,その一部は六君子湯に含まれるフラボノイド類の5-HT_<2B>受容体拮抗作用が関与していることを明らかにした.

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.