CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia.
Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities.
Tsumura Research Laboratories, Tsumura &Co., Ibaraki 300-1192, Japan.
Sachiko
S
Mogami
Tsumura Research Laboratories, Tsumura &Co., Ibaraki 300-1192, Japan.
Chiharu
C
Sadakane
Tsumura Research Laboratories, Tsumura &Co., Ibaraki 300-1192, Japan.
Miwa
M
Nahata
Tsumura Research Laboratories, Tsumura &Co., Ibaraki 300-1192, Japan.
Yasuharu
Y
Mizuhara
Tsumura Research Laboratories, Tsumura &Co., Ibaraki 300-1192, Japan.
Chihiro
C
Yamada
Tsumura Research Laboratories, Tsumura &Co., Ibaraki 300-1192, Japan.
Tomohisa
T
Hattori
Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.|Hokkaido University Hospital Gastroenterological Medicine, Sapporo, Hokkaido 060-8648, Japan.
Hiroshi
H
Takeda
D000818:Animals; D000855:Anorexia / Q000209:etiology / Q000517:prevention & control*; D001921:Brain / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications*; D000099052:CRF Receptor, Type 1
D004365:Drugs, Chinese Herbal; D018019:Receptors, Corticotropin-Releasing Hormone; C084136:liu-jun-zi-tang; D000099052:CRF Receptor, Type 1