CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia.

Sachiko Mogami,Chihiro Yamada,Chiharu Sadakane,Tomohisa Hattori,Miwa Nahata,Yasuharu Mizuhara,Hiroshi Takeda

doi:10.1038/srep27516

Abstract

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.

Highlights

Late-life anxiety and depression is a social problem in aging societies, and the recognition of this condition and adequate treatment are increasingly required[1]
The present study was conducted to determine 1) whether the activation of anorexigenic corticotropin-releasing factor (CRF) or 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 anorexigenic CRF or POMC neurons and downstream signal transduction; and 3) the plasma and brain distributions of RKT active components
We showed that 1) several components of RKT exhibited antagonistic activities against CRFR1; 2) hesperetin (Citri Unshiu Pericarpium-derived) and isoliquiritigenin (Glycyrrhizae Radix-derived), which are major active components of RKT that possess both CRFR1 and 5-HT2CR antagonistic activities, were distributed in the plasma and brain after a single oral administration of RKT; and 3) CRFR1 and melanocortin-4 receptor (MC4R) antagonists, in addition to RKT and a 5-HT2CR antagonist, restored the initial decrease in food intake that occurred after novelty stress exposure in aged mice

Summary

Introduction

Late-life anxiety and depression is a social problem in aging societies, and the recognition of this condition and adequate treatment are increasingly required[1]. It has been reported that 5-HT2CR is expressed in anorexigenic pro-opiomelanocortin (POMC) neurons in the arcuate nucleus and that 5-HT2CR activation promotes α-melanocyte-stimulating hormone (α-MSH) production[19,20,21] This production contributes to appetite suppression via melanocortin-4 receptor (MC4R) activation. It remains to be determined whether the ameliorative effects of RKT are associated with these anorexigenic neurons and downstream signal transduction. The present study was conducted to determine 1) whether the activation of anorexigenic CRF or 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 anorexigenic CRF or POMC neurons and downstream signal transduction; and 3) the plasma and brain distributions of RKT active components

Objectives

Methods

Results

Conclusion