Chaihu-Shugan-San Administration Ameliorates Perimenopausal Anxiety and Depression in Rats

Shujiao Chen,Shanshan Ding,Hiroki Namba,Lingyuan Zhang,Jie Yu,Linghong Liao,Kenji Sugiyama,Candong Li,Jianying Shen,Tetsuya Asakawa,Tiziana Rubino

doi:10.1371/journal.pone.0072428

Abstract

Chaihu-Shugan-San (CSS) is a traditional Chinese herbal formula that is widely used for treating perimenopausal symptoms in China; however, its mechanisms remain unknown. The present study was designed to investigate potential CSS mechanisms in rats with unpredicted chronic mild stress (UCMS) and normally aging rats (52 weeks of age). We performed the sucrose consumption test along with the forced swimming test to confirm depression-like behavior and the open field test (OFT) to confirm anxiety-like behavior in the animals. In addition, we used an enzyme-linked immunosorbent assay to measure serum and hippocampal estradiol (E2) levels and a quantitative real-time polymerase chain reaction to assess hippocampal mRNA levels of estrogen receptors (ERs) α and β as well as G protein-coupled receptor 30 (GPR30). We found that CSS administration resulted in a significant increase in the ratio of hippocampal ERα and ERβ mRNA (ERα/ERβ ratio) in UCMS rats (p<0.001). However, no significant changes were observed in E2 levels, ERα mRNA expression, and GPR30 mRNA expression. In contrast, changes in ERα/ERβ mRNA ratio were sensitively associated with changes in mood states in the animal models. These findings suggest that enhancement of ERα/ERβ ratio may play a role in the pharmacological mechanisms of CSS. Furthermore, this ratio can be employed as a potential index for evaluating mood states in animal models and can be considered as a therapeutic target for perimenopausal anxiety and depression in the future.

Highlights

IntroductionIn addition to physical symptoms such as hot flashes and night sweats, psychological changes such as anxiety, depression, and memory loss are major complaints among perimenopausal women [1,2,3]
Perimenopause is a period of profound transition in women's lives
It has been reported that women with a history of psychological problems are at increased risk for an earlier perimenopausal transition with higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and lower estradiol (E2) levels [6]

Summary

Introduction

In addition to physical symptoms such as hot flashes and night sweats, psychological changes such as anxiety, depression, and memory loss are major complaints among perimenopausal women [1,2,3]. It is believed that serum estrogen levels progressively decrease during perimenopause, and this may cause neurological problems. Gyllstrom (2007) reported that depressive symptoms are accompanied by a significant decrease in plasma follicle-stimulating hormone (FSH) levels [4]. Freeman (2004) reported that depressive symptoms can follow fluctuations in FSH levels [5]. It has been reported that women with a history of psychological problems are at increased risk for an earlier perimenopausal transition with higher FSH and luteinizing hormone (LH) levels and lower estradiol (E2) levels [6]. Walf (2007) directly administered ERbselective ligands to the hippocampus and relieved the symptoms of depression and anxiety; this suggests a potential role of hippocampal ERb in the development of neurological symptoms [8]

Methods

Results

Conclusion