Integrated Network Pharmacology and GC-MS–Based Metabolomics to Investigate the Effect of Xiang-Su Volatile Oil Against Menopausal Depression

Menopausal depression perplexes a great number of women in later life. Xiangfu-Zisu (Xiang-Su), a traditional Chinese herbal pair composed of rhizomes of Cyperus rotundus L. (Xiangfu) and leaves of Perilla frutescens (L.) Britt. (Zisu), is frequently reported with antidepressant-like effects. The volatile oil from Xiangfu and Zisu has shown good antidepressant action, but its mechanism is still unclear. This study aimed to investigate the pharmacological mechanism of Xiang-Su (XS) volatile oil against menopausal depression through gas chromatography–mass spectrometry (GC-MS)-based network pharmacology and metabolomics. First, ADME screening was performed on actual detected components of XS volatile oil to obtain active constituents, and then duplicates of active constituent–related targets and menopausal depression–related targets were collected. These duplicates were considered as targets for XS volatile oil against menopausal depression, followed by GO and KEGG enrichment analyses. It showed that a total of 64 compounds were identified in XS volatile oil, and 38 active compounds were screened out. 42 overlapping genes between 144 compound-related genes and 780 menopausal depression–related genes were obtained. Results showed that targets of SLC6A4 and SLC6A3, regulation of serotonergic and dopaminergic synapses, were involved in the antidepressant mechanism of XS volatile oil. Next, antidepressant-like effect of XS volatile oil was validated in menopausal rats by ovariectomy (OVX) combined with chronic unpredictable mild stress (CUMS). Behavioral tests, biochemical analysis, and GC-MS–based non-targeted plasma metabolomics were employed to validate the antidepressant effect of XS volatile oil. Experimental evidence demonstrated that XS volatile oil reversed behavioral parameters in the sucrose preference test (SPT), open-field test (OFT), forced swim test (FST), and serum estradiol levels in OVX rats. Furthermore, results of metabolomics indicated that XS volatile oil mainly acts on regulating metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, tyrosine metabolism, and tryptophan metabolism, which were corresponding with the above-predicted results. These data suggest that network pharmacology combined with metabolomics provides deep insight into the antidepressant effect of XS volatile oil, which includes regulating key targets like SLC6A4 and SLC6A3, and pathways of serotonergic and dopaminergic synapses.

The Effect Combination of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi Extract on Menopause Symptoms in an Ovariectomized Rat Model

Objectives Menopause causes ovarian hormone decline, followed by symptoms including weight gain, bone loss, hot flashes, and menopausal depression. We had a purpose that a combination of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi (LEPE) would alleviate menopausal symptoms in an ovariectomized menopausal rat model. Methods Female rat underwent surgery to resect bilateral ovarian and were randomly assigned to five groups: (1) Sham, (2) Vehicle, negative control, (3) LEPE (100 mg/kg bw), (4) LEPE (200 mg/kg bw), and (5) Estradiol (E2, 3 μg/kg bw). LEPE was orally gavaged daily for 12 weeks. Results There is no effect on growth performance, including body weight and feed intake, or body composition, including lean mass and fat in tissue. LEPE did not cause hepatotoxicity (aspartate aminotransferase and alanine aminotransferase) and endocrine disturbance (estradiol, follicle-stimulating hormone levels, and uterine weight). Despite decreasing type I collagen (CTX-1), LEPE did not affect bone mineral density and osteocalcin. LEPE supplement reduced the tail temperature and increased the rectal temperature, improving menopause-associated vasomotor symptoms such as hot flashes and night sweat. Furthermore, LEPE relieved behavior related to menopausal depression, including in forced swimming and tail suspension tests. Conclusions These findings suggest that LEPE ameliorates menopausal symptoms via improving menopause-associated vasomotor symptoms and depression behavior in a female rat model of surgical menopause. Funding Sources This research was funded by Nong Shim.

(−)-Gallocatechin gallate from green tea rescues cognitive impairment through restoring hippocampal silent synapses in post-menopausal depression

Post-menopausal depression (PMD) is a common psychological disorder accompanied by a cognitive deficit, which is caused by a series of uncontrolled emotional disruptions by strong environmental stressors during menopause. To overcome PMD-induced cognitive deficit, Green tea has been suggested as a dietary supplement because of its ameliorating effect on cognitive dysfunction induced by normal aging or neurodegenerative syndromes; however, its clinical use to improve PMD-accompanied cognitive deficit is still limited due to the controversy for the active ingredients and ambiguous mechanism of its action. Here, we developed modified high-temperature-processed green tea extract (HTP-GTE), which showed lower neuronal toxicity than the conventional green tea extract (GTE). We also demonstrated that HTP-GTE administration prevented the development of learned helplessness (LH) in a rat post-menopausal model. Additionally, HTP-GTE improved LH-induced cognitive impairments simultaneously with rescued the long-term synaptic plasticity. This occurred via the restoration of silent synapse formation by increasing the hippocampal BDNF-tyrosine receptor kinase B pathway in the helpless ovariectomized (OVX) rats. Likewise, we also identified that (−)-gallocatechin gallate was the main contributor of the HTP-GTE effect. Our findings suggested that HTP-GTE has a potential as a preventive nutritional supplement to ameliorate cognitive dysfunctions associated with PMD.

Asparagus cochinchinensis extract ameliorates menopausal depression in ovariectomized rats under chronic unpredictable mild stress

Background Depression is a serious and common psychiatric disorder generally affecting more women than men. A woman’s risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model. Methods To model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6 weeks, which promotes the development of depression-like symptoms. During the final 4 weeks of CUMS, rats were treated with either AC extract (1000 or 2000 mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10 mg/kg, IP). Results We report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels. Conclusion These results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.

Jiao-Tai-Wan Ameliorates Depressive-Like Behavior through the A1R Pathway in Ovariectomized Mice after Unpredictable Chronic Stress

Objective. This study was aimed at observing the effect Jiao-Tai-Wan in menopausal depression. Methods. In this paper, we used ovariectomized mice subjected to chronic unpredictable stress as a menopausal depression model. After the chronic stress, mice were administrated with JTW (3.3 and 6.6mg/kg) and imipramine (10 mg/kg) for 14 days. On the 14th day, mice were subjected to the behavior test like the forced swim test, tail suspension test, and locomotor activity or were sacrificed to assess the protein changes in different brain regions. Results. The administration of JTW at doses of 3.3 and 6.6mg/kg (p.o.) significantly shortened the duration of immobility in forced swim and tail suspension tests. There was no obvious difference in locomotor activity among all the groups. The western blot analysis data indicated that treatment with JTW (3.3 and 6.6 mg/kg, p.o.) prominently increased the A1R protein and the downstream protein ERK1/2 levels in the prefrontal cortex and hippocampus. However, the administration of JTW did not influence c-Fos protein in either the prefrontal cortex or hippocampus. Conclusion. Our findings suggest that JTW plays a vital role in ameliorating menopausal depression symptoms in the A1R-ERK1/2 pathway in the prefrontal cortex and hippocampus.

Origination Progress and Utility of Selective Estrogen Receptor Modulators in Clinical Practice as an Efficient Substitute of Estrogen for Treating Hormone Dependent Issues

The discovery, development and utility of selective estrogen receptor modulators (SERMs) are presented in this study. As per literature review SERMs used in the treatment of estrogen hormone responsive diseases like osteoporosis, Alzheimer, angiogenesis, hyperlipidemia, coronary heart disease, atherosclerosis, endometriosis, breast cancer, post-menopausal depression, dysfunctional uterine bleeding, gynacomastia, Albright syndrome, ovarian cancer, dyspareunia, cyclical mastalgia, hypogondism and induced ovulation in sub-fertile woman, etc. Basically world wide a large no. compounds available those function as SERMs successfully or under different phase clinical trials or discontinued because of unwanted side effects during clinical trials. This work describes the specific reference compounds which have created a substitute of estrogen for treating hormone dependent issues.

Effects of Camellia Sinensis Extract on Repeated Restraint Stress-Induced Ovariectomized Female Rats

The mortality of individuals suffering from depression has been increasing, noticeably of postmenopausal women; consequently, their care and treatment are significant to retain a high quality of life. The aim of this study was to examine the effect of Camellia sinensis (CS) on repeated stress-induced changes of the depression related function on the tail suspension test (TST), forced swimming test (FST) in ovariectomized female rats. After behavioral test, we evaluated the changes in the neurotransmitter by measuring the level of dopamine in the nucleus accumbens (NaC) and the serum levels of estrogen and oxytocin. We used 18F-2-fluoro-deoxy-D-glucose positron emission tomography (18F-FDG-PET) to examine the effects of CS on glucose metabolism in ovariectomized rats. Female rats were randomly segregated into three groups. Nor group was considered as nonoperated and nonstressed group, while the control was the ovariectomized and stressed group (OVX+ST), and CS was the ovariectomized, stressed and CS treated group. The rats were exposed to immobilization stress (IMO) for 14 d (2 h/d), and CS (300 mg/kg, i.p.) was treated 30 min before IMO stress. Significant reduction of immobility in the TST and FST was indicated in rats treatment with CS compared to the control group (OVX+ST). The levels of estrogen in the serum of the Nor and CS groups were significantly elevated compared to the OVX+ST group. Also, CS activated brain glucose metabolism in the cortex. The present findings suggested that CS had antidepressant effectiveness in a menopausal depression animal model. These findings suggest evidence that CS plays a crucial role in stressful situation, providing that CS might be a dependable antidepressant medicine to treat menopausal depression.