Skip to main content
PMC home page
Brain and Behavior logoLink to Brain and Behavior
. 2022 Jul 18;12(8):e2705. doi: 10.1002/brb3.2705

Ginsenoside Rh2 administration produces crucial antidepressant‐like effects in a CUMS‐induced mice model of depression

Lin‐Sheng Shi 1, Chun‐Hui Ji 2,3, Yue Liu 2,3, Jiang‐Hong Gu 2,3, Wen‐Qian Tang 2,3, Wei Zhang 2,3, Wei Guan 2,4,✉
PMCID: PMC9392527  PMID: 35848938

Abstract

Introduction

The most striking feature of depression is sadness and a loss of interest in activities, which represents a major cause of disability globally. Therefore, it is necessary to identify novel antidepressants for clinical practice. Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides that can be extracted from Panax ginseng and has been demonstrated to improve both memory and learning. The purpose of this study was to provide broad insight into the mechanisms underlying depression and gain greater insights into antidepressant therapy.

Methods

In this study, we first established an effective and feasible depression animal model of chronic unpredictable mild stress (CUMS) and behavioral testing was evaluated by the forced swim test (FST), the tail suspension test (TST) and the sucrose preference test. Following pretreatment with Rh2 (10 and 20 mg/kg), the immobility time of mice was reduced without affecting locomotor activity in both the FST and TST. Western blotting and immunofluorescence were used to investigate the activation of the hippocampal BDNF signaling pathway and hippocampal neurogenesis.

Results

Different concentrations of Rh2 significantly reduced depressive‐like symptoms in CUMS‐induced mice and downregulated the effects of the BDNF signaling cascade and neurogenesis in the hippocampus. Furthermore, the administration of K252a completely prevented the antidepressant‐like activity of Rh2 in mice.

Conclusion

The results indicated that Rh2 possesses the antidepression action via the positive regulation of the BDNF‐TrkB pathway.

Keywords: brain‐derived neurotrophic factor, chronic unpredictable mild stress, depression, ginsenoside Rh2

Graphical Abstract

Graphical Abstract.

graphic file with name BRB3-12-e2705-g002.jpg

1. INTRODUCTION

Depression is a common clinical mood disorder that affects more than 350 million people at a high recurrence rate around the world, which results in heavy public health and a serious social burden (Ledford, 2014). However, most of the classic antidepressants used in the clinic at present are designed to improve the levels of monoamine neurotransmitters. These drugs can have some undesirable side effects, such as substantial side effects, slow onset, and high recurrence (Schechter et al., 2005). Thus, it is imperative and necessary to elucidate the pathogenesis of depression and develop novel drugs that are efficient and safe (Shafiee et al., 2018).

BDNF, a member of the neurotrophin family, plays a critical role in neurogenesis, neuronal survival, and brain homeostasis (Begni et al., 2017). BDNF and the mechanisms underlying its actions are currently being used to treat these diseases, such as antidepressants and antipsychotics (Autry & Monteggia, 2012). BDNF binds TrkB, a member of the family of Trk receptors, to regulate many different cellular processes involved in the development of brain function (Colucci‐D'Amato et al., 2020). For example, Asparagus cochinchinensis extract has been confirmed to exert antidepressant effects in an animal model of menopausal depression by activating the hippocampal BDNF‐TrkB pathway (Kim et al., 2020). The activation of AMPK produces a range of anti‐depressant effects that can mediate hippocampal neurogenesis via the BDNF/TrkB/CREB signaling pathways in neurons (Odaira et al., 2019). Recent animal studies have proven that chronic unpredictable mild stress can significantly reduce the expression of BDNF in the pathogenesis of depression (Duman et al., 2021; Gudasheva et al., 2019; Peng et al., 2018).

Evidence indicates that natural products can be an alternative and cost‐efficient complementary medicine for the treatment of depression, largely due to their multitarget efficacy and low toxicity (Chong et al., 2019). Ginseng is a traditional neuroprotective herbal medicine. The major active ingredients of ginseng are ginsenosides, which have been confirmed to improve cognitive and memory abilities in animal models (Kezhu et al., 2017; F. Li et al., 2016; Zhu et al., 2015). Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides from Panax ginseng. Rh2 has been demonstrated to possess antimetastasis, antiproliferation, and anti‐invasion effects and can promote differentiation (X. Li et al., 2020). In 2018, Lu et al. (2018) found that ginsenosides Rh2 may protect against the spatial and nonspatial memory deficits induced by SD mice. Later, Lv et al. (2021) demonstrated that Rh2 exhibited neuroprotective effects in a model of Scop‐induced memory dysfunction in mice. Thus far, there have been no investigations relating to the possibility of Rh2 as a potential antidepressant. Therefore, we investigated the mechanisms by which Rh2 can exert antidepressant actions in CUMS‐induced mice.

2. MATERIALS AND METHODS

2.1. Animals

Seven‐week‐old of adult male mice (20–22 g) were purchased from the Experimental Animal Centre of Medical College at Nantong University. Before the start of the study, the animals were divided into five groups per cage and kept under a 12‐h dark/light cycle, in a room temperature of 24 ± 1°C. Food and water were provided ad libitum for 1 week (Jiang et al., 2019). Prior to the experiments, the mice were acclimatized for 7 days. All animal protocols and procedures were approved by the Institutional Animal Ethical Committee of Nantong University (approval No., 20171220‐005) and conducted according to the NIH Guidelines.

2.2. Materials

The ginsenoside Rh2 (Rh2) was obtained from Puda Biological Technology Co. Ltd. (Suzhou, China). Fluoxetine was purchased from Sigma–Aldrich (St. Louis, MO, USA). K252a was obtained from Alomone Laboratories (Jerusalem, Israel). Rh2, fluoxetine and K252a were dissolved in 1% dimethyl sulfoxide in normal saline (vehicle) and intraperitoneally (i.p.) injected with different doses. The dosages of Rh2 (10 and 20 mg/kg), fluoxetine (20 mg/kg), and K252a (25 μg/kg) were chosen based on previous reports (Mu et al., 2019; J. J. Zhang, Gao, et al., 2019).

2.3. Chronic unpredictable mild stress

The chronic unpredictable mild stress (CUMS) procedure was performed as described with a slight modification (Mavrakis et al., 2010; J. Xu et al., 2015). Mice were subjected to a random sequence of unpredictable and mild stressors for 42 days. Different stressors are listed as follows: water or food deprivation (23 h), overnight illumination, restraint (2 h), cage shaking (15 min), tail pinching (2 min), remaining in the cage at a 45° tilt (17 h), and remaining in a soiled cage (5 h). After 4 weeks, the CUMS model was prepared, while administration of Rh2, fluoxetine, and K252a was performed during the last 2 weeks. The depression‐like behavior of the mice was detected using the forced swim test (FST), tail suspension test (TST), and sucrose preference test (SPT).

2.4. Forced swim test

FST was performed according to Jiang et al. with some modifications (Jiang, Huang, Chen, et al., 2015; Jiang, Huang, Zhu, et al., 2015; Ren et al., 2017; D. Xu et al., 2018). The equipment for the FST consisted of a transparent glass cylinder (45 cm height × 30 cm diameter) containing 22 cm of water (room temperature), and mice were floated in water for a total of 6 min. The total immobility time was recorded for the last 4 min by the automatic analyzer system. The water in the cylinder was replaced at the end of each trial.

2.5. Tail suspension test

The TST is another widely used pharmacological in vivo model for the evaluation of depression‐like behavior in mice. During the experiment, each mouse was individually suspended on a metal rod by tail 50 cm above the floor for 6 min. During the last 4 min, the immobility time of the mice was automatically recorded with behavioral software (Leng et al., 2018; Wu et al., 2018).

2.6. Open field test

An open field test (OFT) was conducted to eliminate the influence of mice locomotor activity and evaluated by the time spent in predefined central or peripheral areas (P. Xu et al., 2017). Mice were gently placed in the center of an open field (a wooden box, 100 × 100 × 40 cm) with its floor divided into 25 squares for 5 min. The total distance of the animals was recorded by the camera system for 5 min under dim light conditions. The apparatus ground was cleaned for each trial (Jiang, Huang, Zhu, et al., 2015; L. Y. Lin et al., 2016; D. Xu et al., 2018).

2.7. Sucrose preference test

Before the test, the mice were adapted to the environment with 1% (w/v) sucrose solution and tap water for 24 h (Stepanichev et al., 2016; Zhao et al., 2019). Afterward, the animals were not given food and water for 18 h, and then given preweighed bottles containing 1% sucrose solution and tap water for 6 h testing (two‐bottle test, 2‐h periods) (Gao et al., 2020; J. L. Wang, Wang, et al., 2020). Preference value is given as (%) = sucrose intake (g)/(sucrose intake (g) + water intake (g)) × 100%.

2.8. Western blot analysis

Total proteins from the hippocampus were homogenized on ice in 100 μl lysis buffer (Thermo Fisher Scientific, Waltham, MA, USA) plus protease inhibitors. The extract was centrifuged, and the supernatant was collected. Protein concentrations were measured by the BCA Protein Assay Kit (Beyotime Biotechnology, China). Equivalent amounts of protein were loaded in sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) gels. Proteins were transferred to polyvinylidene difluoride membranes (Millipore, Billerica, MA, USA). The membranes were blocked with TBST containing 5% skim milk for 2 h at room temperature. Then, the membranes were treated overnight at 4°C with the different antibodies: β‐actin (1:2000; Cell Signaling), rabbit anti‐BDNF (1:500; Abcam), rabbit anti‐ERK1/2 (1:1000; Cell Signaling), rabbit anti‐pERK1/2 (1:500; Cell Signaling), rabbit anti‐AKT (1:1000; Abcam), rabbit anti‐pAKT (1:500; Abcam), rabbit anti‐CREB (1:1000; Cell Signaling), and rabbit anti‐pCREB (1:500; Cell signaling). Next, the membranes were incubated with the respective secondary antibodies for 2 h at room temperature. Then, the membrane was detected using enhanced chemiluminescence reagent (Guan et al., 2017, 2021).

2.9. Immunofluorescence

As we have frequently described (Jiang, Huang, Chen, et al., 2015; Jiang, Huang, Zhu, et al., 2015; Jiang et al., 2017), the mice from each group were anesthetized with 0.5% sodium pentobarbital (Macklin, Shanghai), pericardial perfused with 0.9% saline, and then fixed in 800 ml of 4% paraformaldehyde (PFA) overnight. The brain was removed and placed in 4% PFA for postfixation (24 h, 4°C). The brain was dehydrated in 30% sucrose (48 h, 4°C), and opti‐mum cutting temperature compound (OCT) was then embedded. Next, the 25‐μm‐thick sections were cut by using a Leica freezing microtome and immediately adhered to the slide. First, the slides were washed in phosphate‐buffered saline with 0.5% Triton X‐100 (Beyotime, China) for 5–10 min. Second, the slices were incubated in a blocking solution containing 3% bovine serum albumin (BSA) for 30 min at room temperature, and the following primary antibodies diluted in 3% BSA: DCX (1:100; Cell Signaling) were incubated overnight. Third, the FITC‐labeled secondary antibody (1:50; Thermo Fisher, USA) was added for 2 h at 37°C. Finally, the nuclei were stained with DAPI (Sun et al., 2020).

2.10. Statistical analysis

The statistical analyses and bar graphs were generated with GraphPad Prism 6.0. The differences among treatment groups were analyzed using SPSS software including one‐way or two‐way analysis of variance (ANOVA) as appropriate, by post hoc Bonferroni's test for multiple comparisons. The results were considered significant when p < .05.

3. RESULTS

3.1. Rh2 treatment exerts antidepressant‐like feasibility in the behavioral experiments

Behavioral tests involving the FST and TST were used to evaluate the antidepressant activity in mice (Cryan et al., 2005; Yankelevitch‐Yahav et al., 2015). Compared with the untreated vehicle group, the FST and TST results demonstrated that the groups treated with fluoxetine and Rh2 significantly reduced the immobility time of the mice (Figure 1a,b). FST data revealed a significant effect of Rh2 treatment (ANOVA: F 3, 36 = 25.428, p < .01) similar to the TST (ANOVA: F 3, 36 = 34.516, p < .01). To eliminate the effects of enhancing locomotor activity in mice after Rh2 treatment (Guan et al., 2021), the OFT was performed later. Fluoxetine or Rh2 showed no significant differences in all the tested mice, indicating that neither Rh2 nor fluoxetine affected the locomotor hyperactivity of mice (Figure 1c). Therefore, Rh2 displayed antidepressant‐like potential based on the FST and TST.

FIGURE 1.

FIGURE 1

Open in a new tab

Rh2 improved depression‐like behavior without affecting the locomotor activity of mice. The forced swim test (FST) (a) and the tail suspension test (TST) (b) showed that the immobility time of mice taken by the Rh2 and fluoxetine groups was lower than the vehicle. The open field test (OFT) (c) showed that neither Rh2 nor fluoxetine groups affected the locomotor activity of mice. Data are shown as mean ± SEM. ** p < .01 when compared to the vehicle, n = 10. The Comparisons were made by one‐way analysis of variance (ANOVA) followed by Tukey's test

3.2. Effects of Rh2 on depression‐like behaviors in CUMS‐exposed mice

CUMS is a rodent model of depression and used to simulate the main symptoms of depression in mice (Antoniuk et al., 2019; Willner, 2017). Behavioral evaluations in the FST, TST, and SPT were also performed on days 43 to 48 to demonstrate the antidepressant‐like effects of Rh2 against CUMS. Compared to CUMS mice, Rh2 administration markedly shortened the immobility time in the FST and TST and notably improved sucrose consumption (Figure 2b–d). For the FST data (ANOVA: [interaction: F 3, 72 = 24.783, p < .01; CUMS: F 1, 72 = 37.594, p < .01; Rh2: F 3, 72 = 18.149, p < .01]). For the TST data (ANOVA: [interaction: F 3, 72 = 19.257, p < .01; CUMS: F 1, 72 = 30.226, p < .01; Rh2: F 3, 72 = 25.163, p < .01]). A significant difference in the SPT was found (ANOVA: [interaction: F 3, 72 = 15.249, p < .01; CUMS: F 1, 72 = 23.473, p < .01; Rh2: F 3, 72 = 14.464, p < .01]).

FIGURE 2.

FIGURE 2

Open in a new tab

Rh2 treatment remarkably ameliorated the depression‐like behaviors in chronic unpredictable mild stress (CUMS)‐induced mice. The timeline of the experimental design (a). The less immobility duration was taken by the (CUMS + Rh2)‐treated mice than the CUMS‐induced mice in the forced swim test (FST) (b) and in the tail suspension test (TST) (c). The sucrose preference test (d) showed the (CUMS + Rh2)‐treated mice consumed higher sucrose preference than the CUMS‐treated mice. Data are presented as the means ± SEM, n = 10. ** p < .01 when compared to the Vehicle; ## p < .01 when compared to the CUMS. The comparisons were made by two‐way analysis of variance (ANOVA) followed by Bonferroni's test

3.3. Effects of Rh2 treatment on the activation of the BDNF signaling pathway in the hippocampus of CUMS‐exposed mice

Subsequently, the levels of the BDNF protein signaling pathways in the hippocampus were determined by western blotting. The relative levels of BDNF, pERK, pAKT, and pCREB proteins were lower in tissue homogenates from the hippocampus in the CUMS group. However, the CUMS‐exposed changes in protein were considerably increased by exposure to Rh2, and fluoxetine also showed the same effect at a dose of 20 mg/kg. BDNF (ANOVA: [F 3, 17 = 29.247, p < .01]), ERK (ANOVA: [F 3, 17 = 28.124, p < .01]), AKT (ANOVA: [F 3, 17 = 24.173, p < .01]), and CREB (ANOVA: [F 3, 17 = 28.443, p < .01]) were indicated in Figure 3.

FIGURE 3.

FIGURE 3

Open in a new tab

Rh2 promoted BDNF‐CREB signaling cascade in the hippocampus in the model of chronic unpredictable mild stress (CUMS). BDNF, ERK, AKT, and CREB protein levels were assessed by western blotting in the hippocampus. All data are expressed as the means ± SEM, n = 5. ** p < .01 when compared to the vehicle; ## p < .01 when compared to the CUMS. The comparisons were made by two‐way analysis of variance (ANOVA) followed by Bonferroni's test

3.4. Rh2 administration prevented CUMS‐induced decreases in neurogenesis

Depression is often accompanied by behavior despair and hippocampal neurogenesis reduction, which is effectively reversed by common antidepression drugs, including fluoxetine and citalopram (Boldrini et al., 2012; Dranovsky & Hen, 2006). DCX is a microtubule‐associated protein that is a marker of cellular growth and is expressed in newborn neurons in the DG (Brown et al., 2003). As presented in Figure 4, a lower number of DCX cells were counted in the CUMS group than in the vehicle group in the DG region, while the decreased number of DCX cells was completely reversed by Rh2 treatment (ANOVA: [interaction: F 3, 17 = 29.971, p < .01; CUMS: F 1, 17 = 40.276, p < .01; Rh2: F 3, 17 = 25.824, p < .01]).

FIGURE 4.

FIGURE 4

Open in a new tab

Rh2 treatment revert the hippocampal neurogenesis in the chronic unpredictable mild stress (CUMS) depression model. Immunofluorescences images containing of the DCX in green. Scale bar: 100 μm. All data are shown as the means ± SEM, n = 5. ** p < .01 when compared to the vehicle; ## p < .01 when compared to the CUMS. The comparisons were made by two‐way analysis of variance (ANOVA) followed by Bonferroni's test

3.5. Blockade of BDNF‐TrkB signaling abolished the antidepressant effects of Rh2 in CUMS‐exposed mice

To explore whether hippocampal BDNF‐TrkB signaling contributes to the antidepressant effects of Rh2, we coinjected CUMS‐treated mice with Rh2 (20 mg/kg), and K252a, a specific inhibitor of the BDNF receptor (TrkB), was used (H. C. Yan et al., 2010). K252a (25 μg/kg) and Rh2 (20 mg/kg, 1 h later) were injected into mice for 2 weeks, and then behavioral tests (FST, TST, and SPT) were conducted. K252a significantly blocked the antidepressant effects of Rh2 in CUMS‐exposed mice in the FST, TST, and SPT (Figure 5a–c).

FIGURE 5.

FIGURE 5

Open in a new tab

K252a decreased the antidepressant action of Rh2 in chronic unpredictable mild stress (CUMS)‐stressed mice. Co‐treatment with (K252a + Rh2) of the mice against CUMS showed the longer immobility time than the (CUMS + Rh2)‐treated mice in the forced swim test (FST)(a) and tail suspension test (TST) (b). K252a blocked the reversing effects of Rh2 on sucrose consumption of the CUMS‐treated mice (c). All data are expressed as the means ± SEM, n = 10. **p < .01 when compared to the Vehicle; ## p < .01 when compared to the CUMS. The comparisons were made by two‐way analysis of variance (ANOVA) followed by Bonferroni's test

Next, the impact of K252a infusion on the BDNF‐TrkB signaling pathway and the immunoreactivity of DCX after Rh2 administration in mice (exposed to CUMS) were determined. It was observed that (Rh2 + K252a) treatment inhibited the effect of Rh2 on the expression of BDNF, p‐ERK, p‐AKT, and p‐CREB in the hippocampus of CUMS‐exposed mice (Figure 6). Similarly, Figure 7 indicates that compared to the Rh2 group, the increased numbers of DCX‐positive cells in the DG were reversed by the (K252a + Rh2) group in the mice (exposed to CUMS). To summarize, the hippocampal BDNF‐CREB system is required for the antidepressant mechanism of Rh2.

FIGURE 6.

FIGURE 6

Open in a new tab

The enhancing influence of Rh2 on the expression of BDNF‐CREB signaling pathway was blocked by the inhibitor K252a in mice exposed to chronic unpredictable mild stress (CUMS). BDNF, pERK/ERK, pAKT/AKT, and pCREB/CREB protein levels were lower in (CUMS + Rh2 + K252a)‐treated mice than the (CUMS + Rh2)‐treated mice. The obtained data are expressed as the means ± SEM, n = 5. ** p < .01 when compared to vehicle; ## p < .01 when compared to CUMS. The comparisons were made by two‐way analysis of variance (ANOVA) followed by Bonferroni's test

FIGURE 7.

FIGURE 7

Open in a new tab

K252a blocked the enhancing effects of Rh2 on neurogenesis. Compared to the (chronic unpredictable mild stress [CUMS] + Rh2)‐treated group, the increase of DCX+ neurons in the DG of mice exposed to CUMS were significantly blocked by K252a. Scale bar: 100 μm. The results of analysis are expressed as the means ± SEM, n = 5. ** p < .01 when compared to vehicle; ## p < .01 when compared to CUMS. The comparisons were made by two‐way analysis of variance (ANOVA) followed by Bonferroni's test

4. DISCUSSION

In our research, we demonstrated that Rh2 exerted neuroprotective effects in chronic stress mice and has potential in the treatment of depression. We carried out a series of behavioral tests, and the FST and TST are two of the most extensively used tests for evaluating different depressive‐like behaviors (Cryan et al., 2005; Petit‐Demouliere et al., 2005) and screening antidepressants. The SPT is also commonly used to analyze depressive‐like behavior since this test provides information relating to anhedonia, one of the main depressive‐like symptoms (Goñi‐Balentziaga et al., 2018). As a widely applied animal model for depression, the CUMS model presents many core depressive behaviors, including helplessness, anhedonia, and reduced locomotor activity (Z. Zhang et al., 2020). In particular, K252a, a TrkB antagonist was injected into mice exposed to CUMS and completely blocked the BDNF‐TrkB signaling cascade.

Rh2 is a major bioactive constituent of the traditional Chinese medicine ginseng with multiple pharmacological effects, such as antitumor, antifatigue, and antimicrobial effects, along with the ability to enhance immunity (M. Wang et al., 2017; B. Yan et al., 2018; X. Yang et al., 2017). Recent studies have reported that ginsenoside may improve depressive behavior and induce neuroprotective effects in rodents. For example, J. Wang et al. (2016) reported that mice receiving Rh2 treatment showed a significant improvement in their behavioral tests and increased the survival time of CRC‐mice. Chen et al. showed that (24R)‐pseudoginsenoside HQ (R‐PHQ) significantly reduced the immobility time of mice in the FST and TST and produced promising antidepressant‐like effects in mice. These effects may be related to the Sirt1/NF‐κB or BDNF/TrkB signaling pathways (Chen et al., 2019). H. Zhang et al. (2016) provided evidence that ginsenoside Rb3 exerted antidepressant effects by promoting the monoamine neurotransmitter system. Although the mechanisms by which Rh2 exerts its neuroprotective effects in depression remain largely uncharacterized, our study indicated that as well as the ginsenoside derivatives described above, Rh2 also possesses antidepressant‐like efficacy. Over recent years, some studies have clearly supported a relationship between the neuroprotective effect of Rh2 and its antioxidant activity. Hsieh et al. (2018) suggested that Rh2 ameliorated lipopolysaccharide (LPS)‐induced oxidative stress by regulating signaling pathways (HO‐1/Trx‐1/KAP‐1/Nrf2) in mice. In another study, Rh2 suppressed oxidative stress, had antioxidant activity in vivo, and restored the balance of the antioxidant defense system (Qi et al., 2019). Therefore, these results suggest that Rh2 has potential as a new antidepressant candidate to treat depression in clinical practice.

BDNF is associated with adult neurogenesis and reduced levels of BDNF have been implicated in depression (Szuhany & Otto, 2020). In addition to depression, BDNF also represents a promising therapeutic agent for Parkinson's disease and epilepsy while also providing cardiovascular protection, and response to exercise (T. W. Lin et al., 2020; Palasz et al., 2020; Trombetta et al., 2020). Therefore, Rh2 may exert further pharmacological effects involving BDNF; this possibility needs to be investigated further. By searching the existing literature, we found that mice receiving Rh2 treatment exhibited significantly improved behaviors in the FST, TST, and SPT. These effects appear to be related reductions in depression‐associated cytokines, such as tumor necrosis factor‐alpha (TNF‐α), interleukin‐18 (IL‐18), and IL‐6 (J. Wang et al., 2016). It is important to mention that depression is accompanied not only by BDNF dysfunction and “depression‐like” symptoms but also by proinflammatory cytokines (Clark et al., 2009). Many antidepressants, including notoginsenoside R1, Hericium erinaceus, lipopolysaccharide, and baicalin, have been shown to reverse the positive effects on the expression of TNFα, caspase‐3, and IL‐6 in the hippocampus against CUMS‐induced animals (Chong et al., 2019; Guo et al., 2019; B. Zhang, Wang, et al., 2019). In addition, some reports have shown a negative correlation between the expression levels of TNFα, caspase‐3, IL‐6, and BDNF in the brain (Liu et al., 2017; L. Wang, Wei, et al., 2020; Y. Zhang et al., 2018). Collectively, we propose that Rh2 produces antidepressant effects and enhances hippocampal BDNF expression by inhibiting the expression levels of TNFα, caspase‐3, and IL‐6 in mice; this possibility requires further explanation.

The present study has some limitations that need to be considered. First, we used a CUMS model of depression. Apart from CUMS, there are some other established models of depression such as chronic restraint stress and chronic social defeat stress. Furthermore, although depression is accompanied by dysfunction in the BDNF‐TrkB system and neurogenesis, many other pathological symptoms including neuroinflammation, the HPA axis and monoaminergic deficiency are also involved (Blier, 2016; Krishnan & Nestler, 2008). It is possible that Rh2 might ameliorate these symptoms. Furthermore, we observed that BDNF plays an important role in other central nervous system (CNS) disorders in addition to depression, such as schizophrenia and Parkinson's disease (W. Yang et al., 2020). We plan to investigate these possibilities in our future research. Collectively, our data provide more insights into the pharmacological effects of Rh2, which will contribute to the development of the next generation of more effective and safer antidepressants.

5. CONCLUSIONS

These findings indicate that Rh2 has antidepressant effects by regulating the BDNF/CREB signaling.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS

Wei Guan and Wei Zhang designed the research. Wei Guan wrote and amended the manuscript. Chun‐hui Ji, Lin‐sheng Shi, and Yue Liu performed the behavioral experiments, and Jiang‐Hong Gu and Wen‐Qian Tang conducted the molecular biology experiments. Lin‐sheng Shi and Wen‐Qian Tang organized and analyzed the data. All authors read and gave the final approval.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1002/brb3.2705

ACKNOWLEDGMENTS

This work was supported by two grants from the National Natural Science Foundation of China (No. 81900551 for Wei Guan; No. 81873795 for Bo Jiang), the Science Foundation of Nantong City (Grant No. JC2021139) and the research grant of Nantong Commission of Health (Grant No. MA2021013).

Shi, L.‐S. , Ji, C.‐H. , Liu, Y. , Gu, J.‐H. , Tang, W.‐Q. , Zhang, W. , & Guan, W. (2022). Ginsenoside Rh2 administration produces crucial antidepressant‐like effects in a CUMS‐induced mice model of depression. Brain and Behavior, 12, e2705. 10.1002/brb3.2705

Lin‐Sheng Shi and Chun‐Hui Ji contributed equally to this study.

DATA AVAILABILITY STATEMENT

Some or all data, models, or code generated or used during the study are available from the corresponding author upon request.

REFERENCES

  1. Antoniuk, S. , Bijata, M. , Ponimaskin, E. , & Wlodarczyk, J. (2019). Chronic unpredictable mild stress for modeling depression in rodents: Meta‐analysis of model reliability. Neuroscience and Biobehavioral Reviews, 99, 101–116. 10.1016/j.neubiorev.2018.12.002 [DOI] [PubMed] [Google Scholar]
  2. Autry, A. E. , & Monteggia, L. M. (2012). Brain‐derived neurotrophic factor and neuropsychiatric disorders. Pharmacological Reviews, 64(2), 238–258. 10.1124/pr.111.005108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Begni, V. , Riva, M. A. , & Cattaneo, A. (2017). Cellular and molecular mechanisms of the brain‐derived neurotrophic factor in physiological and pathological conditions. Clinical Science (London, England: 1979), 131(2), 123–138. 10.1042/cs20160009 [DOI] [PubMed] [Google Scholar]
  4. Blier, P. (2016). Neurobiology of depression and mechanism of action of depression treatments. Journal of Clinical Psychiatry, 77(3), e319. 10.4088/JCP.13097tx3c [DOI] [PubMed] [Google Scholar]
  5. Boldrini, M. , Hen, R. , Underwood, M. D. , Rosoklija, G. B. , Dwork, A. J. , Mann, J. J. , & Arango, V. (2012). Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biological Psychiatry, 72(7), 562–571. 10.1016/j.biopsych.2012.04.024 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown, J. P. , Couillard‐Després, S. , Cooper‐Kuhn, C. M. , Winkler, J. , Aigner, L. , & Kuhn, H. G. (2003). Transient expression of doublecortin during adult neurogenesis. Journal of Comparative Neurology, 467(1), 1–10. 10.1002/cne.10874 [DOI] [PubMed] [Google Scholar]
  7. Chen, L. X. , Qi, Z. , Shao, Z. J. , Li, S. S. , Qi, Y. L. , Gao, K. , Liu, S.‐X. , Li, Z. , Sun, Y.‐S. , & Li, P. Y. (2019). Study on antidepressant activity of pseudo‐ginsenoside HQ on depression‐like behavior in mice. Molecules (Basel, Switzerland), 24(5), 870. 10.3390/molecules24050870 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chong, P. S. , Fung, M. L. , Wong, K. H. , & Lim, L. W. (2019). Therapeutic potential of Hericium erinaceus for depressive disorder. International Journal of Molecular Sciences, 21(1), 163. 10.3390/ijms21010163 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clark, K. , Bardwell, W. A. , Arsenault, T. , DeTeresa, R. , & Loscalzo, M. (2009). Implementing touch‐screen technology to enhance recognition of distress. Psycho‐Oncology, 18(8), 822–830. 10.1002/pon.1509 [DOI] [PubMed] [Google Scholar]
  10. Colucci‐D'Amato, L. , Speranza, L. , & Volpicelli, F. (2020). Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. International Journal of Molecular Sciences, 21(20), 7777. 10.3390/ijms21207777 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cryan, J. F. , Mombereau, C. , & Vassout, A. (2005). The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neuroscience and Biobehavioral Reviews, 29(4–5), 571–625. 10.1016/j.neubiorev.2005.03.009 [DOI] [PubMed] [Google Scholar]
  12. Dranovsky, A. , & Hen, R. (2006). Hippocampal neurogenesis: Regulation by stress and antidepressants. Biological Psychiatry, 59(12), 1136–1143. 10.1016/j.biopsych.2006.03.082 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Duman, R. S. , Deyama, S. , & Fogaça, M. V. (2021). Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants. European Journal of Neuroscience, 53(1), 126–139. 10.1111/ejn.14630 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gao, T. T. , Wang, Y. , Liu, L. , Wang, J. L. , Wang, Y. J. , Guan, W. , Chen, T.‐T. , Zhao, J. , & Jiang, B. (2020). LIMK1/2 in the mPFC plays a role in chronic stress‐induced depressive‐like effects in mice. The International Journal of Neuropsychopharmacology, 23(12), 821–836. 10.1093/ijnp/pyaa067 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goñi‐Balentziaga, O. , Perez‐Tejada, J. , Renteria‐Dominguez, A. , Lebeña, A. , & Labaka, A. (2018). Social instability in female rodents as a model of stress related disorders: A systematic review. Physiology & Behavior, 196, 190–199. 10.1016/j.physbeh.2018.09.001 [DOI] [PubMed] [Google Scholar]
  16. Guan, W. , Cheng, F. , Wu, H. , Cao, Q. , Zhu, X. , Fan, Y. , Zhu, H. , & Zhou, Y. (2017). GATA binding protein 3 is correlated with leptin regulation of PPARγ1 in hepatic stellate cells. Journal of Cellular and Molecular Medicine, 21(3), 568–578. 10.1111/jcmm.13002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Guan, W. , Gu, J. H. , Ji, C. H. , Liu, Y. , Tang, W. Q. , Wang, Y. , & Jiang, B. (2021). Xanthoceraside administration produces significant antidepressant effects in mice through activation of the hippocampal BDNF signaling pathway. Neuroscience Letters, 757, 135994. 10.1016/j.neulet.2021.135994 [DOI] [PubMed] [Google Scholar]
  18. Gudasheva, T. A. , Povarnina, P. , Tarasiuk, A. V. , & Seredenin, S. B. (2019). The low molecular weight brain‐derived neurotrophic factor mimetics with antidepressant‐like activity. Current Pharmaceutical Design, 25(6), 729–737. 10.2174/1381612825666190329122852 [DOI] [PubMed] [Google Scholar]
  19. Guo, L. T. , Wang, S. Q. , Su, J. , Xu, L. X. , Ji, Z. Y. , Zhang, R. Y. , Zhao, Q.‐W. , Ma, Z.‐Q. , Deng, X.‐Y. , & Ma, S. P. (2019). Baicalin ameliorates neuroinflammation‐induced depressive‐like behavior through inhibition of toll‐like receptor 4 expression via the PI3K/AKT/FoxO1 pathway. Journal of Neuroinflammation, 16(1), 95. 10.1186/s12974-019-1474-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hsieh, Y. H. , Deng, J. S. , Chang, Y. S. , & Huang, G. J. (2018). Ginsenoside Rh2 ameliorates lipopolysaccharide‐induced acute lung injury by regulating the TLR4/PI3K/Akt/mTOR, Raf‐1/MEK/ERK, and Keap1/Nrf2/HO‐1 signaling pathways in mice. Nutrients, 10(9), 1208. 10.3390/nu10091208 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jiang, B. , Huang, C. , Chen, X. F. , Tong, L. J. , & Zhang, W. (2015). Tetramethylpyrazine produces antidepressant‐like effects in mice through promotion of BDNF signaling pathway. The International Journal of Neuropsychopharmacology, 18(8), pyv010. 10.1093/ijnp/pyv010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jiang, B. , Huang, C. , Zhu, Q. , Tong, L. J. , & Zhang, W. (2015). WY14643 produces anti‐depressant‐like effects in mice via the BDNF signaling pathway. Psychopharmacology, 232(9), 1629–1642. 10.1007/s00213-014-3802-0 [DOI] [PubMed] [Google Scholar]
  23. Jiang, B. , Wang, H. , Wang, J. L. , Wang, Y. J. , Zhu, Q. , Wang, C. N. , Song, L. , Gao, T.‐T. , Wang, Y. , Meng, G.‐L. , Wu, F. , Ling, Y. , Zhang, W. , & Li, J. X. (2019). Hippocampal salt‐inducible kinase 2 plays a role in depression via the CREB‐regulated transcription coactivator 1‐cAMP response element binding‐brain‐derived neurotrophic factor pathway. Biological Psychiatry, 85(8), 650–666. 10.1016/j.biopsych.2018.10.004 [DOI] [PubMed] [Google Scholar]
  24. Jiang, B. , Wang, Y. J. , Wang, H. , Song, L. , Huang, C. , Zhu, Q. , Wu, F. , & Zhang, W. (2017). Antidepressant‐like effects of fenofibrate in mice via the hippocampal brain‐derived neurotrophic factor signalling pathway. British Journal of Pharmacology, 174(2), 177–194. 10.1111/bph.13668 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kezhu, W. , Pan, X. , Cong, L. , Liming, D. , Beiyue, Z. , Jingwei, L. , Yanyan, Y. , & Xinmin, L. (2017). Effects of ginsenoside Rg1 on learning and memory in a reward‐directed instrumental conditioning task in chronic restraint stressed rats. Phytotherapy Research, 31(1), 81–89. 10.1002/ptr.5733 [DOI] [PubMed] [Google Scholar]
  26. Kim, H. R. , Lee, Y. J. , Kim, T. W. , Lim, R. N. , Hwang, D. Y. , Moffat, J. J. , Kim, S. , Seo, J.‐W. , & Ka, M. (2020). Asparagus cochinchinensis extract ameliorates menopausal depression in ovariectomized rats under chronic unpredictable mild stress. BMC Complementary Medicine and Therapies, 20(1), 325. 10.1186/s12906-020-03121-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Krishnan, V. , & Nestler, E. J. (2008). The molecular neurobiology of depression. Nature, 455(7215), 894–902. 10.1038/nature07455 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ledford, H. (2014). Medical research: If depression were cancer. Nature, 515(7526), 182–184. 10.1038/515182a [DOI] [PubMed] [Google Scholar]
  29. Leng, L. , Zhuang, K. , Liu, Z. , Huang, C. , Gao, Y. , Chen, G. , Lin, H. , Hu, Y. , Wu, D. , Shi, M. , Xie, W. , Sun, H. , Shao, Z. , Li, H. , Zhang, K. , Mo, W. , Huang, T. Y. , Xue, M. , Yuan, Z. , & Zhang, J. (2018). Menin deficiency leads to depressive‐like behaviors in mice by modulating astrocyte‐mediated neuroinflammation. Neuron, 100(3), 551–563.e557. 10.1016/j.neuron.2018.08.031 [DOI] [PubMed] [Google Scholar]
  30. Li, F. , Wu, X. , Li, J. , & Niu, Q. (2016). Ginsenoside Rg1 ameliorates hippocampal long‐term potentiation and memory in an Alzheimer's disease model. Molecular Medicine Reports, 13(6), 4904–4910. 10.3892/mmr.2016.5103 [DOI] [PubMed] [Google Scholar]
  31. Li, X. , Chu, S. , Lin, M. , Gao, Y. , Liu, Y. , Yang, S. , Zhou, X. , Zhang, Y. , Hu, Y. , Wang, H. , & Chen, N. (2020). Anticancer property of ginsenoside Rh2 from ginseng. European Journal of Medicinal Chemistry, 203, 112627. 10.1016/j.ejmech.2020.112627 [DOI] [PubMed] [Google Scholar]
  32. Lin, L. Y. , Zhang, J. , Dai, X. M. , Xiao, N. A. , Wu, X. L. , Wei, Z. , Fang, W.‐T. , Zhu, Y.‐G. , & Chen, X. C. (2016). Early‐life stress leads to impaired spatial learning and memory in middle‐aged ApoE4‐TR mice. Molecular Neurodegeneration, 11(1), 51. 10.1186/s13024-016-0107-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lin, T. W. , Harward, S. C. , Huang, Y. Z. , & McNamara, J. O. (2020). Targeting BDNF/TrkB pathways for preventing or suppressing epilepsy. Neuropharmacology, 167, 107734. 10.1016/j.neuropharm.2019.107734 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Liu, Y. , Zhou, L. J. , Wang, J. , Li, D. , Ren, W. J. , Peng, J. , Wei, X. , Xu, T. , Xin, W.‐J. , Pang, R.‐P. , Li, Y.‐Y. , Qin, Z.‐H. , Murugan, M. , Mattson, M. P. , Wu, L.‐J. , & Liu, X. G. (2017). TNF‐α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia‐dependent mechanisms after peripheral nerve injury. Journal of Neuroscience, 37(4), 871–881. 10.1523/jneurosci.2235-16.2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lu, C. , Wang, Y. , Lv, J. , Jiang, N. , Fan, B. , Qu, L. , Li, Y. , Chen, S. , Wang, F. , & Liu, X. (2018). Ginsenoside Rh2 reverses sleep deprivation‐induced cognitive deficit in mice. Behavioural Brain Research, 349, 109–115. 10.1016/j.bbr.2018.03.005 [DOI] [PubMed] [Google Scholar]
  36. Lv, J. , Lu, C. , Jiang, N. , Wang, H. , Huang, H. , Chen, Y. , Li, Y. , & Liu, X. (2021). Protective effect of ginsenoside Rh2 on scopolamine‐induced memory deficits through regulation of cholinergic transmission, oxidative stress and the ERK‐CREB‐BDNF signaling pathway. Phytotherapy Research, 35(1), 337–345. 10.1002/ptr.6804 [DOI] [PubMed] [Google Scholar]
  37. Mavrakis, K. J. , Wolfe, A. L. , Oricchio, E. , Palomero, T. , de Keersmaecker, K. , McJunkin, K. , Zuber, J. , James, T. , Khan, A. A. , Leslie, C. S. , Parker, J. S. , Paddison, P. J. , Tam, W. , Ferrando, A. , & Wendel, H. G. (2010). Genome‐wide RNA‐mediated interference screen identifies miR‐19 targets in notch‐induced T‐cell acute lymphoblastic leukaemia. Nature Cell Biology, 12(4), 372–379. 10.1038/ncb2037 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mu, R. H. , Tan, Y. Z. , Fu, L. L. , Nazmul Islam, M. , Hu, M. , Hong, H. , & Tang, S. S. (2019). 1‐Methylnicotinamide attenuates lipopolysaccharide‐induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis. International Immunopharmacology, 77, 105918. 10.1016/j.intimp.2019.105918 [DOI] [PubMed] [Google Scholar]
  39. Odaira, T. , Nakagawasai, O. , Takahashi, K. , Nemoto, W. , Sakuma, W. , Lin, J. R. , & Tan‐No, K. (2019). Mechanisms underpinning AMP‐activated protein kinase‐related effects on behavior and hippocampal neurogenesis in an animal model of depression. Neuropharmacology, 150, 121–133. 10.1016/j.neuropharm.2019.03.026 [DOI] [PubMed] [Google Scholar]
  40. Palasz, E. , Wysocka, A. , Gasiorowska, A. , Chalimoniuk, M. , Niewiadomski, W. , & Niewiadomska, G. (2020). BDNF as a promising therapeutic agent in Parkinson's disease. International Journal of Molecular Sciences, 21(3), 1170. 10.3390/ijms21031170 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Peng, S. , Li, W. , Lv, L. , Zhang, Z. , & Zhan, X. (2018). BDNF as a biomarker in diagnosis and evaluation of treatment for schizophrenia and depression. Discovery Medicine, 26(143), 127–136. [PubMed] [Google Scholar]
  42. Petit‐Demouliere, B. , Chenu, F. , & Bourin, M. (2005). Forced swimming test in mice: A review of antidepressant activity. Psychopharmacology, 177(3), 245–255. 10.1007/s00213-004-2048-7 [DOI] [PubMed] [Google Scholar]
  43. Qi, Z. , Li, W. , Tan, J. , Wang, C. , Lin, H. , Zhou, B. , Liu, J. , & Li, P. (2019). Effect of ginsenoside Rh(2) on renal apoptosis in cisplatin‐induced nephrotoxicity in vivo. Phytomedicine, 61, 152862. 10.1016/j.phymed.2019.152862 [DOI] [PubMed] [Google Scholar]
  44. Ren, Y. , Wang, J. L. , Zhang, X. , Wang, H. , Ye, Y. , Song, L. , Wang, Y.‐J. , Tu, M.‐J. , Wang, W.‐W. , Yang, L. , & Jiang, B. (2017). Antidepressant‐like effects of ginsenoside Rg2 in a chronic mild stress model of depression. Brain Research Bulletin, 134, 211–219. 10.1016/j.brainresbull.2017.08.009 [DOI] [PubMed] [Google Scholar]
  45. Schechter, L. E. , Ring, R. H. , Beyer, C. E. , Hughes, Z. A. , Khawaja, X. , Malberg, J. E. , & Rosenzweig‐Lipson, S. (2005). Innovative approaches for the development of antidepressant drugs: Current and future strategies. NeuroRx, 2(4), 590–611. 10.1602/neurorx.2.4.590 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Shafiee, M. , Arekhi, S. , Omranzadeh, A. , & Sahebkar, A. (2018). Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. Journal of Affective Disorders, 227, 330–337. 10.1016/j.jad.2017.11.020 [DOI] [PubMed] [Google Scholar]
  47. Stepanichev, M. Y. , Tishkina, A. O. , Novikova, M. R. , Levshina, I. P. , Freiman, S. V. , Onufriev, M. V. , Levchenko, O. A. , Lazareva, N. A. , & Gulyaeva, N. V. (2016). Anhedonia but not passive floating is an indicator of depressive‐like behavior in two chronic stress paradigms. Acta Neurobiologiae Experimentalis, 76(4), 324–333. 10.21307/ane-2017-031 [DOI] [PubMed] [Google Scholar]
  48. Sun, Y. , Zhao, Z. , Li, Q. , Wang, C. , Ge, X. , Wang, X. , Wang, G. , & Qin, Y. (2020). Dl‐3‐n‐butylphthalide regulates cholinergic dysfunction in chronic cerebral hypoperfusion rats. Journal of International Medical Research, 48(7), 300060520936177. 10.1177/0300060520936177 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Szuhany, K. L. , & Otto, M. W. (2020). Assessing BDNF as a mediator of the effects of exercise on depression. Journal of Psychiatric Research, 123, 114–118. 10.1016/j.jpsychires.2020.02.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Trombetta, I. C. , DeMoura, J. R. , Alves, C. R. , Carbonari‐Brito, R. , Cepeda, F. X. , & Lemos, J. R. Jr. (2020). Serum levels of BDNF in cardiovascular protection and in response to exercise. Arquivos Brasileiros De Cardiologia, 115(2), 263–269. 10.36660/abc.20190368 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wang, J. , Chen, Y. , Dai, C. , Shang, Y. , & Xie, J. (2016). Ginsenoside Rh2 alleviates tumor‐associated depression in a mouse model of colorectal carcinoma. American Journal of Translational Research, 8(5), 2189–2195. [PMC free article] [PubMed] [Google Scholar]
  52. Wang, J. L. , Wang, Y. , Gao, T. T. , Liu, L. , Wang, Y. J. , Guan, W. , Chen, T.‐T. , Zhao, J. , Zhang, Y. , & Jiang, B. (2020). Venlafaxine protects against chronic stress‐related behaviors in mice by activating the mTORC1 signaling cascade. Journal of Affective Disorders, 276, 525–536. 10.1016/j.jad.2020.07.096 [DOI] [PubMed] [Google Scholar]
  53. Wang, L. , Wei, Y. , Hu, H. , Zhang, X. , Zheng, M. , & Fei, G. (2020). Correlation between anxiety, depression and changes in Th17/Treg and inflammatory levels in patients with pulmonary nodules. Zhongguo Fei Ai Za Zhi, 23(7), 554–560. 10.3779/j.issn.1009-3419.2020.102.30 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wang, M. , Yan, S. J. , Zhang, H. T. , Li, N. , Liu, T. , Zhang, Y. L. , Li, X.‐X. , Ma, Q. , Qiu, X.‐C. , Fan, Q.‐Y. , & Ma, B. A. (2017). Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. Oncology Letters, 13(2), 681–685. 10.3892/ol.2016.5490 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Willner, P. (2017). The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiology Stress, 6, 78–93. 10.1016/j.ynstr.2016.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wu, Z. , You, Z. , Chen, P. , Chen, C. , Chen, F. , Shen, J. , & Xu, H. (2018). Matrine exerts antidepressant‐like effects on mice: Role of the hippocampal PI3K/Akt/mTOR signaling. The International Journal of Neuropsychopharmacology, 21(8), 764–776. 10.1093/ijnp/pyy028 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Xu, D. , Sun, Y. , Wang, C. , Wang, H. , Wang, Y. , Zhao, W. , Bao, G. , Wang, F. , Cui, Z. , & Jiang, B. (2018). Hippocampal mTOR signaling is required for the antidepressant effects of paroxetine. Neuropharmacology, 128, 181–195. 10.1016/j.neuropharm.2017.10.008 [DOI] [PubMed] [Google Scholar]
  58. Xu, J. , She, Y. , Su, N. , Zhang, R. , Lao, L. , & Xu, S. (2015). Effects of electroacupuncture on chronic unpredictable mild stress rats depression‐like behavior and expression of p‐ERK/ERK and p‐P38/P38. Evidence‐Based Complementary and Alternative Medicine, 2015, 650729. 10.1155/2015/650729 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Xu, P. , Wang, K. , Lu, C. , Dong, L. , Gao, L. , Yan, M. , Aibai, S. , Yang, Y. , & Liu, X. (2017). The protective effect of lavender essential oil and its main component linalool against the cognitive deficits Induced by D‐galactose and aluminum trichloride in mice. Evidence‐Based Complementary and Alternative Medicine, 2017, 7426538. 10.1155/2017/7426538 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yan, B. , Liu, Y. , Shi, A. , Wang, Z. , Aa, J. , Huang, X. , & Liu, Y. (2018). Investigation of the antifatigue effects of Korean ginseng on professional athletes by gas chromatography‐time‐of‐flight‐mass spectrometry‐based metabolomics. Journal of AOAC International, 101(3), 701–707. 10.5740/jaoacint.17-0220 [DOI] [PubMed] [Google Scholar]
  61. Yan, H. C. , Qu, H. D. , Sun, L. R. , Li, S. J. , Cao, X. , Fang, Y. Y. , Jie, W. , Bean, J. C. , Wu, W.‐K. , Zhu, X.‐H. , & Gao, T. M. (2010). Fuzi polysaccharide‐1 produces antidepressant‐like effects in mice. The International Journal of Neuropsychopharmacology, 13(5), 623–633. 10.1017/s1461145709990733 [DOI] [PubMed] [Google Scholar]
  62. Yang, W. , Liu, M. , Zhang, Q. , Zhang, J. , Chen, J. , Chen, Q. , & Suo, L. (2020). Knockdown of miR‐124 reduces depression‐like behavior by targeting CREB1 and BDNF. Current Neurovascular Research, 17(2), 196–203. 10.2174/1567202617666200319141755 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yang, X. , Zou, J. , Cai, H. , Huang, X. , Yang, X. , Guo, D. , & Cao, Y. (2017). Ginsenoside Rg3 inhibits colorectal tumor growth via down‐regulation of C/EBPβ/NF‐κB signaling. Biomedicine & Pharmacotherapy, 96, 1240–1245. 10.1016/j.biopha.2017.11.092 [DOI] [PubMed] [Google Scholar]
  64. Yankelevitch‐Yahav, R. , Franko, M. , Huly, A. , & Doron, R. (2015). The forced swim test as a model of depressive‐like behavior. Journal of Visualized Experiments, 97, e52587. 10.3791/52587 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zhang, B. , Wang, P. P. , Hu, K. L. , Li, L. N. , Yu, X. , Lu, Y. , & Chang, H. S. (2019). Antidepressant‐like effect and mechanism of action of honokiol on the mouse lipopolysaccharide (LPS) depression model. Molecules (Basel, Switzerland), 24(11), 2035. 10.3390/molecules24112035 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Zhang, H. , Li, Z. , Zhou, Z. , Yang, H. , Zhong, Z. , & Lou, C. (2016). Antidepressant‐like effects of ginsenosides: A comparison of ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K, and 20(S)‐protopanaxadiol in mice models of despair. Pharmacology Biochemistry and Behavior, 140, 17–26. 10.1016/j.pbb.2015.10.018 [DOI] [PubMed] [Google Scholar]
  67. Zhang, J. J. , Gao, T. T. , Wang, Y. , Wang, J. L. , Guan, W. , Wang, Y. J. , Wang, C.‐N. , Liu, J.‐F. , & Jiang, B. (2019). Andrographolide exerts significant antidepressant‐like effects involving the hippocampal BDNF system in mice. The International Journal of Neuropsychopharmacology, 22(9), 585–600. 10.1093/ijnp/pyz032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhang, Y. , Fang, X. , Fan, W. , Tang, W. , Cai, J. , Song, L. , & Zhang, C. (2018). Interaction between BDNF and TNF‐α genes in schizophrenia. Psychoneuroendocrinology, 89, 1–6. 10.1016/j.psyneuen.2017.12.024 [DOI] [PubMed] [Google Scholar]
  69. Zhang, Z. , Cai, X. , Yao, Z. , Wen, F. , Fu, Z. , Zhang, J. , Zhong, Z. , Huang, Y. , & Qu, S. (2020). EA ameliorated depressive behaviors in CUMS rats and was related to its suppressing autophagy in the hippocampus. Neural Plasticity, 2020, 8860968. 10.1155/2020/8860968 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Zhao, H. , Mohamed, N. E. , Chan, S. J. , Tan, C. T. , Tao, R. , Yu, V. C. , & Wong, P. T. (2019). Absence of stress response in dorsal raphe nucleus in modulator of apoptosis 1‐deficient mice. Molecular Neurobiology, 56(3), 2185–2201. 10.1007/s12035-018-1205-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Zhu, G. , Wang, Y. , Li, J. , & Wang, J. (2015). Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long‐term potentiation in middle‐aged mice. Neuroscience, 292, 81–89. 10.1016/j.neuroscience.2015.02.031 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all data, models, or code generated or used during the study are available from the corresponding author upon request.

Articles from Brain and Behavior are provided here courtesy of Wiley

RESOURCES