Mechanisms of Panax ginseng action as an antidepressant

Abstract Objectives Panax ginseng, a well‐known traditional Chinese medicine with multiple pharmacological activities, plays a crucial role in modulating mood disorders. Several recent studies have identified an underlying role of Panax ginseng in the prevention and treatment of depression. However, the cellular and molecular mechanisms remain unclear. Materials and Methods In this review, we summarized the recent progress of antidepressant effects and underlying mechanisms of Panax ginseng and its representative herbal formulae. Results The molecular and cellular mechanisms of Panax ginseng and its herbal formulae include modulating monoamine neurotransmitter system, upregulating the expression of neurotrophic factors, regulating the function of HPA axis, and anti‐inflammatory action. Conclusions Therefore, this review may provide theoretical bases and clinical applications for the treatment of depression by Panax ginseng and its representative herbal formulae.


| INTRODUC TI ON
Depression, academically known as major depressive disorder (MDD), is a prevalent mental disorder which is characterized by a pervasive and sustained low mood, low interest, low motivation and even suicidal tendencies. 1 MDD reduces the quality of life for numerous people all around the world. 2,3 Nevertheless, little is known about the underlying pathogenesis and aetiology of depression. Widely accepted molecular theories of depression include monoaminergic hypothesis, monoaminergic receptor hypothesis, neurotrophic hypothesis, the hypothesis of neuroplasticity, neuroendocrine and neuroimmune hypothesis. [4][5][6][7][8][9][10] For the treatment of depression, current clinical therapy mainly depends on traditional antidepressants. However, traditional antidepressants have a limitation in long onset time, high relapse rates and severe side effects, such as cognitive dysfunction, sexual dysfunction and sleep disorders. [11][12][13] Besides, depression poses a huge physiological and economic burden on patients with depression. Therefore, it is critically important to develop efficient and safe drugs for depression treatment. Recent studies have revealed that traditional herbal medicines may offer promising alternatives for depression treatment with high safety and tolerance. [14][15][16] Panax ginseng Meyer is a well-known traditional medicinal herb which has been used as a vital energy reinforcing agent with a long history in Chinese medicine theory. Ginseng exerts diversified biological activities, for instance, anti-tumour, antiinflammatory, anti-oxidation, inhibition of cell apoptosis and neuroprotective effects. 17 Recently, some studies have shown that ginseng plays a significant role in depression and may act as a potential antidepressant. Moreover, ginseng can be taken for a long duration with a high safety profile and less adverse reactions. Although some relevant mechanisms have been discussed, studies on the antidepressant-like effects of ginseng are still in their infancy.
In the theory of traditional Chinese medicine, depression is a general term for a class of diseases and syndromes caused by emotional impairments and dysfunctions of Qi and blood. Deficiency of Qi and blood leads to disorder of Qi, damaging the Qi of viscera and affecting the normal function of viscera. Qi was considered as a specific substance which is essential to survival for the human body, and it is also the general name of the functional activities of human organs. Ginseng is deemed to play a role of invigorating vital energy by sufficiently tonifying Qi of spleen, lung, heart and kidney.
Meanwhile, Qi promotes blood production. Ginseng makes the body produce blood, smooth blood vessels and restore Qi and blood, and subsequently nourish the heart and calm the mind via tonifying Qi.
In the present paper, we systematically reviewed the likely underlying mechanisms of antidepressant effects of ginseng and its herbal formulae and pave a way for the further study of ginseng in the treatment of depression.

| G IN S ENG AND ITS AC TIVE ING RED IENTS
Ginseng, a precious herb in traditional Chinese medicine, has a long history of medicinal use in the improvement of mental state and modulation of neurological diseases, such as insomnia, depression, anxiety and neurasthenia. It has been honoured as "the king of herbs" and was listed as the top grade in Shennong Materia Medica. According to different origins, there are basically Panax ginseng, Panax quinquefolium L. and Panax notoginseng. They are also the most extensively studied species. Panax ginseng, which has the greatest tonic effect, is mainly cultivated in northeast China, Korea, Japan and eastern Russia. It is best for people who are physically weak and infirm, preferably taken in winter. Panax quinquefolium L., also known as American ginseng, is mainly produced in the United States, Canada and other countries. It is the mildest in nature and suitable for most people and all seasons.
Panax notoginseng is only grown in parts of China, including Jilin, Guangxi and Yunnan. 18 In addition, according to the different processing methods, ginseng can also be divided into white ginseng, sugar ginseng and red ginseng (Table 1). Ginseng has attracted the attention of many researchers all over the world because of its wide range of pharmacological effects and medical application efficacy. Modern studies show that ginseng contains a large number of active ingredients, including ginsenosides, ginseng polypeptides, ginseng polysaccharides and so on ( Table 2). Among them, ginsenosides are considered to be major active ingredients of ginseng physiological activity, which have impacts on the nervous system, cardiovascular system, immune system and so on. 19 On the basis of different chemical structures of their aglycons, ginsenosides can be classified into three main types: protopanaxadiols (PPDs), protopanaxatriols (PPTs) and oleanolic acids. PPD-type includes ginsenosides Rb1, Rb2, Rc and Rd, while PPT-type includes ginsenosides Rg1, Rg2, Rf and Re. Besides, Ro is the main oleanolic acid-type ginsenoside. The structural formulae of ginsenosides with antidepressant effects are presented in Table 3

| Effect on monoamine neurotransmitters
In the past years, monoamine neurotransmitters have become a focus on the pathophysiology of depression. It is reported that depression is caused by a decline in the function of monoamine transmitters, such as serotonin (5-HT), noradrenaline (NA) and dopamine (DA). Indeed, reduction of plasma 5-HT level has been observed in depressed patients resulting from alcohol withdrawal. 22  when combined with caffeine and fluoxetine. 26 Besides, ginsenoside Rb1 and its metabolite compound K acted as antidepressants by regulating 5-HT 2A receptors, which was demonstrated by blockade action of ritanserin pre-treatment. 27 Gintonin, an active constituent of the Panax ginseng extract, could improve depression-related symptoms in mice with alcohol withdrawal through elevating the level of plasma 5-HT which was released from intestinal enterochromaffin cells. 28 Chronic treatment of total saponins extracted from Panax notoginseng also could improve the rats depression-like behaviours in chronic mild stress (CMS) mice via increasing the levels of 5-HT, DA and NA and decreasing cytoplasmic free intracellular Ca 2+ concentration. 29 Other neurotransmitters, such as acetylcholine and glutamate, also have been found to be strongly associated with depression.

| Effect on hypothalamic-pituitary-adrenal axis
The neuroendocrine hypothesis points out that dysfunction of the endocrine system is the main cause of the occurrence of depression. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and the consequently potentiated stress response have many adverse impacts on the brain and many other peripheral organs. 30,31 It has been demonstrated that hyperactivity of the HPA axis leads to the depressive behaviours mainly by elevating blood cortisol (CORT) levels and facilitating brain corticotropin-releasing factor transmission. 32 Hyperactivity of stress hormones can cause atrophy or apoptosis of neurons and decrease nerve regeneration in the hippocampus, amygdala and other depression-related brain regions.
There is growing evidence that neuroendocrine functional disorder might be the physiological basis of pathological changes of depression and other mood disorders. 33 Researches over the last couple of years indicated that Rg1 could return the HPA axis to normal function, by improving serum CORT as well as testosterone levels and modulating glucocorticoid receptor (GR) levels in both prefrontal cortex (PFC) and hippocampus in rats with the CUMS-induced depression. 34 Ginsenoside Rh1 and Rg3 as oestrogen receptor (ERs) ligands and Rh2 and K as GRs ligands may also affect the function of HPA axis mediated by ERs or GRs. 35 Furthermore, Rb1 and Rg3 could attenuate neuronal toxicity, which is related to glucocorticoid activity. 36 In a study of CORT-induced depression in mice, researchers found that ginseng total saponins (GTS) treatments improved depressant behaviours without changing the heightened serum CORT levels, as well as increased the downregulated levels of inhibitory GSK-3β phosphorylation in the hippocampus, which was opposite to fluoxetine. 37 In addition, studies have shown that some disorders of the gonadal hormones, such as oestrogen and progesterone, might affect feelings, emotions, and cognition which involved in the development of depression. There is strong evidence that menopause is a time of increased vulnerability to dysphoric mood. 38 Moreover, in depressed patients, the HPG axis that regulates gonadal function was weakened. 39 Rg1 showed antidepressant-like effects not only by regulating the function of the HPA axis, but also the HPG axis.

| Effect on BDNF
Brain-derived neurotrophic factor (BDNF), one of the neurotrophic factors, does main favour in neurogenesis, neural survival and growth. 40,41 BDNF binds to its tropomyosin receptor kinase B (TrkB) to activate downstream signalling pathways and then completes phosphorylation and activation of the cAMP response element-binding protein (CREB). 42 The BDNF reduction in both hippocampus and PFC is closely associated with depression. Besides, the serum BDNF level also decreases in depression patients. 43,44 BDNF has acted as a biomarker for depression in many studies. [45][46][47] The previous study illustrated that the extracts from Panax ginseng produce antidepressant-like effect via accommodation of BDNF expression in various classic animal depression models, including FST, tail suspension test (TST), CMS, CUMS and so on. [48][49][50] It has been reported that ginseng extract G115 could notably improve BDNF expression in the hippocampus and PFC of ethanol-induced depression mice, even superior to amitriptyline, indicating that the antidepressant effects may contribute to some BDNF-related signalling pathway. 51 Interestingly, G115 did not influence the BDNF levels in normal brain areas. GTS could reverse alterations in depressive behaviours resulted from CORT through intervening in GSK-3 β-CREB signalling pathway in the hippocampus and reversing the reduction of some proteins related to plasticity. 52 In the lipopolysaccharide (LPS) immunoreactive mice model which act as an inflammatory-related animal model of depression, levels of BDNF and TrkB in the hippocampus were upregulated by sesquiterpenoids, suggesting that BDNF/TrkB pathway may be a target of the antidepressant effects of sesquiterpenoids. 53 In addition, ginseng pectin also showed the antidepressant effect to some extent, 54 which may be related to its neuroprotective role through the activation of ERK/MAPK and Akt survival signalling pathways. 55 Ginsenoside monomers could similarly lead to apparent physiological behaviour changes in depressed murine. Ginsenoside Rg1 enhanced hippocampal BDNF signalling pathway while reduced serum CORT level, and it also reversed the decline in both dendritic spine density and hippocampal neurogenesis in the CMS model. 56 Moreover, Rg1 could increase CREB phosphorylation and BDNF expression in the amygdala of CUMS rats. 57 Downregulation of the Akt/mTOR signalling pathway has been also shown to be associated with decreased senescence of neural stem cells induced by ginsenoside Rg1. 58 However, Rg1 seemed to have no distinguishable effect on the monoaminergic system. 56 The same as sesquiterpenoids, ginsenoside Rg2 and Rg5 regulated the BDNF/ TrkB pathway, which was confirmed by the blocking effect of TrkB shRNA and TrkB inhibitor. 59,60 Beyond this, researches showed that infusion of the BDNF signalling inhibitor blocked the antidepressant effects of Rg3. 61

| Effect on the neuroimmune system
Increasing evidence has indicated that inflammatory cytokine disor- also decreased the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, IL-1β and IL-6 in brain tissue after LPS injection. 75 Moreover, Rb1 attenuates damage to cerebral cortex neurons by downregulation of nitric oxide, superoxide and TNF-α expression in hypoxia-activated microglia. 76 These studies may provide therapeutic potential for the treatment of depression with microglia activation ( Figure 1).

| Effect on other mechanisms
Panax quinquefolium has shown the protective effects against olfactory bulbectomy-induced depression-like behaviours and nitric oxide pathway might be involved. 77  Overall, many studies have shown that the regulatory role of Panax ginseng appears to be crucial in depression (Table 4). The action of Rg1 is shown in Figure 2 89 KXS was found to ameliorate 5-HT defects, which is achieved by raising the synthesis, inhibiting the reuptake and ultimately increasing the concentration of intracephalic 5-HT. 90,91 In an earlier study, impacts and potential mechanisms of KXS2012 on depression in both cell and animal models were validated. Moreover, it promoted neurogenesis via inducing the expression of synaptotagmin and dendritic spine density in cultured neurons and increased neurotrophins in astrocytes which might concern the regulation of Erk1/2 and CREB phosphorylation. 92 In   95 There is also evidence that KXS seems to improve memory impairment induced by hindlimb suspension mainly by decreasing serum ROS, 8-OHdG and 3-nitrotyrosine and inhibiting oxidative stress injury, rather than influencing the central cholinergic system. 96 In addition, KXS treatment effectively improved depressive symptoms in fluoxetine-resistant depression rats by the reduction of COX-2, IL-2, IL-6, TNF-α levels and increase of IL-10, IFN-γ level. 97 With the deepening of research, the neurobiological mechanism of KXS and its specific active ingredients in preventing and treating depression will be further elucidated.

| Xiaochaihu Decoction
Xiaochaihu These studies lay the foundation for the study of pharmacodynamic substances of XD's antidepressant effect.
As mentioned above, Panax ginseng herbal formulae have multiple functions on anti-depression and the confirmation of the mechanisms is progressing (

| EFFEC TS OF PANA X G IN S ENG ON OTHER CN S D IS E A S E S
Effects of Panax ginseng and its active ingredients on other neurological diseases, like Alzheimer's and Parkinson's, are well documented in several studies. 106,107 Since the NTFs are implicated in some other CNS disorders, extracts and natural products of Panax ginseng exhibit therapeutic effects on various kinds of disease models. 108 It is possible that Rg3 could be used to treat these disorders based on the regulation of BDNF expression, which needs to be further studied. 61 Furthermore, Rg1 could alleviate cognitive and sexual dysfunctions, which might be associated with depressive Increases the protein levels of BDNF, NGF and GDNF, as well as the mRNA expressions of Trk receptors [92][93][94] Promotes neurogenesis and synaptogenesis 92,95 Influences the inflammatory processes via reduction of COX-2, IL-2, IL-6, TNF-α levels and increase of IL-10, IFN-γ levels symptoms. 109,110 Ginsenosides Rg5 and Rh3 might inhibit AChE activity dose dependently and reverse the reduction of BDNF and phosphorylated CREB in the hippocampus, resulting in protection of memory deficit. 111 American ginseng could play a protective role by regulating nitrergic signalling cascade to resist the cognitive impairment, neuroinflammation and biochemical alterations induced by chronic unpredictable stress. 112

| CON CLUS IONS
In conclusion, in this study we summarized the recent progress of

CO N FLI C T S O F I NTE R E S T
The authors declare no conflict of interest.

AUTH O R CO NTR I B UTI O N S
BL contributed conception and design of the study; YJ wrote the first draft of the manuscript; LZ and JF wrote sections of the manuscript; RC provided the critical revisions. All authors revised the manuscript and approved the submitted version.

DATA AVA I L A B I L I T Y S TAT E M E N T
Research data are not shared.