Scholarly article on topic 'The effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis'

The effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Seungyeop Lee, Dong-Kwon Rhee

Abstract Ginseng effectively regulates the immune response and the hormonal changes due to stress, thus maintaining homeostasis. In addition to suppressing the occurrence of psychological diseases such as anxiety and depression, ginseng also prevents stress-associated physiological diseases. Recent findings have revealed that ginseng is involved in adjusting the hypothalamic–pituitary–adrenal axis and controlling hormones, thus producing beneficial effects on the heart and brain, and in cases of bone diseases, as well as alleviating erectile dysfunction. Recent studies have highlighted the potential use of ginseng in the prevention and treatment of chronic inflammatory diseases such as diabetes, rheumatoid arthritis, and allergic asthma. However, the mechanism underlying the effects of ginseng on these stress-related diseases has not been completely established. In this review, we focus on the disease pathways caused by stress in order to determine how ginseng acts to improve health. Central to our discussion is how this effective and stable therapeutic agent alleviates the anxiety and depression caused by stress and ameliorates inflammatory diseases.

Academic research paper on topic "The effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis"

Accepted Manuscript

The effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis

Seungyeop Lee, Dong-Kwon Rhee

PII: S1226-8453(16)30224-X

DOI: 10.1016/j.jgr.2017.01.010

Reference: JGR 249

To appear in: Journal of Ginseng Research

Received Date: 1 October 2016 Revised Date: 12 November 2016 Accepted Date: 18 January 2017

Please cite this article as: Lee S, Rhee D-K, The effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis, Journal of Ginseng Research (2017), doi: 10.1016/ j.jgr.2017.01.010.

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The effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis

Seungyeop Lee and Dong-Kwon Rhee

8 School of Pharmacy, Sungkyunkwan University, Su-Won 16419, South Korea

9 10 11 12

To whom correspondence may be addressed: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, South Korea. Tel: +82 31 2907707; e-mail: dkrhee@skku.edu

17 Running title: Adaptogenic effects of ginseng

20 Abstract

22 Ginseng effectively regulates the immune response and the hormonal changes due to stress,

23 thus maintaining homeostasis. In addition to suppressing the occurrence of psychological

24 diseases such as anxiety and depression, ginseng also prevents stress-associated physiological

25 diseases. Recent findings have revealed that ginseng is involved in adjusting the

26 hypothalamic-pituitary-adrenal axis and controlling hormones, thus producing beneficial

27 effects on the heart and brain, and in cases of bone diseases, as well as alleviating erectile

28 dysfunction. Recent studies have highlighted the potential use of ginseng in the prevention

29 and treatment of chronic inflammatory diseases such as diabetes, rheumatoid arthritis, and

30 allergic asthma. However, the mechanism underlying the effects of ginseng on these stress-

31 related diseases has not been completely established. In this review, we focus on the disease

32 pathways caused by stress in order to determine how ginseng acts to improve health. Central

33 to our discussion is how this effective and stable therapeutic agent alleviates the anxiety and

34 depression caused by stress and ameliorates inflammatory diseases.

36 Keywords: Ginseng; inflammatory cytokines; hypothalamic-pituitary-adrenal (HPA) axis;

37 stress; depression; anxiety

1. Introduction

In order to survive, all organisms must manage the physical and psychological effects of a variety of stressful situations. Stress represents a necessary response that maintains in vivo homeostasis upon exposure to environmental changes. When affected by a certain stressor, changes occur in the human body. This programmed response is known as a stress response. Stress can be divided into four types: chronic eustress (too little stress), acute stress (optimum stress), acute distress (too much stress), and chronic stress (burnout). When stress increases beyond a certain level, it leads to adverse health effects. Furthermore, chronic stress can cause depression and/or anxiety [1]. Thus, in this review, we will consider the beneficial effects of ginseng on the multidimensional symptoms and typical diseases caused by stress.

Ginseng is traditionally used as a medicinal herb in Korea, Japan, China, and the United States of America [2, 3]. The reason for this long established usage is that ginseng contains natural antioxidant compounds. These ginsenosides, which are extracted from the ginseng roots, leaves, stems, and fruit, have multiple pharmacological effects. They are subdivided into about 100 different categories [4]. In many studies, ginsenosides have been presented as an effective treatment for organ damage and cell death, as well as for immunological and metabolic diseases [5-7]. In addition, these pharmacologically active constituents have been shown to support neurogenesis, synaptogenesis, neuronal growth, and neurotransmission, thus helping to protect the central nervous system (CNS) from unexpected events; ginseng is also reported to be excellent for improving memory [8, 9].

As a powerful natural antioxidant, ginseng effectively modulates apoptosis by reducing the excessive inflammatory response in acute or chronic inflammation [10]. Abnormal apoptosis can result in functional impairment of organs. The human body contains many different protein types and their interactions maintain the balance of mechanisms related to

63 proliferation, differentiation, and apoptosis. When this homeostasis is disturbed, it can

64 damage the immune system and lead to several fatal diseases [11, 12].

65 Many studies conducted over the past decade have revealed that ginseng has a range of

66 positive effects on the human body, but a systematic perspective on the efficacy of ginseng in

67 the treatment of stress in vivo is not available. Therefore, this review will consider whether

68 ginseng modulates human stress-related changes and diseases, and evaluate how ginseng

69 could potentially act as a therapeutic agent for stress-induced diseases.

71 2. Ginseng and stress

72 Ginseng has been used as an adaptogen to treat illness, both as a tonic and as a rejuvenator.

73 In modern societies, we rarely depend on herbal remedies as the only treatment for critical

74 and potentially fatal diseases. However, owing to an excessive amount of brain activity, over-

75 work, and group living conditions, modern life involves constant exposure to stress.

76 Moreover, the level of stress can be sustained over time because of the repetitive nature of

77 some occupations; this can cause detrimental biological stress responses. When under certain

78 kinds of stress, the human body secretes hormones and inflammatory cytokines, and chronic

79 stress can promote the development of anxiety, depression, and even panic disorders, in

80 severe cases. Therefore, adaptogens are often used to cope with day-to-day and/or workplace

81 stress. Ginseng shows superior regulation of stress, as compared with that shown by other

82 adaptogens [13]. This efficacy as an anti-stress agent has been demonstrated using various

83 behavioral conditioned stress tests, such as swimming and immobilization tests. In vivo

84 studies have also shown that ginseng has excellent anti-stress effects, as compared to

85 appropriate controls [14, 15].

This article considers the adaptogenic effects of ginseng and focuses on whether these can mitigate any diseases. To achieve this, we will explore the physical changes and symptoms associated with stress, and discuss whether ginseng ameliorates these phenomena.

3. Stress hormones

Hormones act as chemical messengers and are vital regulators of biorhythms such as physical growth, appetite, blood pressure, emotion, sexual function, body temperature, sleep, and hydration. When the human body undergoes changes, various organs secrete hormones into the bloodstream. Hormones then bind with specific receptors in the cells of the target organs to regulate particular biological mechanisms. When subjected to stress, the stress hormone, cortisol, is secreted to counteract stress and maintain homeostasis. However, prolonged cortisol secretion results in immunosuppression. Cortisol is produced and regulated by a major hormonal control center, the hypothalamic-pituitary-adrenal (HPA) axis, regulated by the sympathetic nervous system [16].

The HPA plays a pivotal role in regulating the majority of the endocrine hormones associated with the CNS. External stimuli can trigger secretion of the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus, the starting point of the HPA. These hormones then act at the core of the HPA, the pituitary gland. CRH constitutes the primary pathway regulating the secretion of adrenocorticotropin (ACTH). AVP then acts on the pituitary gland after the CRH receptors have been desensitized. ACTH then stimulates the adrenal cortex, the last region of the HPA, triggering the release of cortisol (in humans) and corticosterone (in humans, rats, and mice) [16, 17] [Fig. 1].

Cortisol interacts with the cytoplasmic glucocorticoid receptor. This hormone-receptor complex moves to the nucleus and regulates the expression of several genes [18].

110 In this manner, cortisol regulates the expression levels of a number of messenger RNAs

111 and the expression of important cytokines in various organs and immune cells in order to

112 counteract the effects of stress, or to regulate the action of T lymphocytes in a number of

113 diseases.

115 4. Ginseng and the hypothalamic-pituitary-adrenal axis

116 When a person faces a stressful environment, ginseng can improve their response by

117 regulating the function of the HPA axis [19]. Ginseng also has applications beyond everyday

118 use in healthy people. It provides a potential treatment agent for patients with HPA axis

119 disorders associated with hypersecretion of cortisol, including depression, asthma,

120 hypertension, and post-traumatic stress disorder [20]. However, it remains unclear how

121 ginseng regulates chronic inflammation via HPA axis to inhibit various diseases.

122 Identification of underlying mechanisms of ginseng effects on HPA could have the potential

123 to provide approaches to the prevention of various diseases [Fig. 1]. Therefore, further

124 research is needed to investigate how ginseng modulates hormone secretion.

126 5. Ginseng in depression and anxiety

127 Depression is a severe mental illness without any apparent physical symptoms. However,

128 physical problems can emerge as depression becomes more advanced. About 10-30% of

129 patients with depression are unable to overcome the initial stages, and eventually succumb to

130 extreme physical harm; this includes committing suicide, inflicting self-harm, and developing

131 drug dependence, which affects their quality of life. Furthermore, the prevalence of

132 depression is increasing and this represents a major clinical challenge [21].

Ginseng effectively suppresses stress, which is a major cause of depression. This activity has been demonstrated in depression tests using animal models. Ginseng demonstrated similar levels of efficacy as the commercially available antidepressant, fluoxetine [22]. In addition, depression can be associated with memory loss. This is because depression results in progressive damage to nerve cells [23]. This neuronal cell damage, coupled with a neuroinflammation-induced reduction in neurogenesis, can result in hippocampal cell death

Ginseng is traditionally employed to protect the nervous system. Ginseng is effective in memory improvement, and in the direct prevention of degenerative brain diseases such as Alzheimer's disease. The neuroprotective effect of ginseng may be useful in the prevention of depression. Indirectly, enhanced memory can ameliorate anxiety. In clinical studies, it was observed that memory loss was attenuated in elderly patients treated with anxiolytics. These clinical studies may indicate that ginseng has the potential to improve anxiety [25] [Fig. 1].

Research studies can employ self-testing using the depression, anxiety, and stress scale to measure anxiety, depression, and stress levels induced by the environment, including emotional and physical factors [26]. Stress is closely related to psychological disorders such as depression and anxiety. Thus, ginseng is potentially an effective candidate for easing stress and can therefore improve the symptoms of depression and anxiety.

6. Various types of diseases affected by ginseng.

Chronic stress can trigger diseases such as abnormal immune responses and hormonal disorders. However, regular ingestion of ginseng has both preventive and therapeutic effects on several human diseases, including heart disease, stroke, diabetes mellitus (DM), rheumatoid arthritis, osteoporosis, erectile dysfunction (ED), and allergic asthma. These

157 diseases can be more prevalent in patients with depression and anxiety, in comparison to

158 healthy individuals [27] [Fig. 1]. This may reflect an increase in depression and anxiety in

159 patients with a physical illness, due to their physical pain, or indicate that depression and

160 anxiety predispose to secondary physical illnesses.

162 6.1.Vascular disease

163 Ginseng is an effective antioxidant, as well as improving vasomotor function and

164 preventing blood clots. These effects positively improve cardiovascular health [28].

165 Cardiovascular diseases (CVD) have a higher mortality rate than cancers worldwide, and in

166 western countries, CVD account for more than half of the deaths. CVD are also very closely

167 related to stress. Research conducted over many decades has revealed that long working

168 hours, noise, and stressful workplace environments increased the incidence of CVD

169 proportionally [29]. Ginseng alleviates such stress and could thus help to prevent CVD. In

170 animal models, ginseng lowered the levels of reactive oxygen species (ROS) in myocardial

171 tissue and improved blood circulation, helping to maintain heart function [30].

172 Vascular abnormalities can also affect the nervous system, and stroke is the fifth deadliest

173 disease in the United States of America. The resultant changes in the blood supply to the

174 brain can cause necrosis of the brain tissue. Hypertension and atherosclerosis increase the risk

175 for stroke [31]. Ginseng suppresses the oxidative stress induced by ischemia, a major driver

176 of stroke-induced tissue damage. By regulating brain cell necrosis and the production of pro-

177 inflammatory factors, it contributes to the prevention of deadly brain inflammation [32].

179 6.2.Osteoporosis

180 By regulating the HPA axis, ginseng influences the hormonal system. One of the hormones

181 regulated in this manner is estrogen, a sex hormone that acts as an agonist in the brain, bones,

182 and heart. The effects of estrogen reduce the risk of developing CVD, stroke, and

183 osteoporosis [30]. Ginseng has also been shown to upregulate the estrogen receptor in a range

184 of cell types in vitro, indicating that it could increase the tissue effects of this hormone [33].

185 This phenomenon is observed in bone tissue. In postmenopausal women, where there is a

186 sudden decline in estrogen levels, the probability of osteoporosis is proportionally increased.

187 The bone tissue of patients with osteoporosis can fracture easily owing to a reduced bone

188 density. This is related to the amount of estrogen supplied to osteoclasts. Estrogen inversely

189 regulates the expression of interleukin (IL)-6, a pro-inflammatory cytokine. Chronic increases

190 in the level of IL-6 result in osteoporosis and similar increases can also be observed in

191 patients with depression or sleep disorders, or in those experiencing stress due to bad eating

192 habits [34].

193 Ginseng promotes osteogenesis in the bone marrow stromal cell. In addition, by inhibiting

194 receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear factor kappa-light-

195 chain-enhancer of activated B cells (NF-kB), c-Jun N-terminal kinases (JNK), c-Fos, nuclear

196 factor of activated T-cells, cytoplasmic 1(NFATc1), and the pro-inflammatory cytokines,

197 tumor necrosis factor alpha (TNF-a) and IL-6, and by playing a role in osteoclast

198 differentiation and bone resorption, it helps to prevent osteoporosis. However, further

199 research is required to elucidate the exact mechanisms underlying these effects of ginseng

200 [35].

202 6.3.Arthritis

Ginseng contributes to the prevention of the development of autoimmune diseases by suppressing the excessive secretion of pro-inflammatory cytokines induced by persistent stress. Therefore, ginseng is effective in preventing rheumatoid arthritis (RA). TNF-a, a pro-inflammatory cytokine, can cause early joint inflammation or accelerate inflammatory cell infiltration in joints. Chronic destruction and disability of the joints may develop into RA. During this process, ginseng can help to prevent the autoimmune process underlying RA by inhibiting the major pro-inflammatory cytokine, TNF-a [36].

6.4.Erectile dysfunction

In addition to preventing disease by regulating estrogen in women, ginseng is also very effective in men. In modern societies, about 50% of the men aged between 40 and 70 years experience ED due to aging, smoking, obesity, and a variety of other reasons; however, the primary cause of ED is anxiety [37].

Three methods of treatment exist for ED: oral drug administration, drug injections, and the use of a penile prosthesis. Most patients currently use oral drug treatment. Although treatment is available with sildenafil, the active ingredient of Viagra, periodic phytotherapies with herbal medicines may be preferred by some patients. Ginseng, and other plants, have shown excellent effects on sexual function. The effect of ginseng on ED has been verified by animal testing. Moreover, no side effects have been discovered in these studies; therefore, this approach may be appropriate for patients who prefer safer treatments [38, 39].

6.5.Diabetes mellitus

Ginseng also affects metabolic disorders by modulating the HPA axis, the core of the hormonal regulation system. DM is one of the most prevalent metabolic diseases in modern

societies. Stress can affect metabolism and cause chronic hyperglycemia. When an organism encounters an emergency, the autonomic nervous system reacts with the fight or flight response, which includes energy mobilization. Thus, the stress response involves the actions of a variety of hormones that raise the blood glucose concentration. Some patients with DM show increased insulin resistance and consequently have a reduced response to insulin. When stressful situations develop where energy is needed, the body cells of these individuals cannot use the glucose present in the blood and instead metabolize fat as an energy source. Fat metabolism causes inflammation. Therefore, such stress reactions could eventually cause a fatal complication in patients with DM. This effect is only observed in patients with type 2 DM, which accounts for 95% of the total DM patient population. Regarding the correlation between type 1 DM and stress, the results published in the literature are more controversial [40]. Ginseng is more effective in patients with type 2 DM than in those with type 1 DM. This is because type 2 DM is associated with stress [41]. Furthermore, ginseng regulates glucose and lipid metabolism and supplies energy to the body to regulate fat cells. This helps to control certain health issues such as obesity, which can become an underlying cause of type 2 DM [42].

6.6.Allergic asthma

Ginseng is also effective in regulating the adaptive immune response due to its effects on lymphocytes. First, ginseng activates the MAP kinase pathway by activating various transcription factors, thus functioning as an anti-inflammatory agent. In addition to inhibiting the CD40 signaling that stimulates the interaction between antigen-presenting cells and T lymphocytes, ginseng can exert chronic anti-inflammatory and anti-allergic effects [43]. As such, ginseng is effective for the treatment of allergic asthma caused by problems with the

Th2-predominant T cell response. Asthma is an airway inflammation that can narrow the respiratory tract, causing shortness of breath and coughing. This can develop into a serious inflammatory condition that can be fatal [44]. The prevalence of asthma is increasing worldwide, and it is also closely associated with anxiety and depression, which are caused by stress [45].

7. Use of ginseng in the prevention of stress-induced diseases

Based on the association between ginseng and the various diseases caused by stress, several studies on cytokines and receptors involved in this activity are being conducted. The treatment of anxiety and depression caused by stress could reduce the prevalence of inflammatory diseases. Thus, the effects of ginseng on the anxiety and depression associated with the initial stage of chronic inflammation should also be studied.

Patients with anxiety and depression can develop a variety of diseases, as discussed above. This is because anxiety and depression can promote inflammatory responses. First, the pro-inflammatory cytokines such as IL-1, IL-6, IFN-y, and TNF-a play a role. Second, oxidative or nitrosative stress can occur due to the increased levels of ROS and reactive nitrogen species. As a result, anxiety and depression can predispose patients to the development of cancers, neurodegenerative conditions, and inflammatory diseases [46].

In addition to defending against the increase in pro-inflammatory cytokines induced by anxiety and depression, ginseng can defend effectively against oxidative or nitrosative stress [47]. Although not yet fully clinically tested, ginseng effectively suppresses the chronic inflammation caused by stress-induced anxiety and depression and could therefore contribute to the prevention of secondary diseases. When ginsenosides are ingested, a number of biological effects occur. These include the prevention of tissue damage, as well as cellular

regeneration and repair effects. Ginsenoside-mediated effects on target cells in various in vivo models employed in recent studies are shown in Table 1.

8. Conclusion

Although existing drug treatments are often effective, continuous exposure to medicinal products can sometimes cause addiction or undesirable side effects. Moreover, population aging is increasing susceptibility to infectious diseases due to attenuated immune system function. Therefore, new treatment methods are required. Future studies should consider investigating alternatives to conventional drugs, such as medicinal plants. These have been used for more than a thousand years and generally carry a low risk of negative side effects. Ginseng provides a potential approach to regaining homeostasis after abnormal physiological changes caused by the stress of everyday life. The efficacy of this preparation has been demonstrated in various experiments conducted using human cells and animal models. A clearer understanding of the mechanisms underlying the effects of ginseng on human cytokine/metabolic systems and on stress-induced hormonal changes could facilitate the development of a wide range of treatments for patients with psychological and physical diseases.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by the grant from the Korean Society of Ginseng funded by Korea Ginseng Cooperation (DKR). The authors have no conflicting financial interests.

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487 Figure legend

489 Figure 1. The mechanism by which ginseng prevents disease via regulation of the

490 endocrine and immune systems. Ginseng regulates the hypothalamic-pituitary-adrenal

491 (HPA) axis. Ginseng thus prevents various diseases by ameliorating tissue injury and immune

492 cell death, while modulating immune cells in order to limit inflammatory responses. The

493 HPA axis is the major pathway regulating the immune response to stress; this is initiated by

494 hypothalamic secretion of corticotrophin-releasing hormone (CRH) and secretion of arginine

495 vasopressin (AVP) from the pituitary gland. CRH stimulates the pituitary gland to release

496 adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH in turn triggers the

497 release of glucocorticoids, such as cortisol, from the adrenal cortex. In the event of severe

498 stress-induced dysfunction of the HPA axis, endocrine homeostasis is disturbed; this can

499 predispose the patient to a number of diseases. Patients with depression and anxiety exhibit

500 increased production of HPA hormones, including CRH and AVP, as compared to healthy

501 individuals [65]. Additionally, glucocorticoids and norepinephrine modulate pro-

502 inflammatory cytokine production by immune cells. Consequently, chronic and severe stress

503 causes immune dysfunction, which in turn can lead to various diseases [66]. It is well known

504 that glucocorticoids suppress immune function during acute stress, thus increasing

505 susceptibility to disease. However, should the stress become chronic, receptors become

506 resistant to glucocorticoids and can no longer down-regulate inflammatory processes [67].

511 Figure 1

521 Table 1. Effects of ginsenosides in in vivo models of disease

Disease Ginsenoside Effective target Experiment Ref

Cardiovascular Rb1 Myocardial infarction Rat [48]

disease

Re Cardiomyocyte Human, cat [49]

Rgi Ventricular hypertrophy Rat [50]

Rg3 Vascular smooth muscle Rat and mice [51]

Stroke Rd National Institutes of Health human [52]

Stroke Scale

Rgi Formation of new synapses, Mice [53]

cerebral cortex

Hippocampus Rat [54],

Diabetes Rb1 Anti-obesity and anti- Rat [55]

hyperglycemic effect

Re Anti-obesity Mice [56]

Rg3 Insulin signaling and glucose Rat [57]

uptake

Rheumatoid Rb1 Collagen Mice [36]

arthritis

Osteoporosis Rg1 Osteoblast Rat [58]

Rbi Osteoblast Rat [58]

Rb2 Bone mass Mice [59]

Erectile Rg3 Corpus cavernosum Rat [60]

dysfunction

Re Corpus cavernosum Rat [61]

Rg1 Testosterone level, corpus Mice [62]

cavernosum

Asthma Rb1 Bronchoalveolar lavage fluid Mice [63]

Rh2 Bronchoalveolar lavage fluid, Mice [64]