Study on Ginsenoside and Depression

Depression has become a serious threat to human physical and mental health worldwide. It is a disabling disease [1]. Ginseng is a common ingredient in anti-depression Chinese medicine formulas, such as Sijunzi Tang and Dingzhi Fang, which are recorded in ancient formulas. Its main active ingredient is ginsenoside, which accounts for about 4% [2]. Ginsenosides contain a variety of active ingredients that can maximize the desired therapeutic effect through multiple targets. The author reviews the latest research progress on ginsenosides' antidepressant effects and their antidepressant mechanism, thereby revealing the research and development value and application prospects of ginsenosides.

1 Ginsenosides act on the hippocampus to produce antidepressant effects by regulating the HPA axis

Studies have found that the volume of the hippocampus in depressed patients is significantly smaller than that in normal people, and there is atrophy and loss of hippocampal neurons [3]. During the treatment of depression, the remission of depressive symptoms is positively correlated with the degree of hippocampal neurogenesis. This indicates that the process of hippocampal neurogenesis is closely related to the treatment of depression, and the mechanism may involve hormones, receptors, neurotrophic factors, etc. [4]. Therefore, promoting hippocampal neurogenesis and protecting hippocampal neurons has a positive significance for antidepressant treatment.

1.1 Regulating hippocampal hormone levels

Stress can cause the hypothalamic-pituitary-adrenocortical (HPA) axis to become hyperactive, producing large amounts of glucocorticoids (GC), which disrupt the original negative feedback pathway, causing the HPA axis to become more continuously excited. As a result, hippocampal neurons are damaged, which can lead to the development of depression [5]. Ginsenosides can regulate the HPA axis to act on stress [6]. The hippocampus is rich in glucocorticoid receptors (GR), which are most sensitive to stress and are the central high-level regulators of the stress response [3]. GC acts on the GR in the hippocampus, causing the hippocampus to send a negative feedback signal that suppresses HPA axis activity and achieves the goal of reducing high GC in the body [7]. Previous studies have shown that the expression level of GR mRNA in the hippocampus of animals with depression is reduced [2], and ginsenosides can promote the recovery of low-level GR [8]. Therefore, antidepressant effects can be achieved by upregulating the expression level of GR in the hippocampus to feedback regulate abnormal excitation of the HPA axis.

Li Yunfeng et al. showed that excessive GC leads to the atrophy and loss of neurons, which is related to the low expression of neurotrophic factors [9]. Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor that is mainly distributed in the hippocampus and plays a key role in the generation of neurons and the maintenance of normal physiological functions of neurons. Ma Xueping et al. experimentally demonstrated that an increase in GC can reduce the expression of BDNF, and that excessive GC can also interfere with BDNF signaling, affecting BDNF function and leading to damage to the hippocampal structure of patients [7]. These studies suggest that increasing the level of BDNF in the hippocampus has a positive effect on the treatment of depression. Liu Liqin et al. demonstrated that after 6 weeks of chronic stress, rats exhibited significantly depressive-like behavior, and the mRNA expression levels of hippocampal GR and BDNF were significantly reduced. After 6 weeks of ginsenoside administration, the mRNA expression levels of hippocampal GR and BDNF were significantly increased. Therefore, ginsenosides can achieve an antidepressant effect by feedback regulation of the hyperactivity of the HPA axis, thereby increasing the expression level of BDNF in brain tissue [2].

In addition, while chronic stress causes an increase in GC, the level of the androgen testosterone decreases. There is a negative correlation between blood GC and testosterone. Ginseng saponin Rg1 can reduce the increased level of GC caused by the hyperactive HPA axis and simultaneously increase the level of testosterone in the blood. Depressed patients have impaired hippocampal synaptic function and synaptic loss. Huang Qian et al. have experimentally demonstrated that oral administration of ginsenoside Rg1 at doses of 5, 10, and 20 mg/kg has a significant antidepressant effect in both acute and chronic stress models. Further exploration of the mechanism revealed that intracerebral administration of testosterone has the effect of enhancing basic synaptic transmission and inducing long-term potentiation. Therefore, ginsenosides can increase brain testosterone levels and increase hippocampal basal synaptic transmission to combat depression [10].

1.2 Regulating hippocampal amino acid levels

Glutamic acid (Glu) is an excitatory amino acid neurotransmitter in the hippocampus [11]. When stressed, the HPA axis is continuously activated, causing Glu to accumulate [12]. Excess Glu can have an excitotoxic effect on primary cultured hippocampal neurons [13], causing toxic damage to the hippocampus. Wu Haifen et al. used high-performance liquid chromatography to determine the amino acid content of the hippocampus, and found that compared with the normal group, the hippocampal Glu content was significantly higher. After intervention with ginsenoside Rg1, the hippocampal Glu content decreased. Ginsenoside Rg1 has a significant ameliorating effect on depressive symptoms, and the mechanism is to regulate the levels of hippocampal amino acids in response to chronic stress [12]. In addition, ginsenosides can also directly counteract the neurotoxic effects of Glu. Experiments by Yunsuk Ham et al. have shown that excessive Glu acts on the postsynaptic membrane, causing intracellular Ca2+ to accumulate and the concentration to rise, which causes damage and death of neurons. Ginsenosides can selectively reduce the abnormally high intracellular free Ca2+ concentration, ultimately protecting nerve cells.

2 Ginseng saponins regulate cytokines to resist depression

The onset of depression is usually accompanied by activation of the immune system, which increases the secretion of cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) in the body, producing depressive symptoms. Abnormally expressed TNF in patients can cross the blood-brain barrier and activate the nuclear factor-κB (NF-κB) signaling pathway, which affects the balance of central neuron activity. In the pathological process of depression, changes in NF-κB can accelerate the onset of depressive symptoms. IL-6 is a product of monocytes and macrophages. Patients whose depressive symptoms are relieved have significantly lower IL-6 levels [15].

Therefore, antidepressants can be used by reducing the secretion of cytokines. Zhang Chunwu et al. have experimentally demonstrated that ginsenosides can significantly reduce the level of TNF in rat serum [16]. Feng Mei and others have demonstrated that ginsenoside Rg1 can reduce NF-κB activation and the release of the inflammatory factor IL-6 [17]. These studies all show that ginsenosides can be antidepressant by regulating cytokines.

3 Ginsenosides increase the content of monoamine neurotransmitters in the brain to combat depression

Adaptive changes in receptors and post-receptor signal transduction pathways caused by decreased levels of monoamine neurotransmitters are key factors in the development of depression [18]. Monoamine neurotransmitters mainly include serotonin (5-HT), norepinephrine, dopamine, etc. 5-HT can maintain a good mood, regulate appetite and sexual life, etc. Norepinephrine maintains a normal mood and a certain state of arousal. Dopamine maintains the body's motor, cognitive, learning and memory functions, and is closely related to human emotional activity. Studies have shown that the functional activity of 5-HT and dopamine is reduced in patients with depression, and the concentration of norepinephrine in the hypothalamus is reduced [5]. Experiments have shown that the plasma 5-HT and norepinephrine levels of depressed patients are lower than those of normal people, and that after the symptoms of depression have improved significantly, the plasma 5-HT and norepinephrine levels of patients rise. Therefore, depression can be relieved by increasing the content of monoamine neurotransmitters in the brain [19].

Zheng Min et al. used high performance liquid chromatography-electrochemical methods to detect the levels of the monoamine neurotransmitters norepinephrine, dopamine and 5-HT in the hippocampus and hypothalamus of rats in each group. The results showed that ginsenosides in both the low and high dose groups significantly increased the levels of monoamine neurotransmitters in the brain tissue of rats [20]. Since the chemical composition of ginsenosides has few side effects on the body and has a significant effect on increasing the levels of monoamine neurotransmitters in the brain, using ginsenosides to increase the levels of monoamine neurotransmitters in the brain has significant and far-reaching implications for the treatment of depression.

4 Outlook

Since the pathogenesis of depression is still unclear, preventive measures have been almost non-existent. As depression increasingly affects people's lives, the exploration of new treatments for depression is just around the corner. Using ginsenosides from traditional Chinese medicine to treat depression can reduce the harm of treatment to the human body. At the same time, its development also has huge economic benefits and is worthy of attention.

References :

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