WANG Tian, SU Sheng-yong, ZHANG Xi, LIN Xin-ying, WANG Qiong-xiao, SU Ting,XIE Cai-yun, HUANG Lin

1.Guangxi University of Chinese Medicine, Nanning 530000, China

2.The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530000, China

Keywords:

ABSTRACT Depression and insomnia have become a frequent disease in the clinic.Clinically, depression and insomnia occur synchronously.Most researchers believe acupuncture treats insomnia and depression comorbidity through mechanisms such as inflammation theory, HPA axis theory, neurotransmitter theory, nervous system structure theory,immunoregulation theory,etc.Acupuncture has a clear effect on depression and insomnia comorbidity, and is twoway, specific, and integral.Therefore, a summary on the mechanism of using acupuncture to treat depression and insomnia comorbidity is made, to provide reference for future clinical application and laboratory research.

Depression is a common clinical mental disorder and the most common mood disorder in the 21st century[1].The mental state of its patients is mainly characterized by low mood, slow thinking, and often accompanied by sleep disorders[2].Insomnia, as a common cosymptom of depression, is also a risk factor for many discomforts in patients with depression, which will increase the recurrence rate of depression[3].According to a large number of experimental data[4-5], depression presents a significant positive correlation with the severity of sleep disorders.It has been reported[6] that up to 70%of elderly patients with depression may experience comorbidity of insomnia, which is often seen as a concomitant symptom of depression rather than a comorbidity,In the clinical treatment of patients with depression, doctors are easy to neglect targeted treatment of patients with sleep disorders.The occurrence and development of insomnia is not only detrimental to the treatment of depression and the rehabilitation of patients, but also may lead to the delay or aggravation of patients’ abnormal mood symptoms[7].At present, oral western medicine is the most commonly used way to treat Depression Comorbided with Insomnia (DCI).There are a series of disadvantages in treating DCI in this way.In mild cases, the side effects are relatively large, the effect is slow, and the disease is easy to relapse, and gastrointestinal dysfunction, insomnia, obesity and other discomfort may occur.In severe cases, the symptoms of depression may be progressively aggravated, the quality of life of patients may be affected, and even life and health may be endangered[8,9].However, acupuncture therapy has the unique advantages of multi-target, multi-layer and multi-pathway, and has a significant therapeutic effect on DCI[10,11].However, at present,acupuncture and moxibustion therapy for DCI is still limited to clinical efficacy observation, and the comorbidities mechanism of acupuncture and moxibustion therapy is not completely clear.This article aims to summarize the mechanism of action of acupuncture and moxibustion in treating depressive comorbidity insomnia in recent years, in order to provide new ideas for the treatment of DCI and improve the clinical curative effect.

1.The effect on related neurobiochemical factors

The decrease of various neurobiochemical factors in the body can lead to depression and sleep disorders.At present, based on the changes in neurobiochemicalfactors in DCI patients, studies on the mechanism of acupuncture and moxibustion mainly focus on monoamine neurotransmitters, inhibitory neurotransmitters and otherneurotransmitters, as well as brain-derived neurotrophic factors and neuropeptide substances.

1.1 Monoamine neurotransmitter

Monoamine neurotransmitters mainly include 5-hydroxytryptamine(5-HT), Noradrenaline (NE) and Dopamine (Dopamine (DA), etc.Maintaining the content of these neurotransmitters in the body at a normal level is not only beneficial to improving sleep quality and maintaining emotional stability, but also can help the body to recover the normal stress response mechanism[12].

The decrease of 5-HT level in the central nervous system is considered to be a sign of depression or other mental diseases[13],and the decrease of 5-HT content and function in the brain will lead to poor sleep quality and depression[14].Liu Yi[15] adopted the acupuncture method of “soothing the liver and yangling the heart”in combination with western medicine to alleviate the symptoms of depression and sleep disorder in patients.The study showed that compared with the control group, the levels of serum NE, DA and 5-HT in patients in the acupuncture group were increased,and the symptoms of mood disorder and associated insomnia were significantly improved.Zou Tianyu etc.[16] with electric acupuncture intervention depression model rats, rats will best hole, god court hole shall be electric acupuncture, the results showed that 5 - HT in rats, NE, DA levels increased significantly, and its mechanism may be the curative effect in the model rats court hole, the hole,god make the prefrontal cortex and hippocampus single amine neurotransmitter content increases, the brain network connection was strengthened,Depression and insomnia were improved in rats.Wang Lingling[17] believed that wheat grain moxibustionwould lead to different degrees of local tissue damage, and the moxibustion sores produced could cause the body to release 5-HT and other substances, producing non-specific effects on the body as a whole, so as to correct the immune system disorder of patients and make their immune function return to the normal state, which is suitable for the treatment of depression and sleep disorders.Acupuncture playsa role in regulating sleep and emotion by increasing DA, NE and 5-HT levels in central nervous system.

1.2 Inhibition of neurotransmitters

As an important inhibitory neurotransmitter, γ-aminobutyric acid(GABA) has an inhibitory effect on excited neurons, can inhibit the excessive discharge and excitation conduction of central nerve,and has a certain impact on the emotional state and sleep state of the body.The increase of GABA content has certain effect on the improvement of insomnia and depression symptoms.Wu Wenzhong et al.[18] proposed that long-term chronic stress can reduce GABA level, increase cortisol (CORT) level, and cause symptoms such as insomnia and abnormal mood.Acupuncture can increase serum GABA level and reduce serum CORT content at the same time, so as to improve discomfort such as sleep disorder and depression in DCI patients.Liang Wei[19] selected the prescription of intra-umbilical ring point and insomnia point to conduct acupuncture intervention on the model rats with depression and insomnia.The study found that GABA content and open field test score in the acupuncture group were significantly increased compared with the model group.Acupuncture treatment significantly alleviated the tension of the rats, and effectively alleviated insomnia and its associated symptoms such as depression and anxiety.Acupuncture and moxibustion can effectively regulate the synthesis and release of GABA in the human body and improve the clinical effect.

1.3 Brain derived Neurotrophic factor (BDNF)

Related studies[20] show that significant decrease of BDNF level is common in patients with depression and chronic insomnia.As the most widely distributed neurotrophic factor and an important neuroplasticity factor in the hippocampus of the brain, BDNF can regulate related nutritional proteins, improve neuroatrophy in the brain, increase the number of neurons in the hippocampus,improve nerve excitability, and improve the mood and sleep disorder symptoms of DCI patients[21].

Xu Xiaohong[22] discussed through research that “sedative and calming” acupuncture was used to intervene sleep deprivation model rats, and it was found that the expression of BDNF in the rats was increased after acupuncture, and the symptoms of insomnia and emotional abnormality in the acupuncture group were significantly improved compared with the model group.Therefore, acupuncture can repair the damage to synaptic plasticity, improve the level of BDNF to treat insomnia, depression and other symptoms, and improve the clinical recovery rate.

1.4 Neuropeptide substances

Neuropeptide Y (NPY) and substance P (SP) have neuroregulatory effects on various brain functions[23].Peripheral SP levels are closely related to body mood and sleep, and the activity of SP neurons is enhanced in both depression and insomnia patients[24].Related studies have found that NPY and SP can interact with monoamine neurotransmitters and directly affect the mood and sleep state of DCI patients[25].

Professor Wang Shun[26] proposed the “tiao-Shen chang-qing San-69-Jiu” acupuncture method, which selected the sanyin meridian points of the hands and feet, head points and abdominal points of the patients for acupuncture.Through research, it was found that the acupuncture method could reduce the content of NPY in serum and brain tissue, protect dopaminogenic neurons, and then improve depression and its associated insomnia symptoms.Ms liu[27]proposed, can choose “l(fā)ine for needle” sun-style abdomen needle area buried line therapy to treat insomnia with depressive symptoms,such as abdominal area, eight area and abdominal area, abdominal acupuncture point of acupuncture in this site and continuous stimulation, detection after acupuncture patients was significantly reduced the serum levels of NPY, analysis the effect of the treatment mechanism can draw the conclusion:Catgut embedding therapy can directly stimulate the neurons of the enteric nervous system and reduce the level of NPY in patients, thus improving their sleep and depression symptoms.

2.Regulation of The Hypothalamic-pituitary-adrenal(HPA) axis

HPA axis is the neuroendocrine axis of the body, which plays a key role in regulating the body’s spirit and emotion, and has a crucial influence on the pathogenesis and development process of DCI[28].Long-term chronic stress can lead to dysfunction of HPA axis[29].Corticotropin-releasing hormone (CRH) and adrenal corticotropic hormone were found to be long-lastingExcessive release of hormone,ACTH and glucocorti-coid (GC), meanwhile increases CORT content and further leads to hyperactivity of HPA axis[30],thus causing body dysfunction and a series of pathological changes,including depression and sleep disorders, etc.[31].

Acupuncture can reduce depressive symptoms and their concomitant symptoms by regulating HPA axis function and increasing hippocampal activity[32-33].Shi Rong weed from[34] of Yin tang hole, the wind pool of rats, the acupuncture point, shenshu point to acupuncture intervention on depression model rats, observe the acupuncture group; CORT levels and related factors in hippocampus of rats, found that acupuncture group rats; CORT level dropped significantly, open field test scores compared with model group, thus,acupuncture and moxibustion can be raised; CORT level,The normal function of HPA axis was restored, and the symptoms of depression and sleep disorder were alleviated in model rats.In order to understand the clinical efficacy of acupuncture on chronic insomnia and the mechanism of effect on HPA axis, Xi Hanqing et al.[35]selected the “Tongdu TiaoShen” acupuncture method to acupuncture patients in the treatment group.The study found that the acupuncture method could significantly reduce the levels of hormones related to HPA axis, such as CRH, ACTH and CORT.It can effectively regulate the function of HPA axis, and relieve the patients’ insomnia and accompanying bad emotions such as depression to a certain extent.

2.Inhibition of inflammatory cytokine levels

Many studies[36-38]suggest that long-term stimulation from the outside can induce the body to produce the cytokine Interleukin(IL), produce inflammatory response, and then cause changes in cell signal transduction, neurotransmitter transmission and secretory function, and induce various symptoms such as depression and insomnia.

Zhao Ya[39] observed the influence of acupuncture on inflammatory factors in depressive model rats, and selected Baihui and Yintang points in rats.After treatment, the levels of IL-1β and IL-6 in the acupuncture group were significantly decreased, and the scores of behavioral experiments were significantly higher than those in the control group.Experiment also found damaged prefrontal area can produce the performance such as depression, sleep disorders, and through the acupuncture model rats will cave, glabella point to the protection of neurons play a strong role, repair damaged prefrontal regions, IL - 1 beta, the content of IL - 6, eventually rats with depression, sleep disorders, effectively relieve symptoms.Kim YJ et al.[40] found that after acupuncture treatment, the levels of Tumor necrosis factor-α (TNF-α) and IL-6 in plasma of DCI patients were significantly decreased, and the symptoms such as insomnia and associated depression were also significantly alleviated.It has also been confirmed in animal experiments[41-42] that acupuncture at Baihui and Sishencong points in DCI rats can reduce the concentrations of IL-1β, IL-6 and TNF-α in the brain tissue of rats,and the results show that acupuncture can down-regulate the levels of inflammatory factors and improve the symptoms of depression combined with sleep disorder.These results suggest that acupuncture and moxibustion may play a therapeutic role in treating DCI by regulating the content of the above inflammatory factors, which provides evidence for the effect of acupuncture and moxibustion on alleviating sleep disorders and depression in patients.

3.Summary and prospect

To sum up, relevant studies in recent years have confirmed that acupuncture may play a role in treating DCI through regulating HPA axis, regulating related neurobiochemical factors and inhibiting inflammatory factors.Acupuncture and moxibustion have unique advantages in improving patients’ sleep quality, improving their mood,preventing recurrence, etc.The application of acupuncture and moxibustion in the treatment of DCI has a clear effect, and is conducive to improving the efficacy and prognosis of current DCI patients.

Based on the above views, although some breakthroughs have been made in the research on the mechanism of acupuncture and moxibustions in treating DCI, there are still many problems.For example, the current relevant studies are generally not supported by experimental studies with a large sample size.In addition, the scope and depth of the research are obviously insufficient, and the mechanism of some treatments is not clear, and there are few literature reports.It mainly focuses on the effect mechanism of acupuncture and moxibustion on DCI model of the same TCM syndrome type.In addition, electroacupuncture alone and acupuncture alone treatment groups were not included in the experiment for control observation;Secondly, most clinical trials were conducted to detect the levels of related neurotransmitters in the serum of subjects,and the consistency of the levels of related neurotransmitters in the serum and brain remains to be further investigated.Therefore, in the future research direction, it is necessary to strengthen the research on the related mechanism of acupuncture and moxibustion in treating DCI, further explore the difference of the effect mechanism of acupuncture and moxibustion on DCI of different TCM syndrome types, and compare and observe the difference of effect between simple electroacupuncture and simple acupuncture.All these issues need to be further studied.

Authors’ contribution

Paper selection and writing: Wang Tian, paper revision: Su Shengyong, Zhang Xi, literature collection: Lin Xinying, Wang Qiongxiao, Xie Caiyun, literature sorting: Su Ting, Huang Lin