Part Ⅰ：Research Progress in The Effect Of Traditional Chinese Medicine For Invigoration On Neurotransmitter Related Diseases
Mar 04, 2022
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Xiting Zhang, Lin Li, Ting Chen, Zuoyan Sun, Weiwei Tang, Shuang Wang, Tianqi Wang, Yi Wang,1and Han Zhang
1 Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
2 Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin 300193, China
This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.
Tonic traditional Chinese medicine is widely used in clinical practice and is categorized into four main drugs, namely, Qi-supplementing, Blood-enriching, Yin-nourishing, and Yang-tonifying. Neurotransmitters play a coordinating role in the nervous system, visceral function, and stress response. Te excitation or suppression of the central nervous system is closely related to various diseases, such as insomnia, depression, Alzheimer’s disease, Parkinson’s disease, and perimenopausal syndrome. An increasing amount of evidence shows that the Chinese tonic herb and its active ingredients can delay the occurrence and development of these diseases by modulating related neurotransmitters and their receptors, including norepinephrine (NE), serotonin (5-HT), dopamine (DA), acetylcholine (ACh), and ?-aminobutyric acid (GABA). In the present report, studies on the treatment of these neurotransmitter-related diseases in relation to the application of tonic Chinese medicine are reviewed.
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1 Introduction
Tonic traditional Chinese herbal medicine can help in promoting the healthy well-being of organisms by replenishing their life essence. According to modern pharmacology research, tonic medicine can enhance immune capacity, strengthen learning and memory function, and regulate the endocrine function of patients with impaired disease. Interestingly, there are other beneficial effects, such as antiageing [1], antioxidant [2], and antistress [3] effects. According to its effect, tonic medicine is divided into Qi-tonifying, Blood-tonifying, Yin-tonifying, and Yang-tonifying prescriptions. Qi-tonifying prescriptions can tonify visceral-Qi to rectify the pathological deviation of the visceral-Qi deficiency [4]. For example, this may include invigorating the spleen and lungs to act on spleen and lung channels. Qi-tonifying prescription is used principally to cure representative medicines, including Radix Ginseng, Acanthopanax senticosus, Rhodiola Rosea, Astragalus, and Licorice. Blood-tonifying prescriptions [5] target blood and heart deficiencies with such medicines as Radix Paeonia Alba, Angelica Sinensis, Polygonum multi forum thumb, and Radix Rehmanniae. Yin-tonifying prescription [6] is commonly applied to nourish Yinfuid and correct the pathological deviation of Yin deficiency with such medicines as Lily, Glossy Privet Fruit, and Eclipta alba. In addition, Yang-tonifying prescriptions [7] can supplement Yang to treat all kinds of Yang deficiency diseases. These medicines can have sweet, pungent, salty, and warm properties and mainly affect the kidney channel. Medicines include Psoralea corylifolia, Morinda Officinalis, Cistanche tubulosa, Folium Epimedii, and Fructus Alpinia oxyphylla (see Table 1).
Recent findings indicate that tonic traditional Chinese herbal medicine can modulate neurotransmitters [8], improve insomnia, exert antidepressant effects, delay the development of neurodegenerative diseases, and improve the climacteric symptoms of women. In this paper, related research progress is reviewed (see Table 2).
2. Methods
We searched PubMed using the following keywords: Related diseases (Depression/Alzheimer’sdisease/Parkinson’s disease/Perimenopausal syndrome/Sleep disorders) AND Neurotransmitters (5-HT, DA, NE, ACh, GABA) AND Tonic traditional Chinese medicine (Representative drugs of Qisupplementing, Blood-enriching, Yin-nourishing, and Yang-tonifying). We limit our search to studies only published in the English language from PubMed. We also searched CNKI for Chinese articles with the same keywords. The time range we searched had no limitation (to present). Overall, we found 155 articles in the two databases, among which 70 were published in English and 85 were published in Chinese. 18 articles were excluded for repetition in the contents. According to the description of the contents such as Qi, blood, Yin, Yang, and the effective components of the tonic traditional Chinese medicine, we finally found 33 Chinese kinds of literature and 44 English kinds of literature.
Based on Chinese Materia Medica and Clinical common medicines, we selected the following representative drugs of tonic traditional Chinese medicine. (1) Qi-supplementing: Radix Ginseng, Acanthopanax senticosus, Rhodiola Rosea, Astragalus, and Licorice; (2) Blood-enriching: Radix Paeonia Alba, Angelica Sinensis, Polygonum multiform thumb, and Radix Rehmanniae; (3) Yin-nourishing: Lily, Glossy privet fruit, and Eclipta alba; (4) Yang-tonifying: Psoralea corylifolia, Morinda Officinalis, Cistanche tubulosa, Folium Epimedii, and Fructus Alpinia oxyphylla.
3. The Relationship between Qi, Blood, Yin, Yang, and Neurotransmitters
Yin and Yang are two substances in the human body closely related to each other and their functional characters [9]. Yang refers to warmth, excitement, promotion, and so on, while Yin refers to nourishing, moistening, inhibiting, and so on. Yin and Yang stand against each other, can transform into each other, and rely on each other by operating in equilibrium. Working in equilibrium means that Yin and Yang have a balance of growth and decline and maintain dynamic balance in the changes of growth and decline [10]. If either side shall decrease or be insufficient, the other side would consequently be reduced or weakened [11]
Qi is an energetic subtle essence that forms the human body and sustains life activities [12]. Blood is a nourishing nutrient that runs in veins and circulates throughout the body. It is one of the basic substances that comprise the human body and sustains life activities. Qi and blood can transform into each other; that is, Qi can generate blood, and vice versa. Blood insufficiency will induce Qi deficiency and can cause mental diminishment, forgetfulness, insomnia, irritability, ability disorders, and other symptoms [13].
From the properties of Yin and Yang, we can determine that Qi possesses the properties of Yang, active and warm, whereas blood possesses the properties of Yin, static and moistening. They depend on and nourish each other to support and promote life activities [14].
The connection among Qi, blood, Yin and Yang is achieved through the meridians [15]. Meridians are channels through which Qi and blood connect organs, body surfaces, and body parts. It works as a controlling system of human bodily functions by transporting Qi and blood to the entire body and nourishing tissues and organs. Meanwhile, meridians have a similar physiological function to the nervous system. Meridian, neuroendocrine neurotransmitters, and receptors are closely linked. It is confirmed that sympathetic nerves, mast cells, calcium, adrenergic neurotransmitters, and other substances are related to meridian regulation. According to Chang et al. [16], the basis of meridian activity is a conditioned reflex with the involvement of the cerebral cortex and several researchers have discovered that there are phenomena of neurotransmitter enrichments in the meridian sensing zone.
For example, in the study of meridian acupuncture points, Omura [17] discovered that most points have highly enriched neurotransmitters and hormones, including acetylcholine, norepinephrine, adrenocorticotropic hormone, 5-HT, and ?- GABA. During the study of signal conduction in acupuncture, Liu’s research group discovered that acupuncture allows meridians to release norepinephrine, epinephrine, and other catecholamines along the skin and that their content was significantly higher than non-acupuncture meridians [18, 19]. The weakness of Qi, Blood, Yin, and Yang may affect neurotransmitters through meridians.
4. The Relationship between Tonic Traditional Chinese Medicine and Neurotransmitter Related Diseases
4.1. Depression.
Depression is defined as a mental disorder characterized by psychomotor retardation, such as slow thinking, accompanied by decreased interest and initiative. Recent studies have demonstrated that a deficiency in the following neurotransmitters is correlated with the onset of depression: 5-HT, DA, NE, Ach, and GABA [20]. Importantly, most antidepressants exert antidepressant effects by increasing levels of neurotransmitters located at synapses.
Depression belongs to the category of “melancholia” in Chinese Medicine. Melancholia is a Chinese medicine syndrome caused by emotional discomfort and Qi-stagnation [21]. Chinese medicine has extensive experience in the prevention and treatment of depression. For example, such medicines invigorate the liver, spleen, kidney, and heart, but also the quiet spirit too. However, the combination of these medicines with antidepressant activity is a widespread concern.
The chronic mild unpredictable stress (CMUS) model is among the most common methods for studying depression [22]. It is primarily used for the screening of antidepressants and the pathophysiology of depression.
The forced swimming tests (FST) and tail suspension tests (TST) are well-established models for studying depression in animals [23, 24]. In the frontal cortex and hippocampus, FST was observed to indicate a significant decrease in 5-HT levels with a slight change in 5-HIAA levels, resulting in an elevation in the 5-HIAA/5-HT ratio [25].
4.2. Alzheimer’s Disease (AD)
Alzheimer’s disease (AD) is an insidious and progressive neurodegenerative disease that affects the nervous system. It is characterized by dementia and includes memory impairment, aphasia, and executive dysfunction. NE, DA, 5-HT, and cholinergic transmitter ACh are important neurotransmitters in the brain. Among them, choline acetyltransferase (ChAT) is a key enzyme in the synthesis of Ach [26], and AchE is a key enzyme in the degradation of ACh. Acetylcholinesterase inhibitor (AChEI) therapy is a frequently used method in the treatment of AD [27]. Both ChAT and AchE activities are strongly correlated with ACh content in the brain. They maintains the dynamic balance of ACh and exert important roles in maintaining normal cognitive function. A reduction in these neurotransmitters can lead to senile dementia. More specifically, studies show that NE modulates the cortex through axons and has broad implications for mood, cognitive function, and movement [28]. DA has been found to reduce oxidative stress, increase blood flow to the brain, and coordinate with NE to regulate the body’s excitability. In addition, 5-HT modulates central cholinergic nerve activity by regulating the release of Ach in brain tissue, which is an important neurotransmitter for mediating intelligence. The decrease of Ach content is suggested to be closely related to the severity of clinical symptoms of AD [29].
In recent times, modern medicine has yet to produce effective prevention and cure for AD. By contrast, traditional Chinese medicine has unique advantages because it is characterized by multiple targets and pathways. It holds the opinion that AD belongs to the category of dementia. Although the basic pathogenesis is symptoms caused by asthenia, kidney vacuity and marrow depletion are the basis of the disease [30]. In this regard, tonic traditional Chinese medicine may help to improve AD symptoms. Many reports from cell and animal experiments found that ?-amyloid (A?) is the key protein in AD patients. Te A? fragment peptide 1–42 (A? 1–42) induced neuronal damage and apoptosis via oxidative stress in vitro [31, 32]. A? 25–35 exhibits similar early neurotropic and late neurotoxic activities as A? [33]. Therefore, A? 1–42 and A? 25–35 are commonly used as a model method.
4.3. Parkinson’s Disease (PD).
Parkinson’s disease (PD) is another multicentral neurodegenerative disease predominated by movement retardation. It is a complicated and poorly understood pathogenesis, with clinical symptoms characterized by tremor, slowness of movement, and postural instability caused by various factors. The most significant change in the disease is the decrease in DA levels in the brain. Tyrosine hydroxylase (TH) is the rate-limiting enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) [34]. LDOPA is a precursor for the neurotransmitter DA. DA is divided into metabolites by a set of enzymes—monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). The final product of DA metabolism is DOPAC and HVA, both of which can be used as an indicator for the change of DA content in the brain [35].
Traditional Chinese medicine defines PD as belonging to a category of diseases, such as paralysis agitans, the basic pathogenesis of which involves the liver and kidney. Therefore, the use of Chinese herbal medicine may be helpful in improving and delaying the symptoms of the disease.
4.4. Sleep Disorders.
Insomnia is a sleep disorder syndrome whereby sleep quality cannot meet individual physiological needs, resulting in fatigue, lack of attention, and a lag in mental response. Long-term insomnia is harmful to human physical and mental health and can cause multiple organ dysfunction and immune function decline related to hypertension, diabetes, and other mental disorders. The dysfunction of neurotransmitters such as 5-HT and DA are closely linked with insomnia. According to the theory of traditional Chinese medicine, palpitation, forgetfulness, insomnia, and tiredness are mostly deficiency syndromes. It is advisable to tonify the nerves and tranquilize the mind by tonifying traditional Chinese herbal medicine.
GABA is the major inhibitory neurotransmitter in CNS and is essential for mediating the overall balance between neuronal excitation and inhibition [36]. The molecular target of medicinal plants with a sedative-hypnotic activity involves the benzodiazepine site of the GABAA (GABAA-BZD) receptor. GABAergic neurotransmission plays a key role in sleep regulation, and the BZD binding site on the GABAA receptor is a target for most sedative-hypnotics [37]. BZD agents, such as diazepam, can stimulate the ability of GABA to induce hyperpolarization of membranes by allowing a Cl− influx.
4.5. Perimenopausal Syndrome.
The perimenopausal syndrome is a series of syndromes characterized by autonomic dysfunction caused by the decline of ovarian function and the decrease of estrogen levels in women during and around menopause. Ovary dysfunction, imbalance of the hypothalamus pituitary-gonadal axis, the disorder of sex hormone secretion, and dysfunction of the autonomic nervous system in perimenopausal women may affect NE, DA, and 5-HT levels in the hypothalamus [38]. This, in turn, may lead to hot flashes, sweating, irritability, insomnia, and other symptoms. NE and DA are two neurotransmitters with extensive function in the brain and can regulate functional activities of several neurons and correct hyperactivity of central and peripheral sympathetic nerves. As an important neurotransmitter in the brain decreased 5-HT levels can reduce impulses released by the body temperature regulating center, thereby helping to control the frequency and amplitude of hot fashes representative of the menopausal syndrome (MPS). MPS may be improved to a certain extent via the adjustment and intervention of the above-mentioned neuroendocrine networks. The surgical removal of bilateral ovaries from female rats is the main method used for a simulation model of MPS. For example, studies have found that levels of DA, NE, 5-HT, and 5-HIAA in the hypothalamus were significantly increased in ovariectomized rats compared with those rats in the control group [39–41].
From the theory of traditional Chinese medicine, perimenopausal syndrome is characterized by deficiencies of the kidney, although dysfunctions of the liver, spleen, and heart are also common [42]. More specifically, the theory of syndrome differentiation is an important aspect of traditional Chinese medicine. According to this theory, not only is the condition of the kidney important but also the condition of the other four major organs in combination with the condition of the five internal organs is important because this shows the complexity of pathological change. Medicines for tonifying deficiency have been shown to be satisfactory in the treatment of perimenopausal syndrome.
