动物实验 z-bo 2020-08-25 440

　　Abstract: To explore the characteristics of licorice in the treatment of depression. Consult the relevant literature on the treatment of depression with traditional Chinese medicine licorice in recent years, and analyze the characteristics of licorice in the treatment of depression from the antidepressant active ingredients of licorice and its application in traditional Chinese medicine compound prescriptions. Licorice is widely used in the treatment of depression, and has good effects in improving animal behavior and biochemical indicators. Its mechanism mainly involves regulating monoamine neurotransmitters and their receptors in the brain, improving the first layer of the hypothalamus; physical exercise adrenal gland (HPA) ) Shaft function, anti-free radical, anti-inflammatory, etc.

　　Effect: Licorice has the characteristics of stable curative effect, long-lasting effect, and small adverse reactions in the treatment of depression. It provides ideas and references for clinical screening of its antidepressant Chinese medicine active ingredients and prescription compatibility.

　　Keywords: depression; licorice; mechanism of action; experimental research; clinical application

　　Depression, also known as "emotional cold", is a common affective disorder of mental illness, characterized by a state of persistent depression. The clinical manifestations are depression, loss of various interests and happiness, and are often accompanied by physical symptoms such as abnormal sleep, loss of appetite, weight loss, and loss of libido, and even extreme behaviors such as suicide. At present, depression is the fourth most common disease in the world. According to WHO's prediction, depression will become the second most common human disease after heart disease by 2020.

　　The pathogenesis of depression has not been clear so far. The most studied monoamine neurotransmitter and its receptor hypothesis, inflammatory response hypothesis, hypothalamic cluster awakening body guarding adrenal gland (HPA axis) dysfunction hypothesis, neurotrophic factor Hypothesis and multi-factor comprehensive action hypothesis, its main drugs for the treatment of depression: tricyclic antidepressants, monoamine oxidase inhibitors and reversible selective monoamine oxidase inhibitors, 5-hydroxytryptamine (SHIT) and norepinephrine (NE) ) Reuptake inhibitors, NE and dopamine (DA) reuptake inhibitors, etc. Although these drugs can improve depression to varying degrees, the side effects of these drugs are relatively large, mainly including apathy, fatigue, sleep disturbance, cognitive dysfunction, sexual dysfunction, and stroke. Natural medicines have low toxic and side effects. Licorice has a long history as a traditional Chinese medicine. The "New Resource Food Management Measures" promulgated by the Ministry of Health of the People's Republic of China stipulates that licorice is both a food and a drug resource. The US FDA has long used licorice extract. Classified as a safe and non-toxic substance, scientific research has proved that licorice extract is an additive with multiple functions such as bacteriostasis, anti-inflammatory, detoxification, and deodorization. It is clinically mainly used for the treatment of stomach, duodenal ulcer, and diabetes insipidus. Disease, tuberculosis, dermatitis, bronchial asthma, etc. In recent years, it has been discovered that licorice has significant effects on the treatment of depression. The active ingredients in licorice for the treatment of depression are reviewed here to provide a theoretical basis for the development of new drugs for the treatment of depression in the future.

　　1 The biochemical properties of licorice

　　Glycyrrhiza is the dried roots and rhizomes of the legumes Glycyrrhiza Uralensis, Glycyrrhiza glabra or Glycyrrhiza inflata. Sweet in taste, calm in nature, Guixin, Lung, Spleen, and Stomach Meridian. It has the effects of invigorating the spleen and qi, clearing away heat and detoxification, eliminating phlegm and relieving cough, relieving pain, relieving pain, and reconciling various medicines. It is the most widely used traditional Chinese medicine in clinical practice. Old country". Modern pharmacological research shows that licorice has many activities such as liver protection, anti-inflammatory, antibacterial, antiviral, antitussive, antimalarial, anti-oxidation, anti-cancer, immune modulation, hypoglycemic and anti-platelet aggregation.

　　The main components of glycyrrhiza are three mushrooms and flavonoids. Among them, glycyrrhizin is an important monomer active ingredient in flavonoids and has a good antidepressant effect.

　　2 The mechanism of action of licorice against depression

　　2. 1 To improve behavioral indicators, Shanghai Xinruan Information Technology Co., Ltd.’s forced swimming test (FST) in rats and mice, Shanghai Xinruan Information Technology Co.’s mouse tail suspension test (TST) and Shanghai Xinruan Information Technology Co.’s The rat and mouse open field experiment (OFT) evaluated the anti-stress and depression behavioral effects of licorice total flavonoids. The results showed that 100, 300 mg/kg licorice total flavonoids can significantly shorten the immobility time of TST and FST in stressed rats and increase 0 FT. The number of horizontal activities, vertical activities and modification times of stressed rats, and reduction of fecal pellets.

　　10, 20, 40 mg/kg glycyrrhizin treatment of depression model animals in 3 weeks, the consumption of sugar water was significantly increased, and the 20, 40 mg/kg group has returned to normal levels. Glycyrrhizin can also significantly shorten the immobility time of chronically stressed rats in the forced swimming experiment, and the 20 mg "kg-' group has the strongest effect [[A]

　　2.2 Improve biochemical indicators

　　2. 2. 1 Regulation of monoamine components. Low levels of monoamine transmitters in the synaptic cleft of nerves in the brain are one of the main pathogenesis of depression. It is mainly exhausted through four pathways: monoamine oxidase (MAO) degradation, presynaptic membrane receptor reuptake, autoreceptor antagonism, and binding to postsynaptic membrane receptors. The total flavonoids extract (LF) of licorice was given for 7 days. Each dose group had a better effect on the symptoms of sagging eyes and dyskinesia induced by reserpine, but had no effect on the symptoms of body temperature drop. Therefore, it is speculated that LF may have central SHITergic nerve function or dopaminergic nerve function enhancement, but not the central a-adrenergic receptor agonistic effect. Compared with the model group, each dose group of glycyrrhizin can significantly resist the decrease in body temperature, exercise immobility and eyelid drooping caused by reserpine in mice (P<0.05, P<0.01), indicating that glycyrrhizin has obvious anti-reserpine effect , Its effect may be related to monoamine transmitter antagonism.

　　2.2.2 Regulation of HPA axis Hyperfunction of HPA axis can cause HPA axis imbalance, which is also one of the important mechanisms of depression. HPA axis disorders are mainly related to hippocampal glutamate and N-methyl-D-aspartate (NMDA) receptors and glucocorticoid receptors. Hyperfunction of HPA, increased secretion of corticotropin-releasing hormone (CRH), increased plasma (serum) and urinary free corticosterone concentrations. The hippocampus contains a large number of glucocorticoid receptors, and the increase of corticosterone can choose to damage the hippocampus dangerously, causing it to shrink and the number of synapses to decrease. Through repeated stress, except for the blank group, the rats in the other groups showed obvious depressive symptoms, and serum interleukins and cortisol increased significantly, and interleukins decreased significantly. After 21 days of drug treatment, the positive group and the middle-dose glycyrrhizin group (20 mg/kg) can reverse IL-1p, and the increase in cortisol (P<0.05)} IL-6 concentration increased (P <0.05), the effect on IL-2 is not obvious.

　　2. 2. 3 Anti-free radicals The decrease of antioxidant enzyme activity in the body and the increase of lipid peroxide content are also one of the important mechanisms of depression. Superoxide dismutase is an important antioxidant enzyme in the body, which can effectively remove free radicals in the body. Malondialdehyde is a metabolite of lipid peroxidation. When it accumulates in a large amount in the brain, it can cross-link with protein through the reaction of the primary amino group of the protein, destroy the lipid bilayer of the cell membrane, and cause the cell permeability to change, and finally cause Degeneration and apoptosis of neurons. Animal experiments also found that the activity of superoxide dismutase in the colon of rats with chronic stress depression decreased, and the content of malondialdehyde increased. Licorice can be obvious

　　reverse the damage of chronic stress to the behavior of rats, and may be achieved by increasing the body's superoxide dismutase activity, scavenging free radicals, preventing lipid peroxidation, reducing the production of malondialdehyde, so as to achieve antidepressant-like effects.

　　2.2.4 Protecting neurons The hyperfunction of the HPA axis and the increase of corticosterone levels caused by stress are closely related to the decline of cell regeneration in the hippocampus, including neurons, and the occurrence of depression. It was confirmed from three aspects: experimental animal models, changes in brain morphology and autopsy of patients with depression, and the therapeutic effect of antidepressants that the recovery of the number of BrdU-labeled positive cells during the onset and outcome of depression was characterized by the number of hippocampal dentate gyrus particles. The restoration of nerve regeneration ability in depression (SGZ) is very important [CI3-la7. The total flavonoid extract of licorice has the effect of anti-depressive behavior in rats caused by CUS, and its antidepressant effect is related to its ability to reduce the level of corticosterone and protect the regeneration of cells including neurons in the hippocampus. However, it is worth noting that some of the indicators observed in the experiment are effective at high doses, while medium and small doses are ineffective or there is no statistical difference.

　　2.2.5 Anti-inflammatory effects The body activates peripheral immunity by releasing inflammatory cytokines, which in turn causes neuroendocrine and immune system dysfunction is one of the causes of depression. Studies have found that IL-6, an inflammatory factor, can increase the activity of SHIT and DA neurons in the hippocampus and prefrontal lobe of rats. The increased activity of these neurons can accelerate the reuptake of central monoamine neurotransmitters and reduce the concentration of neurotransmitters in the synaptic cleft. The inflammatory cytokine IL-6 can regulate the negative feedback inhibition of the HPA axis by glucocorticoids in the peripheral circulation, which can lead to the excessive activation of the HPA axis. Nuclear transcription factor-KB (NF1kB) plays an important role in the survival of central nervous system cells. Especially in the hippocampus, NF1cB may activate nitric oxide (NO) synthase and increase the synthesis of NO, while too much NO inhibits hippocampal neurogenesis. At the same time, NF1cB can also increase the synthesis of inflammatory cytokines, active oxides, and excitotoxins that lead to neurodegeneration, and affect the changes in the central nervous system process, which is also considered to be closely related to the occurrence of depression. The total flavonoids of licorice and the licorice flavonoids licorice chalcone A and isoliquiritin can inhibit iNOS, cyclooxygenase (COX) gene and protein level expression and inflammatory mediator IL-6 gene expression, and can also upregulate peroxidation Proteasome proliferator activated receptor }y (PPAR}y) gene expression, so isoliquiritin may be the anti-inflammatory active ingredient of total flavonoids of licorice [[I9] licorice total saponin can significantly reduce LPS-induced RAW264. 7 Cell NO} ILK and tumor necrosis factor 2 (TNF}) release, and by inhibiting phospholipase Az (PLAz) enzyme activity and COX} expression to reduce prostaglandin E2 (PGEz) synthesis.

　　3 Research and application of licorice antidepressant

　　Although licorice has good therapeutic effects on behavioral and biochemical indicators in animal models of depression in experimental studies, licorice is generally not used alone to treat depression patients in clinical practice, but is often given as a compound combination.

　　3.1 The composition ratio of licorice in the antidepressant Chinese medicine compound prescriptions. By reviewing recent studies on the treatment of depression with Chinese medicine compound prescriptions, the application of Chinese medicine licorice in its prescription compatibility was summarized.

　　Licorice is contained in most of the prescriptions of traditional Chinese medicine for the treatment of depression. Ganmai Dazao Decoction is particularly typical, indicating that the traditional Chinese medicine licorice does have a very good effect in the treatment of depression.

　　3.2 Experimental research Chaihu Shugan Powder (Bupleurum, Chenpi, Cyperus rotundus, Radix Paeoniae Rubra, Licorice) can increase the content of monoamine neurotransmitters 5HT, NE and DA in the hippocampus of depression rats. The dosage group improved significantly, and its antidepressant effect was similar to that of western medicine fluoxetine. Suanzaoren decoction (suanzaoren, licorice, Zhimu, Huo, etc., Sichuan peony) can significantly improve the psychomotor depression symptoms such as loss of interest and decreased mobility in rats with diffuse stress. The antidepressant effect may be related to the increase of brain single Related to the content of amine neurotransmitters. Xiaoyao Powder (Bupleurum, Angelica, White Peony, Atractylodes macrocephala, Huo, etc., ginger, peppermint, and licorice) can increase the level of neurotransmitters in the hippocampus, cortex, and serum of depression model animals; it has an effect on the expression level of hippocampus and cortex of model rats Increasing trend, there is a tendency to suppress the expression level, and the dose of Xiaoyao San 7.5 g/kg significantly increased the expression level of cortex.

　　3.3 Clinical application In clinical practice, depression is mainly divided into adolescent depression, postpartum depression, menopausal depression, postoperative depression and elderly depression. Feng Zhenyu and others applied Jiawei Ganmai Dazao Decoction (licorice, wheat, jujube) to treat 43 cases of female menopausal depression, 2 cases were cured, 24 cases were significantly improved, 11 cases were improved, and 6 cases were ineffective, with a significant efficiency of 88.4%. Xu Lei[25] observed Liujunzi Decoction (Ginseng, Baizhu, Huo etc., Licorice, Chenpi, Pinellia) and Banxia Houpu Decoction in the treatment of 29 patients with postoperative depression of gastric cancer. 0 cases were cured, 6 cases were significantly improved, and 15 cases were improved. , 8 cases were ineffective, with a marked efficiency of 72.4%. Feng Guangming et al. Cz}l used Xiaoyao San to treat 62 cases of depression. Of the 58 effective cases, after 8 weeks of treatment, 38 cases were cured, 14 cases were significantly improved, and progress 4 cases and 2 cases were invalid, the apparent efficiency was 90%.

　　4 Conclusion

　　The traditional Chinese medicine licorice was first seen in "Shen Nong's Materia Medica" and has been used to this day, and its role is still being explored by people. The active ingredients in licorice include flavonoids, three mushrooms, polysaccharides, etc. The pharmacological research mainly focuses on glycyrrhizic acid, glycyrrhetinic acid, total flavonoids, single flavonoids and polysaccharides. In the treatment of depression, licorice total flavonoids and glycyrrhizin are the main active substances. The main antidepressant mechanism of licorice involves the regulation of monoamine transmitters and their receptors; regulation of the HPA axis; anti-free radicals; protection of neuronal cells; anti-inflammatory The effects of cytokines are shown in Figure 1. In addition to its anti-depressant effects, licorice also has liver protection, anti-inflammatory, anti-bacterial, anti-virus, antitussive, anti-malarial, anti-oxidation, anti-cancer, immune mediation, hypoglycemic and anti-platelet agglutination effects. It is mostly used clinically to protect the liver. Liver, antibacterial, antiviral, anti-inflammatory and anti-allergic, treatment of cardiovascular disease and nephropathy. Although the traditional Chinese medicine licorice is in the position of adjuvant in most traditional Chinese medicine compounds for the treatment of depression and the dosage is small, it does not mean that the traditional Chinese medicine licorice is dispensable for the treatment of depression. Ganmai Dazao Decoction is a very good one. Good evidence.