Depression is a pathological process involving a variety of neurotransmitters, brain regions and circuits, and multiple mechanisms, including the theory of monoamine transmitters, changes in the interaction between GABA and its receptors, neurobiochemical mechanisms, abnormal elevation of glutamate concentration in the brain, changes in neuropeptides and receptors in the brain, changes in cytokine levels, hippocampal neuronal nutrition / regeneration theory, astrocyte dysfunction, abnormal cellular signal mechanism, etc.[22-24]
4.1 Research on Drug targets based on Network Modeling
The characteristic of traditional Chinese medicine (TCM) decoction is that it contains a lot of active ingredients. Because of the untraceability of these ingredients, the properties of multi-components, multi-components and multi-targets of traditional Chinese medicine decoction are often confusing. Therefore, the concept of network pharmacology is put forward. In network pharmacology, the effect of multi-target drugs is often more than that of single-target drugs[25, 26].In this study, we analyzed thousands of compounds, targets and evidence-based factors in Huanglian Wendan decoction. In addition, we also analyzed the related genes and signal pathways of depression in order to find out the part of Huanglian Wendan decoction that can act on depression. The active substances in Huanglian Wendan decoction were found by constructing a network of 156 molecules interacting with depression.
Subsequently, we analyzed the compounds of each drug in Huanglian Wendan decoction [Coptis chinensis Franch, Pinellia ternata (Thunb.) Breit, Citrus reticulata Blanco, Citrus aurantium L., Poria Cocos (Schw) Wolf, Glycyrrhiza uralensis Fisch, and Zingiber officinale Roscoe] and their corresponding related genes, and constructed a network. The network model seems to show us the homogeneity and heterogeneity of each traditional Chinese medicine in Huanglian Wendan decoction. In order to better distinguish, we express the unique components of each drug separately, while the common ingredients are displayed together. Then, we get several interesting conclusions: (1) most of the ingredients in Zingiber officinale Roscoe are the same as other drugs; (2) Glycyrrhiza uralensis Fisch contains many and complex ingredients. It not only covers most of the common ingredients, but also has a lot of independent ingredients; (3) Citrus aurantium L. contains most of the ingredients in Citrus reticulata Blanco, both of which have a high degree of identity and heterogeneity. (4) Poria Cocos (Schw) Wolf does not have the same composition as other drugs, and there is a high degree of heterogeneity.
4.2 Antidepressant mechanism of main active substances
In this study, we found many active substances in Huanglian Wendan decoction which can act on depression-related targets, we selected the key and important targets, based on the existing literature, made a simple discussion on its mechanism.
4.2.1 Antidepressant effect of luteolin
In our study, we found that luteolin, the active ingredient in Huanglian Wendan decoction, has a strong effect on the key targets of depression.
Some studies support the link between inflammation, neurodegenerative diseases, oxidative stress, neuropsychological disorders (such as depression) and mild cognitive impairment[27-30]. Luteolin(3’,4’,5,7-tetrahydroxyflavone) is a common flavonoid in many fruits, vegetables, and medicinal herbs. Flavonoids show many neuroprotective and inflammatory effects[32, 33].
Previous studies have shown that the oral bioavailability of flavonoids is very low. However, Zhou et al drew different conclusions when studying the bioavailability of luteolin in peanut shell extract.
Recent studies have shown that neuroinflammation has been shown to be related to the pathogenesis of different central nervous system diseases such as depression.
Mariem Achour et al showed that luteolin significantly alleviated neuroinflammation by reducing the production of IL-6 by brain-derived astrocytes, decreasing the levels of serum IL-6, TNF α and corticosterone, and increasing the levels of dopamine and norepinephrine in hypothalamus. Luteolin showed the potential of astrocyte differentiation for the first time, thus highlighting its possible therapeutic role in neuroinflammatory and neurodegenerative diseases. Although the antidepressant behavioral effect of luteolin is not statistically significant, luteolin therapy regulates many signal pathways involved in the pathophysiology of depression.
4.2.2 Antidepressant effect of beta-carotene
In this study, we found that beta-carotene is the active ingredient second only to luteolin in Huanglian Wendan decoction. At present, the mechanism of the effect of beta-carotene on depression is not clear, but a series of social surveys and clinical studies have shown that the total intake of beta-carotene carotene may be inversely proportional to the risk of depressive symptoms[38-40].
4.2.3 Antidepressant effect of Kaempferol
In this study, we found that kaempferol is also a key active substance acting on the key target of depression in Huanglian Wendan decoction. In 1930, Professor Gyorgyti discovered a new chemical isolated from oranges. He was considered a new member of the vitamin family, initially identified as vitamin P, but later considered flavonoids[41, 42]. As mentioned above, luteolin has many neuroprotective and inflammatory effects as flavonoids, and kaempferol has similar effects as luteolin[32, 33]. Studies by Graza et al have shown that taking kaempferol and other flavonoids can show an important antidepressant regulatory effect, and the female sex of flavonoids supplementation shows sensitivity to the antidepressant imipramine, which can reverse the depression-like behavior of offspring. This may be that kaempferol plays an antidepressant effect mediated by antioxidant and anti-inflammatory ability by increasing the AKT/ β-catenin cascade in the frontal cortex.
4.3 Shared signaling pathways of pharmacogenomics
The effect of drugs on biological cells depends more on signal pathways, and the most important thing is to determine whether the molecular nodes in the network can be identified as members of the pathway, so as to eliminate "path orphans". Fortunately, the KEGG database is constantly updating about genomes, pathways, diseases and drugs. After marking the path of the network model of Huanglian Wendan decoction, 111 shared pathways and some non-shared pathways related to depression were marked.
4.4 Inflammation and depression
Inflammatory factor is the general name of all kinds of cytokines involved in inflammatory response, which is considered to be one of the important links in the pathogenesis of depression. The inflammatory process represents a series of dynamic phenomena, and the inflammatory process represents a series of dynamic phenomena, which are shown by strong vascular reactions. Neuritis is the response of central nervous system (CNS) and peripheral nervous system (PNS) to changes in dynamic balance. There are two cell systems that mediate this process: glial cells in the central nervous system and lymphocytes, monocytes and macrophages in the hematopoietic system. In 1991, Smith first proposed that depression is related to excessive secretion of inflammatory factors by macrophages. Subsequently, many patients with depression were found to have abnormal genetic regulation of the immune system and immune dysfunction[47-49].In-depth studies have found that inflammatory factors can affect neurotransmitter metabolism, neuroendocrine and neuroplasticity[22-24]. Further studies have confirmed that the pathological process mediated by inflammatory factors is closely related to depression. According to the different effects, inflammatory factors can be divided into pro-inflammatory factors (such as IL-6) and anti-inflammatory factors (such as IL-13). The study found that the expression of anti-inflammatory factors decreased in the pathological process of depression, if the supplement of exogenous anti-inflammatory factors has a certain antidepressant effect, at the same time, the antidepressant effect of drugs may also be related to the up-regulated expression of anti-inflammatory factors[48, 49]. Therefore, anti-inflammatory strategies have an important prospect in the treatment of depression.
The main active components of Huanglian Wendan decoction, such as luteolin and kaempferol, can enhance the expression of anti-inflammatory factors. In the central nervous system, the active components of Huanglian Wendan decoction also show good anti-inflammatory effects. Luteolin can inhibit the activation of microglia induced by polysaccharides and the release of a variety of pro-inflammatory factors such as TNF- α. Kaempferol can also effectively and safely treat depression by enhancing antioxidant capacity and anti-inflammatory effects. Therefore, we believe that Huanglian Wendan decoction through the regulation of inflammatory factors and its mediation is its main mechanism for the treatment of depression.
4.5 The limitations of this study
This study is only based on network pharmacology to analyze the relevant mechanism of Huanglian Wendan decoction in the treatment of depression, and the conclusions have not been verified by experiments. follow-up studies will make further research and exploration on its related mechanism.