Research progress on the mechanism of TCM treatment of depression based on NLRP3 pathway

LIU Qi-qi, HE Qian-chao, LIU Yong-hui, GAO Yu-guang,MO Qiong-ze, LIAO Yuxiong

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

2. The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China

Keywords:NLRP3 Traditional Chinese medicine Depression Review

ABSTRACT To review the research progress on the mechanism of traditional Chinese medicine (TCM)treatment of depression based on NLRP3 pathway in the past five years, in order to provide the basis for the clinical application of TCM treatment of depression. NLRP3, TCM and depression were used as key words to search PubMed and China Journal Fulltext Database(CNKI) and other databases for the relevant experimental literatures on antidepressant effects of TCM based on NLRP3 pathway in recent years. Chinese medicine can protect nerve cells by inhibiting the activation of NLRP3 and reduce the depression-like behavior in animal model. TCM can inhibit NLRP3 pathway and exert anti-depressive effect.

1. Introduction

Depression, also known as depression disorder, is characterized by persistent and significant low mood. According to the latest statistics released by the World Health Organization (WHO),the total number of people suffering from depression in the world is about 322 million, accounting for an estimated 4.4%of the global population suffering from depression. Among them, women suffer from depression more than men (5.1% and 3.6% respectively)[1]. Depression is the fourth leading disease in the world and is expected to become the second leading disease by 2030. Among the biological and psychological theories to explain the causes of depression, hypotheses involving active inflammatory processes occurring in the human organism have become increasingly important, and clinically elevated levels of inflammatory cytokines have been detected in the brain and surrounding blood of patients with depression [2]. In this paper,the oligomeric domain with nucleotide binding, the leucine-rich repeat sequence and the nod-like receptor3 (NLRP3) inflammatory signaling pathway containing pyridine domain were selected to explore the mechanism of anti-depression effect of traditional Chinese medicine. NLRP3, as the most critical inflammasome in NLRP3 inflammation signaling pathway, is an induction product of innate immune response, consisting of NLRP3 scaffold, apoptosis associated speck-like protein containing CARD (ASC) and cysteine aspase-1 (caspase-1) [3].

2. Understanding of the etiology and pathogenesis of depression in traditional Chinese medicine

Traditional Chinese medicine will be classified as "depression"category, "Su asked. On pain" cloud: "thinking is the heart is there, God is there, the healthy qi stay but not, so the qi. The onset of depression syndrome is mostly caused by internal emotional injury, and the basic pathogenesis is stagnation of qi mechanism and dysfunction of zang-fu organs. The basic pathological factors were qi, blood, fire, phlegm, food and dampness. At the beginning, Qi stagnation was the main cause of depression syndrome, which gradually led to the pathogenesis transformation,such as deactivation of fire, blood stasis, sputum constipation,food stagnation and dampness arrest, etc. At present, it is mostly empirical. Sad for a long time, spleen, kidney and other organs,damage the function of the viscera.

3. The mechanism of NLRP3 inflammasome acting as an antidepressant

The NLRP3 pathway is mainly produced in immune and inflammatory cells. In general, the activation of NLRP3 pathway mainly involves two steps. The first step is that the initiation signal is triggered by some conserved molecule-pathogen-associated molecular mode (PAMP) on Toll-like receptor 4 (TLR4), thereby activating the pathway mediated by nuclear transcription factorkappa B(NF-κB). Triggerent activation of NF-κB leads to increased transcription of components of the NLRP3 pathway, including NLRP3 protein, interleukin 1β(interleukin 1β, PROIL-1β), and interleukin 18(interleukin 18, PROIL-18). In a second step,following further stimulation of immune and inflammatory cells,the NLPR3 protein is oligomerized and the NLRP3 protein, ASC and Procaspase-1 are then assembled into a complex of NLRP3 inflammasomes. The successful formation of NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1, thereby catalysing the formation of mature IL-1β and IL-18 from PROIL-1β and PROIL-18 [4]. Recent studies have shown that the basal level of the NLRP3 pathway is necessary for conditioned induced plasticity in the ventral hippocampus and basolateral amygdala in the brain of young mice. Loss of the NLRP3 pathway impairs synaptic transduction and induces depression-anxiety-like behavior,suggesting that low-grade inflammation mediated by NLRP3 expression plays a key role in neurological diseases [5]. In the brain, the NLRP3 pathway is primarily expressed in microglia in the hippocampus and other emotion-regulating regions that are particularly susceptible to stress. NLRP3 pathway activation and production of activation products may contribute to the development of depression and memory disorders [6], and its activation and production of activation products are of great help to delay the occurrence and development of depression.

4. Single Chinese medicine can regulate NLRP3 pathway to exert antidepressant effect

Trans cinnamic aldehyde as the main active ingredients of traditional Chinese medicine cinnamon, anti-inflammatory, fall blood sugar and improve the effect of nerve function, Wang Meng research trans cinnamaldehyde antidepressant mechanism experiment found that trans cinnamaldehyde inhibit the chronic unpredictable mild stress model in the prefrontal cortex and hippocampus of rats NLRP3 pathway activation and the nf-kappa B pathway activation[7]; Recent studies in Neurorport have shown that ginsenoside Rg1 can reverse the increase of IL-1β induced by chronic unpredictable mild stress model (CUMS) by inhibiting the activation of NLRp3 inflammasome and activation of NF-κB pathway, and play a potential antidepressant role [8]. Extracted from curcuma rhizome of curcumin, a natural composition in its antidepressant effect is based on effectively reduce the proinflammatory cytokines (IL - 1 beta,etc.) mRNA expression, and suppress the nf-kappa B activation, and inhibit the stress induced by activation of NLRP3 pathways, while reducing the pro-IL-1 beta to mature and IL-1 beta, etc., studies have shown that curcumin can be mainly by inhibiting the activation of NLRP3 pathways to alleviate the depression behavior [9]; Brain Research Bulletin confirmed that crocus can inhibit the activation of NLRP3 pathway and the activation of NF-κB pathway, so that crocus can reduce depression [10]. Ginkgo ester is a novel fifth-generation Ginkgo biloba extract that was independently developed in the early stage. In Liu Fuqun's experiment on Ginkgo ester, it was found that its improvement of depression-like behavior may be mainly related to the inhibition of NLRP3 pathway activation and conversion of TLR4/NF-κB signaling pathway [11]. Polygonin is the main bioactive component of Radix Polygoni. The experimental results of Li Hongwang et al. aimed to explore its antidepressant effect showed that Polygonin may exert its antidepressant effect by inhibiting the activation of NLRP3 inflammasome related pathway [12].Resveratrol has been shown to play a beneficial role in the treatment of depression by inhibiting the activation of NLRP3 and NF-κB in the hippocampus and reversing the increase of microglial cells in the dentate hippocampus [13]. Int Immunopharmacol found that baicalin plays an antidepressant role in the CUMS model by activating the NLRP3 pathway and reducing the levels of caspase-1 and IL-1β in the hippocampus [14]. Perillaldehyde, the main component of Perilla Perilla, is reported to have anti-inflammatory and antioxidant effects, and its depression-reducing effect is mainly through the regulation of NLRP3 pathway activation, which is speculated to be based on the NLRP3 pathway to achieve the inhibitory effect [15].Gao of the experimental results show that the inner fat I limit by inhibiting the activation of NLRP3 pathways in the hippocampus of mice CUMS model and the concentration of IL-1 beta, and thus play a role of antidepressant [16]. Sinomenine is an extract of the Chinese herb, Cyanthus subtilis, which has immunosuppressive and anti-inflammatory effects. To investigate whether sinomenine has an antidepressant effect in CUMS model mice, we found that sinomenine can significantly alleviate depression-like behavior.The mechanism is mainly based on regulating the activation of NLRP3 pathway and reducing the increase of IL-1β, IL-6 and TNF-α levels in the hippocampus of mice [17]. Nerve inflammation in the pathogenesis of depression and antidepressant therapy plays a key role, the ACS Chem Neurosci of a new study has found that astragalus root element, as a kind of flavonoids with antiinflammatory properties can significantly improve the behavior of CUMS rats model defect, its mechanism may be to reduce the NLRP3, NF-kB, cracking capase - 1, cracking of IL-1 beta protein level, at the same time promote the SIRT1, to infer the main astragalus root element based on regulating the activation of NLRP3 pathways, exert the function of antidepressant [18]. Song Meiting et al. 's latest study used astragaloside IV, an active ingredient purified from astragalus, to reduce neuroinflammation in the depressed mouse model, and speculated that astragaloside inhibited neuroinflammation by regulating the NLRP3 pathway and reducing NF-kB phosphorylation to play an antidepressant role [19]. Wu Song,based on previous studies, found that the ginsenoside metabolite -ginsenoside K-treated CumS model mice modulated the NLRP3 pathway in the hippocampus to exert its antidepressant effects [20].Liu Ping's experiment on how Lonicera japonicae polysaccharide extracted from Lonicera japonicae could exert effects on mice with CUMS model concluded that Lonicera japonicae polysaccharide could significantly regulate the expression levels of NLRP3, IL-1β and Caspase-1 in the hippocampus of depressed mice, and thus exert anti-depressive effects [21]. Menthone, as the main active component of mint, plays an anti-depressive role by regulating the NLRP3 pathway and mediating inflammatory cytokines and central neurotransmitters [22]. Recent studies in MoL Med Rp have shown that asiatica glycoside, a triterpenoid from Centella asiatica, regulates the NLRP3 pathway, reduces the levels of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), and reduces the phosphorylation of NFκB, thereby reducing the expression of mature caspase-1, and thus plays an anti-depressive role [23]. Musk is an antidepressant secreted by the male musk gland, which regulates the NLRP3 pathway,reduces the expression of TLR4 and Caspase-1, and inhibits the activation and production of inflammatory cytokines by microglia cells, thereby inhibiting neuroinflammation in the prefrontal cortex of mice and improving depressed-like behaviors [24]. Mangiferin is the main component from mango glucosylanthrone, which has many biological effects, mainly anti-inflammatory effect.Mangiferin plays an antidepressant role by regulating the NLRP3 pathway, reducing the expression of the binding proteins ASC and Caspase-1, and reducing the production of IL-1β and IL-18 in CMS mice [25]. Allicin is one of the main bioactive compounds in garlic.Recent studies from Metab Brain Dis found that allicin can reduce neuroinflammation, inhibit oxidative stress, and reduce hippocampal neuronal apoptosis by regulating the NLRP3 pathway, thereby alleviating depressive-like behavior [26]. Thymol is a bioactive monoterpene isolated from thyme, which has neuroprotective effect. Deng Xueyang et al. found that the mechanism of action is to regulate the NLRP3 pathway, and subsequently reduce the expression of caspase-1, which plays a role of upregulating the level of central neurotransmitters and inhibiting the expression of pro-inflammatory cytokines, thus playing a potential antidepressant role [27]. Grape seed proanthocyanidins, which mainly contain dimer, trimer,oligomer and other active components of catechin and epicatechin,counteract stress-induced hippocampal neuron loss and depressionlike behavior by regulating the NLRP3 pathway [28]. Depression is the most common non movement symptoms of Parkinson's disease,a large number of clinical studies have shown that the incidence of Parkinson's disease with depression 50%, paeoniflorin is peony root extract, have anti-inflammatory, antioxidant, and enhance the effect of memory, Lu Linyu about study of paeoniflorin by microglia NLRP3 pathway mediated nerve inflammation, conclusion: the treatment of Parkinson's disease depression 1. Paeoniflorin can inhibit the activation of NLRP3 pathway, thereby inhibiting the IL-1β secretion mediated by Paeoniflorin, and inhibiting the proliferation and activation of microglia cells, thus exerting an antidepressive effect. 2. Paeoniflorin plays an antidepressant role by inhibiting neuroinflammation mediated by microglia in the ventral tegmental region of the midbrain [29].

5. Traditional Chinese medicine compound can regulate NLRP3 pathway to exert antidepressant effect

Set sail in the field for the liver spleen and the control pulp source inhibitory cells in the study of depression mechanism of breast cancer in mice for intervention, draw the conclusion: the liver spleen and prompted NLRP3 cells to promote caspase 1 from ASC complex separation, and release the IL-1 beta, and based on TLR4/ NF-kB inflammatory pathways, the source of marrow inhibitory of the mice spleen cells proportion, impact on immunosuppression microenvironment. The experiment speculated that this might be the main mechanism of the effect of Soogan-Jianpi-Fang on the apoptosis of breast cancer with depressive disorder [30]. Recent studies in Biomedicine & Pharmacotherapy have found that Chaihu Shugan San can inhibit inflammation in the liver and prefrontal cortex by regulating NLRP3 pathway activation and mediating TLR4/NF-κB pathway. The above evidences prove that Chaihu Shugan San can improve depression [31]. In order to investigate the antidepressant effect of ephedra aconite asarum decoction and related to anti-inflammatory and neurogenesis, it was concluded that ephedra aconite asarum decoction alleviated depression-like state by regulating NLRP3 pathway and enhancing neurogenesis pathway[32]. J Ethnopharmacol mentioned that in the experiment to discuss the effects of Pinellia magnolia decoction on glucose tolerance and anhedonia in CUMS model rats and its potential pharmacological mechanism, it was proved that Pinellia magnolia decoction regulates the NLRP3 pathway in liver, hypothalamus, hippocampus and prefrontal cortex, respectively, to exert anti-depressive effects [33].Journal of Traditional Chinese Medical Sciences has documented that Xiaoyao SF protects the cortical cells of rats by regulating the NLRP3 pathway and decreasing the expression of caspase-1 and IL-1β to improve depression-like behavior [34].

6. Summary

At present, the understanding of depression based on the study of depression, and for the treatment of the disease, western medicine multi-purpose sedative hypnotic and antidepressant drugs, although work faster, but false ideas made treatment effect is steady, the need to maintain a long time, the resulting adverse reactions and drug dependence, more larger burden and damage to patients. The traditional Chinese medicine treatment of this disease, has certain curative effect, less adverse reactions, high safety advantages. It can effectively relieve the depressed mood of patients. TCM treatment of depression emphasizes the overall review, the combination of four diagnoses, the combination of disease and syndrome, and has achieved very good clinical efficacy. However, TCM treatment of depression is also somewhat inadequate in some aspects, such as the lack of rigorous scientific research design; There is no clear and unified evaluation standard of curative effect. There is no more uniform standard for the evaluation of curative effect, and it depends more on the subjective feelings of patients and the subjective judgment of doctors, and the more objective diagnostic criteria need to be further improved. Different opinions and lack of unity on the syndrome differentiation of this disease; The lack of research on the internal mechanism of treatment affects the reliability and practicability of the research conclusions. In addition, it is necessary to strengthen the exploration of the therapeutic mechanism and the research on the cellular and molecular levels to further prove the exact efficacy of TCM treatment and clarify the specific mechanism of action. The research on TCM treatment of depression still needs to be further strengthened to make better use of the great advantages of TCM in the treatment of depression.

Contribution of the author:

Qiqi Liu: the thought designer of the review research direction,mainly responsible for the writing and submission of articles;

He Ganchao: Responsible for the revision and quality control of the paper, and provide opinions and suggestions for the research direction of the review;

Liu Yonghui: Suggestions and suggestions are provided in the thinking process of this thesis;

Gao Yuguang: Review the correlation between literature and review research direction;

Mo Qiuze: Review the format and details of the article;

Liao Yuxiong: Assist in literature search;