Anti-depressant catechins -
Elevated IL-6 may lead to HPA axis dysfunction, altered synaptic neurotransmission, and reduced neurotrophic factors, which are indirectly involved in the pathogenesis of depression Nukina et al. The results showed that Ziyan green tea could improve the depressive symptoms induced by CUMS by increasing the expression of 5-HT, DA, and BDNF in the brain of CUMS-induced mice, and reducing the levels of pro-inflammatory factors IL-6 and TNF-α.
Previous research has shown that changes in the gut microbiome affect depression-like behaviors Lucidi et al. Therefore, we attempted to determine whether CUMS-exposed mice exhibited alterations in the gut microbiome. Alpha diversity was analyzed by calculating the Shannon, Simpson, Chao, Ace, and Sobs indices on the OTU level.
The results show that compared with the Con, the diversity and richness of the intestinal microbiota were significantly reduced after external stimulation, and the results of Coverage, Shannon, and Simpson indices indicated that the diversity of intestinal microbiota was reduced in the Mod, and the Sobs, Ace, and Chao indices indicated that the richness of intestinal microbiota was significantly lower in the Mod than in the Con.
After treatment with Ziyan green tea, the microbial community diversity and richness of CUMS mice was significantly restored. Table 1. Beta diversity was analyzed by PCoA plots, and differences in microbial composition OTU among the five groups were assessed using the nonphylogenetic Bray-Curtis metric Figure 5A.
Figure 5. Effects of Ziyan green tea on the microbial composition of CUMS mice. A Principal coordinate analysis. B Community barplot analysis on phylum level. C Community heatmap analysis on Genus level. D Relative abundance of distinguishable genu. E Cladogram analysis among different groups.
F Column chart of linear discriminant analysis LDA. To further explore the detailed composition of the intestinal microbiota of the five groups of mice, the relative abundance was analyzed at two taxonomic levels of phylum and genus.
As for the genus Lactobacillus , it is worth mentioning that the genus abundance level significantly decreased by In addition, the relative abundance of Bifidobacterium and Faecalibaculum in Mod decreased compared to Con and significantly increased by To explore the specific bacterial taxa associated with CUMS-induced depression and Ziyan green tea intervention, a LEfSe evolutionary branching map was presented between treatments.
Branching plots showed Figure 5E that Verrucomicrobia, Bacteroidetes, Firmicutes, Actinobacteriota, and Proteobacteria at the phylum level were enriched significantly among each group.
LEfSe analysis was performed to identify specific bacterial taxa that could distinguish between samples to account for differences in taxa from phylum to genus level on the phylogenetic tree of bacterial communities in the samples.
LEfSe Bar analysis further showed that the enrichment of intestinal flora in mice was reduced after external stimulation and different doses of Ziyan green tea soup intervened to change the enrichment of intestinal flora thus reducing the depressive symptoms.
We used PICRUSt2 functional prediction to predict the functional information of the microbial community in our samples to further our understanding of some potential microbial functional features during disease development through functional composition and abundance.
And based on 16S rRNA sequencing data, we analyzed all the samples between different Kyoto Encyclopedia of Genes and Genomes KEGG tertiary groups.
The results showed that among all KEGG pathways, the abundance of metabolic pathways and biosynthesis of secondary metabolites were the most correlated Supplementary Figure S1. PCA is an unsupervised multivariate statistical method, which can reveal the internal structure of the overall sample and can visually describe the change trends of different groups by the trajectory of each group on the principal component coordinate graph.
PCA clustering analysis was performed on the fecal samples of each group to obtain the trends of fecal metabolism changes shown in Figure 6A , and the results showed that there were significant differences in the distribution of metabolic profiles among the five groups.
In order to observe the CUMS-induced fecal metabolic differences in depth, the experiment hoped to model and analyze the samples of each group by PLS-DA to find the metabolic changes associated with CUMS-induced depressive behavior, which can be seen in Figure 6B , the Mod and Con clustered into two distinct independent parts, and there was no crossover in the distribution between their samples, indicating that there were significant metabolic differences between the Mod and Con, the modeling was successful, suggesting that CUMS stimulation changed the fecal metabolic profile of the mice.
Meanwhile, focusing on each dosing group, it can be found that the clustering areas of ZY-L, ZY-H, and Fluo can be distinguished from the Mod, indicating that the aqueous extract of Ziyan green tea also has a therapeutic effect on depression, which is consistent with the results in the previous behavioral evaluation experiments.
The clustering area of the Con was relatively farther from the Mod than that of the Ziyan green tea group, suggesting that Ziyan green tea has a lower effect on the recovery of the metabolic network than the positive control drug fluoxetine. Figure 6. A 3D PCA score chart.
B PLS-DA among five groups. C PLS-DA corresponding of random permutation test plots. D Volcano map for differential metabolite screening Mod vs. E Heat map of differential metabolite content in different treatment groups.
The relative levels of 5,8,Eicosatrienoic acid, 10,dihydrotrihydroxy-leukotriene B4 and Indolecarboxaldehyde were significantly higher after ZY-L intervention. After ZY-H intervention, the contents of Ketodeoxycholic acid, Cholic Acid, and 7-Sulfocholic acid were significantly lower compared to the Mod, while the relative contents of L-Glutamate, 10,dihydroxytrihydroxy-leukotriene B4 and Indolecarboxaldehyde were significantly higher.
The pathway analysis can provide biological information on the relevant metabolites, which can help us to further understand the pathogenesis of depression and the antidepressant effect of Ziyan green tea. Based on the identified potential differential metabolites, the relevant metabolic pathways were identified by applying databases such as KEGG 3 and HMDB 4 as well as enrichment analysis.
The results of the enrichment analysis Figure 7A showed that Bile Acid was the most relevant in this analysis, and the metabolic pathway analysis identified three metabolic pathways that were most relevant to the depression-like behavior of CUMS mice Figure 7B ; Supplementary Table S1 , including Purine Metabolism, Bile Acid Biosynthesis and Cysteine Metabolism.
These results suggest that Ziyan green tea mainly affects Purine Metabolism, Bile Acid Biosynthesis, and Cysteine Metabolism in the intestinal tract of CUMS mice.
Figure 7. Metabolic pathway enrichment analysis. A Histogram, the darker the colour, the smaller the value of p , and the more pronounced the enrichment of the corresponding metabolic pathway.
B Bubble chart, Each bubble represents a metabolic pathway, and the horizontal coordinates of the bubble and the size of the bubble indicate the influence factor of the pathway in the enrichment analysis, the larger the bubble, the larger the influence factor; the vertical coordinates of the bubble and the color of the bubble indicate the value of p of the enrichment analysis taking the negative common logarithm, i.
The results showed that a total of four microbial communities at the genus level showed significant correlations with neurobiochemical factors, six genera were significantly correlated with inflammatory factors, and 13 genera were significantly correlated with fecal differential metabolites.
From Figure 8A , Corynebacterium showed a significant positive correlation with 5-HT and BDNF, Faecalibaculum showed a significant negative correlation with IL-6 and TNF-α, Enterorhabdus showed a significant negative correlation with IL-6, and Desulfovibrio showed a significant negative correlation with TNF-α.
Therefore, Corynebacterium , Faecalibaculum , Enterorhabdus , and Desulfovibrio had a positive intervention effect on CUMS-induced depression. Interestingly, these genera, which were significantly positively correlated with neurobiochemical factors and negatively correlated with pro-inflammatory factors, were significantly increased after Ziyan green tea.
In conclusion, these findings reveal that the gut microbiota plays a key role in modulating CUMS-induced depression after Ziyan green tea intervention. A causal relationship may exist between the gut microbiota and the relative abundance of neurobiochemical factors 5-HT, DA, and BDNF in brain tissue and pro-inflammatory factor indicators IL-6 and TNF-α.
Figure 8. Spearman correlation Analysis Heat Map. As seen from Figure 8B , some intestinal bacteria were significantly associated with only one metabolite, e. Here we focused on two aspects: first, the metabolites produced by the direct or indirect metabolism of the intestinal flora, and second, a particular intestinal bacterium that correlates with multiple metabolites, which is important to explore the involvement of the intestinal flora in the pathogenesis of the host.
It suggests that these metabolites may be inextricably linked to the stimulation, synthesis, or increase of neurotransmitters in the brain of depressed mice. Depression is one of the most common mental disorders in the world.
The core symptom of depression is a lack of pleasure, which can be reflected by SPT and food intake Qiao et al. CUMS has been widely used to induce an animal model of depression that mimics several human depressive symptoms as well as key biochemical signs of depression Sharma and Thakur, Our study showed that the body weight, food intake, and sugar-water preference of depressed-like mice were significantly higher after Ziyan green tea intervention than in the Mod, improving the well-being of CUMS-induced depressed mice.
After the gavage intervention of ZY-L and ZY-H, the immobility time of CUMS mice was significantly shortened in the compulsive swimming experiment, moreover, the number of crossing and standing in the open field experiment were significantly increased, indicating that the behavioral activities and the ability to explore the unknown were restored in the depression-like mice, and Ziyan green tea could improve the depression-like behavior of CUMS mice.
People with depression have lower levels of 5-HT and DA compared to healthy individuals Hu, The level of BDNF in the brain of depressed animals and patients decreases, and antidepressant drugs can restore the level of BDNF and reverse the devaluation effect of its behavior and cells Takebayashi et al.
Our study showed that Ziyan green tea significantly modulated the levels of 5-HT, DA, and BDNF in the brain compared to Mod.
Nukina et al. It has been shown that depressive symptoms in depressed patients can be improved by lowering serum TNF-α levels, which in turn improves sleep Postal and Appenzeller, In the present study, we found that the brain levels of IL-6 and TNF-α in CUMS mice were significantly reduced and restored to normal levels after Ziyan green tea intervention, indicating that Ziyan green tea could indirectly interfere with the development of depression by reducing the levels of pro-inflammatory factors in CUMS mice.
Green tea polyphenols GPTs can promote energy conversion in mammals by modulating gut microbial community structure, gene homologs, and metabolic pathways Zhou et al.
Dietary supplements with tea had positive effects on maintaining intestinal microecology Liu et al. The results of this study showed that the degree of neuronal damage was restored after ZY-L and ZY-H treatment, and the number of Nisin bodies was significantly increased, partially inhibiting histopathological damage.
Therefore, Ziyan green tea can inhibit neuronal damage and apoptosis in the hippocampus of CUMS-induced depressed mice to some extent and restore the number of Nisin bodies. There is growing evidence that dysbiosis of gut microbiota has been associated with a variety of neuropsychiatric disorders including major depressive disorder MDD Chang et al.
In this study, we found that CUMS induced significant changes in intestinal flora by PCoA analysis, while low and high doses of Ziyan green tea reversed the CUMS-induced changes in intestinal flora to some extent, indicating its intervention effect on intestinal flora of CUMS mice.
The results of Coverage, Shannon and Simpson indices indicated that the intestinal microbiota diversity was reduced in CUMS-induced mice, and the Sobs, Ace and Chao indices indicated that the intestinal microbiota richness was significantly lower in CUMS-induced mice than in healthy mice.
The microbial community diversity and richness of CUMS mice were significantly restored after Ziyan green tea treatment. Jasmine tea has been shown to modulate depressive symptoms by downregulating Lactobacillus Zhang et al.
Some studies have shown that psychosocial and psychophysical stress alters the intestinal flora and leads to a decrease in the number of Lactobacillus and Bifidobacterium , an important factor in depression Gulbins et al.
Bifidobacteria and Lactobacillus in the gut have been suggested to have beneficial effects on stress response and depression.
Existing studies have demonstrated a reduction in the number of these bacteria in patients with major depressive disorder MDD compared to healthy controls Aizawa et al. Bifidobacterium has been associated with beneficial psychobiological effects Rothenberg and Zhang, , Bifidobacterium breve CCFM was validated to have an antidepressant-like effect in mice, supplementation of Bifidobacterium breve CCFM and Bifidobacterium breve Bif11 to depressed patients and animals can alleviate their depressive behaviors, and their antidepressant mechanisms include attenuating over-responsiveness of the HPA axis and inhibiting the expression of inflammatory factors, enhancing the expression of 5-hydroxytryptophan 5-HT in the intestines and the brain, and ameliorating the damage of intestinal permeability Tian et al.
There was a significant difference in the β-diversity of microbiota in young adults between high and low NCPB groups. Faecalibaculum abundance was shown to be significantly higher in the High-status NCPB treatment group Xu H. et al. It agrees with our findings; our study showed that the relative abundance of Bifidobacterium and Faecalibaculum significantly increased after Ziyan green tea intervention.
The GM gut-brain axis plays an important role in initiating signal transduction and communication between the gut and the central nervous system Chen et al. It has been found that jasmine tea has a significant restorative effect on microorganisms and has a significant relationship with neurotransmitters.
Our study found that Corynebacterium showed a significant positive correlation with 5-HT and BDNF, Faecalibaculum showed a significant negative correlation with IL-6 and TNF-α, Enterorhabdus showed a significant negative correlation with IL-6, and Desulfovibrio showed a significant negative correlation with TNF-α.
Experiments have shown that Corynebacterium abundance was significantly reduced in chronic variable stress CVS -induced depression rats compared to normal controls Yu et al. Current research indicates that CUMS stimulation reduced Enterorhabdus abundance, which was reversed by venlafaxine treatment.
So Enterorhabdus are the key bacteria responsible for venlafaxine-ameliorated depression in mice Shen et al. In a rat model of ACTH-induced depression, chlorogenic acid exerted anti-depressive effects by increasing the relative abundance of Bifidobacterium and reducing the relative abundance of Desulfovibrio Song et al.
Therefore, Corynebacterium , Faecalibaculum , Enterorhabdus , and Desulfovibrio have a positive intervention effect on depression caused by CUMS.
There is much evidence that gut microbiota composition is closely related to host metabolism Koh and Bäckhed, The results of our study showed that Bile Acid was the most enriched, and the metabolic pathway analysis identified three metabolic pathways that were most associated with depression-like behavior in CUMS mice, including Purine Metabolism, Bile Acid Biosynthesis, and Cysteine Metabolism.
The size and composition of the bile acid pool appear to be important factors regulating the structure of the human gut microbial community Ridlon et al.
Bile acids have direct antimicrobial effects on gut microbes, and clinical studies have shown that bile acids are important components of the gut-brain axis, suppress neuroinflammation, and mediate the pathophysiology of Major depressive disorder MDD Begley et al.
It has been found that serum bile acid concentration was significantly increased in model rats Xiong et al. Alistipes have been shown to be pathogenic in colorectal cancer and associated with psychiatric symptoms of depression Parker et al.
This is consistent with our findings, where we found that Alistipes were significantly and negatively correlated with 7-Sulfocholic acid, Ketodeoxycholic acid, and Cholic acid.
Depression leads to a significant decrease in the relative abundance of Corynebacterium , Lactobacillus , and other intestinal flora Yu et al. In addition to this, we also found that Corynebacterium was significantly positively correlated with 5-HT, BDNF, and Corynebacterium showed significant positive correlations with N-Lauroylglycine, 7-Methylhypoxanthine, 5-Hydroxyindoleacetic acid, Indolecarboxaldehyde, Undecylenic acid, and 10,dihydrotrihydroxy-leukotriene B4.
Previous studies have found that Enterorhabdus may be related to bile acid metabolism and that elevated Enterorhabdus affects the synthesis of beneficial bile acids Wang et al. It is suggested that Ziyan green tea may act as an antidepressant through the gut-microbiota-brain axis or microbial-bile acid axis.
In future studies, we will combine various research methods and perspectives, land on the pathways and targets of depression intervention, and further explore the mechanism of Ziyan green tea intervention in depression to alleviate CUMS-induced depression. This study aimed to investigate the improvement of CUMS-induced depression-like symptoms by Ziyan green tea and its possible mechanism of action.
Male mice were gavaged with Ziyan green tea. Depression-like behavior was measured by a series of behavioral tests and neurobiochemical factors 5-HT, DA, and BDNF and pro-inflammatory factors IL-6 and TNF-α were measured in brain tissues, combined with Nissl pathological analysis and determination of gut microorganisms.
Ziyan green tea intervention significantly attenuated CUMS-induced depression-like behaviors in mice. Corynebacterium showed a significant positive correlation with 5-HT and BDNF. Faecalibaculum and Enterorhabdus showed a significant negative correlation with IL-6, Faecalibaculum and Desulfovibrio showed a significant negative correlation with TNF-α.
The microbial community diversity and richness of CUMS mice were significantly restored after Ziyan green tea intervention. And we found that Alistipes were significantly and negatively correlated with 7-Sulfocholic acid, Ketodeoxycholic acid, and Cholic acid. In conclusion, our findings suggest that both low and high-dose interventions of Ziyan green tea have positive preventive effects on CUMS mice without dose dependence, partly because they mainly affect intestinal Purine Metabolism, Bile Acid Biosynthesis, and Cysteine Metabolism in CUMS mice, thus stimulating brain 5-HT, DA and BDNF, and decreasing the inflammatory factors IL-6, TNF-α, activate the composition of intestinal flora, improve the intestinal flora environment and thus promote the production of intestinal metabolites, which can be used for depression treatment.
The datasets presented in this study can be found in online repositories. The animal study was approved by Animal Ethics Committee of the Hunan Provincial Center for Drug Safety Evaluation and Research. The study was conducted in accordance with the local legislation and institutional requirements.
WJ: Conceptualization, Data curation, Formal analysis, Software, Writing — original draft. QT: Investigation, Resources, Writing — original draft. YZ: Conceptualization, Methodology, Writing — original draft. YY: Conceptualization, Methodology, Writing — original draft.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Aizawa, E. Possible association of bifidobacterium and lactobacillus in the gut microbiota of patients with major depressive disorder.
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Psychiatry Fan, L. Total glycosides from stems of cistanche tubulosa alleviate depression-like behaviors: bidirectional interaction of the phytochemicals and gut microbiota. Moreover, mice treated with aortic banding and a high salt diet in a heart failure model showed depressive-like symptoms in the tail suspension test and had reduced expression of the σ1R in the brain Ito et al.
Clinical studies have been conducted with σ1R specific ligands igmesine Roman et al. However, this trial did appear to have a high response rate in the placebo group, which could have clouded the effects. Studies have shown that several regions of the brain are affected in patients suffering from depression.
Additionally, the heterogeneity among depressed patients makes it difficult to identify specific brain regions among depressed populations and interpret findings Graham et al. However, studies have shown the hippocampus as one such region of the brain with atrophy in MDD Sheline et al.
Stress can lead to depression-like symptoms and an excess of cortisol production. The hippocampus is particularly rich in glucocorticoid receptors making it more vulnerable to long-term stress than other regions of the brain, and this is the potential cause of hippocampal atrophy Campbell and Macqueen, For instance, σ1R knockout mice show decreased neurogenesis in the hippocampus Sha et al.
Moreover, SSRIs with σ1R affinity such as fluoxetine can prevent stress-induced atrophy Luo and Tan, and even induce further neurogenesis Santarelli et al. Other regions of the brain have been identified as either hyper or hypoactive in cases of MDD.
The amygdala, part of the brain involved in emotional processing, is hyperactive in those with MDD. The size of the amygdala appears larger in medicated patients than un-medicated, although there is no noticeable difference between depressed patients and healthy people Hamilton et al.
The prefrontal cortex PFC has been identified as underactive in MDD. The PFR regulates emotional processing; its low activity may be involved in the etiology of depression.
Treatment with norepinephrine reuptake inhibitors SNRIs has been shown to increase activity in the PFR, whereas SSRIs are amygdaloid-hippocampal regions Outhred et al.
The different brain regions affected by different antidepressant classes may explain the different efficacies of different drugs between patients. While it is unlikely that inflammation is the primary cause of the MDD, there is evidence that it plays a role.
Also, patients with inflammatory diseases are at greater risk of MDD Choi et al. Multiple studies in animals have identified the effects of inflammatory cytokines serotonin turnover in the brain Dunn and Wang, ; Dunn et al.
Clinical studies have shown that the SSRI paroxetine can reduce symptoms of depression in patients treated with IFN-ɑ Musselman et al. Furthermore, pro-inflammatory cytokines have been shown to affect dopamine production and reuptake in the brain Morón et al. Glutamate is another excitatory neurotransmitter associated with inflammation and neurological disease through excitotoxicity and oxidative stress Brimson et al.
IL-1β prevents the reuptake of glutamate by glial cells, which leads to increased glutamate in the synapse and causes further NMDA-mediated excitotoxicity. Furthermore, IL-1β induces nitric oxide synthase production and thus an increase in nitric oxide NO production, leading to further glutamate release causing further excitotoxicity and oxidative stress Hu et al.
This strongly suggests a genetic link when it comes to the development of the MDD. While there may well be a genetic link to many forms of depression, once again, the heterogeneous nature of MDD has made it difficult to identify genes that contribute to increased risk.
Two possible candidate genes include the serotonin transporter genes and brain-derived neurotrophic factor BDNF. The serotonin transporter genes and genes related to its expression and the serotonin receptor 2A 5Ht-2A receptor have long been candidates due to their proposed role in the monoamine hypothesis of depression Lohoff and Ferraro, A 44 base pair repeat polymorphism in the promoter of the serotonin transporter 5-HTTLPR has been shown, in vitro , to influence the expression of the transporter Lesch et al.
The Val66Met polymorphism in BDNF has been extensively studied in bipolar disorder and MDD. The results for the association between the Val66Met single nucleotide polymorphism SNP and other polymorphisms in BDNF and MDD have been mixed.
Haplotype analysis of BDNF indicated an association with MDD Schumacher et al. Medicinal plants is a rich source of bioactive compounds with diverse pharmacological potentials Mir et al. Polyphenols represent greatly varying group of compounds extensively distributed in plants Ovais et al.
Their chemical structure as well as their composition are significantly influenced by environmental factors and plant species Ofosu et al. According to their structure and complexity, they can be classified in two main sub-groups: flavonoids flavones, flavonols, flavanones, flavanonols, isoflavonoids, flavanols, anthocyanidins and chalcones and non-flavonoid compounds phenolic acids, stilbenes, lignans and tannins Ayaz et al.
Flavonoids constitute a wide group of at least polyphenolic compounds which differ in their structure but generally, they contain two aromatic rings A and B rings linked by a 3-carbon chain making an oxygenated heterocyclic ring C ring.
Based on variations in structure of C ring, as well as functional groups on the rings and the position at which the B ring is connected with the C ring, there are six subclasses of flavonoids, namely flavones, flavonols, flavanones, flavanols, isoflavones and anthocyanidins Ayaz et al.
Six-member ring linked with the benzene ring is either a α-pyrone flavonols and flavanones or its dihydroderivative flavonols and flavanones. According to the position of the benzenoid substituent flavonoids are separated into flavonoids 2-position and isoflavonoids 3-position. Flavonols, the most common flavonoids in food, vary from flavanones based on hydroxyl group at the 3-position and a C2—C3 double bond.
The most investigated flavonol compounds are rutin and quercetin, and they are mainly present in buckwheat, asparagus, and citrus fruits, as well as in peaches, apples, and green tea. In relation to flavones e.
Isoflavones, particularly daidzein, dominantly exist in leguminous plants, and they can be found in large quantities in soybeans and soymilk Truzzi et al. Widely-known flavanones including naringin, neoeriodictyol and neohesperidin are usually found in citrus fruits and their products.
Other flavanones are present in some medicinal plants such as mentha Nazzaro et al. Dietary sources of anthocyanins e. Flavonoids exist in various forms such as aglycones, glycosides and their methylated derivatives.
In case of glycosides, the glycosidic bond is ordinarily placed at positions 3 or 7 and the carbohydrate can be L-rhamnose, D-glucose, glucorhamnose, galactose, or arabinose.
Methyl ethers and acetyl esters of the alcohol group are also identified in nature Kumar and Pandey, Tannins is a group of naturally occurring high molecular weight polyphenols with a relatively complex structure.
In nature they can be found in complexes with alkaloids, polysaccharides, and proteins and further divided into hydrolysable tannins and condensed tannins also known as proanthocyanidins.
The degree of polymerization differs significantly and can range from several to more than 50 flavanol molecules. While small molecules of condensed tannins are soluble in aqueous or organic solvents, the large polymers are insoluble, and this disturbs their analysis, comprising determination of their content in food Khanbabaee and Van Ree, Esters of gallic and ellagic acids are termed hydrolysable tannins.
The center of the hydrolysable tannin molecule represents a glucose ring and its hydroxyl group can be esterified with gallic or ellagic acid, obtaining gallotannins or ellagitannins, respectively Singla et al. Polyphenols with a carboxylic acid are called phenolic acids.
They are abundant in plant-based foods with highest content in seeds, fruits peel and vegetables leaves. Generally, they can be found in bounded form such, in particular as amides, esters, or glycosides and sparsely as free Kumar and Goel, There are two representative parent structures of phenolic acids.
In the case when the carboxyl group is directly attached to the phenol ring, the phenolic compound is known as hydroxybenzoic acid. Substituted derivatives of hydroxybenzoic and hydroxycinnamic acids are the principal phenolic acids in plants, and hydroxycinnamic acids are with greater incidence.
Phenolic acids can varying in the pattern of the hydroxylation and methoxylation in their aromatic rings. The most usual hydroxycinnamic acids are caffeic, p -coumaric and ferulic acids.
They are often present in foods as simple esters with quinic acid or glucose. Perheps the most well-known bound hydroxycinnamic acid is chlorogenic acid, which provide combination of caffeic and quinic acids.
Diverse from hydroxycinnamates, hydroxybenzoic acid derivatives are generally found in foods in the form of glucosides and molecules as p -hydroxybenzoic, vanillic and protocatechuic acids are the most common forms Shahidi and Ambigaipalan, Lignans are a non-flavonoid compounds characterized with two propylbenzene units C6-C3 linked together between the β-position in C8 of the propane side chains.
Positions C9 and C9ˋ are substituted in various arrengements, having as a result in a high diversity of their structural forms. Accordingly, lignans are organized in eight subgroups: furans, furofurans, dibenzylbutanes, dibenzylbutyrolactones, dibenzocyclooctadienes, dibenzylbutyrolactols, aryltetralins and arylnaphthalenes.
Lignans are phytoestrogens and can be found in legumes, seeds, and vegetable oils. In high amounts they can be present in flaxseed and flaxseed oil, with the prominent compounds being secoisolariciresinol and matairesinol Amawi et al.
Lignans are generally present in their free forms, whereas glycosylated molecules are not abundant Ayres and Loike, Another comparably minor class of non-flavonoids is stilbenes 1,2-diarylethenes which are characterized by two phenyl moieties connected together by a two-carbon methylene groups.
In stilbenes, the m-positions in ring A are usually substituted by two hydroxyl groups, while different positions in ring B may be substituted by hydroxyl and methoxyl groups. Stilbenes occur as cis and trans isomers, and they can exist in free minor and glycosylated major forms.
Stilbenes are not usual in plants and they are generated just upon pathogen invasion Amawi et al. Generally, the red wine is accepted as source for stilbenes, and those are resveratrol, piceid, piceatannol, astringin and pterostilbene and their dimers Zhang et al.
Also, some plant species from Polygonum genus, like Polygonum cuspidatum , which have not been applied as dietary ingredients, contain high content of stilbenes Nonaka et al. Nanotechnology and bio-inspired nanoparticles have got great attention these days and are extensively reported in pre-clinical studies against various diseases Ovais et al.
The application of non-targeted antidepressants can provoke various side effects besides their low efficacy Haque et al.
One of the strategies in treatment of depression is to develop nanotechnology-based drug delivery systems. Nano-formulations have numerous advantages since they have specific control, as well as continued and targeted release characteristics Ovais et al. Antidepressant activity of curcumin has been tested in various animal models, and it was shown that it acts through decreasing inflammation, ameliorating oxidative stress induced apoptosis, and regulating the release of serotonin and dopamine.
Animal and in vitro investigations have demonstrated that administration of curcumin could regulate the level of serotonin and dopamine in the central nervous system Asadi et al. Main drawbacks of curcumin use as a therapeutic agent is its considerably low water solubility, insufficient permeability cross the blood-brain barrier BBB , and poor bioavailability.
These major challenges make curcumin problematic for use as an optimal antidepressant agent. Researchers utilized solid lipid nanoparticles SLNs to encapsulate curcumin Cur together with dexanabinol HU HU represents an artificially synthesized cannabinoid derivative without cannabimimetic effects.
Due to its highly lipophilic nature, HU may present a new treatment procedure for MDD. On the contrary to curcumin, HU use is interrupted by its low stability in biological systems and poor cellular uptake. To overreach these limitations, nanotechnology-based drug delivery systems are prospective strategy.
Also, Asadi et al. Eighty patients entered the study and the participants were divided randomly in two groups: intervention and control groups. At baseline of the investigation, as well after it, anthropometric measurements, dietary intake, physical activity, glycemic indices, and severity of neuropathy were evaluated.
Depression, anxiety, stress scale questionnaire was used for measuring of the depression, anxiety, and stress level before and at the end of the intervention.
According to the obtained data, there was a significant reduction in the mean score of depression in the nano-curcumin group after the study completion from These outcomes implied that application of nano-formulation with curcumin during 8 weeks was beneficial in alleviating depression.
Chen et al. These particles were modified using N-acet Pro-Gly-Pro PGP peptide aiming to promote binding of nanoparticles to neutrophiles in vivo and achieve brain-targeted delivery Chen et al.
In previous study, Lee at al. After i. As stated by the same group of authors, chronic administration of equal baicalein doses during 21 days decreased the immobility time and enhanced locomotor activity in chronic unpredictable mild stress model in rats.
According to Chen et al. This region is the major one connected with emotional and psychiatric disturbances. Results of the study also revealed that the tested nanoparticles managed to lower immobility time, improve swimming and climbing time and weaken locomotion in olfactory-bulbectomized rats.
Ashraf et al. During this research mice were exposed to CUMS pattern for 14 days. On the 15th day behavioral and biochemical parameters were analyzed. Silymarin nanoparticles achieved reduction of weight gain, increased immobility time in both the teil suspension test and forced swimming test, in addition to the decreased time spent grooming in the splash test.
In the same study silymarin reversed prefrontal cortical and hippocampal oxidative stress and neuroinflammation induced by CUMS. Additionally, it increased neurotransmitter levels NE and 5-HT levels , strengthened neurogenesis and suppressed the activation of nod-like receptor protein 3 inflammasome.
For certain parameters, nanoparticles of silymarin exhibited higher effect compared to silymarin most likely as a result of significantly higher brain concentration of silybinin that represent the principal active component of silymarin. Namely, its concentration was almost fold higher in the group that received silymarin nanoparticles in comparison to the group treated with silymarin alone.
The authors concluded that antidepressant-like activity of silymarin might be assigned to its antioxidant and anti-inflammatory effects together with enhanced neurogenesis in the prefrontal cortex and hippocampus. Chhillar and Dhingra demonstrated recently anti-depressant effect of gallic acid in mice subjected to unpredictable chronic mild stress Chhillar and Dhingra, Similarly, Nabavi et al.
Aiming to enhance its therapeutic effect, targeted delivery of gallic acid to brain is the imperative for showing an effective; better tolerated anti-depressant activity.
Nagpal et al. Anti-depressant activity was evaluated using Despair Swim Test and Tail Suspension Test. Based on the significant enhancement of in vivo pharmacodynamic activity; better MAO-A inhibition; and stronger in vivo antioxidant activity obtained using cGANP authors presented the favorable outcome of ligand coated nanoparticulate system for the delivery of gallic acid across brain.
Bhutada et al. It improved behavioral disorders in mice and rats with anxiety and depressive-like behaviors provoked with the corticotropin-releasing factor. Nevertheless, low absorption, fast metabolism and narrow capacity for crossing the blood-brain-barrier are restraints for its application in the treatment of neuropsychological diseases.
Due to excessive first-pass metabolism, the effective dose of quercetin required to achieve the neurological activities might be considerably high. Nasal utilization provides various advantages such as avoiding the hepatic presystemic metabolism, simple dose regulation, continuous absorption and great convenience of application in patients Xu et al.
Also, nasal drug delivery bypasses the blood-brain barrier; it targets drugs directly to brain across neural connections between the olfactory epithelium, olfactory bulb, trigeminal nerve, and finally, the brain Trevino et al. Tong-Un et al. Male Wistar rats were received quercetin liposomes, containing 20 μg in one dose, via intranasal route once daily continually for 4 weeks Tong-Un et al.
Anti-depressant effect was assessed employing forced swimming test and the results exhibited that free liposomes and vehicle PEG treatment alone did not provide significant changes in immobility time at all treatment intervals applied in this investigation.
At the same time, quercetin liposomes induced a considerable decrease in the immobility time at all treatment duration. The anti-depressant generally reduces immobility time without stimulating motor activity.
According to the same group of authors, the forced swimming test data showed that the acute and the repeated administration of quercetin liposomes acted like an anti-depressant drug in rat, by decrease of the immobility time.
Altogether, the obtained data proposed that the mechanism underlying the anti-depression activity of nasally applied quercetin liposomes may include the inhibition MAO-A and increase the serotonin level. Furthermore, the electropharmacogram of adult rats which received quercetin have the same pattern as the well-known antidepressant moclobemide, MAO-A inhibitor Dimpfel, The subgroups of phenolic compounds includes flavonoids, coumarins, chromones, antraquinones, phenolic acids carboxylic acid derivatives , lignanes, and stilbenes Garcia-Salas et al.
Flavonoids are phenolic compounds whose antiviral, antibacterial, hepatoprotective, antioxidant and anti-inflammatory activities have also been reported Kumar and Pandey, They have been widely investigated for their antidepressant effects Figures 3 , 4 ; Table 1.
Genistein is an isoflavone that can cross blood brain barrier BBB in mice Si and Liu, and rats Tsai, and its antidepressant effects on chronic use for 21 days, have been reported in male mice on forced swimming test FST and tail suspension test TST Hu et al. The antidepressant mechanism of quercetin may be due to NMDA receptors inhibition that result in reduced intracellular calcium level which further leads to inhibition of protein calmodulin and then neuronal nitric oxide synthase resulting in decreased nitric oxide levels NO Holzmann et al.
In the brain, glutamate is the main excitatory neurotransmitter and its increased level in the synapse causes excessive stimulation of N-methyl-D-aspartate NMDA receptors that result in NMDA-mediated excitotoxicity and various forms of damage, such as a massive influx of calcium and the release of nitric oxide NO Bishop and Anderson, Increase production of nitric oxide NO leading to further glutamate release causing further oxidative stress and excitotoxicity.
Additionally, several studies have reported that nitric oxide synthase inhibition can cause antidepressant-like effect Zeni et al. FIGURE 4. Mechanisms underlying the anti-depressant and anxiolytic effects of phytochemicals. Apart from this fisten reversed depression in mice induced by spatial restraint stress which was demonstrated on FST and TST Wang et al.
Hesperidin is another flavonoid, which may raise hippocampal BDNF levels at 0. Hesperidin produced antidepressant effect at 0. Baicalin is another flavonoid that has been proven to have CNS effects. It may enhance neuronal differentiation by increasing BDNF and extracellular signal-regulated kinase ERK phosphorylation Xiong et al.
The glucuronide glycoside of baicalin showed antidepressant activity by reducing monoamine oxidase MAO -A and B enzymes Zhu et al. et al. Another flavonoid with antidepressant and antioxidant properties is naringin, which decreased immobility on the FST when administered at a dose of 2.
The antidepressant effect of these doses was associated with increased cholinergic transmission as a result of decreased activity of the enzyme acetylcholinesterase and antioxidant defence systems caused by increased GSH levels, as well as increased activity of superoxide dismutase SOD and catalase CAT in mice brains.
Apart from this, naringin decrease ROS level and nitrogen species resulting in inhibition of nitrosative processes and lipid peroxidation Ben-Azu et al. Naringenin is a major flavonoid of grapefruit, whose antidepressant activity has been reported, it increase NE, 5-HT, and BDNF levels and glucocorticoid receptors Yi et al.
Apart from flavonoids, other phenolic compounds are also reported for their antidepressant effects. Bis-eugenol showed antidepressant effect due to synthesis of 5-HT and participation of dopamine DA receptors do Amaral et al.
In depression models, magnolol from Magnolia officinalis bark altered brain BDNF level as well as serotonergic, noradrenergic and dopaminergic neurotransmission Li et al. Among coumarins related compounds, scopoletin by affecting DA D1, D2, and 5-HT2a receptors and α1 and α2 adrenoceptors and psoralen by altering HPA axis demonstrated antidepressant effect in animal depression models Capra et al.
Among the phenolic acids related compounds, the antidepressant like effects of paeoniflorin, galic acids, eugenol, freulic acid and ascorbic acid have been reported previously. Paeoniflorin from Paeonia lactiflora root ancient Chinese antidepressant demonstrated antidepressant effect by affecting HPA axis and by up-regulation of serotonergic system Qiu et al.
Gallic acid decreased plasma nitrite, corticosterone and malondialdehyde levels as well as prevented MAO-A activity induced by stress Chhillar and Dhingra, Eugenol showed antidepressant like effects by increasing hippocampal BDNF level and inhibiting MAO-A and MAO-B effects Irie, Ferulic acid showed antidepressant effects by interaction with 5-HT1a and 5-HT2a receptors Zeni et al.
Another phenolic compound is curcumin, showed antidepressant effects by elevation of BDNF and brain monoamine levels, reduction of pro-inflammatory cytokines and prevention of MAO-A and MAO-B activities Jiang et al. Alkaloids are nitrogenous pharmacologically active secondary plant metabolites having diverse chemical structures and obtained from crude acid-base extracts Perviz et al.
The anti-inflammatory tranquilizer and antiarthritic potential of isoquinoline alkaloids, morphine and colchicine respectively have been demonstrated previously Lopes et al. The antidepressants effects of Annona cherimola extract containing number of alkaloids including liriodenine, anonaine, nornuciferine and 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-3,8,9,tetraol, have been reported in mice FST.
These alkaloids have been suggested to increase 5-HT and DA Martínez-Vázquez et al. The dose dependent antidepressant effects of β-carbolines derivatives such as harmane, norharmane and harmine have been reported previously Farzin and Mansouri, The antidepressants effects of harmine has been compared with imipramine at different doses for 14 days in rats using FST, BDNF protein levels were increased by harmine in the hippocampus of rats while imipramine did not increase BDNF protein levels, reflecting that antidepressant effect is due to rise in hippocampal BDNF level Fortunato et al.
One study reported that harman infusion increases 5-HT concentration and decreases degradation of 5-HT metabolite levels due to MAO-A inhibition Baum et al. Another study suggested that harmane injection increase plasma concentration of corticosterone, adrenocorticotrophic hormone ACTH , noradrenaline NA and 5-hydroxytryptamine 5-HT in the structures of limbic system, suggesting that harman can modulate brain neurochemistry, behavioral alterations and neuroendocrine functions by inhibiting MAO-A Smith et al.
The alkaloid fractions of Rhazya stricta extract containing rhaziminine, akuammidine, and tetrahydrosecamine inhibited MAO-B enzyme after oral administration to male rats for 21 days, which is responsible for antidepressant-like effect Ali et al.
Napelline, hypaconitine, songorine, and mesaconitine are diterpene alkaloids of Aconitum baicalense which have shown antidepressant effects in animals depression model by improving the activity serotonergic system Perviz et al.
Mitragynine is Mitragyna speciosa alkaloid, whose antidepressant effects have been shown on TST and FST in mice, where it reduced immobility time Idayu et al. Apart from this, piperine on FST and protopine on TST showed antidepressant effects which may be due serotonergic mechanism Wattanathorn et al.
The antidepressant potentials of alkaloids have been clearly demonstrated in various preclinical studies but more studies are required to further evaluate their efficacy, potency and safety.
Saponins are secondary metabolites of plants and mostly found in glycosilated forms Ayaz et al. Saponins contain one to three sugar chains which may be straight or branched and usually composed of d-glucose, d-galactose, d-glucuronic acid, l-rhamnose, l-arabinose, d -fucose or d-xylose Vincken et al.
Sapogenins are generally classified into triterpenoidal with 4—5 rings skeleton and steroidal with 5—6 rings backbone groups. The antidepressant effect of bacopaside I from Bacopa monniera in various animal models has reported Liu et al. Ginsenosides from ginseng and intestinal metabolite of ginseng, 20 S -protopanaxadiol demonstrated antidepressant effects by enhancing brain monoamine levels, HPA axis, BDNF signaling pathway and hippocampal neurogenesis Xu et al.
Glycyrrhizin is a triterpene saponin, exhibit antidepressant effect due to participation of α1 adrenoceptor and DA D2 receptor Dhingra and Sharma, Hederagenin of Akebia quinata , showed antidepressant effect by HPA axis modulation Jin et al.
Sarsasapogenin from Anemarrhena asphodeloides possess antidepressant activity by preventing MAO-A and MAO-B activities and increasing NE and 5-HT levels of the hippocampus and hypothalamus Ren et al.
The chemical structure of plant sterols, also called phytosterols is similar to the structure of cholesterol and mostly found in nuts, cereals, fruits and vegetables Ayaz et al. β-sitosterol, stigmasterol fucosterol, and campesterol are among the different identified types of sterols.
Sterols can cross blood brain barrier BBB to exert their effects on CNS due to their glycosylated forms and lipidic nature Tabata et al.
Trevisan et al. suggested that α-spinasterol exhibits antagonistic effects on transient potential receptors V1 TRPV1.
The activation of these receptors in various parts of brain may increase the release of glutamate, GABA, or other catecholamines Martins et al. The antidepressant effect of α-spinasterol in male mice subjected to FST, was verified by Socała and Wlaź Socała and Wlaź further suggested that α-spinasterol may activate CB1 receptors which in turn activate TRPV1 receptors simultaneously to inhibit their anxiolytic effects Socała and Wlaź, FIGURE 6.
Chemical structures of potential anti-depressant alkaloids, saponins and sterols. In mice brains, fucosterol prevented the reduction in the levels of NA, 5-HT and 5-HTIIA caused by stress of FST, suggesting that the antidepressant effects are due to increased monoamines and decreased metabolism rate of 5-HT.
Another study reported the antidepressants potential of α- and β-amyrin αβAMY isolated from the stem resin of Protium heptaphyllum on FST. Administration of αβAMY via p. o route at a dose of 2. Number of clinical studies have reported that polyphenols rich foods or dietary polyphenols intake play a significant role in the prevention and treatment of depression Godos et al.
A recent clinical trial in elderly Japanese demonstrated that higher consumption of green tea is associated with lower prevalence of depression Niu et al.
The anti-depressive potential of saffron has been reported to be similar to that of synthetic antidepressant drugs like imipramine and fluoxetine, without side effects Basti et al. It has been concluded in the meta-analysis review of clinical trials by Hausenblas that saffron supplementation can ameliorate symptoms of depression in adults having MDD Hausenblas et al.
Medicinal plants and their metabolites are being used for the management of various mental disorders. The phytochemicals are widely available, more tolerable and have fewer side effects as compared to synthetic drugs.
The phytochemicals with antidepressant activity include rosmanol, ursolic acid, oleanolic acid, linalool, carnosol, quercetin, fisetin, naringenin, baicalin, genistein, harmine, mitragynine, piperine, protopine, beta sitosterol, fucosterol, alpha spinnasterol, alpha amirine and beta amirine belonging to different chemical classes such as terpenes and terpenoids, saponins and sapogenins, sterols, alkaloids, polyphenols, amines and carbohydrates.
Among them, the most studied phytochemicals in animal depression models are berberine, piperine, curcumin, naringenin, ascorbic acid, and ginsenosides. The antidepressant activity of these phytochemicals seems to be associated with various mechanisms that include activation of tyrosine hydroxylase enzymes, inhibition of alteration of MAO-A and MAO-B, alteration in brain monoamine levels and receptors, prevention of reactive oxygen species ROS and NO synthesis, involvement of D1, D2, 5-HT1A, 5-HT2A, GABAA receptors and α1, α2, β-adrenoceptors, CREB cyclic adenosine monophosphate response element-binding protein , l-arginine-NO-cGMP pathway, and BDNF signaling pathway.
All these mechanisms involves differentiation and inhibition of neuronal cell apoptosis and promotion of neuronal cell survival.
Numerous phytochemicals have been reported for their antidepressant activity but only few of them have subjected into clinical trials. Unfortunately, very few clinical trials have demonstrated antidepressant effects of phytochemicals including clinical study of curcumin in human and hence further randomized and placebo-controlled clinical trials are needed to confirm their antidepressant potential of these phytochemicals.
Further research studies are also needed to investigate their antidepressant mechanisms and to develop cost effective formulations for the treatment of depression.
AK, RG, and MA conceptualized the project. AK, RG, JB, JŽ, MA, AN, SH, and SB collected data, analyzed, wrote the manuscript and prepared the figures. SA revised the manuscript including the clinical aspects, prepared Figures 1 , 2 , revised the table and the mechanism part.
All authors read and approved the manuscript for publishing. The authors wish to thank to University of Oradea, Oradea, Romania for financial support in publishing this paper. The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Food and Drug Administration; SERT, serotonin transporters; FST, forced swimming test; GANP, gallic acid loaded chitosan nanoparticles; MAO, monoamine oxidase; MDD, major depressive disorder; MEM, mitochondrial membrane; NET, norepinephrine reuptake transporters; NMDA, N-methyl D-aspartate; NO, nitric oxide; SERT, serotonin reuptake transporters; SLNs, solid lipid nanoparticles; SNP, single nucleotide polymorphism; SNRIs, Serotonin and norepinephrine reuptake inhibitors; SPT, Standard Penetration Test; SSRIs, Selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TrkB, tropomyosin kinase B receptor; TST, tail suspension test.
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Editor-in-Chief: Liang Cheng College of Bioinformatics Wound healing research and Technology Harbin Medical University Harbin Anti-depreasant China. ISSN Antii-depressant : Wound healing research Online : Wound healing research DOI: Background: Many studies catedhins suggested that tea Anti-depressant catechins antidepressant Pomegranate vinegar uses however, the underlying mechanism is not fully studied. As the main anti-inflammatory polyphenol in tea, catechin may contribute to the protective role of tea against depression. Objective: The objective of this study is to prove that catechin can protect against lipopolysaccharide LPS -induced depressive-like behaviours in mice, and then explore the underlying molecular mechanisms. Elevated Plus Maze EPMTail Suspension Test TSTand Open Field Test OFT were employed to assess depressive- like behaviours in mice.
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