Identification of antidepressant constituents from Xiangfu-chuanxiong herbal medicine pair via spectrum-effect relationship analyses, molecular docking and corticosterone-induced PC12 cells.

Herbal medicine pair, composed of two single herbs, is a relatively fixed minimum prescription unit in the traditional Chinese medicine's formula and has special significance in clinic. The combination of Xiangfu (the rhizoma of Cyperus rotundus L, XF) and Chuanxiong (the rhizoma of Ligusticum chuanxiong Hort, CX) has been recoded as an herbal medicine pair XF-CX in the Yuan Dynasty (1347 CE) of China and widely used in traditional Chinese medicine formula, including Chaihu Shugan San, which has been clinically used for treatment of depression. However, the optimal ratio of the XF-CX herbal medicine pair and its antidepressant constituents are still unclear. Herein, the antidepressive-like effects of XF-CX herbal medicine pairs with different ratios of XF and CX (2:1, 1:1, 1:2) were evaluated using behavioral despair animal models in mice, and then its potential antidepressant constituents were recognized by spectrum-effect relationship analyses. Finally, the potential antidepressant constituents of the XF-CX herbal medicine pair were validated by molecular docking with glucocorticoid receptor and corticosterone (CORT)-induced PC12 cell injury model. The results indicated that different ratios of XF-CX pairs had antidepressive-like effects, and the XF-CX (2:1) exhibited a more significant effect. Thirty-two potential antidepressant constituents in the XF-CX herbal medicine pair were screened out from the spectrum-effect relationship combined molecular docking analyses. Among them, senkyunolide A, cyperotundone, Z-ligustilide, and levistilide A were validated to have protective effects against CORT-induced injury in PC12 cells. Our findings not only obtained the optimal ratio of XF-CX in the herbal medicine pair for the treatment of depression but also its potential antidepressant constituents, which will benefit in elucidating the mechanism of action and promoting the application of the herbal medicine pair in the clinic.

The role of TrkB signaling-mediated synaptic plasticity in the antidepressant properties of catalpol, the main active compound of Rehmannia glutinosa Libosch.

ETHNOPHARMACOLOGICAL RELEVANCE: Rehmannia glutinosa Libosch. (RGL) is a famous ethnic medicine contained in antidepressant Chinese medicine formulas and is traditionally clinically used for depression. We have recently confirmed that RGL enhanced synaptic plasticity in a mouse model of Chinese medical syndrome and that catalpol may be the representatively pharmacological component responsible for its improvement in synaptic plasticity and treatment of depression. Impaired synaptic plasticity is closely linked to major depression. Tyrosine kinase receptor B (TrkB) signaling has recently been discovered as a key pathway for synaptic plasticity improvement and antidepressant discovery. However, to date, it is unknown whether the target of catalpol to improve synaptic plasticity involves TrkB and whether its antidepressant mechanism involves synaptic plasticity mediated by TrkB signaling. AIM OF STUDY: This study aims to elucidate the potential antidepressant target and mechanisms of catalpol, the main active compound of RGL, through TrkB signaling-mediated synaptic plasticity. MATERIALS AND METHODS: We have recently predicted through molecular networking strategy (including network pharmacology, molecular docking, and molecular dynamics simulation) that catalpol may exert its antidepressant effects by regulating TrkB signaling and thus modulating essential synaptic plasticity proteins. Then, this study used classic behavioral tests, targeted diagnostic reagents, Nissl and Golgi staining, immunohistochemical analysis, immunofluorescence analysis, Western blot, enzyme-linked immunosorbent assay, and Real-time PCR to confirm the potential target and signaling of catalpol to improve synaptic plasticity for the treatment of depression. RESULTS: The data showed that catalpol could improve synaptic plasticity and depressive behaviors, and its action pathway was predicted to involve TrkB signaling. Subsequently, the blockade of TrkB abolished the improvement of synaptic plasticity by catalpol and its antidepressant properties, which validated that TrkB signaling was the key pathway for catalpol to improve synaptic plasticity and exert antidepressant properties. Inhibition of COX-2 was likely to be a necessary facilitator for the antidepressant efficacy of catalpol via the TrkB target and TrkB-mediated synaptic plasticity. CONCLUSION: TrkB signaling-mediated synaptic plasticity plays a key role in the antidepressant properties of catalpol. This study provides critical information for the development of new and targeted antidepressant therapies or treatment strategies by catalpol. However, considering the existence of sex differences in depression (female depression is 2-3 times than that of males) and not exploring the antidepressant sex specificity of catalpol is a limitation, we will investigate the sex specificity of the antidepressant effects and molecular mechanisms of catalpol on sex-specific animals in the future to provide a preclinical basis for more accurate and targeted medication of catalpol.

Alleviating depressive-like behavior in DSS-induced colitis mice: Exploring naringin and poncirin from Poncirus trifoliata extracts.

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), often have concomitant mental disorders such as depression and anxiety. Therefore, a bidirectional approach involving the gut and brain axes is necessary for the prevention and treatment thereof. In this study, we explored the potential of Poncirus trifoliata extract (PT), traditionally known for its neuroprotective effects against gastrointestinal diseases, as a natural treatment agent for IBD in a dextran sulfate sodium (DSS)-induced colitis model. Oral administration of PT ameliorated weight loss and inflammatory responses in mice with DSS-induced colitis. Furthermore, PT treatment effectively restored the colon length and ameliorated enterocyte death by inhibiting DSS-induced reactive oxygen species (ROS)-mediated necroptosis. The main bioactive components of PT, poncirin and naringin, confirmed using ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-qTOF), can be utilized to regulate necroptosis. The antidepressant-like effects of PT were confirmed using open field test (OFT) and tail suspension test (TST). PT treatment also restored vascular endothelial cell integrity in the hippocampus. In the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) regions of the hippocampus, PT controlled the neuroinflammatory responses of proliferated microglia. In conclusion, PT, which contains high levels of poncirin and naringin, has potential as a bidirectional therapeutic agent that can simultaneously improve IBD-associated intestinal and mental disorders.

Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.

St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.

Ameliorative effect of Gastrodia elata Blume extracts on depression in zebrafish and cellular models through modulating reticulon 4 receptors and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (G. elata), a traditional Chinese herb, known as "Tian Ma", is widely used as a common medicine and diet ingredient for treating or preventing neurological disorders for thousands of years in China. However, the anti-depressant effect of G. elata and the underlying mechanism have not been fully evaluated. AIM OF THE STUDY: The study is aimed to investigate the anti-depressant effect and the molecular mechanism of G. elata in vitro and in vivo using PC12 cells and zebrafish model, respectively. MATERIAL AND METHODS: Network pharmacology was performed to explore the potential active ingredients and action targets of G. elata Blume extracts (GBE) against depression. The cell viability and proliferation were determined by MTT and EdU assay, respectively. TUNEL assay was used to examine the anti-apoptotic effect of GBE. Immunofluorescence and Western blot were used to detect the protein expression level. In addition, novel tank diving test was used to investigate the anti-depressant effect in zebrafish depression model. RT-PCR was used to analyze the mRNA expression levels of genes. RESULTS: G. elata against depression on the reticulon 4 receptors (RTN4R) and apoptosis-related targets, which were predicted by network pharmacology. Furthermore, GBE enhanced cell viability and inhibited the apoptosis in PC12 cells against CORT treatment. GBE relieved depression-like symptoms in adult zebrafish, included increase of exploratory behavior and regulation of depression related genes. Mechanism studies showed that the GBE inhibited the expression of RTN4R-related and apoptosis-related genes. CONCLUSION: Our studies show the ameliorative effect of G. elata against depression. The mechanism may be associated with the inhibition of RTN4R-related and apoptosis pathways.

The association study of chemical compositions and their pharmacological effects of Cyperi Rhizoma (Xiangfu), a potential traditional Chinese medicine for treating depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyperi Rhizoma (CR) derives from the rhizome or tuber of Cyperus rotundus L. of Cyperaceae. It is an herbal medicine which has been widely used in different healthcare systems like in China, India, Iran, and Japan. In Chinese medicine, CR could promote the flow of Qi in the Liver and Sanjiao channels, regulate menstruation and alleviate pain. Clinically, CR is used for depression, flatulence, hypochondriac pain, and dysmenorrhea. Thus, it has a long history and significant curative effect for the treatment of various Qi stagnation symptoms. AIM OF THIS REVIEW: This review focuses on explaining the major antidepressant mechanisms of CR, and assessing the shortcomings of existing work. Besides, clinical applications, pharmacological effects and their corresponding chemical compositions and quality control of CR have been researched. MATERIALS AND METHODS: The search terms "Cyperus rotundus L." was used to obtain the literatures from electronic databases such as Web of Science, ScienceDirect, PubMed, and China National Knowledge Infrastructure (CNKI). The information provided in this review to illustrate material basis of CR were only limited to papers which reported on the chemical compositions and pharmacological effects simultaneously. RESULT: The study showed that CR has significant application in Qi stagnation, like depressed liver, stomach, and bowel disorders, etc. in different countries or districts. Aqueous extract, EtOH extract, essential oil, total oligomeric flavonoids and five other extracts were effective constituents displaying pharmacological activities such as antibacterial, antioxidant, neuroprotective, antihemolytic, and anti-inflammatory effect. 41 kinds of specific components like α-cyperone, nootkatone exhibited corresponding pharmacological activities mentioned above. Different concentrations of ethanol extract, essential oil, decoction of CR and monomer composition like α-cyperone, rotunduside G had anti-depressant effects. CONCLUSIONS: In the present study, we have provided scientific information and research developments on traditional uses, phytochemical compositions and corresponding pharmacological activities, and quality control status on CR. The antidepression effect and its corresponding chemical compositions were generalized separately. The pharmacological activities studies should be more focused on the reflection of traditional clinical values. CR could be a significant potential herbal medicine to develop antidepressant drugs with lower side effects.

An acute dose-ranging evaluation of the antidepressant properties of Sceletium tortuosum (Zembrin®) versus escitalopram in the Flinders Sensitive Line rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. AIM OF THE STUDY: To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. MATERIALS AND METHODS: The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. RESULTS: Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. CONCLUSIONS: Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST, as assessed in FSL rats. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.

Antidepressant- and anxiolytic-like activities of Rosmarinus officinalis extract in rodent models: Involvement of oxytocinergic system.

BACKGROUND: Oxytocin (OXT), a neuropeptide involved in mammal reproductive and prosocial behaviors, has been reported to interact with various stressor-provoked neurobiological changes, including neuroendocrine, neurotransmitter, and inflammatory processes. In view of disturbances in psychosocial relationships due to social isolation and physical distancing measures amid the COVID-19 pandemic, being one of the triggering factors for the recent rise in depression and anxiety, OXT is a potential candidate for a new antidepressant. METHODS: In this present study, we have aimed to investigate the effects of oral administration of Rosmarinus officinalis extract (RE), extracted from distillation residue of rosemary essential oil, on central OXT level in the context of other stress biomarkers and neurotransmitter levels in mice models. Tail suspension test (TST) and elevated plus maze test (EPMT) following LPS injection were employed to assess depressive- and anxiety-like behavior in mice, respectively. FINDINGS: Pretreatment with RE for seven days significantly improved behavior in TST and EPMT. Whole-genome microarray analysis reveals that RE significantly reversed TST stress-induced alterations in gene expressions related to oxytocinergic and neurotransmitter pathways and inflammatory processes. In both models, RE significantly increased central Oxt and Oxtr expressions, as well as OXT protein levels. RE also significantly attenuated stress-induced changes in serum corticosterone, brain and serum BDNF levels, and brain neurotransmitters levels in both models. INTERPRETATION: Altogether, our study is the first to report antidepressant- and anxiolytic-like activities of RE through modulating oxytocinergic system in mice brain and thus highlights the prospects of RE in the treatment of depressive disorders of psychosocial nature.

Antidepressant and anxiolytic compounds isolated from Salvia elegans interact with serotonergic drugs.

Salvia elegans belongs to a genus plants with biological activities in central nervous system. In this work, the purpose was to evaluate the anxiolytic and antidepressant effects of fractions and compounds isolated from S. elegans and its interaction with serotoninergic drugs by using behavioral tests in mice. Fractions from aerial parts of S. elegans were obtained by column chromatography, SeF1, SeF2, SeF3, and SeF4. Each of them was administered to 25 mg/k in ICR mice subject to forced swimming test (FST), or elevated plus maze test (EPM), or open field test (OFT). The most active fractions were chemically separated until compounds, which were analyzed as anxiolytic or antidepressant and the coadministration of these treatments with 5-HT1A and 5-HT2 drugs was measured in the different biological tests. All fractions were anxiolytic and antidepressant, oleanolic acid (OA) was found in SeF2, and from SeF3, a mixture of terpenes was found; a GC-MS analysis confirmed the presence of two main compounds: rosifoliol and agaraspirol (TM, mixture of terpenes). TM (doses-response curve, 0.01, 0.1, 0.5, 1.0, and 2.0 mg/kg) and OA (5 mg/kg) were also evaluated demonstrating an antidepressant and anxiolytic effect, respectively. The combination of TM (0.5 mg/kg) with 8-OH (selective 5-HT1A receptor agonist) induced an increment of antidepressant activity, while with the antagonist WAY-100635, the effect diminished. But with DOI (5-HT1c/5-HT2 receptor agonist), there was no change, and with KET (5-HT2 receptor antagonist), the activity was increased. When OA is co-administered with 8-OH or with DOI, the anxiolytic activity of this terpene, diminished; but with the combination with antagonists, the effect of OA shows no change. TM and OA were antidepressant and anxiolytic, respectively, on mice exposed to different tests, and these are able to interact with serotoninergic drugs.

Antidepressant effects of total iridoids of Valeriana jatamansi via the intestinal flora-blood-brain barrier pathway.

CONTEXT: Valeriana jatamansi Jones [syn. V. wallichii DC, (Valerianaceae)] (VJJ) is used to treat depression. OBJECTIVE: To explore the effects of total iridoids of VJJ extract (TIV) on chronic unpredictable mild stress (CUMS) in mice. MATERIALS AND METHODS: VJJ roots and rhizomes were extracted with 70% ethanol. CUMS rats were treated daily with fluoxetine (2.6 mg/kg, i.g.) or TIV (5.7, 11.4, and 22.8 mg/kg, i.g.) for 14 days. Male Kun Ming mice on normal chow and 0.5% CMC-Na solution were used as a control. Behavioural tests included the tail suspension (TST) and sucrose preference tests (SPT). Evans blue staining was used to evaluate blood-brain barrier (BBB) permeability. Western blotting was used to measure zonula occludens-1 (ZO-1) and occludin expression. 16S rRNA sequencing was used to analyse intestinal flora abundance. Tax4Fun was used to predict KEGG metabolic pathways. RESULTS: TIV treatment reduced TST time (117.35 ± 8.23 or 108.95 ± 6.76 vs. 144.45 ± 10.30 s), increased SPT (55.83 ± 7.24 or 53.12 ± 13.85 vs. 38.98 ± 5.43%), increased the abundance of phylum Firmicutes (86.99 ± 0.03 vs. 60.88 ± 0.19%) and genus Lactobacillus (75.20 ± 0.19 vs. 62.10 ± 0.13%), reduced the abundance of phylum Bacteroidetes (6.69 ± 0.06 or 11.50 ± 0.09 vs. 25.07 ± 0.20%). TIV increased carbohydrate metabolism (14.50 ± 3.00 × 10-3 or 14.60 ± 2.00 × 10-3 or 14.90 ± 2.00 × 10-3 vs.13.80 ± 4.00 × 10-3%), replication and repair functions (5.60 ± 1.00 × 10-3 or 5.60 ± 1.00 × 10-3 vs. 5.10 ± 4.00 × 10-3%), reduced the frequency of infectious disease (1.60 ± 2.00 × 10-4 or 1.90 ± 5.00 × 10-4 or 1.80 ± 3.00 × 10-4 vs. 2.20 ± 7.00 × 10-3%), BBB permeability (0.77 ± 0.30 vs. 1.81 ± 0.33 µg/g), and up-regulated the expression of ZO-1 (1.42-fold, 1.60-fold, 1.71-fold) and occludin (1.79-fold, 2.20-fold). CONCLUSIONS: TIV may modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect.

Novel antidepressant mechanism of ginsenoside Rg1: Regulating biosynthesis and degradation of connexin43.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer is a valuable medicinal herb and "alternative" remedy for the prevention and treatment of depression. Dysfunction of connexin43 (Cx43)-gap junction in astrocytes is predisposed to the precipitation of depression. Ginsenoside Rg1 (Rg1), the main bioactive constituent extracted from ginseng, is efficacious in the management of depression by upregulating the content of Cx43. Our previous results indicated that pretreatment with Rg1 significantly improved Cx43-gap junction in corticosterone (CORT)-treated astrocytes. However, the antidepressant mechanism underlying how Rg1 upregulates Cx43-gap junction in astrocytes hasn't been proposed. AIM OF THE STUDY: To dissect the mechanisms of Rg1 controlling Cx43 levels in primary astrocytes. METHODS: We examined the changes of the level of Cx43 mRNA, the degradation of Cx43, as well as the ubiquitin-proteasomal and autophagy-lysosomal degradation pathways of Cx43 followed by Rg1 prior to CORT in rat primary astrocytes isolated from prefrontal cortex and hippocampus. Furthermore, the recognized method of scrape loading/dye transfer was performed to detect Cx43-gap junctional function, an essencial indicator of the antidepressant effect. RESULTS: Pretreatment with Rg1 could reverse CORT-induced downregulation of Cx43 biosynthesis, acceleration of Cx43 degradation, and upregulation of two Cx43 degradation pathways in primary astrocytes. CONCLUSION: The findings in the present study provide the first evidence highlighting that Rg1 increases Cx43 protein levels through the upregulation of Cx43 mRNA and downregulation of Cx43 degradation, which may be attributed to the effect of Rg1 on the ubiquitin-proteasomal and autophagy-lysosomal degradation pathways of Cx43.

Determination of 13 antidepressants in blood by UPLC-MS/MS with supported liquid extraction pretreatment.

Antidepressants are widely used nowadays. Due to the potential detrimental consequences and involvement in forensic cases, therapeutic drug monitoring of antidepressants is desired. Herein we report a method for sensitive determination of 13 commonly used antidepressants in blood. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method with supported liquid extraction (SLE) was developed for analysis of imipramine, desipramine, fluoxetine, norfluoxetine, paroxetine, maprotiline, sertraline, citalopram, clomipramine, trazodone, doxepin, clozapine and amitriptyline in this study. The limits of detection (LODs) are in the range of 0.0003-0.003 ng/mL, which are lower than other reported methods by several orders of magnitude. The linear ranges are 0.01-200 ng/mL for norfluoxetine, paroxetine and doxepin, while the linear ranges are 0.001-200 ng/mL for the rest antidepressants. The correlation coefficients are over 0.99. Extraction recoveries (ER) ranging in 82.4-101.5% were obtained for the target analytes. The intra-day relative standard deviations (RSDs) range in 4.5-10.3% and inter-day RSDs range in 5.1-12.7%. Reasonable values of matrix effect (ME) ranging in 82.5-110.4% were obtained for quality control samples. The present methodology was used for the analysis of antidepressants in real cases and is expected to have a wide usage for analysis of antidepressants in biomedical area and forensic practice.

Exposure to noise augments behavioral deficits in mice: Protective effect of banana peel extract.

The study is aimed to evaluate the protective impact of banana peel extract (BPE) following noise induce behavioral deficits in male mice. Animals were separated into two groups (control and test, 12 in each). Control mice were given drinking water, at the same time test group was given BPE (400 mg/kg; oral administration). Animals have received their respective treatment for 14 days. Mice were subdivided (n=6) into unstressed and stressed groups on day 15. Noise stress was given to the respective group for 4-h. Behavioral activities were monitored 24-h after the 4-h noise stress. Forced-swim-test, Elevated-plus-maze and light-dark-activity-box tests were performed for depression/anxiety-like behaviors respectively. Morris-water-maze assessment was used for memory. After behavioral tests animals were sacrificed and brain was detached for biochemical estimations and histopathological studies. In the present study, BPE produced anxiolytic and antidepressant-like effects and enhanced memory. Activity of antioxidant enzymes increased while levels of AChE and MDA decreased in BPE treated animals. Histopathological alterations induced by noise stress were also normalized by BPE. It is concluded that supplementation/administration of banana peel has preventive effects against anxiety, depression and memory impairment via its strong antioxidant potential following NS.

Water extract of Armillaria mellea (Vahl) P. Kumm. Alleviates the depression-like behaviors in acute- and chronic mild stress-induced rodent models via anti-inflammatory action.

ETHNOPHARMACOLOGY RELEVANCE: Armillaria mellea (Vahl) P. Kumm. (AM) is an edible mushroom that has been reported as treatment for several neurological disorders, such as dizziness and epilepsy in Asia. Importantly, AM shares a symbiotic relationship with Gastrodia elata Blume (GE), a medicinal herb with antidepressant-like properties. Researchers believe that AM may possess pharmacological properties similar to GE due to their symbiosis, however, few studies have investigated the pharmacological effect of AM. AIM OF THE STUDY: The aim of this study was to explore the potential of AM as an antidepressant in forced-swimming test (FST) and unpredictable chronic mild stress (UCMS) rodent models and investigate its possible underlying mechanism. MATERIALS AND METHODS: Rats were orally administrated with 250, 500, and 1000 mg/kg body weight (bw) water extract of AM (WAM) for 28 and 35 consecutive days prior to the FST and UCMS protocols, respectively. The cerebral serotonin (5-HT) and the metabolites in the frontal cortex of rats were measured. The brain was dissected and the blood was collected to investigate the levels of inflammatory-related signaling pathway. RESULTS: All doses of WAM reduced the immobility time in the FST without disturbing autonomic locomotion. All doses of WAM prevented stress-induced abnormal behaviors in the UCMS model, including decreased sucrose preference and hypoactivity. 500 and 1000 mg/kg bw WAM attenuated the stress-induced increases in IL-1ß and TNF-α in the serum and cerebrum. 1000 mg/kg bw WAM alleviated brain inflammation by reducing the protein expression of ionized calcium binding adaptor molecule 1. CONCLUSION: WAM exhibited acute and chronic antidepressant-like effects, and may result from the anti-inflammatory actions. Therefore, the development of AM as a dietary therapy or adjuvant for depression treatment should be considered.

Integrated network pharmacology and metabolomics to dissect the combination mechanisms of Bupleurum chinense DC-Paeonia lactiflora Pall herb pair for treating depression.

ETHNOPHARMACOLOGICAL RELEVANCE: The compatibility of Bupleurum chinense DC (Chaihu)-Paeonia lactiflora Pall (Baishao) is one of the most accepted herb pairs in traditional Chinese medicine (TCM) prescriptions for treating depression. However, the combination mechanisms of this herb pair for anti-depression remain unclear. MATERIALS AND METHODS: In this study, the combined effect of Chaihu-Baishao was evaluated by the chronic unpredictable mild stress (CUMS) rat model. Secondly, network pharmacology was constructed to dissect the united mechanisms. Based on the results of network pharmacology analysis, plasma metabolomics based on ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was performed to discover the collaborative effect on metabolite regulation. Furthermore, the targets from network pharmacology and the metabolites from metabolomics were jointly analyzed to select crucial metabolism pathways by MetaScape. Finally, the key metabolic enzymes and metabolites were experimentally validated by ELISA. RESULTS: The antidepressant effect of Chaihu-Baishao herb pair was significantly better than Chaihu or Baishao in sucrose preference test (SPT), open-field test (OFT), and forced swim test (FST). In network pharmacology, herb pair played synergetic effect through regulating shared pathways, such as MAPK signaling pathway and arachidonic acid metabolism, etc. Besides, by metabolomics, the herb pair improved more metabolites (14) than a single herb (10 & 9) and has a stronger regulation effect on metabolites. Correspondingly, herb pair adjusted more metabolism pathways (5) than individual herb (4 & 4). Furthermore, the arachidonic acid metabolism was selected as crucial metabolism pathways by a joint analysis of 199 targets and 14 metabolites. The results showed that herb pair regulated arachidonic acid metabolism by synergetic reducing the level of arachidonic acid, and inhibiting the enzyme activity of prostaglandin-endoperoxide synthase 1 (PTGS1) and prostaglandin-endoperoxide synthase 2 (PTGS2). CONCLUSIONS: This work provided an integrated strategy for revealing the combination mechanisms of Chaihu-Baishao herb pair for treating depression, and also a rational way for clarifying the composition rules of TCM.

Anti-depressant effect of Zhi-zi-chi decoction on CUMS mice and elucidation of its signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-zi-chi decoction (ZZCD) is used for treating depression as an effectively traditional Chinese medicine. Until now, studies on pharmacological research of ZZCD have mostly been centered in pharmacokinetic level. Little was known about its pharmacological mechanism of relieving depression. AIM OF THE STUDY: This study was to evaluate the effect of ZZCD on relieving depression via behavioral tests, serum metabolomics and signaling target expression analysis on chronic unpredictable mild stress (CUMS) model mice. MATERIALS AND METHODS: The CUMS exposure lasted 7 consecutive weeks. The mice were administrated with ZZCD for the last 3 weeks. Behavioral tests were applied and a serum metabolomics method based on UFLC/Q-TOF-MS with multivariate statistical and global metabolic network analysis was performed to identify relevant metabolites and pathways. Finally, the protein expressions in mouse hippocampi were determined by western blot to verify the metabolomics deduction. RESULTS: Behavioral parameters were visibly changed after modeling, while high and medium dosage groups showed status improvement compared to the model group. Seventy six metabolites were identified as potential biomarkers from the metabolomics profiles in C18 and HILIC systems. In addition, 9 significant pathways related to changed biomarkers were conducted. The pathways were closely connected by some key targets, which were significantly reduced in the model group compared with those in control group, while ZZCD treated groups showed corrections after 3-week administration. The results revealed that the anti-depression efficacy of ZZCD might be associated with PKA-CREB-BDNF-TrkB-PSD-95 pathway influenced by metabolic changes, verifying the pathway annotation speculation. CONCLUSION: This study demonstrated that ZZCD had a positive treatment effect on CUMS depression model mice. Metabolomics results revealed the holistic and interconnected metabolic changes of ZZCD in CUMS mice. The metabolic pathway annotation suggested that the anti-depression mechanism of ZZCD might be related to signaling pathway in brain. PKA-CREB-BDNF-TrkB-PSD-95 signaling expression was a verification and complement to the metabolomics results.

Calea zacatechichi Schltdl. (Compositae) produces anxiolytic- and antidepressant-like effects, and increases the hippocampal activity during REM sleep in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.

Iridoids from Gardeniae fructus ameliorates depression by enhancing synaptic plasticity via AMPA receptor-mTOR signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardeniae fructus is a traditional Chinese herb which exerts antidepressant effect. However, its effective constituent and potential mechanism are still unknown. AIM OF THE STUDY: To examine whether iridoids, a type of monoterpenoids from Gardeniae fructus (IGF), exerts antidepressant effect by enhancing synaptic plasticity via AMPA receptor-mTOR signaling. MATERIALS AND METHODS: The antidepressant effect of IGF (15 mg/kg; 30 mg/kg; 45 mg/kg) was investigated in spatial restraint stress (SRS)-induced mice. The expression levels of AMPA receptor-mTOR signaling and synaptic proteins were measured by Western blot, dendritic spine density was observed in Golgi staining. AMPA receptor (AMPAR) inhibitor NBQX and mTOR inhibitor Rapamycin were employed to determine the roles of AMPAR and mTOR signaling in IGF-induced antidepressant effects. RESULTS: After IGF administration, the expression of the AMPA glutamate receptor Glutamate Receptor 1 (GluA1) was inhibited in SRS mice. We also observed a trend toward the up-regulation of the mammalian target of Rapamycin (mTOR) protein kinase, p70 ribosomal protein S6K (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). The protein levels of Synapsin-1 and PSD-95 were decreased after SRS challenge, along with declined dendritic spine density, which were all reversed with IGF treatment. Furthermore, the treatment efficacy of IGF were blocked with AMPA receptor inhibitor NBQX or mTOR inhibitor Rapamycin. CONCLUSION: IGF exerted antidepressive-like effects by stimulating AMPAR-mTOR signaling regulated synaptic plasticity enhancement. This work provided an important basis for developing IGF and Gardeniae fructus as potential anti-depressants.

Effects of different drying methods on the chemical constituents of Lilium lancifolium Thunb. based on UHPLC-MS analysis and antidepressant activity of the main chemical component regaloside A.

The Lilium lancifolium Thunb. is a herb with multiple functions in both medicine and food in China, and its extracts have shown antidepressant effects. In this study, fresh bulbs of Lilium lancifolium Thunb. were processed to study the effects of different drying processes on changes in its main chemical components. We found that different drying methods can affect the chemical constituents of the herb. Among these components, Regaloside A has been found as the characteristic component. Here, Cell Counting Kit-8 assay, and Western blotting were used to evaluate the neuroprotective antidepressant effects of Regaloside A. The results showed the cell survival rate was improved, the phosphorylation levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphatidylinositol 3 kinase, protein kinase B, and mammalian target of rapamycin were increased after Regaloside A treatment. In general, different drying methods have a significant influence on the chemical composition of the herb, and Regaloside A may be the main chemical component of the herb. It can alleviate the damage of corticosterone in SH-SY5Y cells, and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling mediated by brain-derived neurotrophic factor/tyrosine kinase receptor B may play an important role in the neuroprotective antidepressant effects of Regaloside A.

Nine prenylated acylphloroglucinols with potential anti-depressive and hepatoprotective activities from Hypericum scabrum.

In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.