Inhaled Litsea glaucescens K. (Lauraceae) leaves' essential oil has anxiolytic and antidepressant-like activity in mice by BDNF pathway activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Litsea glaucescens K. (Lauraceae) is a small tree from the Mexican and Central American temperate forests, named as "Laurel". Its aromatic leaves are ordinarily consumed as condiments, but also are important in Mexican Traditional Medicine, and among the most important non wood forest products in this area. The leaves are currently used in a decoction for the relief of sadness by the Mazahua ethnic group. Interestingly, "Laurel" has a long history. It was named as "Ehecapahtli" (wind medicine) in pre-Columbian times and applied to heal maladies correlated to the Central Nervous System, among them depression, according to botanical texts written in the American Continent almost five centuries ago. AIM OF THE STUDY: Depression is the first cause of incapacity in the world, and society demands alternative treatments, including aromatherapy. We have previously demonstrated the antidepressant-like activity of L. glaucescens leaves' essential oil (LEO), as well as their monoterpenes linalool, and beta-pinene by intraperitoneal route in a mice behavioral model. Here we now examined if LEO and linalool exhibit this property and anxiolytic activity when administered to mice by inhalation. We also investigated if these effects occur by BDNF pathway activation in the brain. MATERIALS AND METHODS: The LEO was prepared by distillation with water steam and analyzed by gas chromatography-mass spectrometry (GC-MS). The monoterpenes linalool, eucalyptol and ß-pinene were identified and quantified. Antidepressant type properties were determined with the Forced Swim Test (FST) on mice previously exposed to LEO or linalool in an inhalation chamber. The spontaneous locomotor activity and the sedative effect were assessed with the Open Field Test (OFT), and the Exploratory Cylinder (EC), respectively. The anxiolytic properties were investigated with the Elevated Plus Maze Apparatus (EPM) and the Hole Board Test (HBT). All experiments were video documented. The mice were subjected to euthanasia, and the brain hippocampus and prefrontal cortex were dissected. RESULTS: The L. glaucescens essential oil (LEO) contains 31 compounds according to GC/MS, including eucalyptol, linalool and beta-pinene. The LEO has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene, as indicated by OFT and EC tests. The LEO and imipramine have antidepressant like activity in mice as revealed by the FST; however, linalool and ketamine treatments didn't modify the time of immobility. The BDNF was increased in FST in mice treated with LEO in both areas of the brain as revealed by Western blot; but did not decrease the level of corticosterone in plasma. The OFT indicated that LEO and imipramine didn't reduce the spontaneous motor activity, while linalool and ketamine caused a significant decrease. CONCLUSION: Here we report by the first time that L. glaucescens leaves essential oil has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene. This oil also maintains its antidepressant-like activity by this administration way, similarly to the previously determined intraperitoneally. Since inhalation is a common administration route for humans, our results suggest L. glaucescens essential oil deserve future investigation due to its potential application in aromatherapy.

The antidepressant-like effects of Danzhi Xiaoyao San and its active ingredients.

BACKGROUND: Depression is a severe mental illness that endangers human health. Depressed individuals are prone to sleep less and to the loss of appetite for food; their thinking and cognition processes, as well as mood, may even be affected. Danzhi Xiaoyao San (DXS), documented in the Internal Medicine Summary, has been used for hundreds of years in China and is widely applied traditionally to treat liver qi stagnation, liver and spleen blood deficiency, menstrual disorders, and spontaneous and night sweating. DXS can also clear heat and drain the liver. Presently, it is used frequently in the treatment of depression based on its ability to clear the liver and alleviate depression. PURPOSE: To summarize clinical and preclinical studies on the antidepressant-like effects of DXS, understand the material basis and mechanisms of these effects, and offer new suggestions and methods for the clinical treatment of depression. METHODS: "Danzhi Xiaoyao", "Danzhixiaoyao", "Xiaoyao", "depression" and active ingredients were entered as keywords in PubMed, Google Scholar, CNKI and WANFANG DATA databases in the search for material on DXS and its active ingredients. The PRISMA guidelines were followed in this review process. RESULTS: Per clinical reports, DXS has a therapeutic effect on patients with depression but few side effects. DXS and its active ingredients allegedly produce their neuroprotective antidepressant-like effects by modulating monoamine neurotransmitter levels, inhibiting the hypothalamic-pituitary-adrenal (HPA) axis hyperfunction, reducing neuroinflammation and increasing neurotrophic factors. CONCLUSION: Overall, DXS influences multiple potential mechanisms to exert its antidepressant-like effects thanks to its multicomponent character. Because depression is not caused by a single mechanism, probing the antidepressant-like effects of DXS could further help understand the pathogenesis of depression and discover new antidepressant drugs.

Hyperforin: A natural lead compound with multiple pharmacological activities.

Hypericum perforatum L. (Clusiaceae), commonly known as St. John's wort, has a rich historical background as one of the oldest and most widely studied herbal medicines. Hyperforin is the main antidepressant active ingredient of St. John's wort. In recent years, hyperforin has attached increasing attention due to its multiple pharmacological activities. In this review, the information on hyperforin was systematically summarized. Hyperforin is considered to be a lead compound with diverse pharmacological activities including anti-depression, anti-tumor, anti-dementia, anti-diabetes and others. It can be obtained by extraction and synthesis. Further pharmacological studies and more precise detection methods will help develop a value for hyperforin. In addition, structural modification and pharmaceutical preparation technology will be beneficial to promoting the research progress of hyperforin based innovative drugs. Although these works are full of known and unknown challenges, researchers are still expected to make hyperforin play a greater value.

Antidepressant activity of phytochemicals of Mangifera indica seeds assisted by integrated computational analysis.

Mangifera indica L., also known as mango, is a tropical fruit that belongs to the Anacardiaceae family and is prized for its juiciness, unique flavour, and worldwide popularity. The current study aimed to probe into antidepressant power (ADP) of MIS in animals and confirmation of ADP with in silico induced-fit molecular docking. The depression model was prepared by exposing mice to various stressors from 9:00 am to 2:00 pm during 42 days study period. MIS extract and fluoxetine were given daily for 30 min before exposing animals to stressors. ADP was evaluated by various behavioural tests and biochemical analysis. Results showed increased physical activity in mice under behavioural tests, plasma nitrite and malondialdehyde (MDA) levels and monoamine oxidase A (MAO-A) activity decreased dose-dependently in MIS treated mice and superoxide dismutases (SOD) levels increased in treated groups as compared to disease control. With the peculiar behaviour and significant interactions of the functional residues of target proteins with selected ligands along with the best absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, it is concluded that catechin could be the best MAO-A inhibitor at a binding energy of -8.85 kcal/mol, and two hydrogen bonds were generated with Cys406 (A) and Gly443 (A) residues of the active binding site of MAO-A enzyme. While catechin at -6.86 kcal/mol generated three hydrogen bonds with Ala263 (A) and Gly434 (A) residues of the active site of monoamine oxidase B (MAO-B) enzyme and stabilized the best conformation. Therefore, it is highly recommended to test the selected lead-like compound catechin in the laboratory with biological system analysis to confirm its activity as MAO-A and MAO-B inhibitors so it can be declared as one of the novel therapeutic options with anti-depressant activity. Our findings concluded that M. indica seeds could be a significant and alternative anti-depressant therapy.

Antidepressant Effect of Water Extract of Royal Sun Medicinal Mushroom, Agaricus brasiliensis (Agaricomycetes), in Mice Exposed to Chronic Unpredictable Mild Stress.

Our study aimed to investigate whether Agaricus brasiliensis water extract (AWE) possesses antidepressant activity. Depression as a result of chronic unpredictable mild stress (CUMS) was established in mice. The AWE group was administered 3.0 g/kg of AWE. The tail suspension test (TST) was conducted 1 h after the last administration. Then after fasting for 12 h, the mice were sacrificed by euthanasia and the brain and organs (liver, spleen, kidney, and thymus) were collected immediately. Biochemical indexes, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA), were analyzed with biochemical reagent kits. In addition, 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity, inhibition of hydroxyl radical activity, and total antioxidant capacity were used to evaluate the antioxidant activity of AWE. The organ index analysis indicated that AWE had no adverse effect on mice at feeding time. The results suggested that AWE administration could significantly shorten the immobility time of mice in the TST. Particularly, the levels of 5-HT and NE appeared to increase significantly (P < 0.05) after AWE administration. At the same time, in vitro antioxidant experiments also revealed that AWE displayed better antioxidant activity. Collectively, these results suggest that AWE possesses good antidepressant activity, and these effects may be mediated by enhancing monoamine neurotransmitter content in the brain or antioxidant capacity to improve depression.

Platycladus orientalis seed extract as a potential triple reuptake MAO inhibitor rescue depression phenotype through restoring monoamine neurotransmitters.

ETHNOPHARMACOLOGY RELEVANCE: Platycladus orientalis seeds are recorded in traditional Chinese medicine (TCM) formulations for modulation of mood and physical activity in "Shen Nong Ben Cao Jing" and "Compendium of Materia Medica" and so on. Recently, we identified its extracting components and looked for the potentials in treatment for depression by improving the function of monoamine neurotransmitters. AIM OF THE STUDY: We investigated the mechanism of action of the seed extracts of P. orientalis (S4) to rescue depressive behavior in a chronic, unpredicted, mild stress (CUMS)-induced model in rats. MATERIALS AND METHODS: We used ultra-fast liquid chromatography coupled with triple quadrupole-time of flight tandem mass spectrometry to analyze the chemical constituents in S4. An assay platform in zebrafish and molecular docking were used to analyze if S4 regulated rest/wake behavior and predict the biological targets which correlated with monoamine neurotransmitters. Depressive-behavior tests (body weight, sucrose preference test, tail-suspension test, forced-swimming test) were carried in the CUMS model. After behavior tests and killing, rat brains were separated into the hippocampus, frontier cortex and dorsal raphe nucleus. The main monoamine neurotransmitters and their metabolite concentrations in these three brain regions were measured by rapid resolution liquid chromatography coupled with triple quadrupole tandem mass spectrometry. RESULTS: Forty-one compounds were identified in S4, including fatty acids, terpenoids, amino acids, plant sterols and flavonoids. S4 could increase the total rest time and decrease the waking activity of zebrafish. S4 showed high correlation with adrenaline agonists, 5-hydroxytryptamine (5-HT) reuptake inhibitors and dopamine agonists. CUMS-group rats, compared with controls, had significantly decreased body weight and preference for sucrose water, whereas the immobility time in the tail-suspension test and forced-swimming test was increased. S4 could significantly rescue the increased levels of 5-HT, noradrenaline and dopamine in the prefrontal cortex and dorsal raphe nucleus. CONCLUSIONS: We demonstrated that S4 was a potential inhibitor of MAO reuptake that could rescue depression in a CUMS-model rats by restoring monoamine neurotransmitters in different encephalic regions.

Baihe Dihuang (Lilium Henryi Baker and Rehmannia Glutinosa) decoction attenuates somatostatin interneurons deficits in prefrontal cortex of depression via miRNA-144-3p mediated GABA synthesis and release.

ETHNOPHARMACOLOGICAL RELEVANCE: Baihe Dihuang Decoction is a well-known traditional Chinese medicine prescription (Also known as Lilium Henryi Baker and Rehmannia Glutinosa Decoction, LBRD) composed of Lilium Henryi Baker bulb and raw juice from Rehmannia Glutinosa (Gaertn) DC with the curative efficacy of nourishing yin and clearing heat based on the Chinese herbal medicine theory. It has been used as routine medication in treating depression combined with conventional western medicine in China for years. AIM OF THE STUDY: LBRD can attenuates GABAergic deficits in the medial prefrontal cortex (mPFC) of depression. This study aimed to investigate the mechanism of antidepressive properties of LBRD in the prefrontal GABAergic interneuron subtypes, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)-positive neuron. MATERIALS AND METHODS: In this project, chronic unpredicted mild stress paradigm was adopted to construct depression model. After treated with LBRD standard decoction and behaviors test, the level of GABA associated miRNA/mRNA and GABAergic subtype-specific markers were detected by qRT-PCR and Western blot. The lncRNAs/miRNAs/GABA regulatory axis was verified by luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and theses changes were measured in LBRD administration with the use of immunofluorescence staining and RNA-fluorescence in situ hybridization. RESULTS: In the current study, we found that LBRD exhibited high efficacy based on the results of behavioral tests. Meanwhile, LBRD also improved the reduced GABA levels in depression by increasing the expression of lncRNA Neat1 and Malat1, as well as decreasing miRNA-144-3p and miRNA-15b-5p. Moreover, the level of Sst mRNA and protein that were harvested from the mPFC tissues of depression group was significantly lower than those in the control mice. While, these changes can be reverted by LBRD standard decoction administration. Whereas, neither chronic stress nor treatment can change the level of PV and VIP mRNAs and protein expression. In the SST-positive neuron of mPFC tissues, treatment with LBRD standard decoction resulted in the elevation of Gad-67, VGAT, GAT-3 and a reduction of miRNA-144-3p expression. CONCLUSIONS: These findings suggested that LBRD antidepressant activities may be related to ameliorating the SST-positive neuron deficits via regulating the miRNA-144-3p mediated GABA synthesis and release.

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.

Emerging Role of Flavonoids as the Treatment of Depression.

Depression is one of the most frequently observed psychological disorders, affecting thoughts, feelings, behavior and a sense of well-being in person. As per the WHO, it is projected to be the primitive cause of various other diseases by 2030. Clinically, depression is treated by various types of synthetic medicines that have several limitations such as side-effects, slow-onset action, poor remission and response rates due to complicated pathophysiology involved with depression. Further, clinically, patients cannot be given the treatment unless it affects adversely the job or family. In addition, synthetic drugs are usually single targeted drugs. Unlike synthetic medicaments, there are many plants that have flavonoids and producing action on multiple molecular targets and exhibit anti-depressant action by affecting multiple neuronal transmissions or pathways such as noradrenergic, serotonergic, GABAnergic and dopaminergic; inhibition of monoamine oxidase and tropomyosin receptor kinase B; simultaneous increase in nerve growth and brain-derived neurotrophic factors. Such herbal drugs with flavonoids are likely to be useful in patients with sub-clinical depression. This review is an attempt to analyze pre-clinical studies, structural activity relationship and characteristics of reported isolated flavonoids, which may be considered for clinical trials for the development of therapeutically useful antidepressant.

Cynanchum auriculatum Royle ex Wight., Cynanchum bungei Decne. and Cynanchum wilfordii (Maxim.) Hemsl.: Current Research and Prospects.

Cynanchum auriculatum Royle ex Wight. (CA), Cynanchum bungei Decne. (CB) and Cynanchum wilfordii (Maxim.) Hemsl. (CW) are three close species belonging to the Asclepiadaceous family, and their dry roots as the bioactive part have been revealed to exhibit anti-tumor, neuroprotection, organ protection, reducing liver lipid and blood lipid, immunomodulatory, anti-inflammatory, and other activities. Until 2021, phytochemistry investigations have uncovered 232 compounds isolated from three species, which could be classified into C21-steroids, acetophenones, terpenoids, and alkaloids. In this review, the morphology characteristics, species identification, and the relationship of botany, extraction, and the separation of chemical constituents, along with the molecular mechanism and pharmacokinetics of bioactive constituents of three species, are summarized for the first time, and their phytochemistry, pharmacology, and clinical safety are also updated. Moreover, the direction and limitation of current research on three species is also discussed.

Antidepressant activity of Spathodea campanulata in mice and predictive affinity of spatheosides towards type A monoamine oxidase.

The antidepressant activity of Spathodea campanulata flowers was evaluated in mice and in silico. When tested at doses of 200 and 400 mg/kg, the methanol extract of S. campanulata (MESC) showed dose-dependent antidepressant activity in the force swim test (FST), tail suspension test (TST), lithium chloride-induced twitches test and the open field test. In FST and TST, animals treated with MESC demonstrated a significant decrease in the immobility period compared to the control group. The lithium chloride-induced head twitches were significantly reduced following administration of MESC. The latter, at the dose of 400 mg/kg, also significantly reduced locomotor activity. Following administration of MESC, changes in the levels of serum corticosterone, and of norepinephrine, dopamine, serotonin, 4-hydroxy-3-methoxyphenylglycol (MHPG), 4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in different brain regions using HPLC. The presence of spatheoside A (m/z 541) and spatheoside B (m/z 559) in MESC was detected using HPLC/ESI-MS. These two iridoids demonstrated a high predictive binding affinity for the active site of the type A monoamine oxidase (MAO-A) enzyme with scores of 99.40 and 93.54, respectively.  These data suggest that S. campanulata flowers warrants further investigation as a source of novel templates for antidepressive drugs.

Identifying the effectual-combination ingredients of Zhi-zi-Hou-po decoction based on metabolic difference-oriented network regulation strategy.

Zhi-zi-Hou-po decoction (ZZHPD) has been used to treat depression in the clinic for thousand years in China. However, the pharmacodynamic substance of ZZHPD is still not totally clear due to its complex components. The objective of this study was to identify the effectual combination ingredients (ECIs) of ZZHPD, which could represent the antidepressant effect of the original formula. Firstly, differential plasma absorbed components with different variable importance in projection (VIP) value in chronic unpredictable mild stress (CUMS)-induced depression and control rat were revealed by untargeted metabolomics-driven strategy based on HPLC-ESI-TOF/MS, XCMS online and SIMCA-p software. Secondly, network topology scores (NTS) of plasma absorbed components were exposed by protein-protein interaction (PPI) network analysis based on components-related genes and depression-related genes, which were performed by network pharmacology tools. Finally, the ECIs were screened by considered of VIP value and NTS. Then the bioactivity was evaluated by cell viability and expression of glial fibrillary acid protein (GFAP), tumor necrosis factor α (TNFα) and interleukin 1ß (IL-1ß) of a lipopolysaccharide-induced astrocyte depression model. An effective combination composed with 12 components was filtrated as ECIs of ZZHPD, exposed to which the cell viability effect, the expression of GFAP and IL-1ß in astrocytes were essentially equivalent with original ZZHPD (p > 0.05), and that both characteristic constituents and trace compounds of ZZHPD might exert synergistic actions through multi-targets. The result of this study provided useful information for the clinical application and modern development of ZZHPD, and the proposed strategy could be regard as an alternative solution for effective combination screening of herbal medicines.

Screening and Identification of Antidepressant Active Ingredients from Puerariae Radix Extract and Study on Its Mechanism.

Objective. Depression is a common mental disease with long course and high recurrence rate. Previous studies showed that Puerariae Radix and its extracts have powerful antidepressant effects in recent years. The study proposed an integrated strategy, combining network pharmacology and molecular pharmacology experiment to investigate the mechanisms of the antidepressant active ingredients from Puerariae Radix. Methods. TCMSP database, GeneCards database, Venny 2.1, UniProt database, STRING database, Cytoscape 3.7.2, and Metascape database were used to screen the active chemical components, antidepressant-related genes, and core targets, convert the abbreviated gene names in batch, search and predict the interaction between proteins, and construct the PPI network of Puerariae Radix. KEGG pathway and GO biological process enrichment and biological annotation were used to select antidepressant core gene targets. The MTT method was used to detect the effect of puerarin on the damage of PC12 cells induced by corticosterone. The DCFH-DA probe and ROS assay kit were utilized to detect the production of ROS in PC12 cells. PI/Annexin V was used to detect the apoptotic rate of puerarin on PC12 cells. Western blotting was used to verify the regulation of puerarin on the key targets of AKT1, FOS, CASP3, STAT3, and TNF-α in PC12 cells. Results and Conclusion. Eight main active components, 64 potential antidepressant gene targets, and 15 core antidepressant gene targets were obtained. 35 signaling pathways and 52 biological processes related to antidepressant effect of Puerariae Radix were identified. Puerarin was the active ingredient derived from Puerariae Radix which exhibited the antidepression effect by improving the viability of cell, reducing cell apoptosis, regulating ROS production, increasing protein expressions of AKT1 and FOS, and reducing protein expressions of CASP3, STAT3, and TNF-α. The study revealed the pharmacodynamic material basis and possible antidepressant mechanism of Puerariae Radix and provided new theoretical basis and ideas for antidepressant research.

Tualang Honey: A Decade of Neurological Research.

Tualang honey has been shown to protect against neurodegeneration, leading to improved memory/learning as well as mood. In addition, studies have also demonstrated its anti-inflammatory and antioxidant properties. However, a substantial part of this research lacks systematization, and there seems to be a tendency to start anew with every study. This review presents a decade of research on Tualang honey with a particular interest in the underlying mechanisms related to its effects on the central nervous system. A total of 28 original articles published between 2011 and 2020 addressing the central nervous system (CNS) effects of Tualang honey were analysed. We identified five main categories, namely nootropic, antinociceptive, stress-relieving, antidepressant, and anxiolytic effects of Tualang honey, and proposed the underlying mechanisms. The findings from this review may potentially be beneficial towards developing new therapeutic roles for Tualang honey and help in determining how best to benefit from this brain supplement.

Uncovering the active components, prospective targets, and molecular mechanism of Baihe Zhimu decoction for treating depression using network pharmacology-based analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Baihe Zhimu decoction (BZD) is a classical traditional Chinese medicinal herbal formula. It consists of two herbal medicines, Rhizoma Anemarrhenae (Zhimu), the rhizomes of Anemarrhena asphodeloides Bge. (Liliaceae), and Bulbus Lilii (Baihe), the bulbs of Lilium brownii var. Viridulum Baker (Liliaceae). BZD has been widely used in China to treat depression and verified to be effective without evident side effects. AIM OF THE STUDY: The aim of this study was to elucidate the active components, potential targets, and molecular mechanism of Baihe Zhimu decoction for treating depression. MATERIALS AND METHODS: In this research, a chronic unpredictable mild stress (CUMS) mice was first established to evaluate the pharmacological effects of BZD for treating depression. A component database was then constructed for BZD. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) technique was used to identify the components in BZD and blood-absorbed components. Further screening and validation of protein targets were performed by molecule docking. The component-target binding affinity was validated by surface plasmon resonance analysis (SPR) assay. The related pathways were predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Relative proteins in the predicted pathways were finally assessed by Western blot. RESULTS: The pharmacology evaluation experiment demonstrated that BZD could improve depressive-like behavior, inhibit the hippocampal secretion of pro-inflammatory cytokines and reduce neuronal apoptosis in CUMS mice model. A component database containing 163 components and a target database covering 1286 proteins were constructed. HPLC-QTOF-MS assay identified twenty-six components from BZD and ten components absorbed into rat plasma after an intragastric treatment with BZD. Next, 56 underlying targets were screened out by a virtual high-throughput screening approach. Twenty-seven of them were further screened out and confirmed by molecular docking. Afterward, a component-target network was established, and the component-protein binding affinities were validated by SPR assays. By KEGG pathway enrichment analysis, two signaling pathways PI3K/Akt and MAPK were predicted as the potential signaling cascades. Finally, Western blot showed that BZD dramatically reversed the suppression of PI3K/Akt/GSK-3ß pathway and the activation of MAPK pathway in CUMS mice model. CONCLUSIONS: BZD demonstrated a substantial pharmacological effect on CUMS mice model. Network pharmacology-based analysis predicted that ten blood-absorbed components can act on 27 target proteins. KEGG and Western blotting analysis suggested that BZD could exert antidepressant effects by regulating the PI3K/Akt and MAPK signaling pathways.

Network Pharmacology and Experimental Evidence: PI3K/AKT Signaling Pathway is Involved in the Antidepressive Roles of Chaihu Shugan San.

OBJECTIVE: Chaihu Shugan San (CSS) is a common antidepressant prescription in traditional Chinese medicines. However, its active ingredients and mechanisms are unknown. The aim of this study was to explore the potential active ingredients and pharmacological mechanisms of CSS for the treatment of major depressive disorder (MDD). METHODS: Active compounds in CSS were screened using the Traditional Chinese Medicine Systems Pharmacology database. Compound-related targets were retrieved using the SwissTargetPrediction database. MDD-related targets were determined using DisGeNET, Therapeutic Target Database and DrugBank databases. The common targets of active compounds in CSS and MDD were retained to construct a compound-MDD target network. Then, functional enrichment analysis and protein-protein interaction analysis were performed to identify hub targets and explore the underlying molecular mechanisms. Finally, hub-targeted genes and pathways were validated by Western blotting and immunofluorescence using chronic unpredictable mild stress (CUMS) mice with or without CSS treatment. The affinities between the active compounds in CSS and hub-targeted genes were evaluated by molecular docking. RESULTS: Network pharmacology analysis revealed 24 potential targets for treatment of MDD by CSS. Functional enrichment analysis showed that PI3K/AKT signaling pathway was likely to be evidently affected by CSS in the treatment of MDD. In vivo experiments showed that CSS could improve depressive-like behaviors and promote neurogenesis in CUMS mice. Furthermore, CSS could increase phosphorylated (p) PI3K/PI3K and pAKT/AKT levels and decrease the pGSK3ß/GSK3ß level in the hippocampus of CUMS mice. The active compounds mainly included quercetin and luteolin, which showed good docking scores targeting the PI3K protein. CONCLUSION: This network pharmacological and experimental study highlights that the PI3K/AKT pathway is the potential mechanism by which CSS is involved in MDD treatment. Quercetin, luteolin, and kaempferol are probable active compounds in CSS, and these results might provide valuable guidance for further studies of MDD treatment.

Purple Sweet Potatoes from East Java of Indonesia Revealed the Macronutrient, Anthocyanin Compound and Antidepressant Activity Candidate.

INTRODUCTION: The development of new antidepressant is crucial to overcome the remission rate limitation. Anthocyanin on purple sweet potatoes (PSP) from East Java cultivar previously demonstrated a behavioural effect. However, the certain mechanism and the nutritional compound need further exploration. AIM: This study aimed to characterize macronutrient content, amino acids, anthocyanin, and revealed the potential of PSP from East Java-Indonesia as antidepressant agent through D2-dopamine receptor (D2DR). METHODS: This study was characterized the macronutrient content using proximate analysis. The amino acids were analysed using Ultra-Performance Liquid Chromatography (UPLC) and High-Performance Liquid Chromatography (HPLC). Anthocyanin was identified using Ultra High-Performance Liquid Chromatography (UHPLC). Molecular docking was conducted to predict the interaction between anthocyanins and D2 dopamine receptor. RESULTS: We were found the predominance of water on proximate analysis. Alanine was demonstrated as the highest content of amino acid. Cyanidin, cyanidin-3-O-glucoside and peonidin-3-O-glucoside were identified as major anthocyanin content. Molecular docking was showed that cyanidin bound to similar binding site with dopamine on D2DR with stronger interaction than cyanidin-3-glucoside. CONCLUSION: Current study was indicated that cyanidin as major anthocyanin from purple sweet potatoes has potential health beneficial as antidepressant potential candidate.

Korean red ginseng alleviate depressive disorder by improving astrocyte gap junction function.

ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng (KRG), a processed product of Panax ginseng C. A. Mey, show significant anti-depressive effect in clinic. However, its mechanism is still unclear. AIM OF THE STUDY: Gap junction intercellular communication (GJIC) dysfunction is a potential pathogenesis of depression. Therefore, this study's objective is to investigate whether the antidepressant effect of KRG is related to GJIC. MATERIALS AND METHODS: Rat were restraint 8 h every day for 28 consecutive days to prepare depression models, and meanwhile, rats were intragastrically administrated with normal saline, KRG solutions (25, 50 or 100 mg/kg) or fluoxetine (10 mg/kg) 1 h before stress. The behavioral performance was determined by forced swimming test, sucrose preference test and open field test. GJIC was determined by the Lucifer yellow (LY) diffusion distance in prelimb cortex (PLC). In addition, the level of Cx43, one of executors of GJIC, was tested by Western blot. To find out the protective effect of KRG against GJIC dysfunction directly, rats were intracranially injected with carbenoxolone (CBX, blocker of GJIC), and meanwhile normal saline, KRG (100 mg/kg) or fluoxetine (10 mg/kg) was administered daily. The behavioral performance of these rats was detected, and the LY localization injection PLC area was used to detect the gap junction function. RESULTS: Chronic resistant stress (CRS) induced depressive symptoms, as manifested by prolonged immobility time in forced swimming test and decreased sucrose consumption ratio. Administration of KRG alleviated these depressive symptoms significantly. GJIC determination showed that KRG improved the LY diffusion and increased Cx43 level in prefrontal cortex (PFC) significantly, indicated that GJIC dysfunction was alleviated by the treatment of KRG. However, the astrocytes number was also increased by the treatment of KRG, which maybe alleviate depression-like symptoms by increasing the number of astrocytes rather than improving GJIC. Injection of CBX produced depressive symptoms and GJIC dysfunction, as manifested by decreased sucrose consumption ratio and prolonged immobility time in forced swimming test, but no astrocytes number changes, KRG also reversed depressive symptoms and GJIC dysfunction, suggested that the improvement of depressive-like symptoms was improved by GJIC. CONCLUSIONS: KRG alleviate depressive disorder by improving astrocytic gap junction function.

Synthesis and biological evaluation of 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives as potential SSRIs.

A series of novel 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives were synthesized and evaluated for their serotonin (5-HT) reuptake inhibitory activity. The results in vitro indicated that most of the evaluated compounds displayed potent 5-HT reuptake inhibition. The most promising compound A20 was stable in human liver microsomes and possessed good pharmacokinetic properties. Antidepressant study in vivo of the compound A20 showed that A20 could potently antagonize the p-chloroamphetamine (PCA)-induced depletion of serotonin in hypothalamus and reduce immobility times in the rat forced swimming test (FST).

Discovery of Novel and Potent N-Methyl-d-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models.

N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.