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.

Antidepressant Effects of Essential Oils: A Review of the Past Decade (2012-2022) and Molecular Docking Study of Their Major Chemical Components.

Depression is a mental disorder that affects more than 300 million people worldwide. The medications available for treatment take a long time to exhibit therapeutic results and present several side effects. Furthermore, there is a decrease in the quality of life of people suffering from this affliction. Essential oils are traditionally used to relieve the symptoms of depression due to the properties of the constituents of these oils to cross the blood-brain barrier acting on depression-related biological receptors associated with reduced toxicity and side effects. In addition, compared to traditional drugs, they have several administration forms. This review provides a comprehensive assessment of studies on plants whose essential oil has exhibit antidepressant activity in the past decade and the mechanism of action of the major components and models tested. An additional in silico study was conducted with the frequent compounds in the composition of these essential oils, providing a molecular approach to the mechanism of action that has been reported in the past decade. This review is valuable for the development of potential antidepressant medications in addition to providing a molecular approach to the antidepressant mechanism of action of the major volatile compounds that have been reported in the past decade.

Binding Affinity and Mechanisms of Potential Antidepressants Targeting Human NMDA Receptors.

Depression, a mental disorder that plagues the world, is a burden on many families. There is a great need for new, fast-acting antidepressants to be developed. N-methyl-D-aspartic acid (NMDA) is an ionotropic glutamate receptor that plays an important role in learning and memory processes and its TMD region is considered as a potential target to treat depression. However, due to the unclear binding sites and pathways, the mechanism of drug binding lacks basic explanation, which brings great complexity to the development of new drugs. In this study, we investigated the binding affinity and mechanisms of an FDA-approved antidepressant (S-ketamine) and seven potential antidepressants (R-ketamine, memantine, lanicemine, dextromethorphan, Ro 25-6981, ifenprodil, and traxoprodil) targeting the NMDA receptor by ligand-protein docking and molecular dynamics simulations. The results indicated that Ro 25-6981 has the strongest binding affinity to the TMD region of the NMDA receptor among the eight selected drugs, suggesting its potential effective inhibitory effect. We also calculated the critical binding-site residues at the active site and found that residues Leu124 and Met63 contributed the most to the binding energy by decomposing the free energy contributions on a per-residue basis. We further compared S-ketamine and its chiral molecule, R-ketamine, and found that R-ketamine had a stronger binding capacity to the NMDA receptor. This study provides a computational reference for the treatment of depression targeting NMDA receptors, and the proposed results will provide potential strategies for further antidepressant development and is a useful resource for the future discovery of fast-acting antidepressant candidates.

Design, synthesis and biological evaluation of oxadiazole clubbed piperazine derivatives as potential antidepressant agents.

Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural features along with their pharmacological profile. In this study, we have designed and synthesized a series of 10 compounds of piperazine clubbed oxadiazole derivatives (5a-j) and screened for their MAO inhibitory activity. Compound 5f and 5 g were found to be the most potent MAO-A inhibitors of the series with IC50 values of 0.96 ± 0.04 µM µM and 0.81 ± 0.03 µM, respectively with a selectivity index of 18-folds and 9-folds over MAO-B isoform. The compounds were found to be reversible inhibitors of MAO-A with no cytotoxicity against SH-SY5Y neuronal cells. The compounds also displayed good antioxidant activity. Further, in vivo TST studies revealed that both the compounds 5f and 5 g possessed good anti-depressant-like activity and reduced the immobility time significantly although were found inactive in FST studies. The molecular docking studies revealed that both compounds fit well at the active site of MAO-A enzyme as similar to clorgyline and form a stable complex. The results were confirmed via molecular dynamic studies which demonstrate the stable complex formation between MAO-A and 5f & 5 g. The appropriate drug-like characteristics with favourable ADMET profile, these molecules presented this piperazine clubbed oxadiazole structural framework as a key pharmacophore for the development of new antidepressant molecules along with strong candidature for further clinical investigations.

Deciphering Nonbioavailable Substructures Improves the Bioavailability of Antidepressants by Serotonin Transporter.

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose. Thus, it is an excellent model to probe the relationship between substructures and bioavailability. Here, we proposed the concept of "nonbioavailable substructures", referring to substructures that are unfavorable to bioavailability. A machine learning model was developed to identify nonbioavailable substructures based on their molecular properties and shows the accuracy of 83.5%. A more potent SERT inhibitor DH4 was discovered with a bioavailability of 83.28% in rats by replacing the nonbioavailable substructure of approved drug vilazodone. DH4 exhibits promising anti-depression efficacy in animal experiments. The concept of nonbioavailable substructures may open up a new venue for the improvement of drug bioavailability.

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.

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.

Design, synthesis of 1,2,4-triazine derivatives as antidepressant and antioxidant agents: In vitro, in vivo and in silico studies.

The novel series of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides (R: 1-12) were designed, synthesized and evaluated for in-vitro and in-vivo antidepressant-like activity. In MAO-A inhibition assay, compound R: 5 and R: 9 displayed most potent activity with IC50 = 0.12 and 0.30 µM. R: 5 and R: 9 were also evaluated for in-vivo antidepressant using FST and TST. In both models, the test samples R: 5 and R: 9 showed noteworthy antidepressant effect. R: 5 showed 46.48 % and 45.96 % reduction in immobility in FST and TST respectively at dosage of 30 mg/kg (p.o). Whereas compound R: 9 reduced the immobility time by 52.76 % and 47.14 % as compared to control in FST and TST, respectively at same dosage. Both the compounds were also tested for behavioural study using actophotometer and grip tests. None of compounds exhibited decrease in locomotor activity. Further, these compounds were subjected to in silico studies to determine their ADME properties along with binding energies and binding orientions. In ADME studies none of the compounds violated the Lipinski rule and all other parameters were also within the acceptable ranges. In docking study R: 5 (-10.7) and R: 9 (-10.4) were also displayed highest docking score. These encouraging results present the pharmacophoric features of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides as interesting lead for further development of new antidepressant drug molecules.

New, Eco-Friendly Method for Synthesis of 3-Chlorophenyl and 1,1'-Biphenyl Piperazinylhexyl Trazodone Analogues with Dual 5-HT1A/5-HT7 Affinity and Its Antidepressant-like Activity.

Serotonin 5-HT1A and 5-HT7 receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified N-hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7a·HCl), with high affinity for 5-HT1AR and 2-(6-(4-([1,1'-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7b·HCl), a dual-acting 5-HT1A/5-HT7 receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of 7a and 7b involved reductive alkylation under a mild reducing agent. We produced the final compounds with yield of 56-63% using ethanol or 51-56% in solvent-free conditions in 4 min. We then determined the 5-HT7R binding mode for compounds 7a and 7b using in silico methods and assessed the preliminary ADME and safety properties (hepatotoxicity and CYP3A4 inhibition) using in vitro methods for 7a·HCl and 7b·HCl. Furthermore, we evaluated antidepressant-like activity of the dual antagonist of 5-HT1A/5-HT7 receptors (7b·HCl) in the forced swim test (FST) in mice. The 5-HT1AR ligand (7a·HCl) with a much lower affinity for 5-HT7R compared to that of 7b·HCl was tested comparatively. Both compounds showed antidepressant activity, while 5-HT1A/5-HT7 double antagonist 7b·HCl showed a stronger and more specific response.

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN.

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

The Design, Synthesis, and Evaluation of Novel 9-Arylxanthenedione-Based Allosteric Modulators for the δ-Opioid Receptor.

Chronic pain and depression are both widely prevalent comorbid medical conditions. While efficient, µ-opioid receptor-based medications are associated with life-threatening side effects, including respiratory depression, dependence, and addiction. The δ-opioid receptor is a promising alternative biological target for chronic pain and depression due to its significantly reduced on-target side effects compared to the µ-opioid receptor. A previous study identified two δ-opioid receptor positive allosteric modulators. Herein, we report the design of five series of compounds targeting previously unexplored regions of the originally described SAR. Analogs were assessed for their ability to potentiate the agonist response of Leu-enkephalin. Of the 30 analogs, compound 6g displayed trends toward enhancing the ERK1/2 phosphorylation signaling compared to cAMP inhibition, while compound 11c exhibited a trend in shifting the signaling bias toward cAMP inhibition. Both 6g and 11c emerged as promising tool compounds toward the design of prospective therapeutics requiring specific downstream signaling attributes.

The First Dipeptide Mimetic of Neurotrofin-3: Design and Pharmacological Properties.

The dimeric dipeptide mimetic hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301) was created on the basis of the structure of the exposed region of the neurotrophin-3 4th loop. The new compound, as well as the full-length neurotrophin, activated the TrkC and TrkB receptors. GTS-301 showed neuroprotective activity in experiments on HT-22 mouse hippocampal cells under conditions of oxidative stress and glutamate toxicity at concentrations of 10-12 and 10-8 M, respectively, and antidepressant-like activity in the forced swimming test on mice with 7-day intraperitoneal administration in doses of 10-40 mg/kg.

New Ketene Dithioacetals Generated from 2-Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities.

The ketene dithioacetal 3 generated from 2-nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene-N,S,S-acetals and S,S,S-acetals 4a-f, 5a-h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6 µg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50 mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole-induced convulsions after single oral administration both at 3 h and 24 h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.

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.

Allosteric Binding of MDMA to the Human Serotonin Transporter (hSERT) via Ensemble Binding Space Analysis with ΔG Calculations, Induced Fit Docking and Monte Carlo Simulations.

Despite the recent promising results of MDMA (3,4-methylenedioxy-methamphetamine) as a psychotherapeutic agent and its history of misuse, little is known about its molecular mode of action. MDMA enhances monoaminergic neurotransmission in the brain and its valuable psychoactive effects are associated to a dual action on the 5-HT transporter (SERT). This drug inhibits the reuptake of 5-HT (serotonin) and reverses its flow, acting as a substrate for the SERT, which possesses a central binding site (S1) for antidepressants as well as an allosteric (S2) one. Previously, we characterized the spatial binding requirements for MDMA at S1. Here, we propose a structure-based mechanistic model of MDMA occupation and translocation across both binding sites, applying ensemble binding space analyses, electrostatic complementarity, and Monte Carlo energy perturbation theory. Computed results were correlated with experimental data (r = 0.93 and 0.86 for S1 and S2, respectively). Simulations on all hSERT available structures with Gibbs free energy estimations (ΔG) revealed a favourable and pervasive dual binding mode for MDMA at S2, i.e., adopting either a 5-HT or an escitalopram-like orientation. Intermediate ligand conformations were identified within the allosteric site and between the two sites, outlining an internalization pathway for MDMA. Among the strongest and more frequent interactions were salt bridges with Glu494 and Asp328, a H-bond with Thr497, a π-π with Phe556, and a cation-π with Arg104. Similitudes and differences with the allosteric binding of 5-HT and antidepressants suggest that MDMA may have a distinctive chemotype. Thus, our models may provide a framework for future virtual screening studies and pharmaceutical design and to develop hSERT allosteric compounds with a unique psychoactive MDMA-like profile.

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.

Antidepressant-like effect of sodium orthovanadate in a mouse model of chronic unpredictable mild stress.

Depression is a psychiatric disorder characterized by low-esteem, anhedonia, social deficit, and lack of interest. Decreased brain-derived neurotrophic factor (BDNF) and impaired tropomyosin kinase B receptor (TrkB receptor) signaling are associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and enzyme-linked immunosorbent assay (ELISA) for BDNF were performed. Body weight was measured every week. CUMS induced depressive-like behavior was found to be associated with increased oxidative stress in the brain and serum corticisterone with subsequent reduction of BDNF. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor already reported to elevate BDNF levels, was used as the test drug. Sodium orthovanadate (5 mg/kg, 10 mg/kg) and fluoxetine (FLX-10 mg/kg) was given to mice orally for 21days before 30 min of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg demonstrated significant results in the present study characterized by decreased malondialdehyde levels (MDA/LPO), NO levels, and increased GSH level and SOD activity in both the cortex and hippocampus. Besides, ELISA has revealed the significant elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) as compared to the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels observed with SOV (5 & 10 mg/kg), FLX-10 mg/kg, FLX (10 mg/kg) + SOV (5 mg/kg); and SOV-10 mg/kg per-se treatment and elevated BDNF level with SOV (5 & 10 mg/kg), FLX-10 mg/kg were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effects or prevent stress-induced anhedonia and so further molecular mechanisms are warranted for clinical translation.

Design, synthesis, and computational studies of phenylacetamides as antidepressant agents.

In the present work, a hit molecule obtained from zinc 'clean drug-like database' by systematically performed computational studies was modified chemically to obtain different derivatives (VS1-VS25). Structures of synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR, 13C-DEPT, MS, and elemental analysis. All the synthesized compounds were biologically evaluated for their antidepressant activity by using tail suspension test and forced swimming test in albino mice. All these derivatives showed moderate to good antidepressant activity. The most potent compound (VS25) among the synthesized compounds showed better antidepressant potential than the standard drugs moclobemide, imipramine, and fluoxetine. To understand the time-dependent interactions of this most active compound with MAO-A molecular dynamics was carried out and reported here. Additionally, acute oral toxicity was performed for the most active compound as per OECD guidelines.