Potential Antidepressant Mechanism Research Articles

Antidepressant potential of total flavonoids from Astragalus in a chronic stress mouse model: Implications for myelination and Wnt/β-catenin/Olig2/Sox10 signaling axis modulation

Ethnopharmacological relevanceRadix Astragali, a versatile traditional Chinese medicinal herb, has a rich history dating back to “Sheng Nong's herbal classic”. It has been employed in clinical practice to address various ailments, including depression. One of its primary active components, total flavonoids from Astragalus (TFA), remains unexplored in terms of its potential antidepressant properties. This study delves into the antidepressant effects of TFA using a mouse model subjected to chronic unpredictable mild stress (CUMS). Aims of the studyThe study aimed to scrutinize how TFA influenced depressive behaviors, corticosterone and glutamate levels in the hippocampus, as well as myelin-related protein expression in CUMS mice. Additionally, it sought to explore the involvement of the Wnt/β-catenin/Olig2/Sox10 signaling axis as a potential antidepressant mechanism of TFA. Materials and methodsMale C57BL/6 mice were subjected to CUMS to induce depressive behaviors. TFA were orally administered at two different doses (50 mg/kg and 100 mg/kg). A battery of behavioral tests, biochemical analyses, immunohistochemistry, UPLC-MS/MS, real-time PCR, and Western blotting were employed to evaluate the antidepressant potential of TFA. The role of the Wnt/β-catenin/Olig2/Sox10 signaling axis in the antidepressant mechanism of TFA was validated through MO3.13 cells. ResultsTFA administration significantly alleviated depressive behaviors in CUMS mice, as evidenced by improved sucrose preference, reduced immobility in tail suspension and forced swimming tests, and increased locomotor activity in the open field test. Moreover, TFA effectively reduced hippocampal corticosterone and glutamate levels and promoted myelin formation in the hippocampus of CUMS mice. Then, TFA increased Olig2 and Sox10 expression while inhibiting the Wnt/β-catenin pathway in the hippocampus of CUMS mice. Finally, we further confirmed the role of TFA in promoting myelin regeneration through the Wnt/β-catenin/Olig2/Sox10 signaling axis in MO3.13 cells. ConclusionsTFA exhibited promising antidepressant effects in the CUMS mouse model, facilitated by the restoration of myelin sheaths and regulation of corticosterone, glutamate, Olig2, Sox10, and the Wnt/β-catenin pathway. This research provides valuable insights into the potential therapeutic application of TFA in treating depression, although further investigations are required to fully elucidate the underlying molecular mechanisms and clinical relevance.

Astroglial Connexin 43-Mediated Gap Junctions and Hemichannels: Potential Antidepressant Mechanisms and the Link to Neuroinflammation.

Major depression disorder (MDD) is a neuropsychiatric disorder associated with a high suicide rate and a higher disability rate than any other disease. Evidence suggests that the pathological mechanism of MDD is related to astrocyte dysfunction. Depression is mainly associated with the expression of connexin 43 (Cx43) and the function of Cx43-mediated gap junctions and hemichannels in astrocytes. Moreover, neuroinflammation has been a hotspot in research on the pathology of depression, and Cx43-mediated functions are thought to be involved in neuroinflammation-related depression. However, the specific mechanism of Cx43-mediated functions in neuroinflammation-related depression pathology remains unclear. Therefore, this review summarizes and discusses Cx43 expression, the role of gap junction intercellular communication, and its relationship with neuroinflammation in depression. This review also focuses on the effects of antidepressant drugs (e.g., monoamine antidepressants, psychotropic drugs, and N-methyl-D-aspartate receptor antagonists) on Cx43-mediated function and provides evidence for Cx43 as a novel target for the treatment of MDD. The pathogenesis of MDD is related to astrocyte dysfunction, with reduced Cx43 expression, GJ dysfunction, decreased GJIC and reduced BDNF expression in the depressed brain. The effect of Cx43 on neuroinflammation-related depression involving inflammatory cytokines, glutamate excitotoxicity, and HPA axis dysregulation. Antidepressant drugs targeting Cx43 can effectively relieve depressive symptoms.

The regulatory effect of Angelicae Sinensis Radix on neuroendocrine-immune network and sphingolipid metabolism in CUMS-induced model of depression

Ethnopharmacological relevanceConventional antidepressants therapy remains unsatisfactory due to the disadvantages of delayed clinical onset of action and side effects. Traditional Chinese Medicine (TCM) with good efficacy and higher safety have received much attention. Angelicae Sinensis Radix (AS), a well-known TCM, has been proved to exhibit the efficacy of antidepression recently. Aim of the studyThe purpose of this study was to investigate the potential anti-depressant mechanisms of AS based on chronic unpredictable mild stress (CUMS) rat model. Materials and methodsIn this study, behavioral experiments, molecular biology techniques, and ultra performance liquid chromatography-triple-time of flight mass spectrometer (UPLC-Triple-TOF/MS) were combined to explore the potential antidepressant mechanisms of AS based on CUMS rat model. ResultsThe results demonstrated that AS could reduce the contents of serum hypothalamic-pituitary-adrenal (HPA) axis hormones in CUMS rats, including corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol (CORT). In addition, AS regulated the percentage of CD4+ T lymphocytes, the ratio of CD4+/CD8+, and the levels of serum cytokines such as IL-1β, IL-4, IL-6, and TNF-α in CUMS rats. Lipidomics showed that 31 lipids were related to depression and AS could regulate the lipid metabolism alteration induced by CUMS, particularly sphingolipid metabolism. Finally, the key proteins in sphingolipid metabolic pathways in hippocampus of CUMS rats could be back-regulated by AS, including serine palmitoyl transferase (SPTLC2), ceramide synthase (CerS2), sphingomyelinase (SPHK1), and neutral sphingomyelinase (nSMase). ConclusionAS could alleviate NEI network disorder and restore the levels of sphingolipid metabolites and key proteins in CUMS rats. The underlying mechanism by which AS relieved depression-like behavior in CUMS rats may be through modulation of NEI and disturbances in sphingolipid metabolism.

Yueju volatile oil plays an integral role in the antidepressant effect by up-regulating ERK/AKT-mediated GLT-1 expression to clear glutamate

Phytochemical investigation of the volatile oil of Yueju (YJVO) and its constituent herbs induced the detection of 52 compounds in YJVO, mainly monoterpenes and sesquiterpenes as well as a small amount of aromatic and aliphatic compounds. 5 of these compounds were found only in the YJVO instead of the volatile oil of its constituent herbs. The anti-depressant effect of YJVO was proved by behavioral tests in chronic unpredictable mild stress (CUMS) mice. An acute oral toxicity evaluation determined the LD50 of YJVO was 5.780 mL/kg. Doppler ultrasound and laser speckle imaging have detected that the YJVO could improve depression-related cerebral blood flow. In addition, related neurotransmitters and proteins were analyzed through targeted metabolomics and immunofluorescence. The potential antidepressant mechanisms of YJVO related to significantly decreasing Glu in CUMS mice by up-regulating the ERK/AKT-mediated expression of GLT-1.

Gut microbiota-based metabolites of Xiaoyao Pills (a typical Traditional Chinese medicine) ameliorate depression by inhibiting fatty acid amide hydrolase levels in brain

Ethnopharmacological relevanceTraditional Chinese medicines (TCMs) are often prepared in oral dosage forms, making TCMs interact with gut microbiota after oral administration, which could affect the therapeutic effect of TCM. Xiaoyao Pills (XYPs) are a commonly used TCM in China to treat depression. The biological underpinnings, however, are still in its infancy due to its complex chemical composition. Aim of the studyThe study aims to explore XYPs’ underlying antidepressant mechanism from both in vivo and in vitro. Materials and methodsXYPs were composed of 8 herbs, including the root of Bupleurum chinense DC., the root of Angelica sinensis (Oliv.) Diels, the root of Paeonia lactiflora Pall., the sclerotia of Poria cocos (Schw.) Wolf, the rhizome of Glycyrrhiza uralensis Fisch., the leaves of Mentha haplocalyx Briq., the rhizome of Atractylis lancea var. chinensis (Bunge) Kitam., and the rhizome of Zingiber officinale Roscoe, in a ratio of 5:5:5:5:4:1:5:5. The chronic unpredictable mild stress (CUMS) rat models were established. After that, the sucrose preference test (SPT) was carried out to evaluate if the rats were depressed. After 28 days of treatment, the forced swimming test and SPT were carried out to evaluate the antidepressant efficacy of XYPs. The feces, brain and plasma were taken out for 16SrRNA gene sequencing analysis, untargeted metabolomics and gut microbiota transformation analysis. ResultsThe results revealed multiple pathways affected by XYPs. Among them, the hydrolysis of fatty acids amide in brain decreased most significant via XYPs treatment. Moreover, the XYPs' metabolites which mainly derived from gut microbiota (benzoic acid, liquiritigenin, glycyrrhetinic acid and saikogenin D) were found in plasma and brain of CUMS rats and could inhibit the levels of FAAH in brain, which contributed to XYPs’ antidepressant effect. ConclusionsThe potential antidepressant mechanism of XYPs by untargeted metabolomics combined with gut microbiota-transformation analysis was revealed, which further support the theory of gut-brain axis and provide valuable evidence of the drug discovery.

MiR-29a-3p promotes the regulatory role of eicosapentaenoic acid in the NLRP3 inflammasome and autophagy in microglial cells.

Eicosapentaenoic acid (EPA) has been reported to play an anti-inflammatory and antioxidative stress role in a series of human diseases, including major depressive disorder. However, its exact mechanism is still largely unknown. Mouse BV-2 cells were treated with lipopolysaccharide (LPS) to induce an in vitro inflammatory cell model of depression. Cytotoxic effects were assessed with MTT and lactate dehydrigebase release assays. Cytokine mediators were elevated by western blot and enzyme-linked immunosorbent assays. Autophagy-relators were determined by immunofluorescence and western blot analyses. Interaction relationships among molecules were evaluated utilizing chromatin immunoprecipitation and dual luciferase assays. Methylated miR-29a-3p was detected via methylation-specific polymerase chain reaction. EPA treatment at 60 μM had no cytotoxic effects on BV2 cells and significantly inhibited the LPS-induced inflammatory response and NLRP3 inflammasome but activated autophagy, while all these effects were reversed by the autophagy inhibitor 3-MA. Importantly, miR-29a-3p exhibited a role similar to that of EPA in LPS-treated BV2 cells. Mechanistically, EPA treatment elevated miR-29a-3p by repressing its promoter methylation. MAPK8 was a direct target of miR-29a-3p. Inhibition of miR-29a-3p greatly diminished the regulatory roles mediated by EPA in LPS-treated BV2 cells, while these roles were further impeded after MAPK8 silencing. To conclude, our data demonstrated that EPA treatment alleviated LPS-induced NLRP3 inflammasomes by activating autophagy via regulation of miR-29a-3p/MAPK8 signaling, which further elucidates the potential antidepressant mechanism of EPA.

Quantitative proteomics reveals the therapeutic effects of RFAP against depression via pathway regulation of long-term depression and potentiation

Ethnopharmacological relevanceRFAP is a compound extraction complex of four Traditional Chinese Medicine (TCM), including the dry bark of Paeonia lactiflora Pall. (Radix Paeoniae Alba), Gardenia jasminoides J. Ellis (Fructus Gardeniae), Albizia julibrissin Durazz. (Albizia julibrissin Durazz), and Paeonia × suffruticosa Andrews (Peony bark). Not only RFAP but also the individual ingredients have been commonly used for the treatment of depression in the clinic. However, the underlying mechanism of pharmacology is difficult to interpret since its holistic and multidrug nature. Aim of the studyThis study aimed to elucidate the potential antidepressant mechanism of RFAP in the treatment of chronic unpredictable mild stress (CUMS) rats' model via the quantitative proteomics approach. Materials and methodsWe established the CUMS rats' model and evaluated the efficacy of RFAP using multiple behavior assays, including the sugar preference test, open field test, and forced swimming test. Then label-free quantitative proteomics analyses were performed to evaluate the integrated changes of proteome profiling in control, CUMS, RFAP low dose, and RFAP high dose groups. Finally, we validated the critical changed proteins in the pathways of long-term depression and potentiation via RT-PCR and Western blotting assays. ResultsWe successfully established the CUMS rats' model. The behavior assays indicated that the rats demonstrated a tendency to behavioral despair after four weeks. Label-free quantitative proteomics showed that 107 proteins were significantly upregulated and 163 proteins were downregulated in the CUMS group compared to the control group. These differentially expressed proteins were involved in long-term potentiation, long-term depression, nervous system development, neuronal synaptic structural constituent of ribosome, ATP metabolic process, learning or memory, and cellular lipid metabolic process. RFAP treatment partially restored the differentially expressed protein profile. The protective effect of RFAP on behavioral assessment were consistent with the results of proteomics. ConclusionsThe results indicated that RFAP exerted a synergistic effect on CUMS by regulating long-term inhibition and potentiation-related proteins.

Electroacupuncture attenuates LPS-induced depression-like behavior through kynurenine pathway.

A growing body of evidence suggests that inflammation and changes in glutamate neurotransmission are two pathophysiological mechanisms underlying depression. Electroacupuncture (EA) is a common therapeutic tool for the treatment of depression. However, the potential antidepressant mechanism of EA remains obscure. The change of the kynurenine pathway (KP) is the research priority of antidepressant mechanisms. This study will investigate the role of EA on lipopolysaccharide (LPS)-induced depression-like behavior and explore its possible mechanism of action. Lipopolysaccharide was used to induce depression-like behavior, and EA was given at Hegu (L14) and Taichong (LR3) acupoints in C57BL/6J mice. Depression-like behaviors were measured by behavioral tests, including tail suspension test (TST), sucrose preference test (SPT), force swim test (FST), and open field test (OFT). The levels of inflammatory cytokines IL-1β, IL-6, and TNF-α, and KP enzyme IDO1 were measured by qPCR and enzyme-linked immunosorbent assay (ELISA), while high-performance liquid chromatography (HPLC) was performed to detect the content of prefrontal cortex and hippocampal as well as serum glutamate, tryptophan (TRP), kynurenic (KYN), and quinolinic acid (QA). The results showed that (1) as evidenced by increased spontaneous locomotor activities, decreased immobility duration, and a stronger preference for sucrose in the sucrose preference test, EA reversed LPS-challenged depressive-like behavior. (2) EA at L14 and LR3 decreased the levels of inflammatory cytokines, inhibited IDO1, and regulated KP metabolisms, as well as lowered the concentration of glutamate. (3) EA may exert anti-depression effects by acting on the kynurenine pathway. This study evaluated the effects of EA on depression-like behaviors induced by lipopolysaccharide (LPS) and its regulation of inflammation and the glutamatergic system. Our results suggest that EA can ameliorate depression-like behaviors, lower the level of inflammation, and reduce the release of glutamate, possibly through the regulation of the kynurenine pathway in the brain.

The Efficacy of N-Acetyl-Cysteine (NAC) Supplementation in FST Model for Screening Antidepressants.

The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug. Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC). Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug. NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.

Functional connectivity differences in the amygdala are related to the antidepressant efficacy of ketamine in patients with anxious depression

BackgroundThe antidepressant effects of ketamine in patients with anxious depression (AD) remain unclear. Functional connectivity (FC) differences in the amygdala have been linked to depression improvement after ketamine treatment in depressed patients, but their role in AD patients is uncertain. We investigated the correlation between depression improvement after ketamine treatment and amygdala FC in AD patients. MethodsThirty-one AD patients and 18 non-anxious depression (NAD) patients received six intravenous ketamine infusions (0.5 mg/kg) over two weeks. AD patients were further divided into responders (defined as a ≥50% MADRS total score reduction on day 13) and non-responders. The FC of the amygdala subregions, including the laterobasal amygdala (LBA), centromedial amygdala (CMA), and superficial amygdala, were compared between the groups. Receiver operating characteristic curves were used to predict treatment response after ketamine infusions. ResultsThe baseline FC difference in the left LBA and the left precuneus between responders and non-responders among AD patients was found to be associated with depression improvement and was a significant predictor of treatment response to ketamine. A marked reduction in baseline LBA-precuneus FC after ketamine infusion was observed in responders. Unlike in patients with NAD, a lower right CMA-right middle temporal gyrus FC was found in AD patients. LimitationsThe sample size is rather small. ConclusionsOur findings may suggest that amygdala FC is a significant predictor of treatment response to ketamine infusions in patients with AD. Further studies exploring the potential antidepressant mechanisms of ketamine may aid in the treatment of AD patients.

Exploring the potential antidepressant mechanisms of puerarin: Anti-inflammatory response via the gut-brain axis

BackgroundPuerarin has been shown to have a good antidepressant effect, and our previous study found that it can remedy stress-induced dysbiosis. However, its gut microbiota-related mechanism has not been fully elucidated. Therefore, this study aimed to investigate the potential link between puerarin on gut microbiota and inflammatory responses in depressed rats. MethodsA chronic unpredictable mild stress (CUMS) rat model of depression was established, open field test (OFT), sucrose preference test (SPT) and forced swimming test (FST) were used to evaluate its antidepressant effect. 16S rRNA sequencing was performed to identify the rat fecal microflora. At the same time, inflammatory cytokines, colonic histopathological changes, and brain-derived neurotrophic factor (BDNF), nuclear factor kappa-B (NF-κB), inhibitor a of NF-κB (IκB-α) protein expression were detected. ResultsPuerarin attenuated CUMS-induced depressive-like behavior and gut microbiota dysregulation in rats, significantly reducing the abundance of harmful bacteria such as Desulfovibrio, Verrucomicrobiae, and Verrucomicrobia. In addition, puerarin can also reduce the pro-inflammatory factors and increase the level of anti-inflammatory factors in depressed rats, improve the damaged colon tissue, enhance the expression of BDNF and IκB-α in the hippocampus and inhibit the expression of NF-κB. LimitationsDirect evidence that puerarin improves depressive-like behaviors via gut microbiota is lacking. ConclusionThe underlying mechanism of puerarin's antidepressant-like effect is closely related to the bidirectional communication of the microbiota-gut-brain axis by regulating the inflammatory response.

Metabolomics Based on Peripheral Blood Mononuclear Cells to Dissect the Mechanisms of Chaigui Granules for Treating Depression.

Chaigui granules were a traditional Chinese medicine (TCM) preparation with antidepressant effects derived from a famous antidepressant prescription. It was of great significance to clarify the antidepressant mechanism of Chaigui granules for the clinical application of this drug. In this study, a chronic unpredictable mild stress (CUMS) depression model was successfully established, and behavioral indicators were used to evaluate the antidepressant effect. Second, the CD4+, CD8+, and CD4+/CD8+ levels were detected in peripheral blood. Meanwhile, the amount of inflammatory cytokines was determined in serum. Correspondingly, LC/MS-based peripheral blood mononuclear cell (PBMC) metabolomics was used to investigate vital metabolic pathways participating in the antidepressive effects of Chaigui granules. Finally, bioinformatics technology was further employed to discover the potential antidepressant mechanism of Chaigui granules regulating the immune system. The results suggested that the administration of Chaigui granules significantly improved CUMS-induced depressive symptoms. Chaigui granules could improve immune function by regulating T lymphocyte subsets, increasing anti-inflammatory cytokine levels of IL-2 and IL-10, and reducing pro-inflammatory cytokine levels of TNF-α, IL-1β, and IL-6. In addition, metabolomics results of PBMCs showed that Chaigui granules improved 14 of the 25 potential biomarkers induced by CUMS. Metabolic pathway analyses indicated that purine metabolism was the critical metabolic pathway regulated by Chaigui granules. Furthermore, correlation analysis indicated that 13 key biomarkers were related to immune-related indicators. The metabolite–gene network of 13 key biomarkers was investigated by using bioinformatics. The investigation showed that 10 targets (5′-nucleotidase ecto; 5′-nucleotidase, cytosolic IB; 5′-nucleotidase, cytosolic II; etc.), mainly belong to the purine metabolism, might be potential targets for Chaigui granules to exert their antidepressant effects by improving immune function impairment. Together, our results suggested that Chaigui granules might exert antidepressant effects by improving immune function and regulating the purine metabolic pathway in PBMCs. This work used PBMCs metabolomics as an entry point to study the antidepressant mechanism of Chaigui granules, which provided a new way to elucidate the mechanism of a traditional Chinese medicine prescription.

Exploring the mechanisms of action of Cordyceps sinensis for the treatment of depression using network pharmacology and molecular docking.

BackgroundDepression is the most common type of psychological disorder, with continuous, prolonged, and persistent bad moods as the main clinical feature. Cordyceps sinensis is a complex consisting of the ascospores and bodies of insect larvae from the Hepialidae family that have been parasitized by Cordyceps sinensis militaris. Previous studies have reported that this herb has antidepressant activity. The present study used network pharmacology and molecular docking techniques to investigate the potential antidepressant mechanisms of Cordyceps sinensis.MethodsThe active ingredients of Cordyceps sinensis were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the potential targets were predicted using the PharmMapper platform. The GeneCards database was then used to obtain sub-targets for depression. Common targets were screened and enrichment analyses were performed using the Metascape platform. Finally, the relationship between the active ingredients and the core targets were verified by molecular docking.ResultsThrough network pharmacological analysis, 7 active ingredients in Cordyceps sinensis and 41 common targets of drugs and diseases were identified. The active ingredients of Cordyceps sinensis may exert antidepressant effects by acting on important targets such as catalase (CAT), CREB binding protein (CREBBP), epidermal growth factor (EGF), and E1A binding protein P300 (EP300), and by modulating the signaling pathways in which these targets are involved. Subsequently, the core targets were docked to the active ingredients and good binding was observed.ConclusionsThe active ingredients of Cordyceps sinensis may exert antidepressant effects by regulating the CREB binding protein and anti-oxidative stress effects. The foxo signaling pathway (hsa04068), hypoxia-inducible factor 1 (HIF-1) signaling pathway (hsa04066), and Huntington’s disease (hsa05016) may be involved in the underlying mechanisms of Cordyceps sinensis. The joint application of network pharmacology and molecular docking provides a new approach to study the mechanisms of action of traditional Chinese medicine. Cordyceps sinensis may play an important role in the future treatment of patients with depression.

Exploring the Potential Antidepressant Mechanisms of Pinellia by Using the Network Pharmacology and Molecular Docking.

About 350 million people worldwide suffered from depression, but less than half of the patients received effective and regular treatments. Traditional Chinese Medicine (TCM) such as pinellia has been proven effective for antidepressant treatment with fewer side effects. However, the exact mechanisms remain unclear. Herein, we use the methods of network pharmacology and molecular docking to analyze the effective monomer components of pinellia and reveal the involved signaling pathways to produce antidepressant effects. TCMSP, BATMAN-TCM, and TCMID databases were utilized to analyze the bioactive ingredients and target genes derived from pinellia via the screening the molecular weight (MW), oral bioavailability (OB), blood-brain barrier (BBB) and drug similarity (DL). OMIM, TTD, DisGeNET, GeneCards and DrugBank databases were used to obtain key genes of depression. Then, the networks of protein-protein interaction (PPI) and "medicine-ingredients-targets-pathways" were built. The target signaling pathways were enriched by GO and KEGG by using R language. Furthermore, bioactive ingredients binding of the targets were verified by molecular docking. Nine active monomer ingredients and 96 pivotal gene targets were selected from pinellia. 10,124 disease genes and 87 drug-disease intersecting genes were verified. GO analysis proposed that the receptor activity of neurotransmitter, postsynaptic neurotransmitter, G protein-coupled neurotransmitter, and acetylcholine through the postsynaptic membrane could be modulated by pinellia. KEGG pathway analysis revealed that pinellia influenced depression-related neural tissue interaction, cholinergic synapse, serotonin activated synapse and calcium signaling pathway. Besides, the reliability and accuracy of results obtained from the indirect network pharmacology were validated by molecular docking. The bioactive components of pinellia made significant antidepressant effects by regulating the key target genes/proteins in the pathophysiology of depression.

Integrated Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Zhi-Zi-Hou-Po Decoction in Depression.

Zhi-Zi-Hou-Po Decoction (ZZHPD) is a well-known traditional Chinese medicine (TCM) that has been widely used in depression. However, the antidepressant mechanism of ZZHPD has not yet been fully elucidated. The purpose of this study was to explore the pharmacological mechanisms of ZZHPD acting on depression by combining ultra flow liquid chromatography with quadrupole time-of-flight mass spectrometry (UFLC-Q-TOF/MS) and network pharmacology strategy. The chemical components of ZZHPD were identified using UFLC-Q-TOF/MS, while the potential drug targets and depression-related targets were collected from databases on the basis of the identified compounds of ZZHPD. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were used to unravel potential antidepressant mechanisms. The predicted antidepressant targets from the pharmacology-based analysis were further verified in vivo. As a result, a total of 31 chemical compounds were identified by UFLC-Q-TOF/MS; 514 promising drug targets were mined by using the Swiss Target Prediction; and 527 depression-related target genes were pinpointed by the GeneCards and OMIM databases. STRING database and Cytoscape’s topological analysis revealed 80 potential targets related to the antidepressant mechanism of ZZHPD. The KEGG pathway analysis revealed that the antidepressant targets of ZZHPD were mainly involved in dopaminergic synapse, serotonin synapse, cAMP, and mTOR signaling pathways. Furthermore, based on the animal model of depression induced by chronic corticosterone, the regulatory effects of ZZHPD on the expression of MAOA, MAOB, DRD2, CREBBP, AKT1, MAPK1, HTR1A, and GRIN2B mRNA levels as well as the cAMP signaling pathway and monoaminergic metabolism were experimentally verified in rats. Our study revealed that ZZHPD is expounded to target various genes and pathways to perform its antidepressant effect.

Protocatechuic acid attenuates chronic unpredictable mild stress induced-behavioral and biochemical alterations in mice

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice.

Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Promoting Autophagy via the AMPK Pathway.

Multiple lines of evidence have shown that neuroinflammation and autophagy are highly involved in the process of depression. Nobiletin (NOB) displays neuroprotective effects and anti-depressant-like effects. Given the evidence that NOB exerts anti-inflammatory effects and regulates autophagy, we investigate the anti-neuroinflammatory properties and the effect of regulating the autophagy of NOB and subsequently uncover the potential anti-depressant mechanisms of NOB. The behavioral changes of rats were observed after prolonged lipopolysaccharide (LPS) treatment and NOB administration. Rat hippocampus and BV2 cells treated by LPS and NOB were evaluated. The methods of real-time PCR analysis, Western blot, immunostaining, and adenovirus transfection were employed to determine neuroinflammation, autophagic markers, and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) activation. Our study showed LPS enhanced the expression of pro-inflammatory cytokines and NLRP3 inflammasome activation but inhibited autophagy in both rat hippocampus and BV2 cells. NOB significantly improved the behavioral deficits and ameliorated the neuroinflammation induced by LPS in rats. Furthermore, NOB promoted autophagy and attenuated NLRP3 inflammasome activation induced by LPS, involving in the process the adenosine monophosphate-activated protein kinase (AMPK) pathway. Neuroprotective and anti-depressant actions of NOB relied on its effects of promoting autophagy and suppressing the activation of NLRP3, in which process of AMPK pathway may be involved.

Could Suicide Be Fostered Through the Potential Antidepressant Mechanism of Biological Agents? A Psychodermatological Approach to Existing Bibliography

Background: Bipolar disorder (BD) is a biological condition that affects between 2% and 5% of the population. Despite this, it is often underdiagnosed as unipolar depression, which increases the possibility of prescribing errors. This could foster episodes of inverse polarity (“switching”) which, in turn, raises the risk of suicide. Objective: This work reviews the existing literature for evidence that while biological agents could improve the mood of patients with psoriasis treated with these drugs, this same favorable antidepressant effect on humor may trigger a switch into mania, favoring attempted and completed suicide in undiagnosed bipolar patients treated for psoriasis with the abovementioned agents. Method: A systematic review of the literature was performed for evidence. Based on their titles and abstracts, 48 relevant articles from 18 countries in English, Spanish, and French from 2004 to 2019 were selected for this review. Results: Inherently, all antidepressants can be associated with treatment-emergent affective switch (TEAS). Biological agents may modify the neurotransmitter levels either improving or worsening the mood. A plausible hypothesis arises on the double-edged nature of biological agents: they would have an antidepressant effect that would be beneficial to treat the psychiatric comorbidity of the patient with psoriasis. However, this same antidepressant effect, in a patient with genetic vulnerability for depression with a concomitant inflammatory disease, could trigger a mood alteration. Conclusion: Both BD and psoriasis should be considered as a multisystem entity with a common physiopathology. Consequently, it is vital to emphasize the importance of the initial psychiatric evaluation.

Extract of Euryale ferox Salisb exerts antidepressant effects and regulates autophagy through the adenosine monophosphate-activated protein kinase-UNC-51-like kinase 1 pathway.

Positive regulation of autophagy by Euryale ferox Salisb (ES) leads to antidepressant effects. This study focused on the potential antidepressant mechanisms induced by the petroleum ether fraction of ES (ES-PE) in the chronically unpredictable mild stress (CUMS) mouse model. Deficits in the sucrose preference test, open field test, tail suspension test, and forced swim test were observed following CUMS, and were reversed following ES-PE administration. Contrary to the expression of mammalian target of rapamycin, autophagy was decreased after establishment of the CUMS model. We also observed trends for downregulation of adenosine mononphosphate-activated protein kinase (AMPK) and mammalian autophagy-initiating kinase (ULK1), which were differentially affected by ES-PE. HT22 cells and Compound C, an inhibitor of AMPK, were used to verify the results in mice. Gas chromatography-mass spectrometry analysis revealed high level of vitamin E acetate in ES-PE. Taken together, our data indicate that ES-PE activated autophagy by regulating the AMPK pathway. © 2018 IUBMB Life, 70(4):300-309, 2018.

Insights into the potential antidepressant mechanisms of cilostazol in chronically restraint rats: impact on the Nrf2 pathway.

Ample evidence has pointed to a close link between oxidative stress, mitochondrial dysfunction, and depression. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of cellular redox homeostasis and affects mitochondrial function. Nrf2 holds promise for depression prevention and treatment. This study aimed to investigate the potential prophylactic antidepressant effect of cilostazol and the contribution of the Nrf2 pathway toward the putative neuroprotection. The behavioral and neurochemical effects of concomitant treatment of oral cilostazol at doses of 7.5, 15, and 30 mg/kg/day in Wistar rats exposed to chronic restraint stress (CRS) for 4 weeks were assayed. Cilostazol prevented CRS-induced depressive-like behavior shown in sucrose-preference, forced-swimming, and open-field tests, and hypothalamus-pituitary-adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Cilostazol prevented CRS-induced increase in hippocampal lipid peroxidation and 8-hydroxy-2'-deoxyguanosine, and a decrease in antioxidant activities (glutathione level, superoxide dismutase, and catalase). Western blot and PCR showed that cilostazol favorably modulated the Nrf2 protein and heme oxygenase-1 and NAD(P)H: quinone oxidoreductase-1 gene expression in the hippocampus of CRS rats. Cilostazol also prevented the decrease in the hippocampal activities of mitochondrial respiratory enzyme complexes I-IV. These behavioral and biochemical findings indicated the potential prophylactic antidepressant effect and mechanism of cilostazol by preventing oxidative stress by activation of redox defense mechanisms mediated through the Nrf2 pathway and restoring mitochondrial dysfunction.