Biomarker triterpenoids of Centella asiatica as potential antidepressant agents: Combining in vivo and in silico studies.

Although there are various treatments available for depression, some patients may experience resistance to treatment or encounter adverse effects. Centella asiatica (C. asiatica) is an ancient medicinal herb used in Ayurvedic medicine for its rejuvenating, neuroprotective and psychoactive properties. This study aims to explore the antidepressant-like effects of the major constituents found in C. asiatica, i.e., asiatic acid, asiaticoside, madecassic acid, and madecassoside at three doses (1.25, 2.5, and 5 mg/kg, i.p), on the behavioural and cortisol level of unpredictable chronic stress (UCS) zebrafish model. Based on the findings from the behavioural study, the cortisol levels in the zebrafish body after treatment with the two most effective compounds were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, a molecular docking study was conducted to predict the inhibitory impact of the triterpenoid compounds on serotonin reuptake. The in vivo results indicate that madecassoside (1.25, 2.5, and 5 mg/kg), asiaticoside and asiatic acid (5 mg/kg) activated locomotor behaviour. Madecassoside at all tested doses and asiaticoside at 2.5 and 5 mg/kg significantly decreased cortisol levels compared to the stressed group, indicating the potential regulation effect of madecassoside and asiaticoside on the hypothalamic-pituitary-adrenal axis overactivity. This study highlights the potential benefits of madecassoside and asiaticoside in alleviating depressive symptoms through their positive effects on behaviour and the hypothalamic-pituitary-adrenal (HPA)- axis in a chronic unpredictable stress zebrafish model. Furthermore, the in silico study provided additional evidence to support these findings. These promising results suggest that C. asiatica may be a valuable and cost-effective therapeutic option for depression, and further research should be conducted to explore its potential benefits.

Hypothalamic Gene Expression in a Rat Model of Chronic Unpredictable Mild Stress Treated with Electroacupuncture.

Depression is characterized by the loss of pleasure and a depressed mood, and it is a common mental disorder in the twenty-first century. Multiple gene imbalances, which are considered pathological factors in depression, were detected in the brain. Electroacupuncture is an effective therapeutic approach for depression that has minimal side effects. As a crucial structure in the hypothalamus-pituitary-adrenal, the hypothalamus plays a key role in depression. Our study focused on the transcriptome level in the hypothalamus of depressive rats. After chronic unpredictable mild stress, the rats exhibited depressive-like behaviors, such as decreased sucrose consumption in the SPT, increased time in the central area of the OFT and increased immobility in the FST. Moreover, electroacupuncture alleviated depressive behaviors. Because of the importance of the hypothalamus in depression, we next detected gene expression in the hypothalamus. A total of 510 genes (125 upregulated genes and 385 downregulated genes) were detected in the hypothalamus of depressive rats. 15 of the 125 upregulated genes and 63 of the 385 downregulated genes could be altered by electroacupuncture, which suggests the antidepressant effect of electroacupuncture. Our study also provided the evidence that regulation of transcriptome in the hypothalamus might be a potential mechanism of electroacupuncture treatment.

Early-life influenza A (H1N1) infection independently programs brain connectivity, HPA AXIS and tissue-specific gene expression profiles.

Early-life adversity covers a range of physical, social and environmental stressors. Acute viral infections in early life are a major source of such adversity and have been associated with a broad spectrum of later-life effects outside the immune system or "off-target". These include an altered hypothalamus-pituitary-adrenal (HPA) axis and metabolic reactions. Here, we used a murine post-natal day 14 (PND 14) Influenza A (H1N1) infection model and applied a semi-holistic approach including phenotypic measurements, gene expression arrays and diffusion neuroimaging techniques to investigate HPA axis dysregulation, energy metabolism and brain connectivity. By PND 56 the H1N1 infection had been resolved, and there was no residual gene expression signature of immune cell infiltration into the liver, adrenal gland or brain tissues examined nor of immune-related signalling. A resolved early-life H1N1 infection had sex-specific effects. We observed retarded growth of males and altered pre-stress (baseline) blood glucose and corticosterone levels at PND42 after the infection was resolved. Cerebral MRI scans identified reduced connectivity in the cortex, midbrain and cerebellum that were accompanied by tissue-specific gene expression signatures. Gene set enrichment analysis confirmed that these were tissue-specific changes with few common pathways. Early-life infection independently affected each of the systems and this was independent of HPA axis or immune perturbations.

Monomeric pilose antler peptide improves depression-like behavior in mice by inhibiting FGFR3 protein expression.

ETHNOPHARMACOLOGICAL RELEVANCE: It has been found that pilose antler peptide has an antidepressant effect on depression. However, the exact molecular mechanism of its antidepressant effect is still unclear. AIM OF THE STUDY: The study sought to determine the impact of monomeric pilose antler peptide (PAP; sequence LVLVEAELRE) on depression as well as investigate potential molecular mechanisms. MATERIALS AND METHODS: Chronic unexpected mild stress (CUMS) was used to establish the model, and the effect of PAP on CUMS mice was detected by the behavioral test. The influence of PAP on neuronal cells and dendritic spine density was observed by immunofluorescence and Golgi staining. FGFR3 and the CaMKII-associated pathway were identified using quantitative real-time polymerase chain reaction, and Western blot analysis was utilized to measure their proteins and gene expression levels. Molecular docking and microscale thermophoresis were applied to detect the binding of PAP and FGFR3. Finally, the effect of FGFR3's overexpression on PAP treatment of depression was detected. RESULTS: PAP alleviated the changes in depressive behavior induced by CUMS, promoted the growth of nerve cells, and the density of dendritic spines was increased to its original state. PAP therapy successfully downregulated the expression of FGFR3 and ERK1/2 while upregulating the expression of CREB, BDNF, and CaMKII. CONCLUSION: Based on the current research, PAP has a therapeutic effect on depression brought on by CUMS by inhibiting FGFR3 expression and enhancing synaptic plasticity.

Traditional Pediatric Massage Enhanced Hippocampal GR, BDNF and IGF-1 Expressions and Exerted an Anti-depressant Effect in an Adolescent Rat Model of CUMS-induced Depression.

This study aimed to investigate the anti-depressant effect of traditional pediatric massage (TPM) in adolescent rats and its possible mechanism. The adolescent depression model in rats was established by using chronic unpredictable mild stress (CUMS). All rats were randomly divided into five groups (seven per group), including the groups of control (CON), CUMS, CUMS with TPM, CUMS with back stroking massage (BSM) and CUMS with fluoxetine (FLX). The tests of sucrose preference, Morris water maze and elevated plus maze were used to evaluate depression-related behaviors. Plasma corticosterone (CORT) level was measured by ELISA. The gene and protein expressions of glucocorticoid receptor (GR), brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) were measured by RT-qPCR and IHC respectively. The results showed that CUMS induced depression-related behaviors in the adolescent rats, along with decreased weight gain and reduced hippocampal expressions of GR, IGF-1 and BDNF. TPM could effectively prevent depression-related behaviors in CUMS-exposed adolescent rats, manifested as increasing weight gain, sucrose consumption, ratio of open-arm entry, times of crossing the specific quadrant and shortening escape latency. TPM also decreased CORT level in plasma, together with enhancing expressions of GR, IGF-1 and BDNF in the hippocampus. These results may support the clinical application of TPM to prevent and treat adolescent depression.

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

ETHNOPHARMACOLOGICAL RELEVANCE: Radix 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 STUDY: The 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/ß-catenin/Olig2/Sox10 signaling axis as a potential antidepressant mechanism of TFA. MATERIALS AND METHODS: Male 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/ß-catenin/Olig2/Sox10 signaling axis in the antidepressant mechanism of TFA was validated through MO3.13 cells. RESULTS: TFA 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/ß-catenin pathway in the hippocampus of CUMS mice. Finally, we further confirmed the role of TFA in promoting myelin regeneration through the Wnt/ß-catenin/Olig2/Sox10 signaling axis in MO3.13 cells. CONCLUSIONS: TFA 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/ß-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.

Antidepressant effects of Parishin C in chronic social defeat stress-induced depressive mice.

ETHNOPHARMACOLOGY RELEVANCE: Parishin C (Par), a prominent bioactive compound in Gastrodia elata Blume with little toxicity and shown neuroprotective effects. However, its impact on depression remains largely unexplored. AIM OF THE STUDY: This study aims to investigate the antidepressant effects of Par using a chronic social defeat stress (CSDS) mouse model and elucidate its molecular mechanisms. MATERIALS AND METHODS: The CSDS-induced depression mouse model was used to evaluate the therapeutic efficacy of Par. The social interaction test (SIT) and sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were conducted to assess the effects of Par on depressive-like behaviours. The levels of corticosterone, neurotransmitters (5-HT, DA and NE) and inflammatory cytokines (IL-1ß, TNF-α, and IL-6) were evaluated by enzyme-linked immunosorbent assay (ELISA). Activation of a microglia was assessed by immunofluorescence labeling Iba-1. The protein expressions of NLRP3, ASC, caspase-1, and IL-6 verified by Western blot. RESULT: Oral administration of Par (4 and 8 mg/kg) and fluoxetine (10 mg/kg, administration significantly ameliorate depression-like behaviors induced by CSDS, as shown by the increase social interaction in SIT, increase sucrose preference in SPT and the decrease immobility in TST and FST. Par administration decreased serum corticosterone level and increased the 5-HT, DA and NE concentration in the hippocampus and prefrontal cortex. Furthermore, Par treatment suppressed microglial activation (Iba1) as well as reduced levels of IL-1ß, TNF-α, and IL-6) with decreased protein expressions of NLRP3, ASC, caspase-1, and IL-6. CONCLUSIONS: our study provides the first evidence that Par exerts antidepressant-like effects in mice with CSDS-induced depression. This effect appears to be mediated by the normalization of neurotransmitter and corticosterone levels, inhibition of NLRP3 inflammasome activation. This newfound antidepressant property of Par offers a novel perspective on its pharmacological effects, providing valuable insights into its potential therapeutic and preventive applications in depression treatment.

SCFAs Supplementation Rescues Anxiety- and Depression-like Phenotypes Generated by Fecal Engraftment of Treatment-Resistant Depression Rats.

Alteration of gut microbiota and microbial metabolites such as short-chain fatty acids (SCFAs) coexisted with stress-generated brain disorders, including depression. Herein, we investigated the effect of SCFAs in a treatment-resistant depression (TRD) model of rat. Rats were exposed to chronic-unpredictable mild stress (CUMS) and repeated adrenocorticotropic hormone (ACTH) injections to generate a TRD-like phenotype. The cecal contents of these animals were engrafted into healthy-recipient rats and allowed to colonize for 4 weeks (TRD-FMT group). Blood, brain, colon, fecal, and cecal samples were collected for molecular studies. Rats exposed to CUMS + ACTH showed TRD-like phenotypes in sucrose-preference (SPT), forced swim (FST), and elevated plus maze (EPM) tests. The TRD-FMT group also exhibited anxiety- and depression-like behaviors. Administration of SCFAs (acetate, propionate, and butyrate at 67.5, 25, and 40 mM, respectively) for 7 days exerted robust antidepressant and antianxiety effects by restoring the levels of SCFAs in plasma and fecal samples, and proinflammatory cytokines (TNF-α and IL-6), serotonin, GABA, norepinephrine, and dopamine in the hippocampus and/or frontal cortex of TRD and TRD-FMT animals. SCFAs treatment elevated the expression of free-fatty acid receptors 2/3, BDNF, doublecortin, and zonula-occludens, and reduced the elevated plasma levels of kynurenine and quinolinic acid and increased mucus-producing goblet cells in TRD and TRD-FMT animals. In 16S sequencing results, decreased microbial diversity in TRD rats corresponds with differences in the genus of Faecalibacterium, Anaerostipes, Allobaculum, Blautia, Peptococcus, Rombustia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-002, Solobacterium, Subdolibacterium, and Eubacterium ventriosum. SCFAs may impart beneficial effects via modulation of tryptophan metabolism, inflammation, neurotransmitters, and microbiota-gut-brain axis in TRD rats.

Atractylenolide I improves behaviors in mice with depression-like phenotype by modulating neurotransmitter balance via 5-HT2A.

To explore the antidepressant effects and targets of atractylenolide I (ATR) through a network pharmacological approach. Relevant targets of ATR and depression analyzed by network pharmacology were scored (identifying 5-HT2A targets). Through elevated plus maze, open field, tail suspension, and forced swimming tests, the behavioral changes of mice with depression (chronic unpredictable mild stress [CUMS]) were examined, and the levels of neurotransmitters including serotonin, dopamine, and norepinephrine (5-HT, DA, and NE) were determined. The binding of ATR to 5-HT2A was verified by small molecular-protein docking. ATR improved the behaviors of CUMS mice, elevated their levels of neurotransmitters 5-HT, DA, and NE, and exerted a protective effect on their nerve cell injury. After 5-HT2A knockout, ATR failed to further improve the CUMS behaviors. According to the results of small molecular-protein docking and network pharmacological analysis, ATR acted as an inhibitor by binding to 5-HT2A. ATR can improve the behaviors and modulate the neurotransmitters of CUMS mice by targeting 5-HT2A.

Dietary Co-supplements attenuate the chronic unpredictable mild stress-induced depression in mice.

Does it make a difference what we eat when it comes to our mental health? Food and nutrients are essential not only for human biology and physical appearance but also for mental and emotional well-being. There has been a significant increase in the favourable effects of dietary supplements in the treatment of depressive state in the latest days. Co-supplements which can be a great contribution in the management of depression from the future perspective and might help to reduce standard anti-depressant drug doses, which can be a strategic way to reduce the side effect of standard anti-depressants drugs. This study was designed to evaluate and compare the anti-depressant effects of cholecalciferol-D3 (V.D3), n-3 polyunsaturated fatty acid (PUFA), and a combination of V.D3 + n-3 PUFA with fluoxetine treatment in chronic unpredictable mild stress (CUMS) induced depression in the mice model. We established CUMS depressant mice model and treated CUMS mice with V.D3, n-3 PUFA, and a combination of V.D3 + n-3 PUFA with fluoxetine. Behavioral changes were measured by the forced swim and tail suspension test. Oxidative stress markers and anti-depressant activity were assessed through parameters such as superoxide dismutase, reduced glutathione, lipid peroxidation, and serum corticosterone levels. Additionally, we measured the levels of neurotransmitters dopamine and serotonin. CUMS induced mice displayed depressive-like behaviours. Moreover, cholecalciferol-D3, n-3 PUFA, and a combination of Cholecalciferol-D3 + n-3 PUFA with fluoxetine treatment attenuated the depressive-like behaviour in CUMS mice accompanied with suppression of oxidative stress markers by up-regulated the expression of an antioxidant signalling pathway. The results suggested that treatment of cholecalciferol-D3, n-3 PUFA, and a combination of Cholecalciferol-D3 + n-3 PUFA with fluoxetine significantly ameliorated depressive-like behaviours in CUMS induced depression in mice. To delve further into the implications of these findings, future studies could explore the specific molecular mechanisms underlying the observed effects on oxidative stress markers and the antioxidant signaling pathway. This could provide valuable insights into the potential of dietary supplements in the management of depression and help in reducing the reliance on conventional antidepressant medications, thus improving the overall quality of treatment for this prevalent mental health condition.

The rapid antidepressant effect of acupuncture on two animal models of depression by inhibiting M1-Ach receptors regulates synaptic plasticity in the prefrontal cortex.

BACKGROUND: It is unclear whether acupuncture has a rapid antidepressant effect and what is the main mechanism. METHODS: In this study, forced swimming stress test (FST) in mice were divided into five groups: control group, acupuncture group, scopolamine group, arecoline group, and acupuncture + arecoline group. Chronic unpredictable mild stress (CUMS) model rats were divided into six groups: naïve (non-CUMS) group, CUMS group, acupuncture group, scopolamine group, arecoline group, and acupuncture + arecoline group. Twenty-four hours after the end of treatment, FST was conducted in mice and rats. The expression of M1-AchR, AMPA receptors (GluR1 and GluR2), BDNF, mTOR, p-mTOR, synapsin I, and PSD95 in the prefrontal cortex was determined by western blot. The spine density of neurons in the prefrontal cortex was detected by golgi staining. RESULTS: The results showed that acupuncture reduced the immobility time of FST in two depression models. Acupuncture inhibited the expression of M1-AchR and promoted the expression of GluR1, GluR2, BDNF, p-mTOR, synapsin I, PSD95, and increased the density of neuron dendritic spine in the prefrontal cortex. CONCLUSIONS: The rapid antidepressant effect of acupuncture may be activating the "glutamate tide" - AMPA receptor activation - BDNF release - mTORC1 pathway activation through inhibiting the expression of M1-AchR in the prefrontal cortex, thereby increasing the expression of synaptic proteins and regulating synaptic plasticity.

Acupuncture alleviates CUMS-induced depression-like behaviors of rats by regulating oxidative stress, neuroinflammation and ferroptosis.

BACKGROUND: The treatment of depression with acupuncture has been documented. The mechanism behind acupuncture's curative and preventative effects is still unknown. METHODS: The current study examined the effects of acupuncture on depression-like behaviors in a rat model of chronic unpredictable mild stress (CUMS), while also exploring its potential mechanisms. A total of six groups of rats were randomly assigned: control, CUMS, acupuncture, fluoxetine, acupoint catgut embedding and sham acupoint catgut embedding. Fluoxetine (2.1 mg/kg) and acupoint catgut embedding were used for comparative research to acupuncture. The modelling evaluation is measured by body weight and behavior tests. Western blotting and reverse transcription-polymerase chain reaction were used to detect the proteins and mRNA expression of Silent information regulator 1 (Sirt1)/ nuclear factor-erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1)/ Glutathione peroxidase 4 (GPX4) pathway in the hippocampus. The expression of oxidative stress (OS)-related proteins and inflammatory cytokines in the serum was detected with ELISA. Immunofluorescence showed microglia and astrocytes activity in the hippocampus. RESULTS: Acupuncture and fluoxetine could alleviate CUMS-induced depression-like behaviors. Acupuncture was also found to effectively reverse the levels of MDA, SOD, GSH, GSH-PX and T-AOC, IL-1ß, IL-6 and TNF-α in the serum of CUMS-induced rats. Rats with CUMS showed decreased levels of Sirt1, Nrf2, HO-1 and GPX4 in the hippocampus, while acupuncture treatment could partly reverse the diminished effects. In addition, acupuncture treatment significantly reduced the activation of hippocampal microglia and astrocytes in CUMS-induced rats. CONCLUSION: The study's findings indicate that acupuncture has the potential to mitigate depression-like behaviors in rats induced with CUMS by mitigating OS and reducing neuroinflammation.

Zhi-Zi-Hou-Po decoction alleviates depressive-like behavior and promotes hippocampal neurogenesis in chronic unpredictable mild stress induced mice via activating the BDNF/TrkB/CREB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-Zi-Hou-Po decoction (ZZHP), a traditional Chinese medicine (TCM) classic recipe, has been extensively applied for the remedy of depression. However, the underlying mechanism of ZZHP hasn't been fully elucidated and it needs to be further clarified. AIM OF STUDY: The aim of the study is to uncover the mechanisms of ZZHP's effect on depression. MATERIALS AND METHODS: C57BL/6 mice were employed to establish Chronic Unpredictable Mild Stress (CUMS) models. Behavioral tests were conducted for evaluating the antidepressant effects of ZZHP. Then, the monoamine neurotransmitters in the hippocampus through High Performance Liquid Chromatography Electrochemical Detection (HPLC-ECD) were utilized to assess the effect of ZZHP on the maintenance of monoamine neurotransmitter homeostasis. Immunofluorescence staining and Golgi staining were detected to analyze the effects of ZZHP on neuroplasticity in the hippocampus. Western Blot (WB) was utilized to examine the effects of ZZHP on BDNF/TrkB/CREB pathways. Finally, behavioral tests, WB and immunofluorescence staining were repeated after TrkB receptor antagonist was added to further confirm the underlying mechanism. RESULTS: Our results shown that ZZHP attenuated depressive-like symptoms in CUMS mice. Moreover, ZZHP remarkably reversed the reduction and maintained the homeostasis of monoamine neurotransmitters in the hippocampus. Simultaneously, ZZHP protected neuronal synaptic plasticity and promoted hippocampal neurogenesis. Furthermore, ZZHP stimulated the BDNF/TrkB/CREB pathway in the hippocampus. The addition of TrkB receptor antagonist inhibited the antidepressant effects of ZZHP, suggesting that ZZHP could not work without triggering the BDNF/TrkB/CREB pathway. CONCLUSION: This study demonstrates that ZZHP can alleviate depressive-like behavior and promote hippocampal neurogenesis in CUMS mice via activating the BDNF/TrkB/CREB pathway.

Antidepressant-like Effect of Oroxylum indicum Seed Extract in Mice Model of Unpredictable Chronic Mild Stress.

Major depressive disorder (MDD) is one life-threatening disorder that is prevalent worldwide. The evident etiology of this disease is still poorly understood. Currently, herbal medicine is gaining more interest as an alternative antidepressant. Oroxylum indicum, which is used in traditional medicine and contains a potential antidepressive compound, baicalein, could have an antidepressive property. An in vitro monoamine oxidase-A (MAO-A) inhibitory assay was used to preliminarily screening for the antidepressant effect of O. indicum seed (OIS) extract. Mice were subjected to unpredictable chronic mild stress (UCMS) for 6 weeks, and the daily administration of OIS extract started from week 4. The mechanisms involved in the antidepressive activity were investigated. The OIS extract significantly alleviated anhedonia and despair behaviors in the UCMS-induced mouse model via two possible pathways: (i) it normalized the HPA axis function via the restoration of negative feedback (decreased FKBP5 and increased GR expressions) and the reduction in the glucocorticoid-related negative gene (SGK-1), and (ii) it improved neurogenesis via the escalation of BDNF and CREB expressions in the hippocampus and the frontal cortex. In addition, an HPLC analysis of the OIS extract showed the presence of baicalin, baicalein, and chrysin as major constituents. All of the results obtained from this study emphasize the potential of OIS extract containing baicalin and baicalein as an effective and novel alternative treatment for MDD.

Cucurbitacin B Exerts Significant Antidepressant-Like Effects in a Chronic Unpredictable Mild Stress Model of Depression: Involvement of the Hippocampal BDNF-TrkB System.

BACKGROUND: Although depression has been a serious neuropsychiatric disorder worldwide, current antidepressants used in clinical practice have various weaknesses, including delayed onset and low rates of efficacy. Recently, the development of new antidepressants from natural herbal medicine has become one of the important research hotspots. Cucurbitacin B is a natural compound widely distributed in the Cucurbitaceae and Cruciferae families and has many pharmacological activities. The present study aimed to investigate whether cucurbitacin B possess antidepressant-like effects in mice. METHODS: The antidepressant-like effects of cucurbitacin B on mice behaviors were explored using the forced swim test, tail suspension test, open field test, sucrose preference test, and a chronic unpredictable mild stress model of depression together. Then, western blotting and immunofluorescence were used to examine the effects of cucurbitacin B on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling cascade and neurogenesis in the hippocampus of mice. Furthermore, BDNF-short hairpin RNA, K252a, and p-chlorophenylalanine methyl ester were adopted together to determine the antidepressant mechanism of cucurbitacin B. RESULTS: It was found that administration of cucurbitacin B indeed produced notable antidepressant-like effects in mice, which were accompanied with significant promotion in both the hippocampal BDNF-TrkB pathway and neurogenesis. The antidepressant mechanism of cucurbitacin B involves the hippocampal BDNF-TrkB system but not the serotonin system. CONCLUSIONS: Cucurbitacin B has the potential to be a novel antidepressant candidate.

Sex shapes cell-type-specific transcriptional signatures of stress exposure in the mouse hypothalamus.

Stress-related psychiatric disorders and the stress system show prominent differences between males and females, as well as strongly divergent transcriptional changes. Despite several proposed mechanisms, we still lack the understanding of the molecular processes at play. Here, we explore the contribution of cell types to transcriptional sex dimorphism using single-cell RNA sequencing. We identify cell-type-specific signatures of acute restraint stress in the paraventricular nucleus of the hypothalamus, a central hub of the stress response, in male and female mice. Further, we show that a history of chronic mild stress alters these signatures in a sex-specific way, and we identify oligodendrocytes as a major target for these sex-specific effects. This dataset, which we provide as an online interactive app, offers the transcriptomes of thousands of individual cells as a molecular resource for an in-depth dissection of the interplay between cell types and sex on the mechanisms of the stress response.

[Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway].

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1ß), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

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.

Anti-depression-like effect of Mogroside V is related to the inhibition of inflammatory and oxidative stress pathways.

Siraitia grosvenorii (SG) is an edible medicinal plant found mainly in Guangxi, China, and Mogroside V (MGV) is the main component of SG extract. Previous research has shown that SG and MGV exert anti-inflammatory, antioxidative and neuroprotective effects. However, it is not clear whether MGV has anti-depression-like effect. In this study, we evaluated the neuroprotective effects and anti-depression-like effect of MGV both in vitro and in vivo. By performing in vitro tests, we evaluated the protective effects of MGV on PC12 cells with corticosterone-induced injury. In vivo tests, we used the chronic unpredictable mild stress (CUMS) depression model. Fluoxetine (10 mg/kg/day) and MGV (10 or 30 mg/kg/day) were administered by gavage for 21 days, and the open field test (OFT), novelty suppressed feeding test (NSFT), Tail suspension test (TST), and forced Swimming test (FST) were used to evaluate the depressive-like behaviors. In addition, we investigated the role of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and anti-inflammatory cytokine (IL-4) in the hippocampal and cortex tissues. The levels of Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-PX) in hippocampal and cortex tissues were also measured. Pathological changes in the hippocampal dentate gyrus and cortex regions were detected by immunofluorescence and Western blotting was used to measure the protein expression of BDNF, TrkB, TNF-α, and AKT. The results showed that MGV had a protective effect on PC12 cells with corticosterone-induced incurred injury. In addition, MGV treatment relieved the depressive symptoms and significantly reduced inflammatory levels (IL-1ß, IL-6, and TNF-α). MGV also significantly reduced oxidative stress damage and reduced the levels of apoptosis in hippocampal nerve cells. These results suggested that the anti-depressive effect of MGV may occur through the inhibition of inflammatory and oxidative stress pathways and the BDNF/TrkB/AKT pathway. These findings provide a new concept for the identification of new anti-depressive strategies.

The effects of acupuncture on depression by regulating BDNF-related balance via lateral habenular nucleus BDNF/TrkB/CREB signaling pathway in rats.

Depression is a major mental disease worldwide, causing dysfunction of Lateral Habenular (LHb). As a non-invasive alternative, acupuncture (AP) has been widely used to treat depression in clinic, yet few basic studies have been focused on the effects and mechanism of acupuncture on synaptic plasticity in LHb. Therefore, this study aimed to explore the potential mechanism of the antidepressant effect of acupuncture. Male Sprague-Dawley (SD) rats were randomly divided into control, chronic unpredictable mild stress (CUMS), AP, fluoxetine (FLX), acupoint catgut embedding (ACE), sham-ACE groups (n = 9/group). Rats were given a 28-day treatment at the Shangxing (GV23) and Fengfu (GV16) acupoints with acupuncture, ACE, sham-ACE or fluoxetine (2.1 mg/kg). The results showed that AP, FLX and ACE suppressed the behavioral deficits, increased the level of the 5-hydroxytryptamine and FNDC5/IRISIN in serum, also reduced the expression of pro-BDNF impacted by CUMS. Both AP and FLX ameliorated the %area of IBA-1, GFAP, BrdU and DCX in the LHb and increased the expression of BDNF/TrkB/CREB, with non-significant difference between the two groups These findings suggest that AP therapy relieves depression-related manifestations in depressed rats, suggesting a potential mechanism via the BDNF/TrkB/CREB pathway in LHb.