Chronic Unpredictable Mild Stress Model Research Articles

Aurantii fructus immaturus carbonisata-derived carbon dots and their anti-depression effect.

Introduction: Depression is a common illness worldwide. However, the current treatments available for depression only achieve relative success, often come with several side effects, and are associated with high costs. Aurantii Fructus Immaturus (AFI) has a rich historical legacy in Traditional Chinese Medicine (TCM) for its traditional use as a treatment for depression. In this research, our primary objective is to examine the potential antidepressant properties and the mechanisms at play behind a particular bioactive compound found in AFI, which is referred to as carbon dots derived from AFI Carbonisata (AFIC-CDs). Methods: Extracted and isolated the AFIC-CDs from the decoction of AFIC, then characterized the morphological structure and functional groups comprehensively. We then utilized two distinct models to investigate the anti-depressive properties of AFIC-CDs: the chronic unpredictable mild stress (CUMS) model and the reserpine-induced pain-depression dyad model. In the CUMS model, we assessed immobile time and measured neurotransmitter levels in the mouse brain cortex. In the pain-depression dyad model, we evaluated immobile time, neurotransmitter levels, interleukin-1 (IL-1β) and tumor necrosis factor-α (TNF-α) levels, and the expression of mRNA of brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (Tph2). Results: AFIC-CDs were found to have abundant chemical groups, and their diameter ranged from 2 to 10nm. In the CUMS model, AFIC-CDs demonstrated significant effects. They reduced the immobile time of the mice and increased the levels of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in the mouse brain cortex. In the pain-depression dyad model, the AFIC-CDs groups decreased the immobile time, showed effect in increasing both the neurotransmitters' levels and the expression of mRNA of BDNF and Tph2, and decreased the IL-1β and TNF-α levels in mouse brain cortex. Taken together, these results strongly indicate that AFIC-CDs possess significant antidepressant activity. Conclusion: AFIC-CDs demonstrate promising therapeutic potential in the treatment of depression, suggesting that they may become a valuable candidate for depression management. This not only extends the understanding of the biological activity of carbon dots (CDs) but also opens up new possibilities for the development of effective depression treatment strategies.

Bifidobacterium pseudonumeratum W112 alleviated depressive and liver injury symptoms induced by chronic unpredictable mild stress via gut-liver-brain axis.

Several studies indicated that depression is associated with liver injury. The role of probiotics in alleviating depression is focused on improving the abnormalities of the central nervous system through the gut-brain axis, while the effect on liver injury is still unclear. The aim of this study was to elucidate the potential link between the antidepressant effect of a potential probiotic strain Bifidobacterium pseudocatenulatum W112 and its effect on alleviating liver injury. The 4-week-old Kunming mice were exposed to chronic stress for 4 weeks to establish a depression model. The depression-like behavior and related biomakers in chronic unpredictable mild stress (CUMS) mice were altered by supplemented with W112 for 2 weeks. Meanwhile, the modulation effect of W112 the gut microbiota in CUMS mice also result in an increase in the abundance of beneficial bacteria and a decrease in the abundance of harmful bacteria. Significantly, liver injury was observed in CUMS model mice. W112 improved liver injury by reducing AST/ALT in serum. Quantitative PCR results indicated that the mechanism of action of W112 in ameliorating liver injury was that the altered gut microbiota affected hepatic phospholipid metabolism and bile acid metabolism. In short, W112 could significantly improve the depressive and liver injury symptoms caused by CUMS. The gut-liver-brain axis is a potential connecting pathway between the antidepressant effects of W112 and its alleviation of liver injury.

Mechanism of GW117 antidepressant action: Melatonin receptor-mediated regulation of sleep rhythm

Alterations in circadian sleep patterns constitute a salient manifestation in major depressive disorder. GW117, an emergent antidepressant, functions as an agonist for melatonin 1 and melatonin 2 (MT1/MT2) receptors, in tandem with antagonism of the serotonin (5-HT) 2C receptor. The present investigation is dedicated to elucidating the role and underlying mechanisms by which GW117 ameliorates circadian sleep disruptions. Utilizing an adapted chronic unpredictable mild stress protocol, we induced a depressive-like phenotype and perturbed circadian rhythms in rodent models. Our methodological approach integrated quantitative polymerase chain reaction (qPCR) in real-time, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques to probe alterations in the expression of core circadian genes and homeostatic sleep markers. The impact of GW117 was assessed across various dosages (10, 20, and 40 mg/kg) on these molecular signatures. In a parallel examination, we evaluated the influence of GW117 (administered at 15, 40, and 60 mg/kg) on the sleep patterns of healthy mice. The results showed that GW117 significantly improved sleep-wake circadian rhythms, altered sleep architecture, and shortened sleep latency. Furthermore, GW117 increased the expression of several clock genes in the hypothalamus of chronic unpredictable mild stress model rats and normal mice. It also regulated circadian biomarkers, including melatonin and cortisol. Based on our findings, we propose that the beneficial effects of GW117 on sleep rhythms may be due to the melatonin system-mediated activation of the Wnt/β-catenin signaling pathway.

Kaempferol-3-O-sophoroside (PCS-1) contributes to modulation of depressive-like behaviour in C57BL/6J mice by activating AMPK.

Kaempferol-3-O-sophoroside (PCS-1) is the main component in Crocus sativus (Saffron), a herb with mood-enhancing properties. AMP-activated protein kinase (AMPK) is a potential therapeutic target for depression. This study explores the antidepressive-like properties of PCS-1 and its AMPK activation to confirm AMPK as a target for antidepression. Corticosterone (CORT)-induced PC12 cell injury served as an in vitro model to evaluate the neuroprotective effect of PCS-1. Neuro-2a cells and primary neurons were utilized to evaluate the synaptogenesis role of PCS-1. CORT-induced mouse depression model and chronic unpredictable mild stress (CUMS) model were used to assess the antidepressive-like properties of PCS-1 through behavioural tests, magnetic resonance imaging, and biochemical index measurements. Western blot and immunofluorescence assays were used to study the mechanisms of PCS-1. Cellular thermal shift assay was used to confirm the binding target. PCS-1 (12.5-50 μM) ameliorated CORT-induced PC12 cell damage, oxidative stress and inflammation. PCS-1 alone promoted an increase in synapses in Neuro-2a cells and primary neurons. Oral administration of PCS-1 (10 and 20 mg·kg-1 ) ameliorated weight loss, dyskinesia, and hippocampal volume reduction induced by CORT and CUMS. PCS-1 bound to AMPK to improve the expression of brain-derived neurotrophic factor (BDNF) and induce autophagy. PCS-1 binds to AMPK to promote BDNF production and autophagy enhancement, ultimately achieving antidepressant effects. This study provides support for the clinical application of saffron petals and provides further evidence for AMPK as a potential target for antidepression.

Preparation and Evaluation of Curcumin Derivatives Nanoemulsion Based on Turmeric Extract and Its Antidepressant Effect.

The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect. The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted. The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC(0-t) of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the Cmax was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration. TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.

The Antidepressant Activity of a Taurine-Containing Derivative of 4-Phenylpyrrolidone-2 in a Model of Chronic Unpredictable Mild Stress

This study investigates the therapeutic potential of a new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner’s chronic unpredictable mild stress model of male Wistar rats was used as a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group with saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light–dark box, were used to assess the animals’ conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to the intact animals. These results suggest that Compound I has reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

The antidepressant-like effect of NevGro® Forte in chronic unpredictable mild stress (CUMS) model of depression in rats

Depression is a leading cause of disability worldwide and it is a major contributor to the overall global burden of disease. Almost 320 million individuals globally are left untreated with depression and it has the highest prevalence. Although there are multiple conventional antidepressant types available, patients are still left untreated due to inadequate pharmacological effectiveness as well as the high rate of remissions, side effects, and patients’ non-compliance. Therefore, this study aims to determine the therapeutic effects of NevGro® Forte. The NevGro® Forte that contains a combination of three types of mushrooms, Lignosus rhinocerotis, Ganoderma lucidum and Hericium erinaceus, has been reported to have the therapeutic potential for alleviating depressive symptoms. Sixty Sprague Dawley rats induced to chronic unpredictable mild stress (CUMS) protocol were orally treated with NevGro® Forte daily for 4 weeks. Histological analysis was performed to probe the role of neurogenesis in mediating the therapeutic effect of NevGro® Forte. Fluoxetine (FLX) was orally administered to validate the neurogenesis-dependent mechanism of NevGro® Forte. The present study exhibited that 4 weeks of NevGro® Forte treatment ameliorated the depressive symptoms in CUMS rat model. There is a significant improvement in body weight, brain’s weight, and increased thickness of the pyramidal layer in the hippocampus following the treatment of NevGro® Forte. Scanning electron microscopy also revealed decreased degeneration characterised by flattened with less dense surface composition in the hippocampus. This research shows a positive outcome of using NevGro® Forte in ameliorating depressive symptoms.

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 relevanceZhi-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 studyThe aim of the study is to uncover the mechanisms of ZZHP's effect on depression. Materials and methodsC57BL/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. ResultsOur 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. ConclusionThis study demonstrates that ZZHP can alleviate depressive-like behavior and promote hippocampal neurogenesis in CUMS mice via activating the BDNF/TrkB/CREB pathway.

Ketamine Improves the Glymphatic Pathway by Reducing the Pyroptosis of Hippocampal Astrocytes in the Chronic Unpredictable Mild Stress Model.

Ketamine as a glutamate receptor antagonist has a rapid, potent, and long-lasting antidepressant effect, but its specific mechanism is still not fully understood. Depression is associated with elevated levels of glutamate and astrocyte loss in the brain; the exploration of the relationships between ketamine's antidepressant effect and astrocytes has drawn great attention. Astrocytes and aquaporin 4 (AQP4) are essential components of the glymphatic system, which is a brain-wide perivascular pathway to help transport nutrients to the parenchyma and remove metabolic wastes. In this study, we investigated pyroptosis-associated protein Nlrp3/Caspase-1/Gsdmd-N expression in the hippocampus of mice and the toxic effect of high levels of glutamate on primary astrocytes. On this basis, the protective mechanism of ketamine is explored. A single administration of ketamine (10 mg/kg) remarkably relieved anxious and depressive behaviors in the sucrose preference test, elevated plus maze test, and forced swim test. Meanwhile, ketamine reduced the level of hippocampus Nlrp3 and the expression of its downstream molecules in chronic unpredictable mild stress (CUMS) mice model by western blot and reduced the colocalization of Gfap and Gsdmd by nearly 25% via immunofluorescent staining. Ketamine also increased the Gfap-positive cells and AQP4 expression in the hippocampus of the CUMS mice. More important, ketamine increased the distribution of the fluorescent tracer of CUMS mice. Treatment with 128 mM glutamate in cortical and hippocampus astrocytes increased the level of Nlrp3, and Gsdmd-N, and ketamine alleviated high glutamate-induced pyroptosis-associated proteins. In summary, these results suggest that high glutamate-induced astrocyte pyroptosis through the Nlrp3/Caspase-1/Gsdmd-N pathway which was inhibited by ketamineandketamine can improve the damaged glymphatic function of the CUMS mice. The present study indicates that inhibiting astrocyte pyroptosis and promoting the glymphatic circulation function are a new mechanism of ketamine's antidepressant effect, and astrocyte pyroptosis may be a new target for other antidepressant medicines.

Widely targeted metabolomics unveils baicalin-induced hippocampal metabolic alternations in a rat model of chronic unpredictable mild stress

Baicalin has various neuroprotective effects in models of nervous system disease. Our study has shown baicalin could alleviate depressive-like behaviors in a neuroendocrine mouse model. But the systematic metabolic characteristic and particular targets of baicalin in regulating depressive behaviors have never been investigated. Therefore, this study aims to reveal the hippocampal metabolic profiling of chronic unpredictable mild stress (CUMS) induced depressive rats and the potential metabolic variations after baicalin treatment. We first used the sucrose preference test and open field test to access the antidepressant effects of baicalin. Then, metabolites of the hippocampus after baicalin therapy were monitored by widely-targeted metabolomics based on ultra-performance liquid chromatography-tandem mass spectrometry technology. Finally, the potential mechanism associated with neurogenesis obtained from metabolomics was verified by immunohistochemistry. The results showed that baicalin(40,80 mg/kg) could significantly alleviate depressive behaviors induced by CUMS as demonstrated by an increase in sucrose preference and movement distance and stand-up times in open field test. In the metabolomic analysis, a total of 733 metabolites were identified after baicalin treatment including 15 differential metabolites such as organic acid and its derivatives, heterocyclic compounds, fatty acid, bile acids, amino acid and its metabolites, and so on. Enrichment for differential metabolites showed that the differential metabolites might be involved in the process of folate and cofactor biosynthesis, cholesterol metabolism, primary bile acid biosynthesis, tyrosine metabolism and dopaminergic synapse. Moreover, immunohistochemical analysis confirmed baicalin could facilitate hippocampal neurogenesis of depressive rats in CUMS model. These results suggested baicalin might exert antidepressant effects through regulating the differential metabolites which might play a crucial role in inhibiting oxidative stress and improving neurogenesis. Our findings wish to discover the potential mechanism of baicalin on depression from the metabolomics perspective and promote its clinical application.

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

BackgroundIt is unclear whether acupuncture has a rapid antidepressant effect and what is the main mechanism. MethodsIn 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. ResultsThe 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. ConclusionsThe 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.

The Effects of Chronic Unpredictable Mild Stress and Semi-Pure Diets on the Brain, Gut and Adrenal Medulla in C57BL6 Mice.

Chronic stress is known to perturb serotonergic regulation in the brain, leading to mood, learning and memory impairments and increasing the risk of developing mood disorders. The influence of the gut microbiota on serotonergic regulation in the brain has received increased attention recently, justifying the investigation of the role of diet on the gut and the brain in mood disorders. Here, using a 4-week chronic unpredictable mild stress (CUMS) model in mice, we aimed to investigate the effects of a high-fat high-glycaemic index (HFD) and high-fibre fruit & vegetable "superfood" (SUP) modifications of a semi-pure AIN93M diet on behaviour, serotonin synthesis and metabolism pathway regulation in the brain and the gut, as well as the gut microbiota and the peripheral adrenal medullary system. CUMS induced anxiety-like behaviour, dysregulated the tryptophan and serotonin metabolic pathways in the hippocampus, prefrontal cortex, and colon, and altered the composition of the gut microbiota. CUMS reduced the catecholamine synthetic capacity of the adrenal glands. Differential effects were found in these parameters in the HFD and SUP diet. Thus, dietary modifications may profoundly affect the multiple dynamic systems involved in mood disorders.

Research on the mechanism of antidepressive effect of Suanzaoren Decoction through TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway

Ethnopharmacological relevanceIncreased inflammatory response and disruption of neuroplasticity are important mechanisms in the hypothesis of the pathogenesis of depression. Thus, these two aspects are conducive to the development of treatments for depression. Suanzaoren Decoction (SZRD) is a classic traditional Chinese medicine compound for the treatment of insomnia, which can clinically relieve depression symptoms, but its antidepressant pharmacological mechanism remains to be elucidated. Aim of this studyBased on the hypothesis of inflammation and neuroplasticity in depression, this study aimed to investigate the antidepressant effect of SZRD and its specific molecular mechanism through chronic unpredictable mild stress (CUMS) induced SD rat model and lipopolysaccharide (LPS) induced BV2 cell neuroinflammation model. Materials and methodsThe body weight and behavioral indexes of CUMS model rats treated with orally or without oral SZRD for 4 weeks were detected. Hematoxylin and eosin staining was used to observe brain pathological damage. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was used to observe neuronal apoptosis. Immunofluorescence, ELISA kit and Western blotting were used to detect the inflammatory index Iba-1 and inflammatory factors, as well as the important inflammatory pathway TLR4/MyD88/NF-κB. Enzyme linked immunosorbent assay (ELISA) and western blotting were used to detect neuroplasticity indexes proteins-brain-derived neurotrophic factor (BDNF), presynaptic membrane protein-synaptophysin (SYP), and postsynaptic protein- 95(PSD95), and the key pathway Wnt/β-catenin. The possible mechanism of SZRD antidepressant was further explored in LPS-induced BV2 cells. ResultsIn vivo and in vitro experiments showed that SZRD treatment significantly reversed the depression-like behaviors in rats, decreased the levels of inflammatory factors and increased the expression levels of BDNF, SYP, PSD95 in depression model rats. Furthermore, SZRD treatment inhibited the activation of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways and reduced the massive nuclear translocation of NF-κB and β-catenin. The addition of NF-κB pathway agonists could partially offset the inhibitory effect of SZRD on the Wnt pathway, and the addition of Wnt pathway agonists could also partially offset the inhibitory effect of SZRD on the TLR4 pathway. ConclusionThis study suggestted that SZRD may exert its antidepressant effect by regulating TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway in combination.

Akkermansia muciniphila Improves Depressive-Like Symptoms by Modulating the Level of 5-HT Neurotransmitters in the Gut and Brain of Mice

Accumulating evidence has suggested that the gut microbiome plays an important role in depression. Akkermansia muciniphila (AKK), a next-generation probiotic, shows a beneficial effect on immune and metabolic homeostasis. The relative abundance of AKK was found negatively correlated with depressive symptoms in both clinical and pre-clinical studies. To evaluate the potential antidepressant effect of AKK and explore the possible mechanism, we used chronic alcohol exposure and chronic unpredictable mild stress (CUMS) to induce depressive-like behaviors in mice. We found that oral AKK administration significantly reduced the immobility time in the force swimming test (FST) and tail suspension test (TST) in the mice with chronic alcohol exposure and the CUMS mice. The sucrose preference in the mice receiving AKK was significantly increased in the sucrose preference test (SPT). More importantly, AKK implantation significantly increased the level of 5-HT in the gut and PFC of both the alcohol exposure mice and the CUMS mice. Furthermore, AKK had inhibited the expression of SERT in the gut but not in the brain for both NIAAA and the CUMS model mice. Interestingly, the expression of cFos in enteric nerves in the gut significantly decreased after AKK administration. In conclusion, our study demonstrated the antidepressant effect of AKK in mice exposed to alcohol exposure and CUMS, with the potential mechanism that AKK implantation might lead to an increased level of 5-HT and inhibited SERT expression in the gut, and might alter the gut-to-brain signal through suppression of enteric nerves activation.

Fluoxetine Ameliorates the Aggravation of UC Symptoms in C57BL/6 Mice Induced by CUMS.

Patients with chronic ulcerative colitis (UC) often have mental symptoms such as depression and anxiety, and stress can lead to gastrointestinal diseases. However, the correlation between mental stress and UC is unclear. In this paper, chronic unpredictable mild stress (CUMS) was utilized to evaluate the involvement of mental factors in the pathogenesis of UC. The CUMS model was used to evaluate the direct/indirect involvement of mental factors in the pathogenesis of UC. The behavior was evaluated by the open field, forced swimming, and tail suspension tests. Body weight, the disease activity index (DAI) score, colon length, and HE staining of colon tissue were used to evaluate the action of CUMS and fluoxetine. The results showed that weight loss and the DAI score increased in CUMS mice, but they had no meaningful effect on colon length and morphological structure of colon tissue. However, CUMS aggravated dextran sulfate sodium (DSS)-induced colon length shortening and colon morphological structure damage. Fluoxetine significantly improved the DAI score, shortened colon length, and damaged morphology and structure of the colons induced by CUMS combined with DSS in mice. Fluoxetine also decreased the level of IL-6 in the serum and the TNF-α and IFN-γ levels of colon tissue. Fluoxetine simultaneously improved behavioral abnormalities induced by CUMS combined with DSS in mice. CUMS aggravated the UC symptoms induced by DSS, and fluoxetine could improve the UC symptoms due to its improvement in the inflammatory level and behavioral abnormalities.

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

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. 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. 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. Cucurbitacin B has the potential to be a novel antidepressant candidate.

Propolis prevents vascular endothelial dysfunction by attenuating inflammation and oxidative damage in the chronic unpredictable stress model of depression in rats.

Chronic stress may lead to depression and vascular endothelial dysfunction. We aimed to evaluate the effects of propolis on vascular functions and the possible mechanisms of its vascular effects in the rat model of chronic unpredictable mild stress (CUMS)-induced depression. Male Wistar rats were divided into control, stress (exposure to CUMS), control+propolis and stress+propolis groups (n = 8/each group). CUMS model was induced by exposing rats to various mild stressors daily for 5 weeks. The extract of propolis (100 mg/kg/day) was administered orally to propolis-treated groups for 5 weeks. The depression-like behaviours were assessed with the forced swimming test (FST). Chronic stress resulted in increased immobility response in FST and elevated serum corticosterone levels. Thoracic endothelial functions and expressions of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha (TNFα), interleukin-1beta (IL-1β), Heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) level were assessed. Compared to control group, stress group exhibited a significant decrease in endothelium-dependent relaxations, and eNOS, SOD and HO-1 expressions, whereas a significant increase in the thoracic expressions of TNFα and IL-1β. Propolis ameliorated depression-like behaviours, vascular endothelial dysfunctions and alterations of protein expressions. Propolis exerted antidepressant-like and vasculoprotective effects in CUMS-induced depression in rats. Chronic propolis treatment may have a protective effect on CUMS-induced vascular endothelial dysfunction by its anti-inflammatory and antioxidant effects.

Aerobic Exercise Improves Depressive-like Behavior in CUMS-Induced Rats via the SIRT3/ROS/NLRP3 Signaling Pathway.

This study aimed to investigate the effect of exercise on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in rats and to explore the role of the SIRT3/ROS/NLRP3 signaling pathway in this process. Twenty-nine male 8-week-old Sprague Dawley rats were divided into a control group (CON) (nine rats) and a model group (twenty rats). Thirteen chronic stress stimuli were randomly applied once or twice per day for 35 days to induce depression in the model group rats. After the model was established, the model group rats were randomly divided into the CUMS group (CUMS) and the aerobic exercise + CUMS group (EX + CUMS). The EX + CUMS group received 8 weeks of aerobic exercise intervention for 6 days per week. Behavioral assessments were performed using the sucrose preference test and forced swimming test. The expression of SIRT3, NLRP3, IL-1β, and IL-18 in the hippocampus was detected using RT-PCR. The ROS level in the hippocampus was detected using immunofluorescence. The protein levels of SIRT3 and NLRP3 in the hippocampus were detected using western blotting. The protein levels of IL-1β and IL-18 in the hippocampus were measured using ELISA. After 5 weeks of chronic stress stimuli, the hippocampal function of rats in the CUMS model group was impaired, and their sucrose preference was reduced, while their forced swimming time was prolonged. The expression of SIRT3 decreased, ROS increased, and the expression of NLRP3 and the levels of IL-1β and IL-18 increased. Aerobic exercise increased the sucrose preference of rats, shortened their immobility time, increased the expression of SIRT3, and reduced the levels of ROS, NLRP3, IL-1β, and IL-18. Exercise can improve the depressive behavior of CUMS model rats, and its mechanism may be related to the upregulation of SIRT3 in the hippocampus, which plays an anti-inflammatory role.

The beneficial effects of vortioxetine on BDNF, CREB, S100B, β amyloid, and glutamate NR2b receptors in chronic unpredictable mild stress model of depression.

Depression, one of the most significant mental disorders, is still poorly understood in terms of its pathogenetic mechanisms despite its well-recognized association with stress. The current study's goal was to ascertain how the novel antidepressant drug vortioxetine (VOR) affected the BDNF (brain-derived neurotrophic factor), S100, amyloid β (Aβ), CREB (cAMP response element-binding protein), and NR2B, as well as its impact on depression-like behaviors, and tissue damage in an experimental rodent model of depression caused by chronic unpredictable stress. We employed twenty-eight Wistar albino male rats, and we randomly divided them into four groups, each consisting of 7 rats: control, CUMS (chronic unpredictable mild stress), CUMS+vortioxetine (CUMS+VOR), and CUMS+fluoxetine (CUMS+FLU). Sucrose preference and forced swimming tests (SPT and FST, respectively), PCR, ELISA, and histopathological and immunohistochemical evaluation were made on brains. The behaviors of reduced immobility in the FST and increased sucrose preference were observed in the CUMS group and they improved in the groups treated with VOR and FLU. Compared with the control group, the group exposed to CUMS showed increased Aβ and decreased BDNF, CREB, and S-100 expressions, as well as neuronal degeneration (p<0.001). VOR and FLU treatment ameliorate the findings. This study demonstrated significant ameliorative effects of VOR in an experimental model of chronic unpredictable depression to reduce brain tissue damage and depression-like behaviors in rats. Effects of CUMS on the brain and possible effects of VOR.

Preclinical evidence evaluation of Xiaoyao san in treating chronic unpredictable mild stress model of depression based on meta-analysis

BackgroundIn view of the current challenges in the treatment of depression, in order to improve the efficacy and avoid adverse reactions, people pay attention to the treatment of traditional Chinese medicine. Xiaoyao san is a classic prescription commonly used in the treatment of depression, with the role of harmonizing liver and spleen, and shows great potential in the treatment of depression. PurposeThe purpose of this study is to comprehensively evaluate the efficacy and specific mechanism of Xiaoyao san in the treatment of chronic unpredictable mild stress (CUMS) model of depression through systematic evaluation and meta-analysis, so as to provide strong preclinical evidence for the clinical treatment of Xiaoyao san and provide a new strategy for the development of antidepressants. MethodsThe preclinical literature published before March 2023 was searched in Cochrane Library, PubMed, Web of Science, EMbase, CNKI, VMIS, Wan-Fang, and CBM and other database systems. Stata15 was used for overall effect analysis and subgroup analysis, and summarized the potential mechanism of action. ResultsA total of 25 studies were included, involving 569 animals. The average score of methodological quality was 7.48/10. Meta-analysis shows that Xiaoyao san can effectively improve food intake and body weight, restore sucrose consumption, reduce the immobility time in forced swimming, and increase the total exercise distance, grid crossing and upright times in the open field experiment. Its therapeutic effect is closely related to improving the abnormal activation of Hypothalamic-pituitary-adrenal axis and inhibiting the expression of glutamate. ConclusionTo sum up, in CUMS animal model, Xiaoyao san can significantly improve the symptoms of depression, restore the lost pleasure behavior and curiosity about the new environment, relieve tension and anxiety, and improve the occurrence of depression in many ways, which may be a new treatment strategy for CUMS model of depression.