Chronic Unpredictable Mild Stress-induced Depression Research Articles

Low polarity fraction of Radix Bupleuri alleviates chronic unpredictable mild stress-induced depression in rats through FXR modulating bile acid homeostasis in liver, gut, and brain

Radix Bupleuri (BR, Bupleurum chinense DC.) is a well-known traditional Chinese medicine (TCM) known for its effects on soothing the liver and alleviating depression, and is widely used in clinical settings to manage depressive symptoms. A dosage of 12.5g crude drug/kg/d of the low-polarity fraction of Radix Bupleuri (LBR) demonstrated effectiveness in treating depression in our previous study. However, the mechanism through which BR ameliorates depression remains unclear. This study aimed to explore the polar fractions of BR and their mechanisms of action in the treatment of depression. Chronic unpredictable mild stress (CUMS) rats were continuously administered BR by oral gavage for 4 weeks. Behavioral and biochemical indicators were evaluated to assess the antidepressant effects of LBR, and transcriptomics was used to explore the relevant pathways. In addition, pseudo-targeted bile acid (BA) metabonomics was used to quantify the BA profiles. Molecular biology techniques have been used to investigate the underlying mechanisms. LBR serves as a more effective active fraction with antidepressant activity. Intervention with LBR, which is characterized by a clearly defined chemical composition, significantly ameliorated depression-like behavior and biochemical indicators in rats subjected to CUMS. Notably, marked improvements were observed in the levels of total bile acids (TBAs) in the blood, liver, and ileum. Mechanistically, liver transcriptome analysis suggested that bile secretion may be a crucial pathway for alleviating depression after LBR treatment. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) BA metabonomics indicated that TCA, β-MCA, γ-MCA, Tβ-MCA, and UDCA in the liver, Tβ-MCA, TCA, βMCA, GHDCA, and GLCA in the ileum, and β-MCA, CA, and DCA in the hippocampus were the potential therapeutic targets. In addition, molecular biology experiments showed that LBR exerts antidepressant effects by regulating the FXR/SHP/CYP7A1 pathway in the liver, the FXR/FGF15/ASBT pathway in the ileum, and the FXR/CREB/BDNF pathway in the hippocampus. In conclusion, LBR attenuated depression by moderating BA homeostasis through FXR and related genes within the liver-gut-brain axis.

Effects of chronic unpredictable mild stress-induced depression on bitter taste receptor expression in mice

ObjectiveWith the rapid increase in the pace of life, people are facing increasing pressures of all kinds, and depression has gradually become a serious psychological disorder in human society, strongly affecting normal social and physiological activities. Depression can disrupt an individual's taste perception and potentially result in taste disorders by affecting and altering taste receptors. This disruption can consequently impact their food preferences and overall eating experiences. DesignIn this study, we used the chronic unpredictable mild stress (CUMS) method to establish a depression model in male C57BL/6 J mice and explored the changes in taste receptor expression in the lingual circumvallate papillae (CP) to elucidate the effects of depression on taste. After 6 weeks of CUMS, behavioral performance evaluations, such as forced swim, open field, and elevated plus maze tests, were conducted in depression model mice. A further two-bottle choice test was subsequently performed to determine the effect of depression on bitter taste, and the expression of bitter taste receptors in the lingual CP was detected via immunofluorescence staining. ResultsIn this study, we found for the first time that mice with CUMS-induced depression had decreased bitter taste sensitivity through a two-bottle choice test and demonstrated that the expression of T2r5, a receptor related to bitter taste perception, and the expression of secondary taste signaling proteins in the lingual CP were significantly decreased in mice exposed to CUMS, as determined via qRTPCR and immunofluorescence staining. ConclusionsOur study highlights how CUMS influences the perception of bitterness in the peripheral taste system, potentially elucidating stress-induced changes in eating habits.

Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-Induced Depression Model in Rats

Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-Induced Depression Model in Rats

Evaluation of Anti-Depressant Potential of Standardized Hydroethanolic Extract of S. barbata D. Don Using Chronic Unpredictable Mild Stress Model

Background: S. barbata D. Don is a Chinese herb, that belongs to the family Lami-aceae. It has established traditional use in ethnomedicine for treating various ailments, includ-ing mood disorders and sleep disorders, which led to growing interest in exploring its neuro-logical potential, particularly as a potential anti-depressant agent. Aims: This study explores the anti-depressant potential of the HSBE utilizing a Chronic Un-predictable Mild Stress-induced depression model in mice. Additionally, the research aims to elucidate the underlying mechanisms of action. Methods: Swiss albino mice were subjected to a 3-week CUMS paradigm and subsequently administered HSBE at doses of 200 and 400 mg/kg via oral administration. The behavioral alterations were evaluated using the FST, TST, OFT, and SPT. Brain levels of serotonin, dopa-mine, and nor-epinephrine were estimated in different brain regions (cortex, hippocampus, and hypothalamus) to uncover the molecular mechanism. Additionally, assays for monoamine oxi-dase-A, monoamine oxidase-B, and antioxidant enzyme activities were conducted. Plasma ni-trite and corticosterone levels were also measured to get further insight into potential mecha-nisms underlying the anti-depressant effects of HSBE. Results: HSBE significantly ameliorated depressive-like behavior induced by CUMS para-digm, as evidenced by reduced immobility in FST and TST, increased locomotor activity in OFT, and improved sucrose preference in SPT. Neurochemical analysis revealed a significant increase in serotonin, dopamine, and norepinephrine levels in the cortex, hippocampus, and hypothalamus of HSBE-treated mice, implying a potential regulation of monoaminergic neuro-transmitter levels. Moreover, biochemical analyses demonstrated a significant inhibition of both MAO-A and MAO-B activity, contributing to the increase of the brain levels of neuro-transmitters. The administration of HSBE also led to a significant enhancement of antioxidant enzyme activities and reduced brain lipid peroxidation, indicating a pronounced antioxidant effect of HSBE. Furthermore, decreased plasma nitrite and corticosterone levels provided ad-ditional insights into HSBE's potential multi-targeted anti-depressant mechanism. Conclusion: This study indicates that HSBE exhibits robust anti-depressant properties, sup-ported by behavioral, neurochemical, and biochemical alterations. These findings underscore the therapeutic promise of HSBE as a natural intervention for depressive disorders, warranting further clinical exploration.

Light and classical music therapies attenuate chronic unpredictable mild stress-induced depression via BDNF signaling pathway in mice

Depression, a pervasive mental health issue, often necessitates innovative therapeutic interventions. This study explores the efficacy of music therapy, a non-pharmacological approach, in ameliorating depression symptoms in a murine model. Employing a chronic unpredictable mild stress (CUMS) model to induce depressionlike behaviors in mice, we investigated the therapeutic potential of four distinct music genres: light, classical, atonal composition, and rock music. Behavioral assessments, including sucrose preference and immobility time, were conducted to evaluate the impact of music therapy. Additionally, we measured the levels of brain-derived neurotrophic factor (BDNF), synaptic proteins and neurogenesis to elucidate the underlying biological mechanisms. Our findings indicated that light and classical music significantly alleviated depression-like behaviors in mice, evidenced by increased sucrose preference and reduced immobility time. Conversely, atonal composition and rock music did not yield similar therapeutic benefits. Biochemically, light and classical music were associated with decreased levels of corticosterone and increased levels of glucocorticoid receptor, alongside enhanced BDNF signaling, synaptic proteins and neurogenesis. In conclusion, the study demonstrates that specific genres of music, notably light and classical music, may contribute to alleviating depression-like symptoms, potentially through mechanisms associated with BDNF signaling and neurogenesis. These results highlight the potential of targeted music therapy as a complementary approach in treating depression, with implications for its incorporation into broader therapeutic regimes. Further re-search is warranted to translate these findings into clinical practice.

Plasma exosomal miR-30a-5p inhibits osteogenic differentiation of bone marrow mesenchymal stem cells from a chronic unpredictable mild stress-induced depression rat model

With rising society stress, depression-induced osteoporosis is increasing. However, the mechanism involved is unclear. In this study, we explored the effect of plasma exosomal miRNAs on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation in a chronic unpredictable mild stress (CUMS)-induced depression rat model. After 12 weeks of CUMS-induced depression, the pathological changes in the bone tissue and markers of osteogenic differentiation were tested by micro-computed tomography, hematoxylin-eosin staining, and quantitative real-time reverse transcription PCR (qRT-PCR). Plasma exosomes from rats were isolated and co-incubated with BMSCs for 14 d to detect the effect on osteogenic markers. Next-generation sequencing identified the miRNAs in the plasma exosomes, and the differential miRNAs were analyzed and verified by qRT-PCR. BMSCs were infected with lentivirus to upregulate miRNA-30a-5p and incubated in a medium that induced osteogenic differentiation for 14 d. The effect of miR-30a-5p on osteogenic differentiation was determined by qPCR and alizarin red staining. CUMS-induced depression rat model was established successfully, and exhibited reduced bone mass and damaged bone microstructure compared to that of the controls. The observed pathological changes suggested the occurrence of osteoporosis in the CUMS group, and the mRNA expression of osteogenic markers was also significantly reduced. Incubation of BMSCs with plasma exosomes from the CUMS group for 14 d resulted in a significant decrease in the expression of osteogenic markers. Twenty-five differentially expressed miRNAs in plasma exosomes were identified and upregulation of miR-30a-5p was observed to significantly inhibit the expression of osteogenic markers in BMSCs. Our findings contributed to a comprehensive understanding of the mechanism of osteoporosis caused by depression, and demonstrated the potential of miR-30a-5p as a novel biomarker or therapeutic target for the treatment of osteoporosis.

Quercetin attenuates brain apoptosis in mice with chronic unpredictable mild stress-induced depression

BackgroundDepression is a common psychiatric disorder with limited effective treatments. Research suggests that depression involves apoptosis mechanisms. Quercetin (QUE) has been reported to have anti-apoptotic activities. In this study, we aimed to investigate the effects and mechanisms of QUE in chronic unpredictable mild stress (CUMS)-induced depression. MethodsAfter establishing mouse models of CUMS-induced depression, the mice were randomly assigned into four groups: control, CUMS, CUMS+QUE, and CUMS+Fluoxetine (FLX). The body weight of the mice was measured during the study. Then, depression-associated behaviors were evaluated using the sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST) and tail suspension test (TST). Apoptosis in the hippocampus and prefrontal cortex was determined using flow cytometry. Bcl-2 and Nrf2 protein expressions in the hippocampus and prefrontal cortex were also detected. Furthermore, Western blot was used to measure the protein levels of p-ERK, ERK, p-CREB, CREB, and Nrf2 in brain tissues. ResultsQUE or FLX administration increased the body weight of the CUMS mice. Behavioral tests indicated that CUMS mice developed a state of depression, but QUE or FLX treatment improved their depression-associated behaviors. Meanwhile, QUE or FLX treatment decreased apoptosis in the hippocampus and prefrontal cortex. Furthermore, the decreased Nrf2 protein expression, ERK and CREB phosphorylation in CUMS group were enhanced by QUE or FLX administration. ConclusionQUE could attenuate brain apoptosis in mice with CUMS-induced depression, and the mechanism may be related to the ERK/Nrf2 pathway, indicating that QUE could be a potential treatment for depression.

Retracted: Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-induced Depression Model in Rats

Retracted: Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-induced Depression Model in Rats

Methanol leaf extract of Leptadenia hastata ameliorates chronic, unpredictable, mild stress-induced depression

Leptadenia hastata (Pers) Decne is a tropical herb widely used in the phytotherapy of neuropsychiatric disorders, including depression. Despite the availability of synthetic antidepressant drugs, depression remains a major medical problem. The study aimed to evaluate the effect of methanol leaf extract of Leptadenia hastata (LHME) on chronic unpredictable mild stress-induced depression. Acute toxicity of Leptadenia hastata was determined using Organization for Economic Co-operation and Development (OECD) guidelines. The chronic unpredictable mild stress (CUMS) model-induced depression involves the evaluation of baseline behavioural changes in the sucrose preference test, open field test, and tail suspension test. The brain-derived neurotrophic factor (BDNF) concentrations and serum cortisol were assessed using an enzyme-linked immunosorbent assay (ELISA). The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were also assessed using standard procedure. The median lethal dose (LD50) value was > 5000 mg/kg. LHME at doses of 250 – 1000 mg significantly (p<0.01) decreased CUMS-induced depression in a dose-dependent manner. LHME significantly (p<0.01) reversed depression associated weight loss from 14.00±0.62 g in week two to 22.57±1.13 g in week five of the experiment. It also increased sucrose consumption in the sucrose preference test (SPT) from 4.29±0.52 ml in week two to 9.71±0.68 ml in week five. The LHME also significantly (p<0.01) decreased the duration of immobility from 190.00±4.55 sec in week two to 158.00±3.83 sec in week five in the tail suspension test (TST). Furthermore, LHME at the tested dose significantly (p<0.01) increased the locomotor activity from 36.29±1.25 sec in week two to 62.43±1.73 sec in week five in the open field test (OFT). LHME significantly (p<0.01) and dose-dependently increased the levels of BDNF (204.74±22.97 pg/ml) and decreased the levels of plasma cortisol (0.98±0.06 ng/ml). However, treatment with LHME and the standard drug imipramine did not significantly change SOD activity and the MDA level in CUMS-induced mice. The findings demonstrated that LHME ameliorates CUMS-induced depressive-like behaviours, and its effect is possibly mediated via the neuroendocrine (cortisol) and neurotrophic (BDNF).

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.

Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model.

To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on 1H-NMR metabolomics techniques, and to explore the potential mechanisms of exercise for the treatment of depression. Rats were randomly divided into blank control group (C), CUMS control group (D), pre-exercise with CUMS group (P), CUMS with aerobic exercise group, CUMS with resistance exercise group (R), and CUMS with aerobic + resistance exercise group (E). The corresponding protocol intervention was applied to each group of rats. Body weight, sucrose preference and open field tests were performed weekly during the experiment to evaluate the extent of depression in rats. Plasma samples from each group of rats were collected at the end of the experiment, and then the plasma was analyzed by 1H-NMR metabolomics combined with multivariate statistical analysis methods to identify differential metabolites and perform metabolic pathway analysis. (1) Compared with the group D, the body weight, sucrose preference rate, and the number of crossings and standings in the different types of exercise groups were significantly improved (p < 0.05 or p < 0.01). (2) Compared to group C, a total of 15 differential metabolites associated with depression were screened in the plasma of rats in group D, involving 6 metabolic pathways. Group P can regulate the levels of 6 metabolites: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group A can regulate the levels of 6 metabolites: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose and acetoacetic acid. Group R can regulate the levels of 6 metabolites: choline, lactate, inositol, glucose, phosphocreatine and acetoacetic acid. Group E can regulate the levels of 5 metabolites: choline, citric acid, glucose, acetone and acetoacetic acid. The different types of exercise groups can improve the depressive symptoms in CUMS rats, and there are common metabolites and metabolic pathways for their mechanism of effects. This study provides a powerful analytical tool to study the mechanism of the antidepressant effect of exercise, and provides an important method and basis for the early diagnosis, prevention and treatment of depression.

Development of a novel UHPLC-MS/MS method for the quantification of corynoxeine: Application to pharmacokinetics and tissue distribution studies in normal and chronic unpredictable mild stress-induced depression rats

Corynoxeine, a natural active alkaloid found in Genus Uncaria, has been reported to have anti-depressant effects. In this study, a sensitive and efficient ultra-high performance liquid chromatography tandem mass spectrometry method for quantifying corynoxeine in rat plasma and tissues was established, validated and applied to investigate the pharmacokinetics and tissue distribution differences between normal rats and chronic unpredictable mild stress (CUMS)-induced depression model rats following oral administration. All bio-samples were prepared by methanol protein precipitation method with theophylline as internal standard (IS). Chromatographic separation was conducted on an Agilent ZORBAX Eclipse Plus C18 column using mobile phase A (acetonitrile) and B (0.1% formic acid in water) in gradient elution mode with a flow rate of 0.3 mL/min. Mass spectrometric detection was performed in multiple-reaction monitoring mode with positive electrospray ionization source. The transitions of m/z 383.0→160.2 for corynoxeine and m/z 181.1→124.0 for IS were chosen for quantification. The method showed good linearity, stability, accuracy, precision, recovery, and non-significant matrix effect, which were within the acceptable ranges. The pharmacokinetic results revealed that the absorption and bioavailability of corynoxeine in depression rats decreased compared to normal rats. The tissue distribution of corynoxeine trended to be mostly in the intestine and stomach and the distribution of this compound in intestine tissue of depression rats was significantly increased compared to the normal rats. The pharmacokinetics and tissue distribution profiles of corynoxeine were altered in CUMS-induced depression rats compared to normal rats and these experimental findings could provide beneficial information to the mechanism research and clinical applications of corynoxeine.

Association between rare earth elements and depression: Evidence from pilot mice model of chronic unpredictable mild stress-induced depression and human studies of major depressive disorder

The etiology of Major Depressive Disorder (MDD) has been associated with levels of trace elements in the human body. The source of trace elements in the human body may be rare earth elements (REEs). Our study aimed to identify the potential relationship between t REEs in blood and brain samples and depression from two paths: animal experiments and population studies. In the animal experiments, 35 adult Sprague–Dawley rats were randomly allocated to the control group (n = 14) and treatment group (n = 21), which received the chronic unpredictable mild stress (CUMS) procedure for four weeks and further categorized into the sensitive group (n = 9) and resilient group (n = 12) by sucrose water preference test. Then, all rats were executed to obtain serum and brain tissue samples. We also recruited 197 participants and divided them into the major depressive disorder (MDD) group (n = 100) and the control group (n = 97) then serum samples were collected for REEs detection. Our finding reported that significant differences were found in the levels of La and Ce in blood samples from different groups in the CUMS rat model (sensitive group < resilient group < control group) (all p < 0.05), with similar patterns for other elements (Pr, Nd, and Y) (but p > 0.5). No significant inter-group difference was reported in rat brain tissue samples. After adjusting for demographic variables, we found that the concentrations of all five REEs (La, Ce, Pr, Nd, Y) were lower in depression group than in control group (all p < 0.01). The current conjoint animal and human data supported appropriate levels of REEs have a certain protective effect on body health. These results may be attributed to Hormesis effects. Whether the possible favorable effects of REEs on improving symptoms of depression or can be applied to drug development remains to be further investigated.

Inhibition of ferroptosis alleviates chronic unpredictable mild stress-induced depression in mice via tsRNA-3029b

Depression is a common mental illness. Ferroptosis is a form of cell death that may be responsible for neurological disease, but the role of ferroptosis in depression remains unclear. tRNA-derived small RNA (tsRNA) is an emerging non-coding small RNA, making it an important medium for studying neurological diseases. Chronic unpredictable mild stress (CUMS) was used to construct the depression model in mice, which was treated with ferrostatin-1 (Fer-1). Classical behavioral test, immunofluorescence and small RNA sequencing were used to detect depression-like behaviors, neuronal proliferation and the expression profile of tsRNAs in mice, respectively. The primary neuronal cell damage model was constructed by corticosterone (CORT), and the function of key tsRNA was investigated by quantitative real-time PCR, western blot and CCK-8 assays. Here, Fer-1 reduced the depression-like behavior of CUMS-induced mice and promoted neuronal growth. In addition, CUMS caused the disorder of tsRNA expression profile in hippocampal tissues of mice, and Fer-1 alleviated the abnormal tsRNA expression, among which tsRNA-3029b was an effective target. In vitro experiments manifested that ROS accumulation and decreased expression of SLC7A11 and GPX4 were found in CORT-induced depression-like cell model, suggesting that ferroptosis was involved in neuronal injury. However, inhibition of tsRNA-3029b suppressed neuronal cell ferroptosis and facilitated neuronal regeneration. In conclusion, Fer-1 showed an antidepressant effect in CUMS-induced mice and alleviated the abnormal expression profile of tsRNA. tsRNA-3029b was a key target in depression, and silencing of tsRNA-3029b reduced the occurrence of ferroptosis and protected neurons from injury, which may provide novel target for the treatment of depression.

Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-induced Depression Model in Rats

Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-induced Depression Model in Rats

Areca catechu L. ameliorates chronic unpredictable mild stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway

ObjectivesIn this study, we have investigated the anti-depressant effects of the fruit Areca catechu L. (ACL) and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress (CUMS). MethodsCUMS was induced in rats to establish a depression animal model for 28 days. According to the baseline sucrose preference, the male rats were divided into 6 different groups. They were treated with paroxetine hydrochloride, ACL, and water once a day until the behavioral tests were performed. The levels of corticosterone (CORT), malondialdehyde (MDA), catalase (CAT), and total superoxide dismutase (T-SOD) in serum were detected using a commercial kit, and the concentrations of 5-hydroxytryptamine (5-HT) and dopamine (DA) monoamine neurotransmitters in the brain tissues were detected by liquid chromatography-tandem mass spectrometry. doublecortin (DCX) expression in the hippocampal dentate gyrus (DG) was determined by immunofluorescence, and the relative abundance of brain-derived neurotrophic factor (BDNF), TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β of brain tissues were assayed by western blot. ResultsACL markedly increased sucrose preference, decreased the immobility time, and shortened the feeding latency of CUMS-induced rats. CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters (5-HT and DA) in the hippocampus and cortex of brain tissues and the levels of CORT, MDA, CAT, and T-SOD in serum, whereas ACL administration alleviated these considerable changes. ACL promoted DCX expression in DG and increased the protein levels of BDNF, TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β in the brains of CUMS-induced rats. ConclusionsOur results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic–pituitary–adrenal axis, stimulating hippocampal neurogenesis, and activating the BDNF signaling pathway.

The alteration of gut microbiota in venlafaxine-ameliorated chronic unpredictable mild stress-induced depression in mice

Depression is associated with intestinal dysbiosis. Venlafaxine is a commonly used antidepressant in clinical practice as a serotonin and noradrenaline reuptake inhibitor. However, its effects on gut bacteria in depression remain unclear. Here, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and investigated the alterations of venlafaxine on the gut microbiota and potential key bacteria. Our data show that venlafaxine exerts antidepressant effects by restoring the serotonin (5-HT) system and glutamate (Glu) levels in CUMS mice. Moreover, we revealed that venlafaxine altered the diversity of gut bacteria in CUMS mice, and at genus level, Blautia, Oscillibacter, Tyzzerella, Butyricicoccus, and Enterorhabdus are the key bacteria responsible for venlafaxine-ameliorated depression in mice. Among these potential key bacteria, Blautia, Oscillibacter, and Butyricicoccus are correlated significantly with the 5-HT and 5-hydroxyindoleacetic acid levels; while Tyzzerella is correlated markedly with Glu levels. We further show that venlafaxine affected multiple functional metabolic pathways of gut bacteria in mice with CUMS-induced depression. Our results suggest that venlafaxine possibly ameliorates depression via modulating gut bacteria, and found the potential targets of its antidepressant effects.

Antidepressant effects of capsaicin in rats with chronic unpredictable mild stress-induced depression

Purpose: This study was conducted to assess the antidepressant effects of capsaicin in chronic depressive rats and elucidate the mechanism underlying its effects.Methods: Male Wistar rats (280~320 g, 8 weeks of age) were subjected to depression induced by chronic unpredictable mild stresses. The rats were exposed to 8 kinds of stresses for 8 weeks. In the last 2 weeks, fluoxetine or capsaicin was injected subcutaneously. The dose of fluoxetine was 10 mg/kg (body weight), while the doses of capsaicin consisted of low (1 mg/kg), middle (5 mg/kg), and high (10 mg/kg). The forced swim test (FST) was conducted to evaluate the immobility time of rats. The immobility time indicates despair, one of symptoms of depression. The change of tryptophan hydroxylase (TPH) in the dorsal raphe was investigated using immunohistochemistry. In the hippocampus cornu ammonis (CA) 1 and 3, glucocorticoid receptor (GR) expression was measured.Results: The immobility time in the FST was significantly lower (p &lt; .05) in the low-dose (M = 32.40 ± 13.41 seconds) and middle-dose (M = 28.48 ± 19.57 seconds) groups than in the non-treated depressive rats (M = 90.19 ± 45.34 seconds). The amount of TPH in the dorsal raphe was significantly higher (p &lt; .05) in the middle-dose (M = 249.17 ± 35.02) and high-dose (M = 251.0 ± 56.85) groups than in the non-treated depressive rats (M = 159.78 ± 41.16). However, GR expression in the hippocampus CA1 and CA3 did not show significant differences between the non-treated depressive rats and the capsaicin-injected rats.Conclusion: This study suggests that capsaicin produces an antidepressant-like effect on chronic unpredictable mild stress-induced depression in rats via the serotonin biosynthesis pathway.

Study on Lactiplantibacillus plantarum R6-3 from Sayram Ketteki to prevent chronic unpredictable mild stress-induced depression in mice through the microbiota-gut-brain axis.

The prevention, mitigation and treatment of depression has become a global issue that needs to be solved urgently. Sayram Ketteki, a traditional natural fermented yoghurt from the region with the world's fourth highest life expectancy, has been known as the "longevity secret", whose longevity and anti-depression factors are speculated to come from its rich microorganisms. Therefore, for the first time, we systematically studied in depth the microbes of Sayram Ketteki, screened a new edible probiotic strain, Lactiplantibacillus plantarum R6-3, and explored its anti-depression effect in chronic unpredictable mild stress (CUMS)-induced depression in mice. It is encouraging that L. plantarum R6-3 was significantly superior to the classic anti-depressant drug, fluoxetine, in the performance of promoting sucrose preference test (SPT) behavior by 18% (p < 0.001), lowering the serum CORT content by 5.6% (p < 0.05), accelerating the brain-derived neurotrophic factor (BDNF) level by 5.9% (p < 0.01), increasing the serum IL-10 concentration by 2.3% (p < 0.05), up-regulating the expression of BDNF and phosphorylated-ERK by 74% (p < 0.01) and 45% (p < 0.001), respectively, and facilitating the secretion of fecal short-chain fatty acids (SCFAs), including n-butyric, n-valeric, and isovaleric acid by 47% (p < 0.01), 42% (p < 0.05) and 38% (p < 0.05), respectively. Through the microbiota-gut-brain axis, L. plantarum R6-3 promoted the secretion of intestinal SCFAs through regulation of the composition and function of the gut microbiota, and activated the production of the monoamine neurotransmitter, renewed the level of brain neurotrophic factor, and suppressed the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis by adjusting the hippocampal BDNF/TrkB/ERK/CREB signaling pathway, thereby improving the immune and oxidative stress status, protecting hippocampal tissue from damage, maintaining a healthy weight and preventing CUMS-induced depressive behavior in mice. It has great prospects for the development of natural functional foods, the prevention and treatment of depression and in innovative microecological preparations.

Synthesis and antidepressant-like effects of new 5-epi-incensole and 5-epi- incensole acetate in chronic unpredictable mild stress model of depression; behavioural and biochemical correlates

In the current investigation, 5-epi-incensole (3) and 5-epi-incensole acetate (5) were synthesized from the most potent anti-depressant constituents incensole (1) and incensole acetate (2) of Boswellia papyrifera Hochst. The resulting compounds were evaluated for their ability to ameliorate depressive symptoms in forced swim test (FST) and tail suspension test (TST) in chronic unpredictable mild stress (CUMS) induced depression paradigm. The results demonstrated that compounds 3 and 5 at the doses of 1 and 3 mg/kg administered for 28 days, significantly reduced the immobility time in FST and TST and were devoid of any effect on locomotor activity in the open field test (OFT). Both compounds 3 and 5 also reversed CUMS-induced reduction in the weight of animals and aversion in sucrose preference. The tested compounds also inhibited Monoamine oxidase-A (MAO) enzyme and increased the levels of brain noradrenaline (NA) and 5-Hydroxytryptamine (5-HT), decreased plasma corticosterone and pro-inflammatory cytokines including TNF-α, IL-6 in hippocampal homogenates. Compounds 3 and 5 also significantly reduced the increased lipid peroxidation and nitrite levels; decreased glutathione levels, and catalase activities in mice undergoing CUMS protocol. The binding mode of compounds 3 and 5 was predicted at the monoamine oxidase substrate binding site by molecular docking having docking scores of > −6 kcal/mol. Taken together these data revealed that compounds 3 and 5 exerted antidepressant-like effects in chronic unpredictable mild stress-induced depression paradigm and are likely mediated via modulating the central oxidative stress, MAO-A activity with a consequent increase in brain NA and 5-HT levels in inflammatory pathways.