Chronic Unpredictable Mild Stress Model Research Articles

Neuroprotective Roles of Daidzein Through Extracellular Signal-Regulated Kinases Dependent Pathway In Chronic Unpredictable Mild Stress Mouse Model.

Depression is a stress-related neuropsychiatric disorder causing behavioural, biochemical, molecular dysfunctions and cognitive impairments. Previous studies suggested connection between neuropsychiatric diseases like depression with estrogen and estrogen receptors (ER). Daidzein is a phytoestrogen that functions as mammalian estrogen and regulates gene expressions through extracellular signal-regulated kinases (ERKs) dependent pathway by activating ERβ. ERβ modulates stress responses, physiological processes by activating protein kinases and plays a significant role in various neurological diseases like depression. However, significant roles of daidzein in depression involving ERK1/2, pERK1/2, and mTOR still unknown. Herein, we examined neuroprotective role of daidzein in chronic unpredictable mild stress (CUMS) mouse model. CUMS model was prepared, and placed in six groups namely, control, CUMS, CUMS vehicle, CUMS DZ (Daidzein 1mg/kgbw, orally), CUMS PHTPP (ERβ blocker, 0.3mg/kgbw, i..p.) and CUMS Untreated. Supplementation of daidzein to CUMS mice exhibits decrease depressive and anxiety-like behaviour, improved motor coordination and memory. Further, immunofluorescence results showed daidzein improved ERK1/2, pERK1/2 and mTOR expressions in the cortex, hippocampus and medulla of stressed mice. SOD, catalase and acetylcholinesterase levels were also improved. Blocking of ERβ with PHTPP stressed mice showed deficits in behaviour, low expression of ERK1/2, pERK1/2 and mTOR, and no significant changes in SOD, catalase and acetylcholinesterase level. Collectively, this study suggests that daidzein may ameliorate depressive and anxiety-like behaviour through ERK downregulating pathway by activating ERβ through ERK1/2, pERK1/2 and mTOR. Such study may be useful to understand daidzein dependent neuroprotection through ERβ in depression.

Hypoxanthine Produces Rapid Antidepressant Effects by Suppressing Inflammation in Serum and Hippocampus.

The occurrence and development of depression are closely related to disorders of the brain and peripheral substances. Abnormal metabolites in the blood affect the signal regulation function of the nerve center, which is one of the key factors for depression episodes. This study was focused on metabolites in serum and the mechanism of its antidepressant in the hippocampus. In the present study, serum metabolites in patients with depression were screened by metabolomic techniques. Various depressive mouse models and behavioral tests were used to assess its antidepressant effects. The expressions of inflammatory signaling were detected by using Western blot, ELISA, and immunofluorescence. We found that the metabolite hypoxanthine in the serum of patients with depression was significantly reduced, and the same result was also found in two mouse models of depression such as chronic unpredictable mild stress (CUMS) and social defeat stress (SD). By administering different doses of hypoxanthine (5, 10, 15 mg/kg), we found that only 15 mg/kg was able to significantly reduce the latency and increase food consumption in the novelty suppressed-feeding test (NSF), which was also able to reverse the depressive phenotypes of mice in the CUMS model after a single administration at 2 h later. Hypoxanthine obviously reduced the expressions of inflammation in serum and downregulated the expressions of MAPK and NLRP3-related pathways in the hippocampus in CUMS mice. Moreover, hypoxanthine also suppressed the activations of glial cells including GFAP and IBA-1 in hippocampal CA1, CA3, and dentate gyrus (DG). To sum up, hypoxanthine exerted antidepressant effect relying on the inhibition of peripheral and hippocampal inflammations by regulating MAPK, NLRP3-related pathways, and glial cells. This was the first time that we have found a disordered metabolite in patients with depression and further systematically demonstrated its efficacy and potential mechanism of antidepressants, providing new ideas for antidepressant drug development.

Chronic stress in adulthood results in microvascular dysfunction and subsequent depressive-like behavior

Depression is a prevalent mental disorder characterized by unknown pathogenesis and challenging treatment. Recent meta-analyses reveal an association between cardiovascular risk factors and an elevated risk of depression. Despite this, the precise role of vascular injury in depression development remains unclear. In this investigation, we assess vascular system function in three established animal models of depression— chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS) and maternal separation (MS)—utilizing ultrasonography and laser Doppler measurement. All three model animals exhibit anhedonia and despair-like behavior. However, significant microvascular dysfunction (not macrovascular) is observed in animals subjected to CUMS and CSDS models, while such dysfunction is absent in the MS model. Statistical analysis further indicates that microcirculation dysfunction is not only associated with depression-like behavior but is also intricately involved in the development of depression in the CUMS and CSDS models. Furthermore, our study has proved for the first time that endothelial nitric oxide synthase-deficient (eNOS+/−) mice, which is a classic model of vascular endothelial injury, showed depression-like behavior which occurred two months later than microvascular dysfunction. Notably, the mitigation of microvascular dysfunction successfully reverses depression-like behavior in eNOS+/− mice by enhancing nitric oxide production. In conclusion, this study unveils the pivotal role of microvascular dysfunction in the onset of depression induced by chronic stress in adulthood and proposes that modulating microvascular function may serve as a potential intervention in the treatment of depression.

Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury Exacerbates Neurological Dysfunctions.

Nearly half of mild traumatic brain injury (mTBI) patients continue to experience residual neurological dysfunction, which may be attributed to exposure to stress. Ferroptosis, a newly discovered form of cell death, is increasingly recognized for its involvement in the pathophysiology of TBI. Understanding the mechanisms by which stress influences mTBI, particularly through ferroptosis, is crucial for the effective treatment and prevention of mTBI patients who are sensitive to stressful events. In our study, a mouse mTBI model was established. An acute restraint stress (RS) and a chronic unpredictable mild stress (CUMS) model then were applied to make acute and chronic stress, respectively. We found acute RS significantly delayed the recovery of reduced body weight and short-term motor dysfunctions and exacerbated cell insults and blood-brain barrier leakage caused by mTBI. Further studies revealed that acute RS exacerbates neuronal ferroptosis, pyroptosis, and apoptosis by promoting iron overloading in the neocortex following mTBI. Interestingly, the inhibition of ferroptosis with iron chelators, including deferoxamine and ciclopirox, reversed pyroptosis and apoptosis. Moreover, CUMS aggravated neurological dysfunctions (motor function, cognitive function, and anxiety-like behavior) and exacerbated brain lesion volume. CUMS also exacerbates ferroptosis, pyroptosis, and apoptosis by intensifying iron deposition, along with decreasing the expression of neuronal brain-derived neurotrophic factor and glucocorticoid receptor in the neocortex post mTBI. These effects were also mitigated by iron chelators. Our findings suggest that alleviating ferroptosis induced by iron deposition may represent a promising therapeutic approach for mTBI patients who have experienced stressful events.

Pathophysiological dynamics of acute myocardial infarction rats under chronic psychological stress at different time points

There is a lack of in-depth research on the impacts and changes in chronic psychological stress (CPS) on the cardiovascular system after acute myocardial infarction (AMI). This study aims to explore the comorbid mechanism and dynamic evolution of AMI exposed to CPS. 120 Wistar rats were randomly divided into Sham Operation group, Sham Operation + Chronic Unpredictable Mild Stress (CUMS) group, AMI group and AMI + CUMS group, with each group further divided into subgroups at days 7, 14, and 28. The AMI model was created by ligating the left anterior descending coronary artery, and CUMS model was used to induce CPS in rats. Behavioral changes were assessed through open field tests and sucrose preference tests. Cardiac function and structure were evaluated via echocardiography. The serum levels of TNFα, IL-6, NO, ET, CK-MB, cTNT, and ANP were measured using assay kits. Pathological changes in cardiac and brain tissues were observed under an optical microscope. Comparative analysis across different models revealed that CUMS significantly reduced behavioral activities in rats, with an interaction between CUMS and AMI affecting total distance (P < 0.05). Both CUMS and AMI significantly reduced cardiac function indicators, with their interaction effects on LVEF, LVFS, and CO (P < 0.05). AMI significantly altered cardiac structural parameters, particularly on day 28 (P < 0.05); while the impact of CUMS on cardiac structure was not significant, except for a notable reduction in LVAW/s on day 7 in AMI + CUMS group (P < 0.05). AMI caused significant changes in the serum biomarkers, while CUMS only significantly increased cTnT on day 7, ANP, TNFα, and IL-6 on day 14, and CK-MB on day 28, with their interaction effects on the three myocardial injury markers and TNFα (P < 0.05). Comparative analysis across different time points demonstrated that behavioral activity, cardiac function, CK-MB, cTnT, ANP, TNFα, and ET levels decreased significantly over time in the AMI model rats, while the left ventricular mass increased significantly (P < 0.05). Pathologically, compared with stress or AMI alone, the AMI + CUMS group exhibited more severe myocardia cellular degeneration and inflammatory infiltration, causing larger infract areas in myocardial tissue, as well as cell number decreases and morphological changes in hippocampal tissue. AMI with CPS exacerbates myocardial injury through sustained inflammation and endothelial dysfunction, leading to heart-brain pathology manifestations characterized by decreased cardiac function and hippocampal tissue damage.

Role of SIRT1-mediated synaptic plasticity and neurogenesis: Sex-differences in antidepressant-like efficacy of catalpol

BackgroundCatalpol, an important compound found in Rehmannia glutinosa (a plant with high nutritional and antidepressant medicinal value), exhibits various biological activities and has the ability to penetrate the blood-brain barrier. Our recent studies revealed a gender difference in the antidepressant activity of Rehmannia glutinosa with females showing better responses than males. Catalpol is likely the key compound responsible for this gender-specific difference, which caters to current clinical observations that the severity and impact of depression are approximately two to three times higher in females than in males. However, the sex-specific mechanism of catalpol's antidepressant effects remains unclear. Purpose and MethodsOur recent molecular network predictions suggest that the gender-specific antidepressant properties of catalpol primarily involve the regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Building on this, the present study used a well-established chronic unpredictable mild stress model of depression in mice to confirm the sex-specific antidepressant characteristics of catalpol over time and intensity. Furthermore, using SIRT1 inhibitors and activators, behavioral tests, hematoxylin & eosin, Nissl, and Golgi staining, western blotting, immunofluorescence, and real-time PCR, we evaluated the key indicators of depressive behavior, synaptic plasticity, and neurogenesis before and after SIRT1 intervention to comprehensively assess whether the sex-specific antidepressant mechanism of catalpol indeed involves SIRT1-mediated synaptic plasticity and neurogenesis. ResultsThe gender-dependent antidepressant effects of catalpol are characterized by a faster onset and stronger effects in females compared to males, with females showing stronger regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Activation of SIRT1 preserved the gender differences in catalpol's effects on depressive behavior, hippocampal synaptic plasticity (including neuronal consolidation, neuronal density, dendritic spines, and PSD95 and SYP gene and protein expression), and neurogenesis (including enhancement of GAP43 and MAP2 expression, activation of c-myc, cyclinD1, Ngn2, and NeuroD1 mRNA levels, and upregulation of the Wnt3a/β-catenin/GSK-3β pathway), while inhibition of SIRT1 abolished these gender differences in the effects of catalpol. ConclusionsCatalpol exhibits higher antidepressant activity in female mice compared to male mice, and the mechanism underlying this gender difference in antidepressant effects may depend on catalpol's higher sensitivity in improving hippocampal SIRT1-mediated synaptic plasticity and neurogenesis in females. The novelty of this study lies in its first-time revelation of the gender-specific phenotypes, targets, and molecular mechanisms of the antidepressant effects of catalpol.

Hypocretin-1/Hypocretin Receptor 1 Regulates Neuroplasticity and Cognitive Function through Hippocampal Lactate Homeostasis in Depressed Model.

Cognitive dysfunction is not only a common symptom of major depressive disorder, but also a more common residual symptom after antidepressant treatment and a risk factor for chronic and recurrent disease. The disruption of hypocretin regulation is known to be associated with depression, however, their exact correlation is remains to be elucidated. Hypocretin-1 levels are increased in the plasma and hypothalamus from chronic unpredictable mild stress (CUMS) model mice. Excessive hypocretin-1 conducted with hypocretin receptor 1 (HCRTR1) reduced lactate production and brain-derived neurotrophic factor (BDNF) expression by hypoxia-inducible factor-1α (HIF-1α), thus impairing adult hippocampal neuroplasticity, and cognitive impairment in CUMS model. Subsequently, it is found that HCRTR1 antagonists can reverse these changes. The direct effect of hypocretin-1 on hippocampal lactate production and cognitive behavior is further confirmed by intraventricular injection of hypocretin-1 and microPET-CT in rats. In addition, these mechanisms are further validated in astrocytes and neurons in vitro. Moreover, these phenotypes and changes in molecules of lactate transport pathway can be duplicated by specifically knockdown of HCRTR1 in hippocampal astrocytes. In summary, the results provide molecular and functional insights for involvement of hypocretin-1-HCRTR1 in altered cognitive function in depression.

Unpredictable chronic mild stress induced anxio-depressive disorders and enterobacteria dysbiosis: Potential protective effects of Detariummicrocarpum

Ethnopharmacological relevanceDetarium microcarpum Guill. & Perr. is used traditionally in Far North Cameroun to treat stomach aches, anxiety, epilepsy, and other mental disorders. Aim of the studyEvaluate the anxiolytic and antidepressant-like effects of D. microcarpum (DM) in unpredictable chronic mild stress (UCMS) model of depression in male rats and its impact on fecal enterobacteria of stressed rats. Materials and methodsRats were handled daily (control) or subjected to the UCMS procedure for 42 days. Anxiety-like behaviors were assessed using the light and dark box test (LBD) and the open field test (OFT). Depressive-like behaviors were assessed using the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). Feces were then collected, followed by blood, brain, and duodenum sections after sacrifice. Monoamine levels, pro-inflammatory cytokines, oxidative stress factors, and nitrosative stress were assessed. Feces were introduced into Hectoen enteric agar for the identification of enterobacteria. An in vitro growth test was performed. ResultsThe DM ethanolic extract has significantly increased the time spent in the light box, in the LBD, and in the center area of the OFT. Moreover, the extract has significantly reduced the preference for sucrose in the SPT, the time of immobility in the FST, and the latency period to consume the pet in the NSFT. DM extract has significantly reduced serum cortisol levels. It also significantly decreased the pro-inflammatory cytokines TNF-α and Il-1β in both brain and duodenum homogenate. DM has increased the brain's serotonin, GABA, and dopamine levels. The DM extract also decreased the MDA and nitrite levels. It also increased the SOD and CAT activities in both brain and duodenal homogenate. Histologically, the DM extract restored the cell's density in hippocampi sections and prevented gut inflammation and peroxidation characterizing leaky gut syndrome. DM extract has no effect on the growth of enterobacteria species isolated in vitro. ConclusionThe ethanolic extract of DM would have anxiolytic and antidepressant effects via the modulation of the HPA axis, brain antioxidant enzyme activities, inflammation, and nitrosative stress. Moreover, it could act by preventing leaky gut syndrome.

Study the Effect of Drakshasava on Dopamine, Serotonin and Cortisol Levels and Behavioural Changes in Acute and Chronic Stress Model in Wistar Rats

Drakshasava is a formulation used as a general tonic also for anxiety, anaemia in the Ayurveda. Our previous study reports for antidepressant property were very promising. This study aims to elucidate the antidepressant mechanisms of Drakshasava by examining its effects on key neurotransmitters and stress hormones, as well as observing related behavioral changes in Wistar rats under stress models. Methods: Wistar rats weighing 150-200 gms were divided into six groups consisting of 6 rats in each group. Two animal models, acute stress (AS) and unpredictable chronic mild stress (UCMS) were used. Drug treatment was given as per groups orally, Drakshasava in the dose of 2ml &amp; 4ml/kg and Fluoxetine standard comparator 10mg/kg for next 7 days for AS. In UCMS group stress was given for 15 days and drug treatment was given along with the stress from day 15-21. Sucrose preference test (SPT) done on day 0 &amp; 8 in AS and on day 0, 15, 22 in UCMS model rats and at the end Forced Swim test (FST) was performed. Blood withdrawal done for estimation of serum Dopamine, Serotonin and cortisol levels with ELISA kit on day 8 in AS &amp; 22 in UCMS. Data obtained analysed with Graph Pad Prism 6. Result: Decrease in Dopamine (p&lt;0.05) and Serotonin (p&lt;0.01) while increase (p&lt;0.01) in cortisol levels was seen in (depressed) disease control group rats in comparison with control group. Both doses of Drakshasava showed significant reduction in immobility time in FST and improved sucrose preference and was found to be effective in both the models of depression. Increase in serum serotonin (p&lt;0.01) and dopamine (p&lt;0.05) levels was evident while at the same time, (p&lt;0.05) cortisol level reduction was seen in all drug treated rats. Findings observed in the FST and SPT were correlated with the biochemical findings. Effects seen with Drakshasava were comparable with that of Fluoxetine. Conclusion: Drakshasava increased serum serotonin and dopamine levels while decreasing cortisol levels in both acute and chronic animal models of depression. These effects were comparable to those observed with the standard antidepressant drug, Fluoxetine.

Study on the interventional effects of Chlamydomonas reinhardtii peptides on chronic unpredictable mild stress-induced depressive-like model mice through metabolomics and microbiota

Depression is a progressive neurodegenerative disease characterized by high prevalence, high suicide rate and high recurrence rate. In this study, the protein from Chlamydomonas reinhardtii was extracted and neutral protease hydrolysate (NPH) was obtained. Its in vitro MAO-A (Monoamine oxidase A) inhibitory activity and in vivo anti-depressive effects in chronic unpredictable mild stress (CUMS) model mice were investigated. The results demonstrated that NPH can improve depressive behaviour in CUMS model mice by elevating neurotransmitter levels and alleviating hippocampal tissue structure damage. The metabolomic analysis of brain and serum samples showed that their common metabolic pathways associated with anti-depressive effects are mainly alanine, aspartate, and glutamate metabolism, glycerophospholipid metabolism, tryptophan metabolism, and caffeine metabolism. Then, the gut microbiota analysis of feces indicated that 8 species with significant changes were associated with anti-depressive effects. Finally, 5 pairs of highly correlated metabolite-bacterium pairs were identified to modulate depressive behaviours. Taken together, the present data suggests that Chlamydomonas reinhardtii-derived hydrolysate could be used for development of functional foods with potential to improve depression.

Prediction of molecular targets for antidepressant potential of hydroalcoholic extract of Tamarindus indica using network pharmacology approach and evaluating its efficacy in Chronic Unpredictable Mild Stress model in mice.

The prevalence of psychological disorders has surged since the 1990s, posing a significant global health burden with depressed individuals averaging six lost hours per week and contributing to over 20% of all missed workdays. Current antidepressants, while effective for some, have limited efficacy, dietary restrictions, and adverse effects, including liver damage and hypertension. Natural remedies offer promising therapeutic potential with minimal side effects. Tamarindus indica (TI) is a plant that grows in the shape of a tree. Network pharmacology of TI revealed the key targets MAPK, D1-6, 5HT, DAT, MAO, COMT, PKA, PKC, AKT, and VMAT, which are linked to prominent key pathways such as dopaminergic and serotonergic. The cell viability assays on SH-Sy5y cells indicated a favourable safety profile with an IC50 of 573.99µg/ml and further, the in vivo efficacy was observed through Chronic Unpredictable Mild Stress (CUMS) model in mice. The hydroalcoholic extract of TI demonstrated antidepressant effects, significantly reducing immobility time in the Tail Suspension Test (TST) and Forced Swim Test (FST). Additionally, locomotor activity, assessed via the Open Field Test (OFT), was significantly increased in the treatment group compared to CUMS mice. Biochemical analyses revealed elevated Brain Derived Neurotropic Factor (BDNF), decreased cortisol levels, and reduced catechol-O-methyltransferase (COMT) concentration in TI-treated (50mg/kg) groups. These findings underscore the potential of TI as a natural antidepressant, offering a promising avenue for further therapeutic development in depression management. The current study did not evaluate the level of neurotransmitters in the brain, which will be evaluated in future studies.

Network pharmacology screening, in vitro and in vivo evaluation of antianxiety and antidepressant drug-food analogue

BackgroundDepression and anxiety disorders are prevalent psychiatric conditions, and currently utilized chemical drugs typically come with significant adverse effects. China boasts a wealth of medicinal and food herbs known for their safe and effective properties. PurposeThis study aimed to develop novel formulations with improved antidepressant and anxiolytic effects derived from medicinal and food herbs. Study designScreening combinations with antidepressant and anxiolytic effects using techniques such as network pharmacology and validating their effects in vitro and in vivo experiments. MethodsUtilizing network pharmacology and molecular docking, we identified the top ten medicinal herbs with anxiolytic and antidepressant potential. Herbs with cytoprotective effects and non-toxic characteristics were further screened to formulate the herbal blends. Subsequently, we established a PC12 cell injury model and a chronic unpredictable mild stress (CUMS) model in mice to assess the effects of our formulations. ResultsTen medicinal herbs were initially screened, and six of them were deemed suitable for formulating the blend, namely Gancao, Dazao, Gouqizi, Sangye, Huangqi, and Jinyinhua (GDGSHJ). The GDGSHJ formulation reduced Lactate Dehydrogenase (LDH) leakage, decreased apoptosis, and demonstrated a favorable antidepressant and antianxiety effect in the CUMS mouse model. Besides, GDGSHJ led to the upregulation of serum 5-Hydroxytryptamine (5-HT) content and brain tissue 5-HT, Gamma-aminobutyric acid (GABA), and Dopamine (DA) levels. It also downregulated the expression of SLC6A4 and SLC6A3 genes in the mouse hippocampus while upregulating HTR1A, DRD1, DRD2, and GABRA1 genes. ConclusionOur formulation exhibited robust antidepressant and antianxiety effects without inducing substantial toxicity. This efficacy appears to be mediated by the expression of relevant genes within the hippocampus of mice. The formulation achieved this effect by balancing 5-HT levels in the serum and DA, GABA, and 5-HT levels within brain tissue.

Exploring the Antidepressant-like Effects of Wogonin: Analysis of Behavioural, Neurochemical, and Biochemical Parameters

Background: Wogonin, a bioactive compound isolated from S. barbata D. Don, has been identified in the literature as a potential inhibitor of monoamine oxidase (MAO), a key enzyme involved in the degradation of neurotransmitters associated with mood regulation. This study aims to investigate the antidepressant-like activity of wogonin in vivo, utilizing a preclinical model. The rationale for selecting wogonin stems from its documented MAO inhibitory properties, suggesting a potential role in modulating neurotransmitter levels implicated in depressive disorder. Method: The study employs a multifaceted approach, incorporating behavioural, neurochemical, and biochemical assessments. The Chronic Unpredictable Mild Stress model is utilized to induce depression-like behavior in rodents for 21 days. Two doses of wogonin (20 and 40 mg/kg per orally) and standard (fluoxetine, 20 mg/kg, and imipramine, 15 mg/kg) were administered to albino mice. Behavioural paradigms, including the Tail Suspension Test, Forced Swim Test, and Open Field Test, are employed to assess the impact of wogonin on depressive-like symptoms on the 21st day. Neurochemical analyses focus on alterations in 5-HT, NE, and DA levels within relevant brain regions, and MAO activity is quantified to ascertain wogonin's potential as an MAO inhibitor on the 22nd day. Biochemical assessments emphasize wogonin's antioxidant properties and its ability to mitigate oxidative stress, a significant factor in depression pathophysiology. Plasma nitrite levels are measured to elucidate wogonin's impact on nitric oxide signalling. Plasma corticosteroid levels are also quantified to delineate wogonin's effect on the hypothalamicpituitary- adrenal (HPA) axis, a central regulator of stress response. Results: Wogonin demonstrates significant antidepressant effects in a dose-dependent manner in the behavioural assessments, showing a marked reduction in depressive-like behaviours across all paradigms. Neurochemical analyses revealed a significant (p ≤ 0.05) restoration of monoamine neurotransmitter levels in the relevant brain regions as compared to CUMS-induced stress group. Additionally, wogonin exhibits a potent (p ≤ 0.05) inhibitory effect on MAO activity. Biochemical assessments demonstrate a significant (p ≤ 0.05) increase in antioxidant capacity and a reduction in oxidative stress markers. Plasma nitrite levels indicate an enhancement of nitric oxide signalling. Corticosteroid levels showed a modulation of the HPA axis, suggesting a regulatory effect on stress response. Conclusion: This comprehensive study establishes wogonin as a promising MAO inhibitor with notable antidepressant potential. The findings provide crucial insights into its mechanisms of action, indicating a multifaceted approach to alleviating depression. Wogonin's demonstrated efficacy across behavioural, neurochemical, and biochemical parameters presents a strong foundation for further research and development of wogonin-based antidepressant interventions.

Comparative Efficacy of Animal Depression Models and Antidepressant Treatment: A Systematic Review and Meta-Analysis.

Animal models are critical tools in the study of psychiatric disorders; however, none of the current models fully reflect human stress-related disorders, even though most of the knowledge about the mechanisms of depression comes from animal studies. Animal studies are useful in pharmacological research, whereby we can obtain results that translate into patient treatment by controlling environmental factors, especially in behavioural research. The authors systematically reviewed this issue since medical databases provide access to many primary studies. A systematic review and meta-analysis were conducted based on 25 primary studies. The studies were identified in databases such as PubMed, Embase, and Web of Science (December 2022) according to the inclusion and exclusion criteria established at the beginning of the research and published in the form of a protocol, following the PRISMA and Cochrane Collaboration methodology for secondary studies and CAMARADES (CAMARADES Berlin, QUEST-BIH Charité) for secondary studies on animals. Forest plot analyses were performed (data presented as Mean Difference, Random Model, Inverse Variance), Risk of Bias assessment (Systematic Review Center for Laboratory animal Experimentation (SYRCLE) evaluation), quality assessment of included studies (Animal research: Reporting of In Vivo Experiments (ARRIVE)), and a range of data from source publications were compiled in tabular form. The study analysed the popularity of both animal depression models (ADM) and rat strains used in pharmacological research to test the efficacy of antidepressant drugs based on the immobility time (IT) factor (Forced Swimming Test). The study examined selective serotonin reuptake inhibitors, namely fluoxetine, sertraline, paroxetine, citalopram, and escitalopram. Additionally, the study addressed issues concerning the "data availability statement" because precise IT data analysis was impossible in the case of 212 papers. Our data confirm that the Chronic Unpredictable Mild Stress (CUMS) model is the most popular and versatile model used in preclinical depression research, while the two most popular rat strains were Wistar and Sprague-Dawley. The quality of included papers based on the ARRIVE assessment showed a ratio value equal to 0.63, meaning that studies were of intermediate overall quality. The Risk of Bias assessment based on the SYRCLE tool revealed a high risk related to the blinding and the random outcome assessment. In the meta-analysis, the results indicate that all analysed drugs demonstrated efficacy in reducing IT, and the most analysed drug was fluoxetine (confirmed based on 17 studies (19 models)). The analysis of the efficacy of ADMs showed that the most effective models were CUMS, Flinders Sensitive Line (genetic model), Social Isolation, Restraint Stress, and Low-dose Lipopolysaccharide (pharmacological model). Only 2.35% (5 out of 212) of corresponding authors responded to our data request. The study highlights the dominance of the CUMS model and the Wistar and Sprague-Dawley rat strains in preclinical depression research, affirming the efficacy of SSRIs, particularly fluoxetine, in reducing IT. The findings underscore the need for better data availability and methodological improvements despite intermediate overall study quality and notable bias risks. Enhanced transparency and rigorous assessment standards are essential for advancing the reliability of animal models in depression research.

Ziziphus Jujube Polysaccharides inhibit over-abundance of fecal butyric acid in mildly stressed growing mice to ameliorate depression-like behavior

The microbial-gut-brain axis is the main pathway that induces depression in adolescents. In Chinese medicine, Ziziphus Jujube Polysaccharides (ZJP) are recognized for their capacity to modulate gut microbiota and bolster immune function, suggesting their potential as a therapeutic agent for mitigating youth depression. In this study, a 44 d chronic unpredictable mild stress (CUMS) model was used to investigate how ZJP alleviates depression-like behavior in male C57BL/6 mice. The administration of ZJP ameliorated depression-like behavior, down-regulated serum levels of TNF-α, IL-1β, IL-2, IL-6, and up-regulated hippocampal 5-HT. Correlation analysis revealed that fecal butyric acid (BA) concentration was positively correlated with depression-like behavior index (P＜0.05). ZJP modified the gut microbiota by replenishing deficient saccharides (fructose, galactose, rhamnose, arabinose), diminishing the prevalence of SCFA-producing bacteria (Alistipes, Lachnospiraceae, Colidextribacter). Additionally, ZJP decreased the gene abundance of the sugar and SCFA metabolism pathways, and related enzymes in the gut of model mice, thereby reversing butyrate enrichment and ameliorating associated depression-like behavior. In summary, ZJP stabilized the intestinal microbiota structure and balanced the BA metabolism in CUMS mice by regulating the metabolism of gut microbiota-sugar-SCFAs, thereby improving depression-like behavior.

Prophylactic effects of Tibetan goat kefir on depression-like behaviors in chronic unpredictable stress model through the gut-brain axis.

Depression is a common psychological disorder, and traditional therapeutic drugs often result in side effects such as emesis, dry mouth, headache, dysentery and constipation. Probiotics and goat milk have garnered widespread attention for their ability to modulate immune function and regulate the endocrine system, and for their anti-inflammatory effects. In this work, the effects of Tibetan goat kefir on the behavior, immune status, neuroendocrine response and gut microbiological composition of chronic unpredictable mild stress (CUMS) mouse models were evaluated. The results indicated that Tibetan kefir goat milk significantly alleviated behavioral despair in mice. Furthermore, the results demonstrated that Tibetan kefir goat milk mitigated the inflammatory response in the mice and moderated the hyperactivity of the hypothalamic-pituitary-adrenal axis and the expression of brain-derived neurotrophic factor. Meanwhile, chronic stress-induced gut microbial abnormalities were restored. In addition, the correlation between gut microbiota and nervous system was evaluated. These results explained the potential mechanism of Tibetan kefir in the antidepressant effect on the CUMS model and enriched diets for depressed patients. © 2024 Society of Chemical Industry.

Sodium-Glucose Co-Transporter-2 Inhibitors Act as AMPK Activators and Ameliorate the Depressive Symptoms Induced by Unpredictable Chronic Mild Stress in Mice

Depression is a prevalent disorder of mental health with a highly multifaceted pathogenesis thus finding an effective therapy for it remains a challenge. Depression is associated with downregulation of AMPK signaling pathways and lowers AMP/ATP and ADP/ATP ratios. Brain AMPK pathway malfunction and metabolic imbalances induce depression. The Unpredictable Chronic Mild Stress (UCMS) model was created centered on the predisposition of the stress-associated assumption of depression. SGLT2 inhibitor drugs canagliflozin and remogliflozin enhance brain AMPK signaling, reduce oxidative stress, increase neurotransmitters, and improve metabolism. SGLT2 inhibitor drugs have promising anti-depressant effects. Thus, in this investigation, we examined Sodium-glucose co-transporter-2 inhibitors to ameliorate depression symptoms in mice induced by unpredictable chronic mild stress by improving AMPK signaling. Seven groups of male mice (Swiss albino) were divided into (n=6). The disease groups received different stressors (unpredictable chronic mild stress model) for one week to produce depression, while normal control groups got 0.5% w/v Saline (orally). The standard group received Fluoxetine (10 mg/kg, orally), while the treatment groups were given canagliflozin (15 and 30 mg/kg, orally) and remogliflozin (10 and 30 mg/kg, orally). Behavioral parameters were assessed for induction of depression. Treatment with SGLT2 inhibitors showed significant (p &lt; 0.05) antidepressant effects on behavioral, oxidative stress, neurotransmitter, brain histopathology, and gene expression evaluation of AMPK, mTOR, BNDF, and TNF-α levels. The current study found that SGLT2 inhibitor drugs have the potential to improve the AMPK signaling pathway and alleviate depression.

Antidepressant-like and antioxidant effects of Morus nigra L. in rats subjected to the unpredictable chronic mild stress model

This study aimed to evaluate the antidepressant-like and antioxidant potential of the aqueous leaf extract of Morus nigra L. in rats subjected to unpredictable chronic mild stress (UCMS). Male Wistar rats were divided into four groups, control and stressed, and treated with saline or aqueous extract of M. nigra. The dose administered was 10 mg/kg daily by gavage for 5 weeks concurrently with UCMS. M. nigra extract which showed syringic acid, quercetin, and rutin, as major phenolic compounds decreased the immobility time without changes in locomotor activity of stressed rats, in the forced swimming and open field tests, respectively. In addition, the extract diminished carbonylated proteins, lipid peroxidation, and nitrite levels in the brains of rats subjected to UCMS. These data reinforced antidepressant-like properties with the involvement of oxidative stress modulation by M. nigra extract pointing it as a possible new adjuvant treatment for depression.

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

BackgroundThe cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns.MethodsRapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels.ResultsScopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC).ConclusionSubchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

Inhalation of Curcumae Rhizoma volatile oil attenuates depression-like behaviours via activating the Nrf2 pathway to alleviate oxidative stress and improve mitochondrial dysfunction.

Curcumae Rhizoma (CR) is a traditional Chinese medicine used frequently in clinics, which contains volatile components that exhibit various active effects. This study explores the effect of Curcumae Rhizoma volatile oil (CRVO) on depressive mice and its possible mechanism of action. Chemical composition of CRVO was analysed by GC-MS. DPPH and ABTS free radical scavenging assays were used to evaluate the in vitro antioxidant capacity of CRVO. A chronic unpredictable mild stress (CUMS) model was used to evaluate the antidepressant effect of CRVO. The effects of CRVO on oxidative stress in vivo were investigated using Nissl staining, ELISA and transmission electron microscopy. The Nrf2/HO-1/NQO1 signalling pathway was detected by western blotting and immunofluorescence. ML385, a Nrf2 inhibitor was used to validate the effect of Nrf2 on CUMS mice with CRVO treatment. Phytochemical analysis showed that CRVO is rich in its characteristic components, including curzerene (31.1%), curdione (30.56%), and germacrone (12.44%). In vivo, the administration of CRVO significantly ameliorated CUMS-induced depressive-like behaviours. In addition, inhalation of CRVO significantly alleviated the oxidative stress caused by CUMS and improved neuronal damage and mitochondrial dysfunction. The results of mechanistic studies showed that the mechanism of action is related to the Nrf2/HO-1/NQO1 pathway and the antioxidant and antidepressant effects of CRVO were weakened when ML385 was used. In summary, by regulating the Nrf2 pathway, inhalation of CRVO can reduce oxidative stress in depressed mice, thereby reducing neuronal damage and mitochondrial dysfunction to alleviate depression-like behaviours. Our study offers a prospective research foundation to meet the diversity of clinical medication.