Mild Stress Rat Research Articles

Peripheral inflammatory cytokines are associated with the microstructural characteristics of the corpus callosum and prefrontal cortex as detected by magnetic resonance T1/T2 mapping in the CUMS rat model

BackgroundSeveral clinical neuroimaging studies have reported structural and functional brain abnormalities associated with peripheral inflammatory cytokines or kynurenine pathway metabolites in patients with depression. However, it is not clear whether the abnormal findings are changes that are intrinsic to depression or whether they are caused by confounding factors such as age, illness duration, or medication. MethodsTo exclude confounding factors, we used chronic unpredictable mild stress (CUMS) rat model and magnetic resonance T1/T2 mapping to investigate the microstructural characteristics of the prefrontal cortex (PFC), hippocampus and corpus callosum and further explored the association between peripheral blood depression-related indicators and microstructural characteristics. ResultsThe results revealed that the T2 relaxation time of the corpus callosum was significantly decreased in the CUMS model compared to the control group. Additionally, positive correlations were found between the levels of inflammatory cytokines (interleukin (IL)-1 and IL-6) and the T1 relaxation time of the corpus callosum and between the level of IL-6 and the T1 relaxation time of the PFC. ConclusionOur study demonstrates that the microstructural abnormality of the corpus callosum is an intrinsic change that accompanies depression and also provides robust evidence that the microstructural characteristics of the corpus callosum and PFC associated with inflammatory cytokines in peripheral blood play an important role in the fundamental pathophysiological mechanism of depression.

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 12.5 g 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 regulating gut microbiota by electroacupuncture in the chronic unpredictable mild stress rat model

ObjectiveThis study aims to investigate the effect of electroacupuncture (EA) treatment on depression, and the potential molecular mechanism of EA in depression-like behaviors rats. MethodsA total of 40 male Sprague Dawley rats were divided into three groups: normal control, chronic unpredictable mild stress (CUMS), and EA (CUMS + EA). The rats in CUMS and EA groups underwent chronic stress for 10 weeks, and EA group rats received EA treatment for 4 weeks starting from week 7. Body weight and behavioral tests, including the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were monitored. Gut microbiota composition was assessed via 16S rDNA sequencing, and lipid metabolism was analyzed by using UPLC-Q-TOF/MS technology. ResultsIn comparison to CUMS group, EA could improve the behavior including bodyweight, immovability time, sucrose preference index, crossing piece index and rearing times index. After 4 weeks of EA treatment, 5-HT in hippocampus, serum and colon of depressive rats were simultaneously increased, indicating a potential alleviation of depression-like behaviors. In future studies revealed that EA could regulate the distribution and functions of gut microbiota, and improve the intestinal barrier function of CUMS rats. The regulation of intestinal microbial homeostasis by EA may further affect lipid metabolism in CUMS rats, and thus play an antidepressant role. ConclusionThis study suggested that EA has potential antidepressant effects by regulating gut microbiota composition and abundance, subsequently affecting lipid metabolism.

Shikonin ameliorates depressive- and anxiogenic-like behaviors in rats via the suppression of inflammation in the hippocampus

Shikonin is an active naphthoquinone with antioxidative, anti-inflammatory, and anticancer properties. In this study, we investigated the effects of shikonin on depressive- and anxiety-like behaviors in lipopolysaccharide- (LPS-) induced depression and chronic unpredictable mild stress (CUMS) rat models and explored the potential mechanism. First, a 14-day intraperitoneal administration of shikonin (10 mg/kg) significantly decreased immobility time in forced swimming test (FST) and increased open arm entries in elevated plus maze (EPM) test, without affecting line crossings in open field test (OFT), indicating that shikonin has anti-depressant- and anxiolytic-like effects. Second, chronic shikonin administration (10 mg/kg) reversed depressive- and anxiety-like behaviors in LPS-induced and CUMS depression models, as shown in the sucrose preference test (SPT), FST, EPM, and novel object recognition test (NORT). Finally, shikonin significantly reduced the levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in hippocampus, indicating that the anti-depressant- and anxiolytic-like effects of shikonin are related to the reduction of neuroinflammation in hippocampus. These findings suggest that shikonin exerts anti-depressant- and anxiolytic-like effects via an anti-inflammatory mechanism of shikonin in the hippocampus.

Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats

PurposeChronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. MethodsIn vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. ResultsDecreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. ConclusionThese findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

Study on the antidepressive effects and mechanism of raw and fried Ziziphi Spinosae Semen via metabolomics and gut microbiota analysis.

Ziziphi Spinosae Semen (ZSS) and fried ZSS (FZSS) have been used for treating insomnia and depression in China. However, the potential influence of chemical variations on their efficacy remains unclear. This study demonstrated that compared with ZSS, FZSS exhibited an increase in the content of seven compounds, while the fatty oil content decreased. Both ZSS and FZSS exhibited antidepressive effects in a chronic unpredictable mild stress rat model, indicating a synergistic regulation of deficiencies in 5-hydroxytryptamine in the brain and the hyperactivation of severe peripheral inflammation. ZSS demonstrated a superior modulatory effect compared with FZSS, as indicated by integrated pharmacodynamic index, metabolic profile, and relative distance value. The potential mechanism underlying their antidepressive effects involved the modulation of gut microbiota structure to alleviate excessive inflammatory responses and imbalanced tryptophan metabolism. Correlation analysis indicated that the higher fatty oil contents should be comprehensively considered as the main reason for ZSS's superior antidepressive effects, achieved through the regulation of pyroglutamic acid levels.

Bergamot essential oil improves CUMS-induced depression-like behaviour in rats by protecting the plasticity of hippocampal neurons.

Bergamot essential oil (BEO) is an extract of the bergamot fruit with significant neuroprotective effect. This study was to investigate the effects and the underlying mechanism of BEO in mitigating depression. GC-MS were used to identify its constituents. Antidepressive properties of BEO were evaluated by sucrose preference test (SPT), force swimming test (FST) and open field test (OFT). Nissl staining was used to determine the number of Nissl bodies in hippocampus (HIPP) of rats. Changes in HIPP dendritic length and dendritic spine density were detected by Golgi-Cox staining. Immunohistochemistry and Western blot were used to detect the postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the HIPP of rats. The enzyme-linked immunosorbent assay was used to determine the 5-hydroxytryptamine (5-HT), insulin-like growth factor 1 (IGF-1) and interleukin-1β (IL-1β) in the HIPP, serum and cerebrospinal fluid (CSF) of rats. Inhaled BEO significantly improved depressive behaviour in chronic unpredictable mild stress (CUMS) rats. BEO increased Nissl bodies, dendritic length and spine density, PSD-95 and SYP protein in the HIPP. Additionally, BEO upregulated serum 5-HT, serum and CSF IGF-1, while downregulating serum IL-1β. Collectively, inhaled BEO mitigates depression by protecting the plasticity of hippocampal neurons, hence, providing novel insights into treatment of depression.

Stable Isotope Tracer Technique and Network Pharmacology to Reveal Antidepressant Targets and Active Components of Xiaoyao San.

In recent years, the research of mitochondrial dysfunction in depression has drawn the focus of researchers. Our research group previously found that Xiaoyao San (XYS) has improved the mitochondrial structure and the blocked tricarboxylic acid cycle (TCA cycle) in the hippocampal tissue of chronic unpredictable mild stress (CUMS) rats. However, the specific targets and active components of XYS remain unclear, and the potential to improve hippocampal mitochondrial TCA cycle disorder was also unexplored. In this research, a strategy to combine stable isotope-resolved metabolomics (SIRM), network pharmacology and transmission electron microscopy (TEM) was used to explore the potential, targets of action, and active components of XYS to improve hippocampal mitochondrial TCA cycle disorder of CUMS rats. The results of TEM showed that the ultrastructure of hippocampal mitochondria could be improved by XYS. A combination of SIRM and molecular docking showed that pyruvate carboxylase (PC), ATP citrate lyase (ACLK), glutamate dehydrogenase (GLDH), glutamate oxaloacetate transaminase (GOT) and pyruvate dehydrogenase (PDH) were targets of XYS to improve TCA cycle disorder. In addition, troxerutin was found to be the most potential active component of XYS to improve TCA cycle disorder. The above research results can provide new insights for the development of antidepressant drugs.

Deciphering the antidepressant effects of Rosa damascena essential oil mediated through the serotonergic synapse signaling pathway

Ethnopharmacological relevanceRosa damascena is an ancient plant with significance in both medicine and perfumery that have a variety of therapeutic properties, including antidepressant, anti-anxiety, and anti-stress effects. Rose damascena essential oil (REO) has been used to treat depression, anxiety and other neurological related disorders in Iranian traditional medicine. However, its precise mechanism of action remains elusive. Aim of the studyThe aim of this study was to investigate the impact and mechanism underlying the influence of REO on chronic unpredictable mild stress (CUMS) rats. Materials and methodsGas chromatography-mass spectrometry (GC-MS) technique coupling was used to analyze of the components of REO. A CUMS rat model was replicated to assess the antidepressant effects of varying doses of REO. This assessment encompassed behavioral evaluations, biochemical index measurements, and hematoxylin-eosin staining. For a comprehensive analysis of hippocampal tissues, we employed transcriptomics and incorporated weighting coefficients by means of network pharmacology. These measures allowed us to explore differentially expressed genes and biofunctional pathways affected by REO in the context of depression treatment. Furthermore, GC-MS metabolomics was employed to assess metabolic profiles, while a joint analysis in Metscape facilitated the construction of a network elucidating the links between differentially expressed genes and metabolites, thereby elucidating potential relationships and clarifying key pathways regulated by REO. Finally, the expression of relevant proteins in the key pathways was determined through immunohistochemistry and Western blot analysis. Molecular docking was utilized to investigate the interactions between active components and key targets, thereby validating the experimental results. ResultsREO alleviated depressive-like behavior, significantly elevated levels of the neurotransmitter 5-hydroxytryptamine (5-HT), and reduced hippocampal neuronal damage in CUMS rats. This therapeutic effect may be associated with the modulation of the serotonergic synapse signaling pathway. Furthermore, REO rectified metabolic disturbances, primarily through the regulation of amino acid metabolic pathways. Joint analysis revealed five differentially expressed genes (EEF1A1, LOC729197, ATP8A2, NDST4, and GAD2), suggesting their potential in alleviating depressive symptoms by modulating the serotonergic synapse signaling pathway and tryptophan metabolism. REO also modulated the 5-HT2A-mediated extracellular regulated protein kinases-cAMP-response element binding protein-brain-derived neurotrophic factor (ERK-CREB-BDNF) pathway. In addition, molecular docking results indicated that citronellol, geraniol and (E,E)-farnesol in REO may serve as key active ingredients responsible for its antidepressant effects. ConclusionsThis study is the first to report that REO can effectively alleviate CUMS-induced depression-like effects in rats. Additionally, the study offers a comprehensive understanding of its intricate antidepressant mechanism from a multi-omics and multi-level perspective. Our findings hold promise for the clinical application and further development of this essential oil.

Anti-neuroinflammatory effect of hydroxytyrosol: a potential strategy for anti-depressant development.

Introduction: Depression is a complex psychiatric disorder with substantial societal impact. While current antidepressants offer moderate efficacy, their adverse effects and limited understanding of depression's pathophysiology hinder the development of more effective treatments. Amidst this complexity, the role of neuroinflammation, a recognized but poorly understood associate of depression, has gained increasing attention. This study investigates hydroxytyrosol (HT), an olive-derived phenolic antioxidant, for its antidepressant and anti-neuroinflammatory properties based on mitochondrial protection. Methods: In vitro studies on neuronal injury models, the protective effect of HT on mitochondrial ultrastructure from inflammatory damage was investigated in combination with high-resolution imaging of mitochondrial substructures. In animal models, depressive-like behaviors of chronic restraint stress (CRS) mice and chronic unpredictable mild stress (CUMS) rats were examined to investigate the alleviating effects of HT. Targeted metabolomics and RNA-Seq in CUMS rats were used to analyze the potential antidepressant pathways of HT. Results: HT protected mitochondrial ultrastructure from inflammatory damage, thus exerting neuroprotective effects in neuronal injury models. Moreover, HT reduced depressive-like behaviors in mice and rats exposed to CRS and CUMS, respectively. HT's influence in the CRS model included alleviating hippocampal neuronal damage and modulating cytokine production, mitochondrial dysfunction, and brain-derived neurotrophic factor (BDNF) signaling. Targeted metabolomics in CUMS rats revealed HT's effect on neurotransmitter levels and tryptophan-kynurenine metabolism. RNA-Seq data underscored HT's antidepressant mechanism through the BDNF/TrkB signaling pathways, key in nerve fiber functions, myelin formation, microglial differentiation, and neural regeneration. Discussion: The findings underscore HT's potential as an anti-neuroinflammatory treatment for depression, shedding light on its antidepressant effects and its relevance in nutritional psychiatry. Further investigations are warranted to comprehensively delineate its mechanisms and optimize its clinical application in depression treatment.

Cherry leaf decoction inhibits NMDAR expression and thereby ameliorates CUMS- induced depression-like behaviors through downregulation of α2δ-1

Depression is a complex and prevalent mental illness. Cherry leaf is a traditional Chinese herbal medicine, which has confirmed to exert a certain antidepressant effect, but its potential neural regulation mechanism is not clear. This paper aims to investigate the improved action of cherry leaf decoction (CLD) on chronic unpredictable mild stress (CUMS) rats and its potential neural regulation mechanism by verifying the role and function of NMDAR regulatory target α2δ-1 in depression due to CUMS. Male SD rats were subjected to random stressors persisting for 5 weeks to establish the CUMS depression rat model. CLD could effectively alleviate depression-like behaviors of CUMS rats in behavioral tests including sucrose preference test, forced swimming test, tail suspension test and open field test. After the administration of the CLD, the expression of corticotropic-releasing hormone (CRH) in the hypothalamus was inhibited. Moreover, the levels of CRH, adrenal cortical hormone (ACTH) and corticosterone (CORT) in serum also decreased significantly. CUMS upregulated the expressions of α2δ-1, N-methyl-d-aspartate receptor 1 (NR1), NR2A and NR2B, and enhanced the binding ability to of α2δ-1 and NR1, which were reversed by CLD. The results demonstrated that CLD could ameliorate depression-like behaviors due to CUMS, which was related to the fact that CLD down-regulated α2δ-1 level and interfered with α2δ-1 binding to NR1, thereby reducing NMDAR expression and ultimately inhibiting HPA axis activity.

Chronic Unpredictable Mild Stress in Rats based on the Mongolian medicine.

Depression is a prevalent affective disorder and constitutes a leading cause of global disability. The limitations of current pharmacological interventions contribute to the substantial health burden attributed to this condition. There is a pressing need for a deeper understanding of the underlying mechanisms of depression, making pre-clinical models with translational potential highly valuable. Mongolian medicine, a subset of traditional medicine, posits that disease occurrence is closely tied to the equilibrium of wind, bile, and Phlegm. In this study, we introduce a protocol for the chronic unpredictable mild stress (CUMS) method in rats. Within this framework, rats are subjected to a series of fluctuating, mild stressors to induce a depression-like phenotype, mimicking the pathogenesis of human depression. Behavioral assays employed in this protocol include the sucrose preference test (SPT), indicative of anhedonia-a core symptom of depression; the open field test (OFT), which measures anxiety levels; and the Morris water maze test (MWM), which evaluates spatial memory and learning abilities. The CUMS method demonstrates the capability to induce anhedonia and to cause long-term behavioral deficits. Furthermore, this protocol is more aligned with Mongolian medical theory than other animal models designed to elicit depression-like behavior. The development of this animal model and subsequent research provide a robust foundation for future innovative studies in the realm of Mongolian medicine.

Changes in neurotrophic signaling pathways in brain areas of the chronic mild stress rat model of depression as a signature of ketamine fast antidepressant response/non-response

Major Depressive Disorder (MDD) is a highly debilitating disorder characterized by a persistent feeling of sadness and anhedonia. Traditional antidepressants have a delayed onset of action and lack of efficacy in up to one third of patients, leading to treatment resistant depression (TRD). Recent years have witnessed a revolutionary treatment of TRD with the introduction of the fast-acting antidepressant ketamine. However, ketamine's mechanisms of action are still poorly understood. Here, we used the chronic mild stress animal model of depression on male rats to investigate the involvement of neurotrophic signaling pathways in stress vulnerability/resilience and fast antidepressant response/non-response to acute subanesthetic ketamine. We performed our analysis on both the hippocampus and the prefrontal cortex, two brain areas implicated in stress-related disorders, considering different subcellular fractions. We measured the activation by phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), glycogen synthase kinase-3 beta (GSK3 β), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2), key effectors in the regulation of neuroplasticity and glutamatergic transmission which were previously associated to ketamine's fast antidepressant effect. We showed here for the first time that both stress and ketamine induced brain area and subcellular fraction specific changes in these pathways. Our study represents the first attempt to identify molecular mechanisms underlying the response/non-response to ketamine in an animal model of depression. This approach could give a crucial contribution to the study of etiopathogenetic mechanisms as well as to the identification of novel targets for the development of innovative therapeutic strategies.

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

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

Integrating UHPLC-MS/MS quantitative analysis and exogenous purine supplementation to elucidate the antidepressant mechanism of Chaigui granules by regulating purine metabolism

Chaigui granules (CG) are a compound composed of six herbal medicines with significant antidepressant effects. However, the antidepressant mechanism of CG remains unclear. In the present study, we attempted to elucidate the antidepressant mechanism of CG by regulating purine metabolism and purinergic signaling. First, the regulatory effect of CG on purine metabolites in the prefrontal cortex (PFC) of chronic unpredictable mild stress (CUMS) rats was analyzed by ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) targeted quantitative analysis. Meanwhile, purinergic receptors (P2X7 receptor (P2X7R), A1 receptor (A1R) and A2A receptor (A2AR)) and signaling pathways (nod-like receptor protein 3 (NLRP3) inflammasome pathway and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway) associated with purine metabolism were analyzed by western blotting and enzyme-linked immunosorbent assay (ELISA). Besides, antidepressant mechanism of CG by modulating purine metabolites to activate purinergic receptors and related signaling pathways was dissected by exogenous supplementation of purine metabolites and antagonism of purinergic receptors in vitro. An in vivo study showed that the decrease in xanthine and the increase in four purine nucleosides were closely related to the antidepressant effects of CG. Additionally, purinergic receptors (P2X7R, A1R and A2AR) and related signaling pathways (NLRP3 inflammasome pathway and cAMP-PKA pathway) were also significantly regulated by CG. The results of exogenous supplementation of purine metabolites and antagonism of purinergic receptors showed that excessive accumulation of xanthine led to activation of the P2X7R-NLRP3 inflammasome pathway, and the reduction of adenosine and inosine inhibited the A1R-cAMP-PKA pathway, which was significantly ameliorated by CG. Overall, CG could promote neuroprotection and ultimately play an antidepressant role by inhibiting the xanthine-P2X7R-NLRP3 inflammasome pathway and activating the adenosine/inosine-A1R-cAMP-PKA pathway.

Folate Deficiency Increased Microglial Amyloid-β Phagocytosis via the RAGE Receptor in Chronic Unpredictable Mild-Stress Rat and BV2 Cells.

Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer's disease (AD). β-amyloid (Aβ) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aβ phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aβ and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aβ phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aβ uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aβ via regulating the expression of RAGE or microglia phenotype under Aβ treatment.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI to Evaluate the Rapid Antidepressant Effects of Ketamine in the Hippocampus of Rat Depression Model.

Ketamine is a quick acting antidepressant drug, and an accurate detection method is lacking. Ketamine's effects in a rat depression model have not previously been well explored using glutamate chemical exchange saturation transfer (GluCEST). To investigate the GluCEST changes of chronic unpredictable mild stress (CUMS) rats after receiving either ketamine or saline injection. Randomized animal model trial. 12 CUMS and 6 Sprague-Dawley rats. Divided into three groups: ketamine (N = 6), saline (N = 6), and control (N = 6). 7.0 T/the sequence is GluCEST and 1 H MR spectroscopy (MRS). The CUMS rats were exposed to different stress factors for 8 weeks. The glutamate concentration in the hippocampus was assessed by the GluCEST,1 H MRS, and the high-performance liquid chromatography (HPLC). The t-test, Mann-Whitney U test, and Pearson's correlation. In depression conditions, GluCEST signals were lower in the bilateral hippocampus than in control group. Thirty minutes after ketamine injection, the GluCEST signals in the bilateral hippocampus were higher compared with the saline group (left: 2.99 ± 0.34 [Control] vs. 2.44 ± 0.20 [Saline] vs. 2.85 ± 0.11 [Ketamine]; right: 2.97 ± 0.28 [Control] vs. 2.49 ± 0.25 [Saline] vs. 2.86 ± 0.19 [Ketamine]). In 1 H MRS, significant changes were only observed in the left hippocampus (2.00 ± 0.16 [Control] vs. 1.81 ± 0.09 [Saline] vs. 2.04 ± 0.14 [Ketamine]). Furthermore, HPLC results showed similar trends to those observed in the GluCEST results (left: 2.32 ± 0.22 [Control] vs. 1.96 ± 0.11 [Saline] vs. 2.18 ± 0.11 [Ketamine]; right: 2.35 ± 0.18 [Control] vs. 1.87 ± 0.16 [Saline] vs. 2.09 ± 0.08 [Ketamine]). GluCEST can sensitively evaluate the ketamine's antidepressant effects by detecting the fast increase in glutamate concentration. 1 TECHNICAL EFFICACY STAGE: 1.

Gramine and zingerone mitigates neuroinflammation related depressive behaviour induced by chronic unpredictable mild stress in rat

Depression is a serious mental illness characterised by sadness, a depressed mood, and anhedonia. It is also associated with oxidative stress and inflammatory biomarkers. The chronic unpredictable mild stress (CUMS) model mimics this type of depression. The effects of zingerone (Zn) and gramine (Ga) on CUMS types of depression have not yet been studied, and the effect of drugs on neuroinflammation is also not clear. So we conducted this study. Induction of depression by different stressor procedures after 60 minutes of Zn (75, 125, and 250 mg/kg), Ga (13, 27.5, and 55 mg/kg), and Ecitalopra (15 mg/kg) given daily to rats for successive 21 days The sucrose preference (SP) test and the force swim test (FST) were used to evaluate antidepressant behavioural studies. Observation of the SP test showed a decrease in consumption of sucrose water in the stressor group, with treatment Zn and Ga showing an increase in consumption of sucrose water. In the stressor group, FST immobility time was prolonged; higher doses of Ga and Zn lowered FST immobility time significantly. Treatment with Ga and Zn successfully restored the stressor group's high MDA level and decreased GSH level. The neurotransmitter 5-HT declined in the stressor group, while Ga (27.5, 55 mg/kg) dosages significantly raised it. Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) were pro-inflammatory cytokines that increased in the stressor group, whereas Ga and Zn both dropped these levels at higher doses. We assumed Zingerone and Gramine were good antidepressants against the CUMS depression model.

Malic Acid Improves Behavioral, Biochemical, and Molecular Disturbances in the Hypothalamus of Stressed Rats.

Stress can lead to emotional and mental symptoms such as anxiety, sadness, panic attacks, and depression. Malic acid was chosen due to malic acid has the ability to improve antioxidant activity and improves liver damage. This study evaluates malic acid anti-depressant activity in the hypothalamus of stressed rats. Thirty-six male albino rats were divided into 2 equal groups; Normal and chronic mild stress (CMS) rats. Normal rats were divided into 3 equal groups; control, malic acid, and venlafaxine drug groups: normal rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. CMS rats were divided into 3 equal groups; CMS, CMS + malic acid, and CMS + venlafaxine drug: CMS rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. All the above-mentioned treatments were administered once a day by oral gavage for 6 weeks. The obtained results revealed that the animal behavioral tests such as forced swimming test, tail suspension test, sucrose preference test, and open-field test (center square entries test, center square duration test, and distance travelled test), norepinephrine, dopamine, serotonin, γ-aminobutyric acid, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity, oxidative index, conjugated dienes, catalase, glutathione peroxidase, superoxide dismutase, malondialdehyde, interleukin-6, tumor necrosis factor-α, interleukin-10, interleukin-1β, sodium/potassium-ATPase activity, and histamine-N-methyl transferase (Hnmt) and tyrosine hydroxylase (TH) enzymes in the hypothalamus of stressed rats, were returned to approaching the normal state in the stressed group after treating with malic acid for 6 weeks. Malic acid ameliorated stressed-related symptoms and it inhibited superoxide anion and neuro-inflammation in the hypothalamus of stressed rats.

Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine

Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress.