Piperine Reverses Chronic Unpredictable Mild Stress-Induced Behavioral and Biochemical Alterations in Rats

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair, which was related to the serotonergic system. The present study aimed to examine the behavioral and biochemical effects of piperine in rats exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. In addition, it was found that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) contents in the hippocampus and frontal cortex were significantly decreased in CUMS-treated rats. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by CUMS. The results suggest that piperine produces an antidepressant-like effect in CUMS-treated rats, which is possibly mediated by increasing 5-HT and BDNF contents in selective brain tissues.     

慢性温和不可预知性刺激致大鼠抑郁症模型的病理机制研究进展

抑郁症是一种伴有行为学、神经化学和其他生理病理导演的心理障碍.慢性暴露于轻度不可预见性应激（CUMS）已被证实可以导致抑郁薅行为,包括糖水消耗减少等.并且CUMS引起的一系列生化改变类似于人类的抑郁症.我们综述了CUMS致抑郁症动物模型的病理变化,包括了受体、信号转导系统等方面的病理改变.     

氟西汀对慢性不可预见应激模型大鼠海马磷脂酰乙醇胺的影响

摘要 目的：探讨氟西汀对慢性不可预见应激（Chronic Unpredictable Mild Stress,CUS）模型大鼠海马内磷脂酰乙醇胺（phosphatidylethanolamine,PE）组成的影响。方法：（1）将24只SD大鼠随机分为对照组（Sham）、模型组（CUS）和氟西汀组（Flx）。CUS组和Flx组均接受CUS造模,并且在造模后接受生理盐水（1 mL/kg）或氟西汀（10 mg/kg）腹腔注射,连续14天;Sham不进行CUS造模,但是每天接受腹腔注射生理盐水。随后处死大鼠,取海马进行脂质组学分析,比较各处理组海马总的PE和PE小分子相对丰度、不同碳链长度和含不同不饱和键PE的相对丰度差异。结果：（1）与CUS组相比,Sham组PE相对丰度明显减低,而Flx组明显增高（P<0.05）;（2）与Sham组相比,CUS组9个PE小分子相对丰度发生变化,PE（34:1e）、PE（36:1p）、PE（36:2）、PE（36:2p）、PE（36:4）、PE（38:2）、PE（38:4）和PE（40:7）共8个上调（P<0.05或0.01）,PE（34:0p）下调（P<0.05）,CUS组碳链长度为36的PE丰度上升（P<0.05）,碳链长度为38的PE丰度下降（P<0.01）,CUS组含0个不饱和键、4个不饱和键的PE丰度下调（P<0.01, P<0.05）,而1个不饱和键的PE丰度上升（P<0.05）;（3）与CUS组相比,Flx组6个PE分子相对丰度减少,包括PE（34:1e）、PE（36:2）、PE（36:4）、PE（38:1p）、PE（38:6e）和PE（40:5p）（P<0.05或0.01）,Flx组碳链长度为34的PE丰度下降（P<0.05）,碳链长度为36的PE水平升高（P<0.05）,Flx组含1个不饱和键的PE丰度下调（P<0.05）,差异具有统计学意义。结论：氟西汀可以调节CUS模型大鼠海马的PE水平。     

逍遥散对CUMS模型大鼠行为学及脑内单胺类神经递质的影响

目的:观察逍遥散对慢性温和不可预知应激(CUMS)模型大鼠的行为学及脑内单胺类神经递质含量的影响。方法:应用慢性温和不可预知应激程序对大鼠进行为期11周的造模,造模后3周,分别采用逍遥散(19.5g/kg、25.0g/kg)和丙咪嗪(15.0mg/kg)对模型大鼠进行为期8周的治疗。实验进程中,定期测定大鼠体重、糖水消耗量;应用开场实验测定大鼠爬行格子数和站立次数;造模、治疗结束后处死大鼠,解剖分离大鼠皮层和海马部位,采用荧光分光光度法测定5-HLAA、5-HT、DA和NE含量。结果:与正常对照组比较。大鼠造模后3周糖水消耗量、爬行格子数和站立次数均明显减少(P<0.01);与模型对照组比较,逍遥散19.5、25.0g/kg连续给药2周能显著增加糖水消耗量,但给药4周、7周对糖水消耗量影响不明显;与模型对照组比较,逍遥散25.0g/kg连续给药7周,对大鼠体重、爬行格子数和站立次数表现出提高趋势(P>0.05),逍遥散25.0g/kg连续给药8周,能明显提高模型大鼠皮层部位5-HT含量及海马部位5-HIAA含量(P<0.05,P<0.01)。结论:逍遥散对CUMS抑郁模型大鼠表现出抗抑郁作用,作用机制与影响脑内单胺类神经递质5-HT活性有关。     

Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state.     

Epigallocatechin-3-Gallate Attenuates Impairment of Learning and Memory in Chronic Unpredictable Mild Stress-Treated Rats by Restoring Hippocampal Autophagic Flux

Epigallocatechin gallate (EGCG) is a major polyphenol in green tea with beneficial effects on the impairment in learning and memory. Autophagy is a cellular process that protects neurons from stressful conditions. The present study was designed to investigate whether EGCG can rescue chronic unpredictable mild stress (CUMS)-induced cognitive impairment in rats and whether its protective effect involves improvement of autophagic flux. As expected, our results showed that CUMS significantly impaired memory performance and inhibited autophagic flux as indicated by elevated LC3-II and p62 protein levels. At the same time, we observed an increased neuronal loss and activated mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6k) signaling in the CA1 regions. Interestingly, chronic treatment with EGCG (25 mg/kg, i.p.) significantly improved those behavioral alterations, attenuated histopathological abnormalities in hippocampal CA1 regions, reduced amyloid beta1–42 (Aβ₁₋₄₂) levels, and restored autophagic flux. However, blocking autophagic flux with chloroquine, an inhibitor of autophagic flux, reversed these effects of EGCG. Taken together, these findings suggest that the impaired autophagy in CA1 regions of CUMS rats may contribute to learning and memory impairment. Therefore, we conclude that EGCG attenuation of CUMS-induced learning and memory impairment may be through rescuing autophagic flux.     

Chronic Treatment with the IDO1 Inhibitor 1-Methyl-D-Tryptophan Minimizes the Behavioural and Biochemical Abnormalities Induced by Unpredictable Chronic Mild Stress in Mice - Comparison with Fluoxetine

We demonstrated that confronting mice to the Unpredictable Chronic Mild Stress (UCMS) procedure—a validated model of stress-induced depression—results in behavioural alterations and biochemical changes in the kynurenine pathway (KP), suspected to modify the glutamatergic neurotransmission through the imbalance between downstream metabolites such as 3-hydroxykynurenine, quinolinic and kynurenic acids. We showed that daily treatment with the IDO1 inhibitor 1-methyl-D-tryptophan partially rescues UCMS-induced KP alterations as does the antidepressant fluoxetine. More importantly we demonstrated that 1-methyl-D-tryptophan was able to alleviate most of the behavioural changes resulting from UCMS exposure. We also showed that both fluoxetine and 1-methyl-D-tryptophan robustly reduced peripheral levels of proinflammatory cytokines in UCMS mice suggesting that their therapeutic effects might occur through anti-inflammatory processes. KP inhibition might be involved in the positive effects of fluoxetine on mice behaviour and could be a relevant strategy to counteract depressive-like symptoms.     

Abnormal Expression of MicroRNAs Induced by Chronic Unpredictable Mild Stress in Rat Hippocampal Tissues

Previous research has demonstrated that the behaviors observed in chronic unpredictable mild stressed (CUMS) rats are similar to the symptoms of depressed patients and that the abnormal expression of cerebral microRNAs is associated with depressive disorder. However, little is known regarding the expression profile of microRNAs induced by CUMS. In this study, we aimed to examine the hippocampal microRNA expression profile in CUMS rats. Forty adolescent male Sprague-Dawley rats were randomly divided into normal and model groups. The rats in the model group were stimulated daily with randomly applied mild stressors from among 14 different mild stressors. The stressors were changed every day and were applied for 35 consecutive days. On the 28th and 35th days after treatment, the weights, physical condition, sucrose preference, and open-field test scores of the rats of the two groups were evaluated. Successful induction of CUMS was considered if the differences of the above metrics between the two groups were statistically significant on the 28th and 35th days after treatment. Cerebral sucrose metabolism images of rats were obtained by 18F-FDG PET/CT. The rats were euthanized under anesthesia, and hippocampal tissues were collected for hematoxylin-eosin (HE) staining. In addition, the samples were used for microRNA array chip and qRT-PCR analysis. The target genes of different microRNAs were predicted using bioinformatic analysis, and the functions and signal pathways of these target genes were investigated by GO and KEGG analyses. Sixteen rats exhibited successful induction of CUMS. Cerebral ¹⁸F-FDG PET/CT imaging showed that the glucose metabolism rate of CUMS rats were significantly lower than normal rats in the central nucleus of the inferior colliculus (CIC, p = 0.022), the retrosplenial agranular area (RSA, p = 0.002), the second sensory cortex (S2, p = 0.028), the first auditory cortex (Au1, p = 0.012), the primary somatosensory cortex, barrel field (SIBF, p = 0.001), and the ventral posteromedial nucleus (VPM) of the right thalamus (p = 0.048). HE staining showed that hippocampal pyramidal cells CUMS rats were thinner, disordered, and exhibited irregular shapes, with many pyknotic cells. The microarray chip and qRT-PCR analysis revealed that five microRNAs were significantly up-regulated [miR-382-3p (p = 0.026), miR-183-5p (p = 0.018), miR-3573-5p (p = 0.042), miR-202-3p (p = 0.016), miR-493-3p (p = 0.009)], and only miR-370-3p was significantly down-regulated (p = 0.036). miRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with depression. Our findings provide supportive evidence for the abnormal expression of multiple CUMS-induced hippocampal microRNAs in rats as well as the involvement of these microRNAs in depressive disorder.     

Association between Repeated Unpredictable Chronic Mild Stress (UCMS) Procedures with a High Fat Diet: A Model of Fluoxetine Resistance in Mice

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS—an already validated animal model of depression—with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression.     

An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms,Behavioral Changes and Negative Health Outcomes in Rodents

Chronic, unresolved stress is a major risk factor for the development of clinical depression. While many preclinical models of stress-induced depression have been reported, the unpredictable chronic mild stress (UCMS) protocol is an established translationally-relevant model for inducing behavioral symptoms commonly associated with clinical depression, such as anhedonia, altered grooming behavior, and learned helplessness in rodents. The UCMS protocol also induces physiological (e.g., hypercortisolemia, hypertension) and neurological (e.g., anhedonia, learned helplessness) changes that are clinically associated with depression. Importantly, UCMS-induced depressive symptoms can be ameliorated through chronic, but not acute, treatment with common SSRIs. As such, the UCMS protocol offers many advantages over acute stress protocols or protocols that utilize more extreme stressors. Our protocol involves randomized, daily exposures to 7 distinct stressors: damp bedding, removal of bedding, cage tilt, alteration of light/dark cycles, social stresses, shallow water bath, and predator sounds/smells. By subjecting rodents 3-4 hr daily to these mild stressors for 8 weeks, we demonstrate both significant behavioral changes and poor health outcomes to the cardiovascular system. This approach allows for in-depth interrogation of the neurological, behavioral, and physiological alterations associated with chronic stress-induced depression, as well as for testing of new potential therapeutic agents or intervention strategies.     

Changes in Gut Microbiota by Chronic Stress Impair the Efficacy of Fluoxetine

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慢性应激抑郁大鼠学习记忆及海马非对称性超微结构的改变

目的：探讨慢性不可预见性应激抑郁模型大鼠大脑海马非对称性超微结构与学习记忆能力的改变。方法：SD雄性大鼠20只,随机分为正常对照组与抑郁模型组,每组10只。采用慢性轻度不可预见性应激21d及单笼饲养方法建立抑郁模型,应激前以及应激21d末对两组大鼠进行旷场实验、液体消耗实验及体重测量,对大鼠进行避暗穿梭实验,测试其学习记忆能力,之后活杀动物,取出大鼠左右海马,制作常规电镜标本,观察海马超微结构的改变。结果：在穿梭变实验中抑郁大鼠学习记忆潜伏期减少,进入暗箱错误积分增多。抑郁大鼠左右侧海马超微结构中左侧海马较正常对照组神经细胞及胶质细胞变化明显,表现为内质网扩张,溶酶体增多。而右侧海马远不及左侧损伤严重。结论：慢性不可预见性应激抑郁大鼠学习记忆能力显著下降,其可能与海马组织在应激过程受到的累积损伤有关,且抑郁大鼠海马损伤呈非对称表现。     

Behavioral and Biochemical Interaction Between Nicotine and Chronic Unpredictable Mild Stress in Mice

Nicotine, the main component of tobacco smoke, exerts influence on mood, and contributes to physical and psychological dependence. Taking into account frequent concomitance of nicotine abuse and stress, we aimed to research behavioral and biochemical effects associated with nicotine administration in combination with chronic unpredictable mild stress (CUMS). Mice were submitted to the procedure of CUMS for 4 weeks, 2 h per day. Our results revealed that CUMS-exposed animals exhibited behavioral alteration like anxiety disorders in the elevated plus maze (EPM) test, the disturbances in memory in the passive avoidance (PA) test and depressive effects in the forced swim test (FST). Moreover, nicotine (0.05–0.5 mg/kg), after an acute or subchronic administration decreased stress-induced depression- and anxiety-like effect as well as memory deficit. Administration of metyrapone (50 mg/kg), a glucocorticosteroid antagonist, alleviated the depressive effect induced by the CUMS. The biochemical experiments showed decreased values of the total antioxidant status (TAS), activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) with simultaneously increased in malondialdehyde (MDA) concentration in mice submitted to the CUMS. The same effects were observed after an acute and subchronic nicotine administration within all examined brain structures (i.e., hippocampus, cortex, and cerebellum) and in the whole brain in non-stressed and stressed mice confirming pro-oxidative effect of nicotine. Our study contributes to the understanding of behavioral and biochemical mechanisms involved in stress-induced disorders such as depression, anxiety and memory disturbances as well as dual nicotine-stress interactions on the basis of the development of nicotine dependence.     

Hydroalcoholic Extract of Rabbiteye Blueberry (Vaccinium ashei) Leaves Mitigates Unpredictable Chronic Mild Stress Model Inducing Depressive-Like Behavior in Rats

Several studies reported that rabbiteye blueberry (Vaccinium ashei Reade) leaves present promising biological properties. To the best of our knowledge, no study investigated the possible application of their hydroalcoholic extract for treating mood disorders. Herein, we evaluated if the hydroalcoholic extract of rabbiteye blueberry (Vaccinium ashei Reade) leaves (HEV) promotes an antidepressant-like effect in rodents using chronic experimental approaches. The effect of repeated administration of HEV (50 mg/kg, p.o.) on the immobility time was assessed in the forced swimming test (FST) in an unpredictable chronic mild stress (UCMS) model. Repeated treatment with HEV reversed the depressive-like behavior induced by UCMS by reducing the immobility time. Besides, the exposure to HEV caused no changes in relative organ weights in rats submitted to UCMS. The results indicated that HEV administration presented antidepressant-like action devoid of toxic effects. Thus, it is possible to suggest its potential as a safe and accessible therapeutic tool in the management of depression and other related mood disorders.     

Antidepressant-like Effect of 3-n-Butylphthalide in Rats Exposed to Chronic Unpredictable Mild Stress: Modulation of Brain-Derived Neurotrophic Factor Level and mTOR Activation in Cortex

3-n-Butylphthalide (NBP), an extract from seeds of Apium graveolens Linn. (Chinese celery), has been demonstrated to have antidepressant effects in suspension chronic-stressed rats by our group. The purpose of this study was to investigate the possible involvement of brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the antidepressant mechanism of NBP. Chronic unpredictable mild stress (CUMS) was applied for 6 weeks to induced a depressive-like behavior, characterized by decreased locomotor activity, sucrose preference and the NE, DA and 5-HT levels in cortex. Oral treatment with NBP (30 or 100 mg/kg, p.o.), similarly to fluoxetine (2 mg/kg, p.o.), can prevention of these alterations. The NBP (30 or 100 mg/kg, p.o.) reversed the decrease in the BDNF, p-ERK, mTOR and synapsin-1 protein levels in rat cortex caused by CUMS. And rapamycin, an mTOR inhibitor, completely inhibited the antidepressant-like activity of NBP in vivo. In conclusion, these findings indicate that NBP treatment attenuated the depression-like behaviors through the modulation of serotonergic system and BDNF-ERK-mTOR signaling in rat.

     

Differential Response of Central Dopaminergic System in Acute and Chronic Unpredictable Stress Models in Rats

We aimed to evaluate the response of dopaminergic system in acute stress (AS) and chronic unpredictable stress (CUS) by measuring dopamine (DA) levels, its receptor densities in the frontal cortex, striatum, hippocampus, amygdala and orbito-frontal cortex regions of rat brain, and investigated the corresponding behavioral locomotor changes. Involvement of D₁ receptor was also examined during AS and CUS using A 68930, a D₁ selective agonist. Rats were exposed to AS (single immobilization for 150 min) and CUS (two different stressors for 7 days). AS significantly decreased the DA levels in the striatum and hippocampus, and A 68930 pretreatment significantly reverted these changes. However, in the frontal cortex significantly increased DA levels were remain unchanged following A 68930. CUS led to a decrease of DA levels in the frontal cortex, striatum and hippocampus, which were normalized by A 68930. Saturation radioligand binding assays revealed a significant decrease in the number of D₁-like receptors in the frontal cortex during CUS, which were further decreased by A 68930 pretreatment. However, in the striatum and hippocampus, A 68930 pretreatment reduced the CUS induced increase in the number of D₁-like receptors. No significant changes were observed in the amygdala and orbito-frontal cortex during AS and CUS, while D₂-like receptors were unchanged in all the brain regions studied. Locomotor activity was significantly decreased in both the stress models, A 68930 pretreatment significantly increased stereotypic counts and horizontal activity. Thus, present investigation provide insights into the differential regional response of dopaminergic system during AS and CUS. Further, neurochemical and behavioral effects of D₁ agonist pretreatment suggest specific modulatory role of D₁ receptor under such stressful episodes.     

Antidepressant Effects of the Ginsenoside Metabolite Compound K,Assessed by Behavioral Despair Test and Chronic Unpredictable Mild Stress Model

Depression is a major social and health problem worldwide. Compound K (CK), an intestinal metabolite of panaxadiol ginsenosides, has been demonstrated to possess significant pharmacological effects on the central nervous system (CNS). Here, we set up this study to investigate the antidepressant effect of CK, and to explore the potential mechanisms underlying this activity. The behavioral despair model and chronic unpredictable mild stress (CUMS) model were established in mice or rats, respectively. Forced swimming test (FST), tail suspension test (TST) and locomotor activity were performed in mice, while the open-field test, food consumption and sucrose preference were assessed in rats. To investigate the underlying mechanism, the levels of endogenous noradrenaline, dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites in the prefrontal cortex (PFC) and hippocampus were detected by HPLC coupled with electron detector. The dopamine degradation enzyme (COMT and MAO) expression was measured by western blot. The BDNF and NGF expression were investigated by immunohistochemical staining analysis. The results showed CK (10, 30 mg/kg) intragastric administration for 14 days significantly shorten the immobility time in FST and TST, which could be partially reversed by a D1 receptor antagonist Sch23390. For CUMS rats, CK alleviated the depressant-like behaviors, including decreased food consumption, spontaneous locomotor activity and lower sucrose preference, while WAY-100635, a 5-HT_1A receptor antagonist, could attenuate this effect. In addition, CK increased the levels of 5-HT, DA and their metabolites in the PFC and hippocampus of CUMS rats, and could reverse overexpression of MAO_B in PFC and hippocampus. CK also increased the GSH and GPx activity in the hippocampus and PFC. The IHC results revealed the BDNF and NGF expression were increased in CK-treated rats. The obtained results indicate that CK exhibits antidepressant effects in rodents, which may be due to the regulation of monoamine neurotransmitter concentration, enhancement of antioxidant capacity, as well as increase of neurotrophin expression in the CNS.     

Genetic Specificity of Stress-Induced Anemia in Rats

There is a genetic difference in rat hemoglobin (Hb) β-chain structure, with alternate alleles, A and B, at a single locus. This study was designed to find out whether marrow sensitivity due to γ exposure and experimentally induced anemia in age-matched adult rats is entirely strain specific or is a combination of both strain and Hb genotype. Eight strains of inbred and outbred rats comprising AA and BB types were examined. The data indicate that there is a relationship between marrow sensitivity and Hb genotypes in response to erythropoietic stress caused by three techniques.     

Loureirin C and Xanthoceraside Attenuate Depression-Like Behaviors and Expression of Interleukin-17 in the Prefrontal Cortex Induced by Chronic Unpredictable Mild Stress in Mice

Neurochemical Research - Major depressive disorder (MDD) is the most prevalent and serious psychiatric disease involving inflammation. Loureirin C and Xanthoceraside are extracts of dragon’s...