Chronic Mild Stress-induced Depression Research Articles

Effects of Saffron Extract (Affron®) with 100 mg/kg and 200 mg/kg on Hypothalamic–Pituitary–Adrenal Axis and Stress Resilience in Chronic Mild Stress-Induced Depression in Wistar Rats

Stress-related symptoms are a global concern, impacting millions of individuals, yet effective and safe treatments remain scarce. Although multiple studies have highlighted the stress- alleviating properties of saffron extract, the underlying mechanisms remain unclear. This study employs the unpredictable chronic mild stress (CMS) animal model to investigate the impact of a standardized saffron extract, Affron® (AFN), on hypothalamic–pituitary–adrenal (HPA) axis regulation and neuroplasticity in Wistar rats following repeated oral administration. The research evaluates AFN’s effects on various stress-related parameters, including hypothalamic gene expression, stress hormone levels, and the sucrose preference test. In animals subjected to continuous unpredictable CMS, repetitive administration of AFN at doses of 100 mg/kg and 200 mg/kg effectively normalized HPA axis dysregulation and enhanced neuroplasticity. Increased concentrations of AFN demonstrated greater efficacy. Following AFN oral administration, adrenocorticotropic and corticosterone hormone levels exhibited significant or nearly significant reductions in comparison to subjects exposed to stress only. These changes align with the alleviation of stress and the normalization of the HPA axis. These findings elucidate AFN’s role in stress mitigation, affirm its health benefits, validate its potential as a treatment for stress-related symptoms, confirm its physiological effectiveness, and emphasize its therapeutic promise.

Cinnamon oil solid self-microemulsion mediates chronic mild stress-induced depression in mice by modulating monoamine neurotransmitters, corticosterone, inflammation cytokines, and intestinal flora

Cinnamon oil (CO) is a classic Chinese medicine with excellent soothing effects on exhaustion, weakness and depression. Cinnamaldehyde is the main active ingredient of cinnamic oil. Although CO have antidepression-like effects, limited information is available. Furthermore, the disadvantages of CO, such as low oral availability and difficult portability, limit its development. In this study, a Cinnamon Oil Solid Self-Microemulsifying Drug Delivery System (CO-S-SME) was designed, prepared. In addition, we explored the effects and mechanisms of CO-S-SME on chronic unpredictable mild stress (CUMS)-induced depression-like behavior, monoamine neurotransmitters, inflammatory factors, intestinal flora in mice. Mice were subjected CUMS to establish the depression model. The antidepressant effect of CO-S-SME was evaluated by behavioral tests. In addition, the expression levels of neurotransmitters, corticosterone (CORT) and inflammatory factors in CUMS mice were analyzed by enzyme-linked immunosorbent assay. In addition, we explored the effects of CO-S-SME on the diversity and richness of intestinal flora of mice in each group. Behavioral tests showed that CO-S-SME could effectively improve depression-like behaviors in CUMS mice. Specifically, CO-S-SME treatment effectively increased neurotransmitter levels and reduced the expressions of corticosterone and inflammatory factors in CUMS mice. CO-S-SME also changed the intestinal flora composition, decreased the ratio of Firmicutes to Bacteroidetes, reduced relative abundances of Lactobacillus, modulated Alpha diversity and beta diversity. These results suggest that CO-S-SME an act as a good antidepressant, exhibiting effects via monoamine neurotransmitters, CORT, inflammation cytokines, and intestinal flora.

Agomelatine Ameliorates Obesity‐Induced Kidney Injury through the Inhibition of Renal Fibrosis and Improvement of Impaired Autophagy

IntroductionChronic kidney disease is the crucial complication that could occur in obesity. Prolong high‐fat diet consumption can stimulate reactive oxygen species (ROS) and contribute to kidney injury through various pathways. Autophagy plays an important role for maintaining intracellular homeostasis. ROS could induce impaired autophagy, subsequently led to kidney damage. Agomelatine (AGOM), a melatonin analogue, is indicated for the treatment of major depressive disorders. The antioxidant and anti‐inflammation effects have been reported in AGOM treatment in chronic mild stress‐induced depression. Previous study found that AGOM inhibited apoptosis and ER stress in the kidney under high‐fat diet condition in rats. However, the effect of AGOM supplementation on renal fibrosis and impaired autophagy in obese condition has never been elucidated.AimsTo evaluate the renoprotective effect of AGOM on kidney function in high‐fat diet‐induced kidney injury, as well as to explore the underlying mechanisms involving autophagy signaling pathway.Materials and methodsMale Wistar rats were received normal diet (ND) or high‐fat diet (HF) for 16 weeks. Then, the HF rats were separated into 4 subgroups including (1) HF; (2) agomelatine20 (AGOM20); (3) AGOM40, the rats were received AGOM at the dose of 20 and 40 mg/kg/day, respectively; and (4) N‐acetylcysteine (NAC), the rats were received NAC at the dose of 100 mg/kg/day by oral gavage for 4 weeks. After 4 weeks of treatment, all rats were sacrificed. Blood, urine and kidney tissues were collected for further investigations.ResultsThe results demonstrated that HF rats developed kidney dysfunction as shown by the raising in serum creatinine, creatinine clearance along with the changes of glomerular structure and the elevating of positive area of α‐SMA, which is renal fibrosis indicator. These alterations were reversed by AGOM and NAC treatment. Moreover, HF rats showed renal oxidative stress as indicated by the increasing in PKCα and NOX4 expression and decreasing in antioxidant enzyme, GCLC. AGOM and NAC administrations reduced oxidative stress and restored antioxidant enzyme. Furthermore, high‐fat diet consumption markedly reduced AMPK, along with the elevation of mTOR expression. Additionally, we found that HF rats aggravated impaired autophagy which could induce oxidative stress, fibrosis and finally led to kidney cell death. AGOM administration restored autophagy process as shown by the increasing in Beclin‐1, LC3B and Atg5 protein. These results demonstrated that AGOM improved kidney injury through the regulation of oxidative stress, fibrosis and autophagy process.ConclusionsThese findings indicated that AGOM prevented kidney injury under obese condition via the inhibition of oxidative stress and fibrosis and improved impaired autophagy via regulating AMPK‐mTOR‐autophagy signaling pathways.

Abstract TP17: Activation Of Erk1/2 Signaling Drives Cardiac Hypertrophy During Chronic Mild Stress-induced Depression In Mice

Background: Major depressive disorder (MDD) is one of the fastest-growing disability disorders in the US and worldwide. Extensive clinical data suggest that MDD is associated with an increased risk of hypertension, coronary heart disease, and other cardiovascular diseases. A close relation between cardiovascular and cerebrovascular diseases and clinical evidence presents a potential link between depression and stroke. MDD when combined with other comorbidities, makes the prognosis worse. Dysregulation of the sympathetic nervous system, impaired hypothalamic-pituitary-adrenal axis, and increased inflammatory response are plausible mechanisms that have been linked to depression-induced cardio- and cerebrovascular complications. In the current study, we investigated cardiac structural and functional alterations in a mouse model of chronic mild stress (CMS) exhibiting depression-like behavior. Methods and Results: The mice were divided into control (CT) and CMS groups. The CMS mice were subjected to various mild, unpredictable stressors for 7 weeks. Depression-like traits were confirmed in the CMS group by analyses of behavioral changes using open field and forced swim tests and a decrease in hippocampal brain-derived neurotrophic factor (BDNF) protein level. To evaluate depression-associated neuronal damage and neuronal plasticity, Fluoro-Jade C staining and expression of microtubule-associated protein 2 were examined. However, we did not observe neuronal damage in the CMS mice as compared to the CT mice. We also observed a decrease in cardiac BDNF expression and upregulation of IL-6 in the CMS mice compared to the CT group. Echocardiographic and histological analyses showed an increase in ventricular wall thickness with increased cardiomyocyte size in the CMS group. However, we did not find changes in fetal gene expression or fibrosis markers. Investigation of underlying mechanisms showed a significant upregulation in ERK1/2 signaling in the left ventricles of the CMS mice as compared to the control group, with no changes in phospho-p38, NFATc3, or JNK levels. Conclusion: In conclusion, these data suggest that ERK1/2 signaling might have an important role in cardiac hypertrophic response during the CMS-induced depression in mice.

Does Sertraline Affect Hypothalamic Food Intake Peptides in the Rat Experimental Model of Chronic Mild Stress-Induced Depression?

Depression is a chronic, recurrent and life-threatening disease affecting approximately 15% of the world population. Depression is responsible for neuropathologies like decreased neurogenesis and increased dendritic atrophy. Antidepressant treatments increase hippocampal neurogenesis and neurotrophic factor expression. Based on this information, it was aimed to investigate effect of sertraline on depression in rats with chronic mild stress (CMS) model and to determine how it affects cell proliferation and hypothalamic peptide levels in hypothalamus. 56 adult male Wistar albino; control, depression(D), depression + sertraline, sertraline were divided into groups. Various stressors were applied to D for 30days. Open field test (OFT) and forced swimming test (FST) were conducted to check whether the animals were depressed. On the 16th day osmotic minipump was placed subcutaneously and sertraline (10mg/kg/day) was administered for 15days. Behavior tests were done. Hypothalamic peptide gene expression levels were analyzed by quantitative RT-PCR. Statistical evaluations were made using ANOVA. It caused a decrease in the percentage of movement in the D and control groups in the OFT, an increase in the immobility time in the D group in the FST, and an increase in the swimming behavior in the DS group. Animals did not show any anxiological behavior based on the elevated plus maze test results. CMS caused a decrease in GLUT2 and NPY gene expression in the hypothalamus of animals, an increase in POMC and FGFR2, and an increase in IGFIR and GLUT2 gene expression in the DS group. Sertraline has been shown to ameliorate the effects of CMS-induced depression. Sertraline is thought to have a positive regulatory effect on both the formation of neural precursor cells and the survival of newly formed neurons in the hypothalamus. Newly formed neurons in the hypothalamus express food intake-related NPY, POMC, GLUT2 neurons, and thus hypothalamic tanycytes may play a key role in the control of energy metabolism.

Antidepressant Effect of Etoricoxib and Ibuprofen on chronic mild stress-induced depression in mice

Antidepressant Effect of Etoricoxib and Ibuprofen on chronic mild stress-induced depression in mice

The antidepressant-like effects of an n-butanol fraction of Ocimum sanctum Linn. extract in unpredictable chronic mild stress-induced depression in mice

We previously reported that Ocimum sanctum Linn. (OS) ethanolic extract and its n-butanol fraction (OS-B) could improve depression-like behaviour in olfactory bulbectomized mice. The present study aims to clarify the antidepressant-like effects of OS-B and the possible mechanism of its action using mice subjected to unpredictable chronic mild stress (UCMS). UCMS mice were administered daily with OS-B (50 mg/kg, 100 mg/kg, p.o.) or imipramine (IMP, 8 mg/kg, i.p.), a reference drug. The UCMS-induced anhedonia in mice was analysed by the sucrose preference test, while behavioural despair was assessed using the tail suspension test (TST) and forced swimming test (FST). Locomotor activities and grooming behaviour of mice were elucidated using the open-field test (OFT). The UCMS procedure for 5 weeks induced anhedonia, and this symptom was significantly ameliorated by the administration of OS-B (100 mg/kg) as well as IMP during the UCMS period. Moreover, the OS-B and IMP treatment attenuated the UCMS-induced enhancement of behavioural despair in the TST and FST. In OFT, mice subjected to UCMS showed a decrease in grooming behaviour, and the effect of UCMS was reversed by OS-B and IMP administrations. No significant difference in locomotor activities between each animal group was observed. The amelioration effects of OS-B and IMP on UCMS-induced behavioural despair in the TST were abolished by administrating of ρ-chlorophenylalanine (PCPA, 80 mg/kg, i.p), a tryptophan hydroxylase inhibitor, and α-methyl-ρ-tyrosine (AMPT, 100 mg/kg), a tyrosine hydroxylase inhibitor. The present results suggest that OS-B attenuates UCMS-induced depression-like symptoms via monoaminergic systems including in the noradrenergic, dopaminergic, and serotonergic system

Merging the Multi-Target Effects of Kleeb Bua Daeng, a Thai Traditional Herbal Formula in Unpredictable Chronic Mild Stress-Induced Depression.

Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between genetics and environment involved. Kleeb Bua Daeng (KBD) is a Thai traditional herbal formula that has been used to promote brain health. It consists of a 1:1:1 ratio of the aerial part of Centella asiatica, Piper nigrum fruit, and the petals of Nelumbo nucifera. According to the pharmacological activities of the individual medicinal plants, KBD has good potential as a treatment for MDD. The present study investigated the antidepressant activity of KBD in an unpredictable chronic mild stress (UCMS) mouse model. Daily administration of KBD to UCMS mice ameliorated both anhedonia, by increasing 2% sucrose intake, and hopeless behavior, by reducing immobility times in the forced swimming test (FST) and tail suspension test (TST) without any effect on locomotor activity. The mechanism of KBD activity was multi-modal. KBD promoted neurogenesis by upregulation of brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding (CREB) mRNA expression in the frontal cortex and hippocampus. Daily treatment with KBD significantly reversed UCMS-induced HPA axis dysregulation by upregulating the glucocorticoid receptor (GR) while downregulating serum- and glucocorticoid-inducible kinase 1 (SGK1) and FK506 binding protein 5 (FKBP5) mRNA expression. KBD treatment also normalized proinflammatory cytokine expression including tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β and IL-6. KBD and its component extracts also exhibited an inhibitory effect in vitro on monoamine oxidase (MAO) A and B. The multiple antidepressant actions of KBD emphasize its potential as an effective, novel treatment for MDD.

Epicatechin treatment generates resilience to chronic mild stress-induced depression in a murine model through a modulatory effect on KAT

Several studies have proposed that cocoa products enriched in flavonoids reduce anxiety and depressive symptoms. (-)–Epicatechin (Epi), a flavonoid present in high concentrations in cocoa, is associated with many effects of dark chocolate and has been postulated to function as an exercise mimetic. Physical exercise is used as an adjuvant treatment for many patients with depression. This study aimed to evaluate the effect of Epi on resilience to depression-like behaviour in a murine model. Male mice were randomly selected and divided into four groups (n = 8/group). At the age of 8–9 weeks, the mice were subjected to chronic mild stress (CMS), and the two groups were treated with Epi for five weeks. Epi was administered by oral gavage twice daily for 5 weeks. The control group was housed under conditions without stress and Epi treatment. Depressive-like behaviour was evaluated by performing sucrose preference and open field tests. Interestingly, Epi reduced anhedonia and anxiogenic behaviour in the murine stress model. Our results provide evidence that Epi induces resilience to stress-induced depression through a modulatory effect on aminotransferase KAT.

RETRACTED: The antidepressant effects of L-arginine on chronic mild stress-induced depression by augmenting the expression of brain-derived neurotrophic factor in rats

In the present study, the antidepressant effects of l-arginine in a rat model of chronic mild stress-induced depression were investigated. Animals were divided into group I (sham), group II (control, depression), group III (10 mg/kg l-arginine), group IV (20 mg/kg l-arginine), and group V (10 mg/kg venlafaxine, positive control). The doses were orally administered for 30 consecutive days. Sucrose preference analysis as well as forced swim and open field tests were performed. Serum cortisol, nitric oxide (NO), and monoamine levels in brain tissue were then measured. Brain-derived neurotrophic factor (BDNF) expression was also examined. Supplementation with l-arginine significantly increased the sucrose preference ratio, locomotor activity, and monoamines and decreased serum cortisol and NO levels. The mRNA and protein expression of BDNF in the brain tissue was significantly reduced (>50 %) in control rats. However, supplementation with l-arginine significantly increased BDNF mRNA expression (>50 %) in both groups. Similarly, increased BDNF protein expression after l-arginine treatment was confirmed using Western blot and immunohistochemical analyses. In conclusion, l-arginine supplementation may be effective against chronic stress-induced depression.

Effects of the Ethanol Extract of Dipterocarpus alatus Leaf on the Unpredictable Chronic Mild Stress-Induced Depression in ICR Mice and Its Possible Mechanism of Action.

Treatment of the unpredictable chronic mild stress (UCMS) mice with the ethanol extract of Dipterocarpus alatus leaf attenuated anhedonia (increased sucrose preference) and behavioral despair (decreased immobility time in tail suspension test (TST) and forced swimming test (FST)). The extract not only decreased the elevation of serum corticosterone level and the index of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, caused by UCMS, but also ameliorated UCMS-induced up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression and down-regulation of cyclic AMP-responsive element binding (CREB) and brain-derived neurotrophic factor (BDNF) mRNAs in frontal cortex and hippocampus. In vitro monoamine oxidase (MAO) inhibition assays showed that the extract exhibited the partial selective inhibition on MAO-A. HPLC analysis of the extract showed the presence of flavonoids (luteolin-7-O-glucoside, kaempferol-3-glucoside, rutin) and phenolic acids (gallic acid, ferulic acid, and caffeic acid) as major constituents.

Ethanol extract of mixture of Astragali Radix and Salviae Miltiorrhizae Radix, alleviates in unpredictable chronic mild stress-induced depression mouse model

Ethanol extract of mixture of Astragali Radix and Salviae Miltiorrhizae Radix, alleviates in unpredictable chronic mild stress-induced depression mouse model

Garlic essential oil mediates acute and chronic mild stress-induced depression in rats via modulation of monoaminergic neurotransmission and brain-derived neurotrophic factor levels

Garlic essential oil (GEO) and its major organosulfur component (diallyl disulfide, DADS) possess diverse biological properties; however, limited information on their antidepressant-like effects is available. This study is the first to investigate these effects of GEO using the forced swimming test (FST) and unpredictable chronic mild stress (UCMS) induced depression in rats. After oral administration for 28 consecutive days, GEO (25 and 50 mg per kg bw) significantly reduced the immobility time in the FST. Additionally, GEO and DADS significantly reversed the sucrose preference index decrease induced by 5 weeks of UCMS. GEO (25 mg per kg bw) effectively decreased the frontal cortex turnover ratio of serotonin (5-HT) and dopamine (DA), thus increasing the 5-HT and DA levels, with no hippocampal effects. Chronic GEO treatment increased hippocampal brain-derived neurotrophic factor (BDNF), c-AMP response element binding protein (CREB), and protein kinase B (AKT) expression, exhibiting its effects via monoamine neurotransmitter modulation and the BDNF-related signaling pathway.

Salvianolic acid B abolished chronic mild stress-induced depression through suppressing oxidative stress and neuro-inflammation via regulating NLRP3 inflammasome activation.

This study was framed to investigate the molecular mechanism behind the anti-depressant effect of salvianolic acid B (SB) against unpredictable chronic mild stress (CMS) induced depression rat model. Control rats received only saline without CMS exposure, whereas CMS model rats were induced to several stress (CMS) for 6weeks. Treatment group rats were induced with CMS for 6weeks but received either 20 or 40mg/kg of SB or 20mg/kg imipramine (CMS+IMP) from the 4th week to 6th week. Treatment with SB or IMP significantly ameliorated body weight, sucrose consumption rate with shorter immobility time than the control group. Also, administration with SB or IMP could reverse the hyperactivity of hypothalamic-pituitary-adrenal axis as well as decreased inflammatory cytokines with improved antioxidant status. Furthermore, the protein expression of NLRP3 (inflammasome) was markedly downregulated upon treatment with SB (both 20 and 40mg) or IMP and thereby confirming its potent anti-depressant activity. PRACTICAL APPLICATIONS: Salvianolic acid B (SB) is a phenolic acid extracted from Salvia militiorrhiza Bunge, a popular Chinese herb, which has been prescribed for various pathological conditions. SB has been previously reported with anti-depressant activity but, the in-depth mechanism behind the anti-depressant effect of SB against CMS is still elusive. Hence, the current study was plotted to explore the in-depth mechanism behind the anti-depressant effect of SB against CMS model of depression in rats. The outcome of the current study has confirmed the anti-depressant activity by abolishing oxidative stress, and neuroinflammatory response in the hippocampus through inhibiting NLRP3 inflammasome activation. Hence, SB can be prescribed to major depression patients with standard anti-depressant agents to abolish oxidative stress, neuro-inflammatory response, and related neurological changes.

Telmisartan Activates PPAR\u03b4 to Improve Symptoms of Unpredictable Chronic Mild Stress-Induced Depression in Mice

Major depression is a common mental disorder that has been established to be associated with a decrease in serotonin and/or serotonin transporters in the brain. Peroxisome proliferator-activated receptor δ (PPARδ) has been introduced as a potential target for depression treatment. Telmisartan was recently shown to activate PPARδ expression; therefore, the effectiveness of telmisartan in treating depression was investigated. In unpredictable chronic mild stress (UCMS) model, treatment with telmisartan for five weeks notably decrease in the time spent in the central and the reduced frequency of grooming and rearing in open filed test (OFT) and the decreased sucrose consumption in sucrose preference test (SPT) compared with the paradigms. Telmisartan also reversed the decrease in PPARδ and 5-HTT levels in the hippocampus of depression-like mice. Administration of PPARδ antagonist GSK0660 and direct infusion of sh-PPARδ into the brain blocked the effects of telmisartan on the improvement of depression-like behavior in these mice. Moreover, telmisartan enhanced the expression of PPARδ and 5HTT in H19-7 cells. In conclusion, the obtained results suggest that telmisartan improves symptoms of stress-induced depression in animals under chronic stress through activation of PPARδ. Therefore, telmisartan may be developed as a potential anti-depressant in the future.

Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation.

BackgroundLeonurine is an active alkaloid that is extracted from Traditional Chinese Medicine Herba leonuri. Emerging evidence indicates that leonurine produces neuroprotective effects in ischemic stroke, Parkinson’s disease, and Alzheimer’s disease. However, the effect of leonurine in neuropsychiatric disorders, especially in major depression, remains unknown.MethodsWe used the chronic mild stress mouse model to explore the antidepressant effects of leonurine and the potential mechanisms. Behavioral tests including sucrose preference test, forced swimming test, and tail suspension test were taken to evaluate depression symptoms. Moreover, the contents of monoamine neurotransmitters in hippocampus and prefrontal cortex were measured by high-performance liquid chromatography. Neuronal morphology was detected by transmission electron microscopy.ResultsAdministration of leonurine (60 mg/kg) for 4 weeks significantly alleviated depression-like behaviors of chronic mild stress mice, including increased sucrose preference and reduced immobility time in forced swimming test and tail suspension test. We further found that leonurine (60 mg/kg) effectively restored the levels of 5-hydroxytryptamine, noradrenaline, and dopamine in the hippocampus and prefrontal cortex of chronic mild stress mice, accompanied by amelioration of hippocampal neuronal damage. Furthermore, leonurine (60 mg/kg) significantly inhibited the production of proinflammatory cytokine interleukin-1β, interleukin-6 and TNF-α, and suppressed the nuclear factor kappa B signaling pathway.ConclusionsThese findings demonstrate that leonurine exerts antidepressant-like effects, which may be mediated, at least in part, by improving monoamine neurotransmitters and inhibiting neuroinflammation. Our study provides insight into the potential of leonurine in depression therapy.

Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice

[Purpose]The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. [Methods]Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST-Cr+Ex, n=9). After five weeks’ treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). [Results]Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. [Conclusion]The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment.

Agomelatine reduces brain, kidney and liver oxidative stress but increases plasma cytokine production in the rats with chronic mild stress-induced depression

Agomelatine (AGOM) as an antidepressant acts both as a melatonin-receptor agonist and a selective serotonin-receptor antagonist. As a potent melatonin derived antioxidant, AGOM might modulate depression-induced lipid peroxidation and pro-inflammatory cytokines in brain, kidney and liver. The present study explores whether AGOM protects against experimental depression-induced brain, kidney and liver oxidative stress, and plasma cytokine production in rats with chronic mild stress (CMS)-induced depression. Thirty-six rats were divided into four groups. The first group was used as an untreated control. The second group received AGOM for 4weeks. The third group was exposed to chronic mild stress (CMS) of 4weeks for induction depression. The fourth group received 40mg/kg AGOM and CMS for 4weeks. Liver and kidney lipid peroxidation levels were high in the CMS group although they were low in AGOM treatments. AGOM and AGOM+CMS treatments increased the lowered glutathione peroxidase activity and reduced glutathione levels in brain, kidney and liver of CMS group. β-carotene, vitamin A and vitamin E concentrations in the brain, kidney and liver of the four groups were not changed by CMS and AGOM treatments. However, plasma TNF-α, interleukin (IL)-1β, and IL-4 levels were high in the CMS and AGOM group and their levels were further increased by the AGOM+CMS treatment. In conclusions, AGOM induced protective effects against experimental depression-induced brain, kidney, and liver oxidative injuries through regulation of the glutathione concentrations and glutathione peroxidase activity. However, plasma cytokine productions were increased by the AGOM treatment.

Hypothalamic Proteomic Analysis Reveals Dysregulation of Glutamate Balance and Energy Metabolism in a Mouse Model of Chronic Mild Stress-Induced Depression.

Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity is observed in many patients suffering from depression. However, the mechanism underlying the dysfunction of the HPA axis is not well understood. Moreover, dysfunction of the hypothalamus, the key brain region of the HPA axis, has not been well-explored. The aim of our study was to examine possible alterations in hypothalamus protein expression in a model of depression using proteomic analysis. In order to achieve this aim, mice were exposed to chronic unpredictable mild stress (CUMS), as the paradigm results in hyperactivity of the HPA axis. Differential protein expression between the hypothalamic proteomes of CUMS and control mice was then assessed through two-dimensional electrophoresis followed by matrix-assisted laser desorption ionization-time of flight-tandem mass spectrometry. Thirty-seven proteins with a threshold of a 1.5-fold change and a p value ≤0.05 were identified as being differentially expressed between CUMS and control mice, and were quantified for bioinformatics analysis. Glycometabolism, citrate cycle (TCA cycle) and oxidation respiratory chain were found to have changed significantly. Glial fibrillary acidic protein and glutamine synthetase were further validated by Western Blot. Our results demonstrated that CUMS mice exhibited a dramatic protein change both in glutamate metabolism and energy mobilization, which may shed some light on the role of the hypothalamus in the pathology of stress-induced depression.

Treadmill exercise alleviates chronic mild stress-induced depression in rats.

Depression is a major cause of disability and one of the most common public health problems. In the present study, antidepressive effect of treadmill exercise on chronic mild stress (CMS)-induced depression in rats was investigated. For this, sucrose intake test, immunohistochemistry for 5-bromo-2′-deoxyuridine, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Western blot analysis for brain-derived neurotrophic factor, cyclic adenosine monophosphate response element binding protein, and endothelial nitric oxide synthase were conducted. Following adaptation to the animal vivarium and two baseline fluid intake tests, the animals were divided into four groups: the control group, the CMS-induced depression group, the CMS-induced depression and exercise group, and the CMS-induced depression and fluoxetine-treated group. The animals in the CMS groups were exposed to the CMS conditions for 8 weeks and those in the control group were exposed to the control conditions for 8 weeks. After 4 weeks of CMS, the rats in the CMS-induced depression and exercise group were made to run on a motorized treadmill for 30 min once a day for 4 weeks. In the present results, treadmill exercise alleviated CMS-induced depressive symptoms. Treadmill exercise restored sucrose consumption, increased cell proliferation, and decreased apoptotic cell death. The present results suggest the possibility that exercise may improve symptoms of depression.