Chronic Unpredictable Mild Stress Exposure Research Articles

Chronic stress induces insulin resistance and enhances cognitive impairment in AD

BackgroundChronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. MethodsMale 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). ResultsFour weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aβ42 and Aβ40 in wild-type mice. ConclusionsChronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

Chronic stress causes ovarian fibrosis to impair female fertility in mice

ObjectiveChronic psychological stress is associated with impaired follicular development and ovarian dysfunction. Many aspects of this dysfunction and the underlying mechanisms remain unclear. Using a chronic unpredictable mild stress (CUMS) mouse model, we investigate the influence of chronic stress on ovarian function and explore potential mechanisms. MethodsA CUMS mouse model was constructed over eight months, covering the period from sexual maturity to the onset of declining fertility in mice. At the end of the 2nd, 4th, 6th, and 8th months of exposure to CUMS, behavioral and physiological assays, including the sucrose preference test, tail suspension test, and serum corticosterone levels, were conducted to validate the effectiveness of the stress model. Fertility and ovarian function were assessed by analyzing the estrous cycle, number of offspring, sex hormone levels, follicle counts, granulosa cell proliferation and apoptosis, and the expression levels of fibrosis markers. Furthermore, proteomic analyses were performed on the ovaries to investigate the molecular mechanisms of ovarian fibrosis induced by CUMS. ResultsWith continued CUMS exposure, there was a gradual decline in both the ovary-to-body weight ratio and the number of offspring. Moreover, the percentage of atretic follicles was notably higher in the CUMS-exposed groups compared to the control groups. It is noticeable that CUMS triggered granulosa cell apoptosis and halted proliferation. Additionally, increased expression of α-SMA and Collagen I in the ovaries of CUMS-exposed mice indicated that CUMS could induce ovarian fibrosis. Proteomic analysis provided insights into the activation of specific biological processes and molecules associated with fibrosis induced by chronic stress. ConclusionsOur results strongly suggest that exposure to CUMS induces ovarian fibrosis, which influences follicular development and ultimately contributes to fertility decline. These findings offer novel perspectives on the impact of chronic stress on ovarian dysfunction.

Antidepressant-like effects of Cimicifuga dahurica (Turcz.) Maxim. via modulation of monoamine regulatory pathways

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways.

Synergistic effects of melatonin and hydrogen sulfide in alleviating cognitive decline and BDNF dysregulation in a rat model of depression

ABSTRACT This research aimed to investigate the possible anti-amnesic effects of a combined therapy involving melatonin and H2S in a rat model displaying Depressive-Like Behaviors caused by Chronic Unpredictable Mild Stress (CUMS). Our study aims to assess the efficacy of this treatment in mitigating oxidative stress and neuroinflammation in the striatum and hippocampus. Furthermore, we seek to investigate its ability to restore BDNF levels within this specific rat model. The rats underwent a 4-week CUMS protocol and were administered sodium hydrosulfide (a H2S donor) at a dose of 5.6 μmol/100 g/day, as well as melatonin at a dose of 1 mg/100 g/day from the first day of the CUMS protocol. Following the CUMS exposure, the rats were assessed through various behavioral tests. Subsequently, the rats were euthanized after the behavioral tests, and blood samples were collected for corticosterone analysis. Oxidative stress (OS) markers, BDNF and TNF-α levels were analyzed in both the striatum and HP. Concurrently administering H2S and melatonin in a rat model of CUMS-induced depression demonstrates antidepressant-like effects. Furthermore, this combined treatment effectively prevents the development of learning and memory impairments associated with CUMS. Additionally, it reduces Malondialdehyde and nitric oxide levels, enhances glutathione peroxidase and superoxide dismutase activity in the striatum and HP, and mitigates CUMS-induced elevations in TNF-α levels in both brain regions. Significantly, long-term administration of this combination reverses the chronic stress-induced reduction of hippocampal BDNF levels. These findings suggest that the synergy between H2S and melatonin holds promise in alleviating cognitive impairments.

Down-regulation of MKP-1 in hippocampus protects against stress-induced depression-like behaviors and neuroinflammation

Chronic stress is the primary environmental risk factor for major depressive disorder (MDD), and there is compelling evidence that neuroinflammation is the major pathomechanism linking chronic stress to MDD. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of MAPK signaling pathways involved in cellular stress responses, survival, and neuroinflammation. We examined the possible contributions of MKP-1 to stress-induced MDD by comparing depression-like behaviors (anhedonia, motor retardation, behavioral despair), neuroinflammatory marker expression, and MAPK signaling pathways among rats exposed to chronic unpredictable mild stress (CUMS), overexpressing MKP-1 in the hippocampus, and CUMS-exposed rats underexpressing MKP-1 in the hippocampus. Rats exposed to CUMS exhibited MKP-1 overexpression, greater numbers of activated microglia, and enhanced expressions of neuroinflammatory markers (interleukin [IL]-6, [IL]-1β, tumor necrosis factor [TNF]-ɑ, and decreased phosphorylation levels of ERK and p38 in the hippocampus as well as anhedonia in the sucrose preference test, motor retardation in the open field, and greater immobility (despair) in the forced swimming tests. These signs of neuroinflammation and depression-like behaviors and phosphorylation levels of ERK and p38 were also observed in rats overexpressing MKP-1 without CUMS exposure, while CUMS-induced neuroinflammation, microglial activation, phosphorylation levels of ERK and p38, and depression-like behaviors were significantly reversed by MKP-1 knockdown. Moreover, MKP-1 knockdown promoted the activation of the MAPK isoform ERK, implying that the antidepressant-like effects of MKP-1 knockdown may be mediated by the ERK pathway disinhibition. These findings suggested that hippocampal MKP-1 is an essential regulator of stress-induced neuroinflammation and a promising target for antidepressant development.

Transcutaneous auricular vagus nerve stimulation ameliorates adolescent depressive- and anxiety-like behaviors via hippocampus glycolysis and inflammation response.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a crucial neuromodulation therapy for depression, yet its molecular mechanism remains unclear. Here, we aim to unveil the underlying mechanisms of antidepression by systematically evaluating the change of gene expression in different brain regions (i.e., hippocampus, anterior cingulate cortex, and medial prefrontal cortex). The adolescent depression rat model was established by chronic unpredictable mild stress (CUMS), followed by the taVNS treatment for 3 weeks. The open field test (OFT), forced swimming test (FST), elevated plus maze test (EPM), and new object recognition (NOR) test were used to evaluate depressive- and anxiety-like behaviors. Gene expression analysis of three brain regions was conducted by RNA sequencing (RNA-seq) and further bioinformatics methods. The depressive- and anxiety-like behaviors in CUMS-exposed rats were manifested by decreased spontaneous locomotor activity of OFT, increased immobility time of FST, increased entries and time in the closed arms of EPM, and decreased new object index of NOR. Furthermore, CUMS exposure also led to alterations in gene expression within the hippocampus (HIP), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC), suggesting a potential link between adolescent stress and pathological changes within these brain regions. TaVNS could significantly ameliorate depressive- and anxiety-like behaviors. Its effects on these three brain regions were found related to regulation of the metabolism, and there were some brain region-specific findings. Compared with ACC and mPFC, taVNS has a more concrete effect on HIP by regulating the inflammation response and glycolysis. taVNS is capable of ameliorating adolescent depressive- and anxiety-like behaviors by regulating plenty of genes in the three brain regions. Suppressed level of inflammatory response and enhanced glycolysis manifests the dominant role of taVNS in HIP, which provides a theoretical foundation and data support for the molecular mechanism of antidepression by taVNS.

Repetitive transcranial magnetic stimulation and fluoxetine attenuate astroglial activation and benefit behaviours in a chronic unpredictable mild stress mouse model of depression

Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been considered as an effective antidepressant treatment; however, the mechanism of its antidepressant effect is still unclear. Fluoxetine, a selective serotonin reuptake inhibitor antidepressant, may be neuroprotective. The objective of the present study was to evaluate the effect and underlying possible neuroprotective mechanism of rTMS and fluoxetine on abnormal behaviours in a depressive mouse model induced by chronic unpredictable mild stress (CUMS).Methods: After 28 days of CUMS exposure, mice were chronically treated with rTMS (10 Hz for 5 s per train, total 20 trains per day) and (or) fluoxetine (5 mg/kg/day, intraperitoneally) for 28 days targeting on the frontal cortex. After the behavioural tests, the protein expressions of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were measured by immunohistochemistry and (or) Western Blot.Results: The results showed rTMS and (or) fluoxetine attenuated the locomotion decrease, anxiety and depressive like behaviours in the CUMS-exposed mice.Conclusion: Our results suggest that both rTMS and fluoxetine could benefit the CUMS-induced abnormal behaviours including depressive-like behaviours, and the beneficial effects of rTMS as well as fluoxetine on depression might be partly related to their neuroprotective effect on attenuating astroglial activation and BDNF decrease

Prolonged ketamine therapy differentially rescues psychobehavioural deficits via modulation of nitro-oxidative stress and oxytocin receptors in the gut-brain-axis of chronically-stressed mice

Ketamine is an anaesthetic known to have short but rapid-acting anti-depressant effects; however, the neurobehavioural effects of its prolonged use and its role on the oxytocin system in the gut-brain axis are largely undetermined. Female BALB/c mice were either exposed to the chronic unpredictable mild stress (CUMS) paradigm for 21 days and then treated with ketamine in four doses for 14 days or exposed to CUMS and treated simultaneously in four doses of ketamine during the last two weeks of CUMS exposure. After each dose, the forced swim test was conducted to assess depressive-like behaviour. Before sacrifice, all the mice were subjected to behavioural tests to assess anxiety, memory, and social interaction. Prolonged treatment of depression with ketamine did not rescue depressive-like behaviour. It did, however, improve depression-associated anxiety-like behaviours, short-term memory and social interaction deficits when compared to the stressed untreated mice. Furthermore, ketamine treatment enhanced plasma oxytocin levels, expression of oxytocin receptors; as well as abrogated nitro-oxidative stress biomarkers in the intestinal and hippocampal tissues. Taken together, our findings indicate that while short-term use of ketamine has anti-depressant benefits, its prolonged therapeutic use does not seem to adequately resolve depressive-like behaviour in mice.

Polydatin Alleviates Chronic Stress-Induced Depressive and Anxiety-like Behaviors in a Mouse Model.

We aimed to investigate whether polydatin could suppress stress-induced depression- and anxiety-like behaviors in a mouse model. Mice were divided into the control group, chronic unpredictable mild stress (CUMS) exposure group, and CUMS mice treated with polydatin group. Following CUMS exposure and polydatin treatment, mice were subjected to behavioral assays to assess depressive-like and anxiety-like behaviors. Synaptic function was determined by the levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and synaptophysin (SYN) in the hippocampus and cultured hippocampal neurons. The number and length of dendrites were assessed in cultured hippocampal neurons. Finally, we investigated the effect of polydatin on CUMS-induced inflammation and oxidative stress in the hippocampus by measuring inflammatory cytokine levels, oxidative stress markers such as reactive oxygen species, glutathione peroxidase, catalase, and superoxide dismutase, as well as components of the Nrf2 signaling pathway. Polydatin alleviated CUMS-induced depressive-like behaviors in forced swimming, tail suspension and sucrose preference tests, and anxiety-like behaviors in marble-burying and elevated plus maze tests. Polydatin increased the number and length of dendrites of cultured hippocampal neurons from mice exposed to CUMS and alleviated CUMS-induced synaptic deficits by restoring BDNF, PSD95, and SYN levels in vivo and in vitro. Importantly, polydatin inhibited CUMS-induced hippocampal inflammation and oxidative stress and suppressed the activation of NFκB and Nrf2 pathways. Our study suggests that polydatin may be an effective drug for the treatment of affective disorders through inhibiting neuroinflammation and oxidative stress. Our current findings warrant further study to investigate the potential clinical application of polydatin.

Lack of bombesin receptor-activated protein homologous protein impairs hippocampal synaptic plasticity and promotes chronic unpredictable mild stress induced behavioral changes in mice

Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004-/- and bc004004+/+ mice exhibited behavioural changes and there was no significant difference between bc004004+/+ and bc004004-/- . However, behavioural changes were observed only in bc004004-/- mice after being exposed to CUMS for 21 days, but not in bc004004+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.

Tanshinone IIA ameliorates chronic unpredictable mild stress-induced depression-like behavior and cognitive impairment in rats through the BDNF/TrkB/GAT1 signaling pathway

BackgroundDepression is a common disorder with a complex pathogenesis. Tanshinone IIA (TAN IIA) is a botanical agent with neuroprotective and antidepressant properties. ObjectiveTo examine the effects of TAN IIA on chronic unpredictable mild stress (CUMS)-induced depression-like behavior and cognitive impairment in rats. MethodsRats were exposed to CUMS for 4 weeks, followed by the oral administration of TAN IIA, Deanxit (DEAN), or normal saline for an additional 4 weeks. The control rats were fed with regular chow and administered with normal saline for 4 weeks. Behavioral tests were performed to assess the effects of TAN IIA on depression-like behavior and cognitive impairment in rats with CUMS. The morphology of dendrites was analyzed by Golgi staining. Immunofluorescence staining was performed to determine protein localization. ResultsTAN IIA treatment ameliorated CUMS-induced depression-like behavior and cognitive impairment in rats. TAN IIA treatment also reversed the effects of CUMS on dendritic complexity and the levels of gamma-aminobutyric acid (GABA) in the hippocampus and prefrontal cortex. Rats with CUMS showed decreased levels of brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin receptor kinase B (TrkB), upregulated expression of GABA transporter 1 (GAT1), and reduced expression of synaptic proteins in the hippocampus, while TAN IIA treatment significantly diminished the effects of CUMS exposure. In addition, GAT1 was colocalized with N-methyl-D-aspartate receptor 2B. ConclusionTAN IIA ameliorates CUMS-induced depression-like behavior and cognitive impairment in rats by regulating the BDNF/TrkB/GAT1 signaling pathway, suggesting that TAN IIA may be a candidate drug for the treatment of depression.

Electrical stimulus combined with venlafaxine and mirtazapine improves brain Ca2+ activity, pre-pulse inhibition, and immobility time in a model of major depressive disorder in schizophrenia

BackgroundThe prevalence of major depressive disorder in patients with schizophrenia (SZ-MDD) has been reported to be about 32.6 %, but it varies considerably depending on the stage (early or chronic) and state (acute or post-psychotic) of schizophrenia. The exploration of ideal strategies for the treatment of major depressive disorder in the context of schizophrenia is urgently needed. Thus, the present study was conducted to investigate the treatment effects of clozapine, electrical stimulation (ECS; the mouse model equivalent of electroconvulsive therapy for humans), venlafaxine, and mirtazapine for SZ-MDD. MethodsA mouse model of SZ-MDD was established with MK801 administration and chronic unpredictable mild stress exposure. Clozapine and ECS, alone and with mirtazapine and/or venlafaxine, were used as treatment strategies. In-vivo two-photon imaging was performed to visualize Ca2+ neural activity in the prefrontal cortex (PFC). Mouse performance on behavioral assays was taken to reflect acute treatment effects. ResultsECS + venlafaxine + mirtazapine performed significantly better than other treatments in alleviating major depressive disorder, as reflected by PFC Ca2+ activity and behavioral assay performance. Clozapine + venlafaxine + mirtazapine did not have an ideal treatment effect. Brain Ca2+ activity alterations did not correlate with behavioral expression in any treatment group. ConclusionsIn this mouse model of SZ-MDD, ECS + venlafaxine + mirtazapine improved brain Ca2+ activity, pre-pulse inhibition, and immobility time. These findings provide useful information for the further exploration of treatment methods for patients with SZ-MDD, although the mechanisms underlying this comorbidity needed to be investigated further.

The antidepressant effects and serum metabonomics of bifid triple viable capsule in a rat model of chronic unpredictable mild stress.

BackgroundProbiotics have shown potential antidepressant effects. This study evaluated the effect and probable mechanisms of bifid triple viable capsules (BTVCs) on a rat model of chronic unpredictable mild stress (CUMS).Materials and methodsRats were randomly divided into Normal, CUMS model, fluoxetine hydrochloride (FLX), BTVCs, and FLX+BTVCs groups. Depressive-like behaviours, pathological changes in the hippocampus, changes in serum metabolites and potential biomarkers, and metabolic pathways were detected via behavioural tests, haematoxylin-eosin staining, nissl staining, non-targetted metabolomics, and ingenuity pathway analysis (IPA).ResultsThe rats displayed depressive-like behaviours after CUMS exposure, but BTVCs ameliorated the depressive-like behaviours. In addition, the pathological results showed that the hippocampal tissue was damaged in rats after CUMS exposure and that the damage was effectively alleviated by treatment with BTVCs. A total of 20 potential biomarkers were identified. Treatment with BTVCs regulated D-phenylalanine, methoxyeugenol, (±)-myristoylcarnitine, 18:3 (6Z, 9Z, 12Z) /P-18:1 (11Z), propionyl-L-carnitine, and arachidonic acid (AA) concentrations, all compounds that are involved with biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, linoleic acid metabolism and AA metabolism. The IPA demonstrated that endothelin-1 signalling and cyclic adenosine monophosphate response element binding protein (CREB) signalling in neurons may be involved in the development of depression.ConclusionOur findings suggest that BTVCs can alleviate depressive-like behaviours, restore damage to the hippocampus in CUMS rats and regulate serum metabolism, which may be related to endothelin-1 signalling or CREB signalling in neurons.

Mechanistic insights into the protective role of eugenol against stress-induced reproductive dysfunction in female rat model

The challenging and highly demanding life rhythm nowadays subjects people to unavoidable chronic stress. Chronic stress is associated with a wide array of serious health complications including neuroendocrine dysregulations. Women are more prone to chronic stress-related hormonal disturbances and their physical and psychological consequences, especially reproductive impairment. Eugenol is a natural phenolic anti-oxidant that has several beneficial biological activities. The current study intended to scrutinize the potential protective effect of eugenol in female Wistar rats exposed to chronic unpredictable mild stress (CUMS). Rats were randomly allocated into 4 groups; group 1 received olive oil, group 2 received eugenol in olive oil, groups 3 and 4 were subjected to CUMS protocol for 8 weeks, with pre- and concomitant treatment with eugenol (50 mg/kg/day; p.o.) in group 4. The results showed that CUMS exposure led to weight loss and depressive-like behaviours. CUMS induced hypothalamic-pituitary-adrenal axis activation with subsequent elevation of serum corticosterone level which, in turn, caused decline in ovarian release of estradiol and antimullerian hormones together with an increased production of follicle-stimulating and luteinizing hormones by the anterior pituitary, leading to reproductive disturbances. In ovaries, CUMS imposed oxidative stress, insulin resistance and molecular damage. Intriguingly, all these adverse effects were significantly mitigated by the administration of eugenol that improved animals’ behaviours, corrected corticosterone upsurge, tempered hormonal disturbances, and amended ovarian damage. All biochemical results were further confirmed by hippocampal and ovarian histopathological examinations. In conclusion, the current study highlights the prophylactic role of eugenol against reproductive disturbances induced by chronic stress in female rats.

Antidepressant-like effects of Rehmannioside A on rats induced by chronic unpredictable mild stress through inhibition of endoplasmic reticulum stress and apoptosis of hippocampus

Depression is one of the most prevalent psychiatric mood diseases worldwide, whose therapy is in urgent need of development. Although the neuroprotective effects of Rehmannioside A (Rea) have been demonstrated, its anti-depressive effect remains unclear. Here, a depression model was induced with chronic unpredictable mild stress (CUMS) in rats. The behavioral trails, including sucrose preference test, forced swim test and open field test were used to determine the success of the CUMS-induced model. The effect of Rea on the neuronal protection, apoptosis and endoplasmic reticulum stress (ERS) was evaluated by HE, NISSL, IF and TUNEL staining, and western blot assays. Mechanically, the MAPK signaling pathway-related proteins expressions were examined by western blot. The results showed that CUMS stimulation evoked a prominent reduction of rat body weight, sucrose preference, and numbers of crossing, rearing and grooming with the enhanced immobility times. Besides, CUMS exposure induced the nuclear shrinkage and damage, as well as the decreased ISSL+ numbers. Moreover, CUMS stimulation increased the relative protein expressions of Bax and Cleaved caspase-3 and the percent of TUNEL positive cells, and decreased the relative protein expressions of Bcl-2. Furthermore, CUMS exposure also increased the relative protein expression of GRP-78, XBP-1, ATF-6, ATF-4 and CHOP. However, the CUMS-induced changes of all these indicators were reversed with Rea introduction in a dose-dependent fashion. Mechanically, Rea supply observably antagonized the CUMS-induced the relative protein levels of p-p38/p-38, p-ERK1/2/ERK1/2 and p-JNK/JNK. Therefore, Rea attenuated depression through suppressing ERS and apoptosis in hippocampus of CUMS-induced rats involved in MAPK signaling.

Icariin Improves Glucocorticoid Resistance in a Murine Model of Asthma with Depression Associated with Enhancement of GR Expression and Function.

Icariin, a flavonoid glycoside isolated from Epimedium brevicornum, exerts a variety of biological activities. However, its effects on depression-induced glucocorticoid resistance in asthma and the underlying mechanisms have not been elucidated. In this study, a murine model of asthma with depression was established by exposure to ovalbumin combined with chronic unpredictable mild stress, and icariin was given orally during ovalbumin challenge and chronic unpredictable mild stress exposure. Depression-like behaviors were assessed by the open field test, forced swim test, and tail suspension test. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, inflammatory cytokine levels in bronchoalveolar lavage fluid, and immunoglobulin E and corticosterone levels in serum, were examined. Following splenocyte isolation in vitro, the inhibitory effects of corticosterone on the proliferation and cytokine secretion of splenocytes, glucocorticoid receptor DNA-binding activity, and expression of p-glucocorticoid receptor s226, glucocorticoid receptor α, and p-p38 mitogen-activated protein kinase in splenocytes were determined. We found that icariin had limited effects on depression-like behaviors, however, it markedly suppressed airway hyperresponsiveness, inflammatory infiltration in lung tissues, levels of interleukin-4, interleukin-5, and interleukin-6 in bronchoalveolar lavage fluid, and immunoglobulin E in serum. Furthermore, icariin improved the inhibitory effects of corticosterone on lipopolysaccharide-stimulated splenocytes, increased the glucocorticoid receptor expression and glucocorticoid receptor DNA-binding activity, and inhibited the phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase. Taken together, icariin improved glucocorticoid resistance in a murine model of asthma with depression associated with enhancement of glucocorticoid receptor function and glucocorticoid receptor expression, and its effects on the glucocorticoid receptor function were related to decreased phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase.

DFO treatment protects against depression-like behaviors and cognitive impairment in CUMS mice

Depression has several negative effects on emotion as well as learning and memory abilities. Previous studies showed that depression could exacerbate inflammation, which in turn further aggravated depression. Deferoxamine (DFO) is a chelating agent binding iron and aluminium, and is clinically applied to treat acute ion poisoning and hemochromatosis. Researches showed that it could reduce inflammation via increasing the expression of hypoxia-inducible factor-1alpha (HIF-1α). Here, we established a chronic unpredictable mild stress (CUMS) model to investigate whether DFO exerted a neuroprotective function in depression. The results demonstrated that CUMS (4 weeks) effectively induced depression-like behaviors in mice based on sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), open field test (OFT), and elevated plus-maze test (EPT). It also brought cognitive deficits based on Morris water maze (MWM) test and the impairment of synaptic plasticity based on in vivo electrophysiological recordings. Additionally, CUMS exposure significantly decreased the expression of hippocampal synapse related proteins and the spine density of neurons in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines, and promoted the activation of microglia in the hippocampus. The expression of HIF-1α was down-regulated as expected. However, DFO distinctly reversed the CUMS-induced impairments. The mechanism is associated with the DFO inhibition of inflammation by upregulating HIF-1 expression, thereby alleviating a series of pathology changes. Together, these findings suggest that DFO likely plays a protective role in cognitive impairments and synaptic plasticity deficits resulting from depression.

Repeated testing modulates chronic unpredictable mild stress effects in male rats

Depression is a highly prevalent, debilitating mental disorder. Chronic unpredictable mild stress (CUMS) is the most widely applied model to study this affliction in rodents. While studies incorporating CUMS prior to an intervention often require long-lasting stress effects that persist after exposure is ceased, the longevity of these effects is rarely studied. Additionally, it is unclear whether behavioural assessments can be performed before and after interventions without repeated testing effects. In rats, we investigated CUMS effects on components of depressive-like behaviour both acutely after stress cessation and after a recovery period, as well as effects of repeated testing. We observed acute disruptions of the circadian locomotor rhythm and a reduced sucrose preference immediately after CUMS exposure. While circadian locomotor rhythm effects persisted up until four weeks after stress cessation, independently of repeated testing, sucrose preference effects did not. Interestingly, CUMS animals tested once after a recovery period of four weeks showed reduced anxiety-like behaviour in the open field and elevated plus maze compared to their control group and repeatedly-tested CUMS animals. These findings suggest that distinct CUMS-induced components of depressive-like behaviour are affected differentially by recovery time and repeated testing; these aspects should be considered carefully in future study designs.

Neuroprotective Efficiency of Prodigiosins Conjugated with Selenium Nanoparticles in Rats Exposed to Chronic Unpredictable Mild Stress is Mediated Through Antioxidative, Anti-Inflammatory, Anti-Apoptotic, and Neuromodulatory Activities.

PurposeDepression is a mood disorder accompanied by intensive molecular and neurochemical alterations. Currently, available antidepressant therapies are not fully effective and are often accompanied by several adverse impacts. Accordingly, the ultimate goal of this investigation was to clarify the possible antidepressant effects of prodigiosins (PDGs) loaded with selenium nanoparticles (PDGs-SeNPs) in chronic unpredictable mild stress (CUMS)-induced depression-like behavior in rats.MethodsSixty Sprague Dawley rats were randomly allocated into six groups: control, CUMS group (depression model), fluoxetine (Flu, 10 mg/kg)+CUMS, PDGs+CUMS (300 mg/kg), sodium selenite (Na2SeO3, 400 mg/kg)+CUMS, and PDGs-SeNPs+CUMS (200 mg/kg). All treatments were applied orally for 28 consecutive days.ResultsPDGs-SeNPs administration prevented oxidative insults in hippocampal tissue, as demonstrated by decreased oxidant levels (nitric oxide and malondialdehyde) and elevated innate antioxidants (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase), in addition to the upregulated expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in rats exposed to CUMS. Additionally, PDGs-SeNPs administration suppressed neuroinflammation in hippocampal tissue, as determined by the decreased production of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, and interleukin-6), increased anti-inflammatory cytokine interleukin-10, and decreased inflammatory mediators (prostaglandin E2, cyclooxygenase-2, and nuclear factor kappa B). Moreover, PDGs-SeNPs administration in stressed rats inhibited neuronal loss and the development of hippocampal apoptosis through enhanced levels of B cell lymphoma 2 and decreased levels of caspase 3 and Bcl-2-associated X protein. Interestingly, PDGs-SeNPs administration improved hormonal levels typically disrupted by CUMS exposure and significantly modulated hippocampal levels of monoamines, brain-derived neurotrophic factor, monoamine oxidase, and acetylcholinesterase activities, in addition to upregulating the immunoreactivity of glial fibrillary acidic protein in CUMS model rats.ConclusionPDGs-SeNPs may serve as a prospective antidepressant candidate due to their potent antioxidant, anti-inflammatory, and neuroprotective potential.

Ketamine abrogates sensorimotor deficits and cytokine dysregulation in a chronic unpredictable mild stress model of depression.

Major depressive disorder (MDD) is a serious mental disorder with influence across the functional systems of the body. The pathogenesis of MDD has been known to involve the alteration of normal body functions responsible for the normal inflammation processes within the CNS; this along with other effects results in the depreciation of the sensorimotor performance of the body. Ketamine hydrochloride, a novel antidepressant agent, has been used as a therapeutic agent to treat MDD with its efficacy stretching as far as enhancing sensorimotor performance and restoring normal cytokine levels of the CNS. While these therapeutic actions of ketamine may or may not be related, this study made use of chronic unpredictable mild stress (CUMS) to generate the mouse model of depression. The efficacy of ketamine as an antidepressant following sequential exposure and co-administrative treatment protocols of administration was evaluated using behavioural tests for sensorimotor performance and depressive-like behaviours. Its effect in managing CNS inflammation was assessed via the biochemical analysis of inflammatory cytokine levels in the cerebrum, spinal cord and cerebellum; and immunohistochemical demonstration of microglial activity in the corpus striatum and cerebellum. The sensorimotor performance which had been diminished by CUMS showed greater improvement under the sequential exposure regimen of ketamine. Ketamine was also efficacious in decreasing the level of inflammation with an evident reduction in microglial activation and pro-inflammatory cytokines in the studied regions, following CUMS exposure. Taken together, our study indicates that ketamine therapy can improve sensorimotor deficits co-morbid with a depressive disorder in parallel with modulation of the inflammatory system.