CUMS-exposed Rats Research Articles

GABAB modulate NF-κB/NLRP3 pathways in electroacupuncture prevention of depression in CUMS rats

BackgroundOur previous research has demonstrated that electroacupuncture (EA) has the potential to mitigate depression-like symptoms resulting from chronic stress. However, further investigation is required to fully understand the underlying mechanisms. The regulatory role of γ-aminobutyric acid type B (GABAB) in synaptic plasticity and the involvement of NF-κB/NLRP3-mediated inflammation in the lateral habenula nucleus (LHb) are key factors in the development of depression. This study sought to investigate the potential of EA in mitigating depression-like symptoms induced by chronic stress through mechanisms such as enhancing GABAB levels, regulating synaptic plasticity in the LHb, and suppressing NF-κB/NLRP3-mediated inflammation. MethodsSprague-Dawley rats were exposed to chronic unpredictable mild stress (CUMS) in order to create a model of depression. Subsequently, the weight and behavioral assessments of all rats were monitored, and samples of the lateral habenula and serum were collected. The protein expression levels were analyzed using western blotting. The 5-hydroxytryptophan (5-HT), Dopamine (DA), and Norepinephrine (NE) in the LHb and serum were measured using ELISA. The alterations in GABAB and NF-κB in the LHb were observed through immunofluorescence. The neuronal damage in the LHb was assessed using Nissl staining. ResultsEA upregulated the expression of GABAB in the LHb of rats subjected to CUMS. Subsequent behavioral assessments indicated that blocking GABAB attenuated the antidepressant effects of EA in CUMS-exposed rats. Furthermore, EA enhanced synaptic plasticity in the LHb of CUMS-exposed rats and mitigated NF-κB/NLRP3-mediated inflammatory responses, with these effects potentially being reversed by GABAB inhibition. ConclusionThrough the promotion of GABAB levels, regulation of synaptic plasticity within the LHb, and inhibition of NF-κB/NLRP3-mediated neuroinflammation in the same region, electroacupuncture at Shangxing and Fengfu acupoints demonstrates efficacy in mitigating depression-like behaviors induced by CUMS.

Sodium propionate oral supplementation ameliorates depressive-like behavior through gut microbiome and histone 3 epigenetic regulation

Major depressive disorder (MDD) is a global health concern, affecting over 250 million individuals worldwide. In recent years, the gut-brain axis has emerged as a promising field for understanding the pathophysiology of MDD. Microbial metabolites, such as short-chain fatty acids (SCFAs)—acetate, butyrate, and propionate-, have gained attention for their potential to influence epigenetic modifications within the host brain. However, the precise mechanisms through which these metabolites participate in MDD pathophysiology remain elusive. This study was designed to investigate the effects of oral SCFA supplementation in adult male Wistar rats subjected to chronic unpredictable mild stress (CUMS). A subset of control and CUMS-exposed rats received different supplementations: sodium acetate (NaOAc) at a concentration of 60 mM, sodium butyrate (NaB) at 40 mM, sodium propionate (NaP) at 50 mM, or a mixture of these SCFAs. The gut microbiome was assessed through 16S rRNA sequencing, and epigenetic profiling was performed using Western blot analysis. Results demonstrated that NaP supplementation significantly alleviated anhedonia in stressed animals, as evidenced by improved performance in the sucrose consumption test. This ameliorative effect was potentially associated with the modulation of gut bacterial communities, accompanied by the attenuation of the region-specific epigenetic dysregulation in the brain of the animals exposed to chronic stress. These findings suggest a potential association between gut dysbiosis and stress response, and NaP could be a promising target for future MDD interventions. However, further studies are needed to fully elucidate the underlying mechanisms of these effects.

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.

GDF11 mediates H2S to prevent chronic stress-induced cognitive impairment by reducing hippocampal NLRP3/caspase-1-dependent pyroptosis

BackgroundWe previously revealed that hydrogen sulfide (H2S) attenuates chronic stress-induced cognitive impairment, but the underlying mechanism needs to be further clarified. Growth differentiation factor 11 (GDF11) plays an important regulatory role in cognitive function and that hippocampal NLRP3/caspase-1-mediated pyroptosis contributes to the pathogenesis of cognitive impairment. Hence, this research aimed to explore whether promoting GDF11 levels and suppressing hippocampal NLRP3/caspase-1-mediated pyroptosis mediate H2S to alleviate chronic stress-induced cognitive impairment. MethodsSprague–Dawley rats were subjected to unpredictable chronic mild stress lasting four weeks to establish an animal model of chronic stress-induced cognitive impairment. Behavioral performance was assessed by the Y-maze test and the novel object recognition test. The expression levels of proteins were analyzed by Western blot analysis. The levels of IL-1β and IL-18 in the hippocampus were measured by ELISA. ResultsNaHS upregulated the expression of GDF11 in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats. Silencing GDF11 blocked NaHS-improved cognitive impairment in CUMS-exposed rats, according to the Y-maze test and the novel object recognition test. Furthermore, NaHS mitigated NLRP3/caspase-1-mediated pyroptosis in the hippocampus of CUMS-exposed rats and this effect was reversed by silencing GDF11. Moreover, overexpression of GDF11 alleviated CUMS-induced cognitive impairment and NLRP3/caspase-1-mediated hippocampal pyroptosis. ConclusionsGDF11 mediates H2S to attenuate chronic stress-induced cognitive impairment via inhibiting hippocampal NLRP3/caspase-1-mediated pyroptosis.

Anti-neuroinflammation effects of transcutaneous auricular vagus nerve stimulation against depression-like behaviors via hypothalamic α7nAchR/JAK2/STAT3/NF-κB pathway in rats exposed to chronic unpredictable mild stress.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a vital neuromodulation for the treatment of depression, but its antidepressant molecular mechanism is unclear. The α7 nicotinic acetylcholine receptor (α7nAchR) is a key mediator of the vagus nerve that mediates its anti-inflammatory efficacy. Here, we investigated whether the antidepressant effect of taVNS in chronic unpredicted mild stress (CUMS)-exposed rats works through the α7nAchR/JAK2/STAT3/NF-κB pathway. The depression model was established by CUMS for continuous 6 weeks in rats. From the 4th week of the experiment, CUMS-exposed rats were subjected to taVNS for 3 weeks. To clarify the role of α7nAchR in the antidepressant effect of taVNS, we used α7nAchR-/- gene knockout rats. The sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) were used to evaluate depression-like behaviors of rats. Immunofluorescent staining was used to observe the morphology of microglia in the hypothalamus. Western blot was used to examine the protein expression of α7nAchR, p-JAK2, p-STAT3, IL-1β, NF-κB p65, and p-NF-κB p65 in the hypothalamus. Depression-like behaviors in CUMS-exposed rats were manifested by decreased SPT ratio, increased FST immobility time, decreased total distance, vertical movement score, and activity time of OFT. Hypothalamic neuroinflammation in CUMS-exposed rats was manifested by an amoebic-like activated state of microglia, downregulated expression of α7nAchR, p-JAK2, p-STAT3, and upregulated expression of NF-κB p65, p-NF-κB p65, and IL-1β. TaVNS could significantly reverse the above-mentioned phenomena, but had a poor improvement effect for CUMS-exposed α7nAchR-/- rats. The hypothalamic α7nAchR/JAK2/STAT3/NF-κB signaling pathway may play an important role in the antidepressant-like behavior of taVNS.

PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1

Ample evidence has pointed to a close link between cardiovascular diseases (CVD) and depression. Inflammatory pathways including the high-mobility-group-box-1 protein, receptor-for-advanced-glycation-end-products and toll-like-receptor-4 (HMGB1/RAGE/TLR4) and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathways are thought to be crucial players in this link. Activation of these pathways ends by releasing of different inflammatory mediators involved in CVD and depression pathophysiology. In the brain, this inflammatory process enhanced indoleamine2,3-dioxygenase-1 (IDO-1) activation with subsequent alteration in kynurenine/tryptophan levels causing depression. Based on the favorable anti-inflammatory effects of Alirocumab, the proprotein-convertase-subtilisin/kexin-type-9 (PCSK9) inhibitor, used in different CVD, this study was designed to investigate its potential antidepressant effect. The behavioral and neurochemical effects of concomitant treatment of Alirocumab at doses of (4, 8 and 16 mg/kg/week subcutaneously) in Wistar rats exposed to chronic unpredictable mild stress (CUMS) for 6 weeks were assayed. Alirocumab prevented CUMS-induced depressive-like-behaviors exhibited in open-field and forced-swimming tests, and hypothalamus–pituitary–adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Alirocumab prevented CUMS-induced alteration in hippocampal kynurenine/tryptophan levels and pro-inflammatory cytokines tumor-necrosis-factor-alpha, interleukin-1beta (IL-1β), IL-2 and IL-6. Western blot and PCR analysis showed that Alirocumab favorably modulated the HMGB1/RAGE/TLR4 axis, nuclear-factor-kappa-beta, NLRP3 inflammasome complex and IDO-1 in the hippocampus of CUMS rats. These effects were correlated to the level of PCSK9 expression. The behavioral and biochemical findings indicated the potential antidepressant effect of PCSK9 inhibition by Alirocumab.Graphical

18β-Glycyrrhetinic Acid Ameliorates Neuroinflammation Linked Depressive Behavior Instigated by Chronic Unpredictable Mild Stress via Triggering BDNF/TrkB Signaling Pathway in Rats.

Evidence shows that inflammatory responses may encompass the onset of severe depressive illness. Traditionally used licorice contains 18β-glycyrrhetinic acid (18βGA), which has been demonstrated to reduce inflammation and oxidative stress. This study investigates the antidepressant effects of 18βGA and the underlying mechanism in rats exposed to chronic unpredictable mild stress (CUMS). Wistar rats were exposed to CUMS for 36 consecutive days to establish depression. 18βGA (10, 20, and 50mg/kg) or fluoxetine was given once daily (from day 30 to day 36). Thereafter, behavior parameters (sucrose preference test, forced-swimming test, open-field test, body weight), pro-inflammatory cytokines, neurotransmitters, adrenocorticotropic hormone (ACTH), corticosterone (CORT), and liver biomarkers were studied. Immunohistochemistry and western blot analyses were conducted to investigate the protein's expression. 18βGA (20 and 50mg/kg) treatment increased sucrose intake, locomotion in the open-field test, decreased immobility time in the forced swim test, and improved body weight in CUMS-exposed rats. The therapy of 18βGAdramatically declined cytokines, ACTH and CORT and improved 5HT and norepinephrine in CUMS rats. Furthermore, BDNF and TrkB proteins were down-regulated in CUMS group, which was increased to varying degrees by 18βGA at doses of 20 and 50mg/kg. Therefore, 18βGA ameliorates depressive-like behavior persuaded by chronic unpredictable mild stress, decreases neuroinflammation, liver biomarkers, stress hormones, and improves body weight, brain neurotransmitter concentration via activating on BDNF/TrkB signaling pathway in both PFC and hippocampus in rats.

Saikosaponin D exerts antidepressant effect by regulating Homer1-mGluR5 and mTOR signaling in a rat model of chronic unpredictable mild stress

BackgroundMany studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown.Materials and methodsA chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD’s antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed.ResultsCUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats.ConclusionsSSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression.

The Antidepressant-Like Effects of Shen Yuan in a Chronic Unpredictable Mild Stress Rat Model.

Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.

The antidepressant-like effects of the water extract of Panax ginseng and Polygala tenuifolia are mediated via the BDNF-TrkB signaling pathway and neurogenesis in the hippocampus

Ethnopharmacology relevanceThe water extract of Panax ginseng (GT) and Polygala tenuifolia (YT), the main constituents of the commonly used kai-xin-san formula of traditional Chinese medicine, represents SY. It possesses strong neuroprotective effects. Using behavioural tests, we have previously established that the SY formulation exerts superior antidepressant activity than that of GT or YT. AimTo elucidate the impact of SY treatment on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours and the prospective mechanism related to hippocampal neurogenesis and the BDNF signaling pathway. MethodsWe exposed Sprague-Dawley rats (male; 180–200 g) to CUMS for 35 days. The rats in the experimental treatment groups were daily treated with either fluoxetine (10 mg kg−1d−1) or SY (67.5, 135, or 270 mg kg−1d−1) orally until the behavioural tests (tail suspension test [TST], novelty-suppressed feeding test [NSFT], sucrose preference test [SPT], and forced swim test [FST]) were completed. We assessed the modifications in the hippocampal neurogenesis and the BDNF signaling pathway post-treatment with CUMS and SY. Additionally, K252a, a tyrosine protein kinase inhibitor, was utilized to evaluate the antidepressant mechanisms of SY. Results: The results of SPT, NSFT, FST, and TST in CUMS-exposed rats confirmed the antidepressant actions of SY. Additionally, SY treatment induced the BDNF signaling pathway and reversed the hippocampal neurogenesis caused by CUMS. Moreover, we found that the TrkB antagonist K252a blocked SY effects on behavioural improvement, inhibited the incremental effects of SY on hippocampal neurogenesis, and eliminated the impact of SY on BDNF-TrkB signaling activation. Thus, the impact of SY treatment on BDNF signaling molecules (pAkt, pERK1/2, and pCREB) were significantly inhibited by K252a. ConclusionsThis study showed that SY acted as an antidepressant in rats exhibiting CUMS-induced depressive-like behaviours, and was facilitated by promoting hippocampal neurogenesis and the BDNF signaling pathway activation. Thus, SY could act as a potential novel supplement or adjuvant to prevent or treat clinical depressive disorders.

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities.

Astrocytes in the hippocampus are immediately relevant to depressive-like behavior. By regulating their activities, Xiaoyaosan (XYS), a traditional Chinese medicine compound, works in the treatment of depression.ObjectiveChronic unpredictable mild stress (CUMS) rat model was established to observe the regulation of XYS. We investigated the behavioral changes of CUMS, the expression of corticosterone (CORT) of the hypothalamo–pituitary–adrenal (HPA) axis, the expression of Glu-NMDA receptor and astrocytes glial fibrillary acidic protein (GFAP) in the hippocampus. We also investigated whether these changes were linked to XYS.Methods80 adult SD rats were randomly divided into four groups, control group, CUMS group, XYS group, and fluoxetine group. The rats in the control group and the CUMS group received 0.5 ml of deionized water once a day by intragastrically administration. Rats in the two treatment groups received XYS (2.224g/kg/d) and fluoxetine (2.0mg/kg/d) once a day, respectively. Rat hippocampus GFAP and Glu-NMDA receptor were respectively detected by real-time fluorescent quantitative PCR and western blot. The CORT of HPA axis was detected by Elisa. Body weight, food intake, and behavioral tests, such as open field tests, the sucrose preference test, and exhaustive swimming test, were used to assess depressive-like behavior in rats.ResultsIn this work, significant behavioral changes and differences in expression of the CORT of HPA axis and hippocampal GFAP and Glu-NMDA receptor were presented in CUMS-exposed rats. Like fluoxetine, XYS improved CUMS-induced rat’s body weight, food intake, and depressive-like behavior. The study also proved that XYS could reverse the CUMS-induced changes of the CORT of HPA axis and affect the astrocytic activities and down-regulate the NR2B subunit of NMDA receptor (NR2B) level in the hippocampus.ConclusionChanges in the hippocampus GFAP and Glu-NMDA receptor may be an essential mechanism of depression. Besides, XYS may be critical to the treatment of depression by intervention the HPA axis, GFAP and Glu-NMDA receptor.

Proteomics-based screening of the target proteins associated with antidepressant-like effect and mechanism of nimesulide

Nimesulide is an inhibitor of COX-2 with antioxidant and anti-inflammatory effects. However, few studies have explored the antidepressant mechanism of nimesulide. Here, we evaluated the therapeutic effects of nimesulide on CUMS rats. iTRAQ technology was used to identify the differentially expressed protein in the hippocampus between CUMS and nimesulide-treated rats to identify the possible molecular mechanism of its effects. We found that nimesulide had positive effects on depressive-like behaviors and inflammatory factors in depressed rats. Using proteomics technologies, we screened 16 differentially expressed proteins in CUMS-exposed rats after nimesulide treatment, 5 of which were related to inflammation. Overall, these results show that nimesulide might mediate its antidepressant effect on depressed rats through the inhibition of oxidative stress inflammatory response.

Susceptibility to Hyperglycemia in Rats With Stress-Induced Depressive-Like Behavior: Involvement of IL-6 Mediated Glucose Homeostasis Signaling.

Depression is a common psychiatric disorder comorbid with diabetes and may lead to high morbidity, disability, and mortality. However, the underlying mechanism behind their association remains unknown. Cytokine-mediated inflammation in brain may play important roles in the pathogenesis of depression and insulin resistance. In the present study, we subjected the rats to chronic unpredictable mild stress (CUMS) for 3 to 8 weeks. The tests to ascertain depression-like behaviors including open field test (OFT) and forced swimming test (FST) were performed, and levels of morning fasting blood glucose, triglyceride (TG), total cholesterol (CHOL), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C), body weight, food intake, histopathological examinations of liver, adipose tissues and hypothalamus, hypothalamic GLUT4 as well as the IL-6-mediated glucose homeostasis signaling pathway were measured. The results showed that CUMS exposure resulted in the depression-like behavior at various time points in rats. Moreover, the rats exhibited increased peripheral glucose levels, impaired hepatocytes and hippocampal neurons, and decreased hypothalamic GLUT4 levels after 6 weeks of CUMS exposure. Meanwhile, activated IL-6 but suppressed IL-6-mediated glucose homeostasis signaling was observed in the hypothalamus. Markers of lipid metabolism including TG, CHOL, HDL-C and LDL-C were dysregulated, and body weight and food intake were decreased in the CUMS-exposed rats. Our results show that depressed rats induced by 6-week CUMS stimulation display susceptibility to hyperglycemia, which is associated with IL-6-mediated inhibition of glucose homeostasis signaling in the hypothalamus.

7, 8-Dihydroxy-4-methylcoumarin reverses depression model-induced depression-like behaviors and alteration of dendritic spines in the mood circuits

Major depressive disorder (MDD) is a common mental disorder characterized by a persistent feeling of sadness, slow thought, impaired focus and loss of interest but the underlying mechanisms are largely unknown. Dendritic spines play an important role in the formation and maintenance of emotional circuits in the brain. Abnormalities in this process can lead to psychiatric diseases. 7,8-Dihydroxy-4-methylcoumarin (Dhmc), a precursor in the synthesis of derivatives of 4-methyl coumarin, plays an important role in protecting the nervous system from developing diseases and its most distinctive feature is safety. The aim of this study was to investigate whether Dhmc alleviates chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and reverses CUMS-induced alterations in dendritic spines of principal neurons in brain areas of the emotional circuits including the hippocampus, medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and basolateral amygdala (BLA) in male rats. Our results showed that CUMS-induced depression-like behaviors were accompanied by a decrease in spine density in pyramidal neurons of both the hippocampal CA3 area and the mPFC, and an increase in spine density in both the neurons of BLA and the medium spiny neurons (MSNs) of the NAc, as well as a decrease in the levels of the AMPA receptor subunit GluA1 and Kalirin-7 in the hippocampus compared with the control group. Intraperitoneal injection (i.p.) of Dhmc to the CUMS-exposed rats ameliorated CUMS-induced depression-like behaviors and reversed CUMS-mediated alterations in spine density and the levels of both GluA1 and Kalirin-7. Our results show an important role of Dhmc in reversing CUMS-induced depression-like behaviors and CUMS-mediated alterations in spine density.

Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats.

Depression is an inflammatory-related condition, with the progression in neuronal damage resulting in major depression disorder. Ginsenoside-Rg1, a sterol extract from the herb Panax ginseng, has been shown to exert neuroprotective effects upon neurodegeneration disorders. However, whether ginsenoside-Rg1 confers antidepressant-like effects on neuroinflammation as associated with depression, as well as the possible mechanism involved in these neuroprotective effects, is currently unclear. In the present report, we show that treatment with ginsenoside-Rg1 (40 mg/kg, i.p.) significantly ameliorated depressive-like behaviors as induced by chronic unpredictable mild stress (CUMS) in a rat model of depression. Moreover, these CUMS rats treated with ginsenoside-Rg1 showed reductions in the levels of the oxidative stress products and the activity in the antioxidant stress kinase. Furthermore, CUMS rats treated with ginsenoside-Rg1 showed ameliorated neuroinflammation and associated neuronal apoptosis along with a reduction in dendritic spine atrophy and display of depressive behaviors. Taken together, the results of this study suggest that ginsenoside-Rg1 produces antidepressant-like effects in CUMS-exposed rats; and one of the mechanisms for these antidepressant-like effects of ginsenoside-Rg1 appears to involve protection against oxidative stress and thus the neuronal deterioration resulting from inflammatory responses. These findings provide evidence for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related depression.

Antidepressant and Neuroprotective Effects of Naringenin via Sonic Hedgehog-GLI1 Cell Signaling Pathway in a Rat Model of Chronic Unpredictable Mild Stress.

Depression is one of the most prevalent and crucial public health problem connected to significant mortality and co-morbidity. Recently, numerous studies suggested that dietary flavanones exhibit neuroprotective and antidepressant effects against various psycho-physiological conditions including depression. The present study is focused on the antidepressant and neuroprotective effects of naringenin (NAR) and the involvement of sonic hedgehog (Shh) signaling in the chronic unpredictable mild stress (CUMS)-induced depression. Twenty-four male Wistar rats were randomly assigned into four groups: CON group (saline s.c.), NAR group (NAR 50mg/kg, p.o.), CUMS group (subjected to CUMS along with saline p.o.), and CUMS + NAR group (NAR 50mg/kg p.o. along with CUMS) for 28days including 1-week pre-treatment with NAR. The results showed that NAR was found to inhibit behavioral abnormalities including increased despair in force swim test, and reduced locomotor activity caused by CUMS in open field test. Moreover, Morris water maze revealed that NAR also mitigates CUMS-associated cognitive impairment. In addition to the antidepressant-like effect, NAR mitigates morphological anomalies in the hippocampal CA1 region and cortex. Furthermore, we observed brain-derived neurotrophic factor (BDNF), Shh, GLI1, NKX2.2, and PAX6 were downregulated in the hippocampus of CUMS-exposed rats, which can be upregulated by NAR pre-treatment. GLI1 is main downstream signaling component of Shh signaling cascade, which further regulates the expression of homeodomain transcription factors PAX6 and NKX2.2.

N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat.

Depression is a heterogeneous disorder and associated with inflammatory responses. The influences of N-acetylcysteine (NAC) on neuroinflammation associated depression-like behavior have not been investigated yet, and associated biochemical changes are currently unclear. Therefore, we assessed the effects of NAC on neuroinflammation associated depression-like behavior induced through chronic unpredictable mild stress (CUMS) in rats. The antidepressant-like effect of NAC was depicted using the sucrose preference test and the forced swimming test (FST) while CUMS-induced alteration in the locomotor index was measured using the open field test (OFT) and actophotometer. Our results revealed that CUMS exposure markedly aggravated depression-like behavior, the levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and reduced the serotonin levels. One-week consecutive NAC (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o., a selective serotonin reuptake inhibitor) treatment significantly increased sucrose preference index, reduced immobility time in the FST, and the increased the number of squares crossed, number of rearing in the OFT and locomotion in the actophotometer in the CUMS-exposed rats. Moreover, the levels of pro-inflammatory cytokines in the hippocampus as well as pre-frontal cortex were suppressed, and remarkably restored the serotonin levels by NAC (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) administration. However, NAC (25 mg/kg, p.o.) exerted insignificant protection against CUMS-induced depressive-like behavior and associated neuro-inflammation. This study demonstrates that NAC exhibited the antidepressant-like effect in the CUMS-exposed rats, which might be mediated by anti-inflammatory potential and restoring serotonergic responses in the stressed rats.

Metoprolol, N-Acetylcysteine, and Escitalopram Prevents Chronic Unpredictable Mild Stress-Induced Depression by Inhibition of Endoplasmic Reticulum Stress.

Background: Endoplasmic reticulum stress (ERS) has been recently suggested to be activated in the major depressive disorder (MDD). However, whether ERS is a potential therapeutic target for MDD is largely unknown. Here we attempted to assess the preventive effect of metoprolol (MET), N-acetylcysteine (NAC), and escitalopram (ESC) on chronic unpredictable mild stress (CUMS)-induced depression and investigate whether ERS mediates the antidepressant role of these drugs.Method: Forty-five sprague-dawley rats were randomly divided into five groups: control, CUMS, CUMS+ESC, CUMS+NAC, and CUMS+MET. Weight measurement, open field activity and sucrose preference were performed before and after stress. Hippocampal nerve cells and capillary ultrastructure were observed by transmission electron microscope, and hippocampal cells apoptosis were detected by flow cytometry. Furthermore, expression of ERS markers glucose-regulated protein 78 (GRP78), C/EBP-homologous protein (CHOP), and caspase-12 were measured by western blot and qRT-PCR.Results: The CUMS-induced rats showed significantly increased depressive-like behaviors including decreased open field activity and sucrose preference. Moreover, CUMS-exposed rats exhibited significantly increased hippocampal cell apoptosis, and showed damage in hippocampal nerve cells and capillary ultrastructure. Furthermore, ESC and NAC not only mitigated depressive-like behaviors, but also decreased apoptosis and pathologies, while MET fail to decrease apoptosis. Moreover, CUMS stimulation significantly elevated ERS by increasing the levels of GRP78, CHOP, and decreasing the level of caspase-12, while ESC, NAC, and MET significantly decreased the ERS.Conclusion: ESC, NAC, and MET might prevent the MDD partly through inactivating the ERS. These findings demonstrated ERS as a novel treatment target for depression.

Protective effect of Convolvulus pluricaulis against neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat

Depression is a heterogeneous disorder and has been regarded as an inflammatory disease. The aerial parts of the Convolvulus pluricaulis are used in Indian traditional medicines for the management of nervous disorders. However, the influence of methanolic extract of aerial parts of Convolvulus pluricaulis (CPE) on a chronic animal model of depression has not been investigated yet, and associated biochemical changes are still unclear. Therefore, this study investigates the effects of CPE on a chronic rat model of depression and explores its underlying mechanism of action on neuroinflammation and brain monoamines. The antidepressant-like effect of CPE (25, 50, and 100 mg/kg, p.o.) was depicted using the sucrose preference test and the forced swimming test (FST) while CUMS-induced alteration in the locomotor index was measured using the open field test (OFT) and actophotometer. A consecutive one-week treatment of CPE (50, and 100 mg/kg) or fluoxetine (10 mg/kg, p.o.) treatment significantly increased sucrose preference index, reduced immobility time in the FST, and increased the number of squares crossed, the number of rearing in the OFT and locomotion in the actophotometer in the CUMS-exposed rats. Moreover, elevated levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and liver biomarkers ALT, AST were also significantly reversed by CPE (50, and 100 mg/kg) or fluoxetine administration in the CUMS-exposed rats. Furthermore, a one-week treatment of CPE (50 and 100 mg/kg) or fluoxetine also remarkably restored the serotonin and noradrenaline levels in the hippocampus as well as in the prefrontal cortex of the CUMS-exposed rats. However, CPE (25 mg/kg) exerted insignificant protection against CUMS-induced depressive-like behavior and associated neuroinflammation. Therefore, this study demonstrates that CPE exerted antidepressant-like effect which could be mediated by anti-inflammatory potential, restoring liver biomarkers or monoaminergic responses in the stressed rats.