Perturbation of mitiglinide metabolism by chronic unpredicted mild stress in rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Zeng Y
PROVIDER: S-EPMC3896903 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:Pentameric GABAA receptors mediate a large share of CNS inhibition. The γ2 subunit is a typical constituent. At least 11 mutations in the γ2 subunit cause human epilepsies, making the role of γ2-containing receptors in brain function of keen basic and translational interest. How small changes to inhibition may cause brain abnormalities, including seizure disorders, is unclear. In mice, we perturbed fast inhibition with a point mutation T272Y (T6'Y in the second membrane-spanning domain) to the γ2 subunit. The mutation imparts resistance to the GABAA receptor antagonist picrotoxin, allowing verification of mutant subunit incorporation. We confirmed picrotoxin resistance and biophysical properties in recombinant receptors. T6'Y γ2-containing receptors also exhibited faster deactivation but unaltered steady-state properties. Adult T6'Y knockin mice exhibited myoclonic seizures and abnormal cortical EEG, including abnormal hippocampal-associated theta oscillations. In hippocampal slices, picrotoxin-insensitive inhibitory synaptic currents exhibited fast decay. Excitatory/inhibitory balance was elevated by an amount expected from the IPSC alteration. Partial pharmacological correction of γ2-mediated IPSCs with diazepam restored total EEG power toward baseline, but had little effect on the abnormal low-frequency peak in the EEG. The results suggest that at least part of the abnormality in brain function arises from the acute effects of truncated inhibition.
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Project description:Depression, a psychiatric and dysthymic disorder, severely affects the learning, work and life quality. The main pathogenesis of depression is associated with central nervous system (CNS) dysfunction. Taurine has been demonstrated to exert protective effects on the brain development and can improve learning ability and memory. Our study investigated the antidepressant-like effects of taurine pre-treatment by examining the changes in depression-like behavior, hormones, neurotransmitters, inflammatory factors and neurotrophic factors in the hippocampus of a chronic unpredictable mild stress (CUMS)-induced depressive rat model. Taurine was found to inhibit the decrease of sucrose consumption and prevent the deficiency of spatial memory and anxiety in rats exposed to CUMS, suggesting a preventive effect of taurine on depression-like behavior. Furthermore, the decreased levels of 5-hydroxytryptamine, dopamine, noradrenaline; the increased levels of glutamate, corticosterone; and the decreased expressions of fibroblast growth factor-2, vascular endothelial growth factor and brain derived neurotrophic factor in depressive rats were hindered by taurine pre-administration. However, tumor necrosis factor-? and interleukin-1? levels were not significantly changed by taurine. The results demonstrated that the anti-depressive effect of taurine may be involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and the promotion of neurogenesis, neuronal survival and growth in the hippocampus.
| S-EPMC5504064 | biostudies-literature
Project description:The negative association between psychological stress and male fertility has been known for many years. This study was aimed at (i) identifying spermatogenesis impairment induced by psychological stress in rats and (ii) exploring the role of glucocorticoid receptor (GR) signaling in these adverse effects (if they exist). Male Sprague Dawley rats were exposed to a six-week period of unpredictable chronic mild stress (uCMS) along with cotreatment of GR antagonist RU486 (1 mg/kg/day). Testicular damage was assessed by testicular pathological evaluation, epididymal sperm concentration, serum testosterone levels, testicular apoptotic cell measurements, and cell cycle progression analyses. Rats in the uCMS group had decreased levels of serum testosterone and decreased epididymal sperm concentration. The uCMS-treated rats also had decreased numbers of spermatids and increased levels of apoptotic seminiferous tubules; additionally, cell cycle progression of spermatogonia was arrested at the G0/G1 phase. Furthermore, uCMS exposure caused an increase in serum corticosterone level and activated GR signaling in the testes including upregulated GR expression. RU486 treatment suppressed GR signaling and alleviated the damaging effects of stress, resulting in an increased epididymal sperm concentration. Overall, this work demonstrated for the first time that the activation of GR signaling mediates stress-induced spermatogenesis impairment and that this outcome is related to cell apoptosis and cell cycle arrest in germ cells.
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Project description:Generally, depression is the result of complex gene-environment interactions. Recent studies have showed that the gut microbiota can affect brain function through the microbiota-gut-brain axis. However, the underlying mechanism of the microbiota and potential influence of depression remain elusive. We aimed to determine how gut microbiome contributes to the process of depression and further influences the host. Chronic unpredictable mild stress (CUMS) is used to establish a depression model. Fecal microbiota transplant (FMT) is applied to illustrate that depression can be transmitted via microbiota, and metabolism of liver analysis is applied to demonstrate further influence to the liver. We also analyzed the astrocyte activation in the brain by immunofluorescence (IF). Here, we show that the structure of the gut microbiome changes markedly after rats undergo CUMS. Notably, we found that the ratio of Lactobacillus to Clostridium can be a vital index for the development of depression. Depression-like behavior can be duplicated through FMT. Moreover, increased zonulin and fatty acid binding protein-2 indicates that gut barrier integrity is broken after FMT. Subsequently, metabolomics shows that liver metabolic disorder occurs and leads to liver coagulative necrosis. In addition, increased inflammatory cytokine expression and higher astrocyte activation indicate an inflammatory process in the brain. These findings suggest that dysbiosis gut microbiome contributes to development of depression and further causes liver metabolic disorders in a way that may be relevant to the Lactobacillus to Clostridium ratio.
| S-EPMC6854967 | biostudies-literature
Project description:To explored the mechanism of pharmacokinetic perturbation in chronic unpredicted mild stress (CUMS) resulting depression, CUMS-induced depression animal model with spontaneous diabetic GK rats were established. The expression profile in GK rats' livers were screened using Affymetrix Rat 230 2.0 Array.
2017-09-25 | GSE94988 | GEO
Project description:BACKGROUND:Depression is a serious and common psychiatric disorder generally affecting more women than men. A woman's risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model. METHODS:To model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6?weeks, which promotes the development of depression-like symptoms. During the final 4?weeks of CUMS, rats were treated with either AC extract (1000 or 2000?mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10?mg/kg, IP). RESULTS:We report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels. CONCLUSION:These results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.
| S-EPMC7590795 | biostudies-literature
Project description:BACKGROUND:It is known that bioenergetics of aerobic and resistance exercise are not the same but both can effectively improve depression. However, it is not clear whether and how different types of exercise can influence depression through the same metabolic regulatory system. Metabolomics provides a way to study the correlation between metabolites and changes in exercise and/or diseases through the quantitative analysis of all metabolites in the organism. The objective of this study was to investigate the effects of aerobic and resistance training on urinary metabolites by metabolomics analysis in a rodent model of depression. METHODS:Male Sprague-Dawley rats were given chronic unpredictable mild stress (CUMS) for eight weeks. The validity of the modeling was assessed by behavioral indices. After four weeks of CUMS, the rats that developed depression were randomly divided into a depression control group, an aerobic training group and a resistance training group. There was also a normal control group. From week 5, the rats in the exercise groups were trained for 30 min per day, five days per week, for four weeks. The urine samples were collected pre and post the training program, and analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. RESULTS:Both types of training improved depression-like behavior in CUMS rats. Compared with normal control, 21 potential biomarkers were identified in the urine of CUMS rats, mainly involved in energy, amino acids and intestinal microbial metabolic pathways. Common responses to the training were found in the two exercise groups that the levels of glutamine, acetone and creatine were significantly recalled (all P<0.05) Aerobic training also resulted in changes in pyruvate and trigonelline, while resistance training modified ?-Oxoglutarate, citric acid, and trimethylamine oxide (all P<0.05). CONCLUSIONS:Aerobic and resistance training resulted in common effects on the metabolic pathways of alanine-aspartate-glutamate, TCA cycle, and butyric acid. Aerobic training also had effects on glycolysis or gluconeogenesis and pyruvate metabolism, while resistance training had additional effect on intestinal microbial metabolism.
| S-EPMC7423134 | biostudies-literature
Project description:Background. This study was to explore the pharmacokinetics of saxagliptin (Sax) in Goto-Kakizaki (GK) rats complicated with depression induced by chronic unpredicted mild stress (CUMS). The comorbidity of diabetic patients with depression is becoming more and more epidemic. Whether depression mental disorder alters the pharmacokinetics of hypoglycemic drugs in diabetes patients is not clear. Methods. Five-week-old male GK rats were kept in the cage for 7 weeks in a specific pathogen free (SPF)-grade lab until the emergence of diabetes and were then divided into two groups: control group and depression model group. Rats in the CUMS-induced depression group were exposed to a series of stressors for 8 weeks. Plasma serotonin and dopamine levels and behavior of open-field test were used to confirm the establishment of the depression model. All rats were given 0.5 mg/kg Sax orally after 8 weeks and blood samples were collected at different time points. The Sax concentration was assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The CYP450 activity of the liver microsomes was determined by using cocktails of probe drugs in which the activities of CYP enzymes were assessed through the determination of the production of the probe drugs. Results. Statistically significant differences in Sax pharmacokinetics were observed for area under curve, clearance, peak concentration, peak time and mean residence time between the depression rats and the control rats, while no statistical differences were observed for half-time and distribution volume by HPLC-MS/MS analysis. The CYP450 activity had different changes in the depression group. Conclusions. These results indicated that CUMS-induced depression alters the drug metabolic process of Sax and CYP450 activity of the liver microsomal enzymes in GK rats.
| S-EPMC4727972 | biostudies-literature
Project description:Purpose:In our present study, a rat depression model induced by 6 weeks of chronic unpredictable mild stress (CUMS) was established, and we investigated how Xiaoyaosan affects the intestinal permeability of depressed rats and alterations in tight-junction proteins (TJs) involved in this process. Methods:The rat depression model was established using CUMS for 6 consecutive weeks. A total of 40 healthy male Sprague-Dawley rats were randomly sorted into four groups: the control group, CUMS group, Xiaoyaosan group, and fluoxetine group. All groups, excluding the control group, were subjected to the 6-week CUMS program to generate the depression model. Body weight, food intake, and behaviors were observed during the modeling period. Histopathological alterations of colon tissue were evaluated by hematoxylin-eosin staining (H&E), and mucus-containing goblet cells were detected by periodic acid-Schiff (PAS) staining. The ultrastructural morphology of colonic mucosa was observed by transmission electron microscopy. Furthermore, immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to determine the expression of TJs. The concentrations of 5-hydroxytryptamine (5-HT) in the hypothalamus and colon were also assessed using enzyme-linked immunosorbent assay (ELISA). Results:Treatment of depressed rats with Xiaoyaosan alleviated depression-like behaviors as demonstrated by increases in the total distance traveled, the number of entries into the central area in the open field test, the duration spent in the central area, and sucrose preference. Xiaoyaosan treatment also increased body weight gain and food intake in depressed rats. Moreover, Xiaoyaosan treatment effectively improved the colonic pathological and ultrastructural changes, upregulated the expression of ZO-1, occludin, and claudin-1 in the colon, and increased 5-HT levels in the hypothalamus and colonic mucosa. Conclusions:Xiaoyaosan treatment attenuates depression-like behaviors caused by CUMS and ameliorates CUMS-induced abnormal intestinal permeability, which may be associated with the expression of TJs. These results suggest that Xiaoyaosan exerts an antidepressant effect that may be related to an improvement of intestinal barrier function via the brain-gut axis.
| S-EPMC7378849 | biostudies-literature
Project description:The gut microbiota has been increasingly correlated with depressive disorder. It was recently shown that the transplantation of the gut microbiota from depressed patients to animals can produce depressive-like behaviors, suggesting that the gut microbiota plays a causal role in the development of depression. In addition, metabolic disorder, which is strongly associated with depression, is exacerbated by changes in the composition of the gut microbiota and is alleviated by treatment with antidepressants. However, the key players and pathways that link the gut microbiota to the pathogenesis of depression remain largely unknown. To evaluate the relationships between depression and metabolic disorders in feces and plasma, we monitored changes in fecal and plasma metabolomes during the development of depressive-like behaviors in rats exposed to chronic unpredictable mild stress (CUMS). In these animals, the fecal metabolome was altered first and subjected to changes in the plasma metabolome. Changes in the abundance of fecal metabolites were associated with depressive-like behaviors and with altered levels of neurotransmitters in the hippocampus. Furthermore, the analysis of the fecal metabolome and the fecal microbiota in CUMS rats demonstrated consistent changes in the levels of several amino acids, including L-threonine, isoleucine, alanine, serine, tyrosine, and oxidized proline. Finally, we observed significant correlations between these amino acids and the altered fecal microbiota. The results of this study suggest that changes in amino acid metabolism by the gut microbiota contribute to changes in circulating amino acids and are associated with the behavior indices of depression.
| S-EPMC6351597 | biostudies-literature