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Objective: To characterize the endogenous metabolites and metabolic changes of feces of chronic unpredictable mild stress (CUMS) rats by 1H-NMR, evaluate the improvement effects of Xiaoyao Powder and investigate the underlying mechanisms. Methods: The depression model was established by CUMS procedure. 1H-NMR coupled with multivariate statistical analysis was employed to reveal the changes of fecal metabolic profiles of CUMS rats and identify potential bio-markers involved in CUMS-induced depression. Based on the potential bio-markers, the relevant metabolic pathways were constructed. Results: A total of 10 metabolites was identified as potential bio-markers in fecal samples for the CUMS model. Compared with the control group, the contents of asparagine, aspartate, lactate and propionic acid in the CUMS rats were significantly increased (P < 0.05, 0.01), while phenylalanine, tyrosine, glutamate, glutamine, alanine and proline were significantly decreased (P < 0.05, 0.01). The administration of Xiaoyao Powder could significantly increase the levels of phenylalanine, tyrosine, glutamate, glutamine and proline, whereas reduced the levels of asparagine, lactate and propionic acid. Compared with the control group, six metabolic pathways were recognized as the most influenced pathways associated with the CUMS-induced depression: (1) aminoacyl-tRNA biosynthesis, (2) alanine, aspartate and glutamate metabolism, (3) arginine and proline metabolism, (4) glutamine and glutamate metabolism, (5) phenylalanine metabolism and (6) pyruvate metabolism. Among them, Xiaoyao Powder significantly mediated abnormalities of five pathways of (2), (3), (4), (5) and (6). Conclusion: It is the first report to investigate the antidepressant-like effects and underlying mechanisms of Xiaoyao Powder from the perspective of fecal metabolites. The current results showed that the anti-depression mechanisms of Xiaoyao Powder might be related to regulating the amino acid metabolism, glucose metabolism and intestinal microbial metabolism. This study provides a solid basis for revealing the anti-depression mechanisms of Xiaoyao Powder comprehensively and deeply.
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OBJECTIVE: To investigate the anti-depressant effect of icariin (Ica)in rats with depression caused by chronic unpredictable mild stress (CUMS) as well as the relevant mechanism. METHODS: The depression-like rat model with chronic unpredicted mild stress was established. Rats were randomly divided into normal control, CUMS model, CUMS+Fluoxetine (10 mg·kg-1) and CUMS + Ica(10, 20, 40 mg·kg-1) groups. Drugs or vehicle were administrated after stress procedures for 21 d. Open-field test (OFT), sucrose preference tests (SPT)and forced swim test (FST) were used to evaluate the anti-depressant effects of Ica. The concentrations of the monoamine neurotransmitters including noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT)in prefrontal cortex, hippocampus, and striatum were measured by HPLC-ECD. RESULTS: Behavioral test indicated that crossing score and rearing score in OFT and sucrose preference index in SPT of model group were significantly lower than normal control group(P<0.01), while immobility time in FST was significantly increased (P<0.01). Compared with those in normal control group, the neurotransmitters including NA, DA and 5-HT were significantly decreased (P<0.01) in prefrontal cortex, hippocampus, and striatum in rats of CUMS. Ica and fluoxetine reversed those changes induced by CUMS. CONCLUSION: Ica improves the depression-like behaviors of rats induced by CUMS, of which the mechanism might be increasing the contents of monoamine neurotransmitters including NA, DA and 5-HT.
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Objective To evaluate the anti-depression effect of astilbin on mice with depressive disorder and to explore its mechanism of action.Methods Seventy-two male mice (C57BL/6J type) were randomly divided into control group,model group,low,middle,high dose of astilbin group and imipramine(IMI) group,with 12 mice in each group.The mice in the control group were adopted in a normal way.The rats in the model group,low,middle,high dose of astilbin group and IMI group were adopted in chronic unexpected mild stress (CUMS) to establish depression model,and the stress was continuously kept for three weeks and daily medicine with physiological saline,10,20,40 mg · kg-1 astilbin and 10 astilbin imipramine were provided in the way of intraperitoneal injection.Examination for behavioural changes of animals was implemented via tail suspension test,forced swimming test,sucrose preference test,open field test.High performance liquid chromatography (HPLC) was adopted to examine the level of dopamine (DA) and 5-hydroxytryptamine(5-HT)in prefrontal cortex.Results There was no significant difference in the number of horizontal movement and vertical movement among the control group,model group,IMI group and low,middle,high dose of astilbin group(P ＞ 0.05).Compared with the control group,the dead time of tail suspension test and forced swimming test in the model group was longer (P ＜ 0.05),and sugar preference,DA and 5-HT in prefrontal cortex decreased dramatically (P ＜ 0.05).Compared with the model group,the dead time of tail suspension test and forced swimming test in the low,middle,high dose of astilbin group was shorter (P ＜ 0.05),and sugar preference and DA level in prefrontal cortex increased dramatically (P ＜ 0.05).The 5-HT level in prefrontal cortex in the middle,high dose of astilbin group and IMI group was higher than that in the model group (P ＜ 0.05),but there was no significant difference in the 5-HT level in prefrontal cortex between low dose of astilbin group and model group (P ＞ 0.05).There was no significant difference in the dead time of tail suspension test and forced swimming test and sugar preference among the control group,IMI group and low,middle,high dose of astilbin group (P ＞ 0.05).Conclusion Astilbin works excellently in anti-depression,and the major mechanism may involve in up-regulating the level of DA and 5-HT in prefrontal cortex.
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Objective To study the effect of TREK-1 potassium channel blocker on the behavior in rats with depression.Methods Forty-eight healthy adult male Sprague Dawley (SD) rats were divided into 6 groups as following:control + saline (CON group),control + fluoxetine (CON + FLU group),control + SID1900 (CON+SID group),CUMS + saline (CUMS group),CUMS + fluoxetine (CUMS+FLU group) and CUMS + SID1900 (CUMS+SID group) with 8 in each group.Isolated living conditions combining chronic unpredicted mild stress (CUMS) were used to establish depression model in rats.Four weeks after modeling,fluoxetine 10 mg· kg-1,SID1900 5.1 mg · kg-1 and 0.9％ sodium chloride were given by intraperitoneal injection respectively.Body weight and behavioral performance of rats in several experiment paradigms were measured after drug administration.The behavioral paradigms included sucrose preference test(SPT),open field test(OFT) and forced swimming test(FST).Results Drug administration had no significant effect on body weight and behavioral performance in non stress rats (P＞0.05),however,after chronic unpredicted mild stress the body weight,percentage of sucrose consumption,movement distances and rearing times in CUMS group were decreased dramatically contrast to CON group,but the immobility duration was increased significantly (all P＜0.001).After treatment with drug for 14 days,the sucrose consumption percentage(62.03± 6.99) ％) and rearing times (18.57 ± 6.37) in CUMS+SID group were increased contrast to C UMS group ((45.46± 15.54) ％,(5.83±3.06)),while the immobility time((123.57±26.73) s) was decreased compared with that in CUMS group((174.33±40.68) s).When drug administration for 28 days,the sucrose consumption percentage((79.64± 11.37) ％),the total distance as well as the rearing times ((13.18 ± 3.17) m,(19.33±3.33)) within OFT in CUMS+FLU group were increased in comparison with CUMS group((48.06± 17.10) ％,(4.45±3.69) m,(5.17± 2.99)),and the immobility duration ((97.83± 18.97) s) in CUMS+FLU group was shorter than that ((194.83±37.97) s) in CUMS group(P＜0.05).Notably,the immobility time in CUMS+SID group ((44.29± 14.30)s) was shortened obviously compared with that in CUMS+FLU group ((97.83± 18.97)s) (P＜0.01).Conclusion Blockade of TREK-1 potassium channel can ameliorate the depression-like behavior rapidly in rats.
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Objective To investigate the effect of chronic stress on the expression of uncoupling protein 4 (UCP4) and Bcl-2 protein in hippocampal neurons of rat depression model.Methods Rat depression models were established by chronic unpredicted mild stress.All rats were randomly assigned to 2 groups:control group and model group.Flow cytometry was applied to detect the apoptosis rate and mitochondrial membrane potential.The level of LDH was measured by enzymes labelling instrument.The number of neurons was measured by immunohistochemistry.The expression of UCP4 and Bcl-2 protein was measured by Western blotting.Results After chronic stress,the apoptosis rate((4.35±0.19) ％)and LDH activity ((445.50±91.70) U/mg) in hippocampal tissue in the model group was significantly higher than the control group((0.34±0.06) ％,(167.20±63.40)U/mg).Compared to control group,the number of hippocampal neurons ((72.50±4.25) vs (45.30±2.54)) and the mitochon drial membrane potential decreased in the model group.The expressions of UCP4 and Bcl-2 protein in hippocampal tissue were significantly lower than the control group.Conclusion Chronic unpredicted mild stress can lead to apoptosis in rat hippocampal neurons,which is related with decline of mitochondrial membrane potential and low expression of UCP4 and Bcl-2 protein.
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Objective: To obtain the potential biomarkers of chronic unpredictable mild stress (CUMS) rats, the change of endogenous metabolites in the faeces of CUMS rats was analyzed using 1H-NMR coupled with metabonomics. Methods: CUMS procedure was conducted for four weeks, CUMS rat model was duplicated, and the faeces of rats was collected at the end of the procedure. The change of endogenous metabolites in faeces was analyzed using 1H-NMR coupled with multivariate statistical analysis. Results: The PLS-DA scores plot demonstrated that behavior indexes of rats in the control group were significantly different from these of rats in CUMS group, suggesting the CUMS model of depression in rats was prepared successfully. Thirty metabolites were identified in the 1H-NMR spectra of faeces, the concentration of glutamine, lactate, and aspartate was increased while that of β-glucose, uracil, tyrosine, and phenylalanine was decreased in CUMS model group with the significant difference compared with the control group (P < 0.05, 0.01). Conclusion: By researching the change of endogenous metabolites in the faeces of CUMS rats, the potential biomarkers in the faeces of CUMS rats are picked up to lay the foundation for the study on the depression pathogenesis and clinical diagnosis.
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Objective To explore the changes of Bcl-xl levels and activities in hippocampus resulting from sleep deprivation, and then to reveal the mechanism for rapid antidepressant aroused by sleep deprivation.Methods 40 SD rats were randomly divided into normal control group, chrinic stress group, sleep deprivation group and tank contral group.10 rats in each group.The depression animal model was established by chronic mild unpredictable stress(CUMS) methods.Sleep deprivation was preformed by the modified multiple platform method ( MMPM ).The animal model and the effect of antidepressant were evaluated by the open field test.The expression levels of Bcl-xl were separately observed by immunohistochemical technology in hippocampus CA1 ,CA3 and DG.Results 1.Compared with the normal control rats, ambulation ( 35.30 ± 18.77,81.30 ± 18.41, P ＜ 0.01 ) and rearing (20.50 ±4.84,27.70 ± 8.19, P＜0.05 ) increased ,and the stopping time in the center decreased (4.60 ± 1.35,2.20 ± 1.55, P ＜ 0.01 ) in the CUMS depressant animal model.2.The Bcl-xl average values of optical density (OD) in hippocampus CA1 ,CA3 ,DG of the model group was lower than that of the normal control group significantly (0.1356 ±0.0224,0.1389 ±0.0250,0.1457 ±0.0162;0.1725 ±0.0327,0.1734 ±0.0261,0.1768 ±0.0271; P＜0.01 ) ,and that of the sleep deprivation group was higher than that of the model group (0.1621 ± 0.0128,0.1603 ± 0.0137,0.1625 ± 0.0192 ;0.1356 ± 0.0224,0.1389 ± 0.0250,0.1457 ± 0.0162; P ＜ 0.05 ).Conclusion Rats showed depressive behaviors after 21 days stresses,while 72 hours sleep deprivation could reverse this effect.The up regulation of the expression and phosphorylation of Bcl-xl by sleep deprivation may participate in the antidepressant-like effect of sleep deprivation.