Modified Xiaoyaosan Alleviates Depression-like Behaviors by Regulating Activation of Hippocampal Microglia Cells in Rat Model of Juvenile Depression / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Baihuan Xiaoyao Decoction （Xiaoyaosan added with Lilii Bulbus and Albiziae Cortex） in alleviating depression-like behaviors of juvenile rats by regulating the polarization of microglia. MethodSixty juvenile SD rats were randomized into normal control， model， fluoxetine， and low-， medium-， and high-dose （5.36， 10.71， 21.42 g·kg-1， respectively） Baihuan Xiaoyao decoction groups. The rat model of juvenile depression was established by chronic unpredictable mild stress （CUMS）. The sucrose preference test （SPT） was carried out to examine the sucrose preference of rats. Forced swimming test （FST） was carried out to measure the immobility time of rats. The open field test （OFT） was conducted to measure the total distance， the central distance， the number of horizontal crossings， and the frequency of rearing. Morris water maze （MWM） was used to measure the escape latency and the number of crossing the platform. The immunofluorescence assay was employed to detect the expression of inducible nitric oxide synthase （iNOS， the polarization marker of M1 microglia） and CD206 （the polarization marker of M2 microglia）. Real-time polymerase chain reaction was employed to determine the mRNA levels of iNOS， CD206， pro-inflammatory cytokines ［tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and IL-6］ and anti-inflammatory cytokines （IL-4 and IL-10） in the hippocampus. Western blotting was employed to determine the protein levels of iNOS and CD206 in the hippocampus. The levels of IL-4 and IL-6 in the hippocampus were detected by enzyme-linked immunosorbent assay. ResultCompared with the normal control group， the model rats showed a reduction in sucrose preference （P<0.05）， an increase in immobility time （P<0.05）， decreased motor and exploratory behaviors （P<0.05）， and weakened learning and spatial memory （P<0.05）. In addition， the model rats showed up-regulated mRNA and protein levels of iNOS and mRNA levels of IL-1β， IL-6， and TNF-α （P<0.05）. Compared with the model group， Baihuan Xiaoyao decoction increased the sucrose preference value （P<0.05）， shortened the immobility time （P<0.01）， increased the motor and exploratory behaviors （P<0.05）， and improved the learning and spatial memory （P<0.01）. Furthermore， the decoction down-regulated the positive expression and protein level of iNOS， lowered the levels of TNF-α， IL-1β， and IL-6 （P<0.01）， promoted the positive expression of CD206， and elevated the levels of IL-4 and IL-10 （P<0.01） in the hippocampus of the high dose group. Moreover， the high-dose Baihuan Xiaoyao decoction group had higher sucrose preference value （P<0.01）， shorter immobility time （P<0.01）， longer central distance （P<0.01）， stronger learning and spatial memory （P<0.01）， higher positive expression and protein level of iNOS （P<0.01）， lower levels of TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01）， lower positive expression and mRNA level of iNOS （P<0.05）， and higher levels of IL-4 and IL-10 （P<0.05， P<0.01） than the fluoxetine group. ConclusionBaihuan Xiaoyao decoction can improve the depression-like behavior of juvenile rats by inhibiting the M1 polarization and promoting the M2 polarization of microglia in the hippocampus.

Exploration of antidepressant effect and mechanism of icariside Ⅱ based on GABAergic nervous system / 中国药房

OBJECTIVE To explore the antidepressant effect and potential mechanism of icariside Ⅱ （ICSⅡ） based on the GABAergic nervous system. METHODS The male Kunming mice were randomly divided into a control group （group C， 10 mice） and a modeling group （50 mice）. The depression model was induced by chronic unpredictable mild stress （CUMS） method in the modeling group. After 21 days of stimulation， the rats of modeling group were randomly divided into depression model group （NS group）， positive control group [ECS group， oxalate escitalopram 15 mg/（kg·d）] and ICSⅡ low-dose， medium-dose and high-dose groups [ICSⅡ-L group， ICSⅡ-M group， ICSⅡ-H group； ICSⅡ 10， 20， 30 mg/（kg·d）]， with 10 mice in each group. Administration groups were given relevant medicine intragastrically， once a day， for 14 consecutive days. The sugar water preference rate， total exercise distance， immobility time in tail suspension and forced swimming experiments were detected in each group. The morphology of neurons and Nissl bodies in the hippocampal CA3 region were observed； the contents of γ-aminobutyric acid （GABA） and glutamic acid （Glu）， GABA/Glu ratio， and the expressions of GABAergic nervous system-related proteins （GABA A receptor α1， GABA B receptor 1， vesicular GABA transporter， glutamate decarboxylase 67， GABA membranal transporter 3） were detected in hippocampus. RESULTS Compared with group C， the sugar water preference rate and the total exercise distance significantly reduced in NS group， while the values of immobility time in the tail suspension test and forced swimming test were significantly prolonged （P＜0.05）. The morphology of neurons in the CA3 area of the hippocampus was irregular and the Nissl bodies were reduced， with a significant decrease in the number of structurally intact neurons （P＜0.05）； the content of Glu was significantly increased， while the content of GABA， GABA/Glu ratio， and the expressions of GABAergic nervous system-related proteins were significantly decreased （P＜0.05）. Compared with NS group， depression behavior in each administration group was improved， and the above indexes were mostly reversed （P＜0.05）. CONCLUSIONS ICSⅡ can improve depression behavior of depression model mice. The mechanisms may be associated with regulating the balance of GABA and Glu， increasing the synthesis， transport and release of GABA， and regulating the expressions of GABA-related receptors， so as to improve GABAergic nervous system.

Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway / 中国中药杂志

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1β), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1β and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1β and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

UPLC-Q-Orbitrap-MS based metabolomics and analysis of the effect of Suanzaoren Decoction on serum of chronic unpredictable mild stress depression rats / 药学学报

A UPLC-Q-Orbitrap-MS based metabolomic approach combined with biochemical assay and histopathological inspection were employed to study the intervention effects of Suanzaoren Decoction (SZRD) on chronic unpredictable mild stress (CUMS) depression rats, and to clarify the metabolic regulation pathway of SZRD. The rats were randomly divided into normal control group, CUMS model group, positive drug venlafaxine group, SZRD high (24 g·kg-1) and low (12 g·kg-1) dose groups, respectively. The CUMS model was replicated by subjecting to a variety of stimulus, such as thermal stimulation, ice water swimming, ultrasonic stimulation, tail clamping, day and night reversal, plantar electric shock and so on for rats. After oral administration of drugs for 28 days, the behavioral indexes of rats in each group were observed and the hippocampus and serum samples of rats were collected for biochemical assay and histopathological inspection. Compared with the CUMS model group, low dose and high dose SZRD groups can significantly reduce the immobility time of forced swimming (P < 0.001, P < 0.001), increase the sucrose preference rate (P < 0.01, P < 0.05), the number of crossings (P < 0.05, P < 0.01) and the number of uprights (P < 0.05, P < 0.01) in the open field test, suggesting that SZRD can significantly improve the depression-like behavior of CUMS model rats. In addition, SZRD could significantly reduce the levels of serum IL-6, IL-1β and TNF-α of CUMS model rats. A total of 21 differential metabolites in serum were identified by comparison with the data from the literature and databases. In addition, low-dose SZRD and high-dose SZRD improved the 8 and 11 perturbed potential serum biomarkers that were induced by CUMS, respectively, which related to alanine, aspartic acid and glutamic acid, tryptophan and arachidonic acid metabolism. This study provides a scientific basis for expanding the clinical indications of SZRD. This experiment was approved by the Animal Ethics Committee of Shanxi University (Approval No. SXULL2020028).

Areca catechu L.ameliorates chronic unpredictable mil stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway / 中国药理学与毒理学杂志

OBJECTIVE To investigated the anti-de-pressant effects of the fruit Areca catechu L.(ACL)and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress(CUMS).METHODS CUMS was induced in rats to establish a depression animal model for 28 d.According to the baseline sucrose preference,the male rats were divided into six different groups.They were treated with parox-etine hydrochloride,ACL,and water once a day until the behavioral tests were performed.The levels of corticoste-rone(CORT),malondialdehyde(MDA),catalase(CAT),and total superoxide dismutase(T-SOD)in serum were de-tected using a commercial kit,and the concentrations of 5-hydroxytryptamine(5-HT)and dopamine(DA)mono-amine neurotransmitters in the brain tissues were detect-ed by liquid chromatography-tandem mass spectrometry.Doublecortin(DCX)expression in the hippocampal den-tate gyrus(DG)was determined by immunofluorescence,and the relative abundance of brain-derived neurotrophic factor(BDNF),TrkB,PI3K,p-Akt/Akt,PSD-95,and p-GSK-3β/GSK-3β of brain tissues were assayed by West-ern blotting.RESULTS ACL markedly increased sucrose preference,decreased the immobility time,and short-ened the feeding latency of CUMS-induced rats.CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters(5-HT and DA)in the hippocampus and cortex of brain tissues and the levels of CORT,MDA,CAT,and T-SOD in serum,whereas ACL administration alleviated these considerable changes.ACL promoted DCX expression in DG and increased the protein levels of BDNF,TrkB,PI3K,p-Akt/Akt,PSD-95,and p-GSK-3β/GSK-3β in the brains of CUMS-induced rats.CONCLUSION Our results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic-pituitary-adrenal axis,stimulating hippo-campal neurogenesis,and activating the BDNF signaling pathway.

Effects of human umbilical cord mesenchymal stem cells exosomes on hippocampal microglia polarization and neuronal apoptosis in depressed model mice / 中华行为医学与脑科学杂志

Objective:To investigate the effects of human umbilical cord mesenchymal stem cells exosomes (hucMSC-Exo) on depression-like behavior and polarization dynamic transition of hippocampal microglia in chronic unpredictable mild stress(CUMS) mice.Methods:The hucMSC was isolated, cultured, and the 5th generation hucMSC-Exo was extracted by ultracentrifugation and identified.Biological markers of CD9 and CD63 of hucMSC-Exo were detected by Western blot.A total of 12 SPF grade male C57BL/6J mice were randomly selected to establish depression model by CUMS method at the same time, and relevant behavioral experiments, including opening field test (OFT) and forced swimming test (FST) were used to detect changes of depression-like behavior in CUMS mice. After modeling, 12 mice were randomly divided into two groups, with 6 mice in each group. One group of mice was the exosome treatment group (CUMS+ Exo group) after stereotactic brain injection of hucMSC-Exo in the hippocampus, and the other group was the CUMS group. The expression of inflammatory signals in the hippocampus of mice in both groups were detected by micro PET/CT scanning technique. The proportion of M2-type microglia and M1-type microglia in the hippocampus of mice was detected by tissue immunofluorescence. β3-tubulin immunofluorescence staining was used to detect the length changes of neuronal axons in the depressed cell model constructed with corticosterone (CORT). EdU staining was used to detect neuronal proliferation. TUNEL staining was used to observe the apoptosis of neurons in the hippocampus of mice.Statistical analysis was conducted by GraphPad 8.0 software, and t-test was used for inter group comparison. Results:Under the electron microscope, hucMSC-Exo showed typical " double-layer cup-like" small vesicle-like changes and the particle diameter was about 100 nm.Western blot confirmed the expression of lconic proteins of CD9 and CD63. In the micro PET/CT scans, the uptake of [18F]DPA-714 in the CUMS+ Exo group was lower than that of the CUMS group, and the difference was statistically significant ((0.91±0.02)g/mL, (0.81±0.05)g/mL, t=4.54, P=0.001 1). In the opening field test, the percentage of central path length ((3.40±0.44)%, (5.17±0.90)%, t=4.33, P=0.001 5) and the time spent on the central path ((7.04±0.60)s, (10.22±1.41)s, t=6.02, P=0.000 1) in CUMS+ Exo group were higher than those in CUMS group, while the total distances of the two groups were not statistically significant ( t=0.48, P>0.05). In the forced swimming test, the immobility time in the CUMS+ Exo group was less than that in the CUMS group ((152.33±7.28) s, (133.50±4.32) s, t=5.45, P=0.000 3). In tissue immunofluorescence experiments, compared with the CUMS group, the proportion of M2-type microglia of hippocampus in the CUMS+ Exo group((0.33±0.04), (0.59±0.12), t=5.11, P=0.000 5)increased and the proportion of M1-type microglia ((0.56±0.06), (0.41±0.03), t=5.15, P=0.000 4) decreased in the CUMS+ Exo group. β3-tubulin-labeled immunofluorescence results showed an increase of neuronal axon length in the CORT+ Exo group compared with that in the CORT group((3.99±0.99) μm, (6.76±1.11) μm, t=6.10, P=0.000 1). The results of cell proliferation test showed an increase of proliferation rate in the CORT+ Exo group compared with that in the CORT group((0.74±0.07), (0.64±0.03), t=3.32, P=0.001 8). In the TUNEL staining experiment, the apoptosis rate of neurons in the hippocampal region of mice in the CUMS+ Exo group was lower than that of CUMS group ((0.24±0.04), (0.39±0.04), t=6.11, P=0.000 1). Conclusion:hucMSC-Exo can promote the conversion of M1 polarized microglia to M2 type microglia to alleviate depression-like behavior and reduce neuronal apoptosis in CUMS mice.

Effects of ginkgo biloba extract on oxidative stress and the balance of excitation/inhibition of pyramidal neurons in the medial prefrontal cortex of depressive model mice / 中华行为医学与脑科学杂志

Objective:To investigate the effect of ginkgo biloba extract (GBE) on oxidative stress in medial prefrontal cortex and excitatory/inhibitory balance of pyramidal neurons in chronic unpredictable mild stress (CUMS)-induced depressive model mice.Methods:Totally 48 SPF grade 7-week-old male C57BL/6J mice were divided into 4 groups according to random number table method: control+ saline group (CTRL+ Veh), control+ GBE group (CTRL+ GBE), model+ saline group (CUMS+ Veh), model+ GBE group (CUMS+ GBE), with 12 mice in each group.Mice in CUMS+ Veh group and CUMS+ GBE group were established by CUMS method, and mice in CTRL+ GBE group and CUMS+ GBE group were intraperitoneally injected with GBE (70 mg/kg) once a day, and mice in CTRL+ Veh group and CUMS+ Veh group were injected intraperitoneally with 0.9% sodium chloride solution.Then, the sucrose preference test, forced swimming test (FST) and tail suspension test (TST) were performed to evaluate the depressive-like behavior of mice, and open field test (OFT) was performed to evaluate the autonomous locomotion and exploration ability and anxiety-like behavior.The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in mPFC were determined by ELISA.Spontaneous excitatory postsynaptic currents (sEPSC) and spontaneous inhibitory postsynaptic currents (sIPSC) were detected by whole-cell recording.SPSS 23.0 was used for data analysis and two-factor analysis of variance(whether to get GBE, whether to mold, show as GBE×CUMS) was used for statistical analysis.Results:(1) Behavioral results: the the time spent in center and total distance of OFT and sugar preference rate of the four groups of mice were compared, and the interaction of GBE×CUMS was significant( F=24.90, 4.82, 3.91, all P<0.05). The results of simple effect analysis showed that the time spent in center ((47.15±3.58) s), the total distance((19.33±0.86) m) and the sugar preference rate((59.11±8.79)%) of the mice in CUMS+ Veh group were lower than those in the CTRL+ Veh group((61.55±2.49) s, (23.24±1.21) m, (84.02±7.45) %) (all P<0.01), and the above indexes in CUMS+ GBE group ((56.51±3.53) s, (20.75±1.31) m, (70.80±11.79)%) were higher than those in CUMS+ Veh group (all P<0.05). In the immobility time of FST and TST of mice in the 4 groups, the interaction of GBE×CUMS were significant( F=85.53, 83.39, both P<0.01). The immobility time of FST and TST in CUMS+ Veh group were higher than those in CTRL+ Veh group (both P<0.01 ), and the above indexes in CUMS+ GBE group were lower than CUMS+ Veh group(both P<0.05). (2)The results of ELISA showed that the interaction of GBE×CUMS of SOD level of mice in the 4 groups was not significant ( F=3.52, P=0.07), but the main effects of GBE factor and CUMS factor were both significant ( F=4.69, 46.93, both P<0.05). The interaction of GBE×CUMS of MDA level was significant( F=16.61, P<0.01). The level of SOD in the CUMS+ Veh group was lower than that in the CTRL+ Veh group ( P<0.01), and the level of SOD in the CUMS+ GBE group was higher than that in the CUMS+ Veh group ( P<0.05). The level of MDA in the CUMS+ Veh group was higher than that of the CTRL+ Veh group ( P<0.01), and the level of MDA in CUMS+ GBE group was lower than that of the CUMS+ Veh group ( P<0.01). (3) The results of whole-cell recording showed that the interaction of GBE×CUMS of frequency and quantification of sEPSC in the four groups were significant ( F=5.45, 6.94, both P<0.05). The sEPSC frequency and quantification in the CUMS+ Veh group were lower than those in the CTRL+ Veh group (both P<0.01), and the sEPSC frequency and quantification in CUMS+ GBE group were higher than those of CUMS+ Veh group (both P<0.05). The interaction of GBE×CUMS of frequency and quantification of sIPSC in the four groups were significant ( F=7.78, 8.96, both P<0.01). The sIPSC frequency and quantification of the CUMS+ Veh group were higher than those of CTRL+ Veh group (both P<0.01), and the above indexes of CUMS+ GBE group were lower than those of CUMS+ Veh group (both P<0.01). As for the sEPSC/sIPSC ratio, GBE×CUMS interaction was significant ( F=5.45, P=0.02). The sEPSC/sIPSC ratio of CUMS+ Veh group (0.09±0.01) was lower than that of CTRL+ Veh group (0.28±0.04) ( P<0.01), and the sEPSC/sIPSC ratio of CUMS+ GBE group (0.14±0.03) was higher than that of CUMS+ Veh group ( P<0.05). Conclusion:Ginkgo biloba extract can improve the depression-like behavior of mice induced by CUMS, reduce the oxidative stress of mPFC and improve the excitation/inhibition balance of pyramidal neurons in depressive model mice.

Effects of chronic stress during pregnancy on depression-like behavior and methylation of imprinted gene IGF-2/H19 in female offspring rats / 中华行为医学与脑科学杂志

Objective:To investigate the effects of chronic stress during pregnancy on depressive behavior and DNA methylation of insulin-like growth factor-2 ( IGF-2 )/long non-coding RNA ( lncRNA ) H19 in hippocampus of female offspring rats.Methods:A total of 32 SPF female SD rats were divided into model group and control group according to the random number table. The rats in the model group were treated with chronic unpredictable mild stress (CUMS) to establish the depression model, and the rats in the control group were fed normally.On the 7th day of stress stimulation, all female rats mated with male rats. One day before stress stimulation and 1, 7, 14, 21, 28 days after stress stimulation, blood samples were collected from the inner canthus vein of the rats to determine the plasma corticosterone concentration. Eight female pups were randomly selected from each group on postnatal day 28(PND28) and postnatal day 42 (PND42). Plasma corticosterone concentration was measured after angular vein blood collection. At PND42, the depression-like behavior of female pups in the two groups was measured by sucrose preference test, tail suspension test and forced swimming test. The expression of IGF-2/H19 and related transferases in hippocampus of offspring rats was detected by RT-PCR and Western blot. Methyl target technology was used to capture and sequence 19 CpG sites of IGF-2 differentially methylated region(DMR) fragment 2, 8 CpG sites in H19 imprinting control region (ICR) fragment 1 and 15 CpG sites in H19-ICR fragment 2, and calculate the methylation level of each CpG site. SPSS 26.0 was used for statistical analysis of relevant data by repeated measurement ANOVA, t test and non-parametric test. Results:(1) The data of plasma corticosterone content of the two groups of female rats at different times were analyzed by repeated measurement variance.The results showed that the the interaction effect between time and group was not significant ( F=2.997, P=0.066), and the main effect of time was significant ( F=4.44, P=0.010). The main effect of group was significant ( F=41.40, P=0.001). According to the independent effect analysis of factors between groups, on the 14th, 21st, and 28th days of stress, the plasma corticosterone concentration of the model group was higher than that of the control group (all P<0.001). (2) In the sucrose preference test, the total liquid consumption (11.10(10.38, 11.58) mL, 13.55(12.00, 15.77) mL, Z=-3.055, P=0.002), 1% sucrose water consumption ((5.50±1.30) mL, (8.56±2.04) mL, t=-3.582, P=0.003) and 1% sucrose preference percentage ( (51.35±8.69) %, (62.11±8.05) %, t=-2.576, P=0.022) of female pups in the model group were significantly lower than those in the control group. (3) The duration of immobility in tail suspension test ((126.95±39.89) s, (54.30±25.00) s, t=4.375, P=0.001) and forced swimming test ((7.97±6.66) s, (1.85±2.12) s, t=2.478, P=0.037) of female offspring in the model group were longer than those in the control group. (4) The expression of IGF-2 mRNA ((0.46±0.24), (1.00±0.00), t=3.821, P=0.019) and H19 mRNA ((0.60±0.25), (1.00±0.00), t=3.574, P=0.007) in hippocampus of female pups in the model group were lower than those of control group. The relative expression of IGF-2 protein in female offspring of model group was lower than that in control group ((0.77±0.04), (1.00±0.00), t=9.876, P=0.01). The relative expression of CCTC-binding factor (CTCF) mRNA ((1.29±0.12), (1.00±0.00), t=-4.850, P=0.003) and protein ((1.90±0.28), (1.00±0.00), t=-5.513, P=0.005) were higher than those in the control group. (5) The methylation levels of three CpG sites in the IGF-2 DMR region of female offspring in the model group were lower than those in the control group ( t=-3.21, -3.00, -3.34, all P<0.05), located at chr1215831028, chr1215831055 and chr1215831205, respectively. The methylation level of IGF-2 DMR fragment was lower than that of the control group ( t=-3.453, P=0.048). The relative expression levels of DNMT3A mRNA ( t=5.102, P=0.002), DNMT3A ( t=10.213, P<0.001) and DNMT3B ( t=4.169, P=0.014) in female offspring of the model group were lower than those in the control group. Conclusion:Chronic stress during pregnancy causes depression and despair in female offspring mice, and the mechanism may be related to the decrease of methylation level of imprinted gene IGF-2 DMR caused by the decrease of methyltransferase expression.

Effects of early sleep deprivation on depressive-like behavior and hippocampus synaptic plasticity in adult depression model mice / 中华行为医学与脑科学杂志

Objective:To investigate the effects of early sleep deprivation(SD) on depressive-like behavior and hippocampus synaptic plasticity in adult mice with chronic unpredictable mild stress(CUMS) model.Methods:Thirty 2-week-old clean grade male mice were randomly divided into control group (CON group), CUMS group and SD + CUMS group according to the random number table, with 10 mice in each group. The mice in SD + CUMS group were subjected with sleep deprivation for 4 hours once a day during puberty (3 ~ 6 weeks old), and then were stimulated by CUMS after adulthood (9 weeks old). The mice in CUMS group were subjected with CUMS at the age of 9 weeks. And the mice in CON group were not given any intervention.The depressive-like behavior was evaluated by body weight, sugar water preference, tail suspension test and forced swimming test.The density of dendritic spines of basal and apical neurons in hippocampal CA1 was measured by Golgi staining, the frequency and amplitude of miniature excitatory postsynaptic current(mEPSC) of pyramidal neurons in the hippocampal CA1 region of mice were measured by electro-physiological patch clamp technique.Graphpad prism 7.0 software was used for statistical analysis and mapping. One-way ANOVA was used for comparison among multiple groups, and Tukey test was used for further pairwise comparison.Results:(1) After stress modeling, there were significant differences in body weight, sugar water preference percentage, forced swimming immobility time and tail suspension time among the three groups ( F=71.63, 39.82, 44.13, 43.07, all P<0.01). Compared with CON group, the mice in CUMS group and SD+ CUMS group had lower body weight ((25.51±0.37) g, (22.92±0.31) g, (20.12±0.27) g, both P<0.01), lower sugar water percentage preference ((87.40±1.65) %, (63.42±3.33) %, (49.68±3.70)%, both P<0.01), longer immobile time of forced swimming ((34.30±5.32) s, (119.20±12.03) s, (153.80±9.17) s, both P<0.01) and longer immobile time of tail suspension test((115.20±8.19)s, (156.80±4.35) s, (192.00±4.12) s, both P<0.01). Compared with CUMS group, SD+ CUMS group had lower body weight ( P<0.01), lower sugar water preference percentage ( P<0.05), longer immobile time in forced swimming test( P<0.05) and longer immobile time in tail suspension test( P<0.01). (2) Golgi staining results showed that the densities of dendritic spines of apical neurons and basal neurons in hippocampal CA1 area of the three groups were significantly different ( F=38.41, 41.34, both P<0.01). The densities of dendritic spines of basal and apical hippocampal neurons in CUMS group and SD+ CUMS group were lower than those in CON group ((7.74±0.22)/10 μm, (6.58±0.27)/10 μm, (5.00±0.13)/10 μm, both P<0.01), ((8.90±0.23)/10 μm, (7.63±0.30)/10 μm, (6.01±0.14)/10 μm, both P<0.01). Compared with CUMS group, the mice in SD+ CUMS group had lower densities of dendritic spines of basal and apical hippocampal neurons(both P<0.01). (3) Electrophysiological results showed that there were significant differences in the frequency and amplitude of mEPSC in hippocampal pyramidal neurons of the three groups ( F=38.90, 63.37, both P<0.01). Compared with CON group, the frequency and amplitude of mEPSC in pyramidal neurons of CA1 in CUMS group and SD+ CUMS group were significantly lower ((0.39±0.03)Hz, (0.20±0.02)Hz, (0.07±0.02)Hz, both P<0.01; (9.98±0.31)pA, (7.74±0.21)pA, 6.36±0.13)pA, both P<0.01). Compared with CUMS group, the frequency and amplitude of mEPSC in SD+ CUMS group were lower (both P<0.01). Conclusion:Adolescent sleep deprivation aggravates depressive behavior and hippocampus synaptic plasticity impairment in adult CUMS model mice.

Effect of Sinisan on NLRP3 Inflammasomes and Depression-like Behaviors in Depressed Rats / 中国实验方剂学杂志

ObjectiveTo observe the effects of Sinisan on behaviors and NOD-like receptor protein 3 （NLRP3） inflammasomes of depressed rats induced by chronic unpredictable mild stress （CUMS） and further explore the anti-depressant mechanism of Sinisan. MethodFifty male rats were randomly divided into a normal group， a model group， an NLRP3 inhibitor （MCC950） group （10 mg·kg-1）， and low- （2.5 g·kg-1） and high-dose （5 g·kg-1） Sinisan groups， with 10 rats in each group. The depression model was induced by 42 d CUMS in rats except for those in the normal group. Drug intervention was performed on the 22nd day of modeling by gavage in the Sinisan groups and by intraperitoneal injection in the MCC950 group. Except for the MCC950 group， the remaining four groups received 10 mg·kg-1 physiological saline by intraperitoneal injection， while the rats in the model group， the normal group， and the MCC950 group were administered with 3 mL of physiological saline by gavage. Twenty-one days later， the sucrose preference test and open field test were performed. Western blot was used to detect the protein expression of NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， cysteinyl aspartate-specific protease-1 （Caspase-1）， B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）， ionized calcium-binding adapter molecule 1 （Iba1）， and CD68 in the hippocampus of rats in each group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） in the hippocampus of rats. Nissl staining and TUNEL were used to assess the pathological changes and apoptosis level in the hippocampal CA1 region of rats， respectively. ResultThe sucrose preference rate and consumption volume in the sucrose preference test， the total distance， the percentage of central movement distance， and the percentage of residence time in the open field test of rats in the model group were lower than those in the normal group （P<0.01）. Compared with the model group， the Sinisan groups and the MCC950 group showed improved depression-like behaviors， apoptosis level in the hippocampal CA1 region， and neuron loss to varying degrees. Sinisan could reduce the levels of IL-1β， IL-18， Bax， Iba1， and CD68 in the hippocampus （P<0.05， P<0.01）， increase the level of Bcl-2 （P<0.05， P<0.01）， and inhibit the protein expression of NLRP3， ASC， and Caspase-1 related to NLRP3 inflammasomes （P<0.05， P<0.01）. ConclusionSinisan can improve the depression-like behaviors and pathological damage of hippocampal neurons in CUMS-induced rats， and the mechanism may be related to the inflammatory response mediated by the NLRP3 inflammasome signaling pathway.

Effect and Mechanism of Lily Polysaccharide Combined with Astragalus Polysaccharide on Depressive Behavior in Chronic Stress Mice / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of antidepressant effect of lily polysaccharide （LLP）and astragalus polysaccharide（APS）. MethodSixty KM mice were randomly divided into blank group， model group， fluoxetine hydrochloride （8 mg·kg-1）group， LLP （0.2 g·kg-1）group， APS （0.2 g·kg-1）group and polysaccharide combination （LLP+APS，0.1 g·kg-1+0.1 g·kg-1）group， with 10 mice in each group. Except the blank group， the other groups were given chronic unpredictable mild stress （CUMS） induced mouse depression model. On the 29th day of modeling，fluoxetine hydrochloride group was given corresponding dose of fluoxetine hydrochloride， and polysaccharide groups were given corresponding drug. The depressive behavior of mice was evaluated by behavioral indexes such as body mass change， open field test. The morphological changes of hippocampal CA1 neurons were observed by Nissl staining. The contents of 5-hydroxytryptamine （5-HT）， adrenocorticotropic hormone （ACTH）， and corticosterone （CORT）， in brain tissue and plasma were measured by enzyme-linked immunosorbent assay （ELISA）. Western blot was used to detect the expression levels of related proteins in adenylate cyclase/cyclic adenylate phosphate/protein kinase A （AC/cAMP/PKA） signal pathway. ResultCompared with the blank group， mice in the model group gained weight slowly， the total distance， central distance and sugar water preference rate decreased significantly （P<0.01）， the depressive behavior was significant， the hippocampal neurons were seriously damaged， the content of 5-HT decreased （P<0.01）， the contents of ACTH and CORT increased significantly （P<0.01）， adenylate cyclase 6（ADCY6）， PKA and cAMP response element binding protein-1 （CREB-1） and brain-derived neurotrophic factor （BDNF） protein expression decreased significantly （P<0.01）. Compared with the model group， depressive behavior of mice in LLP group， APS group and LLP+APS group was significantly improved （P<0.01）. The antidepressant effect of LLP+APS was better than that of LLP and APS. Each administration group could alleviate the damage of hippocampal neurons in varying degrees， significantly increase the content of 5-HT in brain tissue （P<0.01）， and reduce the levels of ACTH and CORT in plasma （P<0.05）. The protein levels of ADCY6， PKA， CREB-1 and BDNF were significantly increased （P<0.05）. ConclusionThe antidepressant effect of LLP+APS is significantly enhanced and has a synergistic effect. The mechanism may be closely related to affecting the content of neurotransmitters， inhibiting HPA axis activity and activating AC/cAMP/PKA signal transduction pathway.

Based on plasma metabonomics and network analysis to research the mechanisms of Chaigui granules for treating depression / 药学学报

The purpose of this study was to systematically analyze the antidepressant mechanism of Chaigui granules from the perspective of biological metabolic network by using integrated metabolomics and biological network analysis tools. The model of chronic unpredictable mild stress (CUMS) depression rat was established, and LC-MS-based plasma metabolomics was used to identify the key metabolites and analyze metabolic pathways underlying the antidepressant effects of Chaigui Granules. The key metabolites regulated by Chaigui granules was integrated with biological network analysis tools to further focus on the key metabolic pathways and explore the potential targets of the antidepressant effect of Chaigui granules. The results showed that there were significant differences in the plasma levels of 20 metabolites in the model group compared with the control group (P < 0.05), Chaigui granules significantly regulated 12 metabolites including docosatrienoic acid, 3-hydroxybutyric acid, 4-hydroxybenzaldehyde, chenodeoxycholic acid, cholic acid, L-glutamine, glycocholic acid, linoleyl carnitine, L-tyrosine, N-acetylvaline, palmitoylcarnitine, arachidonic acid. Further network analysis of the key metabolites regulated by Chaigui granules indicated that plasma arachidonic acid metabolism might be the core pathway for the antidepressant effect of Chaigui granules, with 10 proteins were potential targets for the antidepressant effect of Chaigui granules, including CYP2B6, CYP2E1, CYP2C9, CYP2C8, PLA2G6, PTGS2, ALOX15B, PTGS1, ALOX12 and ALOX5. The animal experimental operations involved in this paper was followed the regulations of the Animal Ethics Committee of Shanxi University and passed the animal experimental ethical review (Approval No. SXULL2020028).

Study on the fecal metabolomics of CUMS-susceptible and CUMS-resilient rats / 药学学报

Proton nuclear magnetic resonance (1H NMR) based metabolomics was applied to characterize the fecal metabolic profiles of chronic unpredictable mild stress (CUMS)-depression (CUMS-D) and CUMS-resilience (CUMS-R) rats. The fecal biomarkers and metabolic pathways involved in CUMS-D and CUMS-R were screened and identified, revealing the underlying mechanisms of two different responses of the body to the same stresses. Firstly, the classic depression model, i.e. CUMS, was constructed. According to the fecal metabolomics profiles, the model rats were divided into two groups, i.e. the CUMS-D group and the CUMS-R group. And then, the depression statuses of CUMS-D rats and CUMS-R rats were verified by their sucrose preference rates. Lastly, multivariate data analysis was applied to clarify the fecal biomarkers and corresponding metabolic pathways involving in CUMS-D and CUMS-R. The results show that compared with the control rats, the sucrose preference rates of CUMS-D rats were significantly reduced. By contrast, the sucrose preference rates of CUMS-R rats had no significant difference. At the same time, CUMS-D and CUMS-R showed both unique and shared biomarkers and pathways. Three pathways are significantly related to CUMS-D, including taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, and arginine and proline metabolism. Glycerolipid metabolism and tryptophan metabolism are specific pathways related to CUMS-R. This study explores the mechanisms of the emergence of susceptible and resilience of rats under the same stimulus from a metabolomics perspective. The current findings provide not only a new perspective for studying depression, and personalized and precision treatments in clinic, but also the research and development of antidepressants.

Antidepressant-like activity of ethanol extract of leaves of Caesalpinia pulcherrima in unstressed and stressed mice

In the present study, antidepressant-like activity of ethanol extract of leaves of Caesalpinia pulcherrima was evaluated in Swiss young male albino mice. Stress was induced in mice by subjecting them to unpredictable mild stress for 21 successive days. Ethanol extract of the leaves (100, 200 and 400 mg/ kg, p.o.) and fluoxetine (20 mg/kg, p.o.) were administered for 21 consecutive days to separate groups of unstressed and stressed mice. Ethanol extract (200 and 400 mg/kg) and fluoxetine significantly decreased immobility period of unstressed as well as stressed mice in tail suspension test (TST). However, the lowest dose (100 mg/kg) of the extract also significantly decreased immobility period of stressed mice in TST. The extract significantly restored reduced sucrose preference in stressed mice. There was no significant effect on locomotor activity of mice. Ethanol extract of the leaves significantly decreased plasma nitrite and corticosterone levels; brain MAO-A activity and MDA level; and increased brain reduced glutathione and catalase activity in unstressed as well as stressed mice as compared to their respective vehicle treated controls. Thus, ethanol extract of leaves of Caesalpinia pulcherrima showed significant antidepressant-like activity in unstressed and stressed mice probably through inhibition of brain MAO-Aactivity, reduction of oxidative stress and plasma corticosterone levels.

Ginkgo diterpene lactone improves depression-like behaviors and affects cytokine and neurotransmitter levels in a rat model of chronic unpredictable mild stress / 中华微生物学和免疫学杂志

Objective:To investigate the effects of Ginkgo diterpene lactone on depression-like behaviors in a rat model of chronic unpredictable mild stress (CUMS) and its mechanism.Methods:Forty SD rats were randomly divided into five groups, which were control group, CUMS group, CUMS+ low-dose Ginkgo diterpene lactone group (1.5 mg·kg -1·d -1), CUMS+ medium-dose Ginkgo diterpene lactone group (3 mg·kg -1·d -1) and CUMS+ high-dose Ginkgo diterpene lactone group (6 mg·kg -1·d -1). CUMS rat model was established by continuous stress for six weeks, and the rats were given corresponding treatment in the last three weeks. Sucrose preference test was performed during the stress and drug administration, and behavior tests were performed after the stress and drug administration. After behavior tests, hippocampus, hypothalamus and serum samples were collected to detect inflammatory factors and neurotransmitter. Results:Chronic stress caused depression-like behaviors in rats, while continuous treatment with Ginkgo diterpene lactone could effectively improve sucrose preference, forced swimming immobility time and open field test scores in CUMS rats. It was found that Ginkgo diterpene lactone could significantly improve the decreased secretion of IL-1β and IFN-γ in plasma, and significantly increase the secretion of IL-10 and IL-4 caused by CUMS. In addition, CUMS caused hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis in rats, which manifested as increased secretion of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol (COR). The negative feedback of HPA hypermodulated the release of neurotransmitters in the hippocampus, causing the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) in the brain of CUMS rats to decrease. However, Ginkgo diterpene lactone could significantly inhibit HPA axis hyperfunction and increase neurotransmitter levels in the brain.Conclusions:Ginkgo diterpene lactone can effectively improve the depression-like behaviors of CUMS rats through regulating the immune environment, inhibiting the HPA axis hyperfunction and increasing neurotransmitter release.

Antidepressant effect of acidic polysaccharides from Poria and their regulation of neurotransmitters and NLRP3 pathway / 中国中药杂志

The rats were exposed to chronic unpredictable mild stress(CUMS) and kept in separate cages for inducing depressive disorder, which was judged by behavioral indicators. The number and morphology of neurons in hippocampal CA3 area and prefrontal cortex were observed by hematoxylin-eosin(HE) staining. The levels of brain-derived neurotrophic factor(BDNF), 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), norepinephrine(NE), glutamic acid(GLU), interleukin-1β(IL-1β), interleukin-18(IL-18), and tumor necrosis factor-α(TNF-α) were detected by enzyme-linked immunosorbent assay(ELISA). Real-time polymerase chain reaction(RT-PCR) and Western blot were conducted to determine the mRNA and protein expression levels of related molecules in NLRP3 pathway. The results showed that compared with the model group, acidic polysaccharides from Poria at the low-, medium-, and high-doses(0.1, 0.3 and 0.5 g·kg~(-1)·d~(-1)) all improved the depression-like behavior of rats, increased the number of neurons and the levels of BDNF, 5-HT, 5-HIAA, DA, and NE in the hippocampus, and reduced GLU and serum IL-1β, IL-18, and TNF-α levels. The mRNA expression levels of ASC, caspase-1, IL-1β, and IL-18 and the protein expression levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in each medication group were down-regulated, whereas the protein expression levels of pro-caspase-1, pro-IL-1β, and pro-IL-18 were up-regulated. All these have indicated that acidic polysaccharides from Poria exerted the antidepressant effect possibly by regulating neurotransmitters and NLRP3 inflammasome signaling pathway.

Antidepressant-Like Effects of Chaihu Shugan Powder () on Rats Exposed to Chronic Unpredictable Mild Stress through Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis / 中国结合医学杂志

OBJECTIVE@#To investigate the antidepressant-like effects of Chaihu Shugan Powder (CSP, ) and to explore its underlying mechanisms.@*METHODS@#Thirty-two Sprague-Dawley rats were randomly divided into control (CON), chronic unpredictable mild stress (CUMS), fluoxetine (FLU), and CSP groups, 8 rats in each group. All of the rats except for those in the control group were subjected to 3 consecutive weeks of CUMS to establish the depression model. The open field test (OFT), forced swimming test (FST), and sucrose preference test were used to assess the anti-anxiety and antidepressant effects of CSP. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling was used to determine the apoptosis rate in the hippocampal tissues. The mRNA and protein levels of glucose-regulated protein (GRP) 78, spliced X-box-binding protein (XBP)-1, CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and c-Jun N-terminal kinase (JNK) in the hippocampus of rats were evaluated by real-time PCR and Western blot analysis, respectively.@*RESULTS@#Administration of CSP alleviated anxiety and depression-like behavior in CUMS rats, as revealed by enhanced time and distance in the center of the OFT (P<0.05), an increased preference for sucrose, and longer swimming time and shorter immobility time during the FST (all P<0.05). In addition, CSP treatment significantly reduced the rate of apoptosis in rat hippocampal neurons (P<0.05). The mRNA and protein expression levels of GRP78, spliced XBP-1, and CHOP were down-regulated along with the expression of caspase-12 and cleaved caspase-12 proteins (all P<0.05), whereas total and phosphorylated JNK1 protein levels did not differ significantly between control and CSP-treated rats.@*CONCLUSION@#CSP can improve depression-like behavior in rats exposed to CUMS, possibly by suppressing CHOP and caspase-12 mediated apoptosis in the rat hippocampus.

Antidepressant Effect of n-Butyl Alcohol Extracts from Xiaoyaosan via IGF-1Rβ/PI3K/Akt Pathway / 中国实验方剂学杂志

Objective:To investigate the intervention effect of <italic>n</italic>-butyl alcohol extracts from Xiaoyaosan against depression-like behavior induced by chronic unpredictable mild stress （CUMS） in model mice and the role of insulin-like growth factor-1 receptor <italic>β</italic> （IGF-1R<italic>β</italic>）/phosphatidylinositol-3 kinase （PI3K）/protein kinase B （Akt） signaling pathway in such intervention. Method:The effective dose of n-butyl alcohol extracts from Xiaoyaosan was preliminarily determined in model mice with behavioral despair. Then the male C57BL/6 mice were randomly divided into the blank group， model group， fluoxetine group， Xiaoyaosan group， and the low- （20 g·kg^-1） and high-dose （40 g·kg^-1） <italic>n</italic>-butyl alcohol extract groups. The mice in all groups except for the blank group were exposed to CUMS for inducing the depression-like behavior， which was judged by the sucrose preference test （SPT）. The successfully modeled mice in the medication groups were intragastrically administered with the corresponding drugs， whereas those in the blank and model groups were treated with an equal volume of solvent for five successive weeks. Following the SPT， tail suspension test （TST）， and novelty suppressed feeding test （NSFT） at the end of the fifth week， the insulin-like growth factor-1 （IGF-1） levels in mouse serum and hippocampus were measured by enzyme-linked immunosorbent assay （ELISA）. The average optical density （<italic>IA</italic>） of Nissl bodies in mouse hippocampal CA3 region was detected by toluidine blue staining. The 5-bromo-2-deoxyuridine （Brdu） and doublecortin （DCX） expression in the dentate gyrus （DG） was assayed using immunofluorescence method. The protein expression levels of IGF-1R<italic>β</italic>， PI3K， phosphorylated-PI3K （p-PI3K）， Akt， p-Akt， cysteine aspartic acid-specific protease 3 （Caspase-3）， and cleaved Caspase-3 in the hippocampus were determined by Western blot. Result:The results of forced swimming test and TST showed that n-butyl alcohol extracts from Xiaoyaosan at 9.1 and 40 g·kg^-1 both significantly shortened the immobility time of mice （<italic>P</italic><0.05， <italic>P</italic><0.01）， indicating that the effective dose ranged from 9.1-40 g·kg^-1. Compared with the model control， the n-butyl alcohol extracts from Xiaoyaosan at 20 and 40 g·kg^-1 significantly increased the sucrose preference percentage （<italic>P</italic><0.05， <italic>P</italic><0.01）， shortened the immobility time in TST （<italic>P</italic><0.01） and the feeding latency in NSFT （<italic>P</italic><0.01）， reversed the down-regulated IGF-1 content in mouse serum and hippocampus （<italic>P</italic><0.01）， increased the AOD of Nissl bodies in the hippocampal CA3 region （<italic>P</italic><0.01）， promoted the expression of Brdu and DCX in DG （<italic>P</italic><0.05， <italic>P</italic><0.01）， and down-regulated the protein expression levels of IGF-1R<italic>β</italic> （<italic>P</italic><0.05， <italic>P</italic><0.01）， p-PI3K/PI3K （<italic>P</italic><0.05， <italic>P</italic><0.01）， p-Akt/Akt （<italic>P</italic><0.05）， and cleaved Caspase-3/Caspase-3 in the hippocampus of CUMS mice. Conclusion:The n-butyl alcohol extracts from Xiaoyaosan are equivalent to Xiaoyaosan in inhibiting expression. They alleviate the depression-like behavior in CUMS mice， induce the production of Nissl bodies in hippocampal CA3 region， enhance neuronal proliferation and differentiation in DG， and facilitate neurogenesis. All these may be related to the inhibition of over-activated IGF-1R<italic>β</italic>/PI3K/Akt pathway and the reduction of neuronal apoptosis.

An experimental study to evaluate the role of aspirin and metformin in prevention of depression in rats

Background: Depression was seen to be associated with an increased level of inflammatory biomarkers along with the disturbance in the monoamine neurotransmitter system. Current therapies are mostly focussed on the neurotransmitters imbalance but due to increasing cases of treatment failure there is a need to shift our treatment focus to other potential therapies. This study aimed to evaluate the preventive role of aspirin and metformin in stress induced model of depression in wistar rats.Methods: Fifty four wistar rats were randomly divided into nine groups as normal control, experimental control, aspirin (30 mg/kg, 60 mg/kg), metformin (50 mg/kg, 100 mg/kg), two combination groups and imipramine (15 mg/kg). Depression model was created by the induction of chronic unpredictable mild stress (CUMS) for consecutive 28 days. Behavioural assessment was done by evaluating immobility time in forced swim test (FST) and sucrose preference ratio (SPR) in sucrose preference test. The data were analysed by analysis of variance (ANOVA) test using SPSS software. P<0.05 was considered to be statistically significant.Results: The CUMS led to an increase in immobility time and decrease in SPR. Aspirin and Metformin alone and their combinations showed statistically significant response in preventing the immobility time to increase (p<0.001) and SPR to decrease (p<0.001). However the response of Aspirin was comparable with Imipramine but the response of Metformin was not as significant as of Imipramine (p>0.05).Conclusions: Aspirin and metformin might have a potential role in the prevention of depression.

Regulatory effect of polar extract of Poria cocos on neurotransmitter and circadian rhythm disorder in CUMS rats / 中草药

Objective: To explore the regulation of polar extract of Poria cocos on neurotransmitter and circadian rhythm metabolic pathway. Methods: Male SD rats were randomly divided into blank group, chronic unpredictable mild stress (CUMS) model group, positive drug venlafaxine hydrochloride group (35 mg/kg), and polar extract of P. cocos group (15 g/kg). Rats were modeled and ig administrated for 28 d simultaneously, and the body weight, sugar preference rate, and opening behavior were observed dynamically after administration. The levels of tryptophan (Trp), 5-hydroxytryptophan (5-HT), and 5-hydroxyindole acetic acid (5-HIAA), noradrenaline (NE), dopamine (DA), acetylcholiner (Ach), γ-aminobutyric acid (GABA), glutamic acid (Glu), the proportion of GABA/Glu in serum were measured by LC-MS. The expression of key genes in the circadian rhythm pathway in liver tissue was detected by using qRT-PCR. Results: Polar extracts of P. cocos significantly improved the abnormality of the sugar preference rate and opening behavior. And polar extracts of P. cocos significantly restored the levels of 5-HT, 5-HIAA, Trp, NE, Ach, GABA, the proportion of GABA/Glu in serum and regulated the gene expression levels of Arntl, Per1, Per2, Per3, and Nr1d1 in hepatocyte. Conclusion: The polar extract of P. cocos could improve neurotransmitters and circadian rhythm disorders in CUMS rats through enhancing the 5-HT metabolic pathway, regulating Ach-NE signaling interaction and the equilibrium of proportion of amino acids neurotransmitter and restoring the expression levels of Arntl, Per1, Per2, Per3, and Nr1d1 involved in the circadian rhythm.