Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P<0.01), and decreased expression of Iba1, IL-1β, and TNF-α(P<0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P<0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.
Rats ; Animals ; Depression/drug therapy* ; Brain-Derived Neurotrophic Factor ; Neuroprotective Agents ; Tumor Necrosis Factor-alpha/metabolism* ; Neuroinflammatory Diseases ; Diabetes Mellitus ; Receptors, Glutamate ; CX3C Chemokine Receptor 1/genetics*

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.
Animals ; Antidepressive Agents ; Depression/drug therapy* ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Neurotransmitter Agents ; Polysaccharides/pharmacology* ; Poria ; Rats

Adolescent ; Adult ; Aged ; Antidepressive Agents ; therapeutic use ; Body Mass Index ; Depression ; microbiology ; Diarrhea ; microbiology ; Duloxetine Hydrochloride ; therapeutic use ; Feces ; microbiology ; Humans ; Irritable Bowel Syndrome ; drug therapy ; microbiology ; Middle Aged ; Pilot Projects ; Probiotics ; therapeutic use ; RNA, Ribosomal, 16S ; genetics ; Young Adult

Sini Powder (SP), a traditional Chinese herbal formula, has long been used to treat depression in patients, although the underlying mechanisms remain to be elucidated. In the present study, we found that rats treated with SP extract for 7 days showed a significant increase in swimming time and reduction in immobility time in forced swimming test in a dose-dependent manner, without changes in locomotion. These effects could be attributed to SP's modulation of the hypothalamus-pituitary-adrenal axis, because a single pretreatment of SP extract could rescue increased serum corticosterone and plasma adrenocorticotropin levels induced by acute elevated platform stress. A single pretreatment of SP extract could also elevate the mRNA expression of hippocampal glucocorticoid receptors. In conclusion, our results suggest that SP extract may act as an anti-stress medication to produce antidepressant-like effects.
Adrenocorticotropic Hormone ; blood ; Animals ; Antidepressive Agents ; administration & dosage ; Corticosterone ; blood ; Depression ; drug therapy ; genetics ; metabolism ; physiopathology ; Drugs, Chinese Herbal ; administration & dosage ; Hippocampus ; drug effects ; Humans ; Male ; Pituitary-Adrenal System ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; genetics ; metabolism

In 2012, the preparation process and quality standard for Guizhi Fuling capsule were improved. To compare the effects and differences of capsules before (2011) and after(2012-2014) the improvement, evaluation models for intrinsic dysmenorrhea, pelvic inflammation and hysteromyoma were applied in rats. Models were induced by oxytocin, liqiud bacteria mixture and estrogen loading, respectively. The capsules (12 batchs/year, 48 bathcs in all), sampled randomly in 2011-2014, the effects were assessed using the three models. In anti-dysmenorrhea models, remarked reduction of writhing frequency, ET-1 and PGF2α content in uterus could be detected, as well as extension of writhing latency. In pelvic inflammation rats, depression of TNF-α and raise of IL-2 were induced by earh batch of capsules. In hysteromyoma model, uterine weight and smooth muscle proliferation, including E2 and P level in plasma, were lowered obviously by all batchs of capsules. Secondly, Guizhi Fuling capsules produced in 2012-2014 revealed better effectiveness than the ones manufactured in 2011. Moreover, pharmacodynamics indexes of the samples made in 2011 differed significantly between groups, which could not be observed in the ones ot 2012-2014. After tne preparation process and quality standard improvement, the effectiveness and homogeneity of Guizhi Fuling capsules were enhanced.
Animals ; Capsules ; administration & dosage ; chemistry ; standards ; Depression ; drug therapy ; genetics ; metabolism ; Dinoprost ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; standards ; Dysmenorrhea ; drug therapy ; genetics ; metabolism ; Female ; Humans ; Interleukin-2 ; genetics ; metabolism ; Pelvic Inflammatory Disease ; drug therapy ; genetics ; metabolism ; Quality Improvement ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

As regulating the function of the liver and spleen of the famous traditional formula, Sini San is widely used in the treatment of various diseases caused by liver depression and Qi stagnation, and its efficacy is significant clinically. Recently it is discovered that Sini San is effective in the treatment of nervous system diseases such as depression. Furthermore, there is a lot of literature about the effect of Sini San on the molecular mechanism of antidepressant. However, the anti-depression mechanism of Sini San is not very clear, in our present study, based on the auxiliary mechanism elucidation system for Chinese medicine and network pharmacology system to construct the chemical ingredients of the target interactions and disease-related protein of the interaction network. Results show that there are 263 chemical ingredients and 19 corresponding targets of depression in Sini San network. Sini San can anti-depressant effect through G-protein coupled receptor protein signaling pathway, cAMP system, neurological system process and neurotransmitter secretion, inflammatory response, neuroendocrine, metal ion transport and so on. These studies provided valuable clues for the mechanism and treatment of anti-depressant.
Animals ; Antidepressive Agents ; administration & dosage ; chemistry ; Databases, Factual ; Depression ; drug therapy ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Gene Regulatory Networks ; drug effects ; Humans ; Signal Transduction

OBJECTIVETo explore the effects and anti-depression mechanisms of Kaixin Jieyu Decoction (, KJD).

METHODSThe rat vascular depression (VD) model was established by ligation of bilateral common carotid arteries (LBCCA) combined with chronic unpredictable mild stress (CUMS). Forty Wistar rats were randomly divided into sham, VD model, VD + high-dose KJD [15.4 g/(kg·d) of crude drug], VD + medium-dose KJD [7.7 g/(kg·d) of crude drug], and VD + fluoxetine [2.4 mg/(kg·d)] groups (n=8 in each group), and the treatments lasted for 21 days. Changes of behavior and hippocampus pathology were observed. The level of glial fibrillary acidic protein (GFAP) protein and mRNA in hippocampus was detected respectively by immunohistochemistry and real-time polymerase chain reaction.

RESULTSCompared with the sham group, rats in model group showed a variety of behavioral obstacles, including a significant reduction in sucrose consumption percentage, horizontal and vertical activity scores in open-field tests (P<0.05 or P<0.01), pathological damage like neuronal degeneration, necrosis, and a significant decrease of GFAP protein and mRNA in hippocampus (P<0.01); compared with the model group, rats in the high-dose KJD group, medium-dose KJD group and fluoxetine group obtained notable higher behavioral scores, and pathological injury lessened in hippocampus with a increased expression of GFAP protein and mRNA P<0.05 or P<0.01); compared with the medium-dose KJD group and fluoxetine group, GFAP mRNA in high-dose KJD group expressed higer (P<0.05).

CONCLUSIONLBCCA combined with CUMS may cause depression-like behavioral changes resulting in the VD model of rats whose depression state can be ameliorated by KJD, and the mechanism of cerebral protection is related possibly with promoting expression of GFAP in hippocampus.

Animals ; Behavior, Animal ; Depression ; drug therapy ; genetics ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Electrophoresis, Agar Gel ; Glial Fibrillary Acidic Protein ; genetics ; metabolism ; Hippocampus ; drug effects ; metabolism ; pathology ; Immunohistochemistry ; Male ; RNA, Messenger ; genetics ; metabolism ; Rats, Wistar ; Transition Temperature

OBJECTIVETo explore the effects of Kaixin Powder (, KXP) on melatonin receptor (MR) expression and (125)I-Mel binding affinity in a depression rat model.

METHODSSeventy-two male Wistar rats were divided into six groups: a blank control group, model group, ramelteon group, KXP high-dosage group (HKXP), medium-dosage group (MKXP) and low-dosage group (LKXP). To establish the depression model, all groups except the blank control group were singly housed and exposed to chronic unpredictable mild stress. Weight gain, sucrose consumption and the open-field test were used to evaluate induction of depression. KXP at 260, 130 and 65 mg/(kg•d) was also respectively administered to the rats in the HKXP, MKXP and LKXP groups for 21 days. Ramelteon [0.83 mg/(kg•d)] was given to the positive drug control group. An equivalent volume of physiological saline was given to the blank and model groups. The liquid chip method was used to measure the concentration of plasma melatonin (MT). Mel1a (MT1) and Mel1b (MT2) expression levels were determined by Western blotting. In addition, a radioactive ligand-binding assay was used to analyze the specific binding properties and dynamic characteristics between MR and (125)I-Mel.

RESULTSThe results of weight gain, sucrose consumption and the open-field test showed that our model successfully produced depressive symptoms and depressive-like behavior. The concentration of plasma MT in the model group decreased significantly at night but increased in the MKXP group (P<0.05). The HKXP group showed significantly increased expression of MT1 (P<0.05); however, the expression of MT2 in all groups exhibited no significant differences (P>0.05). The maximum binding capacity (B(max)) for specific binding between MR and 125I-Mel in the MKXP group was significantly higher than that in the model group (P<0.05), but no significant differences were found in the equilibrium dissociation constant (K(d)) of each group (P>0.05).

CONCLUSIONSKXP may have a similar effect as ramelteon. KXP improved depressive-like behavior by increasing the concentration of plasma MT and MT1 expression, thereby increasing three B(max) of MR to achieve the desired antidepressant effect.

Animals ; Brain ; drug effects ; metabolism ; pathology ; Depression ; blood ; drug therapy ; metabolism ; Disease Models, Animal ; Drinking Behavior ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Gene Expression Regulation ; drug effects ; Indenes ; Iodine Radioisotopes ; Male ; Melatonin ; blood ; metabolism ; Rats, Wistar ; Receptors, Melatonin ; genetics ; metabolism ; Weight Gain ; drug effects

OBJECTIVETo assess the association of BDNF gene Val66Met polymorphism with efficacy of antidepressant treatment and plasma BDNF level.

METHODSTwo hundred and forty-nine ethnic Han Chinese patients with depression(study group), who have met the diagnostic criteria of DSM-IV, were prescribed with venlafaxine or paroxetine. Two hundred and two healthy individuals were recruited as the control group. General demographic information such as gender, age, educational status, occupation, and marriage status were collected. HAMD-17 was adopted as the primary rating tool to evaluate the severity of depression on the baseline and at the end of 1st, 2nd, 4th, 6th week of treatment. PCR-restriction fragment length polymorphism was applied to determine the Val66Met polymorphism of the BDNF gene in the two groups. Plasma BDNF concentration was measured with ELISA before and after 6 weeks of treatment.

RESULTSNo significant differences have been found in HAMD scores and reduction of HAMD scores on the baseline and at the end of 1 st, 2nd, 4th, 6th weeks of treatment for each genotype. Nor were significant differences found in the Val66Met genotypes and allelic frequency between patients who achieved remission or not after 6 weeks' treatment as well as the healthy volunteers. The plasma BDNF level in depression patients was lower than that in healthy controls. The BDNF level has increased significantly after 6 weeks' treatment with both venlafaxine and paroxetine, but was still lower than the healthy controls. The BDNF level in the patients achieved remission who were treated with venlafaxine was similar to the normal controls, while those treated with paroxetine was still lower than normal controls. The BDNF level in patients who have not achieved remission was lower than normal controls. The BDNF level was not associated with the Val66Met polymorphism on the baseline and the end of 6th week.

CONCLUSIONNo association has been found between the efficacy of venlafaxine or paroxetine and the BDNF Val66Met polymorphism. The BDNF level of patients with depression is significantly lower than healthy controls on the baseline, and can be enhanced with the treatment. Particularly, the BDNF level in patients who achieved remission after the treatment of venlafaxine can rise to normal. The level of BDNF has certain value in the forecasting of efficacy in the anti-depression therapy. BDNF level is not associated with the Val66Met polymorphism of the BDNF gene.

Adolescent ; Adult ; Aged ; Antidepressive Agents ; therapeutic use ; Brain-Derived Neurotrophic Factor ; blood ; genetics ; Depression ; blood ; drug therapy ; genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic

OBJECTIVETo observe the effects of Mongolian pharmaceutical Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats.

METHODSixty male Wistar rats were randomly divided into six groups according to the sugar consumption test (10 rats in each group), normal control group,model group,fluoxetine group (3.3 mg x kg(-1)) and low dose, medium dose and high dose group (0.25, 0.5, 1 g x kg(-1)) of Betel shisanwei ingredients pill. Except the normal control,the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely raising for 28 days. 10 mL x kg(-1) of drugs were given to each rat once daily,continuously for 28 days. The AC activity of the hippocampus and prefrontal cortex were determined by radiation immunity analysis (RIA), while cAMP and PKA quantity were determinated by Enzyme-linked immunosorbent (ELISA).

RESULTThe AC activity, cAMP and PKA quantity of hippocampus and prefrontal of mouse model of Chronic stress depression decreased significantly than those of control group (P < 0.05 or P < 0.01). However, the AC activity, cAMP and PKA quantity of rat hippocampus and prefrontal cortex in the fluoxetine group and the Mongolian pharmaceutical Betel shisanwei ingredients pill group indecreased significantly than those of model group (P < 0.01 or P < 0.05). Especially for the high dose group of Mongolian pharmaceutical Betel shisanwei ingredients pill.

CONCLUSIONThe AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depression model of rats is down-regulated, whereas Mongolian pharmaceutical Betel shisanwei ingredients pill could up-regulated it to resist depression.

Adenylyl Cyclases ; genetics ; metabolism ; Animals ; Cyclic AMP ; metabolism ; Cyclic AMP-Dependent Protein Kinases ; genetics ; metabolism ; Depression ; drug therapy ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Hippocampus ; drug effects ; metabolism ; Humans ; Male ; Mice ; Prefrontal Cortex ; drug effects ; metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; drug effects