CN109602884A - A kind of application of the Chinese medicine composition in adjusting Immune inflammatory reaction for treating depression - Google Patents
A kind of application of the Chinese medicine composition in adjusting Immune inflammatory reaction for treating depression Download PDFInfo
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Abstract
The present invention relates to pharmaceutical technology fields, more particularly to a kind of Chinese medicine composition for treating depression in the application adjusted in Immune inflammatory reaction, described includes Radix Curcumae, semen ziziphi spinosae, American Ginseng, the Chinese medicine composition of the treatment depression of Schisandra chinensis is to the Intervention Mechanism and application for adjusting Immune inflammatory reaction, it is intervening the rat body weight reduction induced chronic restricted stress, syrup preference function reduces, TLR4 in chronic restricted stress induction hippocampus has significantly been reversed under the reverse effects such as horizontal movement scoring and vertical movement scoring decline, MyD88 protein upregulation expression, the immunoinflammatory activation that identification receptor TLR4 signal path in mode mediates is adjusted extensively simultaneously.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of Chinese medicine composition for treating depression is exempted from adjusting
Application in epidemic disease inflammatory reaction.
Background technique
Depression (Depression) belongs to affective disorders, seriously affects people's lives quality, psychology and society
Meeting function, is a kind of common disease of psychiatric department, the complicated affective disorders including a variety of mental symptoms and somatization,
Clinical manifestation in addition to having the excessively low mental symptom of low mental state, hebetude, retardation of thinking, self-assessment, further include body not
Just as fatigue, insomnia, loss of appetite, sexual hypoesthesia, headache, dizziness, thirsty, pharyngeal discomfort, uncomfortable in chest, nervous, stomachache, abdominal distension etc.
Can have Deng, serious person from fear sense or even introgression.With the progress of society and economic development, the aggravation of social competition,
The accelerating rhythm of life, the sharply transition of social status, depression have become the common disease of modern society, high morbidity, morbidity
Rate quickly rises.The World Health Organization predicts 2020, and it is the most serious that depressive disorder will become developing country
Disease Spectrum, severe depression can become the dead and disabled second largest reason at that time.
The origin cause of formation of depression be it is complicated, by several factors interaction generate as a result, it mainly includes life cycle
Border factor, genetic factor etc..Obtained by our company many years experiment and research stress be depression important risk factor, it is right
In the mechanism of action of stress reaction have also been made it is deep probe into, wherein Immune inflammatory reaction be connect stress-induced depression weight
Want approach.In the therapeutic process of depression, used antidepressants and alleviation treatment means are also unable to satisfy practice at present
Demand, using being subject to certain restrictions.On the one hand, complicated component used in existing antidepressants is easy to generate row with human body
Reprimand reaction, there are serious side effects, the clinical onset of action time is long；On the other hand, existing antidepressants are for a part of depressive patient
Without the effect initiated to treatment radical cure, and there is after cutting out antidepressants recurrence symptom repeatedly in many depressive patients
Situation.
In conjunction with the patent of invention patent No. ZL03153104.0 of our company, a kind of Chinese medicine composition of depression of patent name
And preparation method thereof disclosed in a kind of think Ji medicine company in developer Guangdong for treating the Chinese medicine composition of depression and persistently exert
Under power, completed new Chinese medicine research and development critical stage, and it is described it is a kind of for treat the Chinese medicine composition of depression with
" ginseng taste is strongly fragrant peaceful " title carries out Clinical Trials, hereinafter referred to as " ginseng taste is strongly fragrant peaceful ", and experiment is adjusted from multi-angle experiment stress
The mechanism for inducing depression, finds potential antidepression target spot, sets out from the root a kind of for treating the Chinese traditional medicine composition of depression
Object-ginseng taste peaceful strongly fragrant in the clinical effective way for adjusting Immune inflammatory reaction and the main effect obtained in Effective target site experimental study
Mechanism and application are answered, prominent achievement is obtained.
Summary of the invention
The Chinese medicine composition that it is an object of that present invention to provide a kind of for treating depression is in adjusting Immune inflammatory reaction
Application.It is a kind of for treating antidepressants made of the Chinese medicine composition of depression disclosed in patent No. ZL03153104.0
It is curative for effect in the clinical treatment of depression.
The present invention is a kind of application of the Chinese medicine composition in adjusting Immune inflammatory reaction for treating depression, special
Sign is: it is described comprising Radix Curcumae, semen ziziphi spinosae, American Ginseng, Schisandra chinensis treatment depression Chinese medicine composition it is immune scorching to adjusting
Property reaction application.
Further, the Chinese medicine composition for testing the treatment depression is adjusting the chronic constriction in Immune inflammatory reaction
The application of stress rats behavior depression.
Further, the Chinese medicine composition for testing the treatment depression is adjusting pair in Immune inflammatory reaction
CRS rat hippocampus Activated Microglia mediates, the application of inflammatory reaction and Apoptosis.
Further, the Chinese medicine composition for testing the treatment depression is adjusting the reverse in Immune inflammatory reaction
The application of TLR4 signal path mediated immunity and the antidepressant effects of inflammatory reaction activation.
Further, a kind of Chinese medicine composition for treating depression, the parts by weight of contained Radix Curcumae are 600-
1200, the parts by weight of semen ziziphi spinosae are 600-1200, the parts by weight of American Ginseng are 100-600, the parts by weight of Schisandra chinensis are 400-
1000。
The present invention mainly includes following three research experiment parts in the application for adjusting Immune inflammatory reaction:
Research one: the influence to chronic restricted stress rat behavior depression is intervened in experiment " ginseng taste is strongly fragrant peaceful "；
Research two: immune and inflammatory reaction that experiment " ginseng taste peaceful strongly fragrant " mediates CRS rat hippocampus Activated Microglia and
The influence of Apoptosis:
Research three: " ginseng taste is strongly fragrant peaceful " anti-suppression in the immune and inflammatory reaction activation mediated based on TLR4 signal path is tested
Strongly fragrant Mechanism Study:
" ginseng taste is strongly fragrant peaceful " has significant antidepression/anxiety effect, finds in clinical experimental stage, and " ginseng taste is strongly fragrant peaceful " is to anxiety
Disease patient's Hamilton depression deduction rate has effect." ginseng taste is strongly fragrant peaceful " intervenes and has significantly reversed chronic restricted stress induction
TLR4, MyD88 protein upregulation expression in hippocampus, " ginseng taste is strongly fragrant peaceful " intervenes the rat induced chronic restricted stress simultaneously
The basic reason for the reverse effects such as weight loss, syrup preference function reduce, horizontal movement is scored and vertical movement scoring declines
Place.Immune inflammatory reaction is the important channel for connecting stress-induced depression, to identification receptor TLR4 signal path in mode
It is the core place that " ginseng taste is strongly fragrant peaceful " plays antidepressant effects that the immunoinflammatory activation of mediation, which carries out extensive adjusting,.
Using advantage and gain effect: currently, the treatment of depression is mainly based on antidepressant therapy, although in mistake
Three gone during the decade, there is nearly that 40 kinds of antidepressants emerge, and still, clinic still has nearly 30% patient for any anti-
Depressed drug all shows unresponsive, and part patients with depression has to change therapeutic modality because side effect is obvious, or
Person suspends treatment.Meanwhile the patient that do not fully recover remains anxiety, insomnia and somatization etc. mostly, these increase the recurrence of depression
Risk.In addition, " target spot " of the anti depressant therapy drug on mechanism of action and approach and depressive illness feature feature are extensive
Property contradiction gradually attracts attention.As it can be seen that seeking more effective or urgently being solved in the new strategy of early stage synergy antidepressants curative effect
Certainly.
The Chinese medicine composition that it is an object of that present invention to provide a kind of for treating depression is in adjusting Immune inflammatory reaction
Application.It is a kind of for treating antidepressants made of the Chinese medicine composition of depression disclosed in patent No. ZL03153104.0
It is curative for effect in the clinical treatment of depression.It is characterized by: described control comprising Radix Curcumae, semen ziziphi spinosae, American Ginseng, Schisandra chinensis
The Chinese medicine composition for treating depression has definite curative effect to Immune inflammatory reaction is adjusted, and finds to identification receptor TLR4 in mode
The immunoinflammatory activation that signal path mediates can play best antidepressant effects.The experimental study that gos deep into of the invention will be to seek
More effectively or in the new strategy research of early stage synergy antidepressants curative effect it is of great significance.
Detailed description of the invention
Fig. 1 is that each group rat different time points changes of weight compares；Fig. 2 is each group rat different time points syrup preference
Index compares；
Fig. 3 is that each group rat different time points horizontal movement scoring is compared；
Fig. 4 is that the vertical movement scoring of each group rat different time points is compared；
Fig. 5 is each group rat hippocampal CA 3 Activated Microglia situation；
Fig. 6 is each group rat hippocampal CA 3 Activation of Astrocytes situation；
Fig. 7 is each group rat hippocampal CA 3 Neuron Apoptosis situation；
Fig. 8 is each group rat blood serum inflammatory factor IL-1 β expression variation；
Fig. 9 is each group rat blood serum inflammatory factor IL-10 expression variation；
Figure 10 is group rat blood serum inflammatory factor TNF-α expression variation；
Figure 11 is that each group rat hippocampus TLR4 protein expression level compares；
Figure 12 is that each group rat hippocampus MyD88 protein expression level compares；
Figure 13 is that each group rat hippocampus TNF-α protein expression level compares.
Specific embodiment
In order to enable juror to be further understood that the purpose, feature and function of the present invention, below below it is dynamic
Object experiment is but to be not meant to any limitation of the invention to further description of the invention:
The invention mainly comprises following three research experiment parts:
Research one: the influence to chronic restricted stress rat behavior depression is intervened in experiment " ginseng taste is strongly fragrant peaceful ":
Depression rat model is simulated using chronic restricted stress, by being grouped and setting up different time points animal behavioral study, is inquired into
" ginseng taste is strongly fragrant peaceful " intervenes the influence to CRS rat model behavior depression.
Conclusion: " ginseng taste peaceful strongly fragrant ", which intervenes, to be improved rat and grows naturally and overall condition, and enhancing Organism of Rats is to syrup
The sensibility of award mitigates anhedonia degree, restores rat spontaneous activity and exploratory behaviour." ginseng taste is strongly fragrant peaceful " intervenes performance
Apparent antidepressant effects out.
Research two: it is strongly fragrant peaceful that " experiment " joins taste " it is anti-to the immune of CRS rat hippocampus Activated Microglia mediation, inflammatory
It should be with the influence of Apoptosis:
Observe stress-induced hippocampus Activated Microglia situation, serum inflammatory factors of senile IL-1 β, IL-10 and TNF-α expression variation
And apoptosis of hippocampus neurons situation, it probes into " ginseng taste is strongly fragrant peaceful " and intervenes the inflammation mediated to CRS rat hippocampus Activated Microglia
Property reaction and Apoptosis influence.
Conclusion: " ginseng taste is strongly fragrant peaceful " is its performance by reversing the apoptosis of hippocampus neurons of lasting chronic restricted stress induction
The important function approach of antidepressant effects.
Research three: " ginseng taste is strongly fragrant peaceful " in the immune and inflammatory reaction activation mediated based on TLR4 signal path is tested
Antidepression Mechanism Study:
Intervene the influence to CRS rat model behavior depression and apoptosis of hippocampus neurons based on " ginseng taste is strongly fragrant peaceful ", further
The immune and inflammatory reaction activated pathway mediated from TLR4 signal path probes into " ginseng taste is strongly fragrant peaceful " antidepression mechanism and clinical effect
It answers.
Influence of the experiment one " ginseng taste is strongly fragrant peaceful (peaceful strongly fragrant Special-shaped sheet) " to CRS rat behavior depression:
This research is based on early-stage study basis, combines lonely feeding stimulation simulation depression rat model using chronic restricted stress, passes through
Different time points are grouped and are set up, are tested using changes of weight, syrup experiment, spacious field experiment, the variation of observation each group rat body weight,
The variation of syrup preference function, flat motion scores, vertical movement scoring variation, discussion " ginseng taste is strongly fragrant peaceful " are intervened big to CRS model
The influence of mouse behavior depression.
1 experimental material
1.1 experimental animal
SPF grades of male SD are included in this research) strain rats, 6 week old.Experimental animal is by dimension company, the tonneau China experimental animal of Beijing
The heart provides [credit number: SCXK (capital) 2012-0001].All operating process of zoopery are cleaned in Beijing University of Chinese Medicine
Grade Animal Lab. carries out, this batch animal welfare lot number: No. Kj-dw-18-20151111.In experimentation, rat is free
It ingests drinking-water, day alternates with night in light control laboratory, and 18-26 DEG C of room temperature, humidity (55 ± 2) %.
1.2 experimental drugs and reagent
Sucrose: 500g/ bottles, Sigma-Aldrich company；
Escitalopram oxalate piece: Xian-Janssen Pharmaceutical Ltd.'s packing；
It is strongly fragrant peaceful to join taste: thinking Ji medicine company in Guangdong.
1.3 laboratory apparatus and equipment
Spacious field experimental box (self-control): cube opens case 80 cm × 80 cm of cm × 40, and spacious field bottom portion is divided into 16 with white line
25 pieces of squares of the cm of cm × 16, area equation；
Chronic restricted stress device (self-control): both ends are made by smooth, soft wire netting (0.19 mm of string diameter, 1.2 mm of mesh)
Open circles column type net cylinder (long 20.5 cm, 6.5 cm of diameter)；
Stainless steel clip: 64 mm/ long, Shanghai M & G Stationery Inc..
2 experimental methods
2.1 experimental groups and interference method
The consistent rat of behaviouristics baseline is divided using table of random number (random digit is generated by SPSS22.0 statistics software)
For normal group, model group, escitalopram group and " ginseng taste peaceful strongly fragrant " group, every group 11, totally 44.
Normal group is normal rat, and 5/cage group rearing freely ingests, drinks water, and continues 21 days；Model group rats are using chronic
Restraint Stress combines lonely support to simulate depression model, continues 21 days.Escitalopram group rat is received daily 1 before Restraint Stress
Hour receives 3mg/kgd escitalopram oxalate stomach-filling intervention successively, continues 21 days；" ginseng taste is strongly fragrant peaceful " group rat day connects
Receive within 1 hour 18mg/kgd " ginseng taste is strongly fragrant peaceful " stomach-filling intervention successively before receiving Restraint Stress, continues 21 days.
The preparation of 2.2 models
This research uses internationally recognized chronic restricted stress (CRS) method, establishes lonely support and combines chronic restricted stress depression big
Mouse model[1-5].Specific modeling method: daily am9:00-pm3:00 fetters rat using homemade chronic restricted stress device
It is tied up in net cylinder 6 hours in self-control soft iron tow, to rat, whole body is all placed in net cylinder end to end, grips net cylinder two with agrafe
End (movement must be soft when operation, avoids injuring rat), is then horizontally placed in former mouse cage.Rat is kept to exhale during constraint
Unobstructed, continuous constraint 21 days is inhaled, it is fasting for solids and liquids during constraint, after constraint, rat is put back in mouse cage, freely ingests, take the photograph
Water.
The selection and medication of 2.3 positive control drugs
This research compares " ginseng taste is strongly fragrant peaceful " antidepressant effects as positive control drug using escitalopram.To prescription
Method: escitalopram tablet is crushed into powder shape, then by escitalopram physiological saline wiring solution-forming 30mg/
100ml suspension, daily CRS stress before 1h with the escitalopram oxalate suspension oral gavage of 3mg/kgd, one time a day,
Continue 21 days.
2.4 " ginseng taste is strongly fragrant peaceful " medications
It is Chinese patent drug dispersible tablet that drug " ginseng taste is strongly fragrant peaceful " is mainly intervened in this research, thinks Ji medicine company by Guangdong and provides.Pass through early period
Research confirms that " ginseng taste is strongly fragrant peaceful " has significant antidepressant effects, finds in clinical experimental stage, and " ginseng taste is strongly fragrant peaceful " is to depression
Disease patient's Hamilton depression deduction rate has effect.This part with escitalopram oxalate using comparing, and " ginseng taste is peaceful for observation
Strongly fragrant " antidepressant effects.
Medication: it is converted according to adult dosage and rat medication metering, 6.3 × 3mg/ of rat dosage concentration
kg·d≈18mg/kg·d." ginseng taste peaceful strongly fragrant " tablet is crushed into powder shape, then matches " ginseng taste is strongly fragrant peaceful " with physiological saline
At solution 30mg/100ml suspension, daily CRS stress before 1h with the escitalopram oxalate suspension of 18mg/kgd
Stomach-filling continues 21 days one time a day.
2.5 animal behavioral study
2.5.1 weight (Body weight) monitors
Start first 1 day (0 day) respectively at experiment and the 21st day (21 days) carries out measured body weight to rat, when more different
Between point each group rat body weight variation.
2.5.2 syrup preference experiment (Sucrose preference test)
Before experiment starts, all rats of training adapt it to drink water containing 1% sucrose.Not in experiment start first 1 day (0 day) and
Progress syrup experiment in 21st day (21 days).Then the syrup preference function of rat is calculated.Syrup preference function=(syrup disappears
Consumption/total liquid-consumed) × 100%, divide the difference of comparative analysis each group rat syrup preference function in different time points.
2.5.3 spacious field experiment (Open field test)
Spacious field experiment ensures indoor sound insulation and state of keeping quite before starting.Rat is placed in the center of spacious field experimental box bottom surface
It entreats in grid, then exploratory behavior, motion frequency and motion conditions of the start recording rat in 3 min.With the double hind legs of rat
The square block number for passing through spacious field bottom face is that level passes through lattice number (four paws, which enters grid, to be counted, and rat is scored at
It is that horizontal movement is scored 1 point that level, which passes through frame counter,；The upright number that spacious field bottom face is left with double forelimbs is to stand vertically number,
Two fore paw of rat empties or seeks connections with spacious case side wall, be scored at stand vertically number be calculated as vertical movement scoring 1 point.Respectively at experiment
Start first 1 day (0 day) and tested for the 21st day (21 days), spacious field is real in different time points for comparative analysis each group rat
The level of test examination passes through lattice number and stands vertically the difference of number.
2.6 statistical analysis
Experimental data is counted using SPSS22.0, experimental result with average value ± standard error () indicate.No
The variance analysis of two factor duplicate measurements is used with the comparison of group behaviouristics data in different time points: if data meet spherical shape
It examines, organizes interior relatively using unary variance analysis；If data are unsatisfactory for sphericity test, organize interior relatively using multivariate analysis of variance；
Comparison among groups use unary variance analysis.P < 0.01 is that statistical significance has conspicuousness.
3 results
3.1 different groups changes of weight in different time points
Different intervention factors are monitored by different time points changes of weight to grow animal naturally and the influence of overall condition.By table
1, Fig. 1 is as it can be seen that before experiment (0 day), and each group rat body weight baseline level is with uniformity, each class mean no statistical difference
Meaning.With time change, the weight of each group rat in different time points has statistical significance because of different intervention factor differences
With otherness.Compared with normal group, model group rats start bright after receiving chronic restricted stress and combining lonely feeding stimulation 21 days
Aobvious to reduce, weight mean value is significantly lower than normal group of (P < 0.01 in 21 days；Compared with model group, the peaceful strongly fragrant group body of ginseng taste
Weight-average value is apparently higher than model group (P < 0.01 in 21 days；Escitalopram group weight mean value is apparently higher than in 21 days
Model group (P < 0.01.It is worth noting that, " ginseng taste is strongly fragrant peaceful " group weight mean value is substantially better than in 21 days (in normal model
In enclosing) escitalopram group (P < 0.01).
1. each group rat different time points changes of weight of table compares (n=11；；g)
| Group | 0 day | 21 days |
| Normal group | 220.091±0.782 | 425.027±10.589 |
| Model group | 221.582±6.143 | 373.682±8.284★★ |
| Escitalopram group | 220.245±1.951 | 402.364±8.378▲▲ |
| Join the peaceful strongly fragrant group of taste | 220.162±0.763 | 412.035±7.613▲▲;■■ |
Note: one-way analysis of variance: F=261.352, P=0.000.Compared with normal group,★★P < 0.01；With model group ratio
Compared with,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
Fig. 1 each group rat different time points changes of weight compares, note: compared with normal group,★★P < 0.01；With model group
Compare,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
The variation of 3.2 each group rat different time points syrup preference functions
Core behavior depression using syrup preference function as rat model monitors different time points difference intervention factor pair
The influence of dynamic anhedonia degree.By table 2, Fig. 2 as it can be seen that before experiment (0 day), each group rat syrup preference function baseline water
Put down with uniformity, each class mean no significant difference.With time change, syrup preference of each group rat at the 21st day
Index because different intervention factor differences with statistical significance have otherness.Compared with normal group, model group rats are receiving
Chronic restricted stress combines lonely syrup preference function after supporting stimulation 21 days to start to be decreased obviously, and syrup preference function mean value is 21
Day is obviously consistently less than normal group (P < 0.01)；Compared with model group, " ginseng taste is strongly fragrant peaceful " intervenes to be started to make at the 21st day
There is unkehr effect in it, and syrup preference function mean value is apparently higher than model group (P < 0.01) in 21 days；Escitalopram is general
Orchid group syrup preference function mean value is apparently higher than model group (P < 0.01) in 21 days.
2. each group rat different time points syrup preference function of table compares (n=11；；%)
| Group | 0 day | 21 days |
| Normal group | 74.012±1.744 | 70.341±3.405 |
| Model group | 74.056±4.190 | 35.320±6.084★★ |
| Escitalopram group | 73.897±2.352 | 69.699±3.573▲▲ |
| Join the peaceful strongly fragrant group of taste | 74.096±1.876 | 69.801±4.137▲▲ |
Note: one-way analysis of variance: F=278.280, P=0.000.Compared with normal group,★★P < 0.01；Compared with model group
,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
Fig. 2 each group rat different time points syrup preference function compares, note: compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
Autonomic activities and the exploratory behaviour variation in different time points of 3.3 different groups
3.3.1 each group rat different time points horizontal movement scoring variation
Observation different time points difference intervention factor is scored to rat using the horizontal movement scoring and vertical movement of spacious field experiment
Spontaneous activity and exploratory behaviour influence.By table 3, Fig. 3 as it can be seen that before experiment (0 day), each group rat horizontal movement scoring
Baseline level is with uniformity, each class mean no significant difference.With time change, each group rat is in different time points
Horizontal movement scoring have statistical significance with otherness because of different intervention factor differences.Compared with normal group, model group
Rat horizontal movement after receiving chronic restricted stress and combining lonely support stimulation 21 days, which is scored, is obviously consistently less than normal group of (P <
0.01), spontaneous activity and exploratory behavior are obviously suppressed；Compared with model group, " ginseng taste rather strongly fragrant " intervene after the 21st day
It is apparently higher than model group (P < 0.01)；Escitalopram group horizontal movement scoring mean value is apparently higher than model group in 21 days
(P < 0.01).
(n=11 are compared in 3. each group rat different time points horizontal movement of table scoring；)
| Group | 0 day | 21 days |
| Normal group | 42.455±2.464 | 39.909±1.921 |
| Model group | 42.545±3.174 | 5.091±1.044★★ |
| Escitalopram group | 42.636±6.281 | 38.273±1.679▲▲ |
| Join the peaceful strongly fragrant group of taste | 41.964±1.694 | 39.216±1.525▲▲ |
Note: one-way analysis of variance: F=103.168, P=0.000.Compared with normal group,★★P < 0.01；With model group ratio
Compared with,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
Fig. 3 each group rat different time points horizontal movement scoring is compared, note: compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
3.3.2 each group rat different time points vertical movement scoring variation
Observation different time points difference intervention factor is scored to rat using the horizontal movement scoring and vertical movement of spacious field experiment
Spontaneous activity and exploratory behaviour influence.By table 4, Fig. 4 as it can be seen that before experiment (0 day), the vertical movement scoring of each group rat
Baseline level is with uniformity, each class mean no significant difference.Compared with normal group, model group rats are chronic in receiving
Restraint Stress combines lonely vertical movement scoring after supporting stimulation 21 days to be obviously consistently less than normal group (P < 0.01), spontaneous activity and
Exploratory behavior is obviously suppressed；Compared with model group, escitalopram and " ginseng taste is strongly fragrant peaceful " intervention are equal in the 21st days
It is apparently higher than model group (P < 0.01；P < 0.01).
(n=11 are compared in the vertical movement scoring of 4. each group rat different time points of table；)
| Group | 0 day | 21 days |
| Normal group | 13.455±1.293 | 10.909±1.375 |
| Model group | 11.818±2.183 | 2.455±1.036★★ |
| Escitalopram group | 13.364±1.690 | 8.364±1.433▲▲ |
| Join the peaceful strongly fragrant group of taste | 12.963±2.147 | 7.645±1.331▲▲ |
Note: one-way analysis of variance: F=106.609, P=0.000.Compared with normal group,★★P < 0.01；Compared with model group
,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
The vertical movement scoring of Fig. 4 each group rat different time points is compared, note: compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.01.
4 discuss and analyze
The display of this result of study, as time goes by stress load increase, chronic restricted stress is as the inducible rat of stressor
It shows a series of behavior depressions: being significantly reduced including weight；Syrup preference function significantly reduces, and Organism of Rats encourages syrup
The sensibility of reward reduces horizontal movement scoring and vertical movement scoring is remarkably decreased, the spontaneous activity and exploratory behaviour of rat by
Influence interference.And the rat body weight drop that " ginseng taste is strongly fragrant peaceful " and antidepressants intervention have effectively reversed chronic restricted stress to induce
Low, syrup consumption and syrup preference function reduce, horizontal movement is scored and vertical movement scoring decline, and it is naturally raw to improve rat
Long and overall condition enhances sensibility, mitigation anhedonia degree that Organism of Rats awards syrup, restores rat spontaneous activity
And exploratory behaviour, " ginseng taste is strongly fragrant peaceful " and antidepressants intervention show apparent antidepressant effects.
Weight (Body weight) reflects the trophic level of body to a certain extent, and studies have shown that rat is in depression
Gastrointestinal function is weaker under state, and food ration reduction causes weight to decline, and is that the ratio of evaluation animal models of depression is more objective
One of index.Having studies have shown that chronic restricted stress to can induce rat table weight as stressor significantly reduces, and " ginseng taste is peaceful
Strongly fragrant " and antidepressants intervention effectively reversed chronic restricted stress induce rat body weight reduce.Anhedonia refers to fast
Happy experience ability lacks and pursues the missing of award activity motivation, it can be used as prediction endogenous depression prognosis and anti-suppression
The core feature of strongly fragrant therapeutic evaluation, the award such as it and award assessment, expectation, decision and motivation working process process are closely related.
Syrup experiment is the core index that depression model anhedonia degree is evaluated based on reward system.Result of study shows, slowly
Property Restraint Stress combine lonely stimulation guidance model group rat syrup preference function of supporting to significantly reduce, Organism of Rats awards syrup
Sensibility reduces, and then anhedonia degree aggravates.Importantly, " ginseng taste is strongly fragrant peaceful " intervenes and effectively chronic constriction has been reversed to answer
Swash induction rat syrup consumption and syrup preference function reduce, enhancing Organism of Rats syrup award sensibility, mitigate fastly
Feel deficiency extent.It can be seen that " ginseng taste is strongly fragrant peaceful ", which intervenes, shows apparent antidepressant effects.Spacious field experiment is that evaluation rodent is dynamic
The common method of object spontaneous activity and anxiety state behavior mainly reflects spontaneous activity, the moving situation of rodent with it
And exploratory behaviour.In this experiment, it is scored by the horizontal movement tested to each group rat spacious field and vertical movement is scored to see
Examine spontaneous activity, moving situation and the exploratory behaviour of rat.
In conclusion this part result of study is shown, chronic restricted stress can induce rat and a series of depressed sample occurs
Behavior is mainly shown as that weight significantly reduces；Syrup preference function significantly reduces, and the sensibility that syrup is awarded drops in Organism of Rats
It is low, and then anhedonia degree aggravates；Horizontal movement scoring and vertical movement scoring are remarkably decreased." ginseng taste is strongly fragrant peaceful ", which intervenes, to be changed
It has been apt to rat to grow naturally and overall condition, sensibility that enhancing Organism of Rats award syrup, mitigation anhedonia degree are extensive
Multiple rat spontaneous activity and exploratory behaviour." ginseng taste is strongly fragrant peaceful ", which intervenes, shows apparent antidepressant effects.Its latent effect machine
System is the subsequent main research of this research.
Experiment two " ginseng taste is strongly fragrant peaceful " is to the immune of CRS rat hippocampus Glial Activation mediation, inflammatory reaction and cell
The influence of apoptosis
In recent years, more and more evidences show that immune/inflammatory reaction of stress-induced is played the part of in depression Pathological Physiology
Potential role.By this process and tool of stress-induced body maincenter and periphery immune system activation, inflammatory reaction enhancing
Body mechanism gradually attracts people's attention.Studies have shown that stress be mainly living by induction microglia and astroglia
Change mediating inflammatory cell factor largely to discharge, lead to apoptosis of hippocampus neurons, to influence to adjust reward system, study and note
Recall, the neural circuitries such as fear, and then participates in the pathologic process of depression.The prompt of one result of this experiment, " ginseng taste is strongly fragrant peaceful " are intervened
Have to the behavior depression of CRS depression rat model and significantly improves effect.But its specific mechanism needs to be explored.Therefore, it originally grinds
Study carefully based on experiment one, observes stress-induced hippocampus microglia and Activation of Astrocytes situation, serum inflammatory factors of senile IL-
1 β, IL-10 and TNF-α expression variation and apoptosis of hippocampus neurons situation are probed into " ginseng taste is strongly fragrant peaceful " and are intervened to CRS rat hippocampus
The influence of inflammatory reaction and Apoptosis that Activated Microglia mediates.
1 experimental material
1.1 experimental animal
SPF grades of male SD are included in this research) strain rats, 6 week old.Experimental animal is by dimension company, the tonneau China experimental animal of Beijing
The heart provides [credit number: SCXK (capital) 2012-0001].All operating process of zoopery are cleaned in Beijing University of Chinese Medicine
Grade Animal Lab. carries out, this batch animal welfare lot number: No. Kj-dw-18-20151111.In experimentation, rat is free
It ingests drinking-water, day alternates with night in light control laboratory, and 18-26 DEG C of room temperature, humidity (55 ± 2) %.
1.2 experimental drugs and reagent
Rat IL-1 β ELISA kit (96T): article No. E02I0010, lot number Lot#:20180112, blue base biology are limited
Company；Rat IL-10 ELISA kit (96T): article No. E02I0023, lot number Lot#:20180112, blue base biology have
Limit company；Rat TNF-α ELISA kit (96T): article No. E02T0008, lot number Lot#:20180112, blue base biology have
Limit company；Rabbit-anti IBA-1 antibody: number ab107159, Abcam company；Rabbit-anti GFAP antibody: Abcam company；Rat TUNEL
Apoptosis kit, blue base biology Co., Ltd.
1.3 laboratory apparatus and equipment
High speed freezing centrifuge: model Beckman Allgre 21R, Beckman company；Oscillator: Kylin-Bell Lab
Instruments；Full-automatic microplate reader: Thermo company；PH measuring instrument: Sartotius company.
2 experimental methods
2.1 experimental group
2.1 experimental groups and interference method
The consistent rat of behaviouristics baseline is divided using table of random number (random digit is generated by SPSS_22.0 statistics software)
For normal group, model group, escitalopram group and " ginseng taste peaceful strongly fragrant " group, every group 11, totally 44.
Normal group is normal rat, and 5/cage group rearing freely ingests, drinks water, and continues 21 days；Model group rats are using chronic
Restraint Stress combines lonely support to simulate depression model, continues 21 days.Escitalopram group rat is received daily 1 before Restraint Stress
Hour receives 3mg/kgd escitalopram oxalate stomach-filling intervention successively, continues 21 days；" ginseng taste is strongly fragrant peaceful " group rat day connects
Receive within 1 hour 18mg/kgd " ginseng taste is strongly fragrant peaceful " stomach-filling intervention successively before receiving Restraint Stress, continues 21 days.
The preparation of 2.2 models
This research uses internationally recognized chronic restricted stress (CRS) method, establishes lonely support and combines chronic restricted stress depression big
Mouse model.Specific modeling method: rat is bound by certainly by daily am9:00-pm3:00 using homemade chronic restricted stress device
Soft iron tow processed is tied up in net cylinder 6 hours, and to rat, whole body is all placed in net cylinder end to end, grips net cylinder both ends with agrafe
(movement must be soft when operation, avoids injuring rat), is then horizontally placed in former mouse cage.Rats breathing is kept during constraint
Unobstructed, continuous constraint 21 days is fasting for solids and liquids during constraint, and after constraint, rat is put back in mouse cage, freely ingests, take the photograph
Water.
The selection and medication of 2.3 positive control drugs
This research compares " ginseng taste is strongly fragrant peaceful " antidepressant effects as positive control drug using escitalopram.To prescription
Method: escitalopram tablet is crushed into powder shape, then by escitalopram physiological saline wiring solution-forming 30mg/
100ml suspension, daily CRS stress before 1h with the escitalopram oxalate suspension oral gavage of 3mg/kgd, one time a day,
Continue 21 days.
2.4 " ginseng taste is strongly fragrant peaceful " medications
It is Chinese patent drug dispersible tablet that drug " ginseng taste is strongly fragrant peaceful " is mainly intervened in this research, thinks Ji medicine company by Guangdong and provides.Pass through early period
Research confirms that " ginseng taste is strongly fragrant peaceful " has significant antidepressant effects, finds in clinical experimental stage, and " ginseng taste is strongly fragrant peaceful " is to depression
Disease patient's Hamilton depression deduction rate has effect.This part with escitalopram oxalate using comparing, and " ginseng taste is peaceful for observation
Strongly fragrant " antidepressant effects.
Medication: it is converted according to adult dosage and rat medication metering, 6.3 × 3mg/ of rat dosage concentration
kg·d≈18mg/kg·d." ginseng taste peaceful strongly fragrant " tablet is crushed into powder shape, then matches " ginseng taste is strongly fragrant peaceful " with physiological saline
At solution 30mg/100ml suspension, daily CRS stress before 1h with the escitalopram oxalate suspension of 18mg/kgd
Stomach-filling continues 21 days one time a day.
2.5 method of drawing material
2.5.1 hippocampus TUNEL dyeing and immunohistochemical staining method of drawing material
After each group survival of rats is expired, 3 are randomly selected using every group of lottery, with 10% chloraldurate (0.35ml/100g) abdomen
Chest is opened after chamber injecting anesthetic, after adequately exposure heart and aorta ascendens carry out 4% paraformaldehyde perfusion, removes rat whole brain group
It knits, moves into 4% paraformaldehyde fixer and fix 48 hours (centre changes the liquid once), then sufficiently washing, then by sample from 50%
It is successively dehydrated to 100% alcohol, paraffin infiltration (60 °, 3h), prepares wax stone at embedding treatment, does 6 μ m-thick continuous horizontals slice, often
Temperature saves backup.
2.5.2 serum ELISA method is drawn materials
After experiment flow (the 21st day), every group of 8 rats through 10% chloraldurate (0.35ml/100g) intraperitoneal injection of anesthesia,
Then broken end takes blood 5ml, and after being stored at room temperature 2 hours, 4 DEG C of centrifugation 3000r/s, 10 minutes take supernatant, and -80 DEG C are moved into after packing
It saves backup.
2.6 Indexs measure
2.6.1 Immunohistochemical study hippocampus microglia and Activation of Astrocytes situation
Using immunohistochemistry technology's observation Hippocampus CA 3 Region microglia work and astroglia situation, briefly walk
It is rapid as follows:
It dewaxes first to slice；Dimethylbenzene is washed away through graded ethanol；Add an antiantibody after tissue treatment, respectively on different slides
Small anti-rat IBA-1 antibody (label microglia, 1:100) or GFAP antibody (label microglia, 1:100) is added
Dilution, every 20 μ l of dropwise addition are then placed in 4 DEG C of wet box overnight；Add two antiantibodys, develop the color, then dehydration, transparent, mountant
Mounting is stored at room temperature.Every group randomly selects 3, and every slice randomly selects 3 high power field of view (200 in Hippocampus CA 3 Region
×), it is observed under mirror with Nikon-50i microscope, and application NIS-ELements-BR3.1 image capturing system shines.
2.6.2 TUNEL Germicidal efficacy apoptosis of hippocampus neurons situation
Apoptosis of hippocampus neurons measurement is carried out using TUNEL staining technique, can detect minimal amount of apoptosis.Specific steps
It is as follows:
It is sliced dewaxing first, aquation, embathes, fix, embathing, cell-permeant, embathe, fix, embathing, adds 100 μ l equilibrium liquids flat
Weighing apparatus；Prepare TUNEL reaction mixture: processing group is balanced using the dUTP+98 μ l of 1 μ l rTdT+1 μ l biotin labeling
Liquid is mixed；And rTdT is then not added in negative control group, uses tri-distilled water；100 μ l DNase 1 are then first added in positive controls
Buffer carries out being incubated for 5 min, then gets rid of liquid, adds 100 μ l DNase 1 (10 U/ml) digestion, 10 min again, then uses
Deionized water is rinsed 4 times, and PBS embathes 5 min, then label reaction；The reaction of enzyme mark；DAB develops the color (being protected from light)；Haematoxylin is redyed；
Neutral gum mounting.After mounting, hippocampus is observed under the different multiples visual field using Japanese Nikon Nikon-50i microscope,
Then distinguish 200 × microscopic observation, nucleus sepia person is staining positive cells.Every slice randomly selects 5 and does not weigh mutually
It takes pictures diplopia open country.It is taken a picture using NIS-ELements-BR3.1 image capturing system.
2.6.3 ELISA detects serum inflammatory factors of senile IL-1 β, IL-10 and TNF-α expression variation
Different group serum IL -1 β, TNF- are detected using enzyme-linked immunosorbent assay technology (ELISA method) (reverse phase competition law)
α and IL-10 content.After detection terminates reaction, OD value (optical is read at 450nm using microplate reader immediately
Density, O.D.), more different -1 β of group serum IL, TNF-α and IL-10 content.
2.7 statistical analysis
Experimental data is counted using SPSS22.0, experimental result with average value ± standard error () indicate.Number
According to carry out test of normality, each group data variance use together one-way analysis of variance (one-way analysis of variance,
One-way ANOVA), comparison among groups use LSD or SNK method；If heterogeneity of variance uses non-parametric test.P < 0.01 is statistics
Meaning has conspicuousness.
3 results
3.1 area each group rat hippocampus CA1, CA2, CA3 and DG Activated Microglia situations
IBA-1 is one of microglia marker, and in microglial activation, its expression can be obviously increased.Using immune group
Change to each group rat hippocampal CA 3 observation microglia situation data living analysis shows that, it is normal that organize the small colloid in Hippocampus CA 3 Region thin
Born of the same parents' negligible amounts, cell space is smaller, and protrusion is few and elongated.CRS stress after, compared with normal group, the small colloid in model group Hippocampus CA 3 Region
Cell significantly activates, and cell space volume increases, and protrusion shortens thickening, and cell quantity significantly increases.As it can be seen that continuing chronic restricted stress
Induce Hippocampus CA 3 Region Activated Microglia.Compared with model group, " ginseng taste is strongly fragrant peaceful " and escitalopram are intervened significant
Chronic restricted stress has been reversed to induce Hippocampus CA 3 Region Activated Microglia, " ginseng taste is strongly fragrant peaceful " group and escitalopram group
Hippocampus CA 3 Region activated microglia and IBA-1 positive cell are considerably less than model group.It can be seen that " ginseng taste is strongly fragrant peaceful " intervenes effectively
Lasting chronic restricted stress induction Hippocampus CA 3 Region Activated Microglia (Fig. 5) is reversed.
Fig. 5 each group rat hippocampal CA 3 Activated Microglia situation
3.2 each group rat hippocampal CA 3 Activation of Astrocytes situations
GFAP is one of marker of astroglia, and in Activation of Astrocytes, its expression can be obviously increased.In the middle
When pivot nervous system damages, astroglia is converted into reactive astrocytes by normality, and it is thin to show as astroglia
The hypertrophy and hyperplasia of born of the same parents.Each group rat hippocampal CA 3 observation Activation of Astrocytes situation is shown using immunohistochemistry, just
Often group Hippocampus CA 3 Region astroglia negligible amounts, cell space is smaller, and protrusion is few and elongated.CRS stress after, with normal group ratio
Compared with model group Hippocampus CA 3 Region astroglia significantly activates, and cell space volume increases, and protrusion shortens thickening, and cell quantity is significant
Increase.As it can be seen that continuing chronic restricted stress induces Hippocampus CA 3 Region Activation of Astrocytes.Compared with model group, ginseng taste is rather strongly fragrant
Piece and escitalopram intervention have significantly reversed chronic restricted stress to induce Hippocampus CA 3 Region Activation of Astrocytes, " ginseng
Taste is strongly fragrant peaceful " it organizes with escitalopram group Hippocampus CA 3 Region activated stellate spongiocyte and GFAP positive cell considerably less than mould
Type group.As it can be seen that " ginseng taste is strongly fragrant peaceful ", which intervenes, has effectively reversed lasting chronic restricted stress induction Hippocampus CA 3 Region astroglia
It activates (Fig. 6).
Fig. 6 each group rat hippocampal CA 3 Activation of Astrocytes situation
3.3 each group rat hippocampal CA 3 Neuron Apoptosis situations
It dyes to observe each group rat hippocampal CA 3 using TUNEL and show, normally group Hippocampus CA 3 Region nucleus is blue, is in equal
With distribution, rarely seen only a few TUNEL positive cell.Compared with normal group, the visible more nucleus in model group Hippocampus CA 3 Region is in
Brown color, pyknosis, cell distribution is at random, and model group Hippocampus CA 3 Region TUNEL positive cell number, which is more normally organized, significantly to be increased.It can
See, continues chronic restricted stress and induce Hippocampus CA 3 Region Neuron Apoptosis.Compared with model group, " ginseng taste is strongly fragrant peaceful " and Ai Sixi
Phthalein Pulan, which is intervened, has significantly reversed chronic restricted stress induction Hippocampus CA 3 Region TUNEL positive cell number to increase, and " ginseng taste is peaceful
Strongly fragrant " group and escitalopram group Hippocampus CA 3 Region TUNEL positive cell number be substantially less than model group.(Fig. 7)
Fig. 7 each group rat hippocampal CA 3 Neuron Apoptosis situation
3.4 each group rat blood serum inflammatory factor IL-1 β, IL-10 and TNF-α expression variation
The results show that compared with normal group, significant guidance model group rat blood serum proinflammatory cytokine after chronic restricted stress 21 days
Factor IL-1 β and TNF-α significantly increase (P < 0.01;P < 0.01) and serum IL -10 significantly reduces (P < 0.01)；With model
Group is compared, and " ginseng taste is strongly fragrant peaceful " and escitalopram intervention have significantly reversed the blood serum induced middle IL-1 β of chronic restricted stress
Height expression and serum IL -10 significantly reduce, and IL-1 β is substantially less than mould in " ginseng taste is strongly fragrant peaceful " group and escitalopram group serum
Type group (P < 0.01;P < 0.01) and serum IL -10 is significantly higher than model group (P < 0.01;P < 0.01), " ginseng taste is strongly fragrant peaceful " group
It is not statistically significant with TNF-α difference in escitalopram group serum.(being shown in Table 5 and Fig. 8-10)
5. each group rat blood serum inflammatory factor IL-1 β of table, IL-10 and TNF-α expression variation ()
| Group | n | IL-1β (pg/ml) | IL-10 (pg/ml) | TNF-α (pg/ml) |
| Normal group | 8 | 76.610±2.432 | 159.127±2.616 | 109.823±1.220 |
| Model group | 8 | 106.687±1.369★★ | 122.005±3.571★★ | 152.708±4.108★★ |
| Escitalopram group | 8 | 91.573±1.224▲▲ | 161.509±4.995▲▲ | 145.098±1.702 |
| Join the peaceful strongly fragrant group of taste | 8 | 92.226±1.217▲▲ | 155.601±6.326▲▲ | 151.369±2.163 |
Note: IL-1 β, intergroup factors one-way analysis of variance: F=138.220, P=0.000；IL-10, intergroup factors single factor test
Variance analysis: F=12.167, P=0.000；TNF-α, intergroup factors one-way analysis of variance: X2=22.369, P=0.000.
Compared with normal group,★★P < 0.01；Compared with model group,▲▲P < 0.01.IL-1β, interleukin 1 beta; IL-
10, interleukin 10; TNF-α, tumor necrosis factor alpha.
Fig. 8 each group rat blood serum inflammatory factor IL-1 β expression variation, note: compared with normal group,★★P < 0.01；With model group
Compare,▲▲P < 0.01.IL-1β, interleukin 1 beta.
Fig. 9 each group rat blood serum inflammatory factor IL-10 expression variation, note: compared with normal group,
★★P < 0.01；Compared with model group,▲▲P < 0.01.IL-10, interleukin 10.
The expression variation of Figure 10 each group rat blood serum inflammatory factor TNF-α, note: compared with normal group,★★P < 0.01；With model group
Compare,▲▲P < 0.01.TNF-α, tumor necrosis factor alpha.
4 discuss and analyze
Currently, stress-induced maincenter/periphery immune system activation, inflammatory reaction enhancing are depression pathomechanism and prevention and treatment plan
Slightly research provides new visual angle.The generation of studies have shown that depression may be activated with immune activation causes inflammatory reaction to enhance,
Cytokine secretion increases related [1-4].As it can be seen that Immune inflammatory reaction activation is close with behavior depression and depression severity
[3-4] is closed in cut phase.Central nervous system is immune/inflammatory reaction activation in, microglia and astroglia swash
Work is its feature sex expression, and the microglia of continuous activation induces a variety of inflammatory cytokine releases, and then inducing cell withers
It dies, participates in depression pathologic process.This result of study tentatively shows, with stress load increase, chronic restricted stress can be significant
Guidance model group rat hippocampus microglia and Activation of Astrocytes cause serum levels IL-1 β, TNF-α content aobvious
Writing to increase reduces with IL-10, and then leads to apoptosis of hippocampus neurons.Meanwhile thering is research to confirm, it stress can activate immunoinflammatory
Reaction, inducible proinflammatory cell factor generates, anti-inflammatory cytokines reduce, and leads to monoamine neurotransmitter, hpa axis and nerve
It is plastic to sexually revise, the morbidity of inducing depression.As it can be seen that immune/inflammatory reaction activation of stress-induced is depression pathologic process
In important link.
IBA-1 is one of microglia marker, and in microglial activation, its expression can be obviously increased；GFAP is
One of marker of astroglia, in Activation of Astrocytes, its expression can be obviously increased.This research is using immune
Groupization is observed each group rat hippocampal CA 3 and is shown, compared with normal group, chronic restricted stress is induction of model group hippocampus CA3
Area microglia and astroglia significantly activate, and cell space volume increases, and protrusion shortens thickening, and IBA-1 and GFAP are positive
Cell dramatically increases.As it can be seen that continuing chronic restricted stress induction Hippocampus CA 3 Region microglia and Activation of Astrocytes.
Importantly, " ginseng taste is strongly fragrant peaceful " group Hippocampus CA 3 Region activated microglia IBA-1 positive cell and astroglia GFAP
Positive cell is considerably less than model group.As it can be seen that " ginseng taste is strongly fragrant peaceful ", which intervenes, has effectively reversed lasting chronic restricted stress induction sea
Horse CA3 area microglia and Activation of Astrocytes.
More and more evidences show that Immune inflammatory reaction plays potential role in depression Pathological Physiology, this
Research combines lonely support as stress stimulation simulation depression and pathologic process using chronic restricted stress.Result of study is aobvious
Show, chronic restricted stress significantly rises as stressor guidance model group rat blood serum pro-inflammatory cytokine IL-1 β and TNF-α
It is high and serum IL -10 significantly reduces.And " ginseng taste is strongly fragrant peaceful " intervenes to it with significant unkehr effect.This research is big to each group
The Apoptosis situation analysis of mouse Hippocampus CA 3 Region shows, after receiving chronic restricted stress stimulation, model group Hippocampus CA 3 Region it is visible compared with
Many cells core is in brown color, pyknosis, and cell distribution is at random.As it can be seen that continuing chronic restricted stress induces Hippocampus CA 3 Region neuron
Apoptosis.Importantly, " ginseng taste is strongly fragrant peaceful ", which intervenes, has effectively reversed lasting chronic restricted stress induction hippocampus compared with model group
The area CA3 Neuron Apoptosis.It is therefore contemplated that " ginseng taste is strongly fragrant peaceful " continues the hippocampal neuron of chronic restricted stress induction by reversing
Apoptosis is its important function approach for playing antidepressant effects.
The antidepressant effects mechanism and application of " ginseng taste is strongly fragrant peaceful " are probed into experiment three based on TLR4 signal path
" ginseng taste is strongly fragrant peaceful " antidepression Mechanism Study based on immune/inflammatory reaction activation that TLR4 signal path mediates.Our department
Divide based on " ginseng taste the is strongly fragrant peaceful " influence of intervention to CRS rat model behavior depression and apoptosis of hippocampus neurons, passes through
Western blot technology observes different group rat hippocampus TLR4 signal path key albumen (TLR4, MyD88, TNF-α)
Expression variation, it is anti-that immune, the inflammatory reaction activated pathway further mediated from TLR4 signal path probes into " ginseng taste is strongly fragrant peaceful "
Depressed effect mechanism.
1 experimental material
1.1 experimental animal
With experiment one.
1.2 experimental drugs and reagent
Rabbit-anti TLR4 antibody: number ab32127, Abcam company；Rabbit-anti MyD88 antibody: number ab22048, Abcam company；
Rabbit-anti TNF-alpha antibody: number ab1872, Abcam company；The anti-BETA-ACTIN antibody of mouse: code T A-09, in Beijing
Bioisystech Co., Ltd, China fir Golden Bridge；Reverse Transcriptase kit: TIANScript RT Kit；SYBR FAST qPCR Kit
Master Mix (2 ×) Universal:KAPA Biosystems company；Protein lysis buffer: number P001,
You Kezhuo industry biotech firm；BCA Protein Assay Kit: number 02912E, cwbiotech；Protein ladder:
Biomed company；PVDF membrane: specification 0.45um, Millipore company；ECL developing solution: number WBKLS0500,
Millipore company；Etc..
1.3 laboratory apparatus and equipment
High speed freezing centrifuge: model Beckman Allgre 21R, Beckman company；Uv and visible light spectrophotometric
Meter: model WFZUV-2000 type, Shanghai You Nike/unico；Gel imager: model BioSens SC 810B, upper seamount
Rich scientific instrument Co., Ltd；Spectrophotometer: model UV-2000, Shanghai essence Science and Technology Ltd.；Etc..
2 experimental methods
2.1 experimental group
The consistent rat of behaviouristics baseline is divided using table of random number (random digit is generated by SPSS22.0 statistics software)
For normal group, model group, escitalopram group and " ginseng taste peaceful strongly fragrant " group, every group 11, totally 44.
Normal group is normal rat, and 5/cage group rearing freely ingests, drinks water, and continues 21 days；Model group rats are using chronic
Restraint Stress combines lonely support to simulate depression model, continues 21 days.Escitalopram group rat is received daily 1 before Restraint Stress
Hour receives 3mg/kgd escitalopram oxalate stomach-filling intervention successively, continues 21 days；" ginseng taste is strongly fragrant peaceful " group rat day connects
Receive within 1 hour 18mg/kgd " ginseng taste is strongly fragrant peaceful " stomach-filling intervention successively before receiving Restraint Stress, continues 21 days.
The preparation of 2.2 models
This research uses internationally recognized chronic restricted stress (CRS) method, establishes lonely support and combines chronic restricted stress depression big
Mouse model.Specific modeling method: rat is bound by certainly by daily am9:00-pm3:00 using homemade chronic restricted stress device
Soft iron tow processed is tied up in net cylinder 6 hours, and to rat, whole body is all placed in net cylinder end to end, grips net cylinder both ends with agrafe
(movement must be soft when operation, avoids injuring rat), is then horizontally placed in former mouse cage.Rats breathing is kept during constraint
Unobstructed, continuous constraint 21 days is fasting for solids and liquids during constraint, and after constraint, rat is put back in mouse cage, freely ingests, take the photograph
Water.
The selection and medication of 2.3 positive control drugs
This research compares " ginseng taste is strongly fragrant peaceful " antidepressant effects as positive control drug using escitalopram.To prescription
Method: escitalopram tablet is crushed into powder shape, then by escitalopram physiological saline wiring solution-forming 30mg/
100ml suspension, daily CRS stress before 1h with the escitalopram oxalate suspension oral gavage of 3mg/kgd, one time a day,
Continue 21 days.
2.4 " ginseng taste is strongly fragrant peaceful " medications
It is Chinese patent drug dispersible tablet that drug " ginseng taste is strongly fragrant peaceful " is mainly intervened in this research, thinks Ji medicine company by Guangdong and provides.Pass through early period
Research confirms that " ginseng taste is strongly fragrant peaceful " has significant antianxiety effect, finds in clinical experimental stage, and " ginseng taste is strongly fragrant peaceful " is to anxiety
Disease patient's Hamilton depression deduction rate has effect.This part with escitalopram oxalate using comparing, and " ginseng taste is peaceful for observation
Strongly fragrant " antidepressant effects.
Medication: it is converted according to adult dosage and rat medication metering, 6.3 × 3mg/ of rat dosage concentration
kg·d≈18mg/kg·d." ginseng taste peaceful strongly fragrant " tablet is crushed into powder shape, then matches " ginseng taste is strongly fragrant peaceful " with physiological saline
At solution 30mg/100ml suspension, daily CRS stress before 1h with the escitalopram oxalate suspension of 18mg/kgd
Stomach-filling continues 21 days one time a day.
2.5 method of drawing material
Hippocampus Western blot and RT-PCR method materials: every group of 8 rats take blood simultaneously in broken end, rapidly move to rat head
On ice, quickly removing, takes out hippocampus, and 4 DEG C of PBS are packed into cryopreservation tube after rinsing, are immediately placed in liquid nitrogen, then move into -80 DEG C of guarantors
It deposits spare.
2.6 Indexs measure
Western Blot detects hippocampus TLR4 signal path key protein expression
Using Western-Blot method determine destination protein TLR4, MyD88 and TNF α in the expression of different group hippocampus, and
Further progress sxemiquantitative makes difference analysis to different groups.Specific step is as follows:
Protein Extraction first；BCA method protein quantification；Protein concentration is adjusted after completing BCA method protein quantification, is adjusted using RIPA
5 × protein sample buffer, 95 degree of 5min are added in protein concentration, the final concentration of 2 μ g/ μ l of sample.Then according to Western
The detection of Blot step；Picture scanning finally is carried out to film after exposure, uses Gel Image ststem ver.4.00
(tanon, china) software carries out gray analysis to image, as a result indicates school with target stripe gray value/β-actin gray value
Positive error.
2.7 statistical analysis
Experimental data is counted using SPASS22.0, experimental result with average value ± standard error () indicate.Number
According to carry out test of normality, each group data variance use together one-way analysis of variance (one-way analysis of variance,
One-way ANOVA), comparison among groups use LSD or SNK method；If heterogeneity of variance uses non-parametric test.P < 0.01 is statistics
Meaning has conspicuousness.
3 results
The variation of 3.1 each group rat hippocampus TLR4 signal path key protein expressions
3.1.1 each group rat hippocampus TLR4 protein expression changes
The results show that compared to the blank group, TLR4 protein expression significantly increases (P < 0.01) in model group hippocampus；With model group phase
Than " ginseng taste is strongly fragrant peaceful ", which intervenes, has significantly reversed TLR4 albumen height expression in chronic restricted stress induction hippocampus, and " ginseng taste is rather strongly fragrant
TLR4 protein expression is substantially less than model group (P < 0.01) in piece " group hippocampus.(being shown in Table 6 and Figure 11)
The variation of 6. each group rat hippocampus TLR4 protein expression of table ()
| Group | n | TLR4 / β-actin |
| Normal group | 5 | 0.163±0.014 |
| Model group | 5 | 0.471±0.046★★ |
| Escitalopram group | 5 | 0.395±0.026 |
| Join the peaceful strongly fragrant group of taste | 5 | 0.335±0.026▲▲ |
Note: intergroup factors one-way analysis of variance: F=22.369, P=0.000；Compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01.TLR4, toll-like receptor 4.
Figure 11 each group rat hippocampus TLR4 protein expression level compares, note: compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01.TLR4, toll-like receptor 4.
3.1.2 each group rat hippocampus MyD88 protein expression changes
The results show that MyD88 protein expression significantly raises (P < 0.01) in model group hippocampus compared with normal group；With model group
Compare, " ginseng taste is strongly fragrant peaceful " and escitalopram intervention have significantly reversed chronic restricted stress induction hippocampus MyD88 albumen high
Expression, in " ginseng taste peaceful strongly fragrant " group and escitalopram group hippocampus MyD88 protein expression be substantially less than model group (P <
0.01；P<0.01).(being shown in Table 7 and Figure 12)
The variation of 7. each group rat hippocampus MyD88 protein expression of table ()
| Group | n | MyD88/β-actin |
| Normal group | 5 | 0.242±0.019 |
| Model group | 5 | 0.504±0.023★★ |
| Escitalopram group | 5 | 0.410±0.010▲▲ |
| Join the peaceful strongly fragrant group of taste | 5 | 0.339±0.041■■ |
Note: intergroup factors one-way analysis of variance: F=12.034, P=0.000；Compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.05.MyD88, myeloid
differentiation primary response gene 88。
Figure 12 each group rat hippocampus MyD88 protein expression level compares, note: compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01；Compared with escitalopram group,■■P < 0.05.MyD88, myeloid
differentiation primary response gene 88。
3.1.3 each group rat hippocampus TNF-α protein expression changes
The results show that TNF-α protein expression significantly raises (P < 0.01) in model group hippocampus compared with normal group；With model group
Compare, " ginseng taste is strongly fragrant peaceful ", which intervenes, has significantly reversed chronic restricted stress induction hippocampus TNF-α albumen height expression, and " ginseng taste is rather strongly fragrant
TNF-α protein expression is substantially less than model group (P < 0.01) in piece " group hippocampus.(being shown in Table 8 and Figure 13)
The variation of 8. each group rat hippocampus TNF-α protein expression of table ()
| Group | n | TNF-α / β-actin |
| Normal group | 5 | 0.165±0.022 |
| Model group | 5 | 0.410±0.053★★ |
| Escitalopram group | 5 | 0.364±0.048 |
| Join the peaceful strongly fragrant group of taste | 5 | 0.289±0.065▲▲ |
Note: intergroup factors one-way analysis of variance: F=26.485, P=0.000；Compared with normal group,★★P < 0.01；With model
Group compares,▲▲P < 0.01.TNF-α, tumor necrosis factor α.
Figure 13 each group rat hippocampus TNF-α protein expression level compares, note: compared with normal group,★★P < 0.01；With mould
Type group compares,▲▲P < 0.01.TNF-α, tumor necrosis factor α.
4 discuss and analyze
This research experiment one and experiment two results prompt, chronic restricted stress are living induction of microglia and astroglia
Change, increase serum pro-inflammatory cytokine level, promote apoptosis of hippocampus neurons, Induction experiments rat shows depressed sample row
For.As it can be seen that the immunoinflammatory that stress be mediated by activated microglia/astroglia activates and apoptosis of hippocampus neurons
It may be the important link of depression pathologic process.There is studies have shown that pattern recognition receptors Toll-like receptor access that may answer
The depression Immune inflammatory reaction activation for swashing induction plays a significant role [1-3].Therefore, this experiment is based on " it is rather strongly fragrant joining taste
Piece " intervenes the influence to CRS rat model behavior depression and apoptosis of hippocampus neurons, is observed by Western blot technology
The expression of different group rat hippocampus TLR4 signal path key albumen (TLR4, MyD88, TNF-α) changes, further from
Immune/inflammatory reaction activated pathway that TLR4 signal path mediates probes into " ginseng taste is strongly fragrant peaceful " antidepressant effects mechanism.
In recent years, depression pathology machine is probed into based on the immunoinflammatory activation that pattern recognition receptors TLR4 signal path mediates
System research attracts attention.There is clinical studies show, patients with depression peripheral blood mononuclear cells (PBMC) expression is higher levels of
TLR4.And the high expression level of TLR4 is reversed after treating, depressive symptom is improved.As it can be seen that TLR4 activity directly participates in
The pathophysiological process of depression.There is studies have shown that TLR4 activity that can influence behavior depression.The disease sample row of TLR4 induction
To be mainly shown as the symptoms such as anhedonia, drowsiness, mobility are reduced and dietary amount is reduced.The horizontal TLR4 letter of hippocampus in this research
Number access key molecule protein expression level analysis shows that, chronic restricted stress is induction of TLR4, MyD88 in hippocampus and TNF-α
Protein upregulation expression.As it can be seen that the immunoinflammatory that stress be mediated by pattern recognition receptors TLR4 signal path activates.It is worth
It is noted that " ginseng taste is strongly fragrant peaceful ", which intervenes, has significant adjustment effect to the activation of hippocampus horizontal Immune inflammatory reaction.With model group
Compare, " ginseng taste is strongly fragrant peaceful ", which intervenes, has significantly reversed TLR4, MyD88 protein upregulation expression water in chronic restricted stress induction hippocampus
It is flat.This, which may be, " ginseng taste is strongly fragrant peaceful ", which intervenes, reduces the rat body weight that chronic restricted stress induce, the reduction of syrup preference function,
Where the basic reason of the reverse effect of horizontal movement scoring and vertical movement scoring decline.
The analysis of cumulated volume result of study: Immune inflammatory reaction is the important channel for connecting stress-induced depression, and " ginseng taste is peaceful
Strongly fragrant " best antidepressant effects can be played to the immunoinflammatory activation that identification receptor TLR4 signal path in mode mediates.
To sum up draw a conclusion, this result of study display, with stress load increase, chronic restricted stress can as stressor
Induced rat shows a series of behavior depressions, and " ginseng taste is strongly fragrant peaceful " has significant antidepressant effects, in clinical experimental stage
It was found that " ginseng taste is strongly fragrant peaceful " has effect to patients with depression Hamilton depression deduction rate." ginseng taste is strongly fragrant peaceful " intervenes significant
TLR4, MyD88 protein upregulation expression in chronic restricted stress induction hippocampus are reversed, simultaneously " ginseng taste is strongly fragrant peaceful " intervention pair
Under the rat body weight of chronic restricted stress induction reduces, syrup preference function reduces, horizontal movement is scored and vertical movement scoring
Where the basic reason of the reverse effects such as drop.And " ginseng taste is strongly fragrant peaceful " and antidepressants intervention show apparent antidepression effect
It answers, but adjust extensively to the immunoinflammatory activation that identification receptor TLR4 signal path in mode mediates is that " ginseng taste is rather strongly fragrant
Piece " plays where the core of antidepressant effects.Immune inflammatory reaction is the important channel for connecting stress-induced depression, to mould
It is that " ginseng taste is strongly fragrant peaceful " plays antidepression that the immunoinflammatory activation that formula identification receptor TLR4 signal path mediates, which adjust extensively,
Where the core of effect.
Using advantage and gain effect: depression causes huge puzzlement to the mankind, China's depression rise year by year with
And involve the rejuvenation of crowd, have become the great illness for influencing national health, and researcher is caused to pay high attention to.2017
23 days 2 months, the publication of (WHO) official, the World Health Organization: global incidence of depression accounted for the 4.3% of total population, has reached 3.22
Hundred million；Patient populations increase 18.4% between 2005-2015；China's depressive disorder illness rate is 4.2%, and total disability loss health is raw
Ordering year (years lived with disabilityYLD) is 8,981,401 man-years.In short, depression is due to its height morbidity
The features such as rate, high disability rate, high relapse rate and high social Disease Spectrum is still a great problem of current puzzlement medical field.Mesh
Before, the pathomechanism research of depression still concentrates on the biological effect evaluation of pathomechanism hypothesis, therefore, the phase of depression
Close the globality and real value for studying urgently valuing researches.
Currently, the treatment of depression is mainly based on antidepressant therapy, although in the past three during the decade, have nearly
40 kinds of antidepressants emerge, and still, clinic still has nearly 30% patient all to show without answering any antidepressant
It answers, and part patients with depression has to change therapeutic modality, or pause treatment because side effect is obvious.Meanwhile it not fullying recover from an illness
More patient remains anxiety, insomnia and somatization etc. mostly, these increase the risk of recurrence of depression.In addition, anti depressant therapy
" target spot " of the drug on mechanism of action and approach gradually attracts attention with depressive illness feature feature popularity contradiction.It can
See, seeks more effective or urgently to be resolved in the new strategy of early stage synergy antidepressants curative effect.
The Chinese medicine composition that it is an object of that present invention to provide a kind of for treating depression is in adjusting Immune inflammatory reaction
Application.It is a kind of for treating antidepressants made of the Chinese medicine composition of depression disclosed in patent No. ZL03153104.0
It is curative for effect in the clinical treatment of depression.It is characterized by: described control comprising Radix Curcumae, semen ziziphi spinosae, American Ginseng, Schisandra chinensis
The Chinese medicine composition for treating depression has definite curative effect to Immune inflammatory reaction is adjusted, and finds to identification receptor TLR4 in mode
The immunoinflammatory activation that signal path mediates can play best antidepressant effects.Experiment and research of going deep into of the invention will be spy
It seeks more effective or is of great significance in the new strategy research of early stage synergy antidepressants curative effect.
Claims (4)
1. a kind of Chinese medicine composition for treating depression is in the application adjusted in Immune inflammatory reaction, it is characterised in that: institute
State comprising Radix Curcumae, semen ziziphi spinosae, American Ginseng, Schisandra chinensis treatment depression Chinese medicine composition to adjusting Immune inflammatory reaction answer
With.
2. a kind of Chinese medicine composition for treating depression according to claim 1 is in adjusting Immune inflammatory reaction
Using, it is characterised in that: the Chinese medicine composition of the treatment depression is adjusting the chronic constriction in Immune inflammatory reaction
The application of stress rats behavior depression.
3. a kind of Chinese medicine composition for treating depression according to claim 1 is in adjusting Immune inflammatory reaction
Using, it is characterised in that: it is described treatment depression Chinese medicine composition adjust Immune inflammatory reaction in CRS rat hippocampus
Activated Microglia mediates, the application of inflammatory reaction and Apoptosis.
4. a kind of Chinese medicine composition for treating depression according to claim 1 is in adjusting Immune inflammatory reaction
Using, it is characterised in that: the Chinese medicine composition of the treatment depression is adjusting the reverse TLR4 in Immune inflammatory reaction
The application of signal path mediated immunity and the antidepressant effects of inflammatory reaction activation.
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