CN105617361A - Neuroprotective effect of interleukin 10 for depression treatment - Google Patents
Neuroprotective effect of interleukin 10 for depression treatment Download PDFInfo
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- CN105617361A CN105617361A CN201610053735.XA CN201610053735A CN105617361A CN 105617361 A CN105617361 A CN 105617361A CN 201610053735 A CN201610053735 A CN 201610053735A CN 105617361 A CN105617361 A CN 105617361A
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Abstract
The invention provides a new application of IL-10. In vivo and in vitro experiments jointly prove that the IL-10 has a neuroprotective effect and is a neuroprotection factor with a better development prospect, so that the IL-10 can be used for preparing medicines for preventing or treating depressed diseases or symptoms with nerve injuries.
Description
Technical field
The present invention relates to pharmaceutical technology field, be the interleukin 10 (Interleukin-10, IL-10) purposes in neuroprotective, belong to course of drug development.
Background technology
Depression (depression) is a kind of affective disorder disease (affectivedisorder). Affective disorder is to describe the medical terminology that mental state is abnormal, show as notable and lasting hypothymergasia, this emotion is generally in person and/or other people significantly feel, degree can from depressed to extremely sad, persistent period is very long, it is difficult to explain by objective reality circumstances or to alleviate, time serious, it is possible to cause suicide. According to World Health Organization's investigation display, the whole world in 2014 has more than 400,000,000 people and suffers from depression, spreads all over each age group, and the Population size estimation committed suiside then is up to 1,500,000. So high sickness rate and homicide rate also make to have a depression becomes the disease that mortality rate in the world is number three.
Traditional antidepressant drug is owing to being all the medicine designed with monoamine systems, although mechanism of action of a great variety is also had nothing in common with each other, the defects such as but the ubiquity clinical treatment cycle is long, and responsiveness is low, the asynchronous and serious side effect that target effect improves with symptom. And recently as scientific circles going deep into the understanding of depression, it was found that the nerve injury mechanism of depression. Here nerve injury, refers to central nervous system, the damaged nerve cell that mainly cerebral nerve inflammation causes. Neurocyte is the neural structural units of higher mammal and functional unit, including neuron and glial cell. Therefore, neuroprotective is that exploitation antidepressant drug provides new thinking and target spot.
IL-10 belongs to a kind of anti-inflammatory cytokines, has minimizing inflammatory reaction, the effect of antagonism inflammatory mediator. There are some researches show: in depression model mice, IL-10 can play the effect alleviating behavior depression by reducing pro-inflammatory cytokine to express. So, IL-10 plays a significant role in the nerve immunity of depression reacts. But the concrete research playing neuroprotective about IL-10 in depression need deeply.
Summary of the invention
It is an object of the invention to provide the IL-10 a kind of neuroprotective purposes in depression.
Find that IL-10 has good neuroprotective through zoopery and cell experiment, be the medicine of the rising treatment depression of a kind of comparison, in particular for by stress be caused by chronic gentleness depression.
Detailed description of the invention
Experimental example 1.IL-10 stress the improvement result of (chronicmildstress, CMS) mice behavior depression to chronic gentleness
Experimental technique:
CMS is the experimental model that a kind of general induction is depressed. This research experiment in vivo adopts mice CMS model, detects mice behavior depression: forced swimming and tail-suspention test. The ultimate principle of forced swimming is, when mice is in a narrow unavoidable container went swimming, at water float with health or can slightly retreat slip and maintains a kind of motionless behavior after struggle originally, and this behavior is applauded prestige behavior. In like manner, tail-suspention test is also the experiment of the desperate behavior of detection, (such as hangs its afterbody in liftoff certain altitude) when mice is in the unavoidable adverse circumstance of a short-term, and its behavior can be transformed into motionless state from kinestate. After mice behavior depression improves, the time of this desperate behavior can be reduced.
C57BL/6J mice with a series of general gentle stress stimulations, such as food deprivation 24 hours, water deprivation 24 hours, is tilted cage 24 hours by this experiment, wet bedding and padding 24 hours, stroboscopic illumination 24 hours, night illumination 24 hours, Restraint Stress 2 hours. Every day one stress, weekly stress order different, continue 4 weeks. 32 mices are divided into: comparison-normal saline, CMS-normal saline, four experimental grouies of comparison-IL-10 and CMS-IL-10, often 8 animals of group. Intraperitoneal injection of saline or IL-10 (1 �� g/kg), continuous injection one week once a day after CMS3 week. After having injected, the time that detection mouse forced swimming test and tail-suspention test mice are not moved at all. Forced swimming is as in depth of water 12cm, water temperature 22 �� 1 DEG C, 21 �� 12cm glass by mice. Maintain swimming 6min, and record what latter four minutes small mouses of statistics were not moved at all time. Tail-suspention test is that mousetail tip is fixed on liftoff 60cm high-altitude suspension, and record video recording 6min also adds up the time wherein do not moved at all.
Experimental result:
IL-10 is on the impact of CMS mice behavior depression such as shown in table 1-2. Experiment display, compared with comparison-normal saline group, in CMS-normal saline group, the time that forced swimming and the mice in tail-suspention test are not moved at all increases. Data statistic analysis shows compared with CMS-normal saline group, and the time that the mice that IL-10 processes is not moved at all substantially is reduced [table 1:F (3,25)=13.551, p < 0.01; Table 2:F (3,25)=9.263, p < 0.01], return to the level close to comparison-normal saline group. Illustrate that IL-10 has significant antidepressant effect in the depressed mice of CMS, it is possible to play protective effect.
The table 1IL-10 impact on CMS mice behavior depression-forced swimming
The table 2IL-10 impact on CMS mice behavior depression-tail-suspention test
Data acquisition mean �� SEM represents;**P < 0.01vs. comparison-normal saline,##P < 0.01vs.CMS-normal saline.
Experimental example 2.IL-10 is to the improvement result expressed of IDO in CMS mouse brain
Experimental technique:
Indoleamine 2,3 dioxygenases (Indoleamine2,3dioxygenase, IDO) are that beyond liver, catalysis tryptophan is along the rate-limiting enzyme of kynurenine pathway metabolism, and tryptophan is the essential amino acids of synthetic protein. Under normal condition, IDO expression is relatively low, but expression significantly increases in the mental disorder such as depression, and makes tryptophan-kynurenine metabolism pathway disorderly, and catalysis tryptophan is sour along 3-hydroxyl dog urinary ammonia approach synthesis of quinoline. 3-hydroxyl dog urinary ammonia and quinolinic acid have neurotoxicity, can produce nerve injury. This experiment adopts the model of internal CMS, extracts mRNA, the mrna expression level of detection IDO from mouse brain tissue. The method of the detection real-time fluorescence quantitative PCR of mRNA level in-site, instrument is Bio-RadCFX96.
C57BL/6J mice with a series of general gentle stress stimulations, such as food deprivation 24 hours, water deprivation 24 hours, is tilted cage 24 hours by this experiment, wet bedding and padding 24 hours, stroboscopic illumination 24 hours, night illumination 24 hours, Restraint Stress 2 hours. Every day one stress, weekly stress order different, continue 4 weeks. 20 mices are divided into: comparison-normal saline, CMS-normal saline, four experimental grouies of comparison-IL-10 and CMS-IL-10, often 5 animals of group. Intraperitoneal injection of saline or IL-10 (1 �� g/kg), continuous injection one week once a day after CMS3 week. After having injected, extracting the total mRNA of mouse brain tissue, detection IDO expresses.
Experimental result:
IL-10 is as shown in table 3 on the impact expressed of IDO in CMS mouse brain. Experiment display, compared with comparison-normal saline group, in CMS-normal saline group, IDO expresses increase. Data statistic analysis shows compared with CMS-normal saline group, and the mrna expression of the mice IDO that IL-10 processes substantially reduces [F (3,18)=7.609, p < 0.01]. Illustrate that the expression of CMS mice IDO is had significant inhibitory action by IL-10, it is possible to play neuroprotective.
Table 3IL-10 is on the CMS mouse brain IDO impact expressed
Data acquisition mean �� SEM represents;**P < 0.01vs. comparison-normal saline,##P < 0.01vs.CMS-normal saline.
The expression increase of IDO in astrocyte caused by bacterial endotoxin-lipopolysaccharide (Lipopolysaccharide, LPS) is had improvement result by experimental example 3.IL-10
Experimental technique:
LPS stimulates can the model of depression in analogue body. Astrocyte is the neurocyte that in brain, quantity is maximum. This experiment adopts the model that external astrocyte is cultivated, and the astrocyte of separation and Culture from mouse brain is stimulated with LPS, then detects the mRNA level in-site of IDO in astrocyte and the expression of protein level. The method of the detection real-time fluorescence quantitative PCR of mRNA level in-site, instrument is Bio-RadCFX96; The method of the detection WesternBlot of protein level, statistical software is ImageJ, version1.45j.
This experiment isolates astrocyte from C57BL/6J mice children Mus (1-3 days big), go down to posterity after 2-3 time, astrocyte is divided into 4 groups: matched group, LPS stimulation group (1 �� g/ml), comparison-IL-10 (10ng/ml) process group and LPS-IL-10 process group, often 5 Duplicate Samples of group, after processing 24 hours respectively, it is proposed to mRNA and the protein of each group detect.
Experimental result:
IL-10 is as shown in table 1 on the impact expressed of IDO in the bacterial endotoxin LPS astrocyte stimulated. Experiment display, compared with matched group, in LPS stimulation group, mRNA and the expressing quantity of IDO all increase. When processing after LPS stimulates with IL-10, mRNA and the expressing quantity of IDO all declines [mRNA:F (3,18)=10.103, p < 0.01; Albumen: F (3,18)=6.774, p < 0.01], and there was no significant difference with the expression of matched group. Illustrate that the exception that in the IL-10 astrocyte to being caused by bacterial endotoxin, IDO expresses has repair, it is possible to play protective effect.
Table 4IL-10 is on the impact expressed of IDO in the bacterial endotoxin LPS astrocyte stimulated
Data acquisition mean �� SEM represents;*P < 0.05,**P < 0.01vs. matched group,#P < 0.05,##P < 0.01vs.LPS stimulation group.
Embodiment 4.IL-10 suppresses bacterial endotoxin to stimulate the quantity of the astrocyte later expressing IDO, plays neuroprotective
Experimental technique:
In order to verify the expression of IDO in astrocyte further, we identify by immunohistochemical method. GFAP (Glialfibrillaryacidicprotein, glial fibrillary acidic protein) it is a kind of specific intermediate filament protein of astrocyte, only identify astrocyte, and nonrecognition neuron, microglia, oligodendrocyte and other type of cell, can be used to labelling astrocyte. Carry out labeled cell core with DAPI, then add up the change of IDO/GFAP/DAPI positive cell quantity with fluorescence microscope. Fluorescence microscope is OlympusBX51, and the software of statistical magnitude is ImageJ, version1.45j.
This experiment isolates astrocyte from C57BL/6J mice children Mus (1-3 days big), go down to posterity after 2-3 time, astrocyte is divided into 4 groups: matched group, LPS stimulation group (1 �� g/ml), comparison-IL-10 (10ng/ml) process group and LPS-IL-10 process group, often 5 Duplicate Samples of group, after processing 24 hours, fluorescence staining, the quantity of statistics IDO/GFAP/DAPI positive cell is carried out respectively with IDO, GFAP and DAPI.
Experimental result:
The impact of the astrocyte quantity that IL-10 expresses IDO after bacterial endotoxin LPS is stimulated is as shown in table 2. Experimental result shows, in LPS stimulation group, and IDO/GFAP/DAPI positive cell quantity showed increased. Statistical analysis shows compared with LPS stimulation group, and in LPS-IL-10 group, IDO/GFAP/DAPI positive cell quantity significantly reduces [F (3,18)=21.118, p < 0.01], and the close quantity to illumination. Illustrate that the expression of IDO in astrocyte after bacterial endotoxin stimulation is had inhibitory action by IL-10, it is possible to play neuroprotective effect.
Table 5IL-10 expresses the impact of the astrocyte quantity of IDO after bacterial endotoxin LPS is stimulated
Data acquisition mean �� SEM represents,**P < 0.01vs. matched group,##P < 0.01vs.LPS stimulation group.
Embodiment 5.IL-10 suppresses bacterial endotoxin to stimulate the expression of neurotoxic substances-3-hydroxyl dog urinary ammonia later
Experimental technique:
In the process of IDO catalysis tryptophan metabolism, there is metabolism branch to have neurovirulent, be the approach along 3-hydroxyl dog urinary ammonia to quinolinic acid. Once synthesis 3-hydroxyl dog urinary ammonia will produce neurotoxicity, and then cause nerve injury. This experiment isolates astrocyte from C57BL/6J mice children Mus (1-3 days big), go down to posterity after 2-3 time, astrocyte is divided into 4 groups: matched group, LPS stimulation group (1 �� g/ml), comparison-IL-10 (10ng/ml) process group and LPS-IL-10 process group, often 5 Duplicate Samples of group, after processing 24 hours, measure the concentration of 3-hydroxyl dog urinary ammonia by ELISA kit.
Experimental result:
IL-10 is as shown in table 3 on the impact of neurotoxic substances-3-hydroxyl dog urinary ammonia after bacterial endotoxin LPS stimulation. Experimental result shows, in LPS stimulation group, and the concentration showed increased of 3-hydroxyl dog urinary ammonia. Statistical result shows compared with LPS stimulation group, and in LPS-IL-10 group, 3-hydroxyl dog urinary ammonia concentration significantly reduces [F (3,18)=17.574, p < 0.01], and the close quantity to illumination. Illustrate that bacterial endotoxin is stimulated the expression of 3-hydroxyl dog urinary ammonia later to have inhibitory action by IL-10, it is possible to play neuroprotective effect.
Bacterial endotoxin LPS is stimulated the impact of neurotoxic substances-3-hydroxyl dog urinary ammonia later by table 6IL-10
Data acquisition mean �� SEM represents;**P < 0.01vs. matched group;#P < 0.05vs.LPS stimulation group.
Claims (6)
1.IL-10 is used for the health product in neuroprotective or the application in medicine in preparation.
2. application according to claim 1, it is characterised in that alleviate and/or treatment has the application in the depressed class disease of nerve injury or the health product of symptom or medicine.
3. application according to claim 1, it is characterised in that the depressed class disease caused by IDO Developmental and Metabolic Disorder that internal CMS stress be caused.
4. application according to claim 1, it is characterised in that described neuroprotective is the neuroprotective to neurotoxic substances-3-hydroxyl dog urinary ammonia expression inhibiting.
5. the application according to claim 1,2 and 3, it is characterised in that described medicine is the IL-10 factor.
6. alleviate and/or the treatment depressed class disease of nerve injury or the medicine of symptom or health product caused by neurotoxic substances for one kind, it is characterised in that be the IL-10 factor.
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| CN201610053735.XA CN105617361A (en) | 2016-01-26 | 2016-01-26 | Neuroprotective effect of interleukin 10 for depression treatment |
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- 2016-01-26 CN CN201610053735.XA patent/CN105617361A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| 卡尔森: "《生化学精华》", 31 December 1989 * |
| 骆春梅: "细胞因子在应激所致抑郁中的病理作用研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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