CN108310365A - A kind of application of the composition of the mutant containing MG53 in preparing nerve protection medicine - Google Patents
A kind of application of the composition of the mutant containing MG53 in preparing nerve protection medicine Download PDFInfo
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- CN108310365A CN108310365A CN201810364732.7A CN201810364732A CN108310365A CN 108310365 A CN108310365 A CN 108310365A CN 201810364732 A CN201810364732 A CN 201810364732A CN 108310365 A CN108310365 A CN 108310365A
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- 230000001953 sensory effect Effects 0.000 description 1
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Abstract
The invention discloses a kind of application of object of mutant combinations containing MG53 in being used to prepare nerve protection medicine.Result of study of the present invention shows; MG53 mutant has neuroprotection outstanding; and may pass through blood-brain barrier, can be applied to prevent or treat include ischemia apoplexy, encephalatrophy, senile dementia, multi-system atrophy, encephalatrophy disease, motor neuron disease, ataxia telangiectasia, spinal muscular atrophy, optic atrophy a variety of neurodegenerative diseases.
Description
Technical field
The invention belongs to biological medicament fields, and in particular to a kind of composition of the mutant containing MG53 is preparing neuroprotective drug
Application in object.
Background technology
In recent years, various neurogenic diseases seriously endanger human life and health, including ischemia apoplexy and various nerves
Degenerative disease, such as encephalatrophy, senile dementia, multi-system atrophy, motor neuron disease, ataxia-telangiectasia
Disease, spinal muscular atrophy, optic atrophy etc. become disable, lethal common disease and frequently-occurring disease, to society and family bring
White elephant.
Ischemia apoplexy accounts for about the 85% of all headstrokes, since brain blood flow is reduced so as to cause the normal of cell
Function changes caused disease.In human body, if cerebral ischemic, cerebral tissue will quickly occur ischemic corresponding
Reaction.Ischemic may result in a series of reaction generation to the important structural unit neuron of brain in a short time, most terminate
Fruit is the forfeiture even cell death for leading to cell function.The treatment of acute ischemic cerebral apoplexy mainly passes through two approach：
One is thrombus, and two be neuroprotection, and the latter refers in the treatment of acute ischemic cerebral apoplexy, prevents brain group caused by ischemic
A series of pathology and biochemical reaction are knitted, the links of interference ischemic waterfall reaction extend the drug of neuronal survival or arrange
It applies.
Neurodegenerative disease is the morbid state that the cellular neural member of a kind of brain and spinal cord is lost, because of brain and spinal cord
It is made of neuron, neuron has different functions, and such as controlled motion, processing sensory information simultaneously make decisions.And brain and ridge
The cell of marrow once it is impaired be will not be regenerated, so excessive damage may be destructive and irreversible, nerve moves back
Row disease can deteriorate over time, to lead to dysfunction.Modern science discovery, oxidative stress and active oxygen
(ROS) exception is generated and removed in the cell, important regulating and controlling effect is played to the damage of neuron.When the generation of ROS increases
Or remove and reduce, or when being reduced to the macromolecular reparation of oxidative modification, oxidative stress will occur.Oxidative stress and active oxygen
(ROS) exception is generated and removed in the cell, important regulating and controlling effect is played to the damage of neuron.
MG53 is skeletal muscle specificity albumen mitsugumin53, abbreviation MG53；Or TRIM72.It is a kind of muscle specific
(family protein often contains three specific block structures to tripartite motif family (TRIM) family protein, is referred to as
RING, B-BOX and frizzled domain.Their collective effects are incorporated on the protein that cell no longer needs, by these protein bands
Upper ubiquitin tag derives from internal body to degrade and a kind of important component of cell membrane repair mechanism, in view of it,
And there is good cell membrane to repair function, therefore have good application prospect, and it is reported that at present only in cardiac muscle, lung, kidney, bone
There are obvious curative effects in multiple organ failures such as bone, skin and reparation, do not find the expression of MG53 albumen in brain, that is to say, that
Exogenous introducing cannot can only be relied on to play by activating endogenous MG53 protein actives to play its cytoprotection and repair
Effect, thus for develop it is a kind of containing MG53 or and its mutant composition, become can be used for enter blood-brain barrier, it is right
The various neurogenic diseases for seriously threatening human health play remarkable effect, will be of great advantage to human health development.According to
It has been reported that MG53 can be used as E3 ligases, the degradation of mediate insulin receptor and substrate 1, Jin Eryin
Play insulin resistance and metabolic disease (such as diabetes B) and its cardiovascular complication, thus select suitable MG53 or
The preparation of its mutant studies its rational effective dose, and the exploitation higher nerve protection medicine of safety will be significant.
Invention content
The purpose of the present invention is being directed to the above technical problems to be solved, a kind of composition of the mutant containing MG53 is provided and is existed
Prepare the application in nerve protection medicine.
To achieve the above object, technical solution provided by the invention is：
A kind of application of the object of mutant combinations containing MG53 in being used to prepare nerve protection medicine.
Further, the MG53 mutant combinations objects are following any or any one and corresponding excitement
One kind in agent and/or antagonist：
1) include MG53 mutant polypeptides；
2) include the nucleic acid for encoding MG53 mutant polypeptides；
3) include MG53 mutant polypeptides, encode the nucleic acid of MG53 mutant polypeptides.
Wherein, the agonist includes phosphatidylserine, zinc or zinc salt, calcium ion, Zn-1- pyridone -2- thioketones
(Zn-HPT), one or more of Radix Notoginseng, oxidant, thiomersalate combine.
Further, the drug includes the preparation or excipient or pharmaceutically acceptable carrier of therapeutic dose.
Further, the therapeutic dose of the drug is the 2mg/kg-50mg/kg in terms of MG53 mutant.
Further, the pharmaceutical preparation is powder-injection, liquid drugs injection, capsule, granule, tablet, pill, sublingual tablet, lung
It sucks any in preparation, enteric coated preparations.
Preferably, the pharmaceutical preparation is powder-injection.
Further, the neurocyte protection refers to neural cell injury caused by mitigating oxidative stress and activity drop
It is low.
Further, the neurocyte protection be to the abnormal death of the specific neuron of central or peripheral nervous system,
Lead to the protection of nervous function major defect.
Further, the application is to prepare to prevent or treat ischemia apoplexy, encephalatrophy, senile dementia, polyphyly
System atrophy, encephalatrophy disease, motor neuron disease, ataxia telangiectasia, spinal muscular atrophy, optic nerve wither
Application in the drug of one or more diseases in contracting.
Further, the serine sites in the Coiled-coil structural domains that the MG53 mutant is MG53 sport
Nonpolar amino acid in addition to threonine and tyrosine, the MG53 mutant be selected from MG53 S150A, MG53 S189A,
It is one or more in MG53 S211A.
Preferably, the serine sites in the Coiled-coil structural domains that the MG53 mutant is MG53 sport non-
Polar amino acid alanine, the MG53 mutant are one kind in MG53 S150A, MG53 S189A, MG53 S211A
Or it is a variety of.
One embodiment of the invention is：The object of mutant combinations containing MG53 is used for the guarantor of nerve cell oxidative damage
The application of shield, the H of the neuron degeneration apoptosis by being widely used in oxidative stress induction2O2Induce SH-SY5Y cell oxygen
Change damage model, reflects the object of mutant combinations containing MG53 to H2O2Caused by cellular damage and work caused by cell oxidative damage
Property reduce cell have significant protective effect.
The present invention another specific embodiment be：The object of mutant combinations containing MG53 is used to prepare in treatment ischemic brain
Application in expelling wind drug object passes through vWF ELISA after immunohistochemical method observation cerebral ischemia
Angiogenesis is observed in the expression of (yonwillebrandfactor, vWF), and test result shows the object of mutant combinations containing MG53
The infarct of improvement cerebral ischemic reperfusion in rats that can be different degrees of, nervous function, can stimulate angiogenesis.
A still further embodiment of the present invention is：The object of mutant combinations containing MG53 is used to prepare treatment quick aging encephalatrophy
And the application in anti-dementia agent reflects the improvement that the object of mutant combinations containing MG53 can be different degrees of by shuttle box test
The learning and remembering ability of SAMP10 mouse, to prove that it can be applied to prepare treatment quick aging encephalatrophy and anti-dementia agent
In.
In addition, inventor has carried out the experiment of safety exploration, gives exogenous MG53 mutant single-dose, connects
Continuous 7 days intravenous injection (i.v.) 12,24mg/kg will not cause rat blood routine, blood biochemistry, weight and behaviouristics, tissue disease
The variation of reason.It is more than clinic dosage from the angle analysis of druggability intravenous injection safety dosage 24mg/kg, therefore does not influence
It is used for the druggability of the treatment of neuroprotection.
In addition, according to acute toxicity early period and long term toxicity test the results show that the composition of the mutant containing MG53 does not have
It observes any security risks, therefore, can be used for a long time from the composition of security standpoint mutant containing MG53, met
The long-term treatment demand of neuroprotection has good popularizing application prospect.
By taking above scheme, the beneficial effects of the invention are as follows：MG53 mutant can penetrate blood-brain barrier, and reach
Rat brain.In treating cerebral ischemia re-pouring case, MG53 mutant group improves rat brain and lacks compared with positive drug Edaravone
The infarct size and nervous function of blood Reperfu- sion are better, and can stimulate angiogenesis；Treatment quick aging encephalatrophy and
In anti-dementia agent, MG53 mutant group is compared with positive drug Piracetam, improvement SAMP10 mouse that can be different degrees of
It practises, memory capability.Therefore, in conjunction with the MG53 mutant advantage of itself, it can will contain MG53 mutant combinations objects and prevent as preparation
With treat neurodegenerative drug, to reach neuroprotection.
Description of the drawings
The MG53 of Fig. 1 various concentrations and the cell survival rate figure of mutant protein；
Rat cerebral tissue's typical pathologic slice of Fig. 2 HE dyeing sham-operation groups；
Rat cerebral tissue's typical pathologic slice of Fig. 3 HE dyeing model groups；
Rat cerebral tissue's typical pathologic slice of Fig. 4 HE dyeing yidalaphon groups；
Rat cerebral tissue's typical pathologic slice of Fig. 5 HE dyeing MG53 mutant 2.25mg/kg dosage groups；
Rat cerebral tissue's typical pathologic slice of Fig. 6 HE dyeing MG53 mutant 3mg/kg dosage groups；
Rat cerebral tissue's typical pathologic slice of Fig. 7 HE dyeing MG53 mutant 4mg/kg dosage groups.
Specific implementation mode
The present invention is described in further detail with reference to the accompanying drawings and examples, but is not limited to the specific implementation
Example.Those of ordinary skill in the art without departing from the spirit and scope of the invention can to the details of technical solution of the present invention and
Form is modified or is replaced, but these modifications and replacement are each fallen in protection scope of the present invention.
In following embodiment, MG53 mutant is that the serine sites in the Coiled-coil structural domains of MG53 sport
Non-polar amino acid alanine, the MG53 mutant are MG53 S189A.
Embodiment 1：Neurocyte protection is tested
(1) experimental principle：
H2O2Caused by cell oxidative damage have become one of the important method of Studies On Neuronal oxidative damage.
SH-SY5Y cell differentiations are relatively low, and cellular morphology, physiology and biochemical function are similar to Normal neuronal cells, and
With apparent aixs cylinder, to H2O2Induced oxidation stress have high susceptibility, H2O2Induce SH-SY5Y cell oxidative damage moulds
Type is widely used in the research of the neuron degeneration apoptosis of oxidative stress induction.
(2) experiment material
SH-SY5Y cells：It is purchased from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences's cell resource center；
1640 culture mediums and FBS (Fetal Bovine Serum)：It is purchased from Gibco companies；
MG53 mutant proteins：Our company builds strain, fermentation, purifying gained, lot number 20170301；
CCK-8 cell Proliferations and activity detection kit：It is purchased from colleague's chemistry institute (CK04).
(3) experimental method
1, the preparation of experimental cell：
SH-SY5Y cell culture, condition of culture：1640 culture mediums, 10%FBS, 5%CO237 DEG C of cultures of incubator.It takes pair
Number phase SH-SY5Y cells adjust concentration of cell suspension after pancreatin digestion, are added in 96 well culture plates, per 100 μ l of hole, 37 DEG C,
5%CO2Condition continues to cultivate, for 24 hours after, be separately added into 25 μ g, 50 μ g, 100 μ g, tri- concentration gradients MG53 and MG53 mutation
Body protein.
2、H2O2Damage and CCK-8 detections：
200 μM of H of final concentration are added in culture medium in each hole cell of 96 porocyte plates2O2Culture medium, handle 1h cells,
The CCK-8 reagents of 10 μ l are added per hole, continue to be incubated 2-4h；Microplate reader measures the OD values at 450nm.The cell for calculating each hole is deposited
Motility rate.
Cell activity (%)=(dosing group OD values-blank OD values/control group OD values-blank OD values) × 100%
(4) experimental result and analysis
As shown in Figure 1, with the increase of MG53 and MG53 mutant protein concentration, H2O2The cell survival rate of damage is gradual
It increases, cell state is significantly improved.Show MG53 and mutant protein to H2O2Caused by caused by cell oxidative damage
Cellular damage and activity reduce, and have significant protective effect to cell.And MG53 mutant effects are slightly excellent.
Embodiment 2：Influence of the composition of the mutant containing MG53 to cerebral ischemic reperfusion in rats
(1) experimental principle
Cerebral artery comes from bilateral internal carotid artery and vertebral artery, before brain bottom forms Basilar Artery Rings, is divided into brain, in,
Artery, the laggard human brain essence of branch in pia mater, therefore the cerebrovascular is divided into as brain parenchym blood vessel and the outer blood vessel of essence.Block branch
Blood vessel with brain tissue can simulate the pathological model close with human brain palsy, for pathology, physiology, Biochemical Research and evaluation medicine
Object is used.Clinical and experimental cerebral ischemia includes global cerebral ischemia and local cerebral ischemia, wherein can be divided into ischemia and permanent again
Ischemic.The cerebrovascular occlusion of people is most commonly seen with arteria cerebri media, and it is that evaluation human brain soldier is most classical to block intraluminal middle cerebral artery occlusion in rats
Method, cortex of cerebral hemispheres and basal nuclei ischemia injury can be caused similar with the pathological change of people's palsy.
Since brain tissue ischemia, anoxic cause half dark space neuronal degeneration of ischemic, necrosis after cerebral ischemia, and lead to neural work(
Energy defect, therefore, the blood supply for restoring ischemic region as early as possible is most important to the recovery of nervous function after ischemic, and ischemic half is dark
The recovery of area's blood flow depends on the foundation of Doppler flow mapping.Angiogenesis is a kind of effective ways for improving tissue blood flow supply,
It is very crucial to the prognosis of paralytic, it is one of the hot spot of apoplexy research in recent years.It is observed by immunohistochemical method
The expression of vWF ELISA (yonwillebrandfactor, vWF) is to observe a public affairs of angiogenesis after cerebral ischemia
Verifying method.
(2) experiment material
SD rats：250g~290g, male, is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., credit number：
SCXK (capital) 2012-0001；
MCAO model nylon embolus lines：Shadong Biological Technology Co., Ltd., Beijing；
Sodium chloride injection：Shijiazhuang Siyao Co., Ltd, lot number：1701023203；
Chloraldurate：Beijing Chemical Plant, lot number：20170119；
MG53 mutant：MG53 mutant is that our company builds strain, fermentation, purifying gained, lot number 20170301；
VWF monoclonal antibodies, Sigma Co., USA, lot number：IMPFG
Rhodamine is red, Sigma Co., USA, lot number：1607UIP
Fluorescein isothiocyanate, Sigma Co., USA, lot number：1609YLQ；
Brd U monoclonal antibodies are purchased from Chemico companies of the U.S., lot number：IgPFG；
SABC kits, Beijing Bioisystech Co., Ltd of Zhong Shan Golden Bridge, lot number：160807；
AEC color developing agents are purchased from Beijing Bioisystech Co., Ltd of Zhong Shan Golden Bridge, lot number：161201；
TTC, Wuhan Boster Biological Technology Co., Ltd., lot number：160402.
(3) preparation of MG53 mutant combinations object freeze-dried powder
Auxiliary material：Mannitol, histidine, sucrose etc..
Preparation method：Auxiliary material is dissolved, while the auxiliary material of dissolving being mixed with corresponding MG53 mutant proteins stoste, is adjusted
PH value to 6.5, to obtain the MG53 mutant proteins comprising 0.5mg/ml, 50mg/ml mannitol, 25mg/ml sucrose,
The solution of 25mg/ml histidines.The solution filtration sterilization that will be obtained, freeze-drying, as lyophilized preparation, packing.
(4) experimental method
1, grouping and modeling：Using SPF grades of male SD rats 60, in 22-25 DEG C of room temperature, relative humidity 50%-60%,
It is tested after adaptability raising 3d in 12h light and shade alternate environments.12h is deprived of food but not water before experiment, and chloraldurate 0.35~
0.4g/kgi.p. is anaesthetized, and rat dorsal position is fixed, and is hit exactly along neck and is made about 2cm long skin incisions, isolates right carotid
And it is spare to wear 2, suture.External carotid artery is isolated again, ligatures it.Below external carotid artery careful separation go out internal carotid and its
One, side subbranch, wears a suture under branch, it is ligatured in nearly crotch.It is used in separated arteria carotis communis proximal part
Nylon bar is inserted into small by artery clamp blocking blood flow, distal end one suture gently pull-up in cutting an osculum on arteria carotis communis
Mouthful, it is slowly pushed at anterior cerebral artery nylon wire scale (20mm) and about 2mm is drawn to brain mesencephalic arteries mouth, to use suture further back
The fixed nylon bar of ligation.Another suture ligature of last proximal part, removes artery clamp, sutures muscle and skin, has performed the operation
Finish and steams again raising.2h carries out Reperfu- sion after modeling：Nylon wire is back extracted at external carotid artery, so that it may carry out Reperfu- sion, then fill
End of line intravenous injection of going forward side by side after note 15min is administered, administered volume 5.4mL/kg.And after modeling for 24 hours, carries out nervous function and comment
Divide (Longa methods).TTC is dyed：By rat anesthesia, cuts head from the back side and take out brain, put at once after being rinsed with 0.01PBS
Enter to be rapidly frozen 30min in -20 DEG C of refrigerators and be preced with from before brain between pole and optic chiasma line midpoint and infundibular stalk and trailing pole
Shape slice cuts 1 every 2mm, generally cuts 5~6, is placed in 2%TTC, and 37 DEG C are protected from light 20~30min of water-bath, and does normal
Rat brain TTC dyeing calculates rat cerebral infarction volume with paired observation degree of ischemia.Then carry out " Hematoxylin-eosin dyeing
(HE dyeing) "：Brain tissue is subjected to dewaxing aquation, histotomy is placed in 65 DEG C of ovens and carries out baking 2h, after taking-up successively
It is dewaxed by following reagent：Dimethylbenzene, 10min → dimethylbenzene, 10min → absolute ethyl alcohol, 3min → absolute ethyl alcohol, 3min
→ 95% ethyl alcohol, the ethyl alcohol of 3min → 80%, the ethyl alcohol of 3min → 75%, 3min.Then start HE dyeing courses, dd H2O are rinsed
5min is put into haematoxylin solution, dyes 5min, is taken out slice and is gently rinsed the slice several seconds using flowing water, washes away bush sperm.
About 3s is impregnated with 1% acidic alcohol differentiation liquid again, quickly removes and is rinsed again no more than 30s with tap water, then washed with dd H2O
2s is immersed in 1% Yihong solution and dyes 3min, then rinses 2s with dd H2O, and passes sequentially through 80% ethyl alcohol, 95% ethyl alcohol,
95% ethyl alcohol each 5s every time, then it is immersed in 10min in absolute ethyl alcohol successively, carboxylol 10min, dimethylbenzene 2min (is followed
Ring impregnates 3 times), entire HE dyeing courses are completed, after slice air-dries, neutral gum mounting.System is observed under inverted microscope
The paraffin section performed.
2, sample disposal：Rats by intraperitoneal injection chloraldurate (4mL/kg) anesthesia to be drawn materials is fixed, thoracic cavity is opened and fills
Divide exposure heart, No. 6 syringe needles of injection are inserted into aorta by the apex of the heart and fix syringe needle, cut off right auricle of heart, quickly instills
0.01mol/LPBS (100mE), while folder closes abdominal aorta, changes drop 4 after the outflow of no blood stains or fore paw and lung's color bleach
DEG C 4% paraformaldehyde (about 200mE) it is fixed, first quick and back slow, open cranium and take brain and remove cerebellum and only retain brain, be put into 4%
It is fixed at 4 DEG C in paraformaldehyde to be then sequentially placed into 20% and 30% sucrose solution for 24 hours and sink to the bottom 48h progress serial dehydrations,
OTC is embedded, and frozen section, taking optic chiasma, coronal cut is done at 8mm arteria cerebri medias blood supply region i.e. hippocampus position to 5mm backward forward
Piece, cuts 3 every 2 and is taken as sample by 25 μm/piece, is respectively used to the dyeing of immunohistochemistry BrdU, vWF zymetology and BrdU/
The double mark dyeing of vWF fluorescence.
3, single mark zymetology immunohistochemical method：OTC is embedded, frozen section；Slice is put into 3%H2O2It is soaked in deionized water
10min inactivates endogenous peroxidase enzymatic activity；0.01mmol/LPBS washes 5min × 3；10 μ L Normal Goat Serum room temperatures are added dropwise
Lower closing 30min；VWF antibody (1: 100) 10 μ L, 37 DEG C of water-bath 3h is added；0.01mol/LPBS washes 5min × 3；It is added general
Biotinylation secondary antibody 10L, 37 DEG C=water-bath 30min；0.01mol/LPBS washes 5min × 3；Horseradish enzyme is added and marks strepto- albumen
10 μ L, 37 DEG C of water-bath 30min of element；0.01mol/LPBS washes 5min × 3；AEC color developing agents 10min is added dropwise；0.01mol/LPBS is washed
3min×2；Patch and with water-soluble mountant mounting；It replaces primary antibody to make blank control with 0.01mol/LPBS simultaneously to check to exempt from
The specificity of epidemic disease reaction simultaneously excludes false positive results.
4, Shuan Biao fluorescent immunohistochemistry methods：3%H2O210min is soaked in deionized water；PBS washes 5min × 3；2mol/
LHC137 DEG C of leaching 15min；PBS washes 5min × 3；5% lowlenthal serum closes 30min at room temperature, sucks and does not wash；BrdU Dan Ke are added
Grand antibody (1: 100) 10 μ L, 37 DEG C of water-bath 3h；PBS washes 5min × 3；Rhodamine (570~590nm of wavelength of transmitted light, feux rouges) contaminates
Color, 37 DEG C of water-bath 30min；PBS washes 5min × 3；5% lowlenthal serum closes 30min at room temperature, sucks and does not wash；vWF(1∶100)
10 μ L37 DEG C water-baths 3h；PBS washes 5min × 3；FITC (wavelength of transmitted light 520~530nm, yellow-green light) is dyed, 37 DEG C of water-baths
30min；PBS washes 5min × 3；Patch uses glycerine mounting after natural air drying.
5, positive cell and new vessels count：AEC colour developings are red, and when list marks immunohistochemistry, red is the positive
Expression.In cortex wavelength in green, rhoda-mine labels take on a red color FITC labels in cortex wavelength, then carry out weight with software
Folded, it is double mark positive cells to dye as yellow.Every animal takes hippocampus position different section to be sliced 5, is placed in 10 × 20 times of light
Under mirror, every slice randomly selects 5 visuals field, is counted automatically with Olympus Image-Pro Plus5.1 image processing systems
Positive cell and new vessels number, calculate its average value.The most region of every slice 3 blood vessel of selection, in 10 × 20 times of light
It is counted under mirror.
(4) experimental result and analysis
Influence of the table 1 to cerebral ischemic reperfusion in rats
It is compared with sham-operation group, * represents p ＜ 0.05, and * * represent p ＜ 0.01, and * * * represent p ＜ 0.001；With model group pair
Than,△P ＜ 0.05 are represented,△△P ＜ 0.01 are represented,△△△Represent p ＜ 0.001；
It is shown by table 1, compared with model group, positive drug Edaravone group, MG53 mutant various dose groups are in Reperfu- sion
Intervene when 15min afterwards, when Neuroscore reduces the cerebral infarction volume percentage of medicine group compared to model group, illustrates MG53
It is mutated the infarct size and nervous function of the different degrees of improvement cerebral ischemic reperfusion in rats of physical efficiency, certain dose-dependant is presented
Property, infarct size is corresponding with nervous function effect height, and is improved largely compared to positive drug Edaravone drug effect.
It shows that sham-operation group is normal cerebral tissue by Fig. 2-Fig. 7, has no that the necrosis of any tissue cell insult, tissue are thin
Intercellular space arrangement is close, and structure is normal.Brain tissue necrotic zone is maximum on the left of model group, and degree of necrosis is most apparent, and cell occurs
Balloon sample becomes, and endochylema is empty thoroughly, and tissue cellularity is disorganized, irregular, and Dilated intercellular space has apparent oedema.Surrounding star
The apparent hyperplasia of shape cell, visible apparent thin vessels expand hyperplasia under mirror, and intravascular have extravasated blood.Compared with model group, according to up to
The left side brain tissue necrotic zone of La Feng groups and MG53 mutant various dose groups significantly reduces, the degree of necrosis of brain tissue cell
Also substantially reduced, space between cells diminution, oedema unobvious, astrocytosis degree and thin vessels hyperplasia degree are all relatively light.
Table 2 is expressed cerebral ischemic reperfusion in rats 5- bromodeoxyuridine nucleosides and the influence of vWF
It is compared with sham-operation group, * represents p ＜ 0.05, and * * represent p ＜ 0.01, and * * * represent p ＜ 0.001；With model group pair
Than,△P ＜ 0.05 are represented,△△P ＜ 0.01 are represented,△△△Represent p ＜ 0.001；
Angiogenesis refers to being given birth to by vascular endothelial cell proliferation, migration, bud on original Vascular basis, blood vessel division,
Branch and form new capillary network, so that its function is needed adaptable biological process with part.Include mainly three companies
Continuous link：(1) vascular remodeling, permeability increase, Basement Membrane Dissolution, extracellular matrix degradation, remodeling；(2) endothelial cell
Proliferation, migration；(3) formation of tube wall and tube chamber, mould again, new vessels network is formed.Meanwhile angiogenesis is a complexity again
Multistep process, and by the regulation and control between a variety of angiogenesis factors, cell factor and its inhibiting factor, reflect positive and negative
The growth and decline of angiogenesis instrumentality balance.Compared with model group, the effect that positive drug Edaravone group increases angiogenesis is not strong；
MG53 mutant various dose groups are intervened after Reperfu- sion when 15min, and sham-operation group and positive controls, MG53 mutant are compared
The expression of 5- bromodeoxyuridine nucleosides and VWF have and significantly increase, dose-effect relationship is apparent, illustrates that MG53 mutant can
Angiogenesis is stimulated, it is consistent with infarct size and Neuroscore result.
Embodiment 3：Influence of the object of mutant combinations containing MG53 to quick aging encephalatrophy and Model of Dementia mouse model
(1) experimental principle
Alzheimer's disease (AD) is the big brain degenerative disease based on progressive dementia that occurs with aging, is mainly faced
Bed shows as memory loss, hypophrenia and behavior personality regression, still lacks effectively preventing measure so far.Behaviors survey
It is the common experimental method for specializing in animal behavior variation, commonly used in observation and research nerve, spirit and psychology etc.
Anomalous variation or performance, had a very important significance in basic research, and judge dull-witted one of basic skills.It wears
Shuttle box experiment is the important means that quantitative test Animal Behavior Science changes.The animal model that the present embodiment uses is introduced from Japan
Natural Senescence-Accelerated Mouse SAM (SenecenceA DEG C of elerateMouse), wherein SAMP10 Strains of Mouse is to learn
Memory disorders, encephalatrophy are characterized, closely similar with mankind's encephalatrophy and dementia, are internationally recognized encephalatrophy and dull-witted mould
Type；SAMR1 is with age normally at the uniform velocity aging is increased, usually as the normal control of P strains.
(2) experiment material
SAMP10 male mices 50, SAMR1 male mices 10, equal 6 monthly age are purchased from Beijing dimension tonneau China experimental animal
Technology Co., Ltd., credit number：SCXK (capital) 2012-0001；
DCS-2 mouse shuttle box auto-controllers, institute of Materia Medica,Chinese Academy of Medical Sciences；
Sodium chloride injection, Shijiazhuang Siyao Co., Ltd, lot number：1701023203；
Piracetam Injection, Tianjin Chasesun Pharmaceutical Co., Ltd, lot number：1701042301；
MG53 mutant：Our company builds strain, fermentation, purifying gained, lot number 20170301；
(3) preparation of MG53 mutant combinations object freeze-dried powder
Auxiliary material：Mannitol, histidine, sucrose etc..
Preparation method：Auxiliary material is dissolved, while the auxiliary material of dissolving being mixed with corresponding MG53 mutant proteins stoste, is adjusted
PH value to 6.5, to obtain the MG53 mutant proteins comprising 0.5mg/ml, 50mg/ml mannitol, 25mg/ml sucrose,
The solution of 25mg/ml histidines.The solution filtration sterilization that will be obtained, freeze-drying, as lyophilized preparation, packing.
(4) experimental method
Using 6 monthly age SAMP10 male mices 50 of propagating and breeding, 5 groups are randomly divided into, tail vein injection is administered 1 day 1
It is secondary, continuous 1 week.Shuttle box：Using DCS-2 mouse shuttle box auto-controllers, in quiet environment, daily 8：00`12：
00 carries out, 22-25 DEG C of room temperature.Mouse is first placed in test box freely activity 5min before test, to eliminate its exploratory reflex.Journey
Sequence is set as：Buzzing 5s, followed by electro photoluminescence 15s are spaced 15s, then repeatedly above procedure, so cycle 20 times.Computer will be certainly
Dynamic record unconditioned reflex number (i.e. number of shocks), get shocked the parameters such as time and active reaction time, with overall merit
The ability of learning and memory of mouse.
(5) experimental result and analysis
Table 3 acts on quick aging encephalatrophy and Model of Dementia mouse model
It is compared with model group,△P ＜ 0.05 are represented,△△P ＜ 0.01 are represented,△△△Represent p ＜ 0.001；
Compared with model group, positive drug Piracetam group and MG53 mutant various dose groups are in number of shocks, electric shock
Between reduce compared to model group, and the active reaction time compared to model group extension, certain dose-effect relationship is presented, explanation
The learning and remembering ability of positive drug and the different degrees of improvement SAMP10 mouse of MG53 mutant energy.
In order to further realize technical scheme of the present invention, freeze-dried powder dosage is only disclosed in above-mentioned experiment is respectively
2.25mg/kg groups, 3mg/kg groups and 4mg/kg groups, but pass through the measurement of inventor, dosage is not limited only to above three groups of feelings
Condition, when being less than 2mg/kg with enema dose, function and effect are less obvious, therefore, freeze-dried powder are limited to for dosage
Injection is not less than 2mg/kg.
In order to further prove that the technique effect of the present invention, inventor have carried out the experiment of safety exploration, give outer
The MG53 mutant single-dose of source property, continuous 7 days intravenous injections (i.v.) 12,24mg/kg will not cause rat blood routine,
The variation of blood biochemistry, weight and behaviouristics, histopathology.From the angle analysis of druggability intravenous injection safety dosage 24mg/
Kg is much larger than effective dose, and safety time limit ＞=1w (it is 3-5 days that the course for the treatment of, which is fixed tentatively), therefore does not influence MG53 mutant and be used for
Neurodegenerative drug is prevented and treated as preparing, to reach neuroprotection
The above is only a preferred embodiment of the present invention, it is not intended to limit the present invention in any form.It should
It points out, for those skilled in the art, without departing from the principle of the present invention, if can also make
Dry improvements and modifications, these improvements and modifications also should be regarded as protection scope of the present invention.Therefore, the present invention is not intended to be limited to
The embodiments shown herein, and it is to fit to widest model consistent with the principles and novel features disclosed in this article
It encloses.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.
Claims (9)
1. a kind of application of object of mutant combinations containing MG53 in being used to prepare nerve protection medicine.
2. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 1
With, which is characterized in that MG53 mutant combinations objects it is following any or any one and corresponding agonist
And/or one kind in antagonist：
1) include MG53 mutant polypeptides；
2) include the nucleic acid for encoding MG53 mutant polypeptides；
3) include MG53 mutant polypeptides, encode the nucleic acid of MG53 mutant polypeptides.
3. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 1
With, which is characterized in that the composition of the mutant containing MG53 can be used for preparing the application in nerve protection medicine, and the drug includes
The preparation or excipient or pharmaceutically acceptable carrier of therapeutic dose.
4. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 3
With, which is characterized in that the pharmaceutical preparation is powder-injection, liquid drugs injection, capsule, granule, tablet, pill, sublingual tablet, lung sucking
It is any in preparation, enteric coated preparations.
5. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 1
With, which is characterized in that the neurocyte protection, which refers to neural cell injury caused by mitigating oxidative stress and activity, to be reduced.
6. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 1
With, which is characterized in that the neurocyte protection is caused to the abnormal death of the specific neuron of central or peripheral nervous system
The protection of nervous function major defect.
7. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 1
With the application is to prepare to prevent or treat ischemia apoplexy, encephalatrophy, senile dementia, multi-system atrophy, encephalatrophy
One kind or more in disease, motor neuron disease, ataxia telangiectasia, spinal muscular atrophy, optic atrophy
Application in the drug of kind disease.
8. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 1
With, which is characterized in that the MG53 mutant is that the serine sites in the Coiled-coil structural domains of MG53 are sported except Soviet Union
Nonpolar amino acid other than propylhomoserin and tyrosine, the MG53 mutant are selected from MG53 S150A, MG53 S189A, MG53
It is one or more in S211A.
9. a kind of object of mutant combinations containing MG53 answering in being used to prepare nerve protection medicine according to claim 8
With the MG53 mutant, which is characterized in that the MG53 mutant is the silk in the Coiled-coil structural domains of MG53
Propylhomoserin site mutation be non-polar amino acid alanine, the MG53 mutant be selected from MG53 S150A, MG53 S189A,
It is one or more in MG53 S211A.
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