CN102389569A - Application of ErbB receptor agonist in preparing medicines for treating ischemic cerebrovascular diseases - Google Patents
Application of ErbB receptor agonist in preparing medicines for treating ischemic cerebrovascular diseases Download PDFInfo
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- CN102389569A CN102389569A CN201110354663XA CN201110354663A CN102389569A CN 102389569 A CN102389569 A CN 102389569A CN 201110354663X A CN201110354663X A CN 201110354663XA CN 201110354663 A CN201110354663 A CN 201110354663A CN 102389569 A CN102389569 A CN 102389569A
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Abstract
The invention provides an application of an ErbB receptor agonist in preparing medicines for treating ischemic cerebrovascular diseases By using neuronal injury models in vivo and in vitro as a research platform, the protection function of NRG1 to neuronal cell injuries and experimental cerebral ischemia are discovered, simultaneously the possible molecular mechanism of NRG1 is fully researched, and the cerebral protection effect by regulating and controlling NRG1-ErbB4 associated signal pathway after ischemic cerebral ischemia is fully argued, thus the study of NRG1 and associated ErbB4 agonist open up wide prospects for developing novel medicines for protecting cerebral neurocyte and controlling ischemic cerebrovascular diseases.
Description
(1) technical field
The present invention relates to the application of ErbB receptor stimulating agent in the medicine of preparation treatment ischemic cerebrovascular.
(2) background technology
Cerebrovascular is the 3rd lethal factor of population of China, and wherein cerebral infarction accounts for 75%, and M & M is constantly soaring, is the major disease that has a strong impact on China's people ' s health and national economy.The sickness rate of cerebrovascular becomes positive correlation with the age, along with China's population aging degree increases the weight of.Its morbidity is in rising trend.With the apoplexy is example, and the annual sickness rate of China is 1,50/,100,000 people, and mortality rate is 1,20/,100,000 people, has 75% to disable in the survival approximately, and 5 years relapse rates have caused society and financial burden to increase the weight of day by day up to 41% thus.
According to World Health Organization's statistics, the M & M of China's apoplexy is high to occupy first place in the world.Patients with cerebral ischemic not only will be tided over the various complication of acute stage, long-term invalid huge material and the financial burden that brings that also faces the future possibly, and therefore, seeking effective and safe medicine is one of biomedical important target.
ErbB4 has abundant expression at brain, and has research to show that ErbB4 participates in regulating neurodevelopment and synaptic plasticity.In case combine with NRG1, ErbB4 promptly is activated, the network propylhomoserin residue generation phosphorylation of its carboxyl terminal is also assembled connection albumen such as Shc and Grb2 etc., and then activate the Ras-Raf-Erk signal path.The intracellular region territory of ErbB4 can also combine and activate PI3 kinases and Akt.Different with many receptor kinases is that the NRG1/ErbB4 signal path also receives the adjusting of RNA montage.First pair of found ErbB4 isomer main distinction is exactly that its born of the same parents' inner segment contains or do not contain one section segment (being called as CYT-1 and CYT-2 respectively) of being made up of 16 aminoacid of exon 26 codings.This segment contains the concensus sequence that network propylhomoserin-X-X-methionine constitutes, and is PI3 kinases calmodulin binding domain CaM.Therefore, CYT-1 can activate the PI3kinase/Akt path, and CYT-2 is this function of tool not then, but CYT-1/2 all can activate the Erk path.Ironically, the CYT-1 isomer is found in the ischemic brain injury brain recently and was expression.On the contrary, the CYT-2 isomer presents similar expression with normal control.Consider that NRG1 and ErbB4 all are tumor susceptibility genes of ischemic brain injury, these are found to be the unusual NRG1/ErbB4 signal path of ischemic brain injury patient and the association between the GABA activity provides a kind of explanation.
(Neuregulin-1 NRG) is one type of polypeptide factor to neuregulin, is made up of the coded product alternative splicing body of nrg21 gene.NRG is a kind of one of growth factor family member with neuroprotective that is proved to be.NRGs can combine with ErbB3, the ErbB4 tryrosinase of ErbB family; Thereby form ErbB homodimer and heterodimer; Generally include ErbB2); Then active cell external signal pathway produces a series of cell effects, comprises hypertrophy, apoptosis, migration, differentiation and adherent active or inhibition.The functional receptor of neuregulin is made up of the ErbB tyrosine kinase receptor, and ErbB albumen is EGF-R ELISA, comprises ErbB2, ErbB3, ErbB4.
In ischemic cerebrovascular, be that the protection medicine of correlation signal transduction pathway under the ischemic brain injury pathologic condition of target spot do not appear in the newspapers and patent as yet with ErbB.
(3) summary of the invention
The present invention has studied the protective effect of ErbB4 agonist NRG1 to ischemic brain injury; For novel effectively " target " molecule of exploring ischemic brain injury protection medicine provides research direction, the brain that is the basis with the brain neuron pathological changes for treatment is that disease provides the candidate therapeutic medicine.
The technical scheme that the present invention adopts is:
The application of ErbB receptor stimulating agent in the medicine of preparation treatment ischemic cerebrovascular.So-called ErbB4 receptor stimulating agent is meant neuregulin-1 NRG-1 Neu Differentiation Factor NDF glial growth factors GGF (Neuregulin-1).Said Neuregulin-1 is divided into two kinds of endogenous and exogenous agonist.Exogenous Neuregulin-1 is people's recombinant protein N euregulin-1beta 2 (NRG1), the polypeptide chain that it is made up of 61 aminoacid.Endogenous Neuregulin-1 produces used ErbB4 extracellular fragment (aa1-659, the part that ecto-ErbB4) neutralizes here by neuron or glial cell.
Preferably, said ErbB receptor stimulating agent is the ErbB4 receptor stimulating agent.
Concrete, said ErbB receptor stimulating agent is used to prepare the medicine of treatment ischemic brain injury or cerebral infarction.
Said ErbB receptor stimulating agent behaviour recombinant protein N RG1, its aminoacid sequence is following: shlvkcaekektfcvnggecfmvkdlsnpsrylckcpneftgdr cqnyvmasfykaeel yq, molecular weight are 7055 dalton.
The present invention with in the body, external brain neuron injury model is research platform; Explore the protective effect of NRG1 to neuronal cell injury and experimental cerebral ischemia; Further investigate it simultaneously and possibly act on molecular mechanism, fully proved through regulation and control and have cerebral protection NRG1-ErbB4 correlation signal approach behind the ischemic brain injury.Therefore the research of NRG1 and related ErbB4 agonist possibly opened vast vistas for newtype drug, the control ischemic cerebrovascular of exploitation protection brain neuron cell.
Beneficial effect of the present invention is mainly reflected in: the present invention has disclosed the protective effect of ErbB4 agonist NRG1 to neuronal cell injury and experimental cerebral ischemia, and NRG1 has good application prospects as brain-protection drugs behind the prompting ischemic brain injury.
(4) description of drawings
Fig. 1 brings out the protective effect of cultivating neuronal cell injury for NRG1 to OGD;
Fig. 2 is that NRG1 is to the inductive mouse cortex neuronal cell of OGD ErbB4 nuclear shift affects;
Fig. 3 participates in ischemic brain injury pathological process (white expression infarct among the figure A) for the NRG1-ErbB4 signal pathway.
(5) specific embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1:NRG1 brings out the protective effect of cultivating neuronal cell injury to OGD
Medicine and reagent:
High sugared DMEM, high sugared DMEM culture medium are purchased the GIBICO company in the U.S., and NRG1 is available from U.S. Prospec company, and hyclone, newborn calf serum are purchased in Sijiqing Bioengineering Material Inst., Hangzhou City.The ErbB4 rabbit resists (Santa Cruz Biotechnology), Mus two anti-(Amersham Bioscience), and other reagent is the domestic and imported AR.
Cell culture:
Take pregnant 18 days tire Mus, aseptic condition takes out brain down fast and places D.Hank ' s liquid, under anatomic microscope, separates divesting meninges and blood vessel, isolates cerebral cortex, the cortex cerebral tissue is shredded be placed on centrifuge tube.Contain EDTA with 0.25% (w/w) trypsin) 37 ℃ of digestion 15min, stop digestion with the DMEM culture fluid that contains 10% (v/v) serum.Make cell be dispersed into single cell suspension, low-speed centrifugal 10min abandons supernatant.Reuse serum-free DMEM washes 2 times, and with Neurobasal culture medium suspension cell, piping and druming forms single cell suspension.Replenish the B27 supplement (Invitrogen) that add 2% (v/v), the glutamine of 25moI/L in the culture medium.Regulate cell concentration to 1 * 10
6Individual/mL, be inoculated in coverslip, the culture dish (35mm) handled through poly-D-lysine in advance, at 37 ℃, saturated air humidity, contain 5% (v/v) CO
2Incubator in routine go down to posterity cultivate 48h after, add cytarabine hydrochloride to suppress the non-neuron growth.Cultivate 7d and be used for subsequent experimental.
External low sugar anoxia (oxygen and glucose deprive is called for short OGD) model construction:
Single cell suspension is moved into 96 orifice plates, 3 * 10
3Cells/well, 37 ℃, 5%CO
2Cultivate in the incubator, add different disposal when cell merges fully: the blank group is cultivated under normal operation; OGD group and OGD merge NRG1 and organize (5nM), and (prepare by following the composition: NaCl 8.00g, KCl 0.20g, CaCl with the HBSS that is preheated to 37 ℃ in every hole
20.14g, MgSO
4.7H
2O 0.20g, Na
2HPO
4.H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g deionized water complements to 1000mL) clean three times, and change to same medium, more than every group every kind dosage establish parallel 3 holes, put into the anoxia closed box earlier and feed mist and (contain 95%N
2, 5%CO
2) about 5min, then closed box is put into incubator and handle 6h, collecting cell carries out protein quantification then.
Adopt the former foster mouse cortex neuronal cell of being commissioned to train to combine anoxia to lack sugared condition and carry out the protective effect research of NRG1 OGD inducing neural unit cell injury.NRG1 lacks the influence of cell survival rate under the sugared condition behind the mtt assay detection OGD 4h to anoxia.The preliminary experiment result show NRG1 (3nM, 5nM 10nM) can effectively alleviate the neuronal cell dead (Figure 1A) that OGD causes, preliminary identification the neuroprotective of NRG1.In addition, adopt flow cytometry ANNEXIN V-FITC to add two the dying of propidium iodide (PI) and detect the anti-neuronal cell apoptotic effect that apoptosis rate is studied NRG1.Consistent with The above results, the neuronal cell apoptosis rate obviously increased after the apoptosis rate of cells were tested by flow cytometry showed OGD 4h, and NRG1 (5nM) intervention has neuronal cell apoptotic effect (Figure 1B) under the significant anti-OGD condition.
Embodiment 2:ErbB4 lacks subcellular fraction changes in distribution and NRG regulation and control medicine and reagent under the sugared condition in anoxia:
High sugared DMEM, high sugared DMEM culture medium are purchased the GIBICO company in the U.S., and NRG1 is available from U.S. Prospec company, and hyclone, newborn calf serum are purchased in Sijiqing Bioengineering Material Inst., Hangzhou City.The ErbB4 rabbit resists (Santa Cruz Biotechnology), rabbit two anti-(Amersham Bioscience), and other reagent is the domestic and imported AR.
Cell culture:
Take pregnant 18 days tire Mus, aseptic condition takes out brain down fast and places D.Hank ' s liquid, under anatomic microscope, separates divesting meninges and blood vessel, isolates cerebral cortex, the cortex cerebral tissue is shredded be placed on centrifuge tube.Contain EDTA with 0.25% trypsin) 37 ℃ of digestion 15min, stop digestion with the DMEM culture fluid that contains 10% serum.Make cell be dispersed into single cell suspension, low-speed centrifugal 10min abandons supernatant.Reuse serum-free DMEM washes 2 times, and with Neurobasal culture medium suspension cell, piping and druming forms single cell suspension.Replenish in the culture medium and add 2% B27 supplement, the glutamine of 25moI/L.Regulate cell concentration to 1 * 10
6Individual/mL, be inoculated in coverslip, the culture dish (35mm) handled through poly-D-lysine in advance, at 37 ℃, saturated air humidity, contain 5%CO
2Incubator in routine go down to posterity cultivate 48h after, add cytarabine hydrochloride to suppress the non-neuron growth.Cultivate 7d and be used for subsequent experimental.
External low sugar anoxia model makes up:
Single cell suspension is moved into 96 orifice plates, 3 * 10
3Cells/well, 37 ℃, 5%CO
2Cultivate in the incubator, add different disposal when cell merges fully: the blank group is cultivated under normal operation; OGD group and OGD merge NRG1 and organize (5nM), and (prepare by following the composition: NaCl 8.00g, KCl 0.20g, CaCl with the HBSS that is preheated to 37 ℃ in every hole
20.14g, MgSO
4.7H
2O 0.20g, Na
2HPO
4.H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g deionized water complements to 1000mL) clean three times, and change to same medium, more than every group every kind dosage establish parallel 3 holes, put into the anoxia closed box earlier and feed mist and (contain 95%N2,5%CO
2) about 5min, then closed box is put into incubator and handle 6h, collecting cell carries out protein quantification then.
Immunoblotting detection by quantitative NRG1 induces former being commissioned to train to support the influence that neuronal cell ErbB4 distributes again to OGD: the former foster neuronal cell OGD that is commissioned to train damages back ErbB4 memebrane protein expression and changes detection by quantitative, and albumen BIAO and BEN electrophoresis, commentaries on classics film, 5% defatted milk powder room temperature were sealed 45 minutes.Drip the ErbB4 rabbit and resist (1: 500), 4 ℃ are spent the night.10mM PBS washed 3 times each 5 minutes.Dripped rabbit anti-two anti-(1: 2000) room temperatures 120 minutes.10mM PBS washed 3 times each 5 minutes, and the ECL chemoluminescence method develops.Band to immunoblotting carries out quantitative analysis.
The preliminary experiment result finds that tangible morphological change has taken place the former foster mouse cortex neuronal cell of being commissioned to train behind OGD 4h: cell shrinkage, conglomeration, projection shorten (Fig. 2 A).Simultaneously, OGD has brought out ErbB4 and has changed nuclear change (Fig. 2) over to by cell membrane.Laser co-focusing immunofluorescence histochemistry (Fig. 2 A) and Western Blot (Fig. 2 B) result all point out the NRG1 processing can effectively suppress the inductive cytoplasm ErbB4 of OGD and are shifted to nucleus.Above-mentioned neuron cell body tests the result outward and aforementioned whole animal experimental result is consistent, has confirmed that further ErbB4 lacks the subcellular fraction changes in distribution under the sugared condition in anoxia.Adopt this experimental system, can be used for further Mechanism Study and evaluating drug effect.
Embodiment 3:NRG1-ErbB4 signal pathway is participated in the pathological process operational approach of ischemic brain injury:
Mouse brain medium-sized artery one is crossed the preparation of ischemia re-perfusion model:
Male C57 mice, body weight 22～27g.Mice is adopted the isoflurane gas anesthesia, and is fixing, and the neck median incision separates left carotid, interior, the external carotid artery of neck.External carotid artery, the ligation of common carotid artery proximal part at clip in neck, before the external carotid artery bifurcated, are inserted the unified 5-0 nylon wire bolt (causing the cerebral ischemia phenomenon) of diameter, and the nylon wire bolt withdraws from (causing brain blood perfusion phenomena again), skin closure after 1.5 hours.
Experiment is divided into groups as follows: sham operated rats, cerebrovascular trauma model group, cerebrovascular trauma+NRG1 treatment group, 8 of every treated animals.NRG1 ventricles of the brain administration (150ng/kg; Adopt
MICRO-OSMOTIC PUMP), successive administration 3 days.Laboratory animal evaluation after 3 days: observe that animal behavior changes, nystagmus can appear in animal usually, ataxia, the performance of a series of function of nervous system such as dyskinesia infringement is learned scoring according to the Longa method to cerebrovascular trauma SD rat behavior.Standards of grading are following: 0 minute: impassivity functional impairment symptom; 1 be divided into can not full extension offside fore paw; 2 are divided into laterally and turn-take; 3 are divided into to offside and topple over; 4 are divided into and can not spontaneously walk loss of consciousness.The laboratory animal of marking 1 minute to 3 minutes is used for infarct size and measures.
Infarct size is measured behind the ischemic brain injury: laboratory mice ischemia 1.5 hours, and pour into after 24 hours the laboratory animal broken end again and get brain, remove XIAONAO and low brain stem, with the crown section of mouse brain mould, every thick 2mm.The brain sheet accounts for percentage ratio with conventional red tetrazolium (TTC) dyeing with Image J computed in software infarct size.
Preliminary experiment has proved NRG1 ventricles of the brain administration (150ng/kg; Adopt
MICRO-OSMOTIC PUMP) can effectively reduce the volume (Fig. 3 A) of cerebral infarction kitchen range.The quantitative statistics result further points out NRG1 at wild-type mice (ErbB4
+ /+) have cerebral protection and at ErbB4 knock out mice (ErbB4
-/-) but fail to see; Otherwise the volume of cerebral infarction kitchen range is at ErbB4
-/-Mice has tangible increase (Fig. 3 B, P＜0.05).
The cerebral protection of The above results prompting NRG1 is to accomplish with the mechanism that exists with ... the ErbB4 receptor.All data represent that with mean ± standard deviation statistical analysis adopts the Dunnett-t check.
SEQUENCE LISTING
< 110>Zhejiang University
< 120>application of ErbB receptor stimulating agent in the medicine of preparation treatment ischemic cerebrovascular
<130>
<160> 1
<170> PatentIn version 3.4
<210> 1
<211> 61
<212> PRT
<213> Unknown
<220>
< 223>artificial sequence
<400> 1
Ser His Leu Val Lys Cys Ala Glu Lys Glu Lys Thr Phe Cys Val Asn
1 5 10 15
Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro Ser Arg Tyr
20 25 30
Leu Cys Lys Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr
35 40 45
Val Met Ala Ser Phe Tyr Lys Ala Glu Glu Leu Tyr Gln
50 55 60
Claims (4)
1.ErbB the application of receptor stimulating agent in the medicine of preparation treatment ischemic cerebrovascular.
2. application as claimed in claim 1 is characterized in that said ErbB receptor stimulating agent is the ErbB4 receptor stimulating agent.
3. application as claimed in claim 2 is characterized in that said ErbB receptor stimulating agent is used to prepare the medicine of treatment ischemic brain injury or cerebral infarction.
4. application as claimed in claim 3; It is characterized in that said ErbB receptor stimulating agent behaviour recombinant protein N euregulin-1beta 2, its aminoacid sequence is following: shlvkcaekektfcvnggecfmvk dlsnpsrylckcpneftgdrcqnyvmasfykaeelyq.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550787A (en) * | 2013-11-11 | 2014-02-05 | 苏州大学 | MicroRNA (ribonucleic acid) antagonist and application thereof |
| CN110714068A (en) * | 2019-11-14 | 2020-01-21 | 南通大学 | Application of membrane protein molecule ErbB4 in preparation of medicines for treating cerebral ischemic injury |
-
2011
- 2011-11-10 CN CN201110354663XA patent/CN102389569A/en active Pending
Non-Patent Citations (5)
| Title |
|---|
| 《Neuroscience Letters》 20081231 Q. Li et al. 《Neuregulin attenuated cerebral ischemia-Creperfusion injury via inhibiting apoptosis and upregulating aquaporin-4》 第155-159页 1-4 第443卷, * |
| Q. LI ET AL.: "《Neuregulin attenuated cerebral ischemia–Creperfusion injury via inhibiting apoptosis and upregulating aquaporin-4》", 《NEUROSCIENCE LETTERS》 * |
| W.-C. SHYU ET AL: "《Neuregulin-1 reduces ischemia-induced brain damage in rats》", 《NEUROBIOLOGY OF AGING》 * |
| 李琴，张睿，梅元武，郭云良: "《神经调节素对大鼠脑缺血损伤的预防性治疗作用和机制》", 《中风与神经疾病杂志》 * |
| 王涛 等: "《神经调节蛋白在脑缺血中的保护作用》", 《国际脑血管病杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550787A (en) * | 2013-11-11 | 2014-02-05 | 苏州大学 | MicroRNA (ribonucleic acid) antagonist and application thereof |
| CN103550787B (en) * | 2013-11-11 | 2016-07-06 | 苏州大学 | A kind of Microrna antagonist and application thereof |
| CN110714068A (en) * | 2019-11-14 | 2020-01-21 | 南通大学 | Application of membrane protein molecule ErbB4 in preparation of medicines for treating cerebral ischemic injury |
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Application publication date: 20120328 |