CN101023944A - Use of indirubin derivative for preparing medicines for treating nerve retrograde affection - Google Patents
Use of indirubin derivative for preparing medicines for treating nerve retrograde affection Download PDFInfo
- Publication number
- CN101023944A CN101023944A CN 200610033791 CN200610033791A CN101023944A CN 101023944 A CN101023944 A CN 101023944A CN 200610033791 CN200610033791 CN 200610033791 CN 200610033791 A CN200610033791 A CN 200610033791A CN 101023944 A CN101023944 A CN 101023944A
- Authority
- CN
- China
- Prior art keywords
- mptp
- indirubin
- apoptosis
- medicine
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an application of indirubin derivative (IO) in the preparation of medicine for curing neural retrograde disease, specially, it relates to an application of indirubin derivative in the preparation of medicine for curing Parkinson's disease. Said invention uses the indirubin derivative as inhibitor and utilizes three kinds of mediated and died kinases of JNK/CDK5/GSK3 beta which are inhibited by said indirubin derivative as clear target to develop the invented new medicine.
Description
[technical field]
The present invention relates to the application of derivatives of indirubin (IO) in preparation treatment nerve retrograde affection medicine, the particularly application in preparation treatment parkinson disease medicine.
[background technology]
Parkinson disease (Parkinson ' s Disease, be a kind of common PD), losing with the carrying out property of dopaminergic neuron of black substance, striatum and nuclear group is the nervous system degeneration disease of feature.Programmed cell death (being apoptosis) plays a significant role in Parkinsonian neuronal degeneration process.Mainly be to give dopamine precursor medicine levodopa to unite symptomatic treatment to alleviate symptoms of Parkinson's disease to Parkinsonian treatment clinically with the periphery decarboxylase inhibitor.The big heat of Recent study also have Parkinsonian gene therapy and stem-cell therapy.But because gene therapy exists target gene selection, carrier and gene controllability problem; Stem-cell therapy exists transplants a large amount of apoptosis of stem cell so that can not produce the problems such as dopamine of treatment concentration, makes back two kinds of methods also just be in conceptual phase now.So clinically Parkinsonian treatment is mainly still depended on medicine at present.But,, can not control Parkinsonian natural pathological changes process effectively, and also have many serious adverse, for example the on-off phenomenon and the dyskinesia because the application of levodopa is a symptomatic treatment.More disappointed is that the therapeutical effect of levodopa can only be kept about 2 years.If life-time service, levodopa also can injured neurons, the apoptosis of accelerator nerve unit.Therefore; press for the neuro-protective medicine that effectively to control the parkinson disease course of disease now: can suppress carrying out property of " constitutional " nigral dopaminergic neuron unit on the one hand and lose; can protectiveness intervene " medicine source property " Neuron Apoptosis that levodopa causes again on the other hand, thereby reach the Parkinsonian purpose of effective treatment.
Since nigral dopaminergic neuron unit carrying out property apoptosis is the basic reason that parkinson disease (PD) take place, so, how effectively the generation of protectiveness intervention dopamine neuron apoptosis just becomes the Parkinsonian key of treatment.The applicant is this fact of key kinases of parkinson disease nigral dopaminergic neuron unit apoptosis according to JNK, determines that (Jun N-terminalkinase JNK) is the target treatment parkinson disease with the terminal kinases of c-Jun N-.Experiment confirm: JNK has mediated nigral dopaminergic neuron unit's apoptosis and has participated in Parkinsonian generation; Jnk inhibitor SP600125 brings into play the effect of treatment parkinson disease animal by suppressing nigral dopaminergic neuron unit apoptosis.Yet the JNK path is not the single signal path of mediation nigral dopaminergic neuron unit apoptosis.(cyclin-dependent kinase5's existing many pieces of report proof Cyclin Dependent Kinases 5 CDK5) plays a significant role in the dopamine neuron apoptosis.Recently, the applicant also first observed arrive: short apoptosis kinases---glycogen synthase kinase-3 β (glycogen synthase kinase-3 β, GSK-3 β) has mediated nigral dopaminergic neuron unit apoptosis; Inhibition GSK3 β has the protectiveness intervention effect, the parkinson disease animal is had therapeutical effect the apoptosis of the former nigral dopaminergic neuron unit that is commissioned to train foster.These studies show that GSK3 β plays a significant role, and may become the Parkinsonian new drug target of potential treatment in parkinson disease take place.
This shows that short apoptosis kinases JNK, CDK5 and GSK3 β have all participated in the generation of dopamine neuron apoptosis, block the purpose that these several kinases can reach effective treatment parkinson disease and other nerve retrograde affection simultaneously.Therefore, the applicant to have proposed with JNK/CDK5/GSK3 β be new departure of the above-mentioned disease of target treatment.
With JNK/CDK5/GSK3 β is that the simplest method of target treatment parkinson disease and other nerve retrograde affection is united exactly and used these three kinds of kinase whose inhibitor, but optimal method is no more than " killing three birds with one stone "---promptly block the short apoptosis kinases of these three keys simultaneously with single medicine.Therefore, find the inhibitor that meets this standard just to become to finish the key of technical solution of the present invention.
[summary of the invention]
The objective of the invention is to overcome the deficiencies in the prior art part, provide a kind of and can block these three kinds of kinase whose inhibitor of short neuronal apoptosis of JNK/CDK5/GSK3 β simultaneously, be Parkinsonian treatment developing new approaches, new method; For parkinson disease and other nerve retrograde affection treatment provide a class brand-new medicine.
The Chinese medicine Indigo Naturalis was used to antileukemie treatment in the past.Applicant's previous work proves: can extract a monomer indirubin (Indirubin) in China's Chinese medicine Indigo Naturalis, its derivative I ndirubin-3 '-oxime (IO) is the inhibitor of JNK/CDK5/GSK3 β.
Derivatives of indirubin (IO), chemical constitution is as follows:
The object of the present invention is achieved like this:
The application of derivatives of indirubin (IO) in preparation treatment nerve retrograde affection medicine.
The application of derivatives of indirubin (IO) in preparation treatment parkinson disease medicine.
It is inhibitor that the present invention is intended to the derivatives of indirubin, three kinds of mediated apoptosis that suppress with its kinases---JNK/CDK5/GSK3 β is clear and definite target spot, the treatment parkinson disease that research and develop out innovatively that a class target spot is clear and definite, toxicity is little, specificity is high, effect are strong and the novel drugs of other nerve retrograde affection, improve above-mentioned disease patient's quality of life, be family and society's releasing heavy burden, have the huge social benefit, and can create huge economic benefit.
[description of drawings]
Fig. 1. derivatives of indirubin (IO) has been protected losing of the inductive substantia nigra dopaminergic neuron of MPTP.
Fig. 2. derivatives of indirubin (IO) has improved the striatum dopamine level that MPTP reduces.
Fig. 3. the behavioristics that derivatives of indirubin (IO) has improved parkinsonian mouse is unusual.
Fig. 4. derivatives of indirubin (IO) suppresses MPP
+Inductive In vitro culture substantia nigra dopaminergic neuron.
[specific embodiment]
1. derivatives of indirubin (IO) anti-parkinson laboratory animal dopamine neuron apoptosis is analyzed (cell experiment)
Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP) induces animal model for parkinsonism to set up and the analysis of the anti-animal dopaminergic neuron of derivatives of indirubin (IO) apoptosis is carried out according to embodiment 1.
2. the outer dopamine neuron apoptosis of derivatives of indirubin (IO) antibody is analyzed (cell experiment)
External nigral dopaminergic neuron unit's cultivation and the analysis of inhibitor Neuron Apoptosis are still carried out according to embodiment 2.
Derivatives of indirubin (IO) has the protectiveness intervention effect to the inductive C57 mice of MPTP animal model for parkinsonism midbrain veutro substantia nigra dopaminergic neuron apoptosis
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP) is a kind of white powder neurotoxin, can destroy the dopamine neurocyte specifically, thereby nigrostriatum path in the infringement brain makes people and animal symptoms of Parkinson's disease occur exactly liking.MPTP is made into desired concn with normal saline.
Experimental technique (Neuroscience, 1997 with reference to Tatton N.A. and Kish S.J. etc.; 77:1037-1048), choose male C
5790 of BL/6N type mices are divided into normal saline (NS) group, MPTP (M) group, three dosage groups of MPTP+IO, 15 every group at random.Tested first day, the IO group is lumbar injection 0.3mg/ml, 1mg/ml, 3mg/ml IO10ml/kg respectively, and NS group and M organize equal lumbar injection 3%DMSO 10ml/kg; IO organized first lumbar injection IO (dosage is all with first day) in second day, all the other group lumbar injection 3%DMSO10ml/kg.IO group, M organize lumbar injection 6mg/ml MPTP 5ml/kg together behind the 30min, the normal saline of capacity such as NS group lumbar injection, continuous 5 days (totally 6 days).At second day of the MPTP injection, examining also after the MPTP injection, recording laboratory animal the incubation period of Parkinsonism symptom occurred and holds time.Incubation period: inject MPTP certainly and finish beginning till the Parkinsonism symptom occurs; Hold time: occur the Parkinsonism symptom certainly and begin till the complete obiteration of Parkinsonism symptom.Injected the 7th day at the MPTP last, every experimental group is got two mices, after 10% chloral hydrate anesthesia, enters aorta from the left ventricle inserting needle, each 50ml of sequence filling blood vessel flushing liquor and 4%PFA.Blood vessel flushing liquor composition is: PBS 1000ml, 1%NaNO
22ml, heparin 0.02g and NaCl 9g.Mice broken end is got full brain, and soaking at room temperature is transferred in 30% sucrose solution 4 ℃ and spends the night after 2 hours in 4%PFA.Utilize freezing microtome to cut the brain sheet of 35 μ m, be suspended in the PBS liquid in 24 orifice plates in the black substance compact part.Get a slice every 5 and do ABC dyeing to detect the content of tyrosine hydroxylase (TH) in the black substance neuron.Analyze remaining neuronic situation in the black substance; MPTP last injection back the 10th day, the mice of each experimental group are after having finished ethological detection, and the cervical vertebra dislocation causes death.Get full brain, boil 2 minutes in the boiling water after, peel off striatum carefully, be stored in-70 ℃ after weighing, prepare to utilize DOPAMINE CONTENT IN RABBIT in the high-efficient liquid phase analysis striatum.
Observation index has the remaining dopamine neuron counting of black substance, striatum DOPAMINE CONTENT IN RABBIT and ethological scoring.
(1) derivatives of indirubin (IO) has been protected losing of the inductive substantia nigra dopaminergic neuron of MPTP
Fig. 1 has protected the experimental result picture of losing of the inductive substantia nigra dopaminergic neuron of MPTP for IO.
Dopamine neuron is identified with the SABC of tyrosine hydroxylase (TH).The frozen section that thickness is 35 μ m is cut into after each experimental group midbrain fixation of tissue in MPTP last injection back the 7th day.(a) solvent control group; (b) MPTP processed group; (c-e) the IO processed group of MPTP and variable concentrations.After noting the MPTP injection, black substance TH positive cell number obviously reduces (a vs.b), but and IO concentration relies on the number (c-e) that ground increases black substance TH positive cell.Image credit is in three independent experiments (amplify: 40 *).(f) counting and statistical result.The result shows: IO is 3,10 in concentration, and 30mg/kg just can obviously protect the inductive TH positive cell of MPTP, makes its unlikely apoptosis (IO compares with the MPTP group for Fig. 1 f, p＜0.01).
Injected back 7 days at the MPTP last, detect the number of remaining dopamine neuron in the black substance with the ABC method.Found that: compare with the solvent control group, what MPTP caused dopamine neuron in the black substance loses (Fig. 1 .b), approximately only 50.06 ± 6.35 (P＜0.01) (Fig. 1 .f) of residual matched group in a large number; And IO has reduced lose (Fig. 1 .c-e) because of the caused dopamine neuron of MPTP toxicity in the mode of concentration dependent.In the high concentration group (30mg/kg) of IO, the number of dopamine neuron and solvent control group is close in the black substance, has promptly reached normal level.
(2) derivatives of indirubin (IO) has improved the striatum dopamine level that MPTP reduces
Fig. 2 has improved the figure as a result of the striatum dopamine level of MPTP reduction for IO.Wherein Fig. 2 A is a counting diagram, and Fig. 2 B is logarithm amount effect curve figure.
Injected back ten days at the MPTP last, with high-performance liquid chromatogram determination striatum DOPAMINE CONTENT IN RABBIT.Fig. 2 A is the counting diagram that IO influences the striatum dopamine concentration, and Fig. 2 B is the semilog amount effect curve figure that IO influences the striatum dopamine concentration.Data are with meansigma methods ± standard error formal representation.
*: p＜0.05,
*: p＜0.01 is compared with the control;
* *P＜0.01 is compared with the MPTP processed group.Regression equation: Y=0.70+1.02X, r=0.96.
Injected back ten days at the MPTP last, we have detected the concentration of striatum dopamine.(7.80 ± 1.07ng/mg) compare, and MPTP has caused the decline significantly of striatum dopamine concentration, have only 1.47 ± 0.29ng/mg (P＜0.01) with matched group; And IO can concentration dependent ground improves the content (Fig. 2 A) of striatum dopamine, and IO 3,10,30mg/kg make dopamine concentration rise to 1.73 ± 0.18,2.36 ± 0.30 and 2.50 ± 0.78 (P＜0.01) respectively.
(3) it is unusual that derivatives of indirubin (IO) has improved the behavioristics of parkinsonian mouse
Inject behavioristics's test of back ten days Mus that experimentize at the MPTP last.The enforcement and the scoring of pole-climbing and suspension experiment are carried out according to the methodology introduction.Data are with meansigma methods ± standard error formal representation.(
*: P＜0.01 is compared with matched group;
*: P＜0.01 is compared with the MPTP processed group).
Injected back ten days at the MPTP last, parkinsonian mouse is implemented behavioristics check.The scope of examination is pole-jump test (pole test) and hanging test (traction test).
1. pole-climbing experiment (pole test)
Purpose: detect the mice limb motion and coordinate situation.
Method: with a diameter is that 2.5 centimetres cork bead is fixed in one long 50 centimetres thick 1 centimetre rod top, be wrapped with gauze on the rod with anti-slip, then tested mice is put on the bead, and writes down the following time: the time that mice stops in heading; Mice has climbed the used time of the first half of pole; Mice has climbed the used time of the latter half of pole.Then by the score of following standard: the note 3 minutes of finishing above-mentioned a certain action in 3 seconds; The note of finishing in 6 seconds 2 minutes; Note above 6 seconds 1 minute.Calculate three cumulative score situations at last, and the credit that takes statistics is analysed.
2. hang experiment (traction test):
Purpose: detect the mice limb motion and coordinate situation.
Method: will be tried mice two fore paws and be suspended from the horizontal wire, and catch electric wire then to remember 3 fens with two rear solid ends as mice; As catching electric wire then to remember 2 fens with a rear solid end.If mice two rear solid ends are all grabbed incessantly electric wire then are remembered 1 fen, the situation that counts the score at last, and the credit that takes statistics is analysed.
Experimental result shows: after MPTP withdrew, we can clearly observe the incoordination (Fig. 3) of laboratory animal limb motion from pole-jump test and hanging test.In pole-jump test, control group mice has been climbed the used time of the first half of pole and has been climbed the much less that used time of the latter half of pole organizes than MPTP.Wherein, the control group mice the first half and used time of the latter half of having climbed pole was respectively 2.61 seconds and 3.94 seconds; MPTP group mice has then been used 7.21 seconds respectively and 8.63 seconds (P＜0.01).Compare with MPTP group, IO obviously reduces the used time, and used time and the matched group of high concentration group (30mg/kg) is similar.
In hanging test, control group mice is caught electric wire with extremity, and MPTP group mice can only catch electric wire with fore paw, and rear solid end is unable; Though the rear solid end that the mice that IO handles has still moves and is obstructed, and can catch electric wire with a rear solid end at least, show that the hind leg motion makes moderate progress.
Embodiment 2.
Derivatives of indirubin (IO) is to 1-methyl-4-phenylpyridinium ion (1-methyl-4-phenylpyiridiniumion, MPP
+) the midbrain veutro substantia nigra dopaminergic neuron apoptosis of inductive In vitro culture has the protectiveness intervention effect
As Fig. 4, with pregnant 14 days tire Mus In vitro culture substantia nigra dopaminergic neurons.In vitro culture the 7th day is with 10 μ M MPP
+Induce Neuron Apoptosis.Specificity tyrosine hydroxylase antibody test TH positive cell (a) solvent control group, red fluorescence is the TH positive cell; (b) 10 μ M MPP
+The TH positive cell number is reduced; IO 1 μ M (c) and 3 μ M (d) have saved apoptosis in neuronal.(amplify: * 200).
MPP
+Be MPTP active metabolite in vivo, MPP
+The tire Mus veutro midbrain dopamine neuron apoptosis of derivable In vitro culture.
The cell culture processes of list of references (J Neurosci, 1998; 18 (13): 4929-37.Restor Neurol Neurosci.2003; 21 (1-2): 29-37.), get pregnant 14 days rat, use CO
2The back cervical vertebra dislocation that suffocates causes death.Vertically cut off abdominal part with shears behind the ethanol disinfection abdominal part, it is tolerant to expose intraperitoneal, prolongs otch to rib to both sides and coerces.Aseptic condition takes out the uterus down, cleans with ice D-Hank liquid, again through 75% ethanol bathing 30s, places the plate that fills ice D-Hank liquid.Cut off the uterus with little shears along the mesometrium oppose side edge, take out the embryo, check down that in anatomic microscope the top buttocks of tire Mus is 10-12mm apart from (CRL), place the plate that fills ice D-Hank liquid stand-by.Pass through the midbrain chirring partial application of face with dissecting knife from eyes up to veutro; The rolling fetus makes it dorsad down, dispels forebrain from brain stem, and exposed side ventricular system and it are as the extension at brain stem of ventriculus tertius and cerebral aqueduct; Cut the ventricles of the brain that cut off both sides to the back side with separation, then caudad is cut a cutter, cuts a cutter again in the bottom of midbrain gauffer; (ventral mesencephalon, remnants VM) have just separated with other parts of brain the veutro midbrain.After with tweezers top meninges being removed isolating VM being put into another is equipped with cold dissection liquid (500ml contains sodium chloride 36.25g, potassium chloride 2g, NaH
2PO
42H
2O 0.91g, glucose 13g, phenol red 50mg, HEPES 29.7g is in ware pH7.4).Peel off meninges, add 0.1% pancreatin solution (must preheating in 37 ℃ of baths) 20ml, 37 ℃ of DNA enzyme and pancreatin inhibitor cessation reactions that add the 10ml preheating down behind the digestion 15min with histotome chopping tissue back.Inhale behind the centrifugal 5min of 1500rpm and remove supernatant, add broken liquid 15ml (contain 1.2mg DNase I, the 7.8mg pancreatin inhibitor, 15ml dissects liquid, 150 μ l 3.82%MgSO
4); Blow and beat gently 10 times with suction pipe, make cell suspension.Leave standstill 15min, supernatant (be about cumulative volume 9/10) is drawn in another test tube.The centrifugal 5min of 1500rpm is with culture medium diluting cells suspension to 5 * 10
5Individual/ml.Cell suspension inoculation is being wrapped in 24 orifice plates (every hole 0.5ml) of quilt with Poly-Lysine in advance.Put 37 ℃, 5%CO
2Cultivate in the incubator, in culture fluid, add 5 μ M Ara-C behind the 24h to suppress the glial cell growth.Changed culture fluid one time, and under inverted phase contrast microscope, dynamic observed the cell growing state in per 3 days.
At the 5th day that cultivates, after the IO of variable concentrations was incubated 2h in advance, adding final concentration in culture medium was the MPP+ of 10 μ M, did TH dyeing behind the 48h, observed IO to the neuronic protective effect of the apoptosis-induced black substance of MPP+.Matched group adds isopyknic DMSO, and negative control group directly adds the MPTP of 10 μ M.Observation index mainly is the TH cell counting of tyrosine hydroxylase stained positive.
Claims (2)
1, the application of derivatives of indirubin in preparation treatment nerve retrograde affection medicine.
2, the application of derivatives of indirubin in preparation treatment parkinson disease medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610033791 CN101023944A (en) | 2006-02-23 | 2006-02-23 | Use of indirubin derivative for preparing medicines for treating nerve retrograde affection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610033791 CN101023944A (en) | 2006-02-23 | 2006-02-23 | Use of indirubin derivative for preparing medicines for treating nerve retrograde affection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101023944A true CN101023944A (en) | 2007-08-29 |
Family
ID=38742789
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610033791 Pending CN101023944A (en) | 2006-02-23 | 2006-02-23 | Use of indirubin derivative for preparing medicines for treating nerve retrograde affection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101023944A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011056222A1 (en) * | 2009-11-05 | 2011-05-12 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods of treating disorders associated with protein aggregation |
| CN101492410B (en) * | 2009-03-05 | 2011-06-22 | 上海交通大学 | Indirubin compounds for antineoplastic medicament |
| US8809617B2 (en) | 2009-11-05 | 2014-08-19 | The University of Pittsburgh—Of the Commonwealth System of Higher Education | Automated high-content live animal drug screening using C. elegans |
| WO2014190758A1 (en) * | 2013-05-28 | 2014-12-04 | 滁州市洛达生物科技有限公司 | Conjugate of benzofuranone and indole or azaindole, and preparation and uses thereof |
| US8906905B2 (en) | 2009-08-03 | 2014-12-09 | University of Pittsburgh—of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein polymerization |
| CN104602675A (en) * | 2012-06-21 | 2015-05-06 | 法斯瑞斯公司 | Nanoparticles of indirubin, derivatives thereof and methods of making and using same |
| US9072772B2 (en) | 2009-11-05 | 2015-07-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein aggregation |
| US9486440B2 (en) | 2011-10-25 | 2016-11-08 | University Of Macau | Uses of indole-ketones or indolidones as neuro-protective drugs |
| CN114521142A (en) * | 2019-11-04 | 2022-05-20 | Ck雷容股份有限公司 | Compositions and methods for inhibiting and/or treating neurodegenerative diseases and/or clinical disorders thereof |
-
2006
- 2006-02-23 CN CN 200610033791 patent/CN101023944A/en active Pending
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101492410B (en) * | 2009-03-05 | 2011-06-22 | 上海交通大学 | Indirubin compounds for antineoplastic medicament |
| US9511074B2 (en) | 2009-08-03 | 2016-12-06 | University of Pittsburgh—of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein polymerization |
| US8906905B2 (en) | 2009-08-03 | 2014-12-09 | University of Pittsburgh—of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein polymerization |
| US8809617B2 (en) | 2009-11-05 | 2014-08-19 | The University of Pittsburgh—Of the Commonwealth System of Higher Education | Automated high-content live animal drug screening using C. elegans |
| US9844605B2 (en) | 2009-11-05 | 2017-12-19 | The University of Pittsburgh—Of the Commonwealth System of Higher Education | Transgenic Caenorhabditis elegans comprising a human protein with a tendency to aggregate fused to a fluorescent protein |
| US9820990B2 (en) | 2009-11-05 | 2017-11-21 | The University of Pittsburgh—Of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein aggregation |
| US9072772B2 (en) | 2009-11-05 | 2015-07-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein aggregation |
| US9452171B2 (en) | 2009-11-05 | 2016-09-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Methods of treating disorders associated with protein aggregation |
| WO2011056222A1 (en) * | 2009-11-05 | 2011-05-12 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods of treating disorders associated with protein aggregation |
| US9486440B2 (en) | 2011-10-25 | 2016-11-08 | University Of Macau | Uses of indole-ketones or indolidones as neuro-protective drugs |
| CN104602675A (en) * | 2012-06-21 | 2015-05-06 | 法斯瑞斯公司 | Nanoparticles of indirubin, derivatives thereof and methods of making and using same |
| CN104602675B (en) * | 2012-06-21 | 2019-06-28 | 法斯瑞斯公司 | The method of the nanoparticle of indigo red, its derivative and the manufacture and use nanoparticle |
| WO2014190758A1 (en) * | 2013-05-28 | 2014-12-04 | 滁州市洛达生物科技有限公司 | Conjugate of benzofuranone and indole or azaindole, and preparation and uses thereof |
| US9868734B2 (en) | 2013-05-28 | 2018-01-16 | Luoda Biosciences, Inc. | Conjugate of benzofuranone and indole or azaindole, and preparation and uses thereof |
| CN114521142A (en) * | 2019-11-04 | 2022-05-20 | Ck雷容股份有限公司 | Compositions and methods for inhibiting and/or treating neurodegenerative diseases and/or clinical disorders thereof |
| EP4010337A4 (en) * | 2019-11-04 | 2023-08-23 | CK Regeon Inc. | Compositions and methods for suppressing and/or treating neurodegenerative diseases and/or a clinical condition thereof |
| CN114521142B (en) * | 2019-11-04 | 2024-07-02 | Ck雷容股份有限公司 | Compositions and methods for inhibiting and/or treating neurodegenerative diseases and/or clinical conditions thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101023944A (en) | Use of indirubin derivative for preparing medicines for treating nerve retrograde affection | |
| Li et al. | Exosomes isolated during dopaminergic neuron differentiation suppressed neuronal inflammation in a rodent model of Parkinson’s disease | |
| CN106913876B (en) | Application of miRNA-30a-5p in target points of Parkinson disease detection, treatment and prognosis | |
| Wang et al. | Activation of neuronal voltage-gated potassium Kv7/KCNQ/M-current by a novel channel opener SCR2682 for alleviation of chronic pain | |
| CN110101715A (en) | Soil preparation and the preparation method and application thereof with prevention and treatment neuroendocrine disorders related disease | |
| Zhang et al. | Effect of huanglian decoction on the intestinal microbiome in stress ulcer (SU) mice | |
| CN109529005A (en) | Jintan is used to treat the new application that ras proto-oncogene is overexpressed tumour | |
| Liu et al. | Effects of bone marrow mesenchymal stem cells transfected with Ang‐1 gene on hyperoxia‐induced optic nerve injury in neonatal mice | |
| CN107213465A (en) | Inhibitors of dipeptidyl IV is preparing the application in preventing and treating the medicine of epilepsy | |
| CN104758883B (en) | A kind of tire snake composition and preparation method thereof for improving the immunity of the human body | |
| CN109223817B (en) | Antagonist of micro non-coding RNA and application thereof | |
| Gao et al. | Administration of miR-195 Inhibitor Enhances Memory Function Through Improving Synaptic Degradation and Mitochondrial Dysfunction of the Hippocampal Neurons in SAMP8 Mice | |
| CN112940001A (en) | Phthalide isoquinoline alkaloid and preparation method and application thereof | |
| CN111557948A (en) | Application of nucleoside hydrogel in preparing medicine for preventing or delaying canceration of oral mucosa potential malignant diseases | |
| CN109745548A (en) | A kind of application of pertussis toxin in treatment cerebral infarction | |
| AU2021105462A4 (en) | Use of fructus corni nano-powder in resisting type 2 diabetes mellitus | |
| CN101095674A (en) | Use of bilobalide in the preparation of medicine for treating parkinsonism | |
| CN107496390A (en) | Application of the protosappanin A derivative in caused by chemotherapeutic medicines heart injury is protected | |
| JP6445879B2 (en) | Pharmaceutical composition for repairing and activating skin | |
| CN108159083A (en) | It is a kind of to be used to prevent composition of traumatic brain injury and preparation method thereof | |
| CN110075131A (en) | Application of the zika virus attenuated strain in treatment glioma | |
| KR102415950B1 (en) | Health functional food for eye comprising mixture of chrysanthemum extract, quince extract, and longan meat extract as an active ingredient and manufacturing method thereof | |
| CN113620932B (en) | Preparation method of drug specifically used for treating ocular angiogenesis | |
| CN100475205C (en) | Use of AR-A014418 in preparing medicine for preventing and treating nerve degenerative diseases | |
| WO2009149621A1 (en) | Use of icariside ii in manufacture of products for preventing or treating male or female sexual dysfunction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20070829 |