CN104258372A - Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease - Google Patents
Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease Download PDFInfo
- Publication number
- CN104258372A CN104258372A CN201410497303.9A CN201410497303A CN104258372A CN 104258372 A CN104258372 A CN 104258372A CN 201410497303 A CN201410497303 A CN 201410497303A CN 104258372 A CN104258372 A CN 104258372A
- Authority
- CN
- China
- Prior art keywords
- rgd tripeptides
- rgd
- tripeptides
- alzheimer disease
- medicines
- 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.)
- Granted
Links
Abstract
The invention discloses application of RGD tripeptides in preparation of medicines for preventing or treating Alzheimer disease, belonging to the field of medicines. The RGD tripeptide disclosed by the invention is clear in dosage, can be prepared into tablets, microspheres, powder, oral liquid and injection and can be in single medication and be combined with other Alzheimer disease medicines of different mechanisms of action in the treatment of Alzheimer disease, and a pharmaceutical composition consisting of the RGD tripeptide, tetrandrine and triptolide is used for treating the Alzheimer disease, so that the toxic and side effects of the medicines can be reduced, and a collaborative treatment effect can be achieved. The pharmacological experiment proves that the RGD tripeptide can effectively inhibit Abeta1-42 aggregation and preventing oligomerization of Abeta1-42 monomers, obviously inhibits deposition of beta amyloid proteins, is exact in curative effect of preventing or treating the Alzheimer disease and has small side effects. Therefore, the RGD tripeptide has wide medical application prospects.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of novelty teabag of known drug, relate to the purposes of RGD tripeptides in preparation treatment Alzheimer disease drug specifically.
Background technology
Alzheimer (Alzheimer ' s disease, AD) be a kind ofly to lose with impermanent memory, persistence cognitive competence goes down and conduct disorder is feature nervous system degenerative disease.Alzheimer have impact on the huge population in the whole world, brings great misery to the life of people.Now, the definite pathogenesis of AD is still not clear, and tentatively thinks common results that is aging, h and E many factors.Also have a variety of theory to want to confirm the definite pathogenesis of AD at present, what wherein accept extensively the most is be polymerized the amyloid hypothesis that amyloid beta (A β) peptide formed with fibril is biomarker.A β is a kind of small peptide be made up of 38 to 42 amino acid residues, comes from the hydrolysis of amyloid precursor protein (APP).And in the brain of AD patient, have a large amount of A β
1-42.By finding the observation of AD patient, the gathering of A β in nervous tissue is relevant with cognitive decrease with the death of neurocyte with deposition.Therefore, A β is potential target spot AD being carried out to therapeutic intervention.And there is a lot of research with A β for target spot finds different medicines.
Finding different medicines with A β for target spot is hot issue in recent years, the A beta hypothesis of falling ill according to document senile dementia (AD) and related drugs progress (Anhui journal of institutes of education, 2007-5,25th volume the 3rd phase) specifically understand the medicine that interference A β is formed and deposits and can play a role in multiple approach with the medicine that the prevention senile plaque that A β is target spot is formed: (1) can reduce the synthesis of A β precursor protein, and the level transcribed and translate stops the synthesis of APP; (2) reduce the generation of A β, regulate the activity of cerebral tissue a, beta-secretase; (3) due to the prerequisite that A beta peptide aggregation is its neurotoxic effect, this process relates to the conversion of A β by a-screw-β-lamellar structure, and this process is relevant with skin section special in molecule; (4) inflammatory reaction of antagonism A β participation.Even if propose much new synthetic molecules as suppression A β
1-42the potential drug built up, but the mechanism of action of these molecules is illustrated not yet completely.Chinese patent CN101346396B discloses g protein coupled receptor antagonist and the application thereof of prevention and therapy Alzheimer's disease, and this antagonist produces toxin, has serious side effect, DeGrain, is unfavorable for applying on a large scale.
Uncertain along with drug research result, the progress for the peptide class mortifier of A β starts to receive much concern, and a lot of polypeptide fragments is considered to can be incorporated into the polymeric central hydrophibic core of A β thus the deposition preventing A β.Multiple small peptide is also proved to be effective molecule for the treatment of AD, such as, as the glutathion of antioxidant.There is also evidence, WMDF and Ac-AVVIA is effective in cure to AD.In addition, research shows that the polypeptide of such as KLVFF and LPFFD and the Development process of peptide quasi-molecule to AD have stronger rejection characteristic.There are a kind of two tetradecapeptides, the cytotoxicity that AD is relevant widely can be resisted, be included in in vitro tests in the environment being exposed to A β, show cell death activity.
Tang Dou hospital of The Fourth Military Medical University Neurology Department has delivered one section about A β
20-29small peptide blocks ApoE/A β and combines and reduce A β
1-42the A β utilizing thioflavin-T (Th-T) fluorescence analysis and transmission electron microscope method to confirm synthetic is disclosed in fibrosis and neurovirulent effect effect (Chin J Clin Neurosci 2009.17 (1) .1 ~ 6) thereof
20-29the effect of small peptide no cytotoxicity, can be combined with ApoE4 competitively, thus blocks A β
1-42be combined with ApoE4, reduce ApoE4 to A β
1-42fibrotic facilitation and neurotoxic effect thereof, illustrate A β
20-29small peptide can become suppression A β
1-42the novel blocker that/ApoE4 combines, provide effective experiment basis, but its effect is still further studied for exploring the Therapeutic Method preventing AD new.
Tripeptides forms through three aminoacid dehydrating condensations, be beneficial to body absorption, the advantage had no side effect, tripeptides ILE-PRO-PRO IPP (IPP) and VAL-PRO-PRO VPP (VPP) have certain therapeutical effect to borderline hypertension.Different types of tripeptides has different drug actions.Arginine-glycine-aspartic acid (Arg-Gly-Asp is called for short RGD tripeptides) tripeptides is easily degraded and is easy to the advantage of absorption in mammalian body, is beneficial to the performance of medicine.
Summary of the invention
-galactose induced mice Alzheimer's disease model has well treatment or preventive effect.RGD tripeptides of the present invention is oral formulations, and its animals administer amount is 100mg/kgd ~ 500mg/kgd, is preferably 50mg/kgd ~ 500mg/kgd, is more preferably 100mg/kgd ~ 500mg/kgd, more preferably 100mg/kgd ~ 300mg/kgd.
Two of object of the present invention is to provide the application of a kind of pharmaceutical composition containing RGD tripeptides in preparation treatment and prevention Alzheimer disease drug, pharmaceutical composition of the present invention comprises RGD tripeptides, tetrandrine and/or triptolide, RGD tripeptides in described pharmaceutical composition: tetrandrine: the weight ratio of triptolide is (1-500): (0.1-5): (0.1-5).
Three of object of the present invention is the pharmaceutical preparation that openly also can realize said medicine purposes containing RGD tripeptides.In above-described medicinal usage, inventor has been prepared into by test makes tablet, microspheres agent, powdery agent, oral liquid and injection.Wherein tablet contains two or more following adjuvant: starch, dextrin, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline Cellulose, hydroxypropyl cellulose, starch slurry lactose, mannitol, micropowder silica gel, cross-linking sodium carboxymethyl cellulose and crospolyvinylpyrrolidone; Described microspheres agent is containing, for example lower adjuvant: gelatin, sodium sulfate, formalin.Described RGD tripeptides is beneficial to mammal vivo degradation and is easy to absorb, and be conducive to the performance of drug effect, the content containing RGD tripeptides in each preparation unit in the oral formulations of described RGD tripeptides medicine is 0.1mg-200mg.
Compared with prior art, the invention has the advantages that:
(1) RGD tripeptides is easily degraded and is easy to absorb in mammalian body, is conducive to the performance of drug effect;
(2) RGD tripeptides and A β
1-42in conjunction with peptide-A β
1-42stable composite, and RGD tri-Toplink stablizes A β
1-42alpha-helix, helical structure and suppression beta sheet structure formation, can effectively suppress A β
1-42gathering and prevent A β
1-42the phenomenon of the oligomerization of single aggressiveness;
(3) RGD tripeptides and other mechanism of action when senile dementia being played to the drug combination of therapeutical effect, its mechanism of drug action is complementary, itself and tetrandrine and triptolide coupling can play the synergism preventing senile dementia or treat, and can improve motion function and the therapeutic effect of patients of senile dementia.
Accompanying drawing explanation
Fig. 1 is RGD tripeptides and A β
1-42thioflavin T result of the test schematic diagram:
Fig. 2 is RGD tripeptides and A β
1-42circular dichroism spectra result of the test schematic diagram:
Fig. 3 is RGD tripeptides and A β
1-42's
transmission electron microscope(TEM) result of the test schematic diagram.
?
Detailed description of the invention
Specific embodiment is adopted to further illustrate content of the present invention below.
Following content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, some simple deduction or replace can also be made, all should be considered as belonging to protection scope of the present invention.
experimental example 1,the thioflavin T test of the RGD tripeptides of a kind of prevention or treatment Alzheimer's disease:
By A β
1-42be dissolved in PH7.4, concentration is the mixed solution being made into 50 μm of ol/L in the phosphate buffer of 0.01mol/L, A β in this mixed solution
1-42be 50 μm of ol/L with the initial concentration of peptide, until when ultimate density is 2.5 μm of ol/L, be placed on 37 DEG C and hatch 48 h, then add ThT(5 μm of ol/L and be dissolved in 50 mmol/L glycine-NaOH solution, PH8.50) detect the fluorescence of 450 nm and 485 nm.Each sample measures 3 times, record fluorescence intensity.
Shown in composition graphs 1, embodiment 1 result shows: thioflavin T can promptly with A β
1-42polymer fiber combine, inspiring a new wavelength is the light of 450nm, and to show as wavelength be that the light of 482nm is aobvious strengthens, and RGD tripeptides and A β
1-42rGD tripeptides-A the β of Dual culture
1-42the sulphur production intensity of complex can reduce, and this fluorescent technique can be used for detecting RGD tripeptides to A β
1-42polymerization or the regulating power decomposed.As shown in Figure 1, compared to resveratrol, the concentration of RGD tripeptides is that 2.5 μm of ol/L show A β
1-42the better inhibition of polymer, shows that RGD tripeptides is A β
1-42polymeric mortifier.
experimental example 2,the circular dichroism spectra test of the RGD tripeptides of a kind of prevention or treatment Alzheimer's disease:
Be the A β of 50 μm of ol/L by concentration
1-42be dissolved in phosphate buffered solution, and add at experimental group the RGD tripeptides that concentration is 50 μm of ol/L, at then placing 37 DEG C, hatch 48 h, A β in this mixed solution
1-42be 5 μm of ol/L with the ultimate density of RGD tripeptides, use the container ware of 1mm thickness, by A β
1-42monomer and RGD tripeptides-A β
1-42composite sample prevents detection architecture in circular dichroism spectrometer respectively, and spectrum is at 25 DEG C, and wavelength is 190-260 nm, is recorded during the wide 0.5nm of ripple.
Shown in composition graphs 2, embodiment 2 result shows: circular dichroism spectra shows that in RGD tripeptides-A beta composite, β-pleated sheet structure can reduce, and as shown in Figure 2, circular dichroism spectra detects A β
1-42find near 217 nm, have a blanking bar time independent, show to there is beta sheet structure, find that when detecting RGD tripeptides-A beta composite the dark fringe near 217nm significantly alleviates, then show that RGD tripeptides can reduce the formation of beta sheet structure, thus suppress A β
1-42the polymerization of monomer.
experimental example 3,the RGD tripeptides of a kind of prevention or treatment Alzheimer's disease
transmission electron microscope(TEM) test:
With phosphate buffer (PBS, pH7.4) by A β
1-42sample dissolution becomes the concentration of 1mg/ml, then RGD tripeptides experimental group and blank group that concentration is 25 μm of ol/L is placed on, until hatch 48 h altogether when the ultimate density of mixed solution is 25 μm of ol/L, by the copper mesh of the sample point sample of 5 μ l in 300 hole Formvar-carbon, add the uranyl formate dyeing 1min of 1%, put and dry in atmosphere, then be placed in electric Microscopic observation, detect A β
1-42with RGD tripeptides-A β
1-42the structure of complex.
Shown in composition graphs 3, embodiment 3 result shows: as shown in the Electronic Speculum figure of Fig. 3, from A β
1-42monomer, can observe the A β of the long wire of high density in figure
1-42fiber, fibril aggregation becomes parallel pencil, crosses one another again between bundle and bundle; But, from RGD tripeptides-A β
1-42a small amount of linear fiber and amorphous polymer is only seen, short A β in complex figure
1-42fibre bundle is cross-linked mutually at random, thus defines irregular polymer; Illustrate that RGD tripeptides can suppress A β
1-42the polymerization of monomer.
embodiment 4,prepared by RGD tripeptides tablet
Preparation technology: take the RGD tripeptides of recipe quantity, starch, dextrin and low-substituted hydroxypropyl cellulose mix homogeneously.Separately get 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, granulated by 16 mesh sieves, less than 60 DEG C dry.After completing after drying, use 18 mesh sieve carries out granulate, sifts out the fine powder in dry granular, mixes with the magnesium stearate of sieving, and then is mixed evenly with dry granule, tabletting, to obtain final product.
embodiment 5,prepared by RGD tripeptides microspheres agent
Preparation technology: RGD tripeptides is dissolved in 5% gelatin and forms suspension and emulsion, be acid by acetic acid adjust ph, then 60% appropriate sodium sulfate is added, be heated to 50 DEG C of mixings and form cohesion capsule, be cooled to 15 DEG C, add appropriate 37% formalin when being alkalescence by alkali adjust ph and form solidification capsule, be washed to formaldehydeless microspheres agent.
embodiment 6,prepared by RGD tripeptides tablet
Preparation technology: take recipe quantity, RGD tripeptides, tetrandrine, starch, dextrin and low-substituted hydroxypropyl cellulose mix homogeneously.Separately get 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, granulated by 16 mesh sieves, less than 60 DEG C dry.After completing after drying, use 18 mesh sieve carries out granulate, sifts out the fine powder in dry granular, mixes with the magnesium stearate of sieving, and then is mixed evenly with dry granule, tabletting, to obtain final product.
embodiment 7,prepared by RGD tripeptides tablet
Preparation technology: take recipe quantity, RGD tripeptides, triptolide, starch, dextrin and low-substituted hydroxypropyl cellulose mix homogeneously.Separately get 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, granulated by 16 mesh sieves, less than 60 DEG C dry.After completing after drying, use 18 mesh sieve carries out granulate, sifts out the fine powder in dry granular, mixes with the magnesium stearate of sieving, and then is mixed evenly with dry granule, tabletting, to obtain final product.
embodiment 8,prepared by RGD tripeptides tablet
?preparation technology: each adjuvant in prescription is crossed 100 mesh sieves, after taking RGD tripeptides, tetrandrine, triptolide, mixing homogeneously with lactose, mannitol, add the micropowder silica gel of recipe quantity, microcrystalline Cellulose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose more respectively, mix homogeneously, add 60% alcoholic solution soft material, 18 mesh sieve granules, wet granular is in 60 DEG C of dryings, and 16 mesh sieve granulate, add magnesium stearate mix homogeneously, tabletting, to obtain final product.
embodiment 9,rGD tripeptides of the present invention is to A β
1-42the therapeutical effect of induced mice Alzheimer's disease model
1 materials and methods
1.1 experiment material
Laboratory animal is mice, 8 weeks ages of Mus, and body weight 35-40g, is provided by Nanjing Experimental Animal Center, A β
1-42purchased from American Sigma company, RGD tripeptides is synthesized by Shanghai Qiang Yao company to be provided, and Morris water maze is purchased from Shanghai Ji Liang company.
The foundation of 1.2 mice Alzheimer's disease models and evaluation
1.2.1 intracerebral ventricle injection A β
1-42the preparation of solution: by A β
1-42be dissolved in physiological saline solution, make A β concentration be 10 mmol/L, put in 37 DEG C of calorstats to hatch and carry out aging in 3 days.
1.2.2 the making of animal model: raise under standard environment, is divided into 2 groups at random: matched group and model group, often organizes 12.2 groups of there was no significant differences on Mus age and body weight.Animal gives after adaptability feeds 1 week, by mice with 2% pentobarbital sodium intraperitoneal anesthesia (40 ~ 50 mg/kg weight), be fixed on stereo brain orienting instrument, cut off head hair, skin is cut after iodine tincture disinfection, select right side tricorn for injection target area with reference to " mouse brain stereotaxic atlas ", in bregma 1.0 mm backward, center line is other opens 1.6 mm places, bore with three edged needle and open skull, expose cerebral dura mater, then use microsyringe with the speed of 12 μm/s from vertical inserting needle 4.0 mm in brain surface, by 10 mmol/L A β
1-42solution 5 μ l slowly injects, and slowly removes pin, sew up the incision after let the acupuncture needle remain at a certain point 2 min.Matched group injects equal-volume physiological saline solution.
1.2.3 Morris water maze behavioristics measures: 2 groups of mices started to carry out the test of Morris water maze respectively at postoperative 10th day.Test program is orientation navigation test: last 5 days, first 2 days is the training adaptation phase, and latter 3 days record achievements, if mice finds platform in 1 min, record its actual escape latency; If find platform not yet in 1 min, then drawn upper mounting plate by experimenter and stop 20 S, escape latency is recorded as 1 min.
1.2.4 the evaluation of animal model
As can be seen from following table, escape latency matched group from the 1st day of experimental record of model group just obviously extends (P < 0.05 or P < 0.01), and escape latency between model group 3 days and escape latency no significant difference between matched group 3 days, show that the Alzheimer's disease type adopting the method to set up is reliably accurate, may be used for the evaluating drug effect of Alzheimer's disease medicine.
2 animal models and grouping administration
According to above-mentioned modeling method modeling, and matched group, normal group are set, often organize 10, raise under standard environment.Each group of administering mode is as described below:
Normal group: gavage gives the normal saline of same volume;
Matched group: gavage gives the normal saline of same volume;
Model group: gavage gives the normal saline of same volume;
Experimental group 1: gavage gives RGD tripeptides 200 mg/kg/d prepared by embodiment 4;
Experimental group 2: gavage gives RGD tripeptides 250 mg/kg/d prepared by embodiment 4;
Experimental group 3: gavage gives RGD tripeptides 300 mg/kg/d prepared by embodiment 4;
Experimental group 4: gavage gives RGD tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/d prepared by embodiment 6;
Experimental group 5: gavage gives RGD tripeptides 250 mg/kg/d+ triptolide 5.6 mg/kg/d prepared by embodiment 7;
Experimental group 6: gavage gives RGD tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/d+ triptolide 5.6 mg/kg/d prepared by embodiment 8;
Above-mentioned administration group is respectively at administration afterwards in 10 days after modeling, within 11st day, be recorded as the 1st day, every day is administered once, observe drinking water for animals and diet situation every day, respectively at administration the 1st day, administration the 5th day, administration the 10th day, administration the 15th day, administration measures the escape latency of mice for 20 days with Morris water maze behavioristics assay method.Mice is put to death after last mensuration completes.Each group of mice Morris water maze behavioristics measurement result is as shown in the table.
The each administration group of table 1 is to A β
1-42the therapeutic effect (escape latency, unit S) of induced mice Alzheimer's disease model
Compared with model group, * P < 0.05, * * P < 0.01;
As can be seen from Table 1: each administration group escape latency there was no significant difference of the 1st day, but along with the prolongation of administration time, the escape latency difference of each administration group mice strengthens, and wherein RGD tripeptides each administration group all has positive therapeutical effect.Be embodied in:
1) the mice escape latency of each treatment group of RGD tripeptides has significant difference compared with model group, all significantly shorten the escape latency of mice, its drug treatment is after 15 days, and the mice escape latency of each treatment group has significant difference compared with model group.RGD tripeptides is to A β
1-42induced mice Alzheimer's disease model has significant therapeutic effect;
2) the mice escape latency of each treatment group of RGD tripeptides is variant, is best by the effect of the known experimental group of table 1 data 2, and this shows that the RGD tripeptides of variable concentrations is to A β
1-42induced mice Alzheimer's disease model has diversity, and wherein the RGD tripeptides of 250 mg/kg/d is to A β
1-42the therapeutic effect of induced mice Alzheimer's disease model is best;
3) each treatment group of compound recipe has significant difference compared with single medicine group, and this shows that the combination of experimental group 4 of the present invention, experimental group 5 and experimental group 6 exists significant synergism, medication effect significantly strengthens, accelerates the therapeutic process of Alzheimer's disease.
embodiment 10,rGD tripeptides of the present invention is to the therapeutical effect of the Alzheimer's disease of APP/PS1 bi-transgenic mice
1 material
RGD tripeptides is synthesized by Shanghai Qiang Yao company to be provided, and APP/PS1 bi-transgenic mice is provided by Nanjing Experimental Animal Center, and keeping away dark auto testing instrument is Chengdu TME Technology Co., Ltd.'s product.
2 experimental techniques
The foundation of 2.1 experimental grouies: get APP/PS1 bi-transgenic mice and be divided into following drug treatment group at random and often organize 10 mices.Each treatment group gives following medicine respectively:
Normal group: gavage gives the normal saline of same volume;
Matched group: gavage gives the normal saline of same volume;
Model group: gavage gives the normal saline of same volume;
Experimental group 1: gavage gives RGD tripeptides 200 mg/kg/d prepared by embodiment 4;
Experimental group 2: gavage gives RGD tripeptides 250 mg/kg/d prepared by embodiment 4;
Experimental group 3: gavage gives RGD tripeptides 300 mg/kg/d prepared by embodiment 4;
Experimental group 4: gavage gives RGD tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/d prepared by embodiment 6;
Experimental group 5: gavage gives RGD tripeptides 250 mg/kg/d+ triptolide 5.6 mg/kg/d prepared by embodiment 7;
Experimental group 6: gavage gives RGD tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/d+ triptolide 5.6 mg/kg/d prepared by embodiment 8;
2.2 step-through test behavioristicss are detected
Keep away active box point light and shade two Room of dark auto testing instrument, have a hole between two Room, at the bottom of case, pass to copper grid.Before formal experiment, each group of APP/PS1 bi-transgenic mice is trained, APP/PS1 bi-transgenic mice head is carried Fang Renming room, hole. first conform 2min, lead to 36V electric current then to darkroom copper grid, APP/PS1 bi-transgenic mice is subject to electric shock and namely runs away to bright room after entering darkroom, copper grid continue energising 5min, and this is training process.Carry out the test of memory of APP/PS1 bi-transgenic mice after 24h, record APP/PS1 bi-transgenic mice enters the time (keeping away dark incubation period) in darkroom for the first time, if enter darkroom not yet in APP/PS1 bi-transgenic mice 5min.Its incubation period, 300s made by meter.
3 statistical methods
Experimental data represents with ± s, carries out statistical analysis with SPSS11.5 software kit, adopts ANOVA and LSD ' S posthoc test to carry out statistical analysis, indicates significant difference with P<0.05.
4 experimental results
The impact of RGD tripeptides on APP/PS1 bi-transgenic mice step-through test is as shown in table 2.
Table 2 RGD tripeptides keeps away dark preclinical impact (± s) to APP/PS1 bi-transgenic mice
| Group | n | Keep away dark incubation period (s) |
| Normal group | 12 | 21.88±6.02 |
| Model group | 12 | 104.08±9.42## |
| Experimental group 1 | 12 | 63.86±8.24* |
| Experimental group 2 | 12 | 63.28±9.12* |
| Experimental group 3 | 12 | 64.18±9.26* |
| Experimental group 4 | 12 | 62.46±8.38* |
| Experimental group 5 | 12 | 52.28±8.24* |
| Experimental group 6 | 12 | 48.56±6.38** |
Compared with normal group, ##P < 0.01; Compared with model group, * P < 0.05, * * P < 0.01;
As can be seen from Table 2, RGD tripeptides treatment group keeps away dark significant prolongation incubation period (P < 0.01) relative to APP/PS1 bi-transgenic mice, and prompting RGD tripeptides has significant prevention and therapy effect to APP/PS1 bi-transgenic mice.Be embodied in:
1) the APP/PS1 bi-transgenic mice of each treatment group of RGD tripeptides is kept away and is had significant difference compared with model group dark incubation period, all significantly shortens APP/PS1 bi-transgenic mice and keeps away dark incubation period, there is significant difference.RGD tripeptides is to A β
1-42the Alzheimer's disease of caused APP/PS1 bi-transgenic mice has significant therapeutic effect;
2) the APP/PS1 bi-transgenic mice escape latency of each treatment group of RGD tripeptides is variant, best by the effect of the known experimental group of table 2 data 2, this shows that the Alzheimer's disease of RGD tripeptides to APP/PS1 bi-transgenic mice of variable concentrations has diversity, and wherein the RGD tripeptides of 250 mg/kg/d is best to the therapeutic effect of the Alzheimer's disease of APP/PS1 bi-transgenic mice;
3) each treatment group of compound recipe has significant difference compared with single medicine group, and this shows that the combination of experimental group 4 of the present invention, experimental group 5 and experimental group 6 exists significant synergism, medication effect significantly strengthens, accelerates the therapeutic process of Alzheimer's disease.
Show in the embodiment of the present invention 9 or embodiment 10 that the mechanism that RGD tripeptides acts on Alzheimer's disease is not conflicted with the medicine that other drug acts on Alzheimer's disease, it can conbined usage, and can obtain the synergism in treatment.
Claims (10)
- The purposes of 1.RGD tripeptides in preparation prevention or treatment Alzheimer disease drug.
- 2. medicinal usage as claimed in claim 1, it is characterized in that, the animals administer amount of RGD tripeptides is 1mg/kgd ~ 500mg/kgd.
- 3. medicinal usage as claimed in claim 1, it is characterized in that, the animals administer amount of RGD tripeptides is 50mg/kgd ~ 500mg/kgd.
- 4. medicinal usage as claimed in claim 1, it is characterized in that, the animals administer amount of RGD tripeptides is 100mg/kgd ~ 500mg/kgd.
- 5. medicinal usage as claimed in claim 2, it is characterized in that, described animals administer amount is 100mg/kgd ~ 300mg/kgd.
- 6. the medicinal usage as described in as arbitrary in claim 2-3, it is characterized in that, described RGD tripeptides makes tablet, microspheres agent, powdery agent, oral liquid, injection.
- 7. the medicinal usage as described in as arbitrary in claim 1-4, is characterized in that, the content containing RGD tripeptides in each preparation unit in the oral formulations of described medicine is 0.1mg-200mg.
- 8. the pharmaceutical composition containing RGD tripeptides, it is characterized in that, it contains tetrandrine.
- 9. the pharmaceutical composition containing RGD tripeptides as claimed in claim 8, is characterized in that, it is also containing triptolide.
- 10. the pharmaceutical composition containing RGD tripeptides as claimed in claim 9, is characterized in that, RGD tripeptides in described pharmaceutical composition: tetrandrine: the weight ratio of triptolide is (1-500): (0.1-5): (0.1-5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410497303.9A CN104258372B (en) | 2014-09-25 | 2014-09-25 | Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410497303.9A CN104258372B (en) | 2014-09-25 | 2014-09-25 | Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104258372A true CN104258372A (en) | 2015-01-07 |
| CN104258372B CN104258372B (en) | 2017-01-25 |
Family
ID=52150029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410497303.9A Expired - Fee Related CN104258372B (en) | 2014-09-25 | 2014-09-25 | Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104258372B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1504469A (en) * | 2002-11-28 | 2004-06-16 | �й���ѧԺ�Ϻ�ҩ���о��� | Tetrandrine and tetrandrine compound, synthesis and uses thereof |
| CN101553567A (en) * | 2006-07-21 | 2009-10-07 | 台拉维夫大学拉莫特 | Method for inhibiting or treating a disease associated with intracellular formation of protein fibrillar inclusions or aggregates |
| EP2322147A1 (en) * | 2008-07-24 | 2011-05-18 | Universidad del Pais Vasco | Use of microparticles containing genetically modified cells in the treatment of neurodegenerative diseases |
| US20130338075A1 (en) * | 2012-06-13 | 2013-12-19 | Thien Nguyen | Methods and compositions for the treatment of axonal and neuronal degeneration |
| CN103648536A (en) * | 2011-04-05 | 2014-03-19 | 弗赖堡大学医院 | Biocompatible and biodegradable gradient layer system for regenerative medicine and for tissue support |
-
2014
- 2014-09-25 CN CN201410497303.9A patent/CN104258372B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1504469A (en) * | 2002-11-28 | 2004-06-16 | �й���ѧԺ�Ϻ�ҩ���о��� | Tetrandrine and tetrandrine compound, synthesis and uses thereof |
| CN101553567A (en) * | 2006-07-21 | 2009-10-07 | 台拉维夫大学拉莫特 | Method for inhibiting or treating a disease associated with intracellular formation of protein fibrillar inclusions or aggregates |
| EP2322147A1 (en) * | 2008-07-24 | 2011-05-18 | Universidad del Pais Vasco | Use of microparticles containing genetically modified cells in the treatment of neurodegenerative diseases |
| CN103648536A (en) * | 2011-04-05 | 2014-03-19 | 弗赖堡大学医院 | Biocompatible and biodegradable gradient layer system for regenerative medicine and for tissue support |
| US20130338075A1 (en) * | 2012-06-13 | 2013-12-19 | Thien Nguyen | Methods and compositions for the treatment of axonal and neuronal degeneration |
Non-Patent Citations (2)
| Title |
|---|
| 吕诚等: "雷公藤内酯醇对阿尔茨海默病模型大鼠学习记忆和海马核因子_κB表达的影响", 《中国老年学杂志》 * |
| 郑焱等: "雷公藤内酯醇对阿尔茨海默病转基因鼠的防治作用研究", 《全国老年性痴呆与相关疾病学术会议会议论文集》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104258372B (en) | 2017-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5503726B2 (en) | Dried plant tissue and plant tissue extract for improving central nervous degenerative diseases accompanied by learning / memory disorders and movement disorders, and pharmaceuticals and foods containing them | |
| IL272596B1 (en) | Pridopidine for use in treating als | |
| CA2873891C (en) | Pharmaceutical composition for the prophylaxis and treatment of psychological, behavioral and cognitive disorders | |
| CN115645388A (en) | Amino acid composition and use thereof | |
| CN102743382B (en) | Nerve is stimulated to be formed and the method and composition of inhibitory neuron degeneration | |
| JP2018515620A (en) | Application of dextrorotatory oxiracetam in the pharmaceutical field | |
| CN111655669A (en) | Compositions and methods for treating neurological disorders including motor neuron diseases | |
| DE212018000131U1 (en) | Nano-drugs with delayed release against a neurodegenerative disease | |
| US20140080903A1 (en) | Application of alpha-mangostin in preparation of medicaments for alzheimer's disease | |
| JP2022511785A (en) | Compositions and Methods for Treating Dementia | |
| CN104324359A (en) | Application of RRY tripeptide in preparation of drug for treating Alzheimer's disease | |
| WO2023202102A1 (en) | Use of sesquiterpenoid compound in inhibiting trpa1 channel activity | |
| WO2019006734A1 (en) | Use of (+)-2-borneol in preparation of drug for promoting upregulation of expression of sphingosine kinase-1 and/or bdnf | |
| CN104248750B (en) | The purposes of FWW tripeptides in preparation treatment Alzheimer disease drug | |
| CN103690581B (en) | A kind of pharmaceutical composition for the treatment of senile dementia | |
| CN104274817B (en) | WRW tripeptides purposes in preparation treatment Alzheimer disease drug | |
| CN104258371B (en) | WWW tripeptides purposes in preparation treatment Alzheimer disease drug | |
| BR112017024126B1 (en) | PHARMACEUTICAL COMPOSITIONS, MICRONIZED COMPOUND A AND/OR AT LEAST ONE MICRONIZED PHARMACEUTICALLY ACCEPTABLE SALT OF COMPOUND A AND USE THEREOF | |
| CN104258372A (en) | Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease | |
| Semeleva et al. | Metal-containing taurine compounds protect rat’s brain in reperfusion-induced injury | |
| JP2013536258A (en) | Pharmaceutical composition for preventing or treating degenerative neurological brain disease | |
| CN104306954A (en) | Use of WRY tripeptide in preparation of drug for treating Alzheimer's disease | |
| ES2935705T3 (en) | A ligand of the GABA A receptor | |
| CN102727484A (en) | Use of silymarin in preparations of drugs for treatment of Alzheimer's disease | |
| CN103520147A (en) | Application of puerarin or medicinal composition containing puerarin in preparation of medicament with effect of preventing or treating senile dementia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170125 Termination date: 20210925 |