CN104258372B - 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
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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, it is related to a kind of new application of known drug, more particularly to rgd tripeptides in preparation
Purposes in treatment Alzheimer disease drug.
Background technology
Alzheimer (alzheimer ' s disease, ad) is a kind of with impermanent memory loss, persistence cognition energy
The nervous system degenerative disease that power goes down and conduct disorder is characterized.Alzheimer have impact on the huge population in the whole world,
The life giving people brings great misery.Now, the definite pathogenesis of ad are still not clear, it was initially believed that being aging, hereditary
Common results with environment many factors.Also a variety of theories are had to want to confirm the definite pathogenesis of ad at present, wherein wide
General acceptance is the amyloid hypothesis as biomarker for amyloid beta (a β) peptide to be polymerized and fibril is formed.a
β is a kind of small peptide being made up of 38 to 42 amino acid residues, comes from the hydrolysis of amyloid precursor protein (app).And ad suffers from
There is substantial amounts of a β in the brain of person1-42.By to ad patient's it has been observed that gathering in nervous tissue for a β and deposition and god
Death through cell is relevant with cognitive decrease.Therefore, a β is the potential target spot that ad is carried out with therapeutic intervention.And have
A lot of research finds different medicines with a β for target spot.
The hot issue that different medicines are in recent years is found for target spot with a β, falls ill according to document senile dementia (ad)
A beta hypothesis and related drugs progress (Anhui journal of institutes of education, 2007-5, the 3rd phase of volume 25) specifically understand interference
The medicine of a β formation and deposition and the medicine that senile plaque is formed that stops with a β as target spot can play a role in multiple approach: (1)
The synthesis of a β precursor protein can be reduced, the synthesis of app is stoped on the level of transcription and translation；(2) reduce the generation of a β, adjust
Cerebral tissue a, the activity of beta-secretase；(3) because a beta peptide aggregation is the premise of its neurotoxic effect, this process is related to a β by a- spiral shell
The conversion of rotation direction-β-lamellar structure, and this process is relevant with skin section special in molecule；(4) inflammatory reaction that antagonism a β participates in.
Even if proposing much new synthetic molecules as suppression a β1-42The potential drug built up, but the mechanism of action of these molecules
Not yet illustrate completely.Chinese patent cn101346396b discloses the g G-protein linked receptor of prevention and treatment Alzheimer's disease
Antagonist and its application, this antagonist produces toxin, has serious side effect, DeGrain, is unfavorable for promoting on a large scale
Application.
Uncertain with drug research result, the progress for the peptides mortifier of a β starts to receive much concern, very
Many polypeptide fragments are believed to be attached to a β polymeric central hydrophibic core thus preventing the deposition of a β.Multiple small peptides
It is proved to be to treat effective molecule of ad, such as the Glutathione of antioxidant.There is also evidence, wmdf and ac-
Avvia is effective in cure to ad.Additionally, research shows that the polypeptide of such as klvff and lpffd and peptide quasi-molecule have to the Development process of ad
Stronger rejection characteristic.There are a kind of two tetradecapeptides, the related cytotoxicity of extensive ad can be resisted, including testing in vitro
In be exposed in the environment of a β, show cell death activity.
Tang Dou hospital of The Fourth Military Medical University Neurology Department has delivered one with regard to a β20-29Small peptide blocks apoe/a β and combines simultaneously
Reduce a β1-42In fibrosiss and its neurovirulent effect effect (chin j clin neurosci 2009.17 (1) .1 ~ 6)
Disclose a β confirming synthetic using thioflavin-t (th-t) fluorescence analysiss and transmission electron microscope method20-29Small peptide acellular poison
Property effect, can competitively be combined with apoe4, thus blocking-up to a β1-42Be combined with apoe4, reduce apoe4 to a β1-42Fiber
The facilitation changed and its neurotoxic effect, illustrate a β20-29Small peptide is possible to become suppression a β1-42It is new that/apoe4 combines
Blocker, provides effective experiment basis for exploring the Therapeutic Method preventing ad new, but its effect is still further studied.
Tripeptides is to form through three aminoacid dehydrating condensations, beneficial to body absorption, the advantage having no side effect, the different bright ammonia of tripeptides
Acid-Pro-Pro (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, abbreviation rgd tri-
Peptide) tripeptides advantage that is degradable and being easy to absorption in mammal body, beneficial to the performance of medicine.
Content of the invention
- galactose induced mice Alzheimer's disease model has good treatment or preventive effect.The rgd tri- of the present invention
Peptide is oral formulations, and its animal dosage is 100mg/kg d ~ 500mg/kg d, preferably 50mg/kg d ~ 500mg/
Kg d, more preferably 100mg/kg d ~ 500mg/kg d, more preferably 100mg/kg d ~ 300mg/kg d.
The second object of the present invention is to provide a kind of pharmaceutical composition containing rgd tripeptides to treat and prevent A Er in preparation
Application in Ci Haimo disease drug, the 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).
The third object of the present invention is to disclose containing rgd tripeptides and be capable of the pharmaceutical preparation of said medicine purposes.With
In upper described medicinal usage, inventor by test be prepared into making tablet, microspheres agent, powdery agent, oral liquid and
Injection.Wherein tablet contains two or more following adjuvants: starch, dextrin, low-substituted hydroxypropyl cellulose, magnesium stearate, micro-
Crystalline cellulose, hydroxypropyl cellulose, starch slurry Lactose, Mannitol, micropowder silica gel, cross-linking sodium carboxymethyl cellulose and crosslinked poly- second
Alkene pyrrolidone；Described microspheres agent contains following adjuvant: gelatin, sodium sulfate, formalin.Described rgd tripeptides is beneficial to suckling and moves
Thing vivo degradation simultaneously is easy to absorb, and is conducive to the performance of drug effect, each preparation unit in the oral formulations of described rgd tri- peptide medicine
In the content containing rgd tripeptides be 0.1mg-200mg.
Compared with prior art, it is an advantage of the current invention that:
(1) rgd tripeptides in mammal body degradable and be easy to absorb, be conducive to the performance of drug effect；
(2) rgd tripeptides and a β1-42In conjunction with peptide-a β1-42Stable composite, and rgd tripeptides can stablize a β1-42α-spiral shell
The formation of rotation, helical structure and suppression beta sheet structure, can effectively suppress a β1-42Gathering and prevent a β1-42Single aggressiveness low
The phenomenon of dimerization；
(3) rgd tripeptides with other mechanism of action and senile dementia is played therapeutical effect drug combination when, its medicine
Mechanism of action is complementary, and it can play the association to senile dementia prevention or treatment with tetrandrine and triptolide combination
Same-action, can improve motion function and the therapeutic effect of patients of senile dementia.
Brief description
Fig. 1 is rgd tripeptides and a β1-42Thioflavin t result of the test schematic diagram:
Fig. 2 is rgd tripeptides and a β1-42Circular dichroism spectra result of the test schematic diagram:
Fig. 3 is rgd tripeptides and a β1-42'sTransmission electron microscope(tem) result of the test schematic diagram.
Specific embodiment
Below present disclosure is further illustrated using specific embodiment.
Herein below is to further describe it is impossible to assert with reference to specific preferred implementation is made for the present invention
Being embodied as of the present invention is confined to these explanations.For general technical staff of the technical field of the invention,
On the premise of present inventive concept, some simple deduction or replace can also be made, all should be considered as belonging to the present invention's
Protection domain.
A kind of thioflavin t test of the rgd tripeptides of experimental example 1, prevention or treatment Alzheimer's disease:
By a β1-42It is dissolved in ph7.4, concentration is made into the mixing of 50 μm of ol/l in the phosphate buffer for 0.01mol/l
Solution, a β in this mixed solution1-42Initial concentration with peptide is 50 μm of ol/l, when ultimate density is 2.5 μm of ol/l, places
It is incubated 48 h at 37 DEG C, be subsequently added into tht(5 μm of ol/l and be dissolved in 50 mmol/l glycine-naoh solution, ph8.50) inspection
Survey 450 nm and the fluorescence of 485 nm.Each sample measures 3 times, records fluorescence intensity.
In conjunction with shown in Fig. 1, embodiment 1 result shows: thioflavin t can promptly with a β1-42Polymer fiber combine, swash
Send the light that a new wavelength is 450nm, and show as the light that wavelength is 482nm and be remarkably reinforced, and rgd tripeptides and a β1-42
Rgd tripeptides-a the β co-culturing1-42The thioflavin t fluorescence intensity of complex can reduce, and this fluorescent technique can be used for detecting rgd
Tripeptides is to a β1-42Polymerization or the regulating power decomposing.As shown in figure 1, compared to resveratrol, the concentration of rgd tripeptides is 2.5 μ
Mol/l shows to a β1-42The more preferable inhibition of polymer, shows that rgd tripeptides is a β1-42Polymeric mortifier.
A kind of circular dichroism spectra test of the rgd tripeptides of experimental example 2, prevention or treatment Alzheimer's disease:
The a β that concentration is 50 μm of ol/l1-42It is dissolved in phosphate buffered solution, and add concentration for 50 μ in experimental group
The rgd tripeptides of mol/l, is incubated 48 h at then placing 37 DEG C, a β in this mixed solution1-42Ultimate density with rgd tripeptides is 5
μm ol/l, using the container ware of 1mm thickness, by a β1-42Monomer and rgd tripeptides-a β1-42Composite sample prevents circular dichroism respectively
Structure is detected, at 25 DEG C, wavelength is 190-260 nm to spectrum, is recorded during ripple width 0.5nm in spectrometer.
In conjunction with shown in Fig. 2, embodiment 2 result shows: circular dichroism spectra shows β-pleated sheet structure meeting in rgd tripeptides-a beta composite
Reduce, as shown in Fig. 2 circular dichroism spectra detection a β1-42Find there is a blanking bar near 217 nm when individually, show there is β-folding
Stack structure, finds that when detecting rgd tripeptides-a beta composite the dark fringe near 217nm significantly mitigates, then show that rgd tripeptides can
To reduce the formation of beta sheet structure, thus suppressing a β1-42The polymerization of monomer.
The rgd tripeptides of experimental example 3, a kind of prevention or treatment Alzheimer's diseaseTransmission electron microscope(tem) test:
With phosphate buffer (pbs, ph7.4) by a β1-42Sample is dissolved into the concentration of 1mg/ml, is then placed within concentration
Rgd tripeptides experimental group for 25 μm of ol/l and blank control group, incubate when the ultimate density of mixed solution is 25 μm of ol/l altogether
Educate 48 h, by the sample point sample of 5 l in the copper mesh of 300 hole formvar-carbon, add 1% uranyl formate dyeing 1min,
It is placed in the air to dry, then is placed in electric Microscopic observation, detect a β1-42With rgd tripeptides-a β1-42The structure of complex.
In conjunction with shown in Fig. 3, embodiment 3 result shows: as shown in the electron microscope of Fig. 3, from a β1-42Monomer, in figure can be seen
Observe a β of the long wire of high density1-42Fiber, fibril aggregation becomes parallel pencil, crosses one another between bundle and bundle again；However, from
Rgd tripeptides-a β1-42Complex in figure only sees linear fiber and amorphous polymer on a small quantity, short a β1-42Fibre bundle with
Machine is crosslinked mutually, thus defining irregular polymer；Illustrate that rgd tripeptides can suppress a β1-42The polymerization of monomer.
Embodiment 4, the preparation of rgd tripeptides tablet
Preparation technology: weigh rgd tripeptides, starch, dextrin and the low-substituted hydroxypropyl cellulose mix homogeneously of recipe quantity.Separately
Take 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, pelletized by 16 mesh sieves, do for less than 60 DEG C
Dry.Carry out granulate with 18 mesh sieves after the completion of after drying, sift out the fine powder in dry granular, mix with the magnesium stearate sieved, Ran Houzai
It is mixed evenly with dry particl, tabletting, obtain final product.
Embodiment 5, the preparation of rgd tripeptides microspheres agent
Preparation technology: rgd tripeptides is dissolved in 5% gelatin and forms suspension and emulsion, it is acid for adjusting ph value with acetic acid,
It is subsequently added into 60% appropriate sodium sulfate, be heated to 50 DEG C and mix formation cohesion capsule, be cooled to 15 DEG C, adjusting ph value with alkali is alkali
Property when add appropriate 37% formalin to form solidification capsule, be washed to formaldehydeless microspheres agent.
Embodiment 6, the preparation of rgd tripeptides tablet
Preparation technology: weigh recipe quantity, rgd tripeptides, tetrandrine, starch, dextrin and low substituted hydroxy-propyl fiber
Plain mix homogeneously.Separately take 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, by 16 mesh sieve series
Grain, less than 60 DEG C are dried.Carry out granulate with 18 mesh sieves after the completion of after drying, sift out the fine powder in dry granular, with the stearic acid sieving
Magnesium mixes, and is then mixed evenly with dry particl, tabletting again, obtains final product.
Embodiment 7, the preparation of rgd tripeptides tablet
Preparation technology: weigh recipe quantity, rgd tripeptides, triptolide, starch, dextrin and low substituted hydroxy-propyl fiber
Plain mix homogeneously.Separately take 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, by 16 mesh sieve series
Grain, less than 60 DEG C are dried.Carry out granulate with 18 mesh sieves after the completion of after drying, sift out the fine powder in dry granular, with the stearic acid sieving
Magnesium mixes, and is then mixed evenly with dry particl, tabletting again, obtains final product.
Embodiment 8, the preparation of rgd tripeptides tablet
Preparation technology: each adjuvant in prescription is crossed 100 mesh sieves, weighs rgd tripeptides, tetrandrine, Radix Tripterygii Wilfordii first
After element is mixed homogeneously with Lactose, Mannitol, then it is separately added into the micropowder silica gel of recipe quantity, Microcrystalline Cellulose, crosslinked polyethylene pyrrole
Pyrrolidone and cross-linking sodium carboxymethyl cellulose, mix homogeneously, add 60% ethanol solution soft material, 18 mesh sieve series granules, wet granular
In 60 DEG C of dryings, 16 mesh sieve granulate, add magnesium stearate mix homogeneously, tabletting, obtain final product.
Embodiment 9, rgd tripeptides of the present invention are to a β1-42The therapeutical effect of induced mice Alzheimer's disease model
1 material and method
1.1 experiment material
Laboratory animal is mice, 8 weeks Mus ages, and body weight 35-40g is provided by Nanjing Experimental Animal Center, a β1-42Purchased from U.S.
Sigma company of state, 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 β1-42The preparation of solution: by a β1-42It is dissolved in physiological saline solution, make a β concentration be
10 mmol/l, put incubation in 37 DEG C of calorstats carry out within 3 days aging.
1.2.2 the making of animal model: raise under standard environment, be randomly divided into 2 groups: matched group and model group, every group 12
Only.2 groups on Mus age and body weight, there was no significant difference.After animal gives adaptability to feed 1 week, by mice 2% pentobarbital sodium
Intraperitoneal anesthesia (40～50 mg/kg weight), is fixed on stereo brain orienting instrument, cuts off head hair, cut after iodine tincture disinfection
Open skin, selecting right side tricorn with reference to " mouse brain stereotaxic atlas " is injection target area, in bregma 1.0 mm backward, by center line
Open at 1.6 mm, bored with three edged needle and open skull, expose cerebral dura mater, then with microsyringe with the speed of 12 μm/s from brain surface
Vertical inserting needle 4.0 mm, by 10 mmol/l a β1-42Solution 5 μ l is slowly injected into, and slowly removes pin, suture is cut after let the acupuncture needle remain at a certain point 2 min
Mouthful.Matched group injects equal-volume physiological saline solution.
1.2.3 morris water maze behavioristicss measure: 2 groups of mices proceeded by morris water respectively at postoperative 10th day
Labyrinth is tested.Test program is tested for orientation navigation: lasts 5 days, is within first 2 days the training adaptation phase, latter 3 days record achievements, if
Mice finds platform in 1 min, records its actual escape latency；If not finding platform in 1 min yet, by testing
Person is drawn upper mounting plate and is stopped 20 s, and escape latency is recorded as 1 min.
1.2.4 the evaluation of animal model
By following table as can be seen that the escape latency of model group matched group from the 1st day of experimental record just substantially prolongs
Long (p ＜ 0.05 or p ＜ 0.01), and escape latency between 3 days for the model group and matched group between 3 days, escape latency is no
Notable difference, shows that the Alzheimer's disease type set up using the method is reliable accurately, can be used for Alzheimer's disease treatment
The evaluating drug effect of medicine.
2 animal models and packet administration
According to above-mentioned modeling method modeling, and matched group, normal group are set, every group 10, raise under standard environment.Each group
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 of embodiment 4 preparation；
Experimental group 2: gavage gives rgd tripeptides 250 mg/kg/d of embodiment 4 preparation；
Experimental group 3: gavage gives rgd tripeptides 300 mg/kg/d of embodiment 4 preparation；
Experimental group 4: gavage gives rgd tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/ of embodiment 6 preparation
d；
Experimental group 5: gavage gives rgd tripeptides 250 mg/kg/d+ triptolide 5.6 mg/kg/ of embodiment 7 preparation
d；
Experimental group 6: gavage gives rgd tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/d of embodiment 8 preparation
+ triptolide 5.6 mg/kg/d；
Above-mentioned administration group is administered for 10 days after modeling afterwards, is recorded as within the 11st day the 1st day, is administered once a day, often
It observes drinking water for animals and diet situation, respectively at administration the 1st day, is administered the 5th day, is administered the 10th day, is administered the 15th day, administration
The escape latency measuring mice with morris water maze behavioristicss assay method in 20 days.Put to death little after the completion of last mensure
Mus.Each group mice morris water maze behavioristicss measurement result is as shown in the table.
The each administration group of table 1 is to a β1-42Therapeutic effect (escape latency, the list of induced mice Alzheimer's disease model
Position is s)
Compared with model group, * p ＜ 0.05, * * p ＜ 0.01；
As can be seen from Table 1: there was no significant difference for each administration group escape latency of the 1st day, but with administration time
Extend, the escape latency difference of each administration group mice increases, and wherein each administration group of rgd tripeptides is respectively provided with positive treatment and makees
With.It is embodied in:
1) the mice escape latency of each treatment group of rgd tripeptides has significant difference compared with model group, all significantly contracts
The escape latency of short and small Mus, its drug treatment is after 15 days, the mice escape latency of each treatment group tool compared with model group
There is significant difference.Rgd tripeptides is to a β1-42Induced mice Alzheimer's disease model has significant therapeutic effect；
2) the mice escape latency of each treatment group of rgd tripeptides is variant, is understood the effect of experimental group 2 by table 1 data
It is optimal, this shows the rgd tripeptides of variable concentrations to a β1-42Induced mice Alzheimer's disease model has diversity, its
In 250 mg/kg/d rgd tripeptides to a β1-42The therapeutic effect of induced mice Alzheimer's disease model is optimal；
3) each treatment group of compound recipe has significant difference compared with single medicine group, and this shows experimental group 4 of the present invention, experiment
There is significant synergism in group 5 and experimental group 6 combination, significantly increase, accelerate Alzheimer's disease on medication effect
Therapeutic process.
Embodiment 10, the therapeutical effect of the Alzheimer's disease to app/ps1 bi-transgenic mice for the rgd tripeptides of the present invention
1 material
Rgd tripeptides is synthesized by Shanghai Qiang Yao company to be provided, and app/ps1 bi-transgenic mice is carried by Nanjing Experimental Animal Center
For keeping away dark auto testing instrument is Chengdu TME Technology Co., Ltd.'s product.
2 experimental techniques
The foundation of 2.1 experimental grouies: take app/ps1 bi-transgenic mice to be randomly divided into following drug treatment group every group 10
Mice.Each treatment group gives following medicines 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 of embodiment 4 preparation；
Experimental group 2: gavage gives rgd tripeptides 250 mg/kg/d of embodiment 4 preparation；
Experimental group 3: gavage gives rgd tripeptides 300 mg/kg/d of embodiment 4 preparation；
Experimental group 4: gavage gives rgd tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/ of embodiment 6 preparation
d；
Experimental group 5: gavage gives rgd tripeptides 250 mg/kg/d+ triptolide 5.6 mg/kg/ of embodiment 7 preparation
d；
Experimental group 6: gavage gives rgd tripeptides 250 mg/kg/d+ tetrandrine 28 mg/kg/d of embodiment 8 preparation
+ triptolide 5.6 mg/kg/d；
The detection of 2.2 step-through test behavioristicss
Keep away active box dark two Room clearly of dark auto testing instrument, have a hole between two Room, bottom passes to copper grid.Formally real
Each group app/ps1 bi-transgenic mice is trained before testing, app/ps1 bi-transgenic mice head is carried hole, and to put people bright
Room. first adapt to environment 2min, lead to 36v electric current then to darkroom copper grid, app/ps1 bi-transgenic mice is subject to electricity after entering darkroom
Hit and run away to bright room, copper grid are persistently energized 5min, this is training process.Carry out the memory of app/ps1 bi-transgenic mice after 24h
Test, record app/ps1 bi-transgenic mice enters the time (keeping away dark incubation period) in darkroom for the first time, if app/ps1 is double turns base
Still it is introduced into darkroom because in mice 5min.Its incubation period is counted as 300s.
3 statistical methods
Experimental data is represented with ± s, carries out statistical analysiss with spss11.5 software kit, using anova and lsd ' s
Posthoc test carries out statistical analysis, indicates significant difference with p < 0.05.
4 experimental results
The impact to app/ps1 bi-transgenic mice step-through test for the rgd tripeptides is as shown in table 2.
Secretly preclinical impact (± s) kept away by table 2 rgd tripeptides on 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 with respect to app/ps1 bi-transgenic mice and significantly prolongs dark incubation period
Long (p ＜ 0.01), points out rgd tripeptides to have significant prevention and treatment effect to app/ps1 bi-transgenic mice.Concrete manifestation
For:
1) the app/ps1 bi-transgenic mice of each treatment group of rgd tripeptides is kept away and is had compared with model group significantly dark incubation period
Sex differernce, all significantly shortens app/ps1 bi-transgenic mice and keeps away dark incubation period, there is significant difference.Rgd tripeptides is to a β1-42
The 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, from table 2 data
The effect of experimental group 2 is optimal, and this shows the rgd tripeptides of the variable concentrations alzheimer ' to app/ps1 bi-transgenic mice
Silent disease has a diversity, and the rgd tripeptides of wherein 250 mg/kg/d is to the Alzheimer's disease of app/ps1 bi-transgenic mice
Therapeutic effect is optimal；
3) each treatment group of compound recipe has significant difference compared with single medicine group, and this shows experimental group 4 of the present invention, experiment
There is significant synergism in group 5 and experimental group 6 combination, significantly increase, accelerate Alzheimer's disease on medication effect
Therapeutic process.
Show in the embodiment of the present invention 9 or embodiment 10 that rgd tripeptides acts on mechanism and other medicines of Alzheimer's disease
The medicine that thing acts on Alzheimer's disease does not conflict, and it can be used in combination, and can obtain the synergism in treatment.
Claims (1)
1. a kind of pharmaceutical composition containing rgd tripeptides is it is characterised in that it also contains tetrandrine and triptolide；
Rgd tripeptides in described pharmaceutical composition: tetrandrine: the weight of triptolide is than for 25:50:15.
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| ATE541038T1 (en) * | 2006-07-21 | 2012-01-15 | Univ Ramot | USE OF A PHAGE DISPLAYING A PEPTIDE OF AN ADHESION PROTEIN FOR THE TREATMENT OF A DISEASE ASSOCIATED WITH INTRACELLULAR FORMATION OF FIBRILLARY PROTEIN INCLUSIONS OR AGGREGATES |
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