CN104306954B - WRY tripeptides purposes in preparation treatment Alzheimer disease drug - Google Patents
WRY tripeptides purposes in preparation treatment Alzheimer disease drug Download PDFInfo
- Publication number
- CN104306954B CN104306954B CN201410497299.6A CN201410497299A CN104306954B CN 104306954 B CN104306954 B CN 104306954B CN 201410497299 A CN201410497299 A CN 201410497299A CN 104306954 B CN104306954 B CN 104306954B
- Authority
- CN
- China
- Prior art keywords
- wry
- tripeptides
- alzheimer
- disease
- treatment
- 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.)
- Expired - Fee Related
Links
Abstract
The present invention is claimed WRY tripeptides purposes in preparation prevention or treatment Alzheimer disease drug, belongs to field of medicaments.WRY tripeptides animal dosage of the present invention is clear and definite, and tablet, microspheres agent, powdery agent, oral liquid, parenteral solution can be made, when WRY tripeptides is used for treating Alzheimer's disease, can individually medication, Alzheimer's disease combination therapies that can also be different from other mechanism of action, the pharmaceutical composition that wherein WRY tripeptides and hanfangchin A, triptolide form is when the treatment of Alzheimer's disease, poisonous side effect of medicine can not only be reduced, and the effect of Synergistic treatment can be obtained, pharmacological evaluation confirms, WRY tri-Toplink effectively suppresses A β1-42Assemble and prevent A β1-42The phenomenon of the oligomerization of single aggressiveness, significantly inhibits the deposition of amyloid beta, and it is for Alzheimer's disease prevention or treatment determined curative effect, and side effect is little, therefore has wide medical application prospect.
Description
Technical field
The invention belongs to field of medicaments, relate to the new application of a kind of known drug, relate to specifically
And the purposes that WRY tripeptides is in preparation treatment Alzheimer disease drug.
Background technology
Suppression A β1-42The potential drug built up, but the mechanism of action of these molecules is the most complete
Illustrate.Chinese patent CN101346396B discloses prevention and the G for the treatment of Alzheimer's disease
Protein coupling acceptor antagonist and application thereof, this antagonist produces toxin, has serious side effect,
DeGrain, is unfavorable for large-scale popularization and application.
Uncertain, for the progress of the peptides mortifier of A β along with drug research result
Starting to receive much concern, a lot of polypeptide fragments is believed to be attached to the polymeric central authorities of A β
Hydrophobic core thus prevent the deposition of A β.Multiple small peptide is also proved to be to treat the effective of AD
Molecule, such as the glutathione of antioxidant.There is also evidence, WMDF and
Ac-AVVIA is effective in cure to AD.Additionally, research shows such as KLVFF's and LPFFD
Polypeptide and peptide quasi-molecule have stronger rejection characteristic to the Development process of AD.Have a kind of 20
Tetrapeptide, it is possible to anti-CDCC relevant for AD widely, is included in in vitro test exposure
In the environment of A β, show cell death activity.
Tang Dou hospital of The Fourth Military Medical University Neurology has delivered one about A β20-29Small peptide hinders
Disconnected ApoE/A β combines and reduces A β1-42Fibrillatable and neurovirulent effect effect (Chin thereof
J Clin Neurosci 2009.17 (1) .1～6) in disclose and utilize thioflavin T (ThT) fluorescence analysis
With the A β that transmission electron microscope method confirms Prof. Du Yucang20-29Small peptide no cytotoxicity effect, it is possible to competing
Be combined with ApoE4 to striving property, thus block A β1-42Be combined with ApoE4, reduce ApoE4
To A β1-42Fibrotic facilitation and neurotoxic effect thereof, illustrate A β20-29Small peptide is by energy
Enough becoming suppresses A β1-42The novel blocking agent that/ApoE4 combines, prevents new the controlling of AD for exploring
Treatment method provides effective experiment basis, but its effect is the most further studied.
Tripeptides is to form through three amino acid dehydrating condensations, and beneficially body absorption has no side effect
Advantage, tripeptides ILE-PRO-PRO (IPP) and VAL-PRO-PRO
(VPP) BH is had certain therapeutic action.Different types of tripeptides has different
Drug action.Tryptophan-Arginine-Tyrosine (Try-Ary-Tyr is called for short WRY tripeptides)
Tripeptides in mammal body degradable and be prone to absorb advantage, the beneficially performance of medicine.
Summary of the invention
Indefinite in order to solve prior art exists the medicine for the treatment of Alzheimer's disease, effect
Inconspicuous, that poisonous side effect of medicine is big defect, it is an object of the invention to provide prevention and treatment
The medicine of Alzheimer's disease.From the foregoing, A β20-29Small peptide blocks ApoE/A β and combines also
Reduce A β1-42Fibrillatable and neurovirulent effect effect thereof, therefore the present invention relates to WRY
A kind of medicinal usage of tripeptides, i.e. WRY tripeptides is used for preparing prevention or treatment senile dementia
Purposes in medicine.Medicine provided by the present invention is used for treatment or the prevention of Alzheimer's disease
Time determined curative effect, poisonous side effect of medicine is little, has medical application prospect widely.
An object of the present invention is to provide WRY tripeptides and treats and prevents alzheimer ' in preparation
Application in silent disease drug.Inventor finds through investigative test, and WRY tripeptides has aobvious
Write ground suppression amyloid beta deposition effect, WRY tripeptides be by with A β1-42It is combined into
Compound stablizes A β1-42Alpha-helix, helical structure and the formation of suppression beta sheet structure,
Thus keep stablizing A β1-42Conformation, thus suppress A β1-42Gathering, due to the gathering of A β
And have the closest between the formation of senile plaque expelling and the generation of Alzheimer's disease and progress
Relation, it can thus be anticipated that WRY tripeptides is for the prevention of Alzheimer's disease in the present invention
Or treatment can improve the state of an illness of patient or delay disease to play a positive role.The present invention
Test examples 6 and test examples 7 confirm that WRY tripeptides is to A β1-42Caused rat A Er
Thatch sea disease model and D-galactolipin induced mice Alzheimer's disease model have well treatment
Or prevention effect.The WRY tripeptides of the present invention 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 two of the purpose of the present invention are to provide a kind of pharmaceutical composition containing WRY tripeptides in system
The standby application treated and prevented in Alzheimer disease drug, the pharmaceutical composition of the present invention comprises
WRY tripeptides, hanfangchin A and/or triptolide, WRY in described pharmaceutical composition
Tripeptides: hanfangchin A: the weight ratio of triptolide is (1-500): (0.1-5):
(0.1-5)。
The three of the purpose of the present invention are that disclosure containing WRY tripeptides and is capable of said medicine use
The pharmaceutical preparation on way.In above-described medicinal usage, inventor is prepared into by test
Make tablet, microspheres agent, powdery agent, oral liquid and parenteral solution.Wherein tablet contains two kinds
Following auxiliary material above: starch, dextrin, low-substituted hydroxypropyl cellulose, magnesium stearate, crystallite
Cellulose, hydroxypropyl cellulose, starch slurry lactose, mannitol, superfine silica gel powder, crosslinking carboxylic first
Base sodium cellulosate and PVPP；Described microspheres agent contains following auxiliary material: gelatin,
Sodium sulphate, formalin.Degrade in described WRY tripeptides beneficially mammal body and be prone to inhale
Receive, the beneficially performance of drug effect, each preparation in the oral formulations of described WRY tripeptides medicine
In unit, the content containing WRY tripeptides is 0.1mg-200mg.
Compared with prior art, it is an advantage of the current invention that:
(1) WRY tripeptides is degradable and be prone to absorb, beneficially drug effect in the mammal body
Play；
(2) WRY tripeptides and A β1-42In conjunction with peptide-A β1-42Stable composite, and WRY tri-
Toplink stablizes A β1-42Alpha-helix, helical structure and the formation of suppression beta sheet structure, can have
The suppression A β of effect1-42Gathering and prevent A β1-42The phenomenon of the oligomerization of single aggressiveness；
(3) WRY tripeptides and other mechanism of action senile dementia is played the medicine of therapeutic action
During combination, its mechanism of drug action is complementary, and it can with hanfangchin A and triptolide combination
To play senile dementia prevention or the synergy for the treatment of, senile dementia can be improved and suffer from
The motion function of person and result for the treatment of.
Accompanying drawing explanation
Fig. 1 is WRY tripeptides and A β1-42Thioflavin T result of the test schematic diagram:
Fig. 2 is WRY tripeptides and A β1-42Circular dichroism spectra result of the test schematic diagram:
Fig. 3 is WRY tripeptides and A β1-42Transmission electron microscope (TEM) result of the test schematic diagram.
Detailed description of the invention
Specific embodiment is used to further illustrate present disclosure below.
Herein below is that to combine concrete preferred embodiment made for the present invention further in detail
Describe in detail bright, it is impossible to assert the present invention be embodied as be confined to these explanations.For the present invention
For person of an ordinary skill in the technical field, 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 the protection model of the present invention
Enclose.
The thioflavin T examination of the WRY tripeptides of experimental example 1, a kind of prevention or treatment Alzheimer's disease
Test:
By A β1-42Be dissolved in PH7.4, concentration be 0.01mol/L PB in join
Become the mixed solution of 50 μm ol/L, A β in this mixed solution1-42With the initial concentration of peptide it is
50 μm ol/L, during until ultimate density is 2.5 μm ol/L, is placed on 37 DEG C and hatches 48h, connect
Addition ThT (5 μm ol/L are dissolved in 50mmol/L glycine-NaOH solution,
PH8.50) fluorescence of 450nm and 485nm is detected.Each sample is measured 3 times, note
Record fluorescence intensity.
Shown in Fig. 1, embodiment 1 result shows: thioflavin T can promptly with A β1-42
Polymer fiber combine, inspiring a new wavelength is the light of 450nm, and shows as ripple
The light of a length of 482nm is remarkably reinforced, and WRY tripeptides and A β1-42The WRY tri-co-cultured
Peptide-A β1-42The sulphur production intensity of compound can reduce, and this fluorescent technique can be used for examining
Survey WRY tripeptides to A β1-42Polymerization or the regulating power decomposed.As it is shown in figure 1, compared to
Resveratrol, the concentration of WRY tripeptides is that 2.5 μm ol/L show A β1-42Condensate is more preferable
Inhibition, show that WRY tripeptides is A β1-42Polymeric mortifier.
The circular dichroism spectra examination of the WRY tripeptides of experimental example 2, a kind of prevention or treatment Alzheimer's disease
Test:
By the A β that concentration is 50 μm ol/L1-42It is dissolved in PBS, and in reality
Test group and add the WRY tripeptides that concentration is 50 μm ol/L, at then placing 37 DEG C, hatch 48h,
A β in this mixed solution1-42It is 5 μm ol/L with the ultimate density of WRY tripeptides, uses 1mm
The container ware of thickness, by A β1-42Monomer and WRY tripeptides-A β1-42Composite sample is prevented respectively
Only detecting structure in circular dichroism spectrometer, spectrum is at 25 DEG C, and wavelength is 190-260nm, ripple width
It is recorded during 0.5nm.
Shown in Fig. 2, embodiment 2 result shows: circular dichroism spectra shows WRY tripeptides-A β
In compound, β-pleated sheet structure can reduce, as in figure 2 it is shown, circular dichroism spectra detection A β1-42Individually
Shi Faxian has a blanking bar near 217nm, shows to there is beta sheet structure, as detection WRY
Find during tripeptides-A beta composite that the dark fringe near 217nm significantly alleviates, then show WRY
Tripeptides can reduce the formation of beta sheet structure, thus suppresses A β1-42The polymerization of monomer.
The transmitted electron of the WRY tripeptides of experimental example 3, a kind of prevention or treatment Alzheimer's disease shows
Micro mirror (TEM) is tested:
With phosphate buffer (PBS, pH7.4) by A β1-42Sample is dissolved into the dense of 1mg/ml
Degree, is then placed within WRY tripeptides experimental group and blank group that concentration is 25 μm ol/L,
Until the ultimate density of mixed solution hatches 48h, altogether by the sample of 5 μ l when being 25 μm ol/L
Point sample, in the copper mesh of 300 hole Formvar-carbon, adds the uranyl formate dyeing of 1%
1min, puts and dries in atmosphere, then is placed in electricity Microscopic observation, detects A β1-42With WRY tri-
Peptide-A β1-42The structure of compound.
Shown in Fig. 3, embodiment 3 result shows: as shown in the Electronic Speculum figure of Fig. 3, from
Aβ1-42Monomer, it is observed that the A β of the long wire of high density in figure1-42Fiber, fibril aggregation
Become parallel pencil, cross one another again between restrainting and restrainting；But, from WRY tripeptides-A β1-42Multiple
Compound figure only sees a small amount of linear fiber and amorphous polymer, short A β1-42Fiber
Shu Suiji cross-links mutually, thus defines irregular polymer；Illustrate that WRY tripeptides is permissible
Suppression A β1-42The polymerization of monomer.
Prepared by embodiment 4, WRY tripeptides tablet
Preparation technology: weigh WRY tripeptides, starch, dextrin and the low-substituted hydroxypropyl of recipe quantity
Base cellulose mixes.Separately take 60% ethanol of Sq, be incorporated in mixed-powder, mixed
Softwood processed after closing uniformly, is pelletized by 16 mesh sieves, and less than 60 DEG C are dried.After completing after drying
Carry out whole grain with 18 mesh sieves, sift out the fine powder in dry granular, mix with the magnesium stearate sieved,
It is mixed evenly with dry particle the most again, compressing tablet, to obtain final product.
Prepared by embodiment 5, WRY tripeptides microspheres agent
Preparation technology: WRY tripeptides is dissolved in 5% gelatin and forms suspension and emulsion, use
Vinegar acid for adjusting pH value is acid, is subsequently added into 60% appropriate sodium sulphate, is heated to 50 DEG C and mixes
Even formation condenses capsule, is cooled to 15 DEG C, adds appropriate 37% when being alkalescence by alkali regulation pH value
Formalin forms solidification capsule, is washed to formaldehydeless microspheres agent.
Prepared by embodiment 6, WRY tripeptides tablet
Preparation technology: weigh recipe quantity, WRY tripeptides, hanfangchin A, starch, dextrin
Mix with low-substituted hydroxypropyl cellulose.Separately take 60% ethanol of Sq, be incorporated in mixed
Close in powder, softwood processed after mixing, pelletized by 16 mesh sieves, less than 60 DEG C are dried.
Carry out whole grain with 18 mesh sieves after completing after drying, sift out the fine powder in dry granular, hard with sieve
Fatty acid magnesium mixes, and is mixed evenly with dry particle, compressing tablet the most again, to obtain final product.
Prepared by embodiment 7, WRY tripeptides tablet
Preparation technology: weigh recipe quantity, WRY tripeptides, triptolide, starch, paste
Essence and low-substituted hydroxypropyl cellulose mix.Separately take 60% ethanol of Sq, be incorporated in
In mixed-powder, softwood processed after mixing, pelletized by 16 mesh sieves, less than 60 DEG C are dried.
Carry out whole grain with 18 mesh sieves after completing after drying, sift out the fine powder in dry granular, hard with sieve
Fatty acid magnesium mixes, and is mixed evenly with dry particle, compressing tablet the most again, to obtain final product.
Prepared by embodiment 8, WRY tripeptides tablet
Preparation technology: each auxiliary material in prescription is crossed 100 mesh sieves, weighs WRY tripeptides, the Chinese
After root of fangji A prime, triptolide mix with lactose, mannitol, then it is separately added into place
Superfine silica gel powder, microcrystalline cellulose, PVPP and the cross-linked carboxymethyl of side's amount are fine
Dimension element sodium, mixes, adds 60% ethanol solution softwood, and 18 mesh sieve particles are wet
Particle is dried in 60 DEG C, the 16 whole grains of mesh sieve, adds magnesium stearate and mixes, compressing tablet, i.e.
?.
Embodiment 9, WRY tripeptides of the present invention are to A β1-42Induced mice Alzheimer's disease model
Therapeutic action
1 material and method
1.1 experiment material
Animal used as test is mouse, 8 weeks ages of mouse, and body weight 35-40g is provided by Nanjing Experimental Animal Center,
Aβ1-42Purchased from Sigma Co., USA, WRY tripeptides is provided by the synthesis of Shanghai Qiang Yao company,
Morris water maze is purchased from Shanghai Ji Liang company.
The foundation of 1.2 mouse Alzheimer's disease models and evaluation
1.2.1 intraventricular injection A β1-42The preparation of solution: by A β1-42It is dissolved in SPSS,
Making A β concentration is 10mmol/L, hatches 3 days and carry out aging in putting 37 DEG C of insulating boxs.
1.2.2 the making of animal model: raise under standard environment, be randomly divided into 2 groups: control group and mould
Type group, often group 12.2 groups on mouse age and body weight, there was no significant difference.Animal gives adaptability
After feeding 1 week, by mouse 2% yellow Jackets intraperitoneal anesthesia (40～50mg/kg physique
Amount), it is fixed on stereo brain orienting instrument, cuts off overhead hair, percutaneous incision after iodine tincture disinfection
Skin, is injection target area with reference to telocoele on the right side of " mouse brain stereotaxic atlas " selection, in bregma
1.0mm backward, opens by center line at 1.6mm, bores with three-edged needle and opens skull, exposes endocranium,
Use micro syringe with the speed of 12 μm/s from brain surface vertical inserting needle 4.0mm again, by 10
mmol/LAβ1-42Solution 5 μ l is slowly injected into, and slowly removes pin, sew up the incision after let the acupuncture needle remain at a certain point 2min.
Control group injects equal-volume SPSS.
1.2.3Morris water maze behaviouristics measures: 2 groups of mouse proceeded by respectively at postoperative 10th day
Morris water maze is tested.Test program is orientation navigation test: last 5 days, within first 2 days, is instruction
Practicing the laundering period, latter 3 days record achievements, if mouse finds platform in 1min, record is in fact
Border escape latency；If not finding platform in 1min yet, then drawn by experimenter
Platform also stops 20S, and escape latency is recorded as 1min.
1.2.4 the evaluation of animal model
By following table it can be seen that the escape latency of model group is from the beginning of the 1st of experimental record the day
Control group is just obviously prolonged (P ＜ 0.05 or P ＜ 0.01), and the escape that model group is between 3 days is dived
Volt phase and control group escape latency no significant difference between 3 days, shows to use the method to build
Vertical Alzheimer's disease type is reliably accurate, may be used for the medicine of Alzheimer's disease medicine
Effect is evaluated.
| Group | First day | Second day | 3rd day |
| Control group | 20.26±9.92 | 20.98±6.42 | 21.08±5.40 |
| Model group | 40.74±10.94 | 39.86±6.24 | 40.88±7.18 |
2 animal models and packet are administered
According to above-mentioned modeling method modeling, and control group, normal group are set, often group 10, mark
Raise under quasi.Each group administering mode is as described below:
Normal group: gavage gives the physiological saline of same volume；
Control group: gavage gives the physiological saline of same volume；
Model group: gavage gives the physiological saline of same volume；
Experimental group 1: gavage gives the WRY tripeptides 200mg/kg/d of embodiment 4 preparation；
Experimental group 2: gavage gives the WRY tripeptides 250mg/kg/d of embodiment 4 preparation；
Experimental group 3: gavage gives the WRY tripeptides 300mg/kg/d of embodiment 4 preparation；
Experimental group 4: gavage gives the WRY tripeptides 250mg/kg/d+ Stephania tetrandra first of embodiment 6 preparation
Element 28mg/kg/d；
Experimental group 5: gavage gives the WRY tripeptides 250mg/kg/d+ thunder godvine first of embodiment 7 preparation
Element 5.6mg/kg/d；
Experimental group 6: gavage gives the WRY tripeptides 250mg/kg/d+ Stephania tetrandra first of embodiment 8 preparation
Element 28mg/kg/d+ triptolide 5.6mg/kg/d；
Above-mentioned administration group is administered after 10 days after modeling, within the 11st day, is recorded as the 1st day, often
It is administered once, and observes drinking water for animals and diet situation every day, respectively at being administered the 1st day, gives
Medicine the 5th day, is administered the 10th day, is administered the 15th day, is administered 20 days with Morris water maze behavior
Learn assay method and measure the escape latency of mouse.Mouse is put to death after having measured for the last time.
Each group mouse Morris water maze behaviouristics measurement result is as shown in the table.
Table 1 each administration group is to A β1-42The result for the treatment of of induced mice Alzheimer's disease model
(escape latency, unit S)
| Group | 1st day | 5th day | 10th day | 15th day | 20th day |
| Normal group | 10.24±1.32 | 9.66±1.16 | 10.22±1.02 | 20.24±1.16 | 10.46±2.00 |
| Control group | 20.16±10.18 | 19.84±4.52 | 21.08±5.30 | 20.14±6.00 | 20.12±6.02 |
| Model group | 41.88±9.96 | 4204±7.06 | 41.02±9.98 | 40.12±6.54 | 40.02±7.04 |
| Experimental group 1 | 41.48±9.98 | 37.66±4.60 | 33.98±5.34 | 29.86±2.00 | 26.12±4.98* |
| Experimental group 2 | 40.98±10.14 | 37.08±4.72 | 33.96±3.24 | 29.04±3.02 | 26.34±3.12* |
| Experimental group 3 | 41.54±9.36 | 37.26±4.52 | 33.58±4.90 | 28.68±3.56 | 26.06±4.02* |
| Experimental group 4 | 40.76±7.98 | 37.56±4.66 | 33.68±4.02 | 28.08±3.36 | 19.98±2.38* |
| Experimental group 5 | 40.70±7.96 | 37.22±4.08 | 33.26±2.14 | 28.00±2.64 | 21.42±2.66* |
| Experimental group 6 | 40.64±8.64 | 37.16±4.02 | 33.14±2.36 | 27.70±2.46 | 18.96±2.98** |
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
Along with the prolongation of administration time, the escape latency difference of each administration group mouse strengthens, wherein
WRY tripeptides each administration group is respectively provided with positive therapeutic action.It is embodied in:
1) the mouse escape latency of WRY tripeptides each treatment group has conspicuousness compared with model group
Difference, significantly shortens the escape latency of mouse, and its drug treatment is after 15 days, respectively
The mouse escape latency for the treatment of group has significant difference compared with model group.WRY tri-
Peptide is to A β1-42Induced mice Alzheimer's disease model has significant result for the treatment of.
2) the mouse escape latency of WRY tripeptides each treatment group is variant, from table 1 data
The effect of experimental group 2 is optimal, and this shows that the WRY tripeptides of variable concentrations is to A β1-42Institute
Cause mouse Alzheimer's disease model and there is otherness, the wherein WRY of 250mg/kg/d
Tripeptides is to A β1-42The result for the treatment of of induced mice Alzheimer's disease model is optimal.
3) compound each treatment group has significant difference compared with single medicine group, and this shows of the present invention
There is significantly synergy, in drug therapy in experimental group 4, experimental group 5 and experimental group 6 combination
It is obviously enhanced in effect, accelerates the therapeutic process of Alzheimer's disease.
Embodiment 10, the WRY tripeptides of the present invention Alzheimer's disease to APP/PS1 bi-transgenic mice
Therapeutic action
1 material
WRY tripeptides is provided by the synthesis of Shanghai Qiang Yao company, and APP/PS1 bi-transgenic mice is real by Nanjing
Testing animal center to provide, keeping away dark auto testing instrument is Chengdu TME Technology Co., Ltd.'s product.
2 experimental techniques
The foundation of 2.1 experimental group: take APP/PS1 bi-transgenic mice and be randomly divided into following drug treatment
Group often 10 mouse of group.Each therapeutic component does not give following medicine:
Normal group: gavage gives the physiological saline of same volume；
Control group: gavage gives the physiological saline of same volume；
Model group: gavage gives the physiological saline of same volume；
Experimental group 1: gavage gives the WRY tripeptides 200mg/kg/d of embodiment 4 preparation；
Experimental group 2: gavage gives the WRY tripeptides 250mg/kg/d of embodiment 4 preparation；
Experimental group 3: gavage gives the WRY tripeptides 300mg/kg/d of embodiment 4 preparation；
Experimental group 4: gavage gives the WRY tripeptides 250mg/kg/d+ Stephania tetrandra first of embodiment 6 preparation
Element 28mg/kg/d；
Experimental group 5: gavage gives the WRY tripeptides 250mg/kg/d+ thunder godvine first of embodiment 7 preparation
Element 5.6mg/kg/d；
Experimental group 6: gavage gives the WRY tripeptides 250mg/kg/d+ Stephania tetrandra first of embodiment 8 preparation
Element 28mg/kg/d+ triptolide 5.6mg/kg/d；
2.2 step-through test behaviouristics detections
Keep away the darkest two Room of active box of dark auto testing instrument, between two Room, have a hole, bottom
Pass to copper grid.Before formal experiment, each group of APP/PS1 bi-transgenic mice is trained, will
APP/PS1 bi-transgenic mice head carries Fang Renming room, hole. first adapt to environment 2min, then
Leading to 36V electric current to darkroom copper grid, APP/PS1 bi-transgenic mice is shocked by electricity after entering darkroom
I.e. running away to bright room, copper grid are persistently energized 5min, and this is training process.APP/PS1 is carried out after 24h
The test of memory of bi-transgenic mice, record APP/PS1 bi-transgenic mice enters dark for the first time
The time (keeping away dark incubation period) of room, if being still introduced into dark in APP/PS1 bi-transgenic mice 5min
Room.Its incubation period is counted as 300s.
3 statistical methods
Experimental data is usedRepresent, carry out statistical analysis with SPSS11.5 software kit, use
ANOVA and LSD ' S posthoc test carries out statistical analysis, indicates notable with P < 0.05
Sex differernce.
4 experimental results
WRY tripeptides is as shown in table 2 on the impact of APP/PS1 bi-transgenic mice step-through test.
APP/PS1 bi-transgenic mice is kept away dark preclinical impact by table 2WRY tripeptides
| Group | n | Keep away dark incubation period (s) |
| Normal group | 12 | 21.98±6.00 |
| Model group | 12 | 105.14±9.22## |
| Experimental group 1 | 12 | 64.00±8.12* |
| Experimental group 2 | 12 | 63.56±9.08* |
| Experimental group 3 | 12 | 64.14±9.56* |
| Experimental group 4 | 12 | 62.26±9.04* |
| Experimental group 5 | 12 | 51.94±8.34* |
| Experimental group 6 | 12 | 48.50±6.46** |
Compared with normal group, ##P ＜ 0.01；Compared with model group, * P ＜ 0.05, * * P ＜ 0.01；
As can be seen from Table 2, WRY tripeptides treatment group is relative to APP/PS1 bi-transgenic mice
Keeping away and significantly extend dark incubation period (P ＜ 0.01), prompting WRY tripeptides turns base to APP/PS1 is double
Because mouse has significantly prevention and result for the treatment of.It is embodied in:
1) the APP/PS1 bi-transgenic mice of WRY tripeptides each treatment group keeps away dark incubation period and model group
Compare and there is significant difference, significantly shorten APP/PS1 bi-transgenic mice and keep away dark latent
, there is significant difference in Fu Qi.WRY tripeptides is to A β1-42Caused APP/PS1 double transgenic
The Alzheimer's disease of mouse has significant result for the treatment of.
2) the APP/PS1 bi-transgenic mice escape latency of WRY tripeptides each treatment group is variant,
The effect being understood experimental group 2 by table 2 data is optimal, and this shows the WRY tri-of variable concentrations
Peptide has otherness to the Alzheimer's disease of APP/PS1 bi-transgenic mice, and wherein 250
The WRY tripeptides of mg/kg/d is controlled the Alzheimer's disease of APP/PS1 bi-transgenic mice
Therapeutic effect is optimal.
3) compound each treatment group has significant difference compared with single medicine group, and this shows of the present invention
There is significantly synergy, in drug therapy in experimental group 4, experimental group 5 and experimental group 6 combination
It is obviously enhanced in effect, accelerates the therapeutic process of Alzheimer's disease.
The embodiment of the present invention 9 or embodiment 10 show that WRY tripeptides acts on Alzheimer
The mechanism of disease acts on the medicine of Alzheimer's disease and does not conflict with other drug, and it can join
Close and use, and the synergy in treatment can be obtained.
Claims (10)
1.WRY tripeptides purposes in preparation treatment Alzheimer disease drug.
2. purposes as claimed in claim 1, it is characterised in that the animal dosage of WRY tripeptides is 1mg/kg d ~ 500mg/kg d.
3. purposes as claimed in claim 1, it is characterised in that the animal dosage of WRY tripeptides is 50mg/kg d ~ 500mg/kg d.
4. purposes as claimed in claim 1, it is characterised in that the animal dosage of WRY tripeptides is 100mg/kg d ~ 500mg/kg d.
5. purposes as claimed in claim 2, it is characterised in that described animal dosage is 100mg/kg d ~ 300mg/kg d.
6. the purposes as described in claim 2-3 is arbitrary, it is characterised in that described WRY tripeptides makes tablet, microspheres agent, powdery agent, oral liquid, parenteral solution.
7. the purposes as described in claim 1-4 is arbitrary, it is characterised in that the content containing WRY tripeptides in the oral formulations of described medicine in each preparation unit is 0.1mg-200mg.
8. the pharmaceutical composition containing WRY tripeptides, it is characterised in that it contains hanfangchin A.
9. the pharmaceutical composition containing WRY tripeptides as claimed in claim 8, it is characterised in that it is possibly together with triptolide.
10. the pharmaceutical composition containing WRY tripeptides as claimed in claim 9, it is characterised in that WRY tripeptides in described pharmaceutical composition: hanfangchin A: the weight ratio of triptolide is (1-500): (0.1-5): (0.1-5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410497299.6A CN104306954B (en) | 2014-09-25 | 2014-09-25 | WRY tripeptides purposes in preparation treatment Alzheimer disease drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410497299.6A CN104306954B (en) | 2014-09-25 | 2014-09-25 | WRY tripeptides purposes in preparation treatment Alzheimer disease drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104306954A CN104306954A (en) | 2015-01-28 |
| CN104306954B true CN104306954B (en) | 2016-08-24 |
Family
ID=52362363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410497299.6A Expired - Fee Related CN104306954B (en) | 2014-09-25 | 2014-09-25 | WRY tripeptides purposes in preparation treatment Alzheimer disease drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104306954B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL354122A1 (en) * | 1999-08-09 | 2003-12-29 | Tripep Abtripep Ab | Pharmaceutical compositions containing tripeptides |
| CN1328280C (en) * | 2002-11-28 | 2007-07-25 | 中国科学院上海药物研究所 | Tetrandrine and tetrandrine compound, synthesis and uses thereof |
| CN104225574B (en) * | 2003-02-04 | 2017-01-11 | 科内尔研究基金会 | Methods for preventing mitochondrial permeability transition |
-
2014
- 2014-09-25 CN CN201410497299.6A patent/CN104306954B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104306954A (en) | 2015-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2018024111A1 (en) | Substance containing gold cluster and preparation method and use thereof | |
| CN104363757B (en) | Methods and compositions for treating pain | |
| EP3320901B1 (en) | Dimethylaminomicheliolide for use in the treatment of pulmonary fibrosis | |
| CN104622930A (en) | Application of babao (Chinese character) pill in treatment of senile dementia and pharmaceutical composition of babao pill | |
| CN104306954B (en) | WRY tripeptides purposes in preparation treatment Alzheimer disease drug | |
| du Sert et al. | The delayed phase of cisplatin-induced emesis is mediated by the area postrema and not the abdominal visceral innervation in the ferret | |
| CN104324359B (en) | RRY tripeptides purposes in preparation treatment Alzheimer disease drug | |
| Yuan et al. | ONO-2506 can delay levodopa-induced dyskinesia in the early stage | |
| DE112018005145T5 (en) | INHIBITION OF AMINOACYLASE 3 (AA3) IN TREATMENT OF CANCER | |
| WO2015060746A1 (en) | Combination for treating and/or preventing manifestations of psychiatric, cognitive, behavioral and neurological disorders in the case of organic diseases of the central nervous system having various origins | |
| CN103690581A (en) | Pharmaceutical composition for treating senile dementia | |
| CN104274817B (en) | WRW tripeptides purposes in preparation treatment Alzheimer disease drug | |
| CN104258371B (en) | WWW tripeptides purposes in preparation treatment Alzheimer disease drug | |
| CN109528719B (en) | Application of vinpocetine in preparation of medicine for preventing and/or treating altitude disease caused by acute altitude advancement | |
| Tang et al. | Rhodiola rosea L extract shows protective activity against Alzheimer’s disease in 3xTg-AD mice | |
| CN104248750B (en) | The purposes of FWW tripeptides in preparation treatment Alzheimer disease drug | |
| CN108042555B (en) | A kind of application of icariin | |
| IT201900002109A1 (en) | COMPOSITIONS INCLUDING AMINO ACIDS FOR USE IN THE TREATMENT OF INJURIES OF THE CENTRAL NERVOUS SYSTEM | |
| CN104258372B (en) | Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease | |
| Shao et al. | Electroacupuncture Attenuates Learning and Memory Impairment via PI3K/Akt Pathway in an Amyloid β 25-35-Induced Alzheimer’s Disease Mouse Model | |
| Zhang et al. | Nanoparticles in the treatment of Alzheimer’s disease with magnetic resonance | |
| Ou et al. | Intranasal hydrogel of armodafinil hydroxypropyl-β-cyclodextrin inclusion complex for the treatment of post-traumatic stress disorder | |
| CN109200051A (en) | Purposes of the huperzine and the like as treatment diseases associated with inflammation drug | |
| CN108697748A (en) | Open loop secoisolariciresinoldiglucoside diglucoside (SDG) and related compound are used to prevent the purposes of radiation injury | |
| CN105456269B (en) | A kind of pharmaceutical composition and its application for treating hyperplasia of prostate |
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: 20160824 Termination date: 20210925 |