CN106265612A - Lourerin C application in preparation preventing and treating central nervous system disease medicine - Google Patents
Lourerin C application in preparation preventing and treating central nervous system disease medicine Download PDFInfo
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Abstract
The invention discloses lourerin C application in the central nervous system disease medicines such as preparation preventing and treating Alzheimer, parkinson disease, vascular dementia, depression, belong to medicinal chemistry arts.The present invention relates to lourerin C and improve cognitive disorder, the dyskinesia and the mood disorders of above-mentioned central nervous system disease animal pattern；In Western blot detection finds lourerin C treated animal brain, neural cell injury alleviates, and synapse-related protein SYP, PSD95 and GAP43 express and significantly improve；Illustrate that lourerin C can be effective against the symptoms such as Alzheimer, parkinson disease, vascular dementia, depression.Therefore, lourerin C can be used for the preparation above-mentioned central nervous system disease medicine of preventing and treating, it is possible to become compositions to prepare the most acceptable tablet, capsule, pill, injection, slow releasing agent and various particulate delivery system with pharmaceutically acceptable vehicle group.
Description
Technical field
The present invention relates to medicinal chemistry arts, be specifically related to lourerin C in preparation preventing and treating Alzheimer, parkinson
Application in the central nervous system disease medicines such as disease, vascular dementia, depression.
Background technology
Along with aging and the expanding economy of world population, the quality of life of old people is more and more paid attention to.
Senile dementia is a kind of disease having a strong impact on life of elderly person quality, and main type has Alzheimer
(A1zheimer ' s disease, AD) and vascular dementia (Vascular dementia, VD), wherein AD is about senile dementia
The 50%-60% of total number of persons, VD account for 10%-20%.The quantity of curing senile dementia medicine is very limited at present.
Parkinson disease (Parkinson ' s disease, PD) it is common nervus centralis degenerative disease, Major Clinical table
Now include inactive chatter, stiff, slow movement, postural reflex are abnormal, and severe patient loses self care ability.Treatment at present
Parkinsonian medicine can improve symptom in a short time, but all can not reverse neuropathologic change, and that long-term prescription brings is different
The side effect such as dynamic disease are notable.
In modern society, work and rhythm of life are progressively accelerated, and the pressure that people are born is with challenge (stressors) also
It is gradually increased.Serious or lasting stress, particularly chronic stress, drastically influence the physical and mental health of the mankind, the many bodies of induction
Body or mental sickness (such as depression).Depression has become as the Mental health problems that modern society is serious, according to world health group
Knitting statistics, for Disease Spectrum, it is contemplated that to the year two thousand twenty, depression will rise to be only second to cardiopathic second largest illness.
To sum up, the central nervous system such as potential Alzheimer, parkinson disease, vascular dementia, depression are sought
The protective agents of disease has important medical significance and social meaning.
Lourerin C is the monomeric compound of isolation identification from Chinese medicine Sanguis Draxonis (Dragon ' s Blood).Sanguis Draxonis is
The most time-honored rare Chinese medicine.Its property sweet-salty, flat, enter the heart, Liver Channel, there is the functions such as dissipating blood stasis analgesic therapy, blood activating and promoting tissue regeneration.Existing
Generation research confirms, Sanguis Draxonis has the multiple pharmacological effect such as anti-inflammatory analgesic, antifungal, arrhythmia, enhancing human body immunity.Sanguis draconis
The English entitled Loureirin C of element C, No. CAS is 116384-24-8, and molecular formula is C16H16O4, chemistry entitled 4,4'-dihydroxy
Base-2-melonia chalcone derivative (4,4'-dihydroxy-2-methoxydihydrochalcone), structure such as formula I institute
Show:
Animal model selection gist: (1) is by excitatory amino acid quinolinic acid (quinolinic acid；QA) inject
Animal Meynert basal nuclei can cause local excitation acidic amino acid to assemble in a large number, continuingly acts on nmda receptor, causes a large amount of
Ca2+Interior stream, causes Ca2+Overload, produces a large amount of products of oxidative stress, trigger cell inflammation, mitochondrial dysfunction then.This
Outer Meynert basal nuclei is that cholinergic neuron assembles the abundantest place, and this model can cause cholinergic neuron degeneration, dead
Die, cholinergic nerve system dysfunction, then cause cognition and memory ability to go down, i.e. quinolinic acid can cause similar AD's
Pathological change and cognitive disorder.(2) can after MPTP (MPTP) vein or lumbar injection
By blood brain barrier, it is toxic product MPP+ by monoamine oxidase, MAO (MAO-B) metabolism in brain, then selects through DAT
Property take in substantia nigra dopaminergic neuron, cause performances such as trembling, bradykinesia, rigid limbs, postural reflex are abnormal, supplement a left side
Rotation DOPA can improve above symptom, and MPTP can cause the PD model of classics.(3) ischemia-reperfusion caused by cerebral infarction is to lure
Send out the one of the main reasons of vascular dementia.Mice cerebral ischemia reperfusion model repeatedly is to close common carotid artery by folder to cause cerebral blood supply
For hypoxgia, cause acute cerebral insult, by machine manufactures such as calcium overload during Reperfu-sion and respiratory bursts (oxygen-derived free radicals is superfluous)
Become delayed cerebral injury.This model brain injury index is obvious, and dysmnesia are notable, are the VD models of a kind of classics.(4) chronic not
It is contemplated that slight irritability depression model (chronic unpredictable mild stress, CMS) and other animal models
Compare the various stimulations that more can be met with in simulating human daily life, there is with clinical depression higher etiology and associate
Property.Clinical research shows, the people being exposed to life events uncontrollable, unpredictalbe for a long time is easier to suffer from depressive disorder.This
Outward, in terms of antidepressant drug research and development, because the curative effect of antidepressant drug can be made an appraisal after needing medication certain time, this
It is accomplished by the Depressive behavior for this type of animal model studied has the time response similar to clinic, i.e. animal to must be able to hold
Continuous several weeks above time, this is also the unique advantage of this depression model.
To sum up, use above animal model to investigate lourerin C and prevent and treat Alzheimer, parkinson disease, vascular dementia
And the central nervous system disease effect such as depression has abundant theoretical foundation.
Up to now, there are no lourerin C preventing and treating Alzheimer, parkinson disease, vascular dementia and depression
Record and report.
Summary of the invention
The present invention is to provide the new application of lourerin C, is i.e. used for preventing and treating Alzheimer, parkinson disease, vascular are crazy about
The central nervous system disease such as slow-witted, depression.
The present invention is respectively by Alzheimer, parkinson disease, vascular dementia, animal models of depression (rat
Meynert basal nuclei injection quinolinic acid model, mouse peritoneal injection MPTP model, mice bilateral common carotid arteries Ischemia Reperfusion repeatedly
Injection molding type, the unpredictable gentle irritability depression model of murine chronic), observe lourerin C to above-mentioned central nervous system disease
Preventive and therapeutic effect.Result of study shows, lourerin C all demonstrates preventive and therapeutic effect to the animal model of above-mentioned disease.
The present invention is with Wistar rat and ICR mice as laboratory animal, and modeling method and dosage regimen are as follows: (1) intends AD
Model: Wistar rat both sides Meynert basal nuclei (position: after bregma by 1.4mm, sagittal line ± 2.4mm, under skull
6.8mm) all injecting 2 μ L (containing quinolinic acid 120nmol) quinolinic acid solution, sham operated rats injects equal-volume PBS solution.Modeling same day
Starting gastric infusion, lourerin C arranges 3 dosage 0.112mg/kg, 0.224mg/kg and 0.448mg/kg.It is administered the 8th day and opens
Begin to carry out Y labyrinth successively, new object distinguishes and Morris water maze laboratory, afterwards, gathers brain cortical tissue, and detection represents prominent
Touch the synapse-related protein of structure and function, growth-associated protein-43 (GAP43), Postsynaptic density-95 (PSD95) and
The expression of synaptophysin (SYP).(2) PD model is intended: ICR mice is according to the dosage lumbar injection MPTP of 20mg/kg body weight, often
Being spaced injection in 3 hours once, injection 4 times, completed in one day altogether.Starting gastric infusion after modeling, lourerin C arranges 3 dosage
0.15mg/kg, 0.3mg/kg and 0.6mg/kg.It is administered the 14th day and starts to carry out turn-club test, pole-climbing experiment, balance beam successively in fact
Test and test with spacious field.(3) vascular dementia model: separate ICR mice bilateral common carotid arteries, closes 20min with bulldog clamp folder, decontrols
10min, then folder close 20min, at tail point 1cm, put 8-10 bleed.Starting gastric infusion after modeling, lourerin C arranges 3 dosage
0.15mg/kg, 0.3mg/kg and 0.6mg/kg.It is administered the 8th day and starts carry out Y labyrinth, Morris water maze successively and passively return
Avert disasters and test, gather hippocampal tissue.The expression of detection synapse-related protein GAP43, PSD95 and SYP.(4) depression model: right
According to group ICR mice group support under standard laboratory conditions, freely take the photograph water and picked-up feedstuff.Model group ICR mice list cage list is only raised
Support, passively accept every day to restrict water supply, limit food, swim, prohibit in the stimulation such as water, fasting, 45 degree of oblique cages, wet cages a kind, stimulation time is not
Fixing, random arrangement 28 days, homologous stimulus discontinuously occurs, makes mice can not expect the generation stimulated.Start during modeling to fill
Stomach is administered.It is administered the 29th day and starts to carry out sucrose solution preference experiment, forced swim test, tail-suspention test, the experiment of spacious field successively.Experiment
As a result, lourerin C high dose significantly improves intend that AD and VD animal Y maze experiment spontaneous alternation response rate, new object distinguish excellent
First index and difficulty, the target quadrant swim time of Morris water maze laboratory, passive avoidance test escape latency etc.,
In Western blot detection finds lourerin C high dose group mouse brain, GAP43, PSD95 and SYP protein expression significantly improves,
Result above prompting lourerin C improves plan AD and VD animal learning dysmnesia, and neurocyte in animal brain is had protection
Effect.Compared with model group, lourerin C high dose significantly extends and intends the incubation period of PD animal turn-club test, shortens pole-climbing experiment
Time of turning round and fall time, raising Beam balance test score, increase horizontal and vertical movement, result above prompting lourerin
C improves plan PD animal movement obstacle.Lourerin C high dose significantly extends the sucrose solution preference mark of animal, shortens forced swimming
Experiment dead time, the tail-suspention test dead time, increasing horizontal and vertical movement, result above prompting lourerin C improves dynamic
The depressive symptom of thing.To sum up, lourerin C can be effectively improved Alzheimer, parkinson disease, vascular dementia, depression
Deng central nervous system disease symptom.
The pharmaceutical composition of the compounds of this invention can be prepared according to method well known in the art.Time for this purpose, if
Needing, can the compounds of this invention and one or more solids or liquid pharmaceutical excipients and/or adjuvant be combined, making can conduct
The suitable administration form of drug use or dosage form.
The compounds of this invention or the pharmaceutical composition containing it can be administered in a unit, and route of administration can be intestinal
Or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc..
The compounds of this invention or the route of administration containing its pharmaceutical composition can be drug administration by injection.Injection includes that vein is noted
Penetrate, intramuscular injection, subcutaneous injection and acupoint injection therapy etc..
Form of administration can be liquid dosage form, solid dosage forms.If liquid dosage form can be true solution class, colloidal type, microgranule
Dosage form, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, capsule, drop pill, aerosol, pill, powder, solution, mixed
Suspension, Emulsion, granule, suppository, lyophilized injectable powder etc..
The compounds of this invention can be made ordinary preparation, can also be slow releasing preparation, controlled release preparation, targeting preparation and various
Particulate delivery system.
Such as in order to unit dosage forms for administration is made tablet, well known in the art various carrier can be widely used.About
The example of carrier is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, Portugal
Grape sugar, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.；Wetting agent and binding agent, such as water, glycerol, poly-second two
Alcohol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethyl cellulose
Sodium, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, as dry starch, alginate, agar powder,
Laminaran, sodium bicarbonate and citric acid, calcium carbonate, Polyoxyethylene Sorbitol Fatty Acid Esters, dodecyl sodium sulfate, methyl fibre
Dimension element, ethyl cellulose etc.；Disintegrate inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；Absorption enhancement
Agent, such as quaternary ammonium salt, sodium lauryl sulphate etc.；Lubricant, as Pulvis Talci, silicon dioxide, corn starch, stearate, boric acid,
Liquid paraffin, Polyethylene Glycol etc..Tablet can also be made coated tablet, such as sugar coated tablet, thin membrane coated tablet, enteric further
Coated tablet, or double-layer tablet and multilayer tablet.
Such as in order to administration unit is made pill, well known in the art various carrier can be widely used.About carrier
Example be that such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidine
Ketone, glyceryl monostearate, Kaolin, Pulvis Talci etc.；Binding agent, such as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid
Sugar, rice paste or batter etc.；Disintegrating agent, such as agar powder, xeraphium, alginate, dodecyl sodium sulfate, methylcellulose, second
Base cellulose etc..
Such as in order to administration unit is made capsule, active ingredient the compounds of this invention lourerin C is various with above-mentioned
Carrier mixes, and is placed in hard gelatine capsule or soft capsule by thus obtained mixture.Also can be by the effective ingredient present invention
Compound makes microcapsule, is suspended in aqueous medium formation suspensoid, also can load in hard capsule or make injection application.
Such as, the compounds of this invention lourerin C is made injection preparation, as solution, suspensoid solution, Emulsion,
Lyophilized injectable powder, this preparation can be aqueous or non-aqueous, can contain acceptable carrier on a kind of and/or multiple pharmacodynamics,
Diluent, binding agent, lubricant, preservative, surfactant, dispersant, osmotic pressure regulator, solubilizing agent and pH adjusting agent.
As dilution can be selected for water, ethanol, Polyethylene Glycol, 1,3-PD, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol,
Polyoxyethylene sorbitol fat, fatty acid ester etc..Osmotic pressure regulator can be sodium chloride, mannitol, glycerol, glucose, phosphoric acid
Salt, acetate etc.；Solubilizing agent or cosolvent can be poloxamer, lecithin, hydroxypropylβ-cyclodextrin etc.；PH adjusting agent is permissible
It is phosphate, acetate, hydrochloric acid, sodium hydroxide etc..As prepared lyophilized injectable powder, it is also possible to add mannitol, glucose etc. and make
For proppant.
Additionally, if desired for adding coloring agent, preservative, spice, correctives, sweeting agent or perfume (or spice) in pharmaceutical preparation
Material etc..These adjuvants are commonly used in the art.
Sterile media used by the present invention can be prepared by standard technique well known to the skilled person.Can
By they sterilizings, such as by via biofilter filtration, by adding biocide in compositions, by compositions being put
Penetrate process or by by compositions heat sterilization.Before use they can also made sterile injectable medium.
In order to reach medication purpose, increasing prevention effect, the medicine of the present invention or pharmaceutical composition can be with any known
Medication is administered.Certainly for implementing the position that the route of administration of the compounds of this invention depends on that disease and needs are prevented and treated.Cause
Pharmacokinetics and pharmacodynamic profile for the compounds of this invention have difference to a certain degree, therefore, obtain treatment in the tissue dense
The most preferred method of degree is to be gradually increased dosage and monitor clinical effectiveness.For such therapeutic dose that is gradually increased, initial agent
Amount will depend upon which route of administration.
For any particular patient, the dosage of the compounds of this invention pharmaceutical composition depends on many factors, such as
The order of severity of disease, the sex of patient, age, personality and individual reaction, route of administration, administration number of times, therapeutic purposes, therefore
The preventing and treating dosage of the present invention can have large range of change.Disease according to treated patient, it may be necessary to dosage is made
Some changes, and under any circumstance, is all determined the suitable dose of individual patient by doctor.
Dosage refers to not including vehicle weight the weight of compound (when a carrier is used).In general,
The using dosage of Chinese materia medica composition of the present invention is to well known to a person skilled in the art.Can be according in the compounds of this invention compositions
Actual drug quantity contained in last preparation, in addition suitable adjustment, to reach the requirement of its therapeutically effective amount, complete
The prevention of the present invention or therapeutic purposes.Or can be divided into several to be the administration of single dose form, such as two, three or four dosage shapes
Formula is administered；This is limited to be administered the clinical experience of doctor and include using the dosage regimen of other treatment means.The present invention's
Compound or compositions can individually be taken, or merge use with other treatment medicine or symptomatic drugs and adjust dosage.
The invention provides the new opplication of lourerin C in preparation preventing and treating Alzheimer, parkinson disease, vascular
Application in the central nervous system disease medicines such as dementia, depression.
Accompanying drawing explanation
Fig. 1 lourerin C impact on Meynert basal nuclei injection quinolinic acid rat Y maze experiment spontaneous alternation response rate
Fig. 2 lourerin C to Meynert basal nuclei injection the new object of quinolinic acid rat distinguish experiment 1h, 24h priority index and
The impact of difficulty
When Fig. 3 lourerin C is to Meynert basal nuclei injection quinolinic acid treated rats in Morris water maze performance object of experiment quadrant swim
Between impact
The impact that Meynert basal nuclei injection quinolinic acid rat cerebral cortex synapse-related protein is expressed by Fig. 4 lourerin C
A: the lourerin C impact on SYP protein expression
B: the lourerin C impact on PSD95 protein expression
C: the lourerin C impact on GAP43 protein expression
Fig. 5 lourerin C is on the lumbar injection MPTP preclinical impact of mice turn-club test
The experiment of lumbar injection MPTP mice pole-climbing is turned round the impact of time and fall time by Fig. 6 lourerin C
Fig. 7 lourerin C impact on lumbar injection MPTP mice Beam balance test score
Fig. 8 lourerin C is on lumbar injection MPTP mice spacious field experimental level and the impact of vertical movement
Fig. 9 lourerin C shadow to bilateral common carotid arteries ischemia-reperfusion mice Y maze experiment spontaneous alternation response rate repeatedly
Ring
Bilateral common carotid arteries ischemia-reperfusion mice Morris water maze laboratory target quadrant repeatedly is swum by Figure 10 lourerin C
Swimming time, the impact of swimming distance
Figure 11 lourerin C shadow to bilateral common carotid arteries ischemia-reperfusion mice passive avoidance test escape latency repeatedly
Ring
The impact that bilateral common carotid arteries ischemia-reperfusion hippocampus of mice synapse-related protein repeatedly is expressed by Figure 12 lourerin C
A: the lourerin C impact on SYP protein expression
B: the lourerin C impact on PSD95 protein expression
C: the lourerin C impact on GAP43 protein expression
Figure 13 lourerin C impact on depressed mice sucrose solution preference mark
Figure 14 lourerin C impact on the depressed mouse forced swimming test dead time
Figure 15 lourerin C impact on the depressed Tail suspension test dead time
Figure 16 lourerin C is on depressed mice spacious field experimental level and the impact of vertical movement.
Detailed description of the invention
The following examples can help those skilled in the art that the present invention be more fully understood, but never in any form
Limit the present invention.
Embodiment 1 lourerin C causes the impact of AD model to rat Meynert basal nuclei injection quinolinic acid
Male Wistar rat, body weight 270-290 gram, it is randomly divided into 5 groups, often group 12.5 groups be respectively sham operated rats,
Model group, lourerin C low dose group (0.112mg/kg), middle dosage (0.224mg/kg) and high dose group (0.448mg/kg).
Rat, with chloral hydrate (350mg/kg) intraperitoneal injection of anesthesia of 3.5%, cuts off calvarium cutout regions hair, alcohol disinfecting, and incites somebody to action
Head is fixed on brain solid positioner, determines rat Meynert basal nuclei position (bregma according to rat brain stereotaxic atlas
By rear 1.4mm, sagittal line ± 2.4mm, 6.8mm under skull), bore with miniature bur after labelling and open skull, by 10 μ L micro-samplings
Device moves into and injects.In addition to sham operated rats, often group rat both sides Meynert basal nuclei all injects 2 μ L (containing quinolinic acid 120nmol)
Quinolinic acid solution (with 0.01mol/L, pH 7.4PBS buffer solution), slowly injects 1min, let the acupuncture needle remain at a certain point 6min, and sham operated rats is noted
Enter equal-volume PBS solution.Modeling animal on the same day starts gastric infusion after reviving, and sham operated rats and model group give the molten of equivalent
Agent.Be administered the 8th day start carry out Y labyrinth successively, new object distinguish with Morris water maze laboratory, Behaviors survey during continue
Being administered, every day 1 time, until behavioristics terminates, puts to death animal, gathers brain cortical tissue.Detection synapse-related protein GAP43,
PSD95 and SYP expresses.
1. rat Y maze experiment
Being administered the 8th day, each group rat carries out Y maze experiment.Rat Y maze experiment is intended to investigate lourerin C to rat certainly
Send out alternating activity and the impact of working memory.Device is made up of the wooden support arm that three angles are 120 °, respectively A, B, C tri-
Arm.Rat being put into during experiment A arm end, allows its three arms that freely come in and go out, in record 8min, every rat enters three arms
Total degree and enter arm order, to continuously enter three different arms for once correct alternation response, records correct alternation response secondary
Number.Spatial working memory function is reflected with spontaneous alternation response rate (%).
Experimental result is as shown in Figure 1: compared with sham operated rats, model group spontaneous alternation response rate significantly reduces；And and mould
Type group is compared, and lourerin C group spontaneous alternation response rate dramatically increases, and prompting lourerin C can significantly improve the work intending AD rat
Make memory ability.Experimental data means standard deviation represents, ##p < 0.01 compared with matched group；Compared with model group * * * p <
0.001, N=12.
2. the new object of rat distinguishes experiment
Being administered the 9th day, each group rat carries out new object and distinguishes experiment.The new object of rat distinguishes that experiment is intended to investigate lourerin
C distinguishes the impact of memory to rat image.Experimental provision is a black plastic circular open field, diameter about 60cm, high 20cm.This
Experiment is divided into adaptive phase and test phase.2～3 rats are put in open field by adaptive phase every time, allow it freely explore
3min, to adapt to environment, every day 2 times, carries out 2 days.Within 3rd day, test, a rat is put in open field the freest every time
Explore 3min, take out rat afterwards, 2 identical objects (A1, A2) are placed in open field central authorities, put into rat, in record 5min
Explore the time (tA1, tA2) of two articles.After 1h, A2 object is changed into new object B, rat is placed again into, record exploration two
The time (tA1, tB) of object.After 24h, changing object B into object C, be placed again into by rat, record is explored used by two articles
Time (tA1, tC).Explore criterion be rat nose directed towards object and distance object 1cm within, or touch nose,
Lick object or touch object with fore paw.Calculate the priority index (Preferential index) to new object and difficulty
(Discrimination index)。
Priority index computing formula is as follows:
Priority index (1h)=tB/ (tA1+tB)
Priority index (24h)=tC/ (tA1+tC)
Difficulty computing formula is as follows:
Difficulty (1h)=(tB-tA1)/(tA1+tB)
Difficulty (24h)=(tC-tA1)/(tA1+tC)
Experimental result is as shown in Figure 2: compared with sham operated rats, model group rats 1h and the priority index of 24h test phase
All significantly reduce with difficulty, hints model group rat imaginal memory reduced capability.Compared with model group, lourerin C group 1h
And 24h priority index and difficulty all dramatically increase, prompting lourerin C can significantly improve plan AD rat image and distinguish memory barrier
Hinder.Experimental data means standard deviation represents, ###p < 0.001 compared with sham operated rats；Compared with model group * * p <
0.01, * * * p < 0.001, N=12.
3. treated rats in Morris water maze performance experiment
Being administered the 13rd day, each group rat carries out Morris water maze laboratory.Morris water maze laboratory is intended to investigate sanguis draconis
The element C impact on Spatial memory obstacle.Water maze device is by a diameter of 1.5 meters, the black rustless steel circle of a height of 50 centimetres
Shape pond and the circular metal platform composition of a diameter of 10 centimetres, platform can move freely position.In experiment forward direction pond
Water filling (water temperature 24 ± 1 DEG C), makes the water surface be higher than 1 centimetre of platform.Training stage, respectively carry out 1 training morning and afternoon every day, last 6
My god.Platform is placed in fourth quadrant, puts in water by rat towards pool wall, records 90 seconds, if rat finds platform in 90 seconds,
It is allowed to have a rest on platform 10 seconds.If 90 seconds do not find platform, rat is guided and has a rest 10 seconds to platform.It is administered the 19th day
Test, remove platform, allow rat free swimming 90 seconds.Labyrinthine system automatically record rat original platform quadrant (target as
Limit) residence time.
Experimental result is as shown in Figure 3: compared with sham operated rats, the model group target quadrant swim time substantially reduces, prompting
Model group rats spatial memory capacity declines.Compared with model group, the lourerin C group target quadrant swim time dramatically increases, and carries
Show that lourerin C can improve the Learning memory disorder of modeling rat dose-dependant.Experimental data means standard deviation represents, with
Sham operated rats compares ###p < 0.001；* p < 0.05, * * * p < 0.001, N=12 compared with model group.
4. Western blot detection synapse-related protein is expressed
Cerebral tissue low temperature is fully homogenized, and is resuspended in protein lysate and PMSF, places 40 minutes on ice, at 4 DEG C 12000
Rev/min, centrifugal 30 minutes, take supernatant.Bradford method is used to carry out protein quantification.40 μ g protein extracts add loading and delay
Rushing liquid, boiling water bath heats 5 minutes, abundant degeneration.10%SDS-PAGE electrophoretic separation albumen → semidry method is by protein delivery extremely
Pvdf membrane → 5% defatted milk powder is closed 2 hours → mono-and anti-is hatched, and 4 DEG C of overnight → anti-incubated at room of PBS eluting → bis-2 hours →
ECL method is developed.
Experimental result is as shown in Figure 4: compared with sham operated rats, model group rats cerebral cortex GAP43, PSD95 and SYP egg
White expression significantly reduces；Compared with model group, lourerin C group significantly improves GAP43, PSD95 and SYP protein expression water
Flat, prompting lourerin C has nerve synapse protective effect.Experimental data means standard deviation represents, # compared with sham operated rats
p<0.05；* p < 0.05, * * p < 0.01, N=5 compared with model group.
Embodiment 2 lourerin C causes the impact of PD model to mouse peritoneal injection MPTP
Male ICR mouse, body weight 22-25 gram, it is randomly divided into 5 groups, often group 10.5 groups be respectively matched group, model group,
Lourerin C low dose group (0.15mg/kg), middle dosage group (0.3mg/kg) and high dose group (0.6mg/kg).According to 20mg/kg
The dosage lumbar injection MPTP of body weight, at interval of injection in 3 hours once, injection 4 times, completed in one day altogether.Administration group after modeling
Gastric infusion continuously, once a day, until putting to death animal, matched group and model group give same volume solvent.It is administered the 14th day
Row turn-club test, within the 15th day, carry out pole-climbing experiment, within the 16th day, be balanced wood experiment, within the 17th day, carry out the experiment of spacious field.
1. mice turn-club test
Being administered the 12nd day, each group mice is placed in transfer rod instrument and is trained, and setting speed 5 encloses/minute, 300 seconds/time, 3 times/
My god；Being administered the 13rd day, each group mice is placed in transfer rod instrument and is trained, and setting speed 10 encloses/minute, 300 seconds/time, 3 times/day；Give
Each group of mice is tested by medicine on the 14th day, and transfer rod instrument setting speed 30 encloses/minute, 200 seconds/time, test 3 times altogether.Record is surveyed
The time that during examination, mice drops from transfer rod instrument, take average i.e. incubation period.
Experimental result is as shown in Figure 5: compared with matched group, model group significantly reduces incubation period；And compared with model group, dragon
Sanguinin C group significantly extends incubation period, and prompting lourerin C can significantly improve the dyskinesia of PD mice.Experimental data average
± standard deviation represents, ##p < 0.01 compared with matched group；* p < 0.05, N=10 compared with model group.
2. mice pole-climbing experiment
It is administered the 15th day, horizontal table top arranges a rough plastic bar being perpendicular to desktop, diameter 10mm, high 30cm.
Mouse head is upwards placed in plastic bar top, and automatic turning until head is downward, and is dropped to desktop along plastic bar by mice.
Record mice turns to the required time and drops to desktop time of (all contacting desktop with double front foots to be as the criterion).
Experimental result is as shown in Figure 6: compared with matched group, model group turns round the time and fall time all significantly reduces；And
Compared with model group, lourerin C group turns round the time and fall time significantly extends, and it is little that prompting lourerin C can significantly improve PD
The dyskinesia of Mus.Experimental data means standard deviation represents, ##p < 0.01 compared with matched group；Compared with model group * p <
0.05, N=10.
3. mice Beam balance test
It is administered the 16th day, the steel round bar two ends of a 100cm length, diameter 10mm are fixed on diameter 20cm, high 30cm
On circular platform.During experiment, mice being put in steel pole central authorities, the testing time is 60s, records mice equilibration time on bar
(i.e. from grabbing bar to the time fallen).If mice is in 60s still on bar or escape one of the platform to two ends, then the record time is
60s.Every mice follow-on test 3 times on bar respectively.Standards of grading: 0 point: animal falls down from bar；1 point: in 60s, animal is not
Fall from bar, but also do not move；2 points: in 60s, animal does not falls from bar, and move on bar, but not up to platform；3
Point: in 60s, animal does not falls from bar, and arrives platform in 40-59s；4 points: in 60s, animal does not falls from bar, and
Platform is arrived in 20-39s；5 points: in 60s, animal does not falls, and in 20s, arrive platform.Record and calculate every mice to exist
The integral mean value of 3 times on bar.
Experimental result is as shown in Figure 7: compared with matched group, model group score significantly reduces；And compared with model group, sanguis draconis
Element C group score dramatically increases, and prompting lourerin C can significantly improve the balanced capacity of PD mice.Experimental data mean value ± mark
Quasi-difference represents, #p < 0.05 compared with matched group；* p < 0.05, N=10 compared with model group.
4. mice spacious field experiment
Being administered the 17th day, carry out the experiment of spacious field, to investigate the exploratory behaviour of mice, experimental provision is that a length is equal
For the uncovered wooden case of 50cm, being divided into 25 length of sides bottom wooden case is the square of 2cm.Experimental period 20min altogether, puts mice
Bottom wooden case one jiao, after adapting to 15min, the horizontal movement (the grid number that extremity are crossed over) of observed and recorded last 5min mice and
Vertical movement (number of times that mice is stood with hind leg).
Experimental result is as shown in Figure 8: compared with matched group, and model group horizontal movement and vertical movement all significantly reduce；And
Compared with model group, lourerin C group horizontal movement and vertical movement dramatically increase, and it is little that prompting lourerin C can significantly improve PD
The dyskinesia of Mus.Experimental data means standard deviation represents, ##p < 0.01 compared with matched group；Compared with model group * p <
0.05, * * p < 0.01, N=10.
Embodiment 3 lourerin C causes the impact of vascular dementia model to mice bilateral common carotid arteries ischemia-reperfusion repeatedly
Male ICR mouse, body weight 22-25 gram, it is randomly divided into 5 groups, often group 10.5 groups are respectively sham operated rats, model
Group, lourerin C low dose group (0.15mg/kg), middle dosage group (0.3mg/kg) and high dose group (0.6mg/kg).First abdominal cavity
Injecting atropine (1mg/kg), 5min pneumoretroperitoneum is injected 3.5% chloral hydrate anesthesia, is carried on the back position and fix.Separate bilateral common carotid arteries,
Close 20min with bulldog clamp folder, decontrol 10min, then folder closes 20min, puts 8-10 and bleed at tail point 1cm.Sham operated rats only separates
Bilateral common carotid arteries, does not press from both sides and closes not blood-letting.Modeling animal on the same day starts gastric infusion after reviving, and sham operated rats and model group give
The solvent of equivalent.It is administered the 8th day and starts to carry out Y labyrinth, Morris water maze and passive avoidance test, Behaviors survey phase successively
Between continue to be administered, every day 1 time, until behavioristics terminates, puts to death animal, gathers cerebral hippocampus tissue.Detection synapse-related protein
GAP43, PSD95 and SYP express.
1. mice Y maze experiment
Being administered the 8th day, each group mice carries out Y maze experiment.Mice Y maze experiment is intended to investigate lourerin C to mice certainly
Send out alternating activity and the impact of working memory.Device is made up of the wooden support arm that three angles are 120 °, respectively A, B, C tri-
Arm.Mice being put into during experiment A arm end, allows its three arms that freely come in and go out, in record 10min, every mice enters three arms
Total degree and enter arm order, to continuously enter three different arms for once correct alternation response, records correct alternation response secondary
Number.Spatial working memory function is reflected with spontaneous alternation response rate (%).
Experimental result is as shown in Figure 9: compared with sham operated rats, model group spontaneous alternation response rate significantly reduces；And and mould
Type group is compared, and lourerin C group spontaneous alternation response rate dramatically increases, and it is little that prompting lourerin C can significantly improve vascular dementia
The working memory ability of Mus.Experimental data means standard deviation represents, #p < 0.05 compared with sham operated rats；With model group phase
Than * p < 0.05, N=10.
2. mice Morris water maze laboratory
Being administered the 9th day, each group mice carries out Morris water maze laboratory.Morris water maze laboratory is intended to investigate lourerin
The C impact on Spatial memory obstacle.Water maze device is circular by the black rustless steel of a diameter of 1.2 meters, a height of 50 centimetres
Pond and the circular metal platform composition of a diameter of 10 centimetres, platform can move freely position.Experiment is noted in forward direction pond
Water (water temperature 24 ± 1 DEG C), makes the water surface be higher than 1 centimetre of platform.Training stage, respectively carry out 1 training morning and afternoon every day, last 5 days.
Platform is placed in fourth quadrant, puts in water by mice towards pool wall, records 60 seconds, if mice finds platform in 60 seconds, allows it
Platform is had a rest 10 seconds.If 60 seconds do not find platform, mice is guided and has a rest 10 seconds to platform.It is administered the 16th day and carries out
Test, removes platform, allows mice free swimming 60 seconds.Labyrinthine system automatically records mice and stops at original platform quadrant (target quadrant)
The time stayed and distance.
Experimental result is as shown in Figure 10: compared with sham operated rats, model group target quadrant swim time and distance significantly drop
Low；And compared with model group, lourerin C group target quadrant swim time and distance dramatically increase, prompting lourerin C can be notable
Improve the spatial memory capacity of fourth ventricle in mice with vascular dementia.Experimental data means standard deviation represents, ##p compared with sham operated rats
<0.01；* p < 0.05, N=10 compared with model group.
3. mice passive avoidance test
Being administered the 15th day, each group mice carries out passive avoidance test.Passive avoidance test is intended to investigate lourerin C to study
The impact of ability.Experimental provision two Room clearly demarcated, dark.Two Room sizes are 15 cm x 10 cm x 11 centimetres, have between two Room
The semicircle door of one a diameter of 3 centimetres of sizes.All spreading with copper grid bottom two Room, darkroom base copper grid can be energized, voltage strength
By manostat control.Mice doorway dorsad is put into bright room, adapts to environment 3 minutes, then pass to 30V voltage.Mice enters dark
Shocked by electricity immediately in room, then flee back bright room from doorway, so training 5 minutes.Testting after 1 hour, record enters dark for the first time
The incubation period of room, in this, as Memory result.
Experimental result is as shown in figure 11: compared with sham operated rats, and model group enters the escape latency in darkroom and significantly shortens；
And compared with model group, lourerin C group enters and dramatically increases the incubation period in darkroom, prompting lourerin C can significantly improve blood vessel
The ability of learning and memory of property dementia mice.Experimental data means standard deviation represents, ##p < 0.01 compared with sham operated rats；With
Model group compares * p < 0.05, N=10.
4. Western blot detects hippocampal synapse correlative protein expression
Method is with embodiment 1 4..
Experimental result is as shown in figure 12: compared with sham operated rats, model group hippocampus of mice GAP43, PSD95 and SYP albumen
Expression significantly reduces；Compared with model group, lourerin C group significantly improves GAP43, PSD95 and SYP protein expression level,
Prompting lourerin C has nerve synapse protective effect.Experimental data means standard deviation represents, compared with sham operated rats #p <
0.05, ##p < 0.01；* p < 0.05, N=5 compared with model group.
The impact of embodiment 4 lourerin C gentle irritability depression model unpredictable on murine chronic
Male ICR mouse, body weight 25-30 gram, it is randomly divided into 5 groups, often group 10.5 groups be respectively matched group, model group,
Lourerin C low dose group (0.15mg/kg), middle dosage group (0.3mg/kg) and high dose group (0.6mg/kg).Control group mice
Group support, under standard laboratory conditions, freely takes the photograph water and feedstuff.Model group mice list cage list is only raised, and every day passively accepts limit
Water, limit eat, swim, prohibit water, fasting, 45 degree of oblique cages, wet cages etc. stimulation in a kind, stimulation time is not fixed, random arrangement 28
My god, homologous stimulus discontinuously occurs, makes mice can not expect the generation stimulated.The while of modeling, the continuous gastric infusion of administration group, often
It once, until put to death animal, matched group and model group give same volume solvent.Be administered the 29th day carry out sucrose solution preference experiment,
Within 30th day, carry out forced swim test, within the 31st day, carry out tail-suspention test, put to death animal after tail-suspention test, gather cerebral cortex.Inspection
Survey synapse-related protein GAP43, PSD95 and SYP to express.
1. mice sucrose solution preference experiment
Being administered the 29th day, each group mice carries out sucrose solution preference experiment.Before test, mice is prohibited water fasting 18 hours, during test
Between be chosen at mice and carry out (7:00pm-12:00pm) movable normal night, and experimentation keeps no light condition.Test
Time mice list cage list only put, give simultaneously feedstuff and weigh in advance, two same drinking bottles of labelling, be respectively provided with 1%
Sucrose water and clear water so that it is unrestricted choice absorb.After 1 hour, take off two drinking bottles, and record of again weighing simultaneously.Depend on
According to following equation calculating sucrose solution preference mark:
Sucrose solution preference mark=sucrose solution intake/(sucrose solution intake+clear water intake) × 100%
Experimental result is as shown in figure 13: compared with sham operated rats, and model group sucrose solution preference mark significantly reduces；And and model
Group is compared, and lourerin C group sucrose solution preference mark dramatically increases, and prompting lourerin C can significantly improve depressed mice to award
Reactive.Experimental data means standard deviation represents, ##p < 0.01 compared with matched group；* p < 0.05, N compared with model group
=10.
2. mouse forced swimming test
Being administered the 30th day, each group mice carries out forced swim test.Forced swim test is by animal in experimentation
Motionless behavior reflects its behavioral despair state, is one of the index evaluated of depression model.Mice movable normal night is chosen in experiment
Between carry out, in experimentation keep dim light.First in transparent cylinder (high: 40cm, diameter: 30cm) glass container
Injecting the deep clear water of 30cm, water temperature is maintained at 25 ± 2 DEG C.During test, mice is put down gently in water, first adapt it to swim 1 point
Clock, the floating dead time of mice in starting to record follow-up 5 minutes for the 2nd minute.
Experimental result is as shown in figure 14: compared with sham operated rats, the model group dead time significantly extends；And with model group phase
Ratio, the lourerin C group dead time significantly shortens, and prompting lourerin C can significantly improve the behavioral despair state of depressed mice.Real
Test data means standard deviation to represent, #p < 0.05 compared with matched group；* p < 0.05, N=10 compared with model group.
3. Tail suspension test
Being administered the 31st day, each group mice carries out tail-suspention test.Tail-suspention test is similar to forced swim test, is also by reality
During testing, the motionless behavior of animal reflects its behavioral despair state, is one of the index evaluated of depression model.Experiment is chosen little
Mus is carried out movable normal night, keeps dim light in experimentation.At mice tail end about 1cm, it is fixed on support during test
On so that it is it is in state of naturally hanging by the feet.First mice is made to adapt to 1 minute, little within second minute, starting to record follow-up 5 minutes
The dead time of Mus.
Experimental result is as shown in figure 15: compared with sham operated rats, the model group dead time significantly extends；And with model group phase
Ratio, the lourerin C group dead time significantly shortens, and prompting lourerin C can significantly improve the behavioral despair state of depressed mice.Real
Test data mean value ± standard error to represent, ##p < 0.01 compared with matched group；* p < 0.05, N=10 compared with model group.
4. mice spacious field experiment
It is administered the 32nd day, carries out the experiment of spacious field, to investigate the behavior depression of mice.Method is with embodiment 2 4..
Experimental result is as shown in figure 16: compared with matched group, and model group horizontal movement and vertical movement all significantly reduce；And
Compared with model group, lourerin C group horizontal movement and vertical movement dramatically increase, and prompting lourerin C can significantly improve mice
Behavior depression.Experimental data means standard deviation represents, ##p < 0.01 compared with matched group；Compared with model group * p <
0.05, * * p < 0.01, N=10.
Claims (9)
1. lourerin C application in preparation treatment central nervous system disease medicine.
2. lourerin C application in preparation treatment Alzheimer, parkinson disease, vascular dementia or antidepressant agents.
3. lourerin C improves the application in cognitive disorder, the dyskinesia and dysthymic disorder's medicine in preparation.
4. lourerin C application in neurocyte medicine in preparation protection brain.
5. according to the application described in claim 1-4 any one, it is characterised in that: described lourerin C, can with pharmaceutically may be used
The carrier accepted makes pharmaceutical composition.
6. according to the application described in claim 1-4 any one, it is characterised in that described lourerin C can with pharmaceutically may be used
The carrier accepted is prepared as the most acceptable tablet, capsule, pill, injection, slow releasing agent and various particulate delivery system.
Application the most according to claim 5, it is characterised in that: described pharmaceutical composition can be with pharmaceutically acceptable
Carrier is prepared as the most acceptable tablet, capsule, pill, injection, slow releasing agent and various particulate delivery system.
8. according to the application described in claim 1-7 any one, it is characterised in that described lourerin C is from Chinese medicine Sanguis Draxonis
Isolated and purified acquisition or synthesis in (Dragon ' s Blood) and obtain.
9. according to the application described in claim 1-7 any one, it is characterised in that lourerin C molecular formula is C16H16O4, chemistry
Entitled 4,4'-dihydroxy-2-melonia chalcone derivative, structure is as shown in formula I:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110840984A (en) * | 2019-12-03 | 2020-02-28 | 北京理工大学 | Application of dragon's blood in preparing medicine for preventing blood brain barrier injury |
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