CN103520147B - Puerarin or the pharmaceutical composition that contains Puerarin have the purposes in the medicine that prevents or treat senile dementia effect in preparation - Google Patents
Puerarin or the pharmaceutical composition that contains Puerarin have the purposes in the medicine that prevents or treat senile dementia effect in preparation Download PDFInfo
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Abstract
The pharmaceutical composition that the invention discloses Puerarin or contain Puerarin has the purposes in the medicine that prevents or treat senile dementia effect in preparation. When Puerarin is used for the treatment of people or mammal senile dementia or prevents, medication separately, senile dementia drug combination that also can be different from other drug mechanism of action; When wherein the pharmaceutical composition of Puerarin and triptolide, galanthamine, borneol composition is used for the treatment of senile dementia, not only can reduces poisonous side effect of medicine, and can obtain the effect of Synergistic treatment. Puerarin can significantly suppress the deposition of amyloid beta, and it is for senile dementia prevention or treatment determined curative effect, and side effect is little, therefore has wide medical application prospect.
Description
Technical field
The invention belongs to Puerarin technical field, the pharmaceutical composition that is specifically related to Puerarin or contains Puerarin has the purposes in prevention or treatment senile dementia in preparation.
Background technology
Senile dementia, claim again Alzheimer disease (Alzhimer ' sDisease, AD), it is a kind of DD of central nervous system, its clinical manifestation is the continuous deterioration of cognitive and memory capability, and carrying out property of activity of daily living goes down and occurs various schizophrenia symptoms and behavior disorder. Along with advancing of disease, patient can lose self care ability gradually, brings white elephant to patient's individual family and society. Illness rate studies show that, the U.S. is 4,500,000 examples at the Alzheimer case load of 2000, every increase of age 5 years old, and Alzheimer disease patient's percentage will rise 2 times, that is to say, and 60 years old crowd's illness rate is 6%, and 85 years old crowd's illness rate is 30%. At present China exceedes the old man of 60 years old approximately 1.29 hundred million, accounts for 10.15% of total population. Thereby prevention and the treatment of paying attention to senile dementia have very important social effect and clinical meaning.
The pathogenesis of senile dementia is still indefinite at present, is amyloid beta cascade hypothesis about the pathogenetic main flow theory of senile dementia. This hypothesis thinks that the abnormal degraded of amyloid beta sample precursor (APP) generates excessive aβ protein, and deposition forms the core of senile plaque expelling in brain, it can activate microglia, reaction causes inflammation, lesion wire plastochondria causes energy metabolism impairment, generate polyoxy freely, caused the oxidative stress infringement of body, active cell apoptosis pathway. On the other hand, A β can also activated protein kinase, impels Protein tau Abnormal Phosphorylation, and damage cholinergic neuron causes the pathology of central cholinergic system. These pathological changes promote again generation and the abnormal stacking of A β, produce the cascade enlarge-effect of positive feedback, finally cause neuronic minimizing and mediator to discharge abnormal.
The drug main for the treatment of AD will comprise the following aspects at present: 1. acetylcholinesteraseinhibitors inhibitors, lose in a large number for AD patient's brain Cholinergic Neurons, acetylcholine mediator famine, use acetylcholinesteraseinhibitors inhibitors, the content that can increase acetylcholine in brain, promotes neuronic recovery. The medicine of this class mainly contains this 2. anti-inflammatory drug such as bright of Tacrine, donepezil, profit now, owing to existing reactive spongiocyte around senile plaque expelling amyloidosis core, therefore someone propose the chronic inflammation theory of AD, and utilize suitable anti-inflammatory drug to reach the object of prevention and treatment. The medicine of this class has aspirin etc. 3. excitability glutamate receptor antagonists, Cell protection is avoided the attack of excitatory transmitter cytotoxic effect. The medicine of this class has Memantine etc. 4. the neural factor that generates, the specific neuron that acts on of its energy, the plasticity of stimulating neuronal, promotes neuronic growth, survival, safeguards the function of cell. 5. other, as estrogenic alternative medicine, the agent of brain cell metabolic activation, the utilization of calcium ion antagonist etc. Although said medicine has shown certain curative effect in clinical practice, in long-term use procedure, exist serious inevitable side effect. As Tacrine has serious hepatotoxicity, need periodic monitoring liver function, therefore Tacrine is now seldom for patient.
In the time that the toxic and side effect of chemical synthetic drug is seriously perplexing medical circle, people start more to pay close attention to natural drug, in recent years, the control that natural drug is applied to AD has accumulated a large amount of invaluable experiences, uses natural drug treatment AD to mainly contain 2 advantages: (1) acts on many target spots can the adjusting through row globality to function of human body; (2) side effect is little. Therefore,, for the treatment of AD, the exploitation of natural drug and utilization have larger advantage and more wide prospect.
Puerarin is the active ingredient in the pulse family platymiscium root of kudzu vine. Its chemistry 8-C-β-D-Glucose by name base-7,4-dihydroxy-isoflavones (8-C-β-D-Glucopyranosyl-7,4-hydroxy-isoflavone) acicular crystal that is white in color, can be water-soluble, but solubility is little, and its aqueous solution is colourless or micro-yellow. Have the immunity of raising, strengthen myocardial contractive power, protection cardiac muscle cell, reduces blood pressure, and has the effects such as platelet aggregation-against.
From Puerarin in 1993 by Ministry of Public Health's approval for clinical because it has very strong resisting cardiovascular hypoxic-ischemic activity, can coronary artery dilator and the cerebrovascular, reduction myocardial oxygen consumption, improve myocardium shrinkage function, improve microcirculation and improve the effects such as learning and memory. This medicine is clinical is mainly used in the diseases such as allevating angina pectoris, treatment heart stalk, hypercoagulable blood, arrhythmia cordis and cerebrovascular disease. This medicine annual turnover of the whole nation reaches approximately 500,000,000 RMB at present has become one of important treating cardiovascular disease. General flavone in the root of kudzu vine can increase brain and CBF coronarius. Puerarin has obvious facilitation to brain circulation and the peripheral circulation of animal and human's body. Pueraria Flavonid improve the cerebrovascular tension force of hypertension and patients with coronary heart disease, elasticity and pollex for because of etc. aspect all have gentle facilitation. Puerarin not only improves the normal brain activity microcirculation of human body, and microcirculation disorder is also improved significantly, and main manifestations is that the amplitude of local capilary blood flow and motion increases. Puerarin is also improved effect to the Microcirculation of Nailfold of patients with sudden sensorineural hearing loss, can accelerate microvascular blood flow velocity, removes blood vessel loop extravasated blood, improves patient's hearing. Puerarin has protective effect to hypoxic cardiac muscle, and Puerarin can obviously reduce the oxygen demand of ischemic myocardium, and cardioprotection is avoided the ischemic ultrastructure damage due to port perfusion again.
Patent application 200610046076.3 discloses a kind of pueraria flavonid composition and for the preparation of the application in control cardiovascular and cerebrovascular disease, senile dementia, cerebral infarction, cerebral ischemia and the other diseases that caused by cerebral ischemia thereof, the composition that these drug regimen species contain Pueraria Flavonid and general ixeris flavone and saponin(e, or the composition of pueraria flavonid composition and total seabuckthorn flavone, in its pharmaceutical composition, contain multiple not clear composition, do not meet the principle of medication of modern medicine, and in use very easily produce violent bad reaction. And it does not also carry out the test of pesticide effectiveness to the application in the other diseases of preventing and treating cardiovascular and cerebrovascular disease, senile dementia, cerebral infarction, cerebral ischemia and caused by cerebral ischemia, and do not know whether this pueraria flavonid composition has the application described in it, and the effect described in it, being the coefficient effect of each component in pueraria flavonid composition, is not the effect that Pueraria Flavonid brings as unique active component.
Summary of the invention
The pharmaceutical composition that the object of the present invention is to provide Puerarin or contain Puerarin has the purposes in the medicine that prevents or treat senile dementia effect in preparation. This Puerarin or the pharmaceutical composition that contains Puerarin determined curative effect during for the treatment of senile dementia or prevention, poisonous side effect of medicine is little, has medical application prospect widely.
Above-mentioned purpose of the present invention is achieved by the following technical solution: Puerarin or the pharmaceutical composition that contains Puerarin have the purposes in the medicine that prevents or treat senile dementia effect in preparation.
Puerarin can be used as medicine for prevention or treatment senile dementia. Present inventor finds through investigative test, Puerarin has the effect that suppresses significantly amyloid beta deposition, between the generation of the gathering of A β and the formation of senile plaque expelling and senile dementia and progress, there is very close relationship, therefore can predict Puerarin in the present invention and can improve patient's the state of an illness or delay playing a positive role of disease for prevention or the treatment of senile dementia. Drug effect embodiment 11 in the specific embodiment of the invention and drug effect embodiment 12 confirm that Puerarin high dose group and Puerarin low dose group are to A β25-35Due to rat Senlie dementia model and D-galactolipin induced mice Senlie dementia model there is good treatment or prevention effect.
For the better effect of the prevention of performance Puerarin or treatment senile dementia, the present patent application people has further studied some pharmaceutical compositions that contain Puerarin, Puerarin of the present invention is mainly the inhibitory action due to its gathering to A β to the therapeutic action of senile dementia, and it adopts the machine-processed senile dementia coupling of different treatments can obtain beyond thought treatment or preventive effect from other. The drug combination that experiment showed, in the specific embodiment of the invention not only can strengthen the result for the treatment of of medicine, and can reduce adverse drug reaction and the drug resistance of body to medicine.
Based on this, the invention provides the pharmaceutical composition of a kind of prevention that contains Puerarin or treatment senile dementia, in this pharmaceutical composition that contains Puerarin, contain Puerarin, triptolide and/or borneol.
Wherein triptolide (Triptolide, TPL) is one of main active of thunder godvine. Triptolide is one and has multiple bioactive natural products, derives from the root of Chinese herb triperygium wilfordii, and to show that it has anti-oxidant in research, resisting rheumatoid disease, anti-senile dementia, the effect such as anticancer. Applicant finds, in the time that triptolide and Puerarin are combined the treatment for senile dementia, two kinds of medicines can embody significant synergy (referring to the embodiment of the present invention 11 and embodiment 12), not only can delay the generation process of senile dementia, more embody significant result for the treatment of, strengthen patient's reminiscence ability.
Wherein borneol has the effect of " brain in tying-in ", and it can further improve speed and the content of pharmaceutical composition Chinese traditional medicine active component of the present invention through blood-brain barrier, plays the effect that reduces the drug effect time and strengthen medication effect.
Preferably, in the pharmaceutical composition that contains Puerarin triptolide and/or borneol, the mass ratio of Puerarin and triptolide is 1: 0.1～1, is preferably 1: 0.5.
Preferably, in the pharmaceutical composition that contains Puerarin, triptolide and/or borneol, the mass ratio of Puerarin and borneol is 1: 0.1～0.5.
As a modification of the present invention: also contain galanthamine in the pharmaceutical composition that contains Puerarin of the present invention. Galanthamine is at first by the Bulgarian research of Sopharma drugmaker and production, and starting is most separation and Extraction from the bulb of snowdrops, multiple countries listing in the whole world at present, and commodity are by name: Nivalin. A little less than its anticholinesterase effect, easily see through blood-brain barrier, therefore central action is stronger, can be used for the treatment of myasthenia gravis. Prior art confirms that it can be for AD(senile dementia) treatment, be AD treatment drug of first choice clinically at present. On aforementioned pharmaceutical compositions basis, add the result for the treatment of that not only can strengthen pharmaceutical composition with galanthamine, embody significant synergy, more can reduce the probability of happening and the motion function of improving patients of senile dementia of senile dementia complication.
Preferably, in the pharmaceutical composition that contains Puerarin of the present invention, the mass ratio of Puerarin and galanthamine is 1: 0.1～10, be preferably 1: 1～and 5, more preferably 1: 2.
Due to the raising of modern animal welfare and the complexity of diet, the ill disease probability of animal also obviously increases. Purposes treatment target of the present invention can be people or animal, and described animal is preferably mammal. In the medicinal usage of Puerarin of the present invention or the pharmaceutical composition that contains Puerarin, Puerarin can individually dosedly also can be combined other senile dementia administrations, it can select suitable method of administration according to the state of an illness and pharmaceutical properties when preventing or treat senile dementia, be preferably oral administration, people is 0.1mg/kgd ~ 5mg/kgd by dosage, be preferably 0.5mg/kgd ~ 3.5mg/kgd, the dosage of other animals can convert and obtain according to man and animal body surface area, and this is known for those skilled in the art. The present invention is used for the treatment of or prevents the form of administration of senile dementia can be the present invention's pharmaceutical preparation described above, as tablet, capsule, and Duracaps, sustained-release tablet, supensoid agent etc.
In above-described medicinal usage, the present patent application people has preferably been prepared into more stable oral formulations by the test in specific embodiment, as tablet, capsule, and Duracaps, sustained-release tablet, supensoid agent etc. Wherein tablet contains two or more following auxiliary materials: starch, dextrin, low-substituted hydroxypropyl cellulose, dolomol, microcrystalline cellulose, hydroxypropyl cellulose, starch slurry lactose, sweet mellow wine, superfine silica gel powder, Ac-Di-Sol and PVPP; Described capsule contains two or more following auxiliary materials: amylum pregelatinisatum, lactose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and superfine silica gel powder; Described supensoid agent contains two or more following auxiliary materials: zinc sulfate, camphor spirit, sodium carboxymethylcellulose, glycerine, carbomer; In described sustained release tablets or spansule, contain two or more following auxiliary materials: microcrystalline cellulose, lactose, methylcellulose (MC), ethyl cellulose (EC), hydroxyethylcellulose (HEC), HPMC (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), pregelatinized starch. In the above-mentioned pharmaceutical preparation that contains Puerarin, the effective dose that Puerarin is contained in each preparation unit is 0.1mg～200mg.
Compared with prior art, the present invention has following outstanding advantage:
(1) Puerarin of the present invention can suppress amyloid beta deposition significantly, determined curative effect when its prevention for senile dementia or treatment, dosage is clear and definite, when the independent treatment for senile dementia or prevention, can significantly delay the Development process of senile dementia, greatly improve patient's cognitive ability and quality of life;
(2) Puerarin of the present invention is the active component extracting in natural plants, when its treatment for senile dementia or prevention, side effect is low, patient's compliance is high, the chemicals coupling of itself and other treatment senile dementia can significantly reduce the consumption of chemicals, thereby reduces the toxic and side effect of chemicals.
(3) Puerarin of the present invention and other mechanism of action when senile dementia is played to the drug combination of therapeutic action, its mechanism of drug action complementation, itself and triptolide coupling can be played the synergy to senile dementia prevention or treatment, on above-mentioned coupling basis, add motion function and the result for the treatment of that can improve patients of senile dementia with galanthamine, add onset speed and the result for the treatment of that can significantly improve medicine with borneol.
Detailed description of the invention
The each raw material adopting in following examples, if no special instructions, is commercially available prod.
Embodiment 1 Puerarin tablet preparation
Puerarin 0.1g
Starch 25g
Dextrin 35g
Low-substituted hydroxypropyl cellulose 5g
60% appropriate amount of ethanol
Dolomol 1g
Preparation technology: the Puerarin, starch, dextrin and the low-substituted hydroxypropyl cellulose that take recipe quantity mix. Separately get the 60%(volumn concentration of Sq, lower same) ethanol, be incorporated in mixed-powder, mix rear softwood processed, granulate by 16 mesh sieves, 60 DEG C are following dry. After completing after dry, use 18 mesh sieves carry out whole grain, sift out the fine powder in dry granular, mix, and then be mixed evenly with dry particle with the dolomol sieving, and compressing tablet, to obtain final product. The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
Embodiment 2 Puerarin tablet preparations
Puerarin 25g
Microcrystalline cellulose 180g
Hydroxypropyl cellulose 15g
8%(quality percentage composition) starch slurry is appropriate
Dolomol 1.5g
Preparation technology: the Puerarin, microcrystalline cellulose and the hydroxypropyl cellulose that take recipe quantity mix. The 8% starch slurry solution of separately getting Sq, adds in mixed-powder, mixes rear softwood processed, granulates by 16 mesh sieves, and 60 DEG C following dry. After completing after dry, use 18 mesh sieves carry out whole grain, sift out the fine powder in dry granular, mix, and then be mixed evenly with dry particle with the dolomol sieving, and compressing tablet, to obtain final product.
The content that contains Puerarin in each preparation unit is 0.1mg ~ 200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
Embodiment 3 Puerarin tablet preparations
Puerarin 25g
Triptolide 2.5g
Starch 25g
Dextrin 35g
Low-substituted hydroxypropyl cellulose 5g
60% appropriate amount of ethanol
Dolomol 1g
Preparation technology: take recipe quantity, Puerarin, triptolide starch, dextrin and low-substituted hydroxypropyl cellulose mix. 60% ethanol of separately getting Sq, is incorporated in mixed-powder, mixes rear softwood processed, granulates by 16 mesh sieves, and 60 DEG C following dry. After completing after dry, use 18 mesh sieves carry out whole grain, sift out the fine powder in dry granular, mix, and then be mixed evenly with dry particle with the dolomol sieving, and compressing tablet, to obtain final product. The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
Embodiment 4 Puerarin tablet preparations
Puerarin 100g
Triptolide 50g
Starch 80g
Dextrin 90g
Low-substituted hydroxypropyl cellulose 8g
60% appropriate amount of ethanol
Dolomol 1.5g
Preparation technology: take recipe quantity, Puerarin, triptolide starch, dextrin and low-substituted hydroxypropyl cellulose mix. 60% ethanol of separately getting Sq, is incorporated in mixed-powder, mixes rear softwood processed, granulates by 16 mesh sieves, and 60 DEG C following dry. After completing after dry, use 18 mesh sieves carry out whole grain, sift out the fine powder in dry granular, mix, and then be mixed evenly with dry particle with the dolomol sieving, and compressing tablet, to obtain final product. The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
Embodiment 5 Puerarin tablet preparations
Puerarin 50g
Triptolide 25g
Galanthamine 5g
Lactose 80g
Sweet mellow wine 10g
Superfine silica gel powder 20g
Microcrystalline cellulose 100g
Ac-Di-Sol 25g
PVPP 25g
60%(volumn concentration) appropriate amount of ethanol
Magnesium stearate 2g
Preparation technology: the each auxiliary material in prescription is crossed to 100 mesh sieves, after taking Puerarin, triptolide, galanthamine and mixing with lactose, sweet mellow wine, the superfine silica gel powder, microcrystalline cellulose, PVPP and the Ac-Di-Sol that add respectively recipe quantity, mix again, and adds 60% ethanolic solution softwood processed, 18 mesh sieve particle processed, wet granular in 60 DEG C dry, the whole grain of 16 mesh sieves, adds dolomol to mix, compressing tablet, to obtain final product.
The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
Embodiment 6 Puerarin capsule preparations
Puerarin 25g
Triptolide 25g
Galanthamine 25g
Amylum pregelatinisatum 40g
Lactose 30g
Low-substituted hydroxypropyl cellulose 5g
60% appropriate amount of ethanol
Preparation technology: the each auxiliary material in prescription is crossed to 100 mesh sieves, after taking Puerarin, triptolide, galanthamine and mixing with amylum pregelatinisatum, lactose and low-substituted hydroxypropyl cellulose, add 60% ethanolic solution softwood processed, 18 mesh sieve particle processed, dry in 60 DEG C, the whole grain of 16 mesh sieves, filling capsule, to obtain final product.
The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
The preparation of embodiment 7 Puerarin supensoid agents
Puerarin 100g
Triptolide 50g
Galanthamine 200g
Zinc sulfate 30g
Camphor spirit 250mL
Sodium carboxymethylcellulose 5g
Glycerine 100mL
Distilled water 1000mL
Preparation technology: the Puerarin, triptolide and the galanthamine that take recipe quantity are put in mortar, glycerol adding grinds to form thin pasty state, and zinc sulfate is dissolved in 200ml water, separately sodium carboxymethylcellulose is made to rubber cement with 200ml water, under agitation slowly add in mortar, move in measuring device, under stirring, add solution of zinc sulfate, stir evenly, under agitation with the thread fine wine that camphorates, adding distil water, to full dose, stirs evenly, and to obtain final product.
The content that contains Puerarin in each preparation unit is 0.1mg～200mgg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
The preparation of embodiment 8 puerarin sustained-release sheets
Puerarin 100g
Borneol 10g
Carboxylic propyl methocel 30g
Lactose 2.5g
80% appropriate amount of ethanol
Dolomol 0.12g
Preparation technology: rear 80 mesh sieves excessively of Puerarin, lactose and the pulverizing of carboxylic propyl methocel that take respectively recipe quantity are placed in mortar and mix, add appropriate 80% ethanol to prepare softwood, the wet grain of the preparation of sieving, whole grain after 60 ~ 70 DEG C of dry particles of dry preparation, adds dolomol compressing tablet can obtain puerarin sustained-release tablet. The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
The preparation of embodiment 9 puerarin sustained-release capsules
Puerarin 200g
Triptolide 100g
Borneol 40g
Carboxylic propyl methocel 30g
Ethyl cellulose 6g
50% appropriate amount of ethanol
Microcrystalline cellulose 4.5g
Preparation technology: took after recipe quantity Puerarin was pulverized respectively 80 mesh sieves with auxiliary material and mix, add 50% appropriate amount of ethanol and make softwood, be extruded into through extruding sieve plate (aperture 0.8mm) fine strip shape that diameter is suitable, then make strip-shaped materials enter spheronizator and make it completely round as a ball, take out micropill, in 60 DEG C of oven dry 3h left and right, make moisture be controlled at 1%～4%, get 18～24 object micropills. Measure the content of micropill, determine the loading amount of capsule, carry out capsule charge with filling machine. The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
The preparation of embodiment 10 puerarin sustained-release capsules
Puerarin 50g
Triptolide 50g
Galanthamine 150g
Borneol 25g
Carboxylic propyl methocel 30g
Ethyl cellulose 6g
50% appropriate amount of ethanol
Microcrystalline cellulose 4.5g
Preparation technology: took after recipe quantity Puerarin was pulverized respectively 80 mesh sieves with auxiliary material and mix, add 50% appropriate amount of ethanol and make softwood, be extruded into through extruding sieve plate (aperture 0.8mm) fine strip shape that diameter is suitable, then make strip-shaped materials enter spheronizator and make it completely round as a ball, take out micropill, in 60 DEG C of oven dry 3h left and right, make moisture be controlled at 1%～4%, get 18～24 object micropills. Measure the content of micropill, determine the loading amount of capsule, carry out capsule charge with filling machine.
The content that contains Puerarin in each preparation unit is 0.1mg～200mg, and medicine people is 0.1mg/kgd ~ 5mg/kgd by dosage.
Embodiment 11 Puerarin pair of the present inventionAβ25-35 Due to the therapeutic action of rat Senlie dementia model
Also do not find at present AD uniqueness, animal model that generally acknowledge, desirable. Existing AD animal model has 2 classes: damaging animal model and transgenic animal model. Damaging animal model mainly comprises physics, chemistry, organic matter damage and autoimmunity damage model. Transgenic animal model mainly refers to single transgene or many transgenic animal models of the related genes such as the precursor sample albumen (APP) relevant with AD, apolipoprotein (Apo) E4, senilism albumen 1 (PSI), senilism albumen 2 (psII). Transgenic models is the focus of studying at present, but modeling process complexity, somewhat expensive, deficient in stability goes down to posterity. One of neuropathological feature that AD patient is main is senile plaque expelling (sP) deposition, and A β is the main component in senile plaque expelling. All oneself confirms the neurotoxic effect of A β to the inside and outside test of body, can cause neure damage and cognitive function decline, be the key factor of AD formation and development, and the AD rat model that hippocampal injection A sets up is observed the multiple pathological changes such as the Abnormal Phosphorylation (being neurofibrillary tangles) of neure damage, A β deposition, Protein tau.
1 materials and methods
1.1 experiment material
Animal used as test is male SD rat, and in 8～12 weeks ages of mouse, body weight 250～300g, is provided by The 2nd Army Medical College Experimental Animal Center. A β25-35Purchased from Sigma company of the U.S., Morris water maze is purchased from Shanghai Ji Liang company.
The foundation of 1.2 rat Senlie dementia models and evaluation
1.2.1 intraventricular injection A β25-35The preparation of solution: by A β25-35Be dissolved in SPSS, making A β concentration is 10mmol/L, puts in 37 DEG C of insulating boxs, to hatch 3d and carry out aging.
1.2.2 the making of animal model: raise under standard environment, be divided at random 2 groups: control group and model group, 10 every group. 2 groups of there was no significant differences in mouse age and body weight. Animal gives adaptability and feeds after 1 week, by 2% yellow Jackets intraperitoneal anesthesia for rat (40～50mg/kg weight), be fixed on stereo brain orienting instrument, cut off crown portion hair, after iodine tincture disinfection, cut skin, select right side telocoele for injection target area with reference to " rat brain stereotaxic atlas ", in bregma 1.0mm backward, the other 1.7mm place that opens of center line, bore and open skull with three-edged needle, expose endocranium, then use micro syringe with the speed of 15 μ m/s from the vertical inserting needle 4.0mm in brain surface, by 10mmol/LA β25-35Solution 5 μ l slowly inject, and after let the acupuncture needle remain at a certain point 2min, slowly remove pin, sew up the incision. Control group injects equal-volume SPSS.
1.2.3Morris water maze behaviouristics is measured: 2 groups of rats are respectively within postoperative the 10th day, starting to carry out the test of Morris water maze. Test program is orientation navigation test: last 5d, front 2d is the training adaptation phase, and rear 3d records achievement, if rat is found platform in 1min, records its actual escape latency; If do not find yet platform in 1min, to be drawn upper mounting plate and stopped 20S by experimenter, escape latency is recorded as 1min.
1.2.4 the evaluation of animal model
Can be found out by following table, the escape latency of model group just obviously extends (P < 0.05 or P < 0.01) from the control group that starts for the 1st day of experimental record, and escape latency no significant difference between escape latency between model group 3 days and control group 3 days, show that the Senlie dementia model that adopts the method to set up is reliably accurate, can be for the evaluating drug effect of curing senile dementia medicine.
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2 animal models and grouping administration
According to above-mentioned modeling method modeling, and control group, normal group are set, 10 every group, under standard environment, raise. 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;
High group of Puerarin: gavage gives Puerarin 28mg/kg/d;
Low group of Puerarin: gavage gives Puerarin 0.5mg/kg/d;
High group of triptolide: gavage gives triptolide 5.6mg/kg/d;
Low group of triptolide: gavage gives triptolide 2.8mg/kg/d;
High group of galanthamine: gavage gives galanthamine 6mg/kg/d;
Low group of galanthamine: gavage gives galanthamine 3mg/kg/d;
Borneol group: gavage gives borneol 0.6mg/kg/d;
One group of compound: gavage gives Puerarin 28mg/kg/d and triptolide 5.6mg/kg/d;
Two groups of compounds: gavage gives Puerarin 28mg/kg/d and triptolide 2.8mg/kg/d;
Three groups of compounds: gavage gives Puerarin 0.5mg/kg/d and triptolide 5.6mg/kg/d;
Four groups of compounds: gavage gives Puerarin 0.5mg/kg/d and tritolide 2.8mg/kg/d;
Five groups of compounds: gavage gives Puerarin 0.5mg/kg/d, triptolide 5.6mg/kg/d and galanthamine 6mg/kg/d;
Six groups of compounds: gavage gives Puerarin 28mg/kg/d, triptolide 2.8mg/kg/d and galanthamine 3mg/kg/d;
Seven groups of compounds: gavage gives Puerarin 0.5mg/kg/d, triptolide 2.8mg/kg/d and galanthamine 3mg/kg/d;
Eight groups of compounds: gavage gives Puerarin 28mg/kg/d and borneol 0.6mg/kg/d;
Nine groups of compounds: gavage gives Puerarin 0.5mg/kg/d, triptolide 2.8mg/kg/d and borneol 0.6mg/kg/d;
Ten groups of compounds: gavage give Puerarin 0.5mg/kg/d, triptolide 2.8mg/kg/d, galanthamine 3mg/kg/d and and borneol 0.6mg/kg/d;
Above-mentioned administration group respectively at modeling after administration after 10 days, within the 11st day, be recorded as the 1st day, be administered once every day, observe drinking water for animals and diet situation every day, respectively at administration the 1st day, administration the 5th day, administration the 10th day, administration the 15th day, the escape latency of rat is measured in administration for 20 days with Morris water maze behaviouristics assay method. Measure for the last time rear execution rat. Each group treated rats in Morris water maze performance behaviouristics measurement result is as shown in the table.
The each administration group of table 1 is to A β25-35Due to the result for the treatment of of rat Senlie dementia model
| Group | The 1st day | The 5th day | The 10th day | The 15th day | The 20th day |
| Normal group | 10.25±1.24 | 9.54±1.16 | 10.14±0.98 | 10.21±1.26 | 10.31±2.15 |
| Control group | 20.34±10.31 | 19.57±4.42 | 21.08±5.28 | 20.16±6.24 | 19.95±5.64 |
| Model group | 41.26±10.24 | 42.16±6.97 | 41.25±9.24 | 39.15±6.25 | 40.27±7.15 |
| High group of Puerarin | 40.16±9.61 | 38.25±7.85 | 34.47±6.24 | 30.12±5.68 | 27.65±6.58 |
| Low group of Puerarin | 40.86±10.13 | 38.64±8.65 | 35.25±6.35 | 31.45±5.64 | 29.64±4.26 |
| High group of triptolide | 40.74±8.59 | 40.16±8.24 | 39.25±6.35 | 39.04±6.58 | 38.64±5.26 |
| Low group of triptolide | 40.85±9.52 | 40.38±8.26 | 40.28±5.28 | 39.89±7.54 | 39.05±4.28 |
| High group of galanthamine | 41.06±8.34 | 38.74±7.68 | 37.48±5.98 | 35.16±5.34 | 33.64±4.26 |
| High group of galanthamine | 41.16±8.34 | 39.16±7.52 | 38.42±5.63 | 37.65±5.61 | 35.62±4.17 |
| Borneol group | 40.79±9.24 | 40.49±8.12 | 40.08±5.16 | 39.57±7.94 | 39.05±4.24 |
| One group of compound | 40.28±10.35 | 36.27±4.65 | 33.47±5.34 | 29.54±2.16 | 25.46±4.86 |
| Two groups of compounds | 40.23±9.34 | 37.27±4.48 | 32.69±4.84 | 28.64±3.45 | 25.67±3.94 |
| Three groups of compounds | 40.15±9.56 | 37.58±4.52 | 33.86±3.24 | 30.12±2.95 | 26.21±3.12 |
| Four groups of compounds | 40.26±8.65 | 38.04±4.26 | 34.15±3.45 | 30.25±2.64 | 26.18±3.15 |
| Five groups of compounds | 40.05±8.62 | 36.15±3.86 | 32.18±3.26 | 27.58±2.46 | 24.59±3.08 |
| Six groups of compounds | 40.12±7.95 | 36.18±3.54 | 32.14±2.97 | 28.12±2.61 | 24.21±2.68 |
| Seven groups of compounds | 40.09±8.06 | 35.84±3.67 | 31.58±4.92 | 26.18±3.26 | 23.95±2.38 |
| Eight groups of compounds | 40.27±8.35 | 39.27±4.65 | 33.49±5.24 | 29.74±2.66 | 26.46±4.86 |
| Nine groups of compounds | 40.22±7.34 | 35.27±4.48 | 29.69±4.84 | 25.64±3.45 | 22.67±3.94 |
| Ten groups of compounds | 40.16±8.21 | 35.04±4.21 | 28.62±3.65 | 24.58±2.95 | 20.16±3.04 |
As can be seen from Table 1: each administration group escape latency thing significant difference of the 1st day, but along with the prolongation of administration time, the escape latency difference of each administration group rat strengthens, and wherein the each administration group of Puerarin and the compound group that contains Puerarin all have positive therapeutic action. Be embodied in:
1) the rat escape latency of the each treatment group of Puerarin has significant difference compared with model group, and no matter low group of the high group of Puerarin or Puerarin are compared with positive drug galanthamine group, all significantly shorten the escape latency of rat, its Chinese traditional medicine treatment is after 15 days, and the escape latency of its escape latency and positive drug has significant difference. Puerarin is to A β25-35Due to the result for the treatment of of rat Senlie dementia model present dose dependent.
2) the rat escape latency of the each treatment group of compound has significant difference compared with model group, and compound group is compared with Puerarin list medicine group or compared with positive drug galanthamine group, the escape latency of its rat all obviously shortens, wherein compound medicine treatment is after 15 days, and its escape latency has significant difference compared with single therapy group escape latency. This shows that Puerarin is to A β25-35Due to therapeutic action and the galanthamine of rat Senlie dementia model its therapeutic action is not repelled, there is synergy to senile dementia rat model in two kinds of medicines.
3) the each treatment group of the compound single medicine group corresponding with it compared and had significant difference, this show Puerarin of the present invention can with triptolide or with the combination of triptolide galanthamine, or there is significant synergy with the combination of triptolide galanthamine borneol, wherein the combination of Puerarin and triptolide galanthamine borneol not only significantly strengthens on medication effect, more can improve the motion function of patients of senile dementia, and effect rapidly, accelerates patient's recovery from illness process.
The therapeutic action of embodiment 12 Puerarin of the present invention to D-galactolipin induced mice Senlie dementia model
1 material
D-galactolipin is Shanghai reagent two factory's products; Puerarin is made by oneself by this research department. Keeping away dark auto testing instrument is Chengdu TME Technology Co., Ltd.'s product.
2 experimental techniques
The foundation of 2.1 Senlie dementia model mouse: get kunming mouse and be divided at random every group of 12 mouse of following drug treatment group. Except control group, each treatment group mouse is pressed 120mg/kg lumbar injection D-galactolipin every day, injects continuously 4 weeks. Each treatment group gives respectively following medicine:
Normal group: gavage gives the physiological saline of same volume;
Model group: gavage gives the physiological saline of same volume;
High group of Puerarin: gavage gives Puerarin 28mg/kg/d;
Low group of Puerarin: gavage gives Puerarin 0.5mg/kg/d;
High group of triptolide: gavage gives triptolide 5.6mg/kg/d;
Low group of triptolide: gavage gives triptolide 2.8mg/kg/d;
High group of galanthamine: gavage gives galanthamine 6mg/kg/d;
Low group of galanthamine: gavage gives galanthamine 3mg/kg/d;
Borneol group: gavage gives borneol 0.6mg/kg/d;
One group of compound: gavage gives Puerarin 28mg/kg/d and triptolide 5.6mg/kg/d;
Two groups of compounds: gavage gives Puerarin 28mg/kg/d and triptolide 2.8mg/kg/d;
Three groups of compounds: gavage gives Puerarin 0.5mg/kg/d and triptolide 5.6mg/kg/d;
Four groups of compounds: gavage gives Puerarin 0.5mg/kg/d and tritolide 2.8mg/kg/d;
Five groups of compounds: gavage gives Puerarin 0.5mg/kg/d, triptolide 5.6mg/kg/d and galanthamine 6mg/kg/d;
Six groups of compounds: gavage gives Puerarin 28mg/kg/d, triptolide 2.8mg/kg/d and galanthamine 3mg/kg/d;
Seven groups of compounds: gavage gives Puerarin 0.5mg/kg/d, triptolide 2.8mg/kg/d and galanthamine 3mg/kg/d;
Eight groups of compounds: gavage gives Puerarin 28mg/kg/d and borneol 0.6mg/kg/d;
Nine groups of compounds: gavage gives Puerarin 0.5mg/kg/d, triptolide 2.8mg/kg/d and borneol 0.6mg/kg/d;
Ten groups of compounds: gavage give Puerarin 0.5mg/kg/d, triptolide 2.8mg/kg/d, galanthamine 3mg/kg/d and and borneol 0.6mg/kg/d;
2.2 keep away dark experiment behaviouristics detects
, there is a hole active box point light and shade two Room of keeping away dark auto testing instrument between two Room, pass to copper grid at the bottom of case. Before formal experiment, each group of mouse trained, mouse head is carried to Fang Renming chamber, hole. the 3min that first conforms, then give darkroom copper grid logical 36V electric current, mouse enters and is subject to electric shock behind darkroom and runs away to bright chamber, and copper grid continue the 5min that switches on, and this is training process. After 24h, carry out the test of memory of mouse, record mouse and enter for the first time the time (keeping away dark incubation period) in darkroom, if do not enter yet darkroom in mouse 5min. Count its incubation period and make 300s.
3 statistical methods
Experimental data is used± s represents, carries out statistical analysis with SPSS11.5 software kit, adopts ANOVA and LSD ' Sposthoctest to carry out statistical analysis, indicates significant difference with P < 0.05.
4 experimental results
The impact that Puerarin is kept away dark experiment to Senlie dementia model mouse is as shown in table 2.
Table 2 Puerarin on Senlie dementia model mouse keep away dark preclinical impact (±s）
Compared with normal group, ##P < 0.01; Compared with model group, * P < 0.05, * * P < 0.01;
As can be seen from Table 2, puerarin for treating group is kept away dark significant prolongation in incubation period (P < 0.01) with respect to model group mouse, prompting Puerarin has significant prevention and result for the treatment of to senile dementia mouse model, and its result for the treatment of is better than galanthamine group. Be embodied in:
(1) mouse of the each treatment group of Puerarin is kept away and have significant difference dark incubation period compared with model group, and no matter low group of the high group of Puerarin or Puerarin are compared with positive drug galanthamine group, all significantly shorten mouse and keep away dark incubation period, have significant difference. Puerarin presents dose dependent to the result for the treatment of of mouse Senlie dementia model.
(2) one group of compound is kept away and have significant difference dark incubation period compared with model group with the mouse of two groups of compounds, and compound group is compared with Puerarin list medicine group or compared with positive drug galanthamine group, its mouse is kept away and all obviously shortens dark incubation period, has significant difference. This shows that therapeutic action and the galanthamine of Puerarin to mouse Senlie dementia model do not repel its therapeutic action, and two kinds of medicines exist synergy to senile dementia mouse model.
(3) the each treatment group of the compound single medicine group corresponding with it compared and had significant difference, this show Puerarin of the present invention can with triptolide or with the combination of triptolide galanthamine, or there is significant synergy with the combination of triptolide galanthamine borneol, wherein the combination of Puerarin and triptolide galanthamine borneol not only significantly strengthens on medication effect, more can improve the motion function of patients of senile dementia, and effect rapidly, accelerates patient's recovery from illness process.
In the embodiment of the present invention 11 or embodiment 12, show that the mechanism that Puerarin acts on senile dementia do not conflict with the medicine that other drug acts on senile dementia, it can combine use, and can obtain the synergy in treatment.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under Spirit Essence of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, be included in protection scope of the present invention.
Claims (3)
1. the pharmaceutical composition that contains Puerarin has the purposes in the medicine that prevents or treat senile dementia effect in preparation, the pharmaceutical composition that contains Puerarin is Puerarin, triptolide, borneol and galanthamine, the mass ratio of described Puerarin and triptolide is 1: 0.1～1, the mass ratio of described Puerarin and borneol is 1: 0.1～0.5, and the mass ratio of described Puerarin and galanthamine is 1: 0.1～10.
2. purposes according to claim 1, is characterized in that: the people of described medicine is 0.1mg/kgd ~ 5mg/kgd by dosage.
3. purposes according to claim 2, is characterized in that: described medicine is oral formulations, and in each preparation unit, the content of Puerarin is 0.1mg～200mg; Wherein said oral formulations is tablet, capsule or supensoid agent.
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