CN104398530A - Compound composition of traditional Chinese medicine monomers for preventing and treating Alzheimer disease - Google Patents
Compound composition of traditional Chinese medicine monomers for preventing and treating Alzheimer disease Download PDFInfo
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- CN104398530A CN104398530A CN201410693128.0A CN201410693128A CN104398530A CN 104398530 A CN104398530 A CN 104398530A CN 201410693128 A CN201410693128 A CN 201410693128A CN 104398530 A CN104398530 A CN 104398530A
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- ligustrazine
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- tenuigenin
- alzheimer disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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Abstract
The invention discloses application of a composition and a compatible method of ligustrazine, tenuigenin and stibene glucoside in preparation of a drug for treating Alzheimer disease. In the invention, the composition of ligustrazine, tenuigenin and stibene glucoside can be compatible according to a ratio to obviously prevent damage on the cognitive function of APP695V717I transgenic mice; proved by a Y electric maze experiment and a Morris water maze experiment, the composition of ligustrazine, tenuigenin and stibene glucoside can obviously improve the capabilities of passive avoidance, active avoidance and spatial memory exploration competence of the model mice, and has the obvious functions of preventing ageing hypomnesia and dysmnesia related to the Alzheimer disease; the further detection shows that the compatible composition of ligustrazine, tenuigenin and stibene glucoside can reduce deposition of age pigments in brains of AD transgenic mice, and improve the activity of acetylcholine esterase, so as to indicate that the composition of ligustrazine, tenuigenin and stibene glucoside compatible according to the ratio can treat the Alzheimer disease remarkably.
Description
Technical field
The present invention relates to a kind of Compound Chinese Herbal Monomer Recipe compositions and the medical usage of proportion compatibility in treatment Alzheimer thereof, particularly relate to ligustrazine, polygalic acid, stilbene glycoside composition at raising ability of learning and memory, suppress old class deposition in brain, improve the purposes of acetylcholine esterase active, belong to medicinal chemistry art.
Background technology
Ligustrazine, molecular formula: C
8h
12n
2, molecular weight: 136, molecular structure:
Polygalic acid: molecular formula: C
30h
45c
lO6, molecular weight: 537.1277, molecular structure:
Stilbene glucoside, molecular formula: C
20h
22o
9, molecular weight: 406, molecular structure:
Above three kinds of monomer components directly commercially can be bought and obtain, and carry out content analysis by high performance liquid chromatography to it.
Alzheimer (Alzheimer ' s disease, AD), also known as alzheimer disease, be a kind of common old nervous system disease.This disease concealment onset, main manifestations is hypomnesis and the cognitive dysfunction of slowly progress.Epidemiological study shows, and Alzheimer prevalence accounts for more than 60 years old old people's about 10%, and sickness rate is in ascendant trend year by year.
Because the pathogenesis of this disease is illustrated so far not yet, clinically still without Therapeutic Method targetedly.The outer clinical treatment Alzheimer of Current Domestic, generally uses cholinesterase inhibitor and glutamate receptor antagonists two class medicine; Controversies in hormone replacement in the elderly can be used for menopausal women in addition, can postpone or alleviate the generation of memory loss.These medicines have certain effect improving in the clinical symptoms of patient, but also there is the situations such as the many or curative effect of untoward reaction is dissatisfied, such as cholinesterase inhibitor donepezil can produce diarrhoea, feel sick and the symptom such as insomnia, produces the case easily enraged with the abalienation of aggressive behavior after even there is patient medication.Glutamate receptor antagonists " memantine " is used for the treatment of middle severe to severe dementia of the Alzheimer type, and medication rear section patient also there will be hallucination, misunderstanding, dizziness, headache and the untoward reaction such as tired.These ill effects limit their Clinical practice to a certain extent, are therefore necessary the pharmaceutical methods seeking new treatment Alzheimer.
All remarkable progress was had to the research of extracting Effective Component of Chinese Medicine in recent years from the exploitation of natural drug.New drug development is previously the medicament research and development theory based on " medicine, a target spot, a disease " substantially, too emphasizes the specificity of molecular drug target, but facts have proved subsequently, there are 2 great defects in this research strategy.One is that the discovery speed of novel targets slows down, and the target spot that the current mankind have found is stuck in about 500, and novel targets finds and cycle of confirming is exactly 3 or five years easily.Two is that clinical practice finds the clinical efficacy of single target agent of high specific and not fully up to expectations.Systems biology research shows that in human body, each bars pathway forms complicated signal networking, and the wherein approach that blocks will certainly cause other path feedbacks to activate or suppress, and therefore the blocking-up of single target is inadequate.
Meanwhile, for the reactive compound that single target spot finds, there is many problems such as the bad or side effect of druggability is large.The curative effect of medication that laboratory and clinical research show " multicomponent, many targets " all exceedes the summation of single target agent curative effect.Therefore Compound Chinese Herbal Monomer Recipe has the advantage of multicomponent, multipath, Mutiple Targets, its target spot is clear and definite on the one hand, is conducive to inquiring into its mechanism of action, alleviates the side effects of single target spot on the other hand, make drug effect specific aim stronger, better follow card foundation for research provides.
Summary of the invention
For above Problems existing, the object of this invention is to provide a kind of Compound Chinese Herbal Monomer Recipe compositions for preventing and treating Alzheimer.
The present invention, for preventing and treating the Compound Chinese Herbal Monomer Recipe compositions of Alzheimer, is made up of the effective ingredient of following proportioning:
Ligustrazine 3 parts, polygalic acid 2 parts, stilbene glucoside are by 2 parts.
The optimum ratio of above-mentioned prescription is:
Ligustrazine 3 parts, polygalic acid 2 parts, stilbene glucoside are by 2 parts.
Above-mentioned ligustrazine, polygalic acid, stilbene glucoside are Powdered, and in powdery after proportioning combination, color and luster is dark yellow, shady and cool place's preservation.
Said composition can adopt Conventional processing methods, makes injection, the dosage form such as oral agents, capsule, tablet, extract remix.
Application in preparation control Alzheimer disease drugs of the present invention:
The compositions that ligustrazine, polygalic acid, stilbene glucoside are prepared in 3:2:2 ratio compatibility; can the deposition of prevention and prohibition cerebral tissue senile plaque; improve acetylcholine esterase active simultaneously, show that said composition has significant protective effect to neural cell injury in Alzheimer.
The main clinical manifestation of Alzheimer is hypomnesis and cognitive dysfunction.Wherein, the neurotoxic effect in brain caused by senile plaque deposition is key factor in pathogenic process, cholinergic system abnormal with memory disorder and dementia characteristic in close relations.
1. the compositions of ligustrazine, polygalic acid, stilbene glucoside improves significantly and increases the relevant amnemonic function of rheological properties hypomnesis and Alzheimer.
2. the compositions of ligustrazine, polygalic acid, stilbene glucoside can suppress the deposition of senile plaque in brain, and reducing senile plaque nucleus amyloid-beta toxicity stimulates the damage of surrounding tissue, has obvious cytoprotection.
3. the compositions of ligustrazine, polygalic acid, stilbene glucoside can be active by improving acetylcholinesterase (AchE), suppresses its re uptake, thus promote the information transmission of neurotransmitter, reach cognitive functions such as improving learning and memory.
Advantage of the present invention and beneficial effect:
1, laboratory and clinical research show that the curative effect of medication of " multicomponent, many targets " all exceedes the summation of single target agent curative effect.Therefore the present invention utilize Compound Chinese Herbal Monomer Recipe to have multicomponent, multipath, Mutiple Targets advantage, its target spot is clear and definite on the one hand, be conducive to inquiring into its mechanism of action, alleviate the side effects of single target spot on the other hand, make drug effect specific aim stronger, better follow card foundation for research provides.
2, in clinical, Chinese Traditional Medicine has good therapeutic effect to Alzheimer, for the Therapy study of primary disease provides thinking.Alzheimer is attributed to the categories such as " forgetful " " slow-witted disease " by the traditional Chinese medical science at present, think that its sick position is at brain, pathogenesis is deficiency in origin and excess in superficiality, deficiency in origin is when to cause saying of declining to suffer from a deficiency of the kidney into, kidney mark mostly is that the pathological product such as gas, fire, expectorant, the stasis of blood piles up caused qi depression to blood stasis, first god becomes deaf actually, the clear key of stagnation of phlegm, god know mist etc. thus treatment mainly with kidney tonifying, essence replenishing, blood circulation promoting and blood stasis dispelling, the regulating QI method for the treatment of such as to reduce phlegm is main.According to disease in conjunction with diagnosis and treatment idea, the i.e. thought that combines with Chinese medical discrimination of doctor trained in Western medicine differential diagnosis of diseases, based under the prerequisite of instruction of Chinese Medicine theory, by the combination of main for Chinese medicine effectively monomer reactivity composition, be used in conjunction with each other, the dialectical compatibility principle compositing monomer compound preparation treated in motherland's medical science is utilized to study, the compatibility of ligustrazine, polygalic acid, stilbene glucoside in the present invention, both the interference of inert matter in Chinese medicine compound had been eliminated, make again effective substance more concentrated, improve curative effect, also improve controllability and the stability of the quality of the pharmaceutical preparations.Rely on motherland's Chinese medicine, treatment Alzheimer is based on invigorating kidney, promoting blood circulation waking the patient from coma by dispelling phlegm, by the Chinese medicine Radix Polygoni Multiflori principle active component stilbene glucoside of kidney tonifying, essence replenishing class, principle active component polygalic acid in activating blood and removing stasis drug Rhizoma Chuanxiong principle active component ligustrazine and waking up the patient from unconsciousness by dissipating phlegm refreshment medicine Radix Polygalae, three's composition is combined into monomer compound recipe research experiment according to a certain percentage, observes this monomer compound preparation to the therapeutic effect of Alzheimer and mechanism of action thereof.
3, the present invention is applied to health product or medicine can be used for delaying and improve the disease of cognitive decrease relevant disease as Alzheimer, improves physical constitution and the quality of life of old people.
Accompanying drawing explanation
Fig. 1 is monomer compound patients before and after intervention ability of learning and memory tendency of changes figure.
Fig. 2 is each group of mice Morris water maze behavioristics comparison diagram.
Fig. 3 is control group mice neurons of hippocampus CA 1 × 200 times SABC figure.
Fig. 4 is neuron × 200, model group CA 1 Zone of Hippocampus in Mouse times SABC figure.
Fig. 5 is neuron × 200, medicine group CA 1 Zone of Hippocampus in Mouse times SABC figure.
Fig. 6 is each group of Mus hippocampus senile plaque deposition conditions comparison diagram.
Fig. 7 is that each group of cowardly alkali system changes comparison diagram.
Detailed description of the invention
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiments are only exemplary, do not form any restriction to scope of the present invention.It will be understood by those skilled in the art that and can modify to the details of technical solution of the present invention and form or replace down without departing from the spirit and scope of the present invention, but these amendments and replacement all fall within the scope of protection of the present invention.
Embodiment
First be animal grouping, intervene and collection of specimens:
3 monthly age APP695V717I transgenic mices 60, purchased from Institute of Experimental Animals, Chinese Academy of Medical Sciences, (licence is numbered: SCKK 20080013), body weight (30 ± 4.5) g, male and female are not limit, with the monthly age with the C57BL/6J mice 20 of background only as blank group.The animal applications table of random number chosen is divided into groups, is divided into each 20 of matched group, model group, medicine group.Matched group, model group gavage liquid are normal saline, medicine group gavage liquid be stilbene glucoside, ligustrazine, polygalic acid compositions suspension (respectively in 3:2:2 ratio compatibility, wherein stilbene glucoside 30mg/kg, ligustrazine 20mg/kg, polygalic acid 20mg/kg, by orthogonal design is rear, early stage confirms that each monomer is to the most obvious best proportion compatibility of memory improvement in preliminary experiment).Above each treated animal in experiment start administration, every day gavage 1 time, continuous 30 days.Each group in 30 days laggard row Behavior test, then get 10 sacrifice, the cerebral tissue got containing hippocampal formation makes the capable conventional H E dyeing of continuous coronal frozen section and congo red staining; Separately get 10 sacrifice, isolate Hippocampus, basal forebrain, cortex frontal lobe all dilute (1:10 buffer suspension liquid), ultrasonic homogenate, measures acetylcholine activity and measures.
Secondly the main reagent adopted and medicine are:
HE dyes and congo red staining reagent is anti-is purchased from Stressgen company; Two Chinese medicine monomer styrene glycosides, ligustrazine, polygalic acid are purchased from the standard substance of Sigma company, and content is 99%, and during experiment, water dissolution is the suspension of 100mg/ml.Acetylcholine (AchE) Activity Assay Kit is purchased from Nanjing and builds up Bioengineering Research Institute.
Test example 1, stilbene glucoside, ligustrazine, polygalic acid compositions are to the improvement result of model mouse cognitive competence
One, test objective
Observe stilbene glucoside, ligustrazine, polygalic acid compositions to the impact of cognitive competence
Two, test method
Adopt Y electric maze testing inspection ability of learning and memory, first mice put into labyrinth box, adapt to 5min, make it all explore 3 arms and enter, then random order conversion test from I arm, to voltage 30-70V, electric current 0.5-0.7m, time delay 5s.After electric shock, mice escapes to place of safety is correct response, otherwise is wrong reaction.Often survey 1 rest 30s, survey 10 rest 5min.When learning and memory achievement is to have 9 (9/10) correct responses in continuous 10 tests, required shock count represents, does not run correct person for 30 times and is eliminated continuously, then animal is divided into matched group at random, model group and treatment group.Each group at the same time between press aforementioned explanation and carry out the test of Y labyrinth, regulation mice directly escapes from starting area to be " correct response " to place of safety after being shocked by electricity, and to reach continuous 9 electric shocks for correct response, required number of shocks represents its study capacitation.If number of times, more than 30 times, is no longer tested, and with 30 times for maximum counting.
Adopt the search of Morris water maze test detection space and directional memory ability, Morris water maze main body is diameter 150cm, the circular stainless steel water pond of black of high 50cm, depth of water 30cm, and water temperature keeps (22 ± 1) DEG C; Pool wall is indicated 4 place of entry, pond is divided into 4 quadrants thus, using first quartile center as target quadrant, a circular hiding escape platform (black platform diameter is 9cm, high 28cm) is placed in waters, center, and platform is lower than water surface 2cm; Experimental session water maze pool wall labelling and ambient room internal reference thing remain unchanged as space with reference to clue, for mice locating platform, directly over water maze, camera head be housed and be connected with computer, by image acquisition and analytical system software (SLY-WMS2.1) synchronous record in good time mouse movement track.
Three, result of the test
1. between each group, mice association hides required electricity irritation number of times and compares: before intervening, each group is hidden required electricity irritation number of times with control group mice association and compared: F=13.866, P=0.000<0.05, have significant difference.Through pharmaceutical intervention, after January, association hides required electricity irritation number of times and reduces, and compare with model group, t=5.70, P < 0.05, has significant difference, illustrates that medicine has cerebral protection to model mice, can improving studing ability, in table 1.Can find out, the electricity irritation number of times of medicine group comparatively model group is obvious downward trend, sees Fig. 1.
The test of 2.Morris water maze laboratory shows, under A β toxic action, the learning and memory of model mouse, spatial orientation, working memory ability obviously decline, and show as escape latency in the test of Morris water maze and extend, total distance of swimming increase and the minimizing of spanning platform number of times etc.; After pharmaceutical intervention, model mouse hides shorter latencies, and swimming distance shortens; spanning platform number of times increases, and stilbene glucoside, ligustrazine, polygalic acid composition for improved model mouse learning and memory, spatial orientation, work and study ability is described, has cerebral protection; in table 2, Fig. 2.
The inhibitory action that test example 2, stilbene glucoside, ligustrazine, polygalic acid compositions deposit senile plaque
One, test objective
The inhibitory action that observation stilbene glucoside, ligustrazine, polygalic acid compositions deposit brain tissue ultrastructure and senile plaque
Two, test method
After Behavior test, the intraperitoneal anesthesia of animal via 1% pentobarbital sodium, cut off thorax, through apex of the heart intubate to aortic root, first rinse with normal saline quick filling, pour into fixative 4% paraformaldehyde subsequently, open cranium and get brain, put 12h in fixative, the cerebral tissue got containing hippocampal formation makes continuous coronal frozen section, thick 5 μm of sheet, gets 1 every 5.
Three, result of the test
HE stain control group and operation group hippocampal pyramidal cell are that multilamellar is regularly arranged, and neatly and closely, form is normal, sees Fig. 3; Model group pyramidal cell has breakoff phenomenon, cell space swelling, karyopycnosis, arrangement disorder, and dendron is sparse, gap enlargement, sees Fig. 4; Medicine group form, arrangement, number comparatively model group obviously improve, and see Fig. 5.
The painted senile plaque reactant of congo red staining Congo red takes on a red color speckle sample, is deposited in extracellular.Adopt positive plaques counting method, the senile plaque number positive in the counting wherein selected visual field, get average as the number positive of each group.Red senile plaque after the congo red staining that model group is a large amount of as seen deposits in hippocampus; Matched group is less sees red speckle; Medicine group comparatively model group compares, and t=5.5928, P < 0.05, has significant difference, illustrates that old speckle obviously reduces.In table 3, Fig. 6.
test example 3,stilbene glucoside, ligustrazine, polygalic acid compositions are on the impact of cholinergic system
One, test objective
Observe stilbene glucoside, ligustrazine, polygalic acid compositions to the active impact of the acetylcholine (AchE) at each treated animal rat cerebral cortex and Hippocampus position
Two, test method
The determination of activity of acetylcholine (AchE) in cerebral tissue: laboratory animal is after 30 days, after often group gets 10 mice By Sodium Pentobarbitals, in ice bath, broken end gets brain, be separated (title weight in wet base) homogenate of the tissue such as cerebral hippocampal, basal forebrain, cortex frontal lobe, after centrifugation, get supernatant standby inspection AchE (building up the reagent and method operation that Bioengineering Research Institute provides by Nanjing).AchE vigor=(mensuration pipe OD value-measure blank tube OD value)/(standard pipe OD value-standard blank tube OD value).× standard pipe concentration × protein content.
Three, result of the test
Each group of mice Different brain region AchE expression activitiy, test result is in table 4.Show medicine group mice Different brain region brain AchE activity in table and be all significantly higher than the corresponding brain district (P<0.01) of model group, but significantly lower than matched group (P<0.01), AchE is active the highest with Hippocampus, basal forebrain areas is minimum, sees Fig. 7.
The result brief summary of the present embodiment: this Compound Chinese Herbal Monomer Recipe compositions obviously can improve model mouse learning and memory, spatial orientation, work and study ability, has and improves cognitive cerebral protection; This Compound Chinese Herbal Monomer Recipe compositions significantly can reduce the deposition of cerebral tissue hippocampus senile plaque, improves the plasticity that neuron micro structure changes; The acetylcholine (AchE) that this Compound Chinese Herbal Monomer Recipe compositions can significantly improve cortex especially Hippocampus position is active, thus improves behavioristics's performance of model mouse.
This result of the test confirms: this Compound Chinese Herbal Monomer Recipe compositions is active by improving cerebral tissue plasticity and improving cholinergic system, significantly improves the ability of learning and memory of Alzheimer, improves cognitive function.There is the effect of drugs of potential treatment Alzheimer.
Claims (2)
1., for preventing and treating a Compound Chinese Herbal Monomer Recipe compositions for Alzheimer, it is characterized in that being made up of the effective ingredient of following proportioning:
Ligustrazine 3 parts, polygalic acid 2 parts, stilbene glucoside are by 2 parts.
2. a kind of Compound Chinese Herbal Monomer Recipe compositions for preventing and treating Alzheimer according to claim 1, is characterized in that adopting Conventional processing methods to make injection, oral agents, capsule or tablet.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107802636A (en) * | 2017-11-28 | 2018-03-16 | 新乡医学院 | A kind of pharmaceutical composition for treating Alzheimer's disease and its application |
| CN112336738A (en) * | 2020-12-25 | 2021-02-09 | 孟胜喜 | Traditional Chinese medicine monomer composition for preventing and treating Alzheimer disease and application thereof |
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| CN1347699A (en) * | 2001-10-30 | 2002-05-08 | 首都医科大学宣武医院 | Use of stilbene glycoside in treating dementia |
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2014
- 2014-11-27 CN CN201410693128.0A patent/CN104398530A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1347699A (en) * | 2001-10-30 | 2002-05-08 | 首都医科大学宣武医院 | Use of stilbene glycoside in treating dementia |
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| 袁树民等: "川芎嗪对痴呆小鼠模型学习记忆能力的影响", 《中国比较医学杂志》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107802636A (en) * | 2017-11-28 | 2018-03-16 | 新乡医学院 | A kind of pharmaceutical composition for treating Alzheimer's disease and its application |
| CN112336738A (en) * | 2020-12-25 | 2021-02-09 | 孟胜喜 | Traditional Chinese medicine monomer composition for preventing and treating Alzheimer disease and application thereof |
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Application publication date: 20150311 |