CN1254263C - Chinese medicine composition for treating senile dementia - Google Patents
Chinese medicine composition for treating senile dementia Download PDFInfo
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Abstract
The present invention provides a traditional Chinese medicine composition for prevention and/ or treatment, which comprises 5 to 40 parts by weight of prepared rhizome of rehmannia, 5 to 35 parts by weight of prepared fleeceflower root, 5 to 35 parts by weight of barbary wolfberry fruit, 5 to 35 parts by weight of epimedium herb, 5 to 35 parts by weight of common curculigo rhizome, 5 to 35 parts by weight of grassleaf sweelflag rhizome and 3 to 20 parts by weight of polygala root. The present invention also relates to the water extract and the alcohol extract of the traditional Chinese medicine composition.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition, especially for the Chinese medicine composition of treatment alzheimer disease.
Background technology
Alzheimer (Alzheimer ' s disease, AD) or alzheimer disease be a kind of carrying out property of common central nervous system degenerative disease, its main clinical manifestation is carrying out property hypomnesis and cognitive disorder.According to the epidemiologic data statistics, the sickness rate of the old people AD more than 60 years old of American-European developed country is 6-8%, and AD is only second to cardiovascular disease, tumor and apoplexy in old people's cause of the death, occupy the 4th.The whole world has 2 at least, 000-3,0,000,000 patients AD.China's population has reached 1,300,000,000 at present, and old people's ratio surpasses 10% more than 60 years old, this means that China has stepped into aging society.According to current research, China Beijing area 60-80 between year the sickness rate of old people AD be about 5%, the sickness rate of old people AD is 7-8% more than 80 years old, promptly China has 500-800 ten thousand patients AD at least.At present this disease is lacked the effectively preventing means in the world.Patient AD is not only to oneself bringing great misery, and bring serious spirit and financial burden for relatives and society, become the global problem of medical science and society, caused the close attention of countries in the world government and researcher, the research of AD control has become one of worldwide focus.From the input of research funding, AD research funding input in all major diseases accounts for second, is only second to AIDS.In China's " 973 plan " and " 863 Program ", be equipped with the key subjects special project of Senile disease, wherein, main allocation of funds especially utilizes the study on prevention of China's traditional medicine (Chinese medicine) to AD in the research and development of AD.The drug development of relevant AD control also will form huge industry.
Alzheimer is a kind of carrying out property of common central nervous system degenerative disease, and its main clinical manifestation is carrying out property hypomnesis and cognitive disorder.The main neuropathological feature of AD is that over-drastic extracellular A amyloid beta precipitation, neurofibrillary tangles increase, the excessive phosphorylation of Protein tau, synaptic density minimizing, neuronal cell minimizing etc.Wherein the deposition of extracellular A amyloid beta forms dispersive senile plaque and amyloid angiopathy, is considered to the key link in this disease pathogenesis.
Chinese patent application discloses a kind of medicine for the treatment of senile dementia and preparation method thereof No. 97116461.4.This invention is made up of 27 flavor Chinese medicines such as Pericarpium Citri Reticulatae, Herba Eupatorii, Rhizoma Gastrodiae, Radix Et Caulis Acanthopanacis Senticosi, Cortex Moutan, Fructus Corni, Radix Rehmanniae Preparata, Radix Morindae Officinalis, Fructus Alpiniae Oxyphyllae, and through pulverizing, water, alcohol percolation method are extracted, and mix supervisor, use the honeyed pill processes to become honeyed pill.Behind the mutual compatibility of in the side 27 flavor Chinese medicine, can improve brain function, suppress dull-witted development indirectly, the orthobiosis of keeping remaining brain function, reduce the symptom and the complication that produce because of dull-witted; Improve cerebral blood circulation rapidly, increase the blood flow and the oxygen supply of ischemic region, prevent the continuation expansion of thrombosis in the cerebrovascular and make great efforts the elimination cerebral edema, the cell that its function is suppressed rejuvenates quickly.
Chinese patent application 98112741.X discloses a kind of oral liquid of preventing and treating senile dementia, it is that through decocting, distill refining forming, the control senile dementia is recovered functions such as aphasia, memory, behavior specially good effect by proportioning by Rhizoma Acori Graminei, the Radix Astragali, Radix Polygalae, Radix Saposhnikoviae, Radix Gentianae Macrophyllae, Poria cum Radix Pini, Fructus Alpiniae Oxyphyllae, Flos Chrysanthemi, Herba Schizonepetae, Rhizoma Et Radix Notopterygii, Fructus Gardeniae.
The most of medicine that is used for treating AD in the prior art all is that i.e. cognitive disorder comprises hypomnesis at this sick cardinal symptom, aphasis, practical activity function reduction etc.Simultaneously, depression, anxiety, hallucination and vain hope are also often followed AD in interior spirit and behavior symptom.Be used for the treatment of depression for a long time, psychotic medicine such as schizophrenia also is used to treat these symptoms of AD recently.But ideal medicine is the medicine at the main neuropathological feature of AD, lacks this class specific drug at present both at home and abroad.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide a kind of Chinese medicine composition that prevents and/or treats is Radix Rehmanniae Preparata 5～40 according to listed as parts by weight, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
Be ripe 3～30 preferably according to listed as parts by weight, Radix Polygoni Multiflori Preparata 3～25, Fructus Lycii 3～25, Herba Epimedii 3～25, Rhizoma Curculiginis 3～25, Rhizoma Acori Graminei 3～25, Radix Polygalae 2～15.
The invention still further relates to a kind of water extract that prevents and/or treats the Chinese medicine composition of alzheimer disease, described Chinese medicine composition is a Radix Rehmanniae Preparata 5～40 according to listed as parts by weight, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
The invention still further relates to a kind of second ethanol extract that prevents and/or treats the Chinese medicine composition of alzheimer disease, described Chinese medicine composition is a Radix Rehmanniae Preparata 5～40 according to listed as parts by weight, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
This shows that Chinese medicine composition of the present invention can use the prior art known method to make the various dosage forms of Chinese medicine, such as but not limited to tablet, capsule, pill, powder, unguentum, or the like oral or injection type, be preferably peroral dosage form.
Chinese medicine composition of the present invention has following beneficial effect:
1) pure natural Chinese herbal and crude drugs preparations is nontoxic, have no side effect;
2) memory and cognitive competence are improved significantly;
3) neuron there is the significant protection effect;
4) can reduce the deposition of A amyloid beta in the cerebral tissue and the formation of senile plaque significantly; Reduce cerebral tissue internal reaction activation of astrocyte.This is the outstanding feature of this Chinese medicinal formulae.Do not find as yet that at present other Chinese medicinal formulae has this effect;
5) not only patient's AD cognitive dysfunction and the low tool of memory ability improved significantly, and normal old people's hypomnesis also tool is improved significantly;
6) ingredient is natural Chinese medicinal herb, and sale is all arranged on the market, and is with low cost.
The 21 century aging of population is a great challenge to human society.China has stepped into the society of the aged at present, and old people's size of population reaches 1.3 hundred million more than 60 years old.Aging along with social population, sharply increase with the generation of population diseases associated with senescence, it is the quality of life that the Senile disease of representative causes hypophrenia, action obstacle and fracture etc. seriously influence the old man particularly, for society and family bring heavy burden with Alzheimer (AD) and osteoporosis.Wherein, patient AD reaches 500～8,000,000.But the most of medicine that is used for treating AD at present all is a medicine at this sick cardinal symptom as Exelon, Huperzine A-Zhulin Antun etc.But ideal medicine is the medicine at the main neuropathological feature of AD, all is being devoted to develop this class specific drug both at home and abroad at present.The 21 century aging of population is a great challenge to human society.China has stepped into the society of the aged at present, and old people's size of population reaches 1.3 hundred million more than 60 years old.Aging along with social population, sharply increase with the generation of population diseases associated with senescence, it is the quality of life that the Senile disease of representative causes hypophrenia, action obstacle and fracture etc. seriously influence the old man particularly, for society and family bring heavy burden with Alzheimer (AD) and osteoporosis.Wherein, patient AD reaches 500～8,000,000.But the most of medicine that is used for treating AD at present all is a medicine at this sick cardinal symptom as Exelon, Huperzine A-Zhulin Antun etc.But ideal medicine is the medicine at the main neuropathological feature of AD, all is being devoted to develop this class specific drug both at home and abroad at present.Chinese medicine composition of the present invention is exactly the medicine at amyloid in the main neuropathological feature cerebral tissue of AD; by reducing the deposition of amyloid in the cerebral tissue; reduce the effect of inflammatory reaction activation of astrocyte and neuroprotective unit; improve patient's AD cognitive function and memory ability, the clinical control that provides effective means to be used for AD is provided.
Therefore, Chinese medicine composition of the present invention relies on himself advantage, in the face of China 500～8,000,000 patients AD and old people's great market more than 1.3 hundred million 60 years old, will develop into the industry that great potential is arranged, and brings huge social benefit and economic benefit to society.
Chinese medicine composition of the present invention is exactly the medicine at amyloid in the main neuropathological feature cerebral tissue of AD; by reducing the deposition of amyloid in the cerebral tissue; reduce the effect of inflammatory reaction activation of astrocyte and neuroprotective unit; improve patient's AD cognitive function and memory ability, the clinical control that provides effective means to be used for AD is provided.
Description of drawings
Fig. 1 shows that PDAPP transgenic mice (A) and non-transgenic mice (B) are in 1～6 day average latency of the hidden platform experiment (result of means ± SEM).
Fig. 2 shows and respectively organizes PDAPP transgenic mice and non-transgenic mice at 1～6 day average latency of hidden platform experiment (result of Mean ± SEM), wherein A matched group; B medicine group of the present invention; C piracetam group.Abbreviation: Tg mice, transgenic mice; Non-Tg mice, the non-transgenic mice.
Fig. 3 show respectively organize mice in exploring experiment in the TQ quadrant the shared percentage ratio of search time.A.PDAPP mice wherein.B. non-transgenic mice.* P＜0.01, * * P＜0.01, with matched group, compare with the piracetam group in #P＜0.05.
Fig. 4 show respectively organize mice in exploring experiment in 30 seconds through the number of times of position of platform.A.PDAPP mice wherein.B. non-transgenic mice.* P＜0.05, * * P＜0.01, with matched group, compare with the piracetam group in #P＜0.05.
Fig. 5 shows and respectively organizes mice in 1～4 day average latency of the visible platform experiments (result of Mean ± SEM).A.PDAPP mice wherein.B. non-transgenic mice.* P＜0.05, * * P＜0.01, with matched group, compare with the piracetam group in #P＜0.05.
Fig. 6 shows that A amyloid beta immunohistochemistry detects (hippocampus) result (4 * 10) in the PDAPP transgenic mice cerebral tissue.A. matched group wherein.B. piracetam group.C. medicine group of the present invention.
Fig. 7 shows PDAPP transgenic mice cerebral tissue Congo red histochemical stain (hippocampus) (4 * 10) result.A. matched group.B. piracetam group.C. medicine group of the present invention.
Fig. 8. show that PDAPP transgenic mice cerebral tissue GFAP immunohistochemistry detects.A. matched group.B. piracetam group.C. medicine group of the present invention.(400×)
Fig. 9 shows that MTT experiment detects the result to the protective effect of SH-SY5Y human neuroblastoma cellular neural toxic action of Chinese medicine composition of the present invention to A β 42 mediations.Compare for 42 groups with A β in * P＜0.01, compare with the piracetam group #P＜0.05.
The specific embodiment
Describe technical scheme of the present invention in detail below with reference to accompanying drawing.
At first, the invention provides a kind of Chinese medicine composition is Radix Rehmanniae Preparata 5～40 according to listed as parts by weight, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.The function of said composition is a kidney tonifying, essence replenishing, the refreshment of having one's ideas straightened out.Cure mainly alzheimer disease (dementia).Disease sees that intelligence descends, the decline of carrying out property of memory, and even partly or entirely forfeiture.Or with the mental act abnormality disease.
Theory of Chinese medical science thinks that the physiological function of spirit, consciousness, thinking and brain, kidney are closely related." the brain being the house of mentality ", " the brain being the reservoir of the marrow ", " kidney governing bones is given birth to marrow, on lead to " (" interior warp ") in brain; Saying of " expectorant can not disappearing ... make the refreshing unclear dementia that forms " also arranged simultaneously.As seen the sound of the god of unit must rely on " marrow is full of ", " empty key is clear ", " brain ruton ", basis as physiological function, in case the evil visitor of expectorant is in brain, hoodwink key, obstruction brain network clearly unavoidably, old in addition brain is gradually empty, certainly will cause simulataneous insufficiency and excessive, it perfects the refreshing mistake of unit, the pathological change of spirit, consciousness, thinking aspect occurs.So the treatment Research of Senile Dementia Treated should heresy just be taken into account, kidney tonifying, essence replenishing, waking up the patient from unconsciousness by dissipating phlegm are also used.
We are monarch with the Radix Rehmanniae Preparata, and the Radix Rehmanniae Preparata sweet in the mouth is warm in nature, returns kidney, Liver Channel, " Bencao Congxin " cloud " kidney nourishing water, packing marrow ".We are that monarch's the kidney invigorating and essence nourishing is filled out marrow with this medicine.
Radix Polygoni Multiflori Preparata, Fructus Lycii are minister.The Radix Polygoni Multiflori " good medicine of flat nourishing YIN blood " (" property of medicine is cut medicine "), Fructus Lycii " deficiency of energy tonification essence " (" property of medicine opinion "), two medicines share the power that increases the Radix Rehmanniae Preparata the kidney invigorating and essence nourishing; Simultaneously with Herba Epimedii, Rhizoma Curculiginis and be ministerial drug.Herba Epimedii " benefit gate of vitality Liver and kidney, energy Yang strengthening and life essence tonifying " (" the medical center bun is wanted. the property of medicine "), Rhizoma Curculiginis warming the kidney to invigorate YANG, and " logical refreshing hypermnesia, length is spiritual ".Last five medicines share the negative and positive that are intended to flat the kidney invigorating.
Rhizoma Acori Graminei, Radix Polygalae are adjuvant drug.The Rhizoma Acori Graminei fragrant odour, its property lightly floats, and can dredge governor vessel, with happy feelings will, thin strongly fragrant gas, turbid, the peaceful brain god of change spleen.The Radix Polygalae mind tranquilizing and the heart calming, " it is forgetful to control the mind, and the peace soul makes us not being confused " (" property of medicine opinion "), and can eliminate the phlegm and have one's ideas straightened out so that " Fructus Alpiniae Oxyphyllae is intelligent for tonifying for the deficiency, sharp nine orifices, and normal hearing and eyesight is not forgotten, strong will times power." (" herbal classic ").Two medicines are for helping the gas that is intended to dredge governor vessel, the merit of the capable Fructus Alpiniae Oxyphyllae of having one's ideas straightened out.
All medicine compatibilities gather altogether the kidney invigorating essence with fill out brains, reduce phlegm turbid to open brain key, refreshment god effect with multiple mind.
Pharmaceutical composition of the present invention is to the control pharmacodynamic study of AD model mice and transgenic mice, further illustrate the mechanism of action of this Chinese medicinal formulae theoretically, become a kind of new drug that cognitive function and the memory ability of AD are had clear improvement and act in the hope of exploitation, be used for clinical treatment patient's AD cognition and memory dysfunction.
1. adopt accumulative beta-amyloid polypeptide 1-[β-AP (25-35)] to be injected into the mice tricorn, change, set up the AD model mice by the histology who observes mice behavioristics's change and cerebral cortex and Hippocampus.
2. use this model mice the plurality of Chinese compound preparation is carried out pharmacodynamic study, and with the Western medicine piracetam in contrast, estimate the improvement effect of Chinese medicine composition of the present invention mouse memory function and cognitive competence.
3. in order further to study the curative effect effect of pharmaceutical composition of the present invention, selected the AD drug screening animal model-PDAPP that generally acknowledges in the world at present for use to AD
V7I7ITransgenic mice carries out the pharmacodynamic study of this prescription.This mice is transfected amyloid protein precursor (APP) gene mutation body (APP
V7I7I), make APP in the cerebral tissue
V7I7IProtein overexpression, A β 42 peptides deposition increases, and human AD sample pathological change appears in secondary.At present, PDAPP
V7I7ITransgenic mice is for research AD pathogenesis and estimate treatment and the gedanken experiment animal model of prevention AD medicine.Experimental result shows that pharmaceutical composition of the present invention not only can improve PDAPP significantly
V7I7IThe cognition of transgenic mice and memory function, and can reduce PDAPP significantly
V7I7IThe deposition of A amyloid beta in the transgenic mice cerebral tissue, senile plaque reduces.Simultaneously, pharmaceutical composition of the present invention can reduce PDAPP
V7I7ITransgenic mice cerebral tissue internal reaction activation of astrocyte.
4. pharmaceutical composition of the present invention is studied neuronic protective effect experiment in vitro.The result shows that Chinese medicine composition of the present invention has the significant protection effect to neuron.
5. show that through toxicology test pharmaceutical composition of the present invention comprises people's avirulence to mammal.
6. the clinical experiment of pharmaceutical composition of the present invention shows veteran form effectively dull-witted.
Choose 5 kilograms in Radix Rehmanniae Preparata, 5 kilograms of Radix Polygoni Multiflori Preparatas, 5 kilograms of Fructus Lycii, 5 kilograms of Herba Epimedii, 5 kilograms of Rhizoma Curculiginises, 5 kilograms of Rhizoma Acori Graminei, 3 kilograms of Radix Polygalaes, pulverize separately also mixes, and makes pulverulent mixture.Make honeyed pill according to the prior art known method.
Choose 40 kilograms in Radix Rehmanniae Preparata, 35 kilograms of Radix Polygoni Multiflori Preparatas, 35 kilograms of Fructus Lycii, 35 kilograms of Herba Epimedii, 35 kilograms of Rhizoma Curculiginises, 35 kilograms of Rhizoma Acori Graminei, 20 kilograms of Radix Polygalaes.Pulverize separately also mixes, and makes pulverulent mixture.Make tablet or capsule according to the prior art known method.
Choose 3 kilograms in Radix Rehmanniae Preparata, 3 kilograms of Radix Polygoni Multiflori Preparatas, 3 kilograms of Fructus Lycii, 3 kilograms of Herba Epimedii, 3 kilograms of Rhizoma Curculiginises, 3 kilograms of Rhizoma Acori Graminei, 2 kilograms of Radix Polygalaes.Add entry through pulverizing the back in extracting still, its addition is boiled then and is boiled extraction at least twice for not have above-mentioned Chinese medicine, removes medicinal residues, gets extracting solution, merge extractive liquid.
Choose Radix Rehmanniae Preparata 40 grams, Radix Polygoni Multiflori Preparata 35 grams, Fructus Lycii 35 grams, Herba Epimedii 35 grams, Rhizoma Curculiginis 35 grams, Rhizoma Acori Graminei 35 grams, Radix Polygalae 20 grams.Through adding ethanol after the suitable pulverizing in extracting still, its addition is removed medicinal residues for not have above-mentioned Chinese medicine extraction 48 hours, gets the ethanol extract of above-mentioned Chinese medicine composition.
Take to prepare pharmaceutical composition of the present invention with embodiment 1 identical step, different is to select 40 kilograms in Radix Rehmanniae Preparata for use, 5 kilograms of Radix Polygoni Multiflori Preparatas, 30 kilograms of Fructus Lycii, 15 kilograms of Herba Epimedii, 10 kilograms of Rhizoma Curculiginises, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
Take to prepare with embodiment 3 identical steps the water extract of pharmaceutical composition of the present invention, different is to select 5 kilograms in Radix Rehmanniae Preparata for use, 5 kilograms of Radix Polygoni Multiflori Preparatas, 5 kilograms of Fructus Lycii, 5 kilograms of Herba Epimedii, 5 kilograms of Rhizoma Curculiginises, 5 kilograms of Rhizoma Acori Graminei, 20 kilograms of Radix Polygalaes.
Embodiment 7
Take to prepare with embodiment 3 identical steps the water extract of pharmaceutical composition of the present invention, different is to select 40 kilograms in Radix Rehmanniae Preparata for use, 35 kilograms of Radix Polygoni Multiflori Preparatas, 35 kilograms of Fructus Lycii, 35 kilograms of Herba Epimedii, 5 kilograms of Rhizoma Curculiginises, 35 kilograms of Rhizoma Acori Graminei, 20 kilograms of Radix Polygalaes.
Experimental example 1
Chinese medicine composition of the present invention is to the cognition of beta-amyloid polypeptide 1-intracerebroventricular injection Alzheimer disease model mice and the research of memory function improvement effect.By Balb/c mice tricorn micro-injection state of aggregation beta-amyloid polypeptide 1-(β-AP
25-35), set up mouse model (the Giovannelli L of simulation AD, Casamenti F, the injections into the rat nucleus basalis.Neuroscience.1995 of the and β of Scali C.Differential effects of amyloidpeptides β-(1-40)-(25-35); 66:781-792.), and detect by behavioristics experiment and cerebral tissue histochemistry, studied and Chinese medicine composition of the present invention to the curative effect effect of this mouse model cognition and memory ability.Simultaneously, do contrast with nootropics Western medicine piracetam.The result shows that Chinese medicine composition of the present invention improves significantly to the cognition and the memory ability tool of AD model mice.
(1) intervenes the step down test that the AD model mice is respectively organized in test
Animals administer carries out the diving tower avoidance test after 30 days.At first, mice is put into diving tower instrument reaction chamber, conformed 3 minutes, pass to the 36V alternating current then, majority was jumped onto diving tower and is escaped electric shock after mice was subjected to shocking by electricity.Mice may be once more or repeatedly skips on the copper grid, after rebound platform again, so trained 5 minutes, the record mouse wrong times, with this as school grade.Again test after 24 hours, the record mice gets an electric shock incubation period, and writes down the errors number in 5 minutes.(Maurice T，Lockhart BP，Privat A.Amnesia induced in mice by centrallyadministeredβ-amyloid peptides involves cholinergic dysfunction.BrainResearch.1996；706：181-193.)
Table 1 intervention experiment respectively organize the AD model mice the diving tower experimental result (x ± S, n=12)
| Group | Incubation period (second) | Error rate (%) |
| The heavy dose of group of AD model control group normal saline group piracetam group Chinese medicine composition small dose group Chinese medicine composition | 84.83±71.6 187.18±120.65 2) 148.92±111.41 1) 264.17±71.58 2，4，5，6，7) 199.33±123.17 2，3) | 83.3 64.3 61.5 30.8 53.9 |
Annotate:
1)P＜0.05,
2)Compare with the AD model control group in P＜0.01;
3)P＜0.05,
4)Compare with the piracetam group in P＜0.01;
5)Compare with the normal saline group in P＜0.05.
As shown in table 1, the leave from office of model group mice is starkly lower than operative control group (P＜0.01) incubation period, and error rate is also apparently higher than normal saline matched group (P＜0.05).
In a word, the leave from office of piracetam group, the heavy dose of group of Chinese medicine composition of the present invention, Chinese medicine composition small dose group of the present invention all prolongs than model control group incubation period significantly.There was no significant difference (P＞0.05) between heavy dose of group of Chinese medicine composition of the present invention and the small dose group.
(2) intervention is tested the avoidance test animals administer of respectively organizing the AD model mice and is kept away dark test after 33 days.Earlier mice is put into bright chamber in the hole dorsad, conformed 3 minutes, then, switched on 3 minutes, the record mice enters the incubation period of being shocked by electricity in the darkroom.Again test after 24 hours write down mice in 3 minutes and is entered number of times and electric shock incubation period (Cai Yongchun, the Li Fengwen that is shocked by electricity in the darkroom.Chinese medicine and compound recipe thereof are to the progress of learning and memory of little mouse influence.China's TCM basis medical journal 1998,4 (8): 58-62).
Table 2 intervention experiment respectively organize the AD model mice the avoidance experimental result (x ± S, n=12)
| Group | Incubation period (second) | Error rate (%) |
| The heavy dose of group of AD model control group normal saline group piracetam group Chinese medicine composition small dose group Chinese medicine composition | 106.42±71.91 173.83±20.45 2) 146.5±65.18 1) 180±0 2) 163.42±40.43 1) | 61.5 21.4 38.5 0 23.1 |
Annotate:
1)P＜0.05,
2)Compare with the AD model control group in P＜0.01.
As shown in table 2, the leave from office of model group mice is starkly lower than operative control group (P＜0.01) incubation period, and errors number is apparently higher than normal saline matched group (P＜0.01).Prolong than model control group the incubation period of piracetam group, the heavy dose of group of Chinese medicine composition and Chinese medicine composition small dose group significantly.The significant difference between Chinese medicine composition small dose group and the model control group the most remarkable (P＜0.01) wherein.
Experimental example 2
Control pharmacodynamic study on the Chinese medicine composition PDAPP transgenic mice of the present invention.
Adopt the PDAPP transgenic mice as experimental animal model, adopt methods such as at present general in the world Animal Behavior Science experiment (Morris Water Maze), the interior amyloid immunohistochemistry of cerebral tissue and histological stain further to study the curative effect effect of Chinese medicine composition of the present invention simultaneously Alzheimer.
2.1 water maze laboratory
2.1.1 hidden platform test
(1) average latency of 1～6 day mice search platform at first adopts the hidden platform experimental evaluation of Morris water maze respectively to organize learning and memory ability (Janus, the C. of mice in order to study the improvement effect of Chinese medicine composition of the present invention to PDAPP transgenic mice cognitive function and memory ability in hidden platform experiment, D ' Amelio, S., Amitay, O., Chishti, M.A., Strome, R., Fraser, P., Carlson, G.A., Roder, J.C., George-Hyslop, P., and Westaway, D. (2000) Neurobiol.Aging 21,541-549).In experimentation, incubation period, detection range and speed that the record mice is searched for hidden platform.Respectively organize the search speed there was no significant difference between the mice by analysis, have very significantly dependency between incubation period and the detection range, so, with incubation period of mice search platform as the index of estimating mice space learning and memory ability.
Shown in Figure 1A, in the 1st～6 day training process, there are differences although respectively organize between incubation period of PDAPP mice search platform, tangible shortening is all arranged incubation period.Adopt post hoc results of statistical analysis to show, Chinese medicine composition group of the present invention is at all obvious average latency short (the p value is all less than 0.05) than matched group and piracetam group of the 4th, 5,6 day average latency.As the 6th day, the average latency of Chinese medicine composition group of the present invention was 25.41 ± 2.53s, and matched group is 36.62 ± 2.96s, and the piracetam group is 36.89 ± 3.04s.There is not tangible statistics difference (p＞0.05) between the average latency of piracetam group and the matched group.This shows Chinese medicine composition group PDAPP of the present invention
V7I7IThe Learning and Memory ability of transgenic mice is significantly improved.
Relatively average latency of each group of non-transgenic mice is found, in the time of the 6th day, Chinese medicine composition group of the present invention at the 6th day average latency obviously than the average latency weak point (p＜0.05) of matched group (p＜0.05) and piracetam group (Figure 1B).This shows that Chinese medicine composition of the present invention also has the improvement effect to the Learning and Memory ability of non-transgenic mice.Find by analyzing the average latency of respectively organizing PDAPP transgenic mice and non-transgenic mice, having only does not have evident difference (Fig. 2 A) between Chinese medicine composition group transgenic mice of the present invention and the non-transgenic mice, and all has evident difference (Fig. 2 B and Fig. 2 C) between transgenic mice and the non-transgenic mice in matched group and the piracetam group.Show, the Learning and Memory ability of Chinese medicine composition group PDAPP transgenic mice of the present invention is compared with the non-transgenic mice does not have significant difference, this means that the Learning and Memory ability of Chinese medicine composition group PDAPP transgenic mice of the present invention is significantly improved.
2.1.2 explore experiment (Probe test)
Because mice is in the hidden platform process of search, have mice once in a while, unconscious or running at random appear on the stage behind the platform, in order to eliminate this randomness, we take platform away from the pond, allow mice search platform 60 seconds in the pond, observe mice in the TQ quadrant search time and through the position of platform number of times, by the percentage ratio of search time and in the TQ quadrant relatively, estimate mice space learning and memory ability through the number of times of platform.Simultaneously, consider that mice may be owing to the behavior that influences the mice back in the position of platform search less than platform, so, we added up preceding 30 seconds mices in the TQ quadrant search time and through the position of platform number of times as the index of estimating mice space learning and memory ability.
(1) mice percentage ratio of search time in the TQ quadrant in exploring experiment
The exploration experimental result shows, the PDAPP mice, the learning and memory ability of Chinese medicine composition group mice of the present invention is significantly improved, and between space learning of Chinese medicine composition group mice of the present invention and memory ability and piracetam group and the matched group evident difference is arranged.As shown in Figure 3A, in 30 seconds inherent TQ quadrants of Chinese medicine composition group mice of the present invention the percentage ratio of search time apparently higher than piracetam group (p＜0.05) and matched group (p＜0.01).The percentage ratio of Chinese medicine composition group of the present invention search time in the TQ quadrant is 43.1 ± 4.4%, and the piracetam group is 35.2 ± 3.6%, matched group 29.9 ± 3.7%.Evident difference (p＜0.05) is all arranged between Chinese medicine composition group of the present invention and matched group and the piracetam group.All there is not evident difference (p＞0.05) between piracetam group and the matched group.But not the percentage ratio of search time is shown in Fig. 3 B in 30 seconds inherent TQ quadrants of transgenic mice, and Chinese medicine composition group of the present invention is apparently higher than matched group (p＜0.05) and piracetam group (p＜0.05).
(2) mice in exploring experiment through the number of times of position of platform
Shown in Fig. 4 A, Chinese medicine composition group PDAPP mice of the present invention average number of times through the position of platform in 30 second search time is (1.20 ± 0.30), apparently higher than piracetam group (0.89 ± 0.24) and matched group (0.65 ± 0.21).In the non-transgenic mice, shown in Fig. 4 B, Chinese medicine composition group mice of the present invention through the number of times (1.98 ± 0.4) of position of platform also all apparently higher than piracetam group (1.60 ± 0.28) and matched group (1.42 ± 0.34).
2.1.3 visible platform experiments (visible platform)
After finishing " probe test ", above platform, plug in a marker post, chequered with black and white, very eye-catching, mice is very easy to find.Simultaneously above marker post, put a white bead, prevent that the image tracing system from causing that to the identification of marker post experiment stops.Visible platform water maze laboratory result shows, beginning in the 2nd day, and the average latency of Chinese medicine composition group of the present invention and piracetam group PDAPP mice is significantly shorter than matched group.Shown in Fig. 5 A, find there is not significant difference (the P value is all less than 0.05) between Chinese medicine composition group of the present invention and the piracetam group through repeating variance analysis.The non-transgenic mice, shown in Fig. 5 B, beginning in the 2nd day has evident difference (P＞0.05) between average latency of Chinese medicine composition group mice of the present invention and the matched group.
Detect discovery by these several water maze laboratories, traditional Chinese medicine composition for treating group PDAPP transgenic mice of the present invention is respectively organized mice with other and is compared, and its learning and memory ability is improved significantly.The non-transgenic mice that Chinese medicine composition of the present invention is handled is compared with other group, and its learning and memory ability is also improved significantly.Show that thus Chinese medicine composition of the present invention not only has therapeutical effect to alzheimer disease, and normal person's learning and memory ability tool is improved significantly.
2.2 amyloid beta immunohistochemical staining in the PDAPP mouse brain tissue
In order further to study the deposition conditions of amyloid beta in the PDAPP transgenic mice cerebral tissue, utilize A β monoclonal antibody specific 3D6 to do immunohistochemical staining.Cerebral cortex and hippocampus (as Fig. 6) at matched group PDAPP mouse brain tissue all can see tangible amyloid beta deposition region being arranged, a large amount of sophisticated senile plaques.Obviously reduce the amyloid beta deposition region in the Chinese medicine composition group mouse brain tissue of the present invention, though the mice that has also can be seen senile plaque, the diameter of senile plaque is obviously little than matched group, can't see big senile plaque.And do not discover a marked discrepancy between interior amyloid beta deposition conditions of piracetam group mouse brain tissue and the matched group.We utilize NIH image J gradation of image scanning quantitative analysis software (http:rsb.info.nih.gov/nih-image) analysis respectively to organize the percentage ratio of amyloid beta deposition region in the PDAPP mouse brain tissue.The result shows that Chinese medicine composition group mouse brain of the present invention organizes the meansigma methods of cerebral cortex and hippocampus amyloid beta to be starkly lower than matched group piracetam group (P＜0.05).
2.3 the PDAPP mouse brain is organized the Congo red histological stain
All can see having at the cerebral cortex of matched group and piracetam group PDAPP mouse brain tissue and hippocampus (as Fig. 7) and significantly have a liking for the Congo red neurocyte in a large number.The cerebral cortex of Chinese medicine composition group mouse brain tissue of the present invention and hippocampus are had a liking for Congo red neurocyte number and are obviously reduced.
2.4 the immunohistochemical staining of astrocyte hypertrophy situation in the PDAPP mouse brain tissue
As shown in Figure 8, matched group and piracetam group PDAPP mouse brain organize cerebral cortex all can see the positive astrocyte hypertrophy of a large amount of significantly GFAP, and the positive astrocyte hypertrophy of very weak GFAP is only arranged in the Chinese medicine composition group PDAPP mouse brain tissue of the present invention.
Chinese medicine composition of the present invention can reduce the content of A amyloid beta in the PDAPP transgenic mice cerebral tissue, reduces inflammatory reaction in the cerebral tissue, and neuroprotective unit cell obviously improves cognition and the memory function of mice.Simultaneously, cognition and the memory function to the non-transgenic aged mouse also has the improvement effect.
Experimental example 3
Chinese medicine composition of the present invention is to the research of neuro-protective effect.
In order further to confirm Chinese medicine composition of the present invention, adopt MTT experiment detection Chinese medicine composition of the present invention whether the neurotoxic effect to SH-SY5Y human neuroblastoma cell of A β 42 mediations is had protective effect to neuronic protective effect.The result shows, Chinese medicine composition of the present invention can part in and the neurotoxic effect to SH-SY5Y human neuroblastoma cell of A β 42 mediations.As shown in Figure 9, Chinese medicine composition of the present invention is when a certain specific dilution factor, can partly prevent the neurotoxic effect (76.2% cell survival rate) of A β 42, comparing with 42 groups of A β and piracetam group has evident difference, and piracetam group and A β compare no significant difference for 42 groups.
Experimental example 4
Chinese medicine composition toxicologic study of the present invention: because of making LD
50, carry out maximum tolerance determination according to " new drug evaluation way " pertinent regulations.20 of the SPF level ICR mices of selection 19-22 gram, male and female half and half.612 gram invention Chinese medicine compositions are fried through Chongwenmen pharmacy of Beijing Tongrentang, simmer down to 200ml medicinal liquid.After the animal fasting 4 hours, disposable filling stomach is tried thing 1ml.At once observe reaction of animals, observed continuously 7 days; Day by day write down toxic reaction and the death condition of mice.The result shows: mouse stomach administration 153g gives birth to and boils medicine/the kg body weight, is 90 times of the clinical consumption of adult (1.7g crude drug/kg body weight), and animal appearance in the experiment, activity, appetite are normal, and no abnormal secretions and defecation are unusual.Do not see toxic reaction and because of the animal of toxicity death.Put to death animal on the 8th day and perform an autopsy on sb, diseased organ is not found in perusal.Histopathologic examination finds that no pathology change.
Experimental example 5
The clinical research of invention Chinese medicine composition.
For further inquiring into curative effect and the mechanism of action of invention Chinese medicine composition control AD, the inventor carries out the clinical research of traditional Chinese medicine composition for treating senile dementia of the present invention, now result of study is reported as follows.
The clinical diagnosis of AD is carried out (American Psychiatric Association.Diagnostic andstatistical manual of mental disorders, 4 according to the standard of Americanism medical diagnosis on disease and statistic handbook IV version revised edition and sick of Americanism and aphasis and apoplexy-Alzheimer and relevant disease country institute
ThEd.Washington:AmericanPsychiatric Association Press.1994.and Mckhann G, Drachman D, Foistein M et al.Clinical diagnosis of Alzheimer ' s disease:Report of theNINCDS-ADRDA Work Group under the auspices of the Department ofHealth and Human Service Task Force on Alzheimer ' s disease.Neurology1984; 34:939-44.).Eliminating suffer from serious nervous system disease, endocrinopathy, serious metabolic disease, serious Liver and kidney and heart and lung diseases, severe dementia and clinical can not cooperation person etc. after, go out 53 routine AD patients (all AD patient MMSE test and assess and all are lower than 25 fens) by medical history and simple and easy mental status examination table (MMSE) and the movable scale investigation of daily life function (ADL) examination.Be divided into Chinese medicine composition group 33 examples of the present invention at random, piracetam matched group 20 examples.Chinese medicine composition group of the present invention is taken invention Chinese medicine composition every day 3 times, each 50ml; The piracetam matched group is taken each 4 of Piracetam Tablet (produced by east doctor group Dongbei Pharmaceutical General Factory, lot number 200006066, every contains piracetam 0.4g), and every day 3 times, be 1 course of treatment March.At viewing duration, give suitable anti symptom treatment, give anti-infective therapy if any the infected, but stop using other nootropics and medicament for expanding vascellum.Adopt the variation of simple and easy mental status examination table (MMSE) and daily life self-care ability scale (ADL) integration to carry out the curative effect assessment.Carry out statistical analysis through SPSS software, adopt the t check before and after the treatment and between two groups.
MMSE, ADL integration (X ± s) relatively before and after the treatment of table 3 Chinese medicine composition group and piracetam group
| The MMSE integration | The ADL integration | ||
| Chinese medicine composition group (n=33) piracetam group (n=20) | After treating before the preceding treatment of the treatment back treatment | 15.03±2.67 19.01±2.39 *# 15.51±2.12 16.71±2.91 | 59.7±7.71 53.60±7.51 *# 58.1±6.19 56.91±7.23 |
*P＜0.01, with the treatment before compare;
#Compare with the piracetam group P＜0.01
The result is shown in 3 tables, MMSE, ADL integration baseline no significant difference (P＞0.05) before two groups of treatments, the MMSE average integral of Chinese medicine composition group of the present invention is significantly improved (P＜0.01) before the treatment after the treatment, but the MMSE average integral of piracetam group changes (P＞0.05) than the preceding no significance of treatment.The MMSE average integral of treatment back Chinese medicine composition group of the present invention is also apparently higher than the MMSE average integral (P＜0.05) of piracetam group.Equally, before the ADL average integral of treatment back Chinese medicine composition group of the present invention is treated obvious reduction (P＜0.01) is arranged, and the ADL average integral of piracetam group there be not obvious the change before the treatment.
Above-mentioned data show that Chinese medicine composition of the present invention can improve patient's AD disturbance of intelligence significantly, improve patient's AD viability; Though and the effect of piracetam is not obvious, the inhibitory action certain to further developing of patient's AD disturbance of intelligence.
Claims (5)
1, a kind of Chinese medicine composition that prevents and/or treats alzheimer disease is characterized in that according to listed as parts by weight be Radix Rehmanniae Preparata 5～40, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
2, Chinese medicine composition as claimed in claim 1 is characterized in that according to listed as parts by weight be Radix Rehmanniae Preparata 3～30, Radix Polygoni Multiflori Preparata 3～25, Fructus Lycii 3～25, Herba Epimedii 3～25, Rhizoma Curculiginis 3～25, Rhizoma Acori Graminei 3～25, Radix Polygalae 2～15.
3, a kind of water extract that prevents and/or treats the Chinese medicine composition of alzheimer disease is characterized in that described Chinese medicine composition is a Radix Rehmanniae Preparata 5～40 according to listed as parts by weight, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
4, a kind of ethanol extraction that prevents and/or treats the Chinese medicine composition of alzheimer disease is characterized in that described Chinese medicine composition is a Radix Rehmanniae Preparata 5～40 according to listed as parts by weight, Radix Polygoni Multiflori Preparata 5～35, Fructus Lycii 5～35, Herba Epimedii 5～35, Rhizoma Curculiginis 5～35, Rhizoma Acori Graminei 5～35, Radix Polygalae 3～20.
5, Chinese medicine composition as claimed in claim 1 is characterized in that said composition makes tablet, capsule, pill, powder or unguentum.
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| CN110742972B (en) * | 2019-11-14 | 2021-12-24 | 甘肃琛蓝生物医药有限公司 | Traditional Chinese medicine composition with cognitive improvement effect and preparation method thereof and traditional Chinese medicine preparation |
| CN113144124A (en) * | 2021-04-16 | 2021-07-23 | 韩旭 | A Chinese medicinal composition for treating Alzheimer type dementia and its decoction |
| CN113521178A (en) * | 2021-08-25 | 2021-10-22 | 昆明市中医医院 | Traditional Chinese medicine composition for preventing and treating senile dementia |
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