CN102078460A - Traditional Chinese medicine for preventing and treating Alzheimer disease and preparation method thereof - Google Patents
Traditional Chinese medicine for preventing and treating Alzheimer disease and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a traditional Chinese medicine for preventing and treating Alzheimer disease and a preparation method thereof. The traditional Chinese medicine is prepared from the following raw materials in parts by weight: 12-16 parts of prepared fleece flower root, 8-12 parts of ginseng, 9-13 parts of rhizoma acori graminei, 5-9 parts of coptis and 6-10 parts of chuanxiong rhizome. The traditional Chinese medicine can be prepared into granules, capsules, soft capsules, dissolved medicines, dripping pills and soft extracts, has the advantages of simple manufacturing process and low cost, is completely prepared from natural plants, does not contain hormones, has no addition of pigments and other chemical synthetics, and does not have toxic side effects on human bodies after being continuously used. The traditional Chinese medicine contains various effective components such as flavones, saponins, phenolic acids, alkaloids, polysaccharides and the like capable of being easily absorbed by human bodies, can be effectively used for nourishing the kidney and invigorating the brain, replenishing qi and dissolving turbidity and promoting blood circulation and eliminating toxicity, and is suitable for treating deficiency of the kidney, mild cognitive impairment caused by obstruction of the orifices by blood stasis, Alzheimer disease and the like.
Description
Technical field
The present invention relates to a kind of Chinese medicine of preventing and treating Alzheimer and preparation method thereof.
Background technology
Alzheimer (Alzheimer disease, AD) be the dementia that chronic progressive external central nervous system degeneration pathological changes is caused, being modal alzheimer disease, is feature with cognitive dysfunction and neural mental symptom such as abnormality of personality in various degree such as slow development dysmnesia, disorientation, language function obstacle.AD is a modal type in the nervous system degeneration disease, and the morbidity of AD is increased with the growth at age, and the over-65s prevalence is 5%-10%; More than 85 years old is 20%-50%.
Along with the aging of world population, the sickness rate of AD is continuous ascendant trend, should disease become the fourth-largest cause of disease (being only second to heart disease, tumor and apoplexy) that jeopardizes old people's life at present, becomes current geriatrics and faces one of the severeest problem.Account for 35%, 80 years old of total population and above old man is about 22% China 65 years old and above old man, and AD patient's expection can reach 2,500 ten thousand, will become important restraining factors that influence family life quality and social development.Because the pathomechanism of AD is very complicated, the cause of disease is still not fully aware of at present, also lacks therapy measure.Therefore, the pathogenesis of active research AD, exploitation effectively control AD medicine is one of vital task of current infirmities of age research field.
The viewpoint of China's Chinese medicine is thought: cognitive disorder, senile dementia belong to sick categories such as " forgetful ", " refreshing sick ", " dementia ", " dementia ".Ancient medicine to its name of disease, sick position, etiology and pathogenesis, distinguish that the aspect such as controlling there are much penetrating argumentations.Ming Dynasty's Zhang Jingyue at first proposes " dementia " name of disease, point out " dementia is all do not have expectorant usually and or with pent-up, or with unsuccessful; or thought is considered; or feeling uncertain, or the heart to be gradually to cause dementia in terror, and words are put upside down; movement is without; or hyperhidrosis, or kind anxious, and it is strange hundred strange that its card is then done; penetrate everywhere ", the various clinical symptoms of dull-witted performance has been described.Qing Dynasty's Wang Qingren errors in Medicine Corrected is pointed out " Nian Gaowu memory person, brains are gradually empty ".Carry among the Wang Ang of the Qing Dynasty " collection of prescriptions with notes " " people's essence and will all are hidden in kidney, and deficiency of kidney-essence then ambition declines, can not on lead in the heart, so confuse also forgetful ".Pointed out cognitive disorder, sick position, the cause of disease and pathogenesis that senile dementia is relevant with deficiency of kidney-essence, the marrow sky of all pointing out to suffer from a deficiency of the kidney is the main pathogenesis basis of its generation.
Mild cognitive impairment, senile dementia basic pathogenesis are deficiency in origin and excess in superficiality, and void is mainly the marrow sky of suffering from a deficiency of the kidney, and the vital essence deficiency is mainly in fact that expectorant is turbid, blood stasis, malicious heresy hoodwink key clearly.Therefore, kidney tonifying, essence replenishing QI invigorating, the turbid detoxifcation of dispelling are invigorated blood circulation, and giving consideration to both the incidental and fundamental is one of basic method of treatment of cognitive disorder, senile dementia.Clinically see deficiency of marrow-reservoir or caused by liver and kidney deficiency pattern of syndrome more, show as that hypophrenia, look slow-witted blunt, reticent few speech, asthenia are thought to crouch, dizziness and tinnitus, soreness of the waist and knees etc., light red tongue, the few or no fur of tongue, the weak or stringy and thready pulse of deep-thready pulse etc.So treatment should be turbid based on kidney tonifying, essence replenishing, QI invigoratingization, detoxifcation is invigorated blood circulation.
The domestic and international at present medicine that does not still have at all to treat AD, so the early treatment is most important.Chang Yong cholinesterase inhibitor can only relief of symptoms the most, and can not change the process of disease.This disease needs the patient to take medicine for a long time, and western medicine result is not good enough, and easily forms drug resistance, and untoward reaction is obvious; And the Chinese medicine aspect has clinical effectiveness preferably at control mild cognitive impairment and alzheimer disease, embodies wholistic therapy, and multipath, the integrally-regulated characteristics of too many levels are arranged, and its utilization compound recipe and determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs are used natural drug, and toxic and side effects is little.Therefore, utilize the extraction of prepared slices of Chinese crude drugs compatibility and its active component to be applied to the control of Alzheimer, the active drug of developing control AD has crucial meaning.
Summary of the invention
The object of the present invention is to provide and a kind ofly can effectively prevent and treat Chinese medicine compound of Alzheimer and preparation method thereof.
A kind of Chinese medicine of preventing and treating Alzheimer, its raw material by following mass fraction is formed, Radix Polygoni Multiflori Preparata 12-16 part, Radix Ginseng 8-12 part, Rhizoma Acori Graminei 10-14 part, Rhizoma Coptidis 5-9 part and Rhizoma Chuanxiong 6-10 part.
The mass fraction of described each raw material can be 16 parts of Radix Polygoni Multiflori Preparatas, 12 parts of Radix Ginsengs, 14 parts of Rhizoma Acori Graminei, 10 parts of 9 parts of Rhizoma Coptidis and Rhizoma Chuanxiongs.
The mass fraction of described each raw material can be 13 parts of Radix Polygoni Multiflori Preparatas, 10 parts of Radix Ginsengs, 12 parts of Rhizoma Acori Graminei, 9 parts of 6 parts of Rhizoma Coptidis and Rhizoma Chuanxiongs.
The mass fraction of described each raw material can be 12 parts of Radix Polygoni Multiflori Preparatas, 9 parts of Radix Ginsengs, 10 parts of Rhizoma Acori Graminei, 6 parts of 5 parts of Rhizoma Coptidis and Rhizoma Chuanxiongs.
Radix Polygoni Multiflori is a monarch drug in the side, invigorating the liver and kidney, replenishing essence marrow; Minister helps Radix Polygoni Multiflori to mend the deficient of internal organs with Radix Ginseng QI invigorating tonify deficiency; Assistant with Rhizoma Acori Graminei, Rhizoma Coptidis dissolving turbidity for resucitation, separate the poison of gods; Rhizoma Chuanxiong is a messenger drug, and the blood circulation promoting and blood stasis dispelling medicine carrying of holding concurrently is up in brain.All medicine mutually 5, play altogether tonify Qi of the kidney, the effect of promoting blood circulation and detoxication.The Chinese medicine of this control Alzheimer cures mainly: tonify Qi of the kidney, promoting blood circulation and detoxication, be applicable to the treatment of vital essence loss, the cognitive disorder of stasis of blood poison aperture-blocking type, alzheimer disease (Alzheimer) etc.Disease is seen slow-witted blunt, the forgetful or hypophrenia of look, be can't take care of oneself, dizziness and tinnitus, asthenia are thought to crouch, light red tongue or ecchymosis is arranged, the weak or stringy and thready pulse number of deep-thready pulse etc.
A kind of preparation method of Chinese medicine of preventing and treating Alzheimer, described preparation method comprise and are prepared into Chinese medicine preparation (dosage form that comprises granule, capsule, soft capsule, electuary, drop pill, soft extract) and are prepared into two kinds of preparation methoies of Chinese medicine active component extract.
The described preparation method that is prepared into Chinese medicine preparation comprises following process:
(1) get Rhizoma Acori Graminei and soak, adopt the vapor distillation reflux, extract,, collect upper strata grease, drying gets Rhizoma Acori Graminei fragrance volatile oil;
(2) medicinal residues and Radix Polygoni Multiflori Preparata behind step (1) the extraction volatile oil are mixed, decoct with water, extract, decocting liquid carries out precipitate with ethanol;
(3) get Radix Ginseng, Rhizoma Coptidis and Rhizoma Chuanxiong, mix the back and add ethanol extraction;
(4) feed liquid of combining step (2) and (3) gained, at 50-60 ℃ of concentrating under reduced pressure, centrifugalize merges centrate, adopts decoction and alcohol sedimentation technique to remove impurity, carries out ultrafiltration then, and ultrafiltrate is become concentrated extracting solution at 50-60 ℃ of concentrating under reduced pressure;
(5) step (4) gained concentrated extracting solution and adjuvant are mixed and made into serosity, and the spray-dried dry extract of making adds adjuvant and granulates, and add the Rhizoma Acori Graminei fragrance volatile ingredient of gained in the step (1).
Add the water logging bubble 2h of 8 times of quality in the described step (1) in the Rhizoma Acori Graminei, adopt the vapor distillation reflux, extract,, the time is 6h.
The decocting that adds 10 times of quality in the described step (2) earlier boils 90min, and it is stand-by to pour out decocting liquid then, and the decocting that adds 7 times of quality again boils 70min, and the decocting liquid that secondary is obtained merges.
The isolating rotating speed of secondary centrifuging is respectively 7000rpm and 16000rpm in the described step (4).
The method that adds Rhizoma Acori Graminei fragrance volatile ingredient in the described step (5) is one of following two kinds: 1. Rhizoma Acori Graminei fragrance volatile ingredient is dissolved in the ethanol, and atomized spray adds; 2. sneak into after making β-CD inclusion.
The medicine that step (5) is made carries out drying, and baking temperature is controlled at 60 ℃ to 80 ℃ oven dry, and temperature rises gradually, and mass water content is controlled at 2%.Cross No. one and screen out bulky grain, cross No. five then and screen out fine powder, detect qualified back packing.
The described Chinese medicine active component preparation method of extract that is prepared into comprises following process:
(1) Radix Polygoni Multiflori Preparata, Radix Ginseng, Rhizoma Acori Graminei, Rhizoma Coptidis and Rhizoma Chuanxiong are pulverized the back mix homogeneously, add ethanol, reflux is repeatedly collected, merging filtrate;
(2) medicinal residues in the step (1) are added water and reflux, add dehydrated alcohol behind the merging water extract and leave standstill, filter;
(3) filtrate in precipitate in the step (2) and the step (1) merge is concentrated extractum.
The backflow number of times is 3 times in the described step (1), and each return time is 90min.
The present invention is a kind of Chinese medicine of preventing and treating Alzheimer and preparation method thereof, with Radix Polygoni Multiflori Preparata, Radix Ginseng, Rhizoma Acori Graminei, Rhizoma Coptidis and Rhizoma Chuanxiong is feedstock production, its processing technology is simple, cost is low, make by natural plants fully, do not contain hormone, also do not add other synthetics such as pigment, after using continuously, human body is had no side effect.This Chinese medicine contains the multiple nutritional components such as flavone, saponin, phenolic acid, alkaloid and polysaccharide that easily are absorbed by the body, and can be effective to tonify Qi of the kidney, promoting blood circulation and detoxication, is applicable to the treatment of Alzheimer.
Description of drawings
Fig. 1 is Chinese medicine active component compatibility extraction process figure;
Fig. 2 is prepared slices of Chinese crude drugs compatibility extraction process figure.
Fig. 3 expresses comparison diagram for drug matching to rat hippocampus NF-kB protein;
Fig. 4 is that drug matching is to rat hippocampus apoptosis map analysis comparison diagram.
The specific embodiment
Below by specific embodiment the present invention is described in further detail.
A kind of Chinese medicine compound component of preventing and treating Alzheimer, its raw material by following mass fraction is formed, 16 parts of Radix Polygoni Multiflori Preparatas, 12 parts of Radix Ginsengs, 14 parts of Rhizoma Acori Graminei, 9 parts of 10 parts of Rhizoma Chuanxiongs and Rhizoma Coptidis.
This preparation method of Chinese medicine can be for being prepared into Chinese medicine preparation, and its preparation method comprises following process as shown in Figure 2:
(1) gets 14 parts of Rhizoma Acori Graminei, the water logging bubble 2h that adds 8 times of quality, adopt the vapor distillation reflux, extract,, time is 6h, collect upper strata grease, add anhydrous chlorides of rase sodium saturated solution and make score layer more obvious, divide water-yielding stratum, anhydrous sodium sulfate drying then, at last light yellow transparency liquid is a Rhizoma Acori Graminei fragrance volatile oil;
(2) medicinal residues and 16 parts of Radix Polygoni Multiflori Preparatas behind step (1) the extraction volatile oil are mixed, the decocting that adds 10 times of quality earlier boils 90min, and it is stand-by to pour out decocting liquid then, and the decocting that adds 7 times of quality again boils 70min, the decocting liquid that secondary is obtained merges, and decocting liquid carries out precipitate with ethanol;
(3) get 12 parts of Radix Ginsengs, 9 portions of Rhizoma Coptidis and 10 parts of Rhizoma Chuanxiongs mix the back and add 80% (V/V) ethanol,, extract 3 times than 1: 20 according to material liquid volume, and extraction time is 90min/ time;
(4) feed liquid of combining step (2) and (3) gained, be evaporated to relative density 1.02-1.04 at 60 ℃, secondary centrifuging is separated, rotating speed is respectively 7000rpm and 16000rpm, merge centrate, adopt decoction and alcohol sedimentation technique to remove impurity, carry out ultrafiltration then, the molecular cut off of ultrafilter membrane is 70,000, and ultrafiltrate is evaporated to the concentrated extracting solution that relative density is 1.06-1.09 at 50-60 ℃;
(5) step (4) gained concentrated extracting solution and Icing Sugar and dextrin adjuvant are mixed and made into serosity, the spray-dried dry extract of making, add adjuvant then, preparation, the Rhizoma Acori Graminei fragrance volatile ingredient of gained in the step (1) is dissolved in an amount of ethanol, atomized spray is on dried granules, and airtight placement certain hour is treated evenly back packing of vexed suction.This Chinese medicine also can be made into the dosage form of capsule, soft capsule, electuary, drop pill, soft extract.
Embodiment 2
A kind of Chinese medicine of preventing and treating Alzheimer, its raw material by following mass fraction is formed, 13 parts of Radix Polygoni Multiflori Preparatas, 10 parts of Radix Ginsengs, 12 parts of Rhizoma Acori Graminei, 9 parts of 6 parts of Rhizoma Coptidis and Rhizoma Chuanxiongs.
This preparation method of Chinese medicine can be for being prepared into Chinese medicine preparation, sneaks into drying after the Rhizoma Acori Graminei fragrance volatile ingredient of gained in the step (1) is made β-CD inclusion.All the other are with embodiment 1.This Chinese medicine can be made into the dosage form of granule, capsule, soft capsule, electuary, drop pill, soft extract.
Embodiment 3
A kind of drug matching that prevents and treats Alzheimer, its raw material by following mass fraction is formed, 12 parts of Radix Polygoni Multiflori Preparatas, 9 parts of Radix Ginsengs, 10 parts of Rhizoma Acori Graminei, 6 parts of 5 parts of Rhizoma Coptidis and Rhizoma Chuanxiongs.
This preparation method of Chinese medicine can be for being prepared into Chinese medicine active component extract, and its preparation method comprises following process with reference to shown in Figure 1:
(1) with 12 parts of Radix Polygoni Multiflori Preparatas, 9 parts of Radix Ginsengs, 10 parts of Rhizoma Acori Graminei, 5 portions of Rhizoma Coptidis and 6 parts of Rhizoma Chuanxiongs are pulverized the back mix homogeneously, add 60% (v/v) ethanol according to 1: 20 ratio of solid-liquid ratio, reflux 3 times, and each return time is 90min, merging filtrate;
(2) water of the medicinal residues in the step (1) with 8 times of volumes is refluxed 2 times, each 120min adds 4 times of volume dehydrated alcohol behind the merging water extract and leaves standstill, and filters;
(3) filtrate in precipitate in the step (2) and the step (1) merge is concentrated extractum.
(4) adopt UV-VIS spectrophotometry to measure, 122g medical material alcohol-extracted extract, wherein each constituent mass content is as follows: total flavones: 14.19%, total saponins: 25.98%, total phenolic acid: 2.27%, total alkaloids: 5.2%, polysaccharide: 51.36%.
This Chinese medicine can be made into the dosage form of granule, capsule, soft capsule, electuary, drop pill, soft extract.
Carried out the pharmacological effect experiment according to embodiment 3 synthetic Chinese medicines:
Experiment one:
Chinese medicinal components of the present invention is to the influence of APP transgenic dementia mice
1 material
1.1 laboratory animal
60 of 3 monthly age APP695V717I transgenic mices (male and female half and half), body weight 17-23g, the cleaning level, 15 of identical genetic background C57BL/6J mices are normal control.Animal licence numbering SCXK capital 2005-0013.
1.2 experiment medicine
Positive control drug is selected donepezil hydrochloride for use, and (trade name: aricept), the 5mg/ sheet is pulverized during use, dissolves with distilled water.Acetylcholine, acetylcholinesterase, choline acetyltransterase and enzyme linked immunological kit are also used in this experiment.Following " Chinese medicine of the present invention " is meant the medicine among the embodiment 1.
1.3 key instrument
DMS-2 type Morris water maze instrument automatic data collection and processing system, STT-2 mice diving tower instrument (or DT-200 diving tower auto testing instrument), BH-2 type biological microscope, DpxView Pro type computer color vision processing system.
2 methods
2.1 grouping and administration
According to random digit (producing random digit) the APP transgenic mice is divided into big group of model group, Chinese medicine of the present invention (9.76g crude drug/kg/d), Chinese medicine of the present invention group (4.88g crude drug/kg/d) and donepezil hydrochloride group (0.65mg/kg/d), 15 every group at random according to the SPSS statistical software; 15 of the same monthly age C57BL/6J mices of identical genetic background are as the normal control group.Normal group and model group are given the equal-volume distilled water and are irritated stomach, every day 1 time.Each organizes 24 weeks of mouse stomach, carries out behavioristics's experiment during to 9 monthly ages.
2.2 behavioristics's test
2.2.1Morris water maze test
Morris water maze pool diameter 120cm, the dark 50cm in pond.During experiment the pond is divided into four quadrant districts with four equidistant points, in the middle of four-quadrant is positioned at the pool wall and the center of circle, places the lucite platform.In the pond, add water, the about 20cm of the depth of water, the water surface exceeds platform surface 0.5cm, water temperature 25+1 ℃, inject milk powder, mixing, make water become opaque milky, reach the animal vision and can't distinguish the purpose that has or not platform in the pond, and make the activity that function is successfully followed the tracks of mice of calculating.Test is carried out in sound damping room, and various experimental conditions such as position, pond, light source position and intensity remain unchanged in whole experiment, come the locating platform position for mice.
Test program comprises: (1) orientation navigation experiment: be used for measuring the learning and memory ability of animal at water maze.Carry out every day 1 time, trained continuously 5 days.Remove platform the 5th day afternoon, optional place of entry, mice is put into the pond towards pool wall, camera system write down the number of times in turnover original platform district in the mice 3min automatically and in original platform place four-quadrant swimming time and distance as the index of estimating the learning and memory of little mouse achievement.
2.2.2 step down test
Diving tower instrument experimental box links to each other with the computer automatic production record.During experiment mice put into diving tower instrument experimental box; 5min conforms; afterwards mice is put down gently on diving tower; and with the energising of copper grid, can be shocked by electricity when diving tower jumps off extremity contact copper grid when mice, normal avoidance response is to jump onto diving tower to return the place of safety; escape electric shock; so learn 5min, and write down the electric shock number of times (errors number) in this 5min, as school grade.Carry out the memory ability test behind the 24h, mice is placed on the diving tower, the record mice from rest on the diving tower to jump off for the first time the time of being shocked by electricity be incubation period with 5min in errors number (the mice extremity contact the number of times that the copper grid get an electric shock simultaneously), with this evaluation index as memory function.
2.3 brain tissue sample handles
Mice is after the test of last behavioristics, and fasting 12h carries out cerebral tissue and serum and draws materials.Eyeball was got blood after each organized mouse anesthesia, centrifugal (2500r/min, 15min), separation of serum maintains the temperature at 4 ℃ in order to follow-up index detection; Broken end is got full brain fast at low temperatures, with ice-cold normal saline cleaning bloodstain, blots with filter paper, weighs.6 of every group of picked at random drop in 4% paraformaldehyde solution fixedly 24h above (4 ℃), change the back fixative afterwards, treat can carry out frozen section after cerebral tissue sinks, or paraffin embedding, carry out pathology and immunohistochemical staining.All the other (except that small dose group is 7, other are 8) mices are rapid selective separating and Hippocampus (carrying out on the ice cream) respectively, and each adds 2ml normal saline (distilled water) homogenate, and the low-temperature and high-speed centrifuge is centrifugal, and separation of supernatant is used for tissue content and measures.In irritating the stomach process, dead 1 of Chinese medicine small dose group; In step down test, the Western medicine group has 1 to get an electric shock and die.
2.4 statistical procedures
The gained data are with mean ± standard deviation
Expression adopts the SPSS13.0 of statistical software to carry out statistical analysis, and data are relatively used one factor analysis of variance between group, adopts LSD, Dunnett ' sC (during heterogeneity of variance) check, is that difference has the significance meaning with P＜0.05.
3 experimental results
3.1 the Chinese medicinal components compatibility is to the influence of APP transgenic mice space learning memory ability
Compare with normal group, model group is passed through original platform position number of times, four-quadrant swimming time and distance and is all significantly reduced (P＜0.01) in the Morris water maze.After each administration group treatment, in the Morris water maze, pass through original platform position number of times, four-quadrant swimming time and distance and all significantly increase (P＜0.05/P＜0.01) than model group.The results are shown in Table 1.
Table 1 Chinese medicinal components compatibility is to the influence of APP transgenic mice space learning memory ability
Annotate: compare with model group:
*P＜0.05;
*P＜0.01; Group compares with often ending:
▲P＜0.05;
▲ ▲P＜0.01.
3.2 the Chinese medicinal components compatibility is to the influence of the disposable avoidance response memory function of APP transgenic mice
Each is organized and compares there was no significant difference (P＞0.05) between the errors number group of mice in step down test, but model group presents the trend that errors number increases.Compare with normal group, obviously shorten (P＜0.01) incubation period of model group; With model group relatively, the donepezil hydrochloride group obviously prolongs (P＜0.05) incubation period, Chinese medicine of the present invention significant prolongation big group of incubation period (P＜0.01), also there is prolongation trend in Chinese medicine of the present invention group incubation period, but there was no significant difference (P＞0.05).The results are shown in Table 2.
Table 2. Chinese medicinal components compatibility is to the influence of the disposable avoidance response memory function of APP transgenic mice
Annotate: compare with model group:
*P＜0.05;
*P＜0.01; Compare with normal group:
▲P＜0.05;
▲ ▲P＜0.01.
3.3 Chinese medicinal components is to the influence of acetylcholine, choline acetyltransterase and acetylcholinesterase content in the APP mice Hippocampus
Ach reduces in the APP transgenic mice Hippocampus at 9 monthly ages, compares with the blank group, and the content of model group Ach obviously reduces, obvious difference (P＜0.05); Compare donepezil, large and small group of content (P＜0.05) that all can improve Ach of Chinese medicine of the present invention with model group.AchE is active in the APP transgenic mice Hippocampus at 9 monthly ages increases, and compares with the blank group, and statistical significance (P＜0.01) is arranged.Compare large and small group of content (P＜0.05) that all can reduce AchE of Chinese medicine of the present invention with model group; CHAT is active in the APP transgenic mice Hippocampus at 9 monthly ages reduces, and compares with the blank group, and the content of model group CHAT obviously reduces (P＜0.01); Compare with model group, donepezil, large and small group of content that all can improve CHAT of Chinese medicine of the present invention all have statistical significance (P＜0.05).The results are shown in Table 3.
Table 3 Chinese medicinal components is to the influence of 9 monthly age APP transgenic mice Hippocampus Ach, AchE, CHAT content
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
3.4 Chinese medicinal components is to the influence of acetylcholine, choline acetyltransterase and acetylcholinesterase content in the cortex
Ach reduces in the APP transgenic mice cortex at 9 monthly ages.Compare with the blank group, the content of model group Ach obviously reduces (P＜0.05); Compare donepezil, large and small group of content that all can improve Ach of Chinese medicinal components of the present invention with model group; AchE content increases in the APP transgenic mice cortex, compares with the blank group, and model group AchE content obviously increases, obvious difference (P＜0.01).Compare donepezil, large and small group of content that all can reduce AchE of Chinese medicinal components of the present invention, but not statistically significant with model group.The content of CHAT reduces in the APP transgenic mice cortex at 9 monthly ages, compares with the blank group, and the content of model group CHAT obviously reduces (P＜0.05); Compare donepezil, large and small group of content (P＜0.05) that all can improve CHAT of Chinese medicine of the present invention with model group.The results are shown in Table 4.
Table 4 Chinese medicinal components is to the influence of 9 monthly age APP transgenic mice cortex Ach, AchE, CHAT content
Annotate: compare * P＜0.05 with model group
4 conclusions
The APP transgenic mice is to utilize the method for microinjection that app gene or genetic fragment are integrated in the genome of mice, makes the mice brain express app gene.By APP albumen overexpression in brain, A β produces increase, causes the neuron excitotoxicity effect, damage ability of learning and memory in mice, and gathering and formation of deposits senile plaque, thus cause mice senile dementia transgenic animal model.
This result of study shows, compare with the normal control group, the number of times that passes through the original platform position in the APP transgene mice model group 3min significantly reduces (P＜0.01), significantly reduce (P＜0.01) in the original platform place four-quadrant time of staying, the swimming distance significantly shortens (P＜0.05), points out its ability of learning and memory obviously to reduce.Compare with model group, large and small group of mice of Chinese medicine of the present invention passed through number of times significantly increases (P＜0.05), all significantly increase (P＜0.05/P＜0.01) in the four-quadrant time of staying and swimming distance, show that this each dosage of Chinese medicine active component can significantly improve the impaired ability of learning and memory of APP transgenic mice.
Step down test is the test of the disposable passive avoidance response memory function of reflection mice.Compare with model group, Chinese medicine of the present invention obviously prolongs (P＜0.01) big group of incubation period, also there is prolongation trend incubation period in Chinese medicine of the present invention group, but there was no significant difference (P＞0.05) shows that the Chinese medicine active component is to having the improvement effect than the long term memory function in the impermanent memory of APP transgenic mice.
APP transgenic mice behavioristics is observed from Morris water maze and step down test two aspects, and the APP695V717I transgenic mice significantly descends at 9 monthly age time space ability of learning and memory and disposable passive avoidance response memory ability; Chinese medicine active component early intervention can obviously be improved the ability of learning and memory that the APP transgenic mice has descended, and its space learning memory and disposable passive avoidance response memory ability are had obvious improvement effect.
This Chinese medicine active component can improve the content of Ach, strengthens the activity of CHAT, suppresses the activity of AchE.Improve aspect indexs such as APP transgenic Model of Dementia pathology, cholinergic system and apoptosis, this may be its main curative effect mechanism and action pathway, has the effect of control Alzheimer.
Experiment two: Chinese medicine preparation is to the influence of old cognitive disorder learning and memory in rats ability
1 experiment material
1.1 animal
Select 20 of Wistar senile rats (cleaning level) for use, 22～24 monthly ages, male and female half and half, body weight 360～650g; Select else with 10 of young rats (cleaning level), 9～10 ages in week, male and female half and half, body weight 180～220g.Animal licence numbering: SCXK (capital)-2007-0001.After the animal adaptability raised for 1 week, be 10 of the senile rats that go down of learning and memory with Morris water maze laboratory screening cognitive disorder, 10 of the normal senile rats of learning and memory, 10 of young rats.
1.2 medicine and reagent
Positive control drug is selected donepezil hydrochloride for use, and (trade name: aricept), the 5mg/ sheet is pulverized during use, dissolves with distilled water.Following " Chinese medicine of the present invention " is meant the medicine among the embodiment 3.
2 experimental techniques
2.1 screening of senile dementia rat and experiment grouping
Organize rat with the youth and on average seek the platform time to add 2 times of standard deviations be lower limit, adding 1 times of standard deviation is the upper limit, and senile rat is divided into learning and memory go down group and learning and memory normal group.Morris water maze positioning experiment when training, water maze depth of water 50cm, water temperature (25 ± 1) ℃, animal go into the position, pond be respectively platform place quadrant relatively and adjacent quadrant, with rat in this quadrant edge central authorities head towards the pool wall entry.If rat stands on the platform behind the 3s not in landing, experiment is ended also to write down it and arrive at the used time of platform and the distance of swimming, and is allowed to condition at and stops 10s on the platform.180s does not find platform person causes platform with it, places 30s, guides its learning and memory.The continuous 4d of ability of learning and memory of test rat tests 1 every day.Formal test in the 5th day, video recording system writes down the active situation of rat automatically, and calculates average time and the average swimming distance that finds platform, determines the rat search strategy simultaneously, estimates the learning and memory situation of animal.
According to random digit (producing random digit) the senile dementia rat is divided into big group of model group, Chinese medicine of the present invention (13.68g crude drug/kg/d), Chinese medicine of the present invention group (6.84g crude drug/kg/d) and donepezil hydrochloride group (4.50mg/kg/d) at random according to the SPSS statistical software.Every group 10, with 10 of normal senile rats of monthly age as the normal control group.Normal group and model group are given the equal-volume distilled water and are irritated stomach, equal every day 1 time, continuous 8 weeks.
2.2 the detection of cognitive disorder rat index of correlation
2.2.1 pathological tissue preparation and form detect
After getting blood, animal broken end is got brain fast and is separated Hippocampus (carrying out on the ice cream), is that (PBS prepares, and PH=7.4) pours into fixing for 4 ℃ the fixative that contains paraformaldehyde 4% with pre-cooling, do the paraffin section hematoxylin-eosin staining, light microscopic is observed the structural change of rat hippocampus pathomorphism down.
2.2.2 the Hippocampus immunohistochemistry is measured
Operate according to SABC method test kit description.Get the brain tissue slice of 5 animals at random, routine is taken off cured, sealing endogenous peroxydase, the sealing of 10% normal goats serum.Drip one anti-(1: 100), the anti-endoplasmic reticulum A β conjugated protein polyclonal antibody of be correlated with is hatched 1h for 37 ℃, and PBS solution washes; Drip two antibiotin goat anti-mouse IgG, room temperature 20min, the flushing of PBS solution; Drip the SABC complex, room temperature 20min, the flushing of PBS solution; DAB-H
2O
2Colour developing, haematoxylin is slightly redyed; Ethanol dehydration, transparent, neutral gum mounting are chosen with batch stained and are carried out microscopic examination.3 different visuals field of every section picked at random, every group amounts to 15 visuals field, dyes the positive cell sign of sepia with endochylema, and with the positive cell number ecbatic, the result is expressed as the meansigma methods of visual field positive cell number.
2.2.3 lipid metabolism and blood vessel endothelium index of correlation detect
T-CHOL (total cholesterin, TC), triglyceride (triglyceride, TG), high density lipoprotein (high density lipoprotein, HDL), low density lipoprotein, LDL (lowdensith lipoprotein, LDL), TC adopts the CHOD-PAP enzymic colorimetric to measure, and TG adopts the GPO-PAP enzymic colorimetric to measure, and HDL-C and LDL-C adopt direct algoscopy to measure.
2.2.4 inflammatory factor and oxidative stress index of correlation detect
10% hippocampal tissue homogenate, 5 every group, ultrasonic disruption is made 10% homogenate under the ice bath, centrifugal 3000r/min, 4 ℃, 10min gets supernatant and detects.
2.2.5 apoptosis index determining
The apoptotic cell counting separates hippocampal tissue with the fresh cerebral tissue of drawing materials, and with the rinsing of PBS liquid, ultrasonic disruption is made 10% homogenate under the ice bath, after adding an amount of 0.5%TritonX-100 cracking tissue, collecting cell suspension, low-speed centrifugal (1000r/min, 4 ℃, 10min), abandon supernatant.Cell is washed 2 times with 0.1mmol/L phosphate buffer (pH7.4) and is suspended it, and adding final concentration is the RNAseA of 50mg/L, and suspension 200ul puts into 3ml75% ice alcoholic solution mixing; Centrifugal, abandon supernatant, 4mlPBS solution mixing is through nylon net filter; Put into 2ml75% ice alcoholic solution, seal, to be measured.
Adopt fluidic cell to detect cell cycle and apoptosis, the argon ion excitation wavelength is 488nm, measures each phase cell DNA content, apoptotic peak, and calculates the apoptotic cell percentage rate.Use EXPOTM32 and carry out the apoptosis analysis, use PHOENIX MutltiCycle 5.0 and carry out cell cycle analysis.
2.3 statistical procedures
The gained data are with mean ± standard deviation
Expression adopts the SPSSl3.0 of statistical software to carry out statistical analysis, and data are relatively used one factor analysis of variance between group, adopts LSD, Dunnett ' sC (during heterogeneity of variance) check, is that difference has the significance meaning with P＜0.05.
3 results
3.1 drug matching is to the influence of old cognitive disorder learning and memory in rats ability
Compare with old cognitive disorder group rat, donepezil hydrochloride group, big group of rat of Chinese medicine of the present invention have remarkable minimizing or raising (P＜0.05 seeking the platform path length, seek the platform time and seek platform time number average, P＜0.05), show the have clear improvement effect of old cognitive disorder learning and memory function of drug matching, the results are shown in Table 5.
Table 5. drug matching is to the influence of old cognitive disorder learning and memory in rats ability
Annotate: compare * P＜0.05 with old cognitive disorder group
3.2. drug matching is to the influence of aged cognitive disorder rat fat index
Compare with old cognitive disorder group, large and small group of TG level (P＜0.05 that can significantly reduce the cognitive disorder rat of donepezil hydrochloride and Chinese medicine of the present invention, P＜0.01), big group of Chinese medicine of the present invention also has remarkable reduction effect (P＜0.05) to the LDL level, shows that drug matching has regulating action to old cognitive disorder rat fat.The results are shown in Table 6.
Table 6. drug matching is to the influence of old cognitive disorder rat fat index
Annotate: compare * P＜0.05, * * P＜0.01 with old cognitive disorder group
3.3. drug matching is to the influence of the aged cognitive disorder rat inflammation factor and NF-κ B expression
Compare with old cognitive disorder model group, neat and big group of IL-6, TNF-alpha levels (P＜0.05 that can significantly reduce the cognitive disorder rat of Chinese medicine of the present invention of the unnecessary piperazine of hydrochloric acid, P＜0.01), there is inhibitory action (P＜0.05) in Chinese medicine of the present invention group to TNF-α, shows that drug matching has inhibitory action to the inflammatory factor level of old cognitive disorder rat.Immunohistochemistry result shows, large and small group of donepezil hydrochloride and Chinese medicine of the present invention can significantly reduced NF-κ B positive cell number (P＜0.01, P＜0.05), shows that drug matching can suppress the expression of senile rat Hippocampus NF-κ B, the results are shown in Table 7 and Fig. 3.
Table 7. drug matching is to the influence of the senile dementia rat hippocampus tissue inflammation factor and NF-κ B expression
Annotate: compare ▲ P＜0.05 with young control; Compare △ P＜0.05 with normal old group;
Compare * P＜0.05, * * P＜0.01 with old cognitive disorder group.
Fig. 3 expresses comparison diagram (immunohistochemical staining * 400) for drug matching to rat hippocampus NF-kB protein, wherein, Fig. 3 A is normal old group, Fig. 3 B is young group, Fig. 3 C is the old group of cognitive disorder, Fig. 3 D is the donepezil hydrochloride group, and Fig. 3 E is the heavy dose of group of Chinese medicine, and Fig. 3 F is the Chinese medicine small dose group.
3.4. drug matching is to the influence of old cognitive disorder β-AP of rat cerebral tissue and P content of material
After 8 weeks of administration, the big group of β of rat cerebral tissue-AP content of Chinese medicine of the present invention significantly reduces (P＜0.05), the P content of material of the neat group of big group of Chinese medicine of the present invention and the unnecessary piperazine of hydrochloric acid obviously raise and old cognitive disorder group relatively there were significant differences (P＜0.05).The results are shown in Table 8.
Table 8. drug matching is to the influence of cognitive disorder senile rat cerebral tissue β-AP and P content of material
Annotate: compare * P＜0.05 with old cognitive disorder group
3.5. drug matching is to the influence of MDA and SOD content in the old cognitive disorder rat blood serum
After 8 weeks of administration, Chinese medicine makes that SOD content significantly raises (P＜0.01, P＜0.05) in the senile rat serum of large and small dosage group, and the MDA content of each administration group does not have significant difference.The results are shown in Table 9.
Table 9 drug matching is to the influence of old cognitive disorder rat blood serum SOD and MDA content
Annotate: compare * P＜0.05 with old cognitive disorder group
3.6. drug matching is to the influence of old cognitive disorder rat hippocampus neuronal apoptosis
3.6.1 drug matching is to the variation of old cognitive disorder rat hippocampus apoptosis and cell cycle
Result of study shows, young group rat hippocampus neurocyte great majority are in the G0/G1 phase, the senile rat group shows as then that apoptotic peak increases, percentage of cell apoptosis obviously rises, especially the most obvious with old cognitive disorder rat, relatively there were significant differences (P＜0.05, P＜0.05) to organize rat with the youth.Large and small group of apoptosis that can obviously suppress and reverse the senile rat hippocampal cell of Chinese medicine of the present invention, relatively there were significant differences (P＜0.05) with old cognitive disorder group rat in the treatment back.The results are shown in Figure 4 and table 10.
Table 10. drug matching is to the influence of old cognitive disorder rat cells apoptosis and cell cycle
Annotate: compare * P＜0.05, * * P＜0.01 with old cognitive disorder group
Fig. 4 for drug matching to rat hippocampus apoptosis map analysis comparison diagram (fluidic cell method), wherein: Fig. 4 A be normal old group, and Fig. 4 B be that the youth organizes, Fig. 4 C is the old group of cognitive disorder, Fig. 4 D is the donepezil hydrochloride group, and Fig. 4 E is the heavy dose of group of Chinese medicine, and Fig. 4 F is the Chinese medicine small dose group.
3.6.2 drug matching is to the influence of old cognitive disorder rat hippocampus apoptosis regulation gene bcl-2 and bax
Immunohistochemical staining shows that senile rat apoptogene bcl-2 has certain reduction, but no difference of science of statistics still.Chinese medicine of the present invention can significantly increase old cognitive disorder rat bcl-2 for large and small group and express quantity (P＜0.05), the apoptogene bax of old cognitive disorder rat expresses quantity to be increased, there were significant differences (P＜0.05) to organize comparison with the youth, and Chinese medicine of the present invention can significantly suppress its expression (P＜0.05) for big group.The results are shown in Table 11.
Table 11. drug matching is to the influence of old cognitive disorder rat cells apoptosis gene bcl-2 and bax
Annotate: compare * P＜0.05 with old cognitive disorder group
4. conclusion
This experiment is based on the pathogenesis evolution process of the harmful network of the traditional Chinese medical science " void-stasis of blood-turbid-poison " of old cognitive disorder, from the stasis of blood resistance of suffering from a deficiency of the kidney, the turbid endogenous toxin of expectorant, thermal burn brain network causes the basic pathology link of AD to be started with, in conjunction with the pathogenesis of modern medicine to dementia understanding, deposit as amyloid beta, apoptosis and neuronic losing greatly, lipid metabolism, oxidative stress, level of inflammation increase and index that fibrinolytic system is hyperfunction changes, and in conjunction with animal hippocampal tissue pathological change, the variation of relevant binding protein expression of Hippocampus A β and apoptosis amount, the scientific meaning of old cognitive disorder is treated in explaination drug matching.
Experimental result shows: this prescription has obvious improvement effect to the space learning memory ability of old cognitive disorder rat, senile rat cerebral tissue β-AP level is had remarkable inhibitory action, and can suppress the expression of Hippocampus ERA β; Inflammatory factor expression to the senile rat hippocampal tissue has remarkable inhibitory action, suppresses the expression of cerebral tissue Hippocampus NF-KB; Increase the P content of material of rat cerebral tissue, improve the quantity that hippocampal tissue bcl-2 expresses, suppress the apoptosis rate in the cell cycle, alleviate the neuronal damage of hippocampus tissue; Blood lipids index to rat has regulating action, improves the hemorheological property of rat, has the effect of blood circulation promoting and blood stasis dispelling; This side also can significantly reduce rat brain IL-6 level and TNF-alpha content, the effect of inflammation-inhibiting factor level, the effect that improves the body antioxidation and remove the free radical ability.In sum, this Chinese medicine improves the pathological change of AD rat cerebral tissue by influencing pharmacological mechanism such as lipid metabolism, oxidative stress, level of inflammation and apoptosis, thereby alleviates the hippocampus neuronal damage, has the effect of control Alzheimer.
Claims (10)
1. Chinese medicine of preventing and treating Alzheimer, it is characterized in that: its raw material by following mass fraction is formed, Radix Polygoni Multiflori Preparata 12-16 part, Radix Ginseng 8-12 part, Rhizoma Acori Graminei 10-14 part, Rhizoma Coptidis 5-9 part and Rhizoma Chuanxiong 6-10 part.
2. prevent and treat the Chinese medicine of Alzheimer according to claim 1, it is characterized in that the mass fraction of described each raw material is: 12 parts of Radix Polygoni Multiflori Preparatas, 9 parts of Radix Ginsengs, 10 parts of Rhizoma Acori Graminei, 6 parts of 5 parts of Rhizoma Coptidis and Rhizoma Chuanxiongs.
As claim 1 or 2 arbitrary as described in the preparation method of Chinese medicine of control Alzheimer, it is characterized in that:
(1) get Rhizoma Acori Graminei and soak, adopt the vapor distillation reflux, extract,, collect upper strata grease, drying gets Rhizoma Acori Graminei fragrance volatile oil;
(2) medicinal residues and Radix Polygoni Multiflori Preparata behind step (1) the extraction volatile oil are mixed, decoct with water, extract, decocting liquid carries out precipitate with ethanol;
(3) get Radix Ginseng, Rhizoma Coptidis and Rhizoma Chuanxiong, mix the back and add ethanol extraction;
(4) feed liquid of combining step (2) and (3) gained, at 50-60 ℃ of concentrating under reduced pressure, centrifugalize merges centrate, adopts decoction and alcohol sedimentation technique to remove impurity, carries out ultrafiltration then, and ultrafiltrate is become concentrated extracting solution at 50-60 ℃ of concentrating under reduced pressure;
(5) step (4) gained concentrated extracting solution and adjuvant are mixed and made into serosity, and the spray-dried dry extract of making adds adjuvant and granulates, and add the Rhizoma Acori Graminei fragrance volatile ingredient of gained in the step (1).
4. as the preparation method of claim 3, it is characterized in that: add the water logging bubble 2h of 8 times of quality in the described step (1) in the Rhizoma Acori Graminei, adopt the vapor distillation reflux, extract,, the time is 6h.
5. as the preparation method of Chinese medicine of control Alzheimer as described in the claim 3, it is characterized in that: the decocting that adds 10 times of quality in the described step (2) earlier boils 90min, it is stand-by to pour out decocting liquid then, adds 7 times of quality decoctings again and boils 70min, and the decocting liquid that secondary is obtained merges.
6. as the preparation method of Chinese medicine of control Alzheimer as described in the claim 3, it is characterized in that: the isolating rotating speed of secondary centrifuging is respectively 7000rpm and 16000rpm in the described step (4).
7. as the preparation method of Chinese medicine of control Alzheimer as described in the claim 3, it is characterized in that: the method that adds Rhizoma Acori Graminei fragrance volatile ingredient in the described step (5) is one of following two kinds: 1. Rhizoma Acori Graminei fragrance volatile ingredient is dissolved in the ethanol, and atomized spray adds; 2. sneak into after making β-CD inclusion.
8. as the preparation method of Chinese medicine of control Alzheimer as described in the claim 3, it is characterized in that: the medicine that step (5) is made carries out drying, and baking temperature is controlled at 60 ℃ to 80 ℃ oven dry, and temperature rises gradually, and mass water content is controlled at 2%.
As claim 1 or 2 arbitrary as described in the preparation method of Chinese medicine of control Alzheimer, it is characterized in that: it comprises following process:
(1) Radix Polygoni Multiflori Preparata, Radix Ginseng, Rhizoma Acori Graminei, Rhizoma Coptidis and Rhizoma Chuanxiong are pulverized in proportion the back mix homogeneously, returned alcohol reflux, cross leaching filtrate;
(2) medicinal residues in the step (1) are added the water reflux, extract,, add dehydrated alcohol behind the merging water extract and leave standstill, filter;
(3) filtrate in precipitate in the step (2) and the step (1) merge is concentrated extractum, (4) make preparation with extractum with adjuvant.
10. preparation method as claimed in claim 9 is characterized in that: the backflow number of times is 3 times in the described step (1), and each return time is 90min.
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