CN108543037A - A kind of Chinese medicine composition and the preparation method and application thereof - Google Patents
A kind of Chinese medicine composition and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of Chinese medicine compositions and the preparation method and application thereof.The Chinese medicine composition is by the coptis, Cortex Phellodendri, cape jasmine, Radix Salviae Miltiorrhizae, turmeric and grass-leaved sweetflag composition, the Chinese medicine composition can significantly improve the study of 5 × FAD transgenic mices, memory dysfunction, reduce the expression of hippocampus A β 40/42, improve the presynaptic of 5 × FAD transgenic mice hippocampus, the expression of albumen afterwards, improve 5 × FAD hippocampus of mice excitatory synapse conductive obstructions, inhibit the proliferation of the apoptosis and microglia of 5 × FAD mouse hippocampal neurons simultaneously, in addition it can inhibit the expression of 5 × FAD mice serums and hippocampus inflammatory factor, for it reliable theoretical foundation is provided in terms of preparing treatment or auxiliary treatment Alzheimer disease drugs or preparing Alzheimer disease relevant healthcare product.
Description
Technical field
The invention belongs to field of medicaments more particularly to a kind of Chinese medicine composition and the preparation method and application thereof.
Background technology
Alzheimer disease (Alzheimer ' s disease, AD), i.e. senile dementia are a kind of progress sexual developments
Nervous system degenerative disease and a kind of main dementia disease.The prevalence of 2016 " global Alzheimer disease report "
Sick data shows, until 2016, there are about 47,000,000 people to suffer from AD in global range, and 74,700,000 will be increased to the year two thousand thirty, and arrives
The year two thousand fifty will be more than 100,000,000 3,150 ten thousand people[1].There are about 58% AD minimal invasive treatments in developing country among these, it is contemplated that the year two thousand fifty is sent out
National AD patient will be more than 68% in exhibition, and 2015 49% AD new cases appear in Asia[1].Currently, Chinese population
It is in quickly aging developing stage, AD incidence to increase year by year, AD patient numbers have ranked first in the world at present, and statistics is aobvious
Show, until 2010, the crowd of middle national trouble AD is 5,690,000, and illness rate is 6.25 ‰, and is just increased with annual 300000 speed[2]。
The clinical symptoms of AD are mainly shown as that gradual memory damage, cognition dysfunction, visual space impairment, linguistic function are gradual
It loses, execute dysfunction and personality and behavior change etc.[1,3-6].At the same time the treatment of AD and nursing expense are also year by year
It is incremented by, in the world, the total cost that nursing senile dementia in 2016 generates was expected to be 818,000,000,000 dollars, with phase in 2010
Than increasing 214,000,000,000 dollars[1].AD treatment after the onset somewhat expensives, not yet specific medicine and means, give at present
Family and society bring heavy spirit and financial burden.
The cause of disease of AD is unclear at present, may be with the unstability of gene and gene mutation, metabolism disorder, neuritis
The correlations such as disease, chronic viral infection, craniocerebral trauma or environmental factor.At present it is believed that pathological characters most crucial AD are brain
Inside there is the amyloid plaque (Amyloid being made of beta-amyloid protein (β-amyloid, A β) outside nerve cell
Plaques), also referred to as senile plaque (Senile Plaques, SP) and intracellular neurofibrillary tangles (Neurofibrillary
Tangles, NFT)[3-7], diseased region is mainly in hippocampus and cortical area.A β are amyloid beta-protein precursor (β-amyloid
Precursor protein, APP) discharged by enzyme degradation reaction, especially A β 42 are extensive and that stablizes is present in old age
In spot and neurofibrillary tangles.Most scholars think at present, and a large amount of depositions of A β are the immediate causes for causing AD to fall ill, and
Inflammatory reaction is the secondary response of the caused part of A β deposition, at the same be also central nervous system retrogression it is important because
Element, outstanding feature are the activation of astroglia and microglia[8].Wherein, inflammatory reaction is the important pathology machine of AD
It makes, there is apparent nospecific immunity inflammatory reactions in AD brain in patients, and are acted as in the morning of patch formation, mid-term
With[9], it is mainly shown as il-1 (Interleukin-1, IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha
Inflammatory factors such as (tumor necrosis factors, TNF-α) significantly raise at positions such as AD brain tissues hippocampus, cortexes.This
Outside, A β can directly activate microglia, cause inflammatory reaction[10], and the microglia activated can discharge peroxidating
Object directly damages neuron, while can also discharge cell factor and be damaged to neighbouring neuron or endothelial cell.This
A little factors include IL-1 β, TNF-α, NO and multiple protein lyase, so as to cause or aggravate neuron degeneration venereal disease occur
Become[11]。
For AD, there are many medicine, as acetylcholinesterase inhibitor (such as donepezil), eserine,
Galanthamine, huperzine are first-class, and such drug can enhance the cognitive ability of patient AD, but because it is with maincenter or peripheral-system
Side effect and make its application be restricted.
AD belongs to the illnesss scopes such as traditional Chinese medicine " not intelligent ", " forgetful ", " slow-witted disease ".Traditional Chinese medicine thinks that the basic pathogenesis of the disease is
" marrow subtracts brain and disappears, refreshing machine appraxia ", i.e., old internal organs void decline, and deficiency of kidney-essence, brains, which lose, supports, and leads to refreshing machine appraxia, sends out as dementia.King
Scorching academician thinks forever, and brain is " mansion of clear spirit ", most avoids the turbid poison of oxious gas, when internal organs void declines or exopathogen is invaded, human-body viscera function
Imbalance, qi-blood-body fluid operation is not normal, and turbid, hemostasis of internal phlegm etc. cannot be discharged in time, hot and suffocating corruption, changes heat into poison, raw in turbid poison.
It is interior contain turbid poison once being formed after, maximum feature is to ruin body, consumption is viscerotrauma channels and collaterals.Internal organs void declines, then empty air-flow is stagnant, water Tianjin
Defeated cloth and QI-blood circulation are not normal, and raw phlegm gives birth to the stasis of blood, and the mutual glue of phlegm-blood stasis is solid, and phlegm resistance blood is difficult to walk, blood stasis phlegm difficulty, and phlegm-blood stasis and hand over resistance detoxification is
Evil, ruin body, brain key caused to be jammed, refreshing machine appraxia and send out as dementia.Internal organs void declines, and deficiency of kidney-essence, marrow subtracts brain and disappears, and refreshing machine loses
With the basic pathology performance for being AD, but it is raw in turbid poison, and the stasis of blood is given birth in resolving sputum, and resistance numbness brain key is the main pathogenesis of AD.This is modern Chinese medicine
Learn the basic concept of " poison damage brain network " theory, heat-clearing and detoxifying herb be used to prevent AD also and become one it is significant, new important
Approach[12], and traditional Chinese medicine is resourceful, and the drug that treatment AD is found in traditional Chinese medicine has larger society and economic effect
Benefit.
Currently, research and clinic show：Huanglian jiedu decoction belongs to treatment disease the old age of hyperactivity of heart-liver fire and extreme noxious heat
Dementia has remarkable result[13-15].Modern pharmacology research shows that huanglian jiedu decoction has anti-inflammatory, decompression, lipid-loweringing, improvement
The effects that gastrointestinal function, anti-oxidant, antiatherosclerosis and promotion study, memory[16-20].Studies have shown that coptis detoxifcation
Soup can raise the activity of superoxide dismutase (superoxide dismutase, SOD), reduce what lipid peroxidation generated
Excessive malonaldehyde (malonaldehyde, MDA), to play lipoid peroxidization resistant[21]；Huanglian jiedu decoction can also press down
The activity of acetylcholinesterase (acetylcholinesterase, AchE) processed improves acetylcholine transferase (choline
Acetyltransferase, ChAT) activity, alleviate acetylcholine hydrolyzation speed, improve AD models study, memory work(
Energy[22,23].In terms of neu- roimmunomodulation, huanglian jiedu decoction can be by reducing inflammatory factor IL-1 β, IL-6 etc. in brain tissue
Expression improves and microenvironment is immunized, and then significantly improves A β intracerebroventriculars and cause AD rat models and APP/PS1 double transgenics
The memory disorders and direction in space of AD mouse models distinguish obstacle, mitigate hippocampus, the deposition of cortex A β plaque block and senile plaque, god
Quantity through first fibre matting plays neuroprotection[24-26].But the party is only applicable to extreme noxious heat Alzheimer
Disease, for turbid malicious blood stasis type, the party still lacks product that are promoting blood circulation and removing blood stasis, eliminating phlegm for resuscitation.
The disease of tcm of AD is broadly divided into marrow sea deficiency, speen-kidney dificiency, the difference disease such as the turbid illiteracy key of phlegm and blood-stasis internal-depression at present
Type.Wherein marrow sea deficiency disease, basic pathogenesis are damage of kidney-essence, and brain is not filled, and are mainly shown as hypophrenia, memory and calculating
Power obviously declines, dizziness and tinnitus, and slacking off, it is sleeping to think, and the withered hair of tooth is burnt, and soreness of waist bone is soft, and walking is difficult, and the thin color of tongue is light, and tongue is thin white, deeptensepulse
It is thin and delicate, it controls and drinks kidney tonifying marrow facilitating with seven good fortune, replenishing essence is reposed；Speen-kidney dificiency disease, basic pathogenesis are the dysfunction of the spleen in transport, deficiency of kidney-essence, mainly
It shows as having a dull expression on one's face, uncommunicative, hypomnesia says that muscular atrophy, deficiency of food is indigestion and loss of appetite, involuntary drooling with shortness of breath lazyness, waist and knee acid
Soft or four limbs are not warm, abdominal pain alleviated by pressure, diarrhea, pale tongue, tongue body fat big, and tongue is white or tongue is red, and tongue is few or without tongue, deep thready pulse
It is weak, it controls with Huanshao pill kidney and spleen invigorating, Mi Gu granule；The turbid illiteracy key disease of phlegm, basic pathogenesis is dysfunction of the spleen, and raw phlegm life is wet, and phlegm wet is covered
Clear key is covered, is mainly shown as dull expression, intelelectual deterioration, do not feel like eating, gastral cavity abdomen, distending pain, feeling of fullness is uncomfortable, mouth polysialia foam, tongue nature
Light, tongue is greasy in vain, slippery, controls turbid with Ditan Tang invigorating the spleenization, eliminates phlegm for resuscitation；Blood-stasis internal-depression disease, basic pathogenesis are that blood stasis is not all right, are blinded
Clear key, main cash is that expression is blunt, and aphasia is forgetful, and easily terrified, scaly dry skin, a symptom of blood stasis, dry is not intended to drink, binocular clouding, tongue
Matter is dark or has petechia ecchymosis, thready and hesitant pulse to control, inducing resuscitation promoting blood circulation and removing blood stasis with TONGQIAOHUOXUE Decoction.
However at present clinically with raw in turbid poison, the stasis of blood is given birth in resolving sputum, and then blinds the turbid malicious blood stasis type that brain key is basic pathogenesis
Patients with Alzheimer disease is in the majority, but the disease has no related traditional Chinese medicine research.
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Invention content
The purpose of the present invention is to provide a kind of Chinese medicine compositions and the preparation method and application thereof.
It inventor provides using the coptis, Cortex Phellodendri, cape jasmine, Radix Salviae Miltiorrhizae, turmeric and grass-leaved sweetflag as the Chinese medicine composition of active constituent.
Further, the mass fraction of each substance is in above-mentioned Chinese medicine composition：10~20 parts of the coptis, 5~10 parts of Cortex Phellodendri,
10~20 parts of cape jasmine, 10~18 parts of Radix Salviae Miltiorrhizae, 5~15 parts of turmeric, 5~15 parts of grass-leaved sweetflag.
Further, mass fraction is：12~18 parts of the coptis, 6~10 parts of Cortex Phellodendri, 12~18 parts of cape jasmine, Radix Salviae Miltiorrhizae 13~
17 parts, 8~12 parts of turmeric, 8~12 parts of grass-leaved sweetflag.
Further：The mass ratio of the coptis, Cortex Phellodendri and cape jasmine is in above-mentioned Chinese medicine composition：(2~6)：(1~3)：(2~
6)。
Further：The mass ratio of the coptis, Cortex Phellodendri and cape jasmine is in above-mentioned Chinese medicine composition：4：2：4.
Further：The mass fraction of above-mentioned Chinese medicine composition is：16 parts of the coptis, 8 parts of Cortex Phellodendri, 16 parts of cape jasmine, Radix Salviae Miltiorrhizae
15 parts, 10 parts of turmeric, 10 parts of grass-leaved sweetflag.
The present invention also provides a kind of Chinese medicine preparation, said preparation is pulvis, tablet, the needle being prepared by above-mentioned composition
Any one dosage form in agent, capsule, decoction, granule, pill, paste, targeting preparation.
The preparation method that inventor additionally provides above-mentioned decoction is：By the coptis, Cortex Phellodendri, cape jasmine, Radix Salviae Miltiorrhizae, turmeric and grass-leaved sweetflag
Chinese medicine composition adds water to cook, and obtains decoction.
Further, above-mentioned Chinese medicine composition is decocted twice.
Further, the water that 5~20 times of volumes are added for the first time is decocted.
Further, the water that 8~15 times of volumes are added for the first time is decocted.
Further, the water that 10 times of volumes are added for the first time is decocted.
Further, further include that immersion treatment is carried out to Chinese medicine composition before decoction.
Further, soaking time is 0.1~5h.
Further, soaking time is 0.5~3h.
Further, second of the water that 3~15 times of volumes are added is decocted.
Further, second of the water that 5~12 times of volumes are added is decocted.
Further, second of the water that 8 times of volumes are added is decocted
Further, 0.1~2h is stood alone as with secondary decocting time for the first time.
Further, 0.5~1.5h is stood alone as with secondary decocting time for the first time.
Further, 1h is stood alone as with secondary decocting time for the first time.
Further：1mL decoctions are obtained in every 2~4g compositions.
Further：1mL decoctions are obtained in per 2.92g compositions.
The decoction of above-mentioned preparation is applied to 5 × FAD transgenic mices by inventor, and has carried out correlative study, research knot
Fruit shows：The decoction prepared using the Chinese medicine composition of the application has the function of stagnation resolvation of detoxifying, therefore the present invention is referred to as to solve
Malicious Huayu Tang can significantly improve study, the memory dysfunction of 5 × FAD transgenic mices, reduce the deposition of hippocampus A β,
Also, Effect of Jiedu Huayu Decoction can significantly improve the glutamate receptor and the forward and backward albumen of cynapse of 5 × FAD transgenic mice hippocampus
Deng expression, improve 5 × FAD hippocampus of mice excitatory synapses transfer function.Meanwhile Effect of Jiedu Huayu Decoction inhibits hippocampus
The proliferation of microglia, the expression of serum and hippocampus inflammatory factor, and be further found that：The solution of the application poisons
Stasis of blood soup also has significant neuroprotection and immunomodulatory effect.
Above-mentioned experimental data shows：The Chinese medicine composition of the present invention is preparing treatment or auxiliary treatment Alzheimer disease medicine
Object is prepared in Alzheimer disease relevant healthcare product with huge potentiality.
Further, the Alzheimer disease of the preferably turbid malicious blood stasis type of the Alzheimer disease.
The beneficial effects of the invention are as follows：
1, tests prove that：The Chinese medicine composition can significantly improve the study of 5 × FAD transgenic mices, memory function
Obstacle reduces the expression of hippocampus A β 40/42, improves the expression of the forward and backward albumen of cynapse of 5 × FAD transgenic mice hippocampus,
Improve 5 × FAD hippocampus of mice excitatory synapse conductive obstructions, while inhibiting the apoptosis of 5 × FAD mouse hippocampal neurons and small glue
In addition the proliferation of cell plastid can raise expression of 5 × FAD hippocampus of mice TREM2 in mRNA level in-site, be its prepare treatment or
Auxiliary treatment Alzheimer disease drugs provide reliable theoretical foundation in terms of preparing Alzheimer disease relevant healthcare product.
2, the Chinese medicine composition have significant neuroprotection and immunological regulation benefit, the composition by pharmacology it is specific in
Medicine forms, and these Chinese medicines are applied in practice, securely and reliably, without notable side effect.
Description of the drawings
Fig. 1：(A) it is shuttle percentage of the different groups of other mouse in the labyrinths T；(B) be different groups of other mouse in the labyrinths Y
Shuttle percentage；(C) time of 5 days arrival platforms is trained for different groups of other mouse；(D) it is different groups of other mouse through instruction
The time of platform quadrant is reached after white silk；(E) be different groups of other mouse in the platform quadrant residence time；(F) it is different groups other
Mouse spanning platform number；(G) it is new object identification Experiment Training and test phase ideograph；(H) it is the training stage, each group is small
Mouse explores percentage of time to A objects；(I) it is the training stage, each group mouse is to B objects exploration percentage of time；(J) it is test
Stage, exploration percentage of time of each group mouse to new object；
Fig. 2：(A) it is the LTP field potential slope percentages of Con, 5 × FAD and JDHYT-L groups；(B) be Con, 5 × FAD and
The LTP field potential slope percentages of JDHYT-H groups；(C) it is the field of different groups of other mouse LTP different times after high frequency stimulation
Current potential intensity；
Fig. 3：(A) it is different groups of other mouse glutamate receptor NR2A, A β 40/42, presynaptic Protein S ynapsin and prominent
Protein expression Western blot figures of the albumen PSD95 in hippocampus after touch；(B) it is different groups of other mouse glutamate receptors
The relative optical density number of 40/42 expressing quantities of NR2A, A β；(C) be different groups of other mouse presynaptic Protein S ynapsin and
The relative optical density number of postsynaptic albumen PSD95 expressing quantity；
Fig. 4：(A) it is that the mEPSC that ampa receptor mediates represents current curve；(B) the mEPSC frequencies mediated for ampa receptor
Cumulative frequency distribution curve figure (left side) and frequency quantitative analysis figure (right side)；(C) it is the receptor-mediated mEPSC amplitudes of APMA
The quantitative analysis figure (right side) of cumulative frequency distribution curve figure (left side) and average amplitude；
Fig. 5：(A) it is the aspect graph of the hippocampal neuron of different groups of other mouse Nissl's stainings observations；(B) it is different groups
The microglia of the Iba1 positives of mouse quantitatively scheme (right side) in the expression figure (left side) and Iba1 positive cells of hippocampus；
Fig. 6：(A) expression for being IL-6 in different groups of other mice serums；(B) it is IL-1 in different groups of other mice serums
The expression of β；(C) it is the expression of TNF-α in different groups of other mice serums；(D) it is different groups of other hippocampus of mice TREM2mRNA
Expression；(E) expression for being different groups of other hippocampus of mice IL-6mRNA；(F) it is different groups of other hippocampus of mice IL-1 β mRNA
Expression；(G) expression for being different groups of other hippocampus of mice TNF-α mRNA.
Specific implementation mode
Embodiment is enumerated further below so that the present invention will be described in detail.It will similarly be understood that following embodiment is served only for this
Invention is further described, and should not be understood as limiting the scope of the invention, those skilled in the art are according to the present invention
Some nonessential modifications and adaptations that the principle of elaboration is made all belong to the scope of protection of the present invention.Following specific works of example
Skill parameter etc. is also only an example in OK range, i.e. those skilled in the art can do suitable model by the explanation of this paper
Interior selection is enclosed, and does not really want to be defined in hereafter exemplary specific data.
Embodiment 1
A kind of Chinese medicine composition, in parts by mass, by the Chinese medicinal composition of following mass fraction：
16 parts of the coptis, 8 parts of Cortex Phellodendri, 16 parts of cape jasmine, 15 parts of Radix Salviae Miltiorrhizae, 10 parts of turmeric, 10 parts of grass-leaved sweetflag.
A kind of preparation method of the decoction comprising above-mentioned Chinese medicine composition：
1) Chinese medicine composition for weighing 7 parts of above-mentioned numbers, is shredded with scissors；
2) distilled water that 10 times of volumes are added impregnates 2h, and 1h is boiled with medicinal cupping, the timing since slightly boiling, 8 layers of filtered through gauze medicine
Liquid；
3) second time single steaming water that 8 times of volumes are added, 1h, 8 layers of filtered through gauze are boiled with method；
4) dregs of a decoction are poured out, crowded, merging filtrate is held with gauze, then medicinal cupping and gauze are cleaned respectively three times with distilled water；
5) merging filtrate and washing lotion again, in packing to 50mL centrifuge tubes, 4000rpm centrifuges 5min；
6) supernatant is collected to 2L round-bottomed flasks, 55 DEG C of spin concentrations to about 180mL (i.e. 2.92g crude drugs/mL)；
7) in packing to 5mL EP pipes, often pipe 3.5mL, marks, and -80 DEG C of preservations take 1 pipe to thaw daily.
Above-mentioned decoction is known as in this application：Effect of Jiedu Huayu Decoction.
Embodiment 2
A kind of Chinese medicine composition, in parts by mass, by the Chinese medicinal composition of following mass fraction：
15 parts of the coptis, 10 parts of Cortex Phellodendri, 15 parts of cape jasmine, 15 parts of Radix Salviae Miltiorrhizae, 10 parts of turmeric, 10 parts of grass-leaved sweetflag.
The formula of the preparation method of decoction such as embodiment, Chinese medicine presses embodiment 2.
1, model selects：
AD animal patterns type is more at present, including A beta oligomers intracerebral injections model, APP/PS1 bi-transgenic mice moulds
Type etc., the application select 5 × FAD transgenic models mouse for studying, and 5 × FAD mouse carry 5 familial gene mutations
(transgenic mice with five familial Alzheimer's disease, 5 × FAD), wherein with Gene A PP
It is relevant to sport K670N/M671L (Swedish), I716V (Florida) and V717I (London), it is related to gene PS 1
Sport M146L and L286V, transgene promoter Thy1, Homologous wild-type C57/B6XSJL.5 × FAD mouse are one
The relatively more generally acknowledged AD model mices of kind, can the various AD Pathologies of preferable simulation：At 1.5 months, A β 42 formed sediment in visible cell
Powder sample albumen is assembled, and starts within 2 months amyloid deposition occur, memory impairment occurs within about 4 months, and with synaptic structure, work(
The various AD pathological characters such as energy damage, neuroinflamation, cone neurone loss, and in various AD model mices, 5 × FAD is small
The Pathology of mouse occurs more early.45 × FAD of monthly age mouse are selected to test in the application.
2, dosage regimen：
The dosage of reference pair people, 75g crude drugs/calculate mouse equivalent dose, warp for 70kg/ days《Herbal pharmacology experiment side
The science of law》Standard determines conversion coefficient 9, and it is 9.64g crude drugs/kg/ days to be multiplied by after the coefficient 9 and obtain mouse equivalent dose.
The decoction that the Chinese medicine preparation of the application selection example 1 is prepared is tested.
According to the pathological characteristics of 5 × FAD transgenosis AD mouse, the dosage regimen that the application uses for：
(1) mouse continuous gavage administration 1 month since 4 monthly ages, 1 times/day, according to people and mouse drug dose substitution ratio
It is 9.64g/kg (crude drug amount/mouse weight) that rate, which show that mouse is administered daily dosage, and high dose group is 2 times of adult's equivalent doses
Effect of Jiedu Huayu Decoction is (i.e.：19.28g/kg is denoted as JDHYT-H), low dose group is the Effect of Jiedu Huayu Decoction of 1/2 times of adult's equivalent dose
(i.e.：4.82g/kg is denoted as JDHYT-L), by administered volume 0.1mL/10g standard gavages；
(2) 5 × FAD transgenic mices of the same age as a control group, are steamed so that 0.1mL/10g mouse weight gavages solvent is double
Water, gavage Effect of Jiedu Huayu Decoction, is not denoted as：5×FAD；
(3) wild type C57BL/6J mouse of the same age are molten with 0.1mL/10g mouse weight gavages as normal reference group mouse
Agent distilled water, gavage Effect of Jiedu Huayu Decoction, is not denoted as：Con；
Point multiple batches of carry out experimental study, advanced row praxiology research after mouse drug therapy, is then given birth to respectively again
Change and molecular biology, morphology and electrophysiologic studies.
3, experimental method：
(1) praxiology research
A：Morris water maze laboratories：Morris water mazes by a big round pool, underwater platform, Image Acquisition and
Processing system forms.During the experiment, pond is averagely divided into four quadrants (quadrant E, S, W, N), is fixed in each quadrant
One point is place of entry, and mouse is put into from place of entry in pond, and camera system records the movement locus of mouse and finds underwater
The time of platform.If mouse cannot still find platform in 60s, then experimenter directs it to platform and stops 10s.It is every small
Mouse enters water from four place of entry respectively daily, and how study smoothly finds platform, continuous training 5 days.Training removed flat to the 5th day
Platform is put into mouse in the offside of platform towards pool wall, and camera system records mouse in 60s in the run duration of all quadrants and rail
Mark includes from water is entered to reaching incubation period of platform, swimming distance, swimming rate, in the platform quadrant residence time and pass through time
Number etc..
B：T maze experiments：The labyrinths T are made of 3 identical arms, and 3 arms are T-shaped.Mouse is placed in the labyrinths T centre, camera shooting
System records the number and residence time that mouse in 5min enters each arm.Shuttle hundred of the every mouse of statistical analysis in 5min
Divide rate.
C：Y maze experiments：The labyrinths Y are made of 3 identical arms, 120 degree of each arm angle.Mouse is placed in the labyrinths Y center
Centre, camera system records mouse in 5min and enters the number and residence time of each arm, and counts the shuttle percentage of every mouse
Rate.
D：New object identification experiment：Experiment first day, mouse is familiar with ambient enviroment in spacious field case；Second day, by mouse
It is placed in spacious field case freely to explore and adapts to two same objects, camera system records in 5min to two respective identifications of object
Time；Third day changes one of object into another face after mouse freely explores two same objects 1 hour
Color and the different new object of shape, camera system record in the 5min since putting spacious field case into animal to new, old two objects
The recognition time of body.With formula：Identify that time/(time for identifying time+identification past heritage body of new object) of new object calculates
Preference (Exploratory preference) is explored, as a result percentage (%) is used to indicate.
(2) Western blot are tested
It is slow that loading is added with BCA kit measurement albumen concentration in the protein sample for extracting hippocampal tissue by a certain percentage
Fliud flushing, 100 DEG C of boiling water bath 5min；By protein delivery to PVDF membrane (polyvinylidene after electrophoresis
Fluoride, abbreviation pvdf membrane), at room temperature, pvdf membrane TBST buffer solutions rinse 5min, and 5%BSA confining liquids close 2h,
TBST buffer solutions rinse 3 times, each 5min；4 DEG C of overnight incubations of primary antibody, TBST buffer solutions rinse pvdf membrane 3 times, each 5min；
Pvdf membrane and secondary antibody are incubated 1h, the rinsing of TBST buffer solutions at room temperature again.By chemical illuminating reagent A liquid and B liquid mixed in equal amounts, incubate
Pvdf membrane 1min is educated, is exposed in exposure instrument, band intensity, application are analyzed using Image J image analysis softwares
SPSS16.0 carries out the statistical analysis processing of data, p<0.05 is considered as and has significant difference.
(3) qRT-PCR is tested
The total serum IgE of hippocampal tissue is extracted with Trizol reagents, and respective volume 5 × gDNAEraser Buffer, gDNA is added
Eraser、RNase Free dH2For O through 42 DEG C, 2min removes genomic DNA, it is added 5 in removing genome reaction solution ×
PrimeScript Buffer 2、PrimeScript RT Enzyme Mix 1、RT Primer Mix、RNase Free
dH2For O through 37 DEG C of 15min, 85 DEG C of 5sec complete reverse transcription reactions, and SYBR Premix Ex Taq and upper are added in DNA profiling
Downstream primer carries out quantitative fluorescent PCR, and PCR reaction conditions are 95 DEG C, 5s；55 DEG C, 30s；72 DEG C, 30s；40 cycles.By mesh
Gene and internal reference compare to obtain opposite CT values, carry out data statistic analysis, p using SPSS16.0<0.05 is to have statistics poor
It is different.
(4) immunohistochemical staining
(I) it is perfused and fixed：Mouse isoflurane anesthesia after, exposure heart and through left ventricle be inserted through pricker to rise actively
Arteries and veins is irrigated using pre- cold saline and 4% paraformaldehyde.There is limb muscle twitch in animal, and limbs, which are hardened, to be prompted to fill
Form work(.It takes mouse brain to be placed in 4% paraformaldehyde, 4 DEG C of fixation about 6h, moves into 20%, 30% sucrose solution successively in 4 DEG C of ice
Serial dehydration in case, OCT embedding mediums investing tissue；
(II) it is sliced：Permanent frozen sheet cutter continuous coronal slice, is affixed on anticreep on piece, is toasted in 65 DEG C of insulating boxs
It is spare to deposit in -80 DEG C of refrigerators by 3.5h；
(III) antigen retrieval：Slice is placed in 0.01M citrate buffer staining jars, 98 DEG C of 10~15min of water-bath, from
It is so cooled to room temperature, PBS is rinsed 3 times, each 5min；
(IV) rupture of membranes：0.3%Triton ruptures of membranes 30min, PBS flushing 3 times, each 5min；
(V) it closes：5%BSA closes 10min；
(VI) it is incubated primary antibody：Primary antibody is added dropwise, is stayed overnight in 4 DEG C of wet box, rear room temperature rewarming 45min, PBS washings are taken out from refrigerator
3 times, each 5min；
(VII) it is incubated secondary antibody：37 DEG C are incubated 60min, and PBS is washed 3 times, each 5min；
(VIII) it develops the color：It is added dropwise under slice, room temperature, mirror and detects the reaction time, tap water flowing water rinses, 10min；
(Ⅸ) it redyes：Haematoxylin redyes 2min, tap water foam washing, 10min, hydrochloride alcohol color separation 1 time, the punching of tap water flowing water
It washes, 10min；
(Ⅹ) gradient alcohol dehydration：70% ethyl alcohol 3min, 80% ethyl alcohol 3min, 90% ethyl alcohol 3min, 95% ethyl alcohol I
3min, 95% ethyl alcohol II 3min, 100% ethyl alcohol I 3min, 100% ethyl alcohol II 5min, dimethylbenzene I 5min, dimethylbenzene II
5min；
(Ⅺ) gummy mounting, microscopy.
(5) Enzyme-linked immunosorbent assay (enzyme-linked immunosorbnent assay, ELISA)
Take serum or prepare hippocampal homogenates liquid, sample to be tested is added in the orifice plate being coated with, then with biology
Antibody incubation 30min~1h of element label after washing, is added the labeled horseradish peroxidase of Avidin, then wash, removes
Unbonded enzyme conjugates, is eventually adding substrate and enzyme conjugates effect generates color, the concentration in the depth and sample of color
In proportionate relationship, the detection of absorbance value is carried out using microplate reader.
(6) electro physiology patch clamp experiments
Quickly broken end takes brain after mouse anesthesia, rapidly sticks at brain tissue on slicer objective table, and merging is equipped with 0~4 DEG C
Ice water artificial cerebrospinal fluid (95%O2/ 5%CO2Saturation) slice slot in, the sea of 400 μ m thicks is cut out using oscillatory type slicer
Horse brain piece；
Brain piece is gone into 32 DEG C of incubation slots and is incubated 30min, rear room temperature of placing continues to be incubated, and is 95%O in incubation slot2/ 5%
CO2The artificial cerebrospinal fluid of saturation；
Using full cell currents tongs technology, observes different group mouse hippocampal neuron action potentials and provide frequency and threshold
Value, situation is sexually revised to understand mouse hippocampal neuron excitement；
Situation is transmitted in whole-cell voltage-clamp mode record difference group hippocampus of mice excitability and inhibitory synapse, including
Hippocampal neuron is recorded by AMPA miniature excited postsynaptic currents (miniature excitatory post-synaptic
Currents, mEPSC), understand the presynaptic and situation is transmitted in postsynaptic excitation cynapse；Hippocampal tissue slice is extracellularly remembered respectively
Record field potential (field-excitatory post-synaptic potential, fEPSP), input-output (input-
Output) curve understands the synaptic plasticities feelings such as the LTP of Hippocampus CA 3 Region Schaffer fibers-CA1 pyramidal cell layer accesses
Condition, the neuronal excitability and cynapse transfer function of comprehensive analysis difference group mouse.
(7) statistical analysis
T inspections or one-way analysis of variance (One Way are carried out to experimental data using SPSS16.0 statistical softwares
ANOVA), One Way ANOVA carry out group difference analysis using post-hoc Dunnett ' s.All measurement datas are with equal
Number ± standard error (x ± S.E.) indicates, with p<0.05 is significant difference,*p<0.05,**p<0.01,*Indicate each group and normal
The difference of reference group；#p<0.05,##p<0.01,#Indicate the difference of Effect of Jiedu Huayu Decoction in Treating group and 5 × FAD transgenic mice groups.
4, interpretation of result：
(1) improve study, the memory dysfunction of 5 × FAD mouse
From Fig. 1 (A) and Fig. 1 (B)：In the labyrinths T and the labyrinths Y, the mouse of JDHYT-H groups and JDHYT-L groups is each
Shuttle percentage between arm is obviously higher than 5 × FAD groups；
From Fig. 1 (C)~(F)：In Morris water mazes, with the increase of training number of days, each group mouse reaches flat
The time of platform is gradually reduced, but relative to 5 × FAD mouse, and during training in 5 days, JDHYT-H groups and JDHYT-L groups reach
The time of platform is obviously partially short, and, JDHYT-H groups are suitable with normal reference group (Fig. 1 (C))；At the 6th day, platform is removed, is recorded
Different group mouse reach the time of platform, as a result show：JDHYT-H groups and JDHYT-L groups reduce the arrival of 5 × FAD mouse
The time of platform, and the time of JDHYT-H groups also be shorter than normal reference group (Fig. 1 (D)), meanwhile, increase 5 × FAD mouse and exist
The residence time of target quadrant and the number (Fig. 1 (E)~(F)) for passing through target quadrant；
From Fig. 1 (G)~(J)：JDHYT-H groups and JDHYT-L groups can be obviously improved 5 × FAD mouse for new object
The identification function of body；
Low, high dose Effect of Jiedu Huayu Decoction, which is explained above, can be obviously improved the study of 5 × FAD mouse, memory function.
From Fig. 2 (A)~(C)：Low, high dose Effect of Jiedu Huayu Decoction improves the areas 5 × FAD hippocampus of mice CA3
The long term potentiation (LTP) of Schaffer fiber-CA1 pyramidal cell layer accesses, LTP are to be happened at two neuron signals
A kind of lasting enhancing phenomenon in transmission, two neurons of the stimulation that can be synchronized, since memory is considered strong by cynapse
Come what is encoded, LTP is generally considered as one of the main molecules mechanism for constituting learning and Memory basis for the change of degree, thus, from electricity
Low, high dose Effect of Jiedu Huayu Decoction is further demonstrated in physiologic result can be obviously improved the study of 5 × FAD mouse, memory work(
It can obstacle.
(2) improve 5 × FAD hippocampus of mice Synaptic dysfunctions
By Western blot and electrophysiology experimental method, 5 × FAD of low, high dose Effect of Jiedu Huayu Decoction pair is analyzed
The expression of albumen, glutamate receptor and A β 40/42 after the hippocampus of mice presynaptic, and its influence to excitatory synapse transmission.
Give the Effect of Jiedu Huayu Decoction of 5 × FAD mouse various doses (i.e.：JDHYT-H groups and JDHYT-L groups) it treats 1 month
Afterwards, materials hippocampal tissue extracts total protein, with Western blot detections glutamate receptor, A β 40/42, egg after the presynaptic
Equal expression in vain, is as a result shown in Fig. 3：
From Fig. 3 (A)~(C)：Compared to 5 × FAD groups, JDHYT-H groups and JDHYT-L groups significantly improve glutamic acid
The expression of receptor NR2A, and it is far above normal reference group, this illustrates that Effect of Jiedu Huayu Decoction can raise the expression of nmda receptor, improves
Excitatory synapse transmits；Meanwhile Effect of Jiedu Huayu Decoction has been significantly reduced the expression of hippocampus A β 40/42, prompts Effect of Jiedu Huayu Decoction can
Pathological hallmark object-A β 40/42 to significantly reduce AD improve the expression of the forward and backward albumen of cynapse in the deposition of hippocampus,
And the expression of 5 × FAD mouse presynaptic Synapsin and postsynaptic PSD-95.
By Whole-cell recording mode, recorded under gap-free modes the cone neurone of Hippocampal CA 1 by
The miniature excited postsynaptic current (mEPSC) that ampa receptor mediates, cell command potential is -65mV, when record, in perfusate
20 μM of Bicuculline (GABA receptor blocking pharmacons) and 1 μM of TTX (tetraodotoxin, sodium channel blockers) is added, as a result sees figure
4：
From Fig. 4 (A)：JDHYT-H groups and JDHYT-L groups can significantly improve the mEPSC frequencies of ampa receptor mediation
And amplitude；
From Fig. 4 (B) and Fig. 4 (C)：By quantifying to Fig. 4 (A) figure, it is seen that the mouse of 5 × FAD is more normally joined
The mEPSC frequencies mediated according to the ampa receptor of group are substantially reduced with amplitude, and JDHYT-H groups and JDHYT-L groups relative to 5 ×
FAD mouse are but increased significantly, and after the treatment of Effect of Jiedu Huayu Decoction, the frequency and amplitude of the mEPSC of ampa receptor mediation is equal
It can be significantly raised；
Excitatory postsynaptic potential (EPSP) (EPSC) refers to the activity by excitatory synapse, generated in postsynaptic neuron
The film potential variation for depolarizing property, can reflect the influence of presynaptic tramsmitter release and mediator to postsynaptic receptor, and then anti-
Reflect excitatory synapse transmit work(, through above-mentioned electro physiology the result shows that：The hippocampus of 5 × FAD mouse is accompanied by glutamate receptor APMA
The downward of receptor-mediated excitatory synapse transfer function, and to improve 5 × FAD mouse APMA receptor-mediated for Effect of Jiedu Huayu Decoction
Excitatory synapse conductive obstruction, it is consistent with above-mentioned molecular biology experiment result, thus, from molecular biology experiment and electro physiology
Known to the consistency result of experiment：Effect of Jiedu Huayu Decoction can mitigate the Synaptic dysfunction of 5 × FAD hippocampus of mice.
(3) improve the Neuroinflammation in 5 × FAD mouse brains
Give the Effect of Jiedu Huayu Decoction of 5 × FAD mouse various doses (i.e.：JDHYT-H groups and JDHYT-L groups) it treats 1 month
Afterwards, it draws materials.The form of Nissl dyeing detection hippocampal neurons, microscope acquire picture, as a result see Fig. 5 (A)；
Give the Effect of Jiedu Huayu Decoction of 5 × FAD mouse various doses (i.e.：JDHYT-H groups and JDHYT-L groups) it treats 1 month
Afterwards, it draws materials, Iba1 marks microglia, immunohistochemical experiment to detect the expression of hippocampus microglia, as a result see Fig. 5 (B)；
Give the Effect of Jiedu Huayu Decoction of 5 × FAD mouse various doses (i.e.：JDHYT-H groups and JDHYT-L groups) it treats 1 month
Afterwards, take blood, ELISA experiments detect the expression of IL-6, IL-1 β and TNF-α in different group mice serums, as a result see Fig. 6 (A)~
(C)；
Give the Effect of Jiedu Huayu Decoction of 5 × FAD mouse various doses (i.e.：JDHYT-H groups and JDHYT-L groups) it treats 1 month
Afterwards, draw materials hippocampal tissue, extract total serum IgE, qRT-PCR experiments detect different group hippocampus of mice TREM2, IL-6, IL-1 β and
As a result Fig. 6 (D)~(G) is shown in the expression of TNF-α：
From Fig. 5 (A)：In the hippocampal tissue of 5 × FAD mouse with the vacuolar degeneration of neuron, apoptosis and
Missing, and Effect of Jiedu Huayu Decoction improves the state and activity of the neuron of 5 × FAD hippocampus of mice, this illustrates Effect of Jiedu Huayu Decoction
There is protective effect to the hippocampal neuron of 5 × FAD mouse；
From Fig. 5 (B)：Effect of Jiedu Huayu Decoction inhibits the proliferation of 5 × FAD hippocampus of mice microglias, illustrates to detoxify
Huayu Tang may inhibit the Neuroinflammation that microglia mediates to a certain extent；
From Fig. 6 (A)~(G)：In the serum and hippocampal tissue of 5 × FAD mouse, with inflammatory factor (IL-6,
IL-1 β and TNF-α) expression up-regulation, and Effect of Jiedu Huayu Decoction can reduce IL-6 in 5 × FAD mice serums and hippocampal tissue,
IL-1 β and TNF-α albumen and mRNA level in-site expression, wherein be with high dose effect especially it is excellent, simultaneously, it was found that low, high agent
The Effect of Jiedu Huayu Decoction of amount can raise expression (see Fig. 6 (D)) of 5 × FAD hippocampus of mice TREM2 in mRNA level in-site, in conjunction with front
Western blot results, thus it is speculated that：Effect of Jiedu Huayu Decoction can play anti-AD effects by adjusting immunoregulation effect.
Claims (10)
1. a kind of Chinese medicine composition, it is characterised in that：The composition is by the coptis, Cortex Phellodendri, cape jasmine, Radix Salviae Miltiorrhizae, turmeric and grass-leaved sweetflag
Composition.
2. composition according to claim 1, it is characterised in that：The mass fraction of each substance is in the composition：It is yellow
10~20 parts of company, 5~12 parts of Cortex Phellodendri, 10~20 parts of cape jasmine, 10~18 parts of Radix Salviae Miltiorrhizae, 5~15 parts of turmeric, 5~15 parts of grass-leaved sweetflag.
3. composition according to claim 2, it is characterised in that：The mass fraction is：12~18 parts of the coptis, Cortex Phellodendri 6
~10 parts, 12~18 parts of cape jasmine, 13~17 parts of Radix Salviae Miltiorrhizae, 8~12 parts of turmeric, 8~12 parts of grass-leaved sweetflag.
4. composition according to claim 3, it is characterised in that：The quality parts ratio of the coptis, Cortex Phellodendri and cape jasmine be (2~
6)：(1~3)：(2~6).
5. a kind of Chinese medicine preparation, it is characterised in that：The preparation is prepared according to 1~4 any one of them composition of power
Pulvis, tablet, injection, capsule, decoction, granule, pill, paste, any one dosage form in targeting preparation.
6. a kind of preparation method of decoction, it is characterised in that：By in Claims 1 to 4 any one of them composition the coptis,
Cortex Phellodendri, cape jasmine, Radix Salviae Miltiorrhizae, turmeric and grass-leaved sweetflag add water to cook, and obtain decoction.
7. preparation method according to claim 6, it is characterised in that：Every 2~4g compositions obtain 1mL decoctions.
8. preparation method according to claim 6, it is characterised in that：The composition is decocted twice, is added for the first time
The water for entering 5~20 times of volumes is decocted, and second of the water that 3~15 times of volumes are added is decocted.
9. Claims 1 to 4 any one of them composition prepare treatment or auxiliary treatment Alzheimer disease drug or
Prepare the application in Alzheimer disease relevant healthcare product.
10. application according to claim 9, it is characterised in that：The Alzheimer disease is the A Er of turbid malicious blood stasis type
Ci Haimo diseases.
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| CN109646668A (en) * | 2019-01-04 | 2019-04-19 | 厦门大学 | A kind of polypeptide is used to prepare the purposes of prevention and treatment Alzheimer disease drugs |
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| CN1669570A (en) * | 2004-03-19 | 2005-09-21 | 丁永芳 | Medicinal composition for treating senile dementia and vascular dementia and preparing process thereof |
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| CN1669570A (en) * | 2004-03-19 | 2005-09-21 | 丁永芳 | Medicinal composition for treating senile dementia and vascular dementia and preparing process thereof |
| CN105079629A (en) * | 2015-08-17 | 2015-11-25 | 齐齐哈尔医学院 | Traditional Chinese medicinal composition for treating Alzheimer's disease, and preparation method and application of traditional Chinese medicinal composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109646668A (en) * | 2019-01-04 | 2019-04-19 | 厦门大学 | A kind of polypeptide is used to prepare the purposes of prevention and treatment Alzheimer disease drugs |
| CN109646668B (en) * | 2019-01-04 | 2019-10-18 | 厦门大学 | A kind of polypeptide is used to prepare the purposes of prevention and treatment Alzheimer disease drugs |
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| CN108543037B (en) | 2021-02-26 |
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