CN1181840C - Application of Guangdong Caulis Caulis and its extracts in the preparation of medicines for treating Alzheimer's disease or cerebral ischemic brain diseases - Google Patents
Application of Guangdong Caulis Caulis and its extracts in the preparation of medicines for treating Alzheimer's disease or cerebral ischemic brain diseases Download PDFInfo
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- CN1181840C CN1181840C CNB011298227A CN01129822A CN1181840C CN 1181840 C CN1181840 C CN 1181840C CN B011298227 A CNB011298227 A CN B011298227A CN 01129822 A CN01129822 A CN 01129822A CN 1181840 C CN1181840 C CN 1181840C
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Abstract
The present invention relates to a medicine for treating Alzheimer's disease, cerebral ischemia and brain disease. The medicine is prepared from kadsura pepper stem as main raw materials in Guangdong province, or is prepared from the extract of kadsura pepper stem as raw materials in Guangdong province. The present invention makes the medicinal materials of kadsura pepper stem in Guangdong province into general clinical extract preparations with stable quality and a stable quantity of effective components, and the extract preparations are convenient for clinical application to treat diseases. Simultaneously, in consideration of low biological availability and slow reaction of oral preparations which are especially unsuitable for acute cerebral ischemia and patients with severe Alzheimer's disease, the present invention prepares kadsura pepper stem into injection.
Description
Technical field
The present invention relates to the application in the medicine of preparation treatment Alzheimer or cerebral ischemia brain diseases of Guangdong Caulis Piperis Kadsurae and extract thereof.
Background technology
The Guangdong Caulis Piperis Kadsurae, another name Caulis Piperis Kadsurae, Cortex Ampelopsis Aconitifoliae Radicis rattan, dry or fresh ratan or root for special-shaped Fructus Schisandrae Sphenantherae Kadsura heteroclita (Roxb.) Craib of Magnoliacea plant, it is the local conventional crude drugs in Guangdong Province, has expelling wind and cold, promoting the circulation of QI to relieve pain, the effect of relaxing muscles and tendons and activating QI and blood in the collateral is distributed widely in ground such as Guangdong, Guangxi, Yunnan, Guizhou.Chemical constitution study shows, special-shaped Fructus Schisandrae Sphenantherae contains schizandrin (schisandrin), Kadsura interior element (kadsurin), heteroclitin A (+)-Heteroclitin A .-G (heteroclitin A-G) and gomisin A, B, G, J, H, M (gomisin A, B, G, J, H, a series of lignan components such as M).The ethanol extraction of special-shaped Fructus Schisandrae Sphenantherae can significantly reduce the lipid peroxidation product content that tetrachloro-methane induction produces in the mouse liver cell, obviously superoxide dismutase activity in the enhance hepatocyte.The Guangdong Caulis Piperis Kadsurae is clinical to be mainly used in cards such as treatment rheumatic arthralgia, gastric abscess, osteodynia and acute chronic gastroenteritis, also is used for the treatment of gynecological's pain as one of primary raw material of Yunnan Caulis Spatholobi cream Guangdong, Yunnan Province Caulis Piperis Kadsurae.Be not applied at present the treatment of brain diseases.
Summary of the invention
The inventor finds that through investigative test its lignan component has antioxidation and platelet activating factor (PAF) antagonism, and wherein Ge Mixin J and heteroclitin D (-)-Heteroclitin D. can suppress Kcl, Cacl
2With the vasoconstriction of NA generation, and has calcium antagonistic activity.
The object of the present invention is to provide the application in the medicine of preparation treatment Alzheimer or cerebral ischemia brain diseases of a kind of Guangdong Caulis Piperis Kadsurae and extract thereof.
The medicine of brain diseasess such as treatment Alzheimer of the present invention and cerebral ischemia is that primary raw material is made by the Guangdong Caulis Piperis Kadsurae.For example directly make as raw material with the Guangdong Kadsura Pepper Stem.Or make as raw material with the extract of Guangdong Caulis Piperis Kadsurae.
Described medicine is any pharmaceutically said dosage form.
The direct medicine of making as raw material with the Guangdong Kadsura Pepper Stem, its preparation method comprises: Guangdong Caulis Piperis Kadsurae medical material is pulverized separately or cooperated other Chinese herbal medicine or Western medicine is common makes 20～200 order fine powders after pulverizing, directly make powder, tablet, capsule;
Or with above-mentioned fine powder in addition Mel, edible wet goods are made honey pill agent;
Or with above-mentioned fine powder water, ethanol or other binding agents are made watered pill in addition;
Or with above-mentioned fine powder binding agent or wetting agent in addition, this binding agent or wetting agent comprise: water, aquiferous ethanol, 0.5～70% sodium carboxymethyl cellulose solution, syrup, gelatinized corn starch etc.;
Make 8～60 order granules with marumerization or two step granulations, make granule after the drying;
Record into capsule or be pressed into tablet after maybe this granule being equipped with additives such as fluidizer, disintegrating agent, controlled release agent.
The medicine of making as raw material with the extract of Guangdong Caulis Piperis Kadsurae, the preparation of its extracting solution comprises: water, acid water, alkaline water, aquiferous ethanol, dehydrated alcohol, aqueous methanol, absolute methanol, petroleum ether, ether, chloroform, ethyl acetate, butanols, acetone, other organic solvents that contain 12 following carbon atoms wherein one or both and above mixture extract, or supercritical CO
2Extraction obtains.
Generally speaking, the extract of Guangdong Caulis Piperis Kadsurae contains the lignan component of at least 0.1% weight.
Described extracting method can adopt heating or mode of heating not, and mode of heating is meant that per kilogram Guangdong Caulis Piperis Kadsurae adds 1～20 liter of solvent, and heating and refluxing extraction 0.5～8 hour, heating-up temperature are 50～120 ℃.Mode of heating is not meant with solvent Guangdong Caulis Piperis Kadsurae merceration, percolation or supersound extraction 0.5～48 hour, or with supercritical CO
2Extract.
The extracting solution that extraction obtains can also be further refining, process for purification is that the extracting solution of Guangdong Caulis Piperis Kadsurae is removed water-solubility impurity with water-pure method, alcohol-water law, Amberlyst process, silica gel column chromatography, polyamide column chromatography method or solvent extraction etc., makes that total lignans content reaches 0.1～50% in the extract.
When preparing medicine, directly or be condensed into 1: 0.5～1: 4 (medicine liquid volume: the crude drug quality) in addition correctives, antibacterial and other additives are made oral liquid after the concentration with extracting solution with the extract of Guangdong Caulis Piperis Kadsurae;
Or said extracted liquid is condensed into fluid extract, be equipped with behind suitable excipient, the filler by directly making preparation as the preparation method of the medicine of raw material with the Guangdong Kadsura Pepper Stem; Or said extracted liquid is ground into 20～200 order fine powders with heating or refrigerated method after eliminating solvent, by directly making preparation as the preparation method of the medicine of raw material with the Guangdong Kadsura Pepper Stem.
The present invention can also be the feedstock production drug injection with the Guangdong Caulis Piperis Kadsurae: the decocting that medical material is added 8～15 times of amounts boiled 0.5～2 hour, medicinal liquid is sucking filtration while hot, repeat 2～3 times, merging filtrate, heating is concentrated into every milliliter and contains 1～2g raw medicinal herbs, is cooled to room temperature, adding ethanol makes and contains the alcohol amount and reach 60～70%, fully stir, 4 ℃ of refrigerators were placed 12～48 hours, the filtering precipitation, filtrate decompression is concentrated into a few nothing alcohol flavors, add 4～8 times of amount distilled water and fully stir, 4 ℃ of refrigerators were placed 12～48 hours, the filtering precipitation, the filtrate heating is concentrated into every milliliter and contains 1～2g raw medicinal herbs, be cooled to room temperature, add ethanol and make and contain the alcohol amount and reach 75～85%, fully stir, 4 ℃ of refrigerators were placed 12～48 hours, the filtering precipitation, filtrate is transferred pH to 8.0～10.0 with 20～40%NaOH, fully stirs, 4 ℃ of refrigerators left standstill 12～48 hours, the filtering precipitation, decompression filtrate recycling ethanol gets fluid extract, vacuum, spraying or lyophilization get loose powder.This powder is dissolved with water for injection and 0.5～2% tween 80 (polyoxyethylene sorbitan fatty acid ester-80), add the abundant stirring and adsorbing of 0.1～0.5% active carbon, the filtering active carbon, filtrate adds 0.5～1.5% benzyl alcohol, transfer pH to 6.5～7.0 with sodium citrate, fill, sealing, flowing steam sterilization 30min promptly gets the medicine finished product.
The present invention can also will make brain diseasess such as various pharmaceutical preparatioies treatment cerebral ischemia diseases, Alzheimer after Guangdong Caulis Piperis Kadsurae and other Chinese herbal medicine collocation composition Chinese medicine compound.
Do not relate in the prior art Guangdong Caulis Piperis Kadsurae medical material is made the stable extract that contains the stable quantity effective ingredient, do not relate to yet Guangdong Caulis Piperis Kadsurae medical material and extract thereof are made the method for pharmaceutical preparation, do not relate to the treatment that the Guangdong Caulis Piperis Kadsurae is applied to brain diseases medicines such as Alzheimer and cerebral ischemia yet.The present invention makes the clinical common dosage forms of stay-in-grade extract that contains the stable quantity effective ingredient with Guangdong Caulis Piperis Kadsurae medical material, is convenient to clinical practice treatment disease.Consider that simultaneously the oral formulations bioavailability is relatively low, onset is also slower, especially is not suitable for acute cerebral ischemia disease and severe Alzheimer's disease patient, and the present invention also is prepared into injection with Caulis Piperis Kadsurae.Injection has the characteristics rapid, determined curative effect that act on.
The invention is further illustrated by the following examples.
Embodiment 1
Get Guangdong Caulis Piperis Kadsurae 60 ℃ of dryings 4 hours in baking oven, be ground into fine powder, cross 100 mesh sieves with pulverizer.Take by weighing 100g, add Mel and 5g medicinal plant oil that 20g refines, manual kneading becomes soft material.Place pellet processing machine to make the pill that weight is about 12g soft material.Seal up the honey pill agent that the wax shell promptly gets the Guangdong Caulis Piperis Kadsurae.
Embodiment 2
Get Guangdong Caulis Piperis Kadsurae 60 ℃ of dryings 4 hours in baking oven, be ground into fine powder, cross 100 mesh sieves with pulverizer.Take by weighing 100g and place quick granulator, add 2% sodium carboxymethyl cellulose solution 12ml, marumerization is made 12 order granules.Granule 60 ℃ of dryings 6 hours in baking oven with oscillating granulator 12 eye mesh screen granulate, are sub-packed in the aluminium foil bag by the 5g/ bag, and sealing promptly gets the granule of Guangdong Caulis Piperis Kadsurae.
Embodiment 3
Get Guangdong Caulis Piperis Kadsurae 60 ℃ of dryings 4 hours in baking oven, be ground into coarse powder with pulverizer.Taking by weighing 200g places round-bottomed flask to add 2000ml 95% ethanol, heating and refluxing extraction 1h, sucking filtration while hot.Repetitive operation twice, filtrate merge 5600ml altogether.Being evaporated to does not have the alcohol flavor, is extracted to several colourlessly with the ethyl acetate gradation, and extract is solvent evaporated in rotary evaporator, obtains the 6.8g dry extract.Silicagel column on the dry method with petroleum ether-dichloromethane gradient eluting, is collected dichloromethane stream part, and solvent evaporated obtains 1.2g dry powder.
Embodiment 4
Get Guangdong Caulis Piperis Kadsurae 60 ℃ of dryings 4 hours in baking oven, be ground into coarse powder with pulverizer.Taking by weighing 200g places round-bottomed flask to add 2000ml distilled water, heating and refluxing extraction 1h, sucking filtration while hot.Repetitive operation twice, merging filtrate, normal pressure is concentrated into 200ml, and 4 ℃ of refrigerators leave standstill 24h, the filtering precipitation, filtrate adds cyclamate 2g, sodium benzoate 2g, fill is to the 20ml vial, and sealing promptly gets Guangdong Caulis Piperis Kadsurae oral liquid.
Embodiment 5
Get exsiccant Guangdong Caulis Piperis Kadsurae and be ground into coarse powder.Take by weighing 5Kg and add 95% ethanol 50L heating extraction 2h in extraction pot, filter.Medicinal residues add 95% ethanol 50L again and extract 1h, merge filtrate twice.Concentrating under reduced pressure obtains dry extract 670g, with distilled water 250ml suspendible, last DA101 macroporous resin column, with the water-ethanol gradient elution, collects the ethanol elution part, and decompression and solvent recovery obtains the 124g dry extract.Dry extract is added 120g starch and 50g dextrin and 2% sodium carboxymethyl cellulose solution 40ml, and abundant mixing is made soft material in agitator.Soft material is made 20 order granules with oscillating granulator, and 60 ℃ of airpillow-dry 1h of fluid bed, dried granule add magnesium stearate 3g after with high speed pelletizing machine granulate, and hydroxypropyl cellulose 3g fully mixes in V-Mixer, and tablet machine is pressed into the plain sheet of 7mm.Packing promptly gets the tablet of Guangdong Caulis Piperis Kadsurae.
Embodiment 6
Getting 20g Guangdong Caulis Piperis Kadsurae coarse powder adds the 250ml distilled water and boils 30min.Centrifugal decoct (3000r/min, 15min), get supernatant liquid filtering after, concentrate, in concentrated solution, add 4 times of amount ethanol (containing the alcohol amount) and, place the elimination precipitation so that starch, polysaccharide, protein are removed more than 80%, reuse 40%NaOH solution adjust pH 8.0 is separated out the matter of mixing, and filters.Readjust pH value, the heat treatment refrigeration eliminates macromolecule impurity, and fill is sealed, and flowing steam sterilization 30min promptly gets the Caulis Piperis Kadsurae injection.If the heat treatment refrigeration eliminates the medicinal liquid of macromolecule impurity, filter through degerming, fill under aseptic condition, lyophilization, sealing by fusing promptly gets lyophilized injectable powder.
Embodiment 7
The dry rattan of Guangdong Caulis Piperis Kadsurae is processed into coarse powder, and heavy 30kg adds 95% soak with ethanol 72 hours (ratio of coarse powder, ethanol is 1: 10) and filters.Medicinal residues add soak with ethanol (1: 6) 24 hours again, filter, and repeat above-mentioned steps 3 times, and the filtrate of 4 gained is merged, and put that concentrating under reduced pressure becomes brown paste in the concentrating under reduced pressure jar into, have tangible fragranced.Overall recovery is 26: 1, and promptly Caulis Piperis Kadsurae 26g reclaims extractum 1g.At last extractum is mixed with dimethyl sulfoxide (DMSO), 10% Caulis Piperis Kadsurae injection (containing 10g extractum among the DMSO10ml) is made concentration and is in dissolving.
Embodiment 8
The protective effect of Guangdong Caulis Piperis Kadsurae cerebral ischemia.1. animal grouping and modelling: 45 of dogs, ♀ ♂ is regardless of, and body weight (9.8 ± 1.5) kg is divided into sham operated rats at random, normal saline matched group (NS group), Guangdong Caulis Piperis Kadsurae medication group (PW group).The back is divided into ischemia 0.5,3,6 again respectively for two groups, 12h group, 5 every group.30gL
-1Pentobarbital sodium (2mgkg
-1) intravenous anesthesia, femoral venous catheter is set up venous access, and tracheal casing pipe, PaCO are inserted in tracheotomy
2Give the artificial respiration during rising, femoral arteriography monitoring arteriotony, intermittent analysis vim and vigour, PaCO
2Maintain between 4.0～5.3kPa.Room temperature is controlled at 24～26 ℃, keeps the anus temperature between 37.0～38.0 ℃.The foundation of the experimental brain stem ischemia model of dog: the other center approach through the throat, expose the basis cranii Foramen magnum and separate cerebral dura mater, sting the bone window forward until the basilar artery distal end from its veutro edge, open cerebral dura mater, expose basilar artery, the silver brain clip folder closes, in, the lower end, be seamed to skin successively.Sham operated rats is not except that carrying out basilar artery folders closes, and all the other operate same ischemia group.2. medication and approach: the ischemia 3h duodenum fistulation that moves ahead.Caulis Piperis Kadsurae processed group 3h before the basilar artery folder closes in Guangdong pours into Guangdong Caulis Piperis Kadsurae solution (5mlkg
-1, 5ml is equivalent to crude drug 1g).The normal saline matched group pours into normal saline (5mlkg
-1).3. the mediator acidic amino acid is measured: put mutually when the brain stem ischemia reaches regulation and open cranium rapidly and get the about 1g of side ischemia brain stem cochlea vestibule nuclear district's tissue, low temperature is called weight in wet base in the following text immediately, adding 50gL
-1Trichloroacetic acid solution 4ml, the homogenate of interior cut refiner, 15000rmin under the low temperature
-1Centrifugal, get supernatant 2ml ,-70 ℃ of preservations are to be measured.Use 6300 gold series of high efficiency amino-acid analyzers (U.S. Beckman company) and measure glutamic acid (Glu), Aspartic Acid (Asp), result μ molg
-1The expression of weight in wet base tissue.4. pathological study: when brain stem ischemia regulation, put mutually and get the opposite side ischemia brain stem cochlea vestibule nuclear district specimen 100mlL of tissue part
-1Neutral formalin is liquid-solid fixed, the dehydration of ethanol gradient, and specimens paraffin embedding slices, HE dyeing, the Olympus microscopic examination is also taken a picture.The part specimen is accomplished 1mm
3Fritter, 30gL
-1Glutaraldehyde is fixed, conventional treatment and section, and uranium-plumbous double staining, the H300 transmission electron microscope observing is also taken a picture.5. result: the variation of each time point excitatory amino acids content behind the brain stem ischemia sees Table 1.
The variation μ molg of each time point excitatory amino acids content of table 1 brain stem ischemia
-1, n=5, x ± s
Glu Asp
NS group PW group NS group PW group
Sham operated rats 3.25 ± 0.73 3.25 ± 0.73 1.56 ± 0.41 1.56 ± 0.41
Ischemia 0.5h 4.25 ± 0.57 3.64 ± 0.44 1.99 ± 0.34 1.71 ± 0.50
Ischemia 3h 5.46 ± 0.41
2)4.25 ± 0.63
4)2.24 ± 0.21
1)1.86 ± 0.33
Ischemia 6h 6.20 ± 0.69
2)4.82 ± 0.77
4)2.83 ± 0.38
3)2.13 ± 0.33
4)
Ischemia 12h 6.89 ± 36
3)5.36 ± 0.47
4)3.08 ± 0.24
3)2.33 ± 0.41
4)
Compare with sham operated rats: 1) P＜0.05,2) P＜0.01,3) P＜0.001; Compare with the NS group: 4) P＜0.05
The NS group is behind ischemia 0.5h, and Glu and Asp compare with sham operated rats, and slight increase is all arranged, but do not have significant difference (P＞0.05).Ischemia 3h, Glu and Asp be significantly rising (difference P＜0.01; P＜0.05).Ischemia 6h, Glu and Asp increase nearly 1 times respectively.Ischemia 12h, both still have rising trend (P＜0.001).The PW group is when ischemia 0.5h, and Glu and Asp compare with the NS group, and increasing degree promptly begins to reduce, but does not have significant difference (P＞0.05).Ischemia 3h, Glu raise and obviously are subjected to press down (P＜0.05).Ischemia 6h, Asp rising amplitude significantly descends (P＜0.05), and to ischemia 12h, both are still suppressed in rising.The sham operated rats neuron morphology is normal.NS group ischemia 0.5h, neuron is mild cerebral ischemic and changes, the mitochondrion mild swelling, endoplasmic reticulum is slightly expanded, and kernel is normal.Ischemia 3h, under the light microscopic, most of pericaryons dwindle, and nuclear morphology is normal substantially, and the visible cell film is damaged under the Electronic Speculum, the swelling of mitochondrion height, the ridge fracture, a large amount of cavitys form, and reticulum dilatation becomes flat, and nuclear chromatin is assembled, and kernel is fuzzy, obscure boundary.Ischemia 6h, most neurons is seriously dwindled, and perikaryon concentrates, and nuclear shape is irregular, and visible nuclear membrane seriality is interrupted under the Electronic Speculum, the chromatin peripheryization, partial nerve unit is downright bad.Ischemia 12h, the neuron chromatolysis, karyopycnosis is triangular in shape, karyolysis.The PW group, ischemia 0.5h, neuron do not have the ischemia performance.Ischemia 3h, neuron are mild cerebral ischemic performance, mitochondrion mild swelling.Ischemia 6h, pericaryon slightly dwindles, and cell membrane is normal, the mitochondrion mild swelling, endoplasmic reticulum is slightly expanded, and nuclear is normal.Ischemia 12h, the after birth seriality is interrupted, the obvious swelling of mitochondrion, cavity forms, and the nuclear membrane seriality exists, chromatin agregation, kernel is fuzzy.
Embodiment 9
1. modelling: 48 of male Wistar rats, 26 months monthly ages, body weight 340～560g, be divided into A, B, C, D group at random, every group each 12, A group lumbar injection Guangdong Caulis Piperis Kadsurae injection each 1 time before and after illumination wherein, each dosage 1ml/100g body weight, the simple injection of B group DMSO, usage and dosage are organized with A, and C organizes not injectable drug.A, B, C group are made photochemically-induced permanent focal brain cortex ischemia model, be that experimental mouse is after the anesthesia of 0.4% pentobarbital sodium 32mg/kg body weight intraperitoneal, sterilization is also vertically cut scalp, expose the right side skull, the careful separation periosteum, the surface is coated with the lucifuge paper of centre band circular hole, aperture 4mm, the center of circle is positioned at about 1.8mm behind the bregma, 2.5mm place, the other right side of center line.Cut burst portion skin, expose femoral vein, with disposable skin test needle tubing behind femoral vein slow injection 2% rose red b (30mg/100g body weight), rat is fixed on the stereotaxic instrument, the cold light source skull surface of popping one's head in, exposure rate is 300～320klx, irradiation time 30 minutes.The D group does not give illumination for matched group, and other processing procedures are organized with C.2. general state is observed: all rat ischemia induction period vital signs stables, heart rate (261 ± 42) is inferior/minute, breathe (68 ± 24) inferior/minute, no anoxia sign, 36.8～37.2 ℃ of anus temperature are shone 38.0～38.8 ℃ of local skull surface temperature.All there is not obvious quadriplegia.Ischemia group is the atrophy of ischemia group spirit more not, the movable and minimizing of ingesting, and the Guangdong Caulis Piperis Kadsurae is intervened the back above-mentioned symptom and sign is not seen significant change.3. blood brain barrier integrity and infarct size are observed: get 6 rats for every group, in the illumination ischemia or after injecting fluorescent dye merely 24 hours rapidly broken end get brain, observe cortex infarction kitchen range and the rose-red situation of exosmosing, estimate the blood-brain barrier disruption degree.Immediately place 37 ℃, 2% tetrazolium chloride nitrogen (TTC) normal saline, lucifuge was hatched 15 minutes, measured infarction kitchen range diameter.All rat blood brain barrier of matched group are complete as a result, and no rose-red oozing out do not seen the infarction kitchen range after the TTC dyeing.The experimental group rat in illumination after 24 hours visible area of illumination pale red dyestuff ooze out, ooze out lighter with the A group.TTC dyeing back circular pale asphyxia infarction kitchen range occurs in the right parietal lobe area of illumination, and the position is constant, and wherein A group focus diameter is compared no significant difference for two groups with B, C.The prompting matched group does not have blood-brain barrier disruption, and the ischemia group blood-brain barrier disruption is obvious, and the Guangdong Caulis Piperis Kadsurae is intervened back destruction and alleviates.4. histological observation: every group of other 6 rats are in same Ischemia Time point, and the perfusion of 4% paraformaldehyde is fixing, break end, get brain, the back is fixing, dehydration is transparent, paraffin embedding, section, HE dyeing, om observation.Matched group blood vessel, cellular morphology are normal, are evenly distributed, and no thrombosis forms.The focus center exists tangible cerebral edema, neurocyte to take off to lose and the neurocyte necrosis behind the experimental group illumination ischemia, and around the focus except that neurocyte takes off mistake, necrosis, remain at reversibility ischemia cell.After the Guangdong Caulis Piperis Kadsurae was intervened, the downright bad neurocyte numbers of poles of every high power field significantly reduced.5. original position terminal deoxynucleotidyl transferase (TdT) labelling (TUNEL): the crown paraffin section of the thick brain of 4 μ m, routine dewaxes to water, with H
2O
2, after compound Digestive system handles, add and contain TdT and DIG-D-UTP reactant liquor, hatched 2 hours for 37 ℃, connect the biotinylation anti digoxin antibody, the DAB colour developing, haematoxylin is redyed.The negative control that does not add TdT is established in experiment, and light microscopic is observed down and dyed brown apoptotic cell by DAB.Matched group (B) and negative control group (C) are all seen the positive expression cell, visible positive cell around the focus of experimental group (A), and under every high power visor, A group positive cell number extremely obviously reduces for two groups than B, C.Table 2 is the comparison of respectively organizing non-viable non-apoptotic cell and apoptotic cell quantity around the rat ischemia kitchen range diameter, ischemic focus (x ± s).
Table 2 is respectively organized the comparison (x ± s) of non-viable non-apoptotic cell and apoptotic cell quantity around the rat ischemia kitchen range diameter, ischemic focus
Group n focus diameter non-viable non-apoptotic cell apoptotic cell
(mm) (number) (number)
A organizes 12 8.0 ± 0.4 64.3 ± 8.6
*15.0 ± 2.1
*
B organizes 12 8.4 ± 0.4
△74.8 ± 11.3
△22.0 ± 3.1
△
C organizes 12 8.3 ± 0.3 78.4 ± 10.5 20.5 ± 2.4
Annotate:
*Compare P＜0.01 with B, C group,
△Compare P＞0.05 with the C group
Embodiment 10
(β-amyloid protein, β-AP) are the Main Ingredients and Appearances of brain senile plaque to amyloid, and the morbidity of β-AP and Alzheimer is closely related.The biological activity position of β-AP is from 35 aminoacid (β-AP of the 25th aminoacid to the
25-35).This research and inquirement the Guangdong Caulis Piperis Kadsurae to β-AP
25-35The influence of rising neurocyte cytoplasm calcium ion.1. method: cell culture: the conventional human nerve's blastoma cell series (LaN1) of cultivating.Culture fluid is made up of 95%DMEM and 5% hyclone, and incubator includes 5%CO
2Humid air and 37 ℃ of constant temperature of maintenance.Test preceding 12～24h collecting cell, be seeded in the DMEM culture fluid of no hyclone, cell carries out various experiments in the index division stage.Measure cell survival rate and lactic acid dehydrogenase (LDH).The cell that the cell colony counting was cultivated the Guangdong Caulis Piperis Kadsurae with trypsin separates from culture dish, dilutes then, counts.Per 500 cell inoculations are to 25cm
2Culture bottle in, conventional use cresyl violet stains after cultivating 10d, carry out cell colony and count (containing 50 above persons of cell).Calculate inoculation effective percentage (cell colony/500 * 100%) at last, to estimate the effect in long term of Guangdong Caulis Piperis Kadsurae pair cell.The neurocyte cytoplasm calcium ion is measured: neurocyte imports aequorin after hypotonic processing, aequorin combines emit blue light with calcium ion, measures and calculate the neurocyte concentration of cytoplasm calcium ion with platelet cytoplasm calcium ion analyzer.The neurocyte that imports aequorin divides experimental group and matched group.Each specimen is for containing the 1ml cell suspension of cell 1 * 106.Experimental group at first adds Guangdong Caulis Piperis Kadsurae solution 10 μ l, and 37 ℃ of preheating 2min add β-AP again
25-35(10mmol/L) 10 μ l measure concentration of cytoplasm calcium ion variation (β-AP
25-35Ultimate density 100 μ mol/L).Cellular control unit does not contact the Guangdong Caulis Piperis Kadsurae, at first adds normal saline 10 μ l preheating 2min (eliminating the effect of Guangdong Caulis Piperis Kadsurae solvent), adds β-AP again
25-35(100 μ mol/L).Observe the Guangdong Caulis Piperis Kadsurae neurocyte is done the time spent, 100 μ l Guangdong Caulis Piperis Kadsurae aqueous solutions join in the 10ml culture fluid; When observation Guangdong Caulis Piperis Kadsurae influenced the neurocyte cytoplasm calcium ion, 10 μ l Guangdong Caulis Piperis Kadsurae aqueous solutions joined in the 1ml cell suspension, and Guangdong Caulis Piperis Kadsurae ultimate density is respectively 25g/L, 10g/L, 5g/L, 2.5g/L.2 results: (2.5g～25g/L), LaN1 contact Guangdong Caulis Piperis Kadsurae 24h light microscopic is no morphological change down in the Caulis Piperis Kadsurae experimental concentration of Guangdong.LaN1 contact Guangdong Caulis Piperis Kadsurae 6h and 24h cell survival rate, LDH and cell colony monitoring are all no abnormal, and visible Guangdong Caulis Piperis Kadsurae is to the neurocyte free of toxic effects.In addition, the Guangdong Caulis Piperis Kadsurae can suppress the inductive neurocyte of β-AP25-35 (LaN1) cytoplasm calcium ion and raise, and strengthens with Guangdong Caulis Piperis Kadsurae concentration.
Generally believe that now β-AP has played the effect of co-channel in the pathogenic process of AD, a variety of causes finally causes β-AP to deposit in brain to bring out AD.β-AP induces the neurocyte degenerative process further to be proved to be apoptosis.Calcium ion concentration raises and has played trigger action in the apoptosis.Calcium ion concentration raises in the endochylema, activates the Cobra venom endonuclease that calcium/magnesium relies on, further degradation of dna and start apoptosis.Suppress the neurocyte calcium ion concentration and raise, might stop the neuronal apoptosis process.
Embodiment 11
Amyloid (β AP) is the nucleus of brain senile plaque, and modern study confirms that the morbidity of it and Alzheimer (AD) has confidential relation, even has the people to think that the deposition of β AP is the cause of disease of AD.β AP derives from amyloid precursor protein (β APP).The β app gene is positioned at the long-armed stage casing of chromosome No. 21, and the β APP of its coding is made up of 695-770 aminoacid, is a transmembrane glycoprotein.β AP is the segment of β APP, is made up of with 12 aminoacid of striding membrane portions 28 aminoacid that cell membrane is outer, and it is folding that the about 4KD of molecular weight, three dimensional structure are the β type, thereby claim β AP.Internal and external test shows that all β AP can cause AD sample pathological change, induces the neurocyte degeneration.Based on above-mentioned research, if expressing, the β app gene is suppressed, and the deposition of β AP in brain will reduce, and AD might effectively be prevented and treated.1. method cell culture: human nerve's blastoma cell series (LaN1), culture fluid is made up of 95%DMEM and 5% hyclone, keeps containing 5%CO in the incubator
2Humid air and 37 ℃ of constant temperature.12h～24h collecting cell before the test is seeded in the DMEM culture fluid of no hyclone, and cell is the index division stage and carries out various experiments.Cell survival rate is measured: allow trypan blue to enter in the cell when cell membrane damages, cell is dyed blueness (dead cell), and int cell is not colored (living cells).Count dead cell and living cells through hyperchromatic cell respectively with hematimeter, calculate cell survival rate (living cells/(living cells+dead cell) * 100%) then.In order to estimate the effect of Guangdong Caulis Piperis Kadsurae pair cell.Lactic acid dehydrogenase (LDH) is measured: when cell death, the LDH in the born of the same parents is discharged in the culture fluid, utilizes the LDH concentration in the colorimetry measurement culture fluid, as an index of cell death, also in order to estimate the effect of Guangdong Caulis Piperis Kadsurae pair cell.The calculating of cell colony: with trypsin cell is separated from culture dish, dilute then, count.Per 500 cell inoculations are to 25cm
2Culture bottle in, conventional use cresyl violet stains after cultivating 10d, carry out cell colony and count (containing 50 above persons of cell).Calculate inoculation effective percentage (cell colony/500 * 100%) at last.This experiment can be estimated the effect in long term of Guangdong Caulis Piperis Kadsurae pair cell through the cultivation of 10d.Northern blot hybridization test: adopt the guanidine hydrochloride organic solvent method to extract the whole RNA of cell, transfer on the hybond membrane after the 15 μ gRNA agar electrophoresises,, show the amount of β APPmRNA at last by autoradiography then with the β APPcDNA hybridization of P32 labelling.After handling with 1%SDS, same hybond membrane use β actin c DNA (β Actin cDNA) and tubulin cDNA (Tubulin cDNA) hybridization more respectively in contrast.2. result: (2.5g/L～25.0g/L), the toxic action of pair cell is not found in various experiments in the Caulis Piperis Kadsurae experimental concentration of Guangdong.LaN1 contact Guangdong Caulis Piperis Kadsurae 24h light microscopic is no morphological change down.LaN1 contact Guangdong Caulis Piperis Kadsurae 6h and 24h, cell survival rate, LDH and cell colony monitoring are no abnormal.The Northern blot hybridization shows that the Guangdong Caulis Piperis Kadsurae suppresses the β app gene and expresses.The Guangdong Caulis Piperis Kadsurae reduces β APPmRNA and strengthens with the prolongation of action time and the increase of concentration.
Kadsura heteroclita suppresses the expression of β app gene following characteristics: 1. Kadsura heteroclita reduces β APPm RNA prolongation and the increase of concentration and strengthening in time; 2. Kadsura heteroclita inhibition β APP expresses and has selection The property.
Claims (5)
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|---|---|---|---|
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