CN1977951A - Gastrodia elata plant extract for preventing senile dementia and its preparing method - Google Patents
Gastrodia elata plant extract for preventing senile dementia and its preparing method Download PDFInfo
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- CN1977951A CN1977951A CN 200510128785 CN200510128785A CN1977951A CN 1977951 A CN1977951 A CN 1977951A CN 200510128785 CN200510128785 CN 200510128785 CN 200510128785 A CN200510128785 A CN 200510128785A CN 1977951 A CN1977951 A CN 1977951A
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Abstract
The present invention relates to a gastrodia root extract containing pericin derivative and its application in preparation of medicine for preventing and curing the diseases of senile dementia. Said invention also relates to a preparation method for extracting gastrodia root to obtain its extract in which its effective component is pericin derivative. Said extract can be made into injection, tablet, capsule, seft capsule, oral liquor or dripping pills.
Description
Technical field
The invention belongs to natural medicine technical field.Be specifically related to a kind of Rhizoma Gastrodiae (Gastrodia elata Blume) plant extract that contains parishin A, B, C and/or its derivant at preparation Fructus Alpiniae Oxyphyllae, hypermnesis or prevent and treat purposes in the medicine of diseases such as alzheimer disease.From the Chinese medicine Rhizoma Gastrodiae, extract, make with extra care the plant extract and the extracting method thereof that obtain.
Background technology
Quickening along with China's aged tendency of population, alzheimer disease patient increases day by day, alzheimer disease, also being Alzheimer (Alzheimer ' s Disease be called for short AD), is the chronic functional obstacle of the senior polymerization process of brain, because the onset concealment, so early symptom easily is left in the basket, the patient who suffers from AD can't take care of oneself, and needs the household to take care of constantly, brings white elephant for patient, family, society.The drug research of treatment alzheimer disease and exploitation scope are comprising precursors of neurotransmitters material, neurotransmitter synthesis accelerant, neurotransmitter catabolic enzyme inhibitor etc. aspect the cranial nerve propagation function improving agent except that brain blood circulation improving agent, brain energy metabolism activator.Also very active in the research of aspects such as neuropeptide, nerve growth factor and Chinese herbal medicine in recent years, and obtained certain progress.
But, the medicine of treatment alzheimer disease has a problem of having to face, because the medication cycle of control memory and cognitive disorder is longer relatively, perhaps be lifelong to AD patient, so the safe handling of medicine is most important.Pharmaceutically active ingredient in extracting from the higher Chinese crude drug of known safety, development and exploitation new Chinese medicine are necessary.
Rhizoma Gastrodiae another name RHIZONA GASTRODIAE, Bai Longcao, rhizoma gastrodiae root.Tuber for the perennial parasitic herbaceous plant Rhizoma Gastrodiae Gastrodia elata Blume of the orchid family.Perennial plant is born in moistening sylvan life, existing many cultivations.Mainly originate from ground such as Sichuan, Yunnan, Guizhou, Hubei and Shaanxi in China.Rhizoma Gastrodiae is mainly used in endogenous wind stopping relieving convulsion, suppressing the hyperactive liver and subsiding YANG, wind-expelling pain-stopping and migraine and general headache etc. in Chinese medicine.
Pai Lixin (parishin) is a kind of main chemical compositions in the plant Rhizoma Gastrodiae, document
1-5The structure of having reported Pai Lixin (parishin) A, B, C is as follows:
Wherein, abbreviate Pai Lixin (parishin) usually as in the former document of parishin A (parishin A),, be referred to as parishin A (parishin A) herein for to distinguish with two other known Pai Lixin compounds (parishin B, C).
List of references:
1、Li Y.M.，Zhou Z.l.，Hong Y.F.New phenolic derivativesfrom Galeola faberi.Planta Med.1993，59(4)：363-5。
2、Lin J.H.，Liu Y.C.，Hau J.P.，et al.Parishins B and Cfrom rhizomes of Gastrodia elata.Phytochemistry，1996，42(2)：549-551。
3, Zhou Jun, Chongqing, Hunan, Pu, Yang Yanbin.Nine kinds of phenolic constituents of fresh gastrodia elata.Science Bulletin, 1981,26 (18): 1118-1120.
4、Dahmen J.，Leander K.Studies on Orchidaceae glucosides.Part 7.The structure of parishin，a glucoside from Vandaparishii.Phytochemistry，1976，15(12)：1986-7。
5、Taguchi H.，Yosioka I.，Yamasaki K.，et al.Studies onthe constituents of Gastrodia elata Blume.Chem.Pharm.Bull.，1981，29(1)：55-62。
Although bibliographical information carry out the repeated multiple times chromatographic isolation by positive and reverse phase silica gel, obtain the method for the monomeric compound of Pai Lixin derivant, never reported these monomeric compounds and Fructus Alpiniae Oxyphyllae and prevented and treated the effect of alzheimer disease relevant.
Because complex chemical composition in the Rhizoma Gastrodiae, and Pai Lixin compounds polarity has than big difference, utilize single chromatographic separation technology enrichment high-load (greater than 50%) the Pai Lixin derivant that is fit to suitability for industrialized production that big difficulty is arranged, also there is not bibliographical information to obtain the Blume plant extract of the Pai Lixin derivant of high-load (greater than 50%) at present, do not report yet and utilize chromatographic separation technology to realize that preparation is rich in the method for the Blume plant extract of its derivant of Pai Lixin, never found to contain the Blume plant extract of Pai Lixin derivant or the monomeric compound of Pai Lixin derivant (parishin A particularly yet, B, C) or mixture have the intelligence of increasing and prevent and treat the alzheimer disease effect.
Summary of the invention
The invention provides the Blume plant extract that contains Pai Lixin derivant (particularly parishin A, B, C) or Pai Lixin monomeric compound or mixture at preparation Fructus Alpiniae Oxyphyllae, hypermnesis or prevent and treat purposes in the medicine of diseases such as alzheimer disease.Wherein Pai Lixin derivant total content is more than 25% in this extract, and preferred Pai Lixin derivant total content is the extract more than 50%.Monomer, particularly parishin A, B, C arbitrarily in the described Pai Lixin derivant Ke Yi Wei Pai Lixin derivant, the also mixture of any multiple monomeric compound in the Ke Yi Wei Pai Lixin derivant.
Now pass through learning and memory of little mouse acquired disturbance model, comprise with scopolamine and cause learning and memory of little mouse acquired disturbance model, cause the research that mouse memory forms obstacle model etc. with actidione (CHX), by the research of camera bellows experiment, diving tower experiment etc., the plant extract that shows the monomeric compound or the mixture of Pai Lixin derivant and contain Pai Lixin derivant (particularly parishin A, B, C) has Fructus Alpiniae Oxyphyllae and prevents and treats the alzheimer disease effect.
Described " monomer " is defined as the unification compound.
The present invention also provides a kind of Blume plant extract of the Pai Lixin of containing derivant, Pai Lixin derivant total content is more than 25% in this extract, preferred Pai Lixin derivant total content is more than 50%, more preferably Pai Lixin derivant total content is 50%-95%, and preferred described Pai Lixin derivant is parishin A, B, C.
The present invention also provides a kind of preparation to contain the method for Pai Lixin derivant plant Rhizoma Gastrodiae extract, wherein Pai Lixin derivant total content is more than 25% in the extract, preferred Pai Lixin derivant total content is more than 50%, more preferably Pai Lixin derivant total content is 50%-95%, and preferred described Pai Lixin derivant is parishin A, B, C.
By our research, find that extraction, the process for refining by uniqueness is the Blume plant extract that can obtain being rich in the Pai Lixin derivant to separation purifying technique.
The present invention also provides pharmaceutical composition and preparation and the application of described Blume plant extract in health product and pharmaceutical field that contains Blume plant extract, particularly preparing Fructus Alpiniae Oxyphyllae and preventing and treating the health product of diseases such as alzheimer disease and the application in the medicine, Pai Lixin derivant total content is more than 25% in the described Blume plant extract, preferred Pai Lixin derivant total content is more than 50%, more preferably Pai Lixin derivant total content is 50%-95%, and preferred described Pai Lixin derivant is parishin A, B, C.Wherein percentage ratio % is without special instruction, and % all is weight percentage.
The present invention assigns upright hot derivant structure general formula as follows:
Wherein, R
1, R
2Be selected from independently of one another with R3:
Deng;
R4 is selected from hydrogen, C1-C6 alkyl (preferable methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group), C1-C6 alkyl phenyl (preferred benzyl), and to hydroxybenzyl, or
Deng;
Glu represents β-D-glucopyranosyl, and Me represents methyl.
The process that the present invention prepares described Blume plant extract is as follows:
1. extracting method: plant Rhizoma Gastrodiae (tuber) is pulverized, use the aqueous solution of 20-100% (wherein preferred 50-95%) C1-C6 alkylol to extract down in the temperature (preferred room temperature is to the temperature of solvent refluxing) of 0 ℃-solvent refluxing as solvent then, extracting solution gets extractum through normal pressure or concentrating under reduced pressure; Wherein said C1-C6 alkylol is preferably the mixed solvent that methanol, ethanol, isopropyl alcohol or n-butyl alcohol or their are formed, wherein more preferably methanol, ethanol.
2 process for purification:
Extractum is refining with chromatographic process, purification are used the eluting solvent eluting, collect the stream part of being rich in parishin A, B, C compounds, concentrate, and filter, and drying detects and collect the plant extract that is rich in the Pai Lixin derivant.
Wherein saidly be used to make with extra care, the chromatographic process of purification is macroporous adsorbent resin chromatography, purification on normal-phase silica gel and reverse phase silica gel chromatograph, perhaps their combination, perhaps the extractum that extraction is obtained is mixed in silica gel or the kieselguhr, dries the back with the eluting solvent eluting that refluxes; Described eluting solvent is a water, the C1-C6 alkylol, as: methanol, ethanol, isopropyl alcohol or n-butyl alcohol etc., halogenated hydrocarbons, as: dichloromethane, chloroform (chloroform) etc., ether solvent, as: ether, methyl tert-butyl ether etc., ketones solvent, as: acetone, 2-butanone etc., esters solvent, as: ethyl acetate, Ethyl formate etc., and by the mixed solvent of above-mentioned solvent composition, wherein preferred eluting solvent is a kind of or several mixed solvents in chloroform (chloroform), ethyl acetate, ethanol, the first alcohol and water.In the described process for purification, when making with extra care with styrene tyle macroporous adsorption resin, eluting solvent is preferably ethanol or the methanol aqueous solution of water and 10-75%; When with the reverse phase silica gel chromatographic refining, eluting solvent is preferably ethanol or the methanol aqueous solution of water and 10-50%; When making with extra care with purification on normal-phase silica gel, eluting solvent is preferably the mixed solvent of chloroform or ethyl acetate and 90-100% ethanol water or methanol composition, and their ratio is preferably 10: 1-2: 1.
In the wherein said preparation method, the stream part of being rich in parishin A, B, C compounds is detected by thin layer chromatography (TLC), ultraviolet (UV), high pressure liquid chromatography methods such as (HPLC), wherein preferred HPLC detection method.
The total content of Pai Lixin derivant detects by the HPLC method in the Blume plant extract that preferred the present invention obtains.Preferably use the high performance liquid chromatogram external standard method, make standard, calculate the wherein total content of Pai Lixin compounds with parishin A.
Pai Lixin derivant total content is more than 25% in the Blume plant extract that obtains according to the method described above, preferred Pai Lixin derivant total content is more than 50%, more preferably Pai Lixin derivant total content is 50%-95%, and preferred described Pai Lixin derivant is parishin A, B, C.
The Blume plant extract that contains the Pai Lixin derivant that obtains according to the method described above has the effect of Fructus Alpiniae Oxyphyllae, hypermnesis.
The preparation method of introduction of the present invention provides a kind of in the Blume plant extract preparation method with high-load Pai Lixin derivant, and does not mean that the Blume plant extract that has only the high-load Pai Lixin derivant that obtains by said method could be used as preparation Fructus Alpiniae Oxyphyllae, hypermnesis or prevent and treat the medicine of diseases such as alzheimer disease.Can infer, those skilled in the art also can have same drug effect with the Blume plant extract that is rich in the Pai Lixin derivant that additive method obtains.
Prepare plant extract in the Chinese medicine Rhizoma Gastrodiae with above extraction and process for purification, wherein effective ingredient-the content of Pai Lixin derivant in plant extract can be up to more than 50%.Wherein the macroporous adsorbent resin method is refining is more suitable in suitability for industrialized production.
The plant extract that utilizes the inventive method to obtain can be made pharmaceutical preparation with pharmaceutically acceptable carrier, for example: injection, tablet, capsule, oral liquid or drop pill etc.When the plant extract that utilizes the inventive method to obtain prepares the various dosage form of required medicine, can be according to the conventional production method preparation of pharmaceutical field.Preferred this class pharmaceutical preparation of the present invention can be by oral, parenteral.Preferred formulation is oral or intravenous administration.
The sterile injectable form of the present composition can be aqueous or oiliness suspensoid.These suspensoids can be prepared according to technology known in the art, the dispersion that utilize to be fit to or wetting agent and suspending agent.Aseptic injectable formulation can also be at nontoxic parenteral acceptable diluent or sterile injectable solution agent or the suspensoid in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's mixture and isoosmotic sodium chloride solution.In addition, aseptic expressed oi is also through being often used as solvent or suspension media.For this reason, can adopt the expressed oi of any gentleness, comprise synthetic list-or two-glyceride.Fatty acid, for example oleic acid and glyceride ester derivatives thereof can be used for preparing injection, and they are natural pharmaceutically acceptable oil, for example olive oil or Oleum Ricini, especially their polyoxy ethylization form.These oily solution or suspensoid can also contain long-chain alcohol diluent or dispersant, for example carboxymethyl cellulose or similar dispersant, and they generally are used to prepare pharmaceutically acceptable dosage form, comprise Emulsion and suspensoid.For the purpose of preparation, can also use other surfactants commonly used, for example Tweens, spans and other emulsifying agents or bioavailability reinforcing agent, they generally are used in the manufacturing of pharmaceutically acceptable solid, liquid or other dosage forms.
Pharmaceutical composition of the present invention can include but not limited to capsule, tablet, aqueous suspension or solution by any oral acceptable forms oral administration.With under the situation of tablet, carrier commonly used comprises lactose and corn starch at mouth.Usually also add lubricant, for example magnesium stearate.With regard to regard to the oral capsule administration, useful diluent comprises lactose and exsiccant corn starch.Very moment is during with the needs aqueous suspension, active component and emulsifying and suspending agent coupling.If necessary, can also add some sweeting agent, correctives or coloring agent.
If necessary, in case patient's condition makes moderate progress, can give the maintenance dose of The compounds of this invention, compositions or combination.Subsequently, can reduce the level that the dosage of administration or frequency or dosage and frequency are kept to the condition of having improved,, should stop treatment when symptom has alleviated to desired level according to symptom.But, in case disease symptoms has any recurrence, the patient may accept intermittent treatment on long-term basis.
Can also comprise other activating agents that are used for the treatment of Alzheimer in the pharmaceutical preparation of the present invention or with the medicine of other treatment Alzheimer (alzheimer disease) or order administration.
It is to be further understood that, any specific patient's concrete dosage and treatment system will depend on multiple factor, comprise activity, age, body weight, general health situation, sex, diet, administration time, discharge rate, drug regimen, attending doctor's the judgement of the concrete extract that is adopted and the seriousness of the specified disease of being treated.
The specific embodiment
Following preparation embodiment and EXPERIMENTAL EXAMPLE can further specify the present invention, but do not limit the present invention in any way.
Embodiment 1:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, pulverize the back and add 50% soak with ethanol extraction 3 times, each 24 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.
2. refining: above-mentioned filtrate is by treated HPD-100 type macroporous adsorbent resin, water and 10%, 20%, 30%, 40%, 50%, 75% ethanol gradient elution, HPLC detects, stream part of Pai Lixin compounds is rich in collection, merge, concentrating under reduced pressure, spray drying promptly get plant extract 4.48g.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 51.8%.
Embodiment 2:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, to pulverize the back and add 50% ethanol, 50 ℃ of warm macerating bubbles extract each 6 hours 3 times.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.
2. refining: above-mentioned filtrate is by treated HP-20 type macroporous adsorbent resin, water and 10%, 20%, 30%, 40%, 50%, 75% ethanol gradient elution, HPLC detects, stream part of Pai Lixin compounds is rich in collection, merge, concentrating under reduced pressure, spray drying promptly get plant extract 4.42g.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 52.6%.
Embodiment 3:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, after adding 50% soak with ethanol is spent the night after pulverizing, heating and refluxing extraction 3 times, each 3.0 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.
2. refining: above-mentioned filtrate is by treated HP-20 type macroporous adsorbent resin, the methanol of water, 10%, 20%, 30%, 40%, 50% and 75% concentration gradient is successively washed, HPLC detects, stream part of Pai Lixin compounds is rich in collection, merge, concentrating under reduced pressure, spray drying promptly get plant extract 4.68g.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 54.4%.
Embodiment 4:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, pulverize the back and add 75% ethanol, room temperature lixiviate 3 times, each 24.0 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.Concentrating under reduced pressure gets concentrated solution.
2. make with extra care: concentrated solution passes through reverse phase silica gel post (C-18), behind water and the 10% alcoholic solution eluting, and the alcoholic solution eluting of reuse 50% concentration, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges concentrating under reduced pressure, the dry plant extract 2.18g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 66.2%.
Embodiment 5:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg after the pulverizing, adds after 75% soak with ethanol spends the night 75 ℃ of heating lixiviates 3 times, each 6.0 hours.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, by purification on normal-phase silica gel (100-200 order) chromatographic column, behind chloroform-methanol (9: the 1) eluting, reuse chloroform-methanol (5: 1) eluting, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merge concentrating under reduced pressure, the dry plant extract 4.51g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 50.3%.
Embodiment 6:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg after the pulverizing, adds after 75% soak with ethanol spends the night heating and refluxing extraction 3 times, each 3.0 hours.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, by purification on normal-phase silica gel (100-200 order) post, behind ethyl acetate-95% ethanol (10: the 1) eluting, reuse ethyl acetate-95% ethanol (3: 1) and ethyl acetate-95% ethanol (2: 1) is eluting successively, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges, concentrating under reduced pressure, the dry plant extract 4.88g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 56.0%.
Embodiment 7:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, pulverize the back and add 95% ethanol room temperature lixiviate 3 times, each 24.0 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.Concentrating under reduced pressure gets concentrated solution.
2. make with extra care: concentrated solution passes through reverse phase silica gel (C-18) post, behind water and the 10% alcoholic solution eluting, and the alcoholic solution eluting of reuse 50% concentration, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges concentrating under reduced pressure, the dry plant extract 1.69g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 60.9%.
Embodiment 8:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, after the pulverizing, add 95% ethanol, 75 ℃ of warm macerating extract each 8.0 hours 3 times.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, by purification on normal-phase silica gel (100-200 order) post, behind chloroform-methanol (9: the 1) eluting, reuse chloroform-methanol (5: 1) eluting, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merge concentrating under reduced pressure, the dry plant extract 1.22g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 55.1%.
Embodiment 9:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg after the pulverizing, adds after 95% soak with ethanol spends the night heating and refluxing extraction 3 times, each 4.0 hours.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, by purification on normal-phase silica gel (100-200 order) post, behind ethyl acetate-95% ethanol (10: the 1) eluting, reuse ethyl acetate-95% ethanol (5: 1) and ethyl acetate-95% ethanol (3: 1) eluting, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges, concentrating under reduced pressure, the dry plant extract 1.86g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 55.8%.
EXPERIMENTAL EXAMPLE
Blume plant extract is for Fructus Alpiniae Oxyphyllae and prevent and treat the effect of alzheimer disease
Hereinafter the abbreviation of Cai Yonging " clb " is meant that parishin A, B, C and/or its derivative content are greater than 50% Rhizoma Gastrodiae extract.
EXPERIMENTAL EXAMPLE 1: cause learning and memory of little mouse acquired disturbance model with scopolamine
[experiment material and instrument]
1. laboratory animal: male mice in kunming, body weight 20-22g is provided by Chinese drug inspection office animal housing, and animal was raised in cages two days at this institute Animal House before the experiment.
2. the plant extract clb (product of embodiment 1, content 51.8%) that is subjected to reagent thing: Pai Lixin (parishin) A and obtains by above preparation embodiment 1 is with the dissolving of distilled water suspendible.
3. route of administration: irritate stomach, matched group is irritated the isopyknic aquae destillata of stomach
4. dosage: parishin:0.25,0.5,1.0mg/kg
Body weightClb:2.5,510mg/kg
Body weight
5. positive control drug: many naphthalenes piperazine is neat: the 2.5mg/kg body weight
6. instrument: mice watermaze protocol auto-controlling apparatus: SMG-2
7. reagent: scopolamine, available from Sigma company
The result:
Detect to find that through the diving tower method parishin A and clb can obviously prolong the incubation period that animal jumps off platform for the first time in 0.25-1.0mg/kg and the 2.5-10mg/kg scope respectively, leave from office number of times (errors number) in 5 minutes simultaneously reduces, show that clb can improve the learning and memory of little mouse acquired disturbance that scopolamine causes effectively, action intensity and positive drug donepezil are approaching.The results are shown in Table 1.
Table 1 clb causes the influence of Model of Dementia mice diving tower experiment incubation period and errors number to scopolamine
| Group | Dosage (mg/kg) | Incubation period (second) | Errors number (inferior) |
| Normal control model group Parishin A Parishin A Parishin A clb clb clb donepezil | 0.25 0.5 1.0 2.5 5 10 3 | 258±18 141±28# 234±22* 256±16* 261±18** 213±16* 238±20* 273±18** 243±25* | 0.3±0.2 1.4±0.3## 0.5±0.2** 0.2±0.1* 0.3±0.2* 0.3±0.1** 0.2±0.1* 0.4±0.2* 0.3±0.2** |
Incubation period and errors number are expressed as in the table: Mean ± SEM (meansigma methods ± standard deviation).
Model group and normal control group be #P＜0.05 relatively, ##P＜0.01,
Administration group and model group be * P＜0.05 relatively, * * P＜0.01.
EXPERIMENTAL EXAMPLE 2: mice is kept away dark experiment
Animal: the SPF Male Kunming strain mice, body weight 19-20g is provided by Chinese drug inspection office animal housing, raises in cages two days at this institute Animal House before the experiment.
Reagent and preparation
Clb (product of embodiment 1, content 51.8%) becomes 2.5mg/10ml (2.5mg/kg), 10mg/10ml (10mg/kg), gastric infusion with distilled water diluting.
Many naphthalenes piperazine is neat: 2.5mg/kg is made into the 2.5mg/5ml gastric infusion with distilled water.
Instrument: the SBA-2 mice is kept away dark instrument, is provided by institute of Materia Medica,Chinese Academy of Medical Sciences.
Method: the SPF Kunming mouse, body weight 19-20g, male, divide 5 groups at random, the normal control group, model group, many naphthalenes piperazine is organized (2.5mg/kg) together, and clb organizes (2.5mg/kg and 10mg/kg).The normal control group gavages water, and all the other gavage administration, administration the 8th and carried out mice on the 9th day and keep away dark experiment.Preceding 20 minutes lumbar injection scopolamine hydrobromides (5mg/kg) of study in the 8th day.
Experimental provision is a trained reflex case, is divided into light and shade two parts, has a small holes that mice can be had free passage in two Room, and the copper grid are arranged at the bottom of the case, and wherein the copper grid of bottom, darkroom pass to 36V voltage.During experiment mice put into bright chamber and darkroom dorsad, because of the mice dark and habit of getting into the cave in the family way,, when entering into darkroom four-footed contact copper grid, mice one will be shocked by electricity so can repeatedly pierce the darkroom at the experiment training period, this behavior is mistake, and its normal reaction is for managing to withdraw from the darkroom at once.During training in first day, the record mice entered the number of times in darkroom and enters the time of camera bellows for the first time in 3 minutes.Do experiment after 24 hours again, observing the time that mice in 5 minutes enters camera bellows first is incubation period, and the number of times that mice enters camera bellows is an errors number.
The number of times that mice enters the incubation period in darkroom for the first time and enter the darkroom is added up and respectively organized to experimental result is errors number.Keep away the dark experiment mice as can be seen from following table, model group has been compared highly significant difference with normal group, the success of experimental technique modeling type.Compare with model group, many naphthalenes piperazine is organized together, clb low dosage (2.5mg/kg) group and high dose (10mg/kg) or middle dosage (5mg/kg) group all can significance increase and enter the incubation period in darkroom for the first time and number of times that minimizing enters the darkroom is an errors number, illustrates that many naphthalenes piperazine is neat, clb keeps away the effect that the memory acquisition disturbance that the antagonism scopolamine hydrobromide causes is arranged in the dark experiment mice.The results are shown in following table.
The effect that table 2 clb keeps away the memory acquisition disturbance that the antagonism scopolamine hydrobromide causes in the dark experiment mice
| Group | Dosage | Number of animals | Incubation period (S) | Errors number (inferior) |
| Many naphthalenes of normal control group model group piperazine is organized clb clb together | 2.5mg/kg 2.5mg/kg 10mg/kg | 18 19 18 18 18 | 225.89±100.2 90.6 8±97.8## 171.83±104.62** 161.39±112.75* 153.17±101.6* | 0.72±1.07 2.32±1.06## 1.0±0.77** 1.28±1.32** 1.39±1.20** |
Compare ##P＜0.01 with normal group, compare * P＜0.05, * * P＜0.01 with model group
The effect that table 3 clb keeps away the memory acquisition disturbance that the antagonism scopolamine hydrobromide causes in the dark experiment mice
| Group | Dosage | Number of animals | Incubation period (S) | Errors number (inferior) |
| Many naphthalenes of normal control group model group piperazine is organized clb clb together | 2.5mg/kg 2.5mg/kg 5mg/kg | 12 13 13 12 11 | 157.58±113.50 71.15±64.54# 162.77±111.21** 182.92±106.13** 144.27±100.56** | 1.08±1.00 4.85±1.63## 1.23±1.17** 1.75±1.42** 1.64±1.29** |
Compare ##P＜0.01 with normal group, compare * P＜0.05, * * P＜0.01 with model group
EXPERIMENTAL EXAMPLE 3: cause mouse memory with actidione (CHX) and form the obstacle model
Method: the SPF Kunming mouse, body weight 19-20g, male, divide 5 groups at random, the normal control group, model group, many naphthalenes piperazine is organized (2.5mg/kg) together, and clb organizes (product of embodiment 1, content 51.8%) (2.5mg/kg, 5.0mg/kg and 10mg/kg).The normal control group gavages water, and all the other gavage administration, administration the 9th and carried out diving tower experiment on the 10th day.Preceding 20 minutes lumbar injection actidiones (5mg/kg) of study in the 9th day
Result: detect discovery clb at 2.5mg/kg through the diving tower method, 5mg/kg and 10mg/kg can effectively prolong the incubation period that mice is left office for the first time, reduce mice leave from office number of times, prompting clb causes mouse memory formation obstacle to actidione the improvement effect, and it is neat that effect is equivalent to many naphthalenes piperazine.
Table 4.clb causes mouse memory to CHX and consolidates the influence of obstacle (diving tower experiment) (X ± SEM)
| Group | Dosage (mg/kg) | Incubation period (s) | Errors number (inferior) |
| Many naphthalenes of contrast CHX (model) clb clb clb piperazine is neat | 2.5 5 10 5 | 249±13 186±24### 166±25 210±19 234±31 206±21 | 0.4±0.1 2.0±0.1### 0.5±0.2 0.3±0.1** 0.4±0.1* 0.7±0.2 |
Model group and normal control group be ###P＜0.001 relatively,
Administration group and model group be * P＜0.05 relatively, * * P＜0.01.
Claims (10)
1. a Blume plant extract is at preparation Fructus Alpiniae Oxyphyllae, hypermnesis or prevent and treat purposes in the medicine of diseases such as alzheimer disease, Pai Lixin derivant total content is more than 25% in the wherein said plant extract, preferred Pai Lixin derivant total content is more than 50%, more preferably Pai Lixin derivant total content is 50%-95%, and preferred described Pai Lixin derivant is parishin A, B, C; Described derivant can be a kind of monomeric compound of Pai Lixin derivant, also the mixture of any multiple chemical compound in the Ke Yi Wei Pai Lixin derivant;
Described Pai Lixin derivant structure general formula is as follows:
Wherein, R
1, R
2Be selected from independently of one another with R3:
Deng;
R4 is selected from hydrogen, C1-C6 alkyl (preferable methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group), C1-C6 alkyl phenyl (preferred benzyl), and to hydroxybenzyl, or
Deng;
Glu represents β-D-glucopyranosyl, and Me represents methyl;
Wherein the structural formula of Pai Lixin (parishin) A, B, C is as follows:
2. the Pai Lixin derivant is at preparation Fructus Alpiniae Oxyphyllae, hypermnesis or prevent and treat purposes in the medicine of diseases such as alzheimer disease, and wherein preferred described Pai Lixin derivant is parishin A, B, C; Described derivant can be a kind of monomeric compound of Pai Lixin derivant, also the mixture of any multiple chemical compound in the Ke Yi Wei Pai Lixin derivant;
Described Pai Lixin derivant structure general formula is as follows:
Wherein, R
1, R
2Be selected from independently of one another with R3:
Deng;
R4 is selected from hydrogen, C1-C6 alkyl (preferable methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group), C1-C6 alkyl phenyl (preferred benzyl), and to hydroxybenzyl, or
Deng;
Glu represents β-D-glucopyranosyl, and Me represents methyl; Wherein the structural formula of Pai Lixin (parishin) A, B, C is as follows:
。
3. Blume plant extract that contains the Pai Lixin derivant, Pai Lixin derivant total content is more than 25% in this extract, and preferred its derivant total content of Pai Lixin is more than 50%, and more preferably Pai Lixin derivant total content is 50%-95%;
Wherein said Pai Lixin derivant structure general formula is as follows:
Wherein, R
1, R
2And R
3Be selected from independently of one another:
Deng;
R
4Be selected from hydrogen, C1-C6 alkyl (preferable methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group), C1-C6 alkyl phenyl (preferred benzyl), to hydroxybenzyl, or
Deng;
Glu represents β-D-glucopyranosyl, and Me represents methyl;
Wherein preferred Pai Lixin derivant is Pai Lixin (parishin) A, B, C, and its structural formula is as follows:
。
4. the preparation method of a Blume plant extract is characterized in that this extract obtains by following step:
(1) plant Rhizoma Gastrodiae tuber is pulverized, the aqueous solution with the 50-95%C1-C6 alkylol extracts to the temperature of reflux in room temperature as solvent then, and extracting solution gets extractum through normal pressure or concentrating under reduced pressure;
(2) extractum is refining with chromatographic process, purification, use the eluting solvent eluting, stream part of Pai Lixin derivant is rich in collection, concentrate, filter drying, obtain containing the extract of Pai Lixin derivant, wherein Pai Lixin derivant total content is more than 25%, and preferred Pai Lixin derivant total content is more than 50%, and more preferably Pai Lixin derivant total content is 50%-95%;
Wherein said Pai Lixin derivant structure general formula is as follows:
Wherein, R
1, R
2Be selected from independently of one another with R3:
Deng;
R4 is selected from hydrogen, C1-C6 alkyl (preferable methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group), C1-C6 alkyl phenyl (preferred benzyl), and to hydroxybenzyl, or
Deng;
Glu represents β-D-glucopyranosyl, and Me represents methyl;
Wherein preferred Pai Lixin derivant is Pai Lixin (parishin) A, B, C, and its structural formula is as follows:
5. preparation method according to claim 4 is characterized in that used material plant Rhizoma Gastrodiae is the Chinese crude drug Rhizoma Gastrodiae.
6. preparation method according to claim 4 is characterized in that described C1-C6 alkylol is the mixed solvent of methanol, ethanol, isopropyl alcohol or n-butyl alcohol or their compositions.
7. preparation method according to claim 4, it is characterized in that being used to making with extra care, the chromatographic process of purification is macroporous adsorbent resin chromatography, purification on normal-phase silica gel, reverse phase silica gel chromatograph, perhaps their combination, perhaps extractum is mixed in silica gel or the kieselguhr, dries back with organic solvent or water backflow eluting.
8. preparation method according to claim 4 is characterized in that the used solvent of eluting is a water, the C1-C6 alkylol, as: methanol, ethanol, isopropyl alcohol or n-butyl alcohol etc., halogenated hydrocarbons, as: dichloromethane, chloroform (chloroform) etc., ether solvent, as: ether, methyl tert-butyl ether etc., ketones solvent, as: acetone, 2-butanone etc., esters solvent, as ethyl acetate, Ethyl formate etc., and by the mixed solvent of above-mentioned solvent composition.
9. preparation method according to claim 8 is characterized in that the used solvent of eluting is preferably a kind of or several mixed solvents in chloroform (chloroform), ethyl acetate, ethanol, the first alcohol and water; Particularly, in the described process for purification, when making with extra care with styrene tyle macroporous adsorption resin, eluting solvent is preferably ethanol or the methanol aqueous solution of water and 10-75%; When with the reverse phase silica gel chromatographic refining, eluting solvent is preferably ethanol or the methanol aqueous solution of water and 10-50%; When making with extra care with purification on normal-phase silica gel, eluting solvent is preferably the mixed solvent of chloroform or ethyl acetate and 90-100% ethanol water or methanol composition, and their ratio is preferably 10: 1-2: 1.
10. a Fructus Alpiniae Oxyphyllae, hypermnesis or prevent and treat the pharmaceutical composition of diseases such as alzheimer disease, wherein contain the Blume plant extract that is rich in the Pai Lixin derivant, and pharmaceutically acceptable carrier, described compositions preferably is made into pharmaceutical preparatioies such as tablet, injection, capsule, soft capsule, oral liquid or drop pill, Pai Lixin derivant total content is more than 25% in the preferred Blume plant extract, preferred Pai Lixin derivant total content is more than 50%, and more preferably Pai Lixin derivant total content is 50%-95%;
Wherein said Pai Lixin derivant structure general formula is as follows:
Wherein, R
1, R
2Be selected from independently of one another with R3:
Deng;
R4 is selected from hydrogen, C1-C6 alkyl (preferable methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group), C1-C6 alkyl phenyl (preferred benzyl), and to hydroxybenzyl, or
Deng;
Glu represents β-D-glucopyranosyl, and Me represents methyl;
Wherein preferred Pai Lixin derivant is Pai Lixin (parishin) A, B, C, and its structural formula is as follows:
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