CN110314156A - Hundred can application of the benefit in preparation prevention and treatment central neurotransmitter disorder and the product that trembles - Google Patents

Hundred can application of the benefit in preparation prevention and treatment central neurotransmitter disorder and the product that trembles Download PDF

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CN110314156A
CN110314156A CN201810267478.9A CN201810267478A CN110314156A CN 110314156 A CN110314156 A CN 110314156A CN 201810267478 A CN201810267478 A CN 201810267478A CN 110314156 A CN110314156 A CN 110314156A
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hundred
tremble
disorder
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杜冠华
杨玉林
张雪
周启蒙
吕扬
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Institute of Materia Medica of CAMS
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

It can sharp (5,6,7- trihydroxyflavone the invention discloses hundred;Baicalein) the application in preparation prevention and/or treatment central neurotransmitter disorder and the caused product to tremble, central neurotransmitter disorder mainly includes one or more above states for being higher or lower than normal level in intracerebral content such as nervous transmitter such as glutamic acid etc., monoamine transmitters such as adrenaline etc., polypeptide mediator such as neuropeptide etc. and acetylcholine, it trembles the limbs athletic performance partly or wholly for being primarily referred to as causing due to central neurotransmitter disorder, product includes drug and/or health care product.It is a discovery of the invention that hundred can benefit can substantially reduce tremble caused by a variety of mediator disorders duration and frequency, increase incubation period, it is horizontal to reduce intracerebroventricuacetylcholine acetylcholine.Show hundred can the benefit products to tremble that can be used for preventing and treating central neurotransmitter disorder and be induced, central neurotransmitter to restore disorder is horizontal, alleviates associated tremor symptom provides a kind of active material safely, effectively, economic.

Description

Hundred can application of the benefit in preparation prevention and treatment central neurotransmitter disorder and the product that trembles
Technical field
The present invention relates to hundred can benefit new opplication in medicine preparation, relate generally to hundred can benefit in preparation prevention and/or control Treat the application that central neurotransmitter disorder causes to tremble in drug, in particular to hundred can benefit in preparation prevention and/or treatment maincenter The application in drug and/or health care product that neurotransmitter disorder and caused disease are such as trembled, belongs to pharmaceutical technology field.
Background technique
It will lead to central neurotransmitter Balance disorders after the reduction of cental system neuronal quantity or dysfunction, and maincenter is refreshing Through the representative clinical symptoms of mediator Balance disorders bring first is that limb tremor.
Mainstream hypothesis thinks that the degeneration of dopaminergic neurons of CNS inhibition and dopamine (DA) are horizontal at present, and corresponding Excitatoty acetylcholine (Ach) functional level, the two are in dynamic balance state, once the two balance is destroyed, will occur The performance that body trembles;But cause the factor trembled very much, in addition to Parkinson's disease has and trembles and show, a variety of diseases and a variety of Factor can cause a large amount of mediators in symptom of trembling, especially central nervous system, including monoamine transmitters, amino acids to be passed Matter, choline mediator and polypeptide mediator etc., and also the form of expression trembled is not also identical, and research prevents and treats performance of trembling Drug can pass through different approach.
Clinically, anticholinergic agents such as anisodamine is given, by blocking Acetylcholine Muscarinic Receptor, inhibits the excitement of Ach Property;Or dopamine and its periphery decarboxylase or metabolic enzyme inhibitor are given, central dopamine level is increased, the DA-Ach of maincenter is made Imbalance state is got rid of, recaptures balance, and then alleviate symptom, in addition to this, the equilibrium state that system adjusts mediator is to realize control One of important channel of symptom.
And existing drug focuses on more and directly adjusts single neurotransmitter levels, is also easy to produce all kinds of adverse reactions.And for Whole regulation metabolism central neurotransmitter level influences limited to be also one of deficiency.Especially for the drug for the treatment of Parkinson's disease It is presented with inhibiting effect only for trembling for Parkinson's disease, is made for trembling caused by other factors without directly treatment With, thus, it is well known that antiparkinsonism drug is not typical anti-shudder drug.
Hundred can be sharp, is flavone compound isolated in Lamiaceae plant radix scutellariae dry root, chemical name: 5,6,7- tri- Flavonol;English name: Baicalein, CAS:491-67-8.Its crystalline substance β type is advantage crystal form that can be medicinal, through the Chinese people The approval of pharmacopoeia commission, republic is named as hundred can be sharp, and chemical structure is as follows:
So far seen in hundred can sharp relevant report patent concentrate on three aspects.First is that all kinds of hundred can sharp and derivative extraction point From or chemical synthesis or formulation method and application;Second is that hundred can the various crystal forms (α, beta, gamma) of benefit and the table of other cocrystalization compounds Sign and preparation and application;Third is that hundred can benefit and combinations thereof the relevant different application of various pharmacological activity.
Hundred can the patent in terms of sharp pharmacological activity and related application focus mostly on antipyretic, analgesia, anti-inflammatory, antibacterial, it is antiviral, Antitumor etc., Chinese patent (publication number: CN 105997986A) shows that it is preparing injury of kidney caused by inhibiting hyperuricemia The effect of drug;Chinese patent (publication number: CN 105902535A) shows it in preparation prevention and treatment anti-parkinson drug Application;Chinese patent (publication number: CN 101732411A) shows that it is preparing answering in hyperlipemia-fatty liver drug With.But prevent and/or treat the effect in central neurotransmitter disorder and caused tremble drug and/or health care product in preparation to it There is not yet related patents.
Hundred can benefit bioactivity and the research Reporting of pharmacological action be related to many aspects, mainly include antipyretic, town Bitterly, anti-inflammatory, antibacterial, antiviral and antitumor etc., " hundred can sharp and scutelloside pharmacological action and machine for the article of Xin Wen Yu etc. Progress processed " compared with thorough review hundred can sharp present Research, but without reference to for " central neurotransmitter disorder and its caused Tremble " prevention and treatment.
Bibliography:
Chinese patent (publication number: 105997986 A of CN)
Chinese patent (publication number: 105902535 A of CN)
Chinese patent (publication number: 101732411 A of CN)
Xin Wenyu, Song Junke, He Guorong, Du Guanhua *.Hundred can sharp and scutelloside pharmacological action and Recent Advances in Mechanism. Chinese Journal of New Drugs, 2013,22 (6): 647-653,659.
Summary of the invention
Present invention solves the technical problem that be to provide hundred can benefit in preparation prevention and treatment central neurotransmitter disorder and its caused It trembles and applies in product, thus to restore central neurotransmitter disorder, alleviate to tremble caused by neurotransmitter disorder a kind of peace is provided Full effective solution method.
For this purpose, the present invention provides the following technical scheme that
Invention provides hundred and sharp can apply in preparation prevention and treatment central neurotransmitter disorder and the product that trembles.
Further, it includes but is not limited to nervous centralis that the state of the central neurotransmitter disorder, which includes but is not limited to state, The neurotransmitters such as system acetylcholine, monoamine such as dopamine, amino acids such as glutamic acid decrease or increase, 3,4- dihydroxy The increased abnormality of phenylacetic acid.
Further, the central neurotransmitter disorder includes but is not limited to that various diseases such as inflammation and exogenous material are drawn The variation of the neurotransmitter content risen, the maincenter includes but is not limited to cerebral cortex and corpus straitum.
Further, described tremble main includes but is not limited to the cholinergic-since intracerebroventricuacetylcholine acetylcholine m receptor is directly exciting The movement for the rhythmicity that limbs caused by dopaminergic mediator Balance disorders and other mediator disorders partly or wholly occur, but not Including simple acetylcholine relevant to Parkinson's disease/dopamine balance imbalance.
Further, described hundred can benefit can include that health food and the acceptable auxiliary material of functional food are routinely made with health care product The health care product that agent method is made various prevention and treatment central neurotransmitter disorders and trembles.
Therefore the present invention further relates to the pharmaceutical composition using the compounds of this invention as active constituent.The pharmaceutical composition can It is prepared according to method well known in the art.Can by invention described hundred can benefit with one or more pharmaceutically acceptable solids or Any dosage form used with human or animal is made in liquid excipient and/or auxiliary material combination.The compounds of this invention is in its pharmaceutical composition Content in object is usually 0.1-99%.
Further, the invention further relates to the Halth-care compositions using the compounds of this invention as active constituent.The composition It can be prepared according to method well known in the art.Can by invention described hundred can benefit with can be connect on one or more health care products and food Any dosage form used with human or animal is made in the solid or liquid excipient and/or auxiliary material combination received.The compounds of this invention exists Content in its pharmaceutical composition is usually 0.1-99%.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be stomach Enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin Skin, vagina, rectum etc..
The drug combination dosage form includes oral preparation, injecting medicine-feeding form, skin and mucosa approach form of administration.According to The application of claim 7, it is characterised in that: affiliated oral preparation includes tablet, sustained release agent, capsule, controlled release agent, dripping pill Agent, liquid preparation, the injecting medicine-feeding form include intramuscular injection, intravenous injection, intravenous drip.
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection And infusion), eye drops, nasal drop, lotion and liniment etc.;Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.;Semisolid dosage form can be ointment, gel Agent, paste etc..
The compounds of this invention can be made ordinary preparation or sustained release preparation, controlled release preparation, targeting preparation and each is made Kind particulate delivery system.
In order to which tablet and other solid pharmaceutical preparations is made in the compounds of this invention, can be widely used well known in the art various Excipient, including diluent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sugarcane Sugar, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.;It is wet Agent can be water, ethyl alcohol, isopropanol etc.;It is fine that adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, crystallite Tie up element, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, carboxylic propyl methocel, ethyl cellulose, Acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.;Disintegrating agent can be dried starch, microcrystalline cellulose, low Replace hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate With citric acid, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate etc.;Lubricant and glidant can be talcum Powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.;PH adjustment agent can be phosphate, cruel hydrochlorate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.;Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition can use any well known medication Administration.The dosage of the compounds of this invention pharmaceutical composition according to the property and severity to be prevented or be treated disease, The individual instances of patient or animal, administration route and dosage form etc. can have large-scale variation.In general, the compounds of this invention Daily Suitable dosage ranges be 0.001-500mg/kg weight.Above-mentioned dosage with a dosage unit or can be divided into several doses Unit administration is measured, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
The beneficial effects of the present invention are: the present invention to cause mouse to be trembled model using oxotremorine, to hundred can benefit it is anti- Control central neurotransmitter disorder and the drug that trembles, especially adjusting intracerebroventricuacetylcholine acetylcholine, dopamine and associated metabolites are horizontal, And increase model mice and tremble incubation period, mitigate the mouse duration trembled, the effect for frequency of trembling is investigated, knot Fruit shows, by gastric infusion hundred can benefit can dramatically increase model mice and tremble incubation period, when reducing model mice and trembling lasting Between, frequency of trembling, and reduce intracerebroventricuacetylcholine acetylcholine level, it is horizontal to increase central dopamine and dopamine metabolites, for prevention and treatment Central neurotransmitter disorder and trembling provides a kind of solution safely, effectively, economic.
Detailed description of the invention
Fig. 1 hundred can benefit on oxotremorine tremble model mice tremble incubation period influence.N=8.
Fig. 2 hundred can benefit on oxotremorine tremble model mice tremble the duration influence.N=8.
Fig. 3 hundred can benefit tremble frequency influence to the oxotremorine model mice that trembles.N=8.
Fig. 4 .HPLC-ECD specificity is investigated.
Specific embodiment
To keep the purpose of the present invention, technical solution, advantage clearer, the present invention is made below in conjunction with attached drawing and subordinate list It is described in further detail.
Experimental example 1. hundred can benefit on oxotremorine tremble model mice tremble incubation period influence.
Experimental material: kunming mice is purchased from Fukang biotech inc, China, Beijing.Hundred can be sharp, by middle traditional Chinese medical science Subject institute institute of materia medica Lv Yang professor repurity be prepared into beta crystal (number of patent application: 200710177330.8), efficient liquid Phase chromatography detects purity 98% or more;Oxotremorine (Oxotremorine M) is purchased from Sigma-Aldrich company;U.S. is more Fragrant plant is purchased from Shanghai company, Roche Group;Anisodamine is purchased from Hangzhou Minsheng Medcine Co., Ltd.
Experimental group: mouse is randomly divided into 7 groups, i.e., control group, model group, hundred can sharp low, middle and high dose groups (120, 240,480mg/kg), Madopar group (50mg/kg), anisodamine group (10mg/kg).Except control group and model group stomach-filling physiology Outside salt water, the daily gastric infusion of remaining each group is primary, and continuous 28 days.Respectively at the 1st, 7,14,21,28 day, each group had been administered Oxotremorine 0.15mg/kg is injected intraperitoneally after 1.5h, control group intraperitoneal injection of saline is observed correlation immediately after and referred to Mark.With mouse peritoneal injection oxotremorine time timing be 0, using timer record mouse occur muscular tremor when Between, calculate incubation period.
As a result: animal pattern stomach-filling hundred can be after sharp (120,240 and 480mg/kg), and oxotremorine leads to incubation period of trembling The increase of dosage correlation, as shown in table 1, Fig. 1.
Table 1. hundred can benefit oxotremorine is caused to tremble the influence of incubation period dosage correlation
Compared with the control group, ###:P < 0.001, compared with model group, b, c:P < 0.05, bb, cc, dd, ee:P < 0.01, Bbb, ccc, ddd, eee:P < 0.001.
Experimental example 2. hundred can benefit on oxotremorine tremble model mice tremble the duration influence.N=8.
Experimental group: mouse is randomly divided into 7 groups, i.e., control group, model group, hundred can sharp low, middle and high dose groups (120, 240,480mg/kg), Madopar group (50mg/kg), anisodamine group (10mg/kg), every group 8.Relevant experimental protocols are the same as real Apply example 1.With the time timing of mouse peritoneal injection oxotremorine for 0, there is muscular tremor using timer record mouse Time and muscular tremor end time, calculating are trembled the duration.
As a result: animal pattern stomach-filling hundred can benefit 2 weeks after (120,240 and 480mg/kg) oxotremorine can be substantially reduced Tremble caused by mouse mouse tremble the duration increase, as shown in Fig. 2, table 2.
Table 2. hundred can tremble duration influence of the benefit on mouse of trembling caused by oxotremorine mouse
Compared with the control group, ###:P < 0.001, compared with model group, c:P < 0.05, aa, bb, cc, dd, ee:P < 0.01, Bbb, ccc, ddd, eee:P < 0.001.
Experimental example 3. hundred can benefit tremble frequency influence to the oxotremorine model mice that trembles.N=8.
Experimental group: mouse is randomly divided into 7 groups, i.e., control group, model group, hundred can sharp low, middle and high dose groups (120, 240,480mg/kg), Madopar group (50mg/kg), anisodamine group (10mg/kg), every group 8.Relevant experimental protocols are the same as real Apply example 1.With the time timing of mouse peritoneal injection oxotremorine for 0, there is muscular tremor using timer record mouse Time, the number for using the 5th minute to the 8th minute mouse of counter records to nod up and down as mouse muscle tremble number with Calculating is trembled frequency.
As a result: animal pattern stomach-filling hundred can benefit 2 weeks after (120,240 and 480mg/kg) can significantly reduce oxotremorine institute Cause tremble frequency increase, as shown in Fig. 3, table 3.
Table 3. hundred can be sharp on the increased influence of frequency of trembling caused by oxotremorine
Compared with the control group, ###:P < 0.001, compared with model group, c:P < 0.05, aa, bb, cc, dd, ee:P < 0.01, Bbb, ccc, ddd, eee:P < 0.001.
Experimental example 4. hundred can benefit tremble acetylcholinesterase in model mice brain cortical tissue to oxotremorine (AchE) activity influence.N=8.
Experimental group: mouse is randomly divided into 7 groups, i.e., control group, model group, hundred can sharp low, middle and high dose groups (120, 240,480mg/kg), Madopar group (50mg/kg), anisodamine group (10mg/kg), every group 8.Relevant experimental protocols are the same as real Apply example 1.AchE kit builds up Bioengineering Research Institute purchased from Nanjing.Administration took brain tissue after 28 days, is placed in culture dish and uses Pre- cold saline rinsing, clean filter paper suck cerebral tissue surface moisture and blood, isolate each position of Mice brain tissues, It is saved in -80 DEG C.When experiment, precision weighs brain tissue, is homogenized in the ratio of brain weight and physiological saline 1:9, preparation 10% brain homogenate is centrifuged 10min with 3500r/min, takes supernatant, according to kit specification measurement AchE activity.
As a result: after administration 28 days, hundred can sharp each group (120,240 and 480mg/kg) acetylcholine ester enzyme activity can be dramatically increased Property, brain tissue acetyl choline content is reduced indirectly, as shown in table 4.
Table 4. hundred can benefit to oxotremorine tremble model mice brain cortical tissue acetylcholinesterase (AchE) activity It influences.(N=8).
Compared with the control group, #:P < 0.05, compared with model group, *: P < 0.05, * *: P < 0.01.
Experimental example 5. hundred can benefit the oxotremorine dopamine level in model mice cerebral cortex that trembles is influenced.n =8.
Experimental group: mouse is randomly divided into 7 groups, i.e., control group, model group, hundred can sharp low, middle and high dose groups (120, 240,480mg/kg), Madopar group (50mg/kg), anisodamine group (10mg/kg), every group 8.Relevant experimental protocols are the same as real Apply example 1.Dopamine (DA), dihydroxyphenyl acetic acid (DOPAC), isoprel (IP), perfluorooctane sulfonate (OSA) are purchased from Sigma-Aldrich company.
Solution is prepared: precision weighs DA, DOPAC mediator to be detected, is dissolved in the perchloric acid of 0.05molL-1, obtains end Concentration is the Standard Stock solutions of 0.2mgmL-1;It prepares 0.02molL-1 perchloric acid and (contains IP1.0 μm of olL-1, EDTA 0.5mmolL-1) it is used as homogenate.
Chromatographic condition: mobile phase: 0.1molL-1NaH2PO4Aqueous solution contains 0.85mmolL-1OSA,0.5mmol·L- 1EDTANa2 and 11% methanol, with concentrated phosphoric acid tune pH to 3.25,0.22 μm of miillpore filter filters degassing;Stationary phase: Column MD-150,3 μm of filling stainless steel columns.Operating voltage 400mV, 35 DEG C of column temperature, flow velocity 0.6mLmin-1, 30 μ L of sample volume.
Standard curve: preparing DA, DOPAC concentration respectively is 2000,1000,500,250,125,67.5,32.5ng/g Serial standards are measured under corresponding chromatographic condition using IP as internal standard, respectively with the peak face of DA, DOPAC peak area and IP Product ratio makees linear regression to the various concentration of each standard items, investigates its linear case.32.5~2000ng/g of its quantification range, DOPAC:y (ug/ml)=0.0543x+0.0157 (R2=0.9995), DA:y (ug/ml)=0.0511x+0.033 (R2= 0.9986)。
The processing of materials and sample: taking cryopreserved tissue, and every 100mg is added 200 μ L and is pre-chilled homogenate buffer, ultrasonic 45s, and 4 DEG C, 12000r/min is centrifuged 30min, and secondary centrifuging takes 30 μ L sample introduction of supernatant, detected.
As a result: under HPLC-ECD chromatographic condition, the retention time of DOPAC, DA and IP are respectively 3.8,4.7 and 7.5min, And each component separation property is good, as a result as shown in Figure 4.Hundred can be during sharp each group (120,240 and 480mg/kg) can dramatically increase Pivot dopamine level reduces dopamine metabolites dihydroxyphenyl acetic acid, reduces DOPAC/DA ratio, such as table 5, shown in 6.
Table 5. hundred can benefit on oxotremorine tremble model mice brain cortical tissue dopamine level influence.(n =8).
Compared with the control group, #:P < 0.05, ##:P < 0.01;Compared with model group, *: P < 0.05, * *: P < 0.01.Table 6. Hundred can benefit on oxotremorine tremble model mice Brain striatal tissue dopamine level influence.(N=8).
Compared with the control group, #:P < 0.05, ##:P < 0.01;Compared with model group, *: P < 0.05, * *: P < 0.01.
In conclusion the present invention using oxotremorine induced mice tremble model to hundred can benefit preparation prevention and treatment nervous centralis Symptom of trembling especially is alleviated in mediator disorder and the effect for the drug that trembles, and restores mediator balanced action and is investigated.As a result it shows Show, by gastric infusion hundred can benefit can substantially reduce tremble duration and frequency, increase incubation period, reduce intracerebroventricuacetylcholine acetylcholine It is horizontal to increase central dopamine for level.Therefore, hundred can benefit can restore central neurotransmitter and balance and can be relieved central neurotransmitter What disorder caused trembles.With hundred can benefit for active material, be used alone or/and other compounds with pharmacological activity and/ Or extract composition compound uses, and the prevention and treatment central neurotransmitter of various dosage forms is made according to the conventional preparation method of pharmaceutical field Disorder and the drug and/or health care product to tremble, or compound preparation is formed with drug, for reducing medicine in the case where keeping curative effect The active adverse reaction of object, can for restore central neurotransmitter balance, alleviate associated tremor symptom provide it is a kind of safely, have Effect, economic product.
Finally, it is stated that the above experimental example is only used to illustrate the technical scheme of the present invention rather than limits, although passing through ginseng According to optimization experiment example of the invention, invention has been described, but it should be understood by one skilled in the art that can be Various changes are made in implementation and to it in details, without departing from the present invention defined by appended claims specification Spirit and scope.

Claims (10)

1. 5,6,7- trihydroxyflavone and its pharmaceutically acceptable salt and crystal form state as shown in general formula I prevent in preparation And/or the application in treatment central neurotransmitter disorder and the caused product to tremble
2. application according to claim 1, which is characterized in that the central neurotransmitter disorder includes central nervous system acetyl Choline, monoamine, amino acid neurotransmitter decrease or increase, 3,4-Dihydroxyphenylacetic acid increased abnormality.
3. application according to claim 2, which is characterized in that the monoamine neurotransmitter is dopamine, amino acids nerve Mediator is glutamic acid.
4. application according to claim 2, which is characterized in that the central neurotransmitter disorder includes various diseases and external source The variation of neurotransmitter content caused by property substance, the maincenter includes cerebral cortex and corpus straitum.
5. application according to claim 4, which is characterized in that the various diseases include inflammation.
6. application according to claim 1, which is characterized in that described to tremble including since intracerebroventricuacetylcholine acetylcholine m receptor directly swashs It is dynamic, the rhythmicity that limbs caused by cholinergic-dopaminergic mediator Balance disorders and other mediator disorders partly or wholly occur Movement.
7. a kind of pharmaceutical composition answering in preparation prevention and/or treatment central neurotransmitter disorder and the caused product to tremble With, which is characterized in that contain effective dose Noroxylin,5,6,7-Trihydroxy flavone described in claim 1 and its pharmaceutically acceptable Salt, crystal form and pharmaceutically acceptable carrier and other active components.
8. application according to claim 7, which is characterized in that the pharmaceutical composition is selected from oral preparation, is administered to medicament Type, skin and mucosa approach form of administration.
9. application according to claim 9, which is characterized in that oral preparation is selected from tablet, sustained release agent, capsule, controlled release agent, drop Pill, liquid preparation, the injecting medicine-feeding form are selected from intramuscular injection, intravenous injection, intravenous drip.
10. application according to claim 1, which is characterized in that the product is selected from drug, health care product or food.
CN201810267478.9A 2018-03-28 2018-03-28 Hundred can application of the benefit in preparation prevention and treatment central neurotransmitter disorder and the product that trembles Pending CN110314156A (en)

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