CN101797267A - Medical composite for preventing and curing Alzheimer's disease - Google Patents
Medical composite for preventing and curing Alzheimer's disease Download PDFInfo
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- CN101797267A CN101797267A CN201010161231A CN201010161231A CN101797267A CN 101797267 A CN101797267 A CN 101797267A CN 201010161231 A CN201010161231 A CN 201010161231A CN 201010161231 A CN201010161231 A CN 201010161231A CN 101797267 A CN101797267 A CN 101797267A
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Abstract
The invention discloses a medical composite for preventing and curing Alzheimer's disease (AD). The composite comprises the following raw materials in parts by weight: 10-40 parts of hyperin, 20-80 parts of icariin and 5-20 parts of Schisandrin B. Experiments of rat place navigation and space exploration prove that the medical composite of the invention can increase the ability of spatial learning and memory of AD rat model, namely reduce the escape latency and scouting distance and obviously increase the percent of scouting time in quadrant of original platform to total time and the percent of scouting distance in quadrant of original platform to total distance in space exploration experiments. Therefore, the extract composite can be used for preventing and curing AD.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for senile dementia prevention and cure.
Background technology
Enter the continuous quickening of paces to aging society along with the whole world, various nervus retrogression infirmitiess of age, become threat health in human old age as diseases such as mild cognitive impairment, senile dementias, reduce the important risk factor of life of elderly person quality, brought serious financial burden and heavy stress for society and family.Therefore, exploitation improves cognitive dysfunction, and the medicine of treatment senile dementia becomes the research emphasis of global various countries medical worker, is subjected to the great attention of Chinese and western medical circle.
West the world of medicine studies anti-mild cognitive impairment and mainly resists (antiinflammatories around four based on the thinking of the medicine for senile dementia of Alzheimer, antioxidation, anti-cholesterol, directed against amyloid-beta albumen) and two intend (intend choline and intend glutamic acid) and carry out, the medicine of the treatment Alzheimer (AD) of FDA's approval at present comprises tacrine, donepezil, Li Fansi's is bright, galantamine and memantine etc., though these medicines can improve the symptom of dementia patients in a short time, but can not delay advancing of disease, and wherein some medicine also has stronger toxic and side effects to liver, use hardly at present, some drug price costliness, patient and family members thereof are difficult to bear, therefore, urgent need will have been developed good efficacy, few side effects, and low-cost newtype drug.
Class diseases such as the mild cognitive dysfunction in the modern medicine, senile dementia probably are covered by senile disease categories such as " dementia " in traditional traditional Chinese medical science, " forgetful ", " melancholia ", " electric shock ", " tremor syndrome ", " shaking ".Generally " husband essence person, root of life also " (" element is asked golden deficient the truth opinion "), therefore, the traditional Chinese medical science thinks that whether old and feeble whether the essence in kidney abundance be decision human body essential condition.And the senile disease of classes such as " dementia ", " forgetful ", how because of deficiency of the kidney, the hollow one-tenth of brains is sick, therefore takes the kidney invigorating and essence nourishing method to treat more.
Summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical composition that prevents and/or treats senile dementia.
Pharmaceutical composition provided by the present invention is made up of the raw material of following mass parts: hyperin 10-40, icariin 20-80 and schisandrin B 5-20.
Pharmaceutical composition of the present invention can further be made up of the raw material of following mass parts: hyperin 18-23, icariin 35-42 and schisandrin B 8-12.
Used raw material hyperin among the present invention has another name called Quercetin-3-O-β-D-galactopyranoside, belongs to the flavonol glycosides compounds, and its chemical structural formula as shown in Equation 1.This chemical compound extensively is present in the various plants, in the fruit and herb as Hypericaceae, Rosaceae, campanulaceae, Labiatae, Ericaceae, kurrajong, Guttiferae, pulse family and Celastraceae etc., obtain so can from plant, extract, obtain hyperin as from Semen Cuscutae, extracting.Also can obtain, or obtain by commercial sources according to disclosed method in the prior art is synthetic.
Used raw material icariin among the present invention, its chemical structural formula as shown in Equation 2.This chemical compound extensively is present in the stem and leaf of Berberidaceae plant Herba Epimedii (Epimedium grandiflorum Morr.), Herba Epimedii (E.koreanumNakai), in the lobus cardiacus Herba Epimedii plants such as (E.brevicornum Maxim.), obtain so can from above-mentioned plant, extract.Also can obtain, or obtain by commercial sources according to disclosed method in the prior art is synthetic.
Used raw material schisandrin B among the present invention, its chemical structural formula as shown in Equation 3.What this chemical compound can extract from Fructus Schisandrae Chinensis obtains, and also can obtain according to disclosed method in the prior art is synthetic, or obtain by commercial sources.
A further object of the present invention provides the application of described pharmaceutical composition.
To be said composition prevent and/or treat the application in the senile dementia disease drug or improve application in the cognitive dysfunction medicine in preparation in preparation in the application of pharmaceutical composition provided by the present invention.Described senile dementia specifically can be Alzheimer.
Simultaneously, be the medicine that prevents and/or treats senile dementia made of active component with pharmaceutical composition provided by the present invention and improve the cognitive dysfunction medicine and also belong to protection scope of the present invention.
Described medicine can import body such as muscle, Intradermal, subcutaneous, vein or mucosal tissue by the method for oral, external, injection, infiltration, absorption, physics or chemistry mediation; Or mixed by other material or wrap up the back and import body.
When needing, in said medicine, can also add one or more pharmaceutically acceptable carriers.Described carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier and the lubricant etc. of pharmaceutical field routine.
This medicine can be made pharmaceutically acceptable any dosage form, as tablet, injection, capsule, granule, pill, micropill, powder, drop pill, decoction, syrup, mixture, soft extract and extractum etc.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of Chinese medicine preparation.
The using dosage of the above-mentioned medicine that prevents and/or treats senile dementia and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the order of severity of disease and diagnosis and treatment doctor's the subjective judgment of patient's age, body weight, sex, natural health situation, nutriture, chemical compound.Those skilled in the art can easily determine pharmaceutical composition using dosage and using method according to above-mentioned factor.
Evidence: through rat orientation navigation and space exploration experiment, total flavones of the present invention and total polysaccharides compositions group can improve the space learning memory ability of AD (Alzheimer) rat model--and shorten its escape latency and detection range and significantly increase the percentage ratio that accounts for original platform place quadrant search time and distance total time and distance in the space exploration experiment.And then show that pharmaceutical composition of the present invention can be used for treating senile dementia, especially treat senile dementia early stage (in earlier stage) as Alzheimer, improve patient's cognitive dysfunction, delay the development of patient's cerebral atrophy, improve patient's memory, especially deficiency of kidney essence type patient in dull-witted early stage, it is the maximum characteristics of this pharmaceutical composition that the kidney invigorating and essence nourishing is given birth to marrow.
The specific embodiment
The present invention will be described below by specific embodiment, but the present invention is not limited thereto.
Experimental technique described in the following embodiment if no special instructions, is conventional method; Described reagent and biomaterial if no special instructions, all can obtain from commercial channels.
Its raw material source is as follows among the following embodiment:
Icariin: Tianjin one side Science and Technology Ltd., BBT00838
Hyperin: Tianjin one side Science and Technology Ltd., BBT00398
Schisandrin B: Nat'l Pharmaceutical ﹠ Biological Products Control Institute, 110765-200205.
The capsule of embodiment 1, pharmaceutical compositions
Take by weighing each raw material according to following mass parts: hyperin 20, icariin 40, schisandrin B 10; Said medicine is mixed the back to add conventional adjuvant according to the preparation technology of the capsule of routine and makes.
The tablet of embodiment 2, pharmaceutical compositions
Take by weighing each raw material according to following mass parts: hyperin 40, icariin 20, schisandrin B 15; Said medicine is mixed the back to add conventional adjuvant according to the preparation technology of the tablet of routine and makes.
The capsule of embodiment 3, pharmaceutical compositions
Take by weighing each raw material according to following mass parts: hyperin 10, icariin 80, schisandrin B 5; Said medicine is mixed the back to add conventional adjuvant according to the preparation technology of the capsule of routine and makes.
The oral liquid of embodiment 4, pharmaceutical compositions
Take by weighing each raw material according to following mass parts: hyperin 20, icariin 80, schisandrin B 20; Said medicine is mixed the back to add conventional adjuvant according to the preparation technology of the oral liquid of routine and makes.
Embodiment 5, pharmaceutical composition of the present invention are for the influence of dementia rats ability of learning and memory
1, material
1.1 animal: SD male rat (SPF grade), body weight 285～315g provides (credit number SCXK-army-2007-004) by Chinese Military Medical Science Institute scientific experiments animal center.
1.2 reagent medicine: 1) trial drug: get compositions A with 20: 40: 10 ratio compatibility of mass ratio in hyperin, icariin, schisandrin B; Get compositions B in hyperin, icariin, schisandrin B with 20: 40: 0.4 ratio compatibility of mass ratio; 2) positive control drug is selected the huperzine A sheet for use, the too imperial Pharmaceutical product in Henan, lot number: H10940156; 3) A β
25-35Available from Sigma company, the physiological saline solution dissolving is mixed with 5 μ g/ml, and 37 ℃ were worn out 7 days, and-20 ℃ of preservations are standby.
1.3 experimental apparatus: SN-3N brain solid positioner (Japanese Narishige), DMS-2Morris water maze system (institute of Materia Medica,Chinese Academy of Medical Sciences).
2, method
2.1 make up the AD rat model
After the rat adaptability is fed 3d, with 2% pentobarbital sodium intraperitoneal anesthesia (40～50mg/kg body weight), be fixed on the brain solid positioner, head is by skin, skin is cut in iodine tincture sterilization back, " rat brain stereotaxic atlas " with reference to the bag new people, select the right side tricorn to be the injection target area, in bregma 1.0mm backward, the other 1.7mm place that opens of center line opens skull with the three edged needle brill, exposes cerebral dura mater, reuse 5 μ l microsyringes are from brain Surface Vertical inserting needle 4.0mm, 5 μ l slowly inject (injection length is no less than 5min) with 10mMA β 25-35 solution, slowly remove pin, sew up wound behind let the acupuncture needle remain at a certain point the 2min; After the sham operated rats brill is opened skull is sew up wound.The conventional lumbar injection benzathine benzylpenicillin of each treated animal postoperative infection.Treat that the clear-headed back treatment of animal group promptly begins gastric infusion.
2.2 medication
Grouping adopts the table of random number method that rat is divided into four groups: blank group, model group, compositions A group, compositions B group, the positive medicine matched group of huperzine A sheet.Every group 6.Dosage is 20 times of adult's clinical dosage: pharmaceutical composition 15mgKg
-1D
-1, huperzine A sheet 20mgKg
-1D
-1All medicines are all given rat oral gavage with the distilled water wiring solution-forming, every day 1 time, and each 2ml, blank and model group are then irritated stomach with the equal-volume distilled water, carry out water maze laboratory behind the 15d continuously.
2.3 behavioristics's experimental technique
Water maze is made up of round pool, black platform and recording system 3 parts.Pool diameter (120 * 50 * 30) cm; Black is dyed with ink in the pond, and water temperature remains on 22 ℃-26 ℃; The pond is placed on the central authorities of 1 cabin.Arbitrarily hang closely visual cues of two objects conducts on the pool wall, indoor door, window, group, the first-class formation long distance vision hint of shooting.Platform in 2cm under water, does not have the surface of several apertures to provide a rat to stand firm easily above.The water maze test comprises orientation navigation test (place navigation) and the primary space exploratory experiment (spatial probetest) of continuous 5d.
The orientation navigation test:
1d puts into pond (not putting into platform) free swimming 2min with rat before the test, makes it be familiar with environment in the labyrinth.Test lasts 5d, divides two time periods of upper and lower noon every day, each time period test 4 times, every day totally 8 times.During the test beginning, platform is placed on the quadrant mid point of near-end, platform is hidden in underwater 1cm, pool wall in the middle part of 4 quadrants in pond is put into the pond with rat leggiero towards pool wall, automatic camera system log (SYSLOG) rat seeks the time (escape latency) and the swimming approach (process) of platform, and computer writes down above-mentioned data automatically; Setting 120s is the longest escape latency, stops record behind the 120s automatically.If rat is found platform in 120s, write down its actual escape latency; If do not find platform at 120s, by the experimenter it to be drawn upper mounting plate and stops 10s, escape latency is designated as 120s.
The space exploration test:
6d removes platform, allows rat from the mid point entry free swimming 120s of original platform offside quadrant tub wall, writes down its swimming track, and software analysis calculates animal in used time of all quadrants and all quadrants path length.Calculate animal and account for the percentage ratio of escape latency, account for the percentage ratio of detection range in the path length of original platform quadrant at original platform place quadrant swimming time.
2.4 statistical method
Statistical procedures: data are with mean ± standard deviation
The SPSS10.0 statistical analysis software is adopted in expression.Orientation navigation experiment adopts multivariate analysis of variance (M-ANOVA), and one factor analysis of variance (OneWay ANOVA) is adopted in the space exploration experiment, relatively adopts the LDS method between group in twos.
3, result
3.1 pharmaceutical composition is to the influence of AD rat model orientation navigation test escape latency
Table 1, each group are to the influence of escape latency and detection range in the AD rat orientation navigation experiment
Annotate: compare with model group
1)P＜0.05
Table 2, each group in the AD rat space exploration experiment in the influence of the percentage ratio of original platform place quadrant search time and distance
Annotate: compare with model group
2)P＜0.01; Compare with the blank group
3)P＜0.01
The result shows: through rat orientation navigation and space exploration experiment, hyperin, icariin and schisandrin B compositions A can improve the space learning memory ability of AD rat model--and shorten its escape latency and detection range and significantly increase the percentage ratio that accounts for original platform place quadrant search time and distance total time and distance in the space exploration experiment.
Embodiment 6, pharmaceutical composition for dementia rats in the enhanced influence of body long time journey
1, material
1.1 animal: with embodiment 5.
1.2 reagent medicine: with embodiment 5.
1.3 experimental apparatus: SN-3N brain solid positioner (Japanese Narishige), VC-11 memory oscilloscope (Japanese Nihon Konden), SEN-7203 three road electronic stimulators (Japanese Nihon Konden), SS-202J stimulus isolator (Japanese Nihon Konden).
2, method
2.1 make up the AD rat model with embodiment 5.
2.2 medication is with embodiment 5.
2.3 electrophysiology experimental technique
(1) heeling-in of electrode is with 20% urethane (urethane, 1.2g/kg, ip.) anesthetized animal, and be fixed on the stereotaxic instrument, positioning of electrode is with reference to pellegrino rat brain collection of illustrative plates, and the bipolar stimulation electrode is imbedded at preceding perforating fibers (the perforant path of entorhinal area, PP), its elements of a fix are AP-7.5mm, L4.2mm, H3.0mm; The recording electrode coordinate is AP-3.8mm, L2.5mm, and H3.5mm is positioned at the granular cell layer of homonymy hippocampal dentate.Bore the aperture that a diameter is 1.5mm at above-mentioned coordinate position, difference heeling-in recording electrode and stimulating electrode, adjust the position of stimulating electrode and recording electrode, (populationspike in the time of PS) fixes electrode to find stimulation with constant intensity to record maximum population spike.
(2) the extracellular recording method is adopted in record and the observation of bringing out current potential.(frequency is 1/30Hz to testing stimulus, ripple is wide to be the square wave of 0.1ms) by after the electronic stimulator generation, transfer to PP through stimulus isolator and stimulating electrode, the action potential that brings out shows on memory oscilloscope through biological amplifier, and import computer analysis simultaneously, write down the PS amplitude, as the excitatoty index of DG granular cell group.Adjust stimulus intensity, adopt cause the required stimulus intensity of maximum PS amplitude 1/2 as testing stimulus intensity, the testing stimulus intensive parameter is invariable in the whole experiment.
(3) the granular cell layer LTP of HFS parameter hippocampal dentate is induced by 10 HFS that go here and there 200Hz, and every train is made up of the square wave stimulation of 5 wide 0.1ms of ripple, and stimulus intervals is 200ms, and stimulus intensity is identical with testing stimulus.
(4) each testing stimulus of the collection of data all induces a PS, with the PS amplitude of the meansigma methods after continuous 10 PS amplitudes stack as a time point, meansigma methods with the PS amplitude of measured 6 time points of 30min before the administration is transmitted level as the own foundation synapse, relative value (%) expression of the synapse transmission level of each time point relatively to draw with basic synapse transmission level.
2.5 statistical method
Statistical procedures: electrophysiology is calculated as follows the PS increasing degree: the PS amplitude before PS increasing degree=(the PS amplitude after the administration before the PS amplitude-administration of certain time point)/administration.The t check is used for comparing between group.There is statistical significance P＜0.05 for difference.
3, result
Respectively organize the enhanced comparison of PS amplitude behind table 3 high frequency stimulation
Group PS amplification (%)
Blank group 220.8 ± 3.6
▲ ▲ #
Model group 173.4 ± 4.5
Huperzine A group 210.3 ± 4.7
▲ ▲ #*
Pharmaceutical composition A group 197.15 ± 4.55
▲ * *
Pharmaceutical composition B group 178.8 ± 4.67
Annotate: compare with model group, ▲ P＜0.05, ▲ ▲ P＜0.01; Compare #P＜0.01 with total side's group; Compare * P＜0.05, * * P＜0.01 with the blank group.
As shown in table 3, the amplitude of each treated animal PS behind high frequency stimulation increases before all stimulating, and shows that each treated animal hippocampal dentate all has the formation of LTP.Though model group PS has certain enhancing, be starkly lower than blank group (P＜0.01); The PS amplitude strengthens obviously greater than model group (P＜0.01) behind the huperzine A group high frequency stimulation, and pharmaceutical composition A group and model group compare, and amplitude also has increase (P＜0.05), and pharmaceutical composition B group increasing degree and model group be not statistically significant relatively.
Claims (10)
1. a pharmaceutical composition that prevents and/or treats senile dementia is made up of the raw material of following mass parts: hyperin 10-40, icariin 20-80 and schisandrin B 5-20.
2. pharmaceutical composition according to claim 1 is characterized in that: described pharmaceutical composition is made up of the raw material of following mass parts: hyperin 18-23, icariin 35-42 and schisandrin B 8-12.
3. pharmaceutical composition according to claim 2 is characterized in that: described pharmaceutical composition is made up of the raw material of following mass parts: hyperin 20, icariin 40 and schisandrin B 10.
4. one kind prevents and/or treats the senile dementia disease drug, and its active component is arbitrary described pharmaceutical composition among the claim 1-3.
5. medicine according to claim 7 is characterized in that: the dosage form of described medicine is pharmaceutically acceptable any one dosage form; Be preferably peroral dosage form.
6. one kind is improved the cognitive dysfunction medicine, and its active component is arbitrary described pharmaceutical composition among the claim 1-3.
7. medicine according to claim 6 is characterized in that: the dosage form of described medicine is pharmaceutically acceptable any one dosage form; Be preferably peroral dosage form.
8. the application of arbitrary described pharmaceutical composition in the following medicine of preparation among the claim 1-3: 1) prevent and/or treat the senile dementia disease drug, described senile dementia is preferably Alzheimer disease; 2) improve the cognitive dysfunction medicine; 3) improve Alzheimer disease rat model space learning memory ability medicine.
9. application according to claim 8 is characterized in that: described senile dementia is an Alzheimer disease.
10. application according to claim 8, it is characterized in that: improve described spatial memory learning capacity and show as: in the orientation navigation test, shorten its escape latency and detection range, and original platform place quadrant accounts for the percentage ratio of total time search time in the increase space exploration experiment, and detection range accounts for the percentage ratio of distance.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102178664A (en) * | 2011-04-21 | 2011-09-14 | 沈阳药科大学 | New application of schizandrol A, schizandrin and schizandrol extract to prevention and treatment of senile dementia |
| CN102397285A (en) * | 2011-12-12 | 2012-04-04 | 新乡医学院 | Application of hyperin in preparation of medicines for resisting vascular dementia |
| JP2017075112A (en) * | 2015-10-14 | 2017-04-20 | ネイチャーパワー株式会社 | Composition against dementia |
| JP2017145266A (en) * | 2017-06-06 | 2017-08-24 | ネイチャーパワー株式会社 | Anti-dementia composition |
| CN113973778A (en) * | 2021-12-15 | 2022-01-28 | 大连医科大学附属第一医院 | Method for preventing and treating senile dementia and improving learning and memory based on terahertz wave intervention |
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| CN102397285A (en) * | 2011-12-12 | 2012-04-04 | 新乡医学院 | Application of hyperin in preparation of medicines for resisting vascular dementia |
| JP2017075112A (en) * | 2015-10-14 | 2017-04-20 | ネイチャーパワー株式会社 | Composition against dementia |
| JP2017145266A (en) * | 2017-06-06 | 2017-08-24 | ネイチャーパワー株式会社 | Anti-dementia composition |
| CN113973778A (en) * | 2021-12-15 | 2022-01-28 | 大连医科大学附属第一医院 | Method for preventing and treating senile dementia and improving learning and memory based on terahertz wave intervention |
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| CN101797267B (en) | 2012-03-21 |
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