CN103751197A - New use of stibene glucoside in preparing medicament for treating Alzheimer disease - Google Patents
New use of stibene glucoside in preparing medicament for treating Alzheimer disease Download PDFInfo
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Abstract
The invention aims to disclose new use of stibene glucoside in preparing medicament for treating Alzheimer disease. Experiments in which APP695V717I transgenic mouse is used to simulate nerve cell damage in Alzheimer disease prove that pre-administered stibene glucoside can significantly improve behavioral disorders of model mouse by improving brain blood circulation, reducing expression of apoptosis factor Fas/FasL and inhibiting excitatory amino acid level, suggesting that stibene glucoside has distinct protective effect on nerve cell damage in Alzheimer disease. Stibene glucoside prevents and treats Alzheimer disease through multi-target action, stibene glucoside and related adjuvants can be prepared into health products or medicaments for improving cognitive function and treating Alzheimer disease by conventional preparation method. The health products or medicaments can be used for delaying and improving cognitive function and slowing down the progression of Alzheimer disease, and improving physical constitution and life quality of the elderly.
Description
Technical field
The present invention relates to a kind of new medical usage of stilbene glucoside, relate in particular in the medicine of preparation control Alzheimer for improving Alzheimer midbrain circulatory function deficiency, reducing antiapoptotic factors Fas/FasL overexpression, suppress the new purposes that excitatory amino acid level increases, belong to pharmaceutical chemistry field.
Background technology
Stilbene glucoside (2,3,5,4-tetrahydroxystilbene-2-O-β-D glucoside, Tetrahydroxy Stilbene Glycoside, TSG) belongs to Polyhydroxystibene, and molecular formula is C20H22O9, and molecular weight is 406, and molecular structure is as follows:
Stilbene glucoside is designated hereinafter simply as TSG, can directly on market, buy and obtain, and can to it, carry out content analysis by high performance liquid chromatography.
Alzheimer (Alzheimer ' s disease, AD) be a kind of common old nervous system disease.This disease concealment onset, main manifestations is hypomnesis and the cognitive dysfunction of slowly progress.Epidemiological study demonstration, Alzheimer prevalence accounts for more than 60 years old old people's 10% left and right, and sickness rate is ascendant trend year by year.Because this sick pathogenesis is illustrated so far not yet, think at present beta-amyloyd peptide (β-amyloid, A β) neurotoxic effect be the key factor of Alzheimer formation and development, but clinically still without Therapeutic Method targetedly, at present the main inhibitor that adopts cholinesterase is used for the treatment of Alzheimer as donepezil etc., controversies in hormone replacement in the elderly can be used for menopausal women, can postpone or alleviate the generation of memory loss.These medicines have certain effect improving aspect patient's clinical symptoms, but also exist the situations such as the many or curative effect of untoward reaction is dissatisfied, have limited to a certain extent their use, are therefore necessary to seek new Therapeutic Method.
In clinical, Chinese Traditional Medicine has good therapeutic effect to Alzheimer, for the treatment research of primary disease provides thinking.The traditional Chinese medical science is attributed to Alzheimer the categories such as " forgetful " " slow-witted disease " at present, think its morbidity with interior because main, sick position is at brain, brains inanition, insufficiency of vital energy and blood causes gods and loses and support, because of kidney storing essence, the logical brain of raw marrow, therefore treatment is main mainly with kidney tonifying, essence replenishing class Chinese medicine.At present conventional kidney tonifying, essence replenishing class Chinese medicine Radix Polygoni Multiflori be few section Plant-Polygonum (
polygonum Multifl-orum Thunb.) dried root, begin to be loaded in Song dynasty work < < Kaibao Bencao > >, record its sweet in the mouth and puckery, tepor is not dry, can nourishing the blood and yin, kidney tonifying, essence replenishing.Document and our research show that Chinese medicine Radix Polygoni Multiflori has defying age and neuroprotective, can effectively improve going down and learning memory disorder of brain function.The main component of Radix Polygoni Multiflori has anthraquinone analog compound, stilbene glycosides compound, amino acids, chromone compounds, lecithin, trace element etc.Wherein, 2,3,5,4-tetrahydroxystilbene-2-O-β-D glucoside (being called for short stilbene glucoside, Tetrahydroxy Stilbene Glycoside, TSG) is distinctive main bioactive ingredients in Radix Polygoni Multiflori extract, good water solubility, the index of its content Chang Zuowei Radix Polygoni Multiflori medical material and quality of the pharmaceutical preparations control.
Up to now, still do not find that stilbene glucoside is by improving cerebral circulation insufficiency of function, apoptosis inhibit factor Fas/FasL overexpression, reduces excitatory amino acid level and increases, and prevents and treats the pharmacological function report of Alzheimer.
Alzheimer is as one of old common disease, to occur that in early days the Cognitive function changes such as hypomnesis are as main, wherein senile plaque is one of main pathological characters of Alzheimer, and Fibrotic amyloid beta (A β) is the main component that forms senile plaque.Therefore, the neurotoxic effect of amyloid beta is the key factor in onset of Alzheimer disease process.
In current research, find, in Alzheimer, around patient, cerebral cortex blood flow (CBF) changes, and in prompting Alzheimer, cerebral microcirculation disturbance may be also an important step of disease progression.Its possible former because: in onset of Alzheimer disease, the local inflammation reaction that amyloid beta causes causes vascular permeability to increase, local microcirculation hyperemia, blood perfusion dysfunction; On the other hand, amyloid beta deposits and causes microcirculatory vascular luminal stenosis in blood vessel, the obturation of even subsiding, microcirculation dysfunction.Therefore in the pathological change of Alzheimer, exist " microangiopathies ".
Fas gene is apoptotic signal gene, and its gene outcome Fas albumen is a kind of receptor of apoptosis signal.Fas part (Fas ligand, FasL) belongs to tumor necrosis factor (TNF) superfamily.Fas/FasL system plays an important role in apoptosis, is one of topmost approach in apoptosis.Fas, FasL be equal up-regulated in the cerebral tissue of Alzheimer and the exsomatizednerve unit of amyloid-beta processing.In addition, FasL expresses significantly in the dystrophic neural axon of senile plaques, neurofilament positive expression to be increased, and in prompting FasL Ahl tribulus sea silent sickness cerebral tissue, caspase activates closely related with aixs cylinder apoptosis.Amyloid-beta can cause the neuronal damage of Fas and FasL normal expression, and in the neuron of Fas or FasL deexcitation sudden change, the nerve injury that this amyloid-beta causes is obviously lowered, this prompting Fas/FasL system may participate in a series of pathophysiological processes of Alzheimer, as neuron loss, axonal degeneration etc.
Excitatory amino acid (EAA) is to participate in the movable important mediator such as neuronal excitability transmission, proliferation, excitatory toxicity.When excitatory amino acid a large amount of discharge or reuptake is obstructed in nervous system, can cause amino acids mediator Developmental and Metabolic Disorder.Its Glutamic Acid (Glu) and aspartic acid (Asp) are important excitatory neurotransmitters in brain, play a part very important at nervous system in growing, send out, learn, remember.The neurotoxicity that experimental results show that excitatory amino acid has following effect link: in Alzheimer, amyloid beta can suppress the Hippocampus glial cell Sugar intake of cultivation and the transhipment of excitatory amino acid, thereby produces toxic action; Excessive excitatory amino acid activates N-methyl-D-aspartate (NMDA) receptor, cause excitatory neuron LLD, cause ion, osmotic pressure and electrochemical change, make its regulation and control calcium channel open, stream in the outer calcium ion of born of the same parents is a large amount of, cause intracellular calcium overload, result causes cellular swelling necrosis; It is mainly pathologic long-term potential (LTP) in hippocampus that the extraordinary release of excitatory amino acid has caused, and has likely caused later information conductive obstruction, forms learning and memory defect.
Summary of the invention
In onset of Alzheimer disease, cerebral microcirculation disturbance is the important step of disease progression, Fas/FasL system is one of topmost approach of apoptosis, excitatory amino acid (EAA) is the key factor of patient's learning and memory defect, stilbene glucoside can promote that in brain, the circulation of part vessel side branch is open, reducing surrounding tissue blood vessel stimulates amyloid-beta toxic damages, makes blood vessel and histiocytic compensation be tending towards stable state, and brain internal recycle function increases; Stilbene glucoside is suppressed at the Fas/FasL overexpression playing an important role in apoptosis process, Neuron Apoptosis and neuron loss in the regulation and control Alzheimer course of disease; Stilbene glucoside can be by suppressing the excessive release of excitatory amino acid or stoping its reuptake, and promotion information is transmitted, thereby reaches cognitive functions such as improving learning and memory.
More than point out stilbene glucoside, by the pharmacological action of many target spots, neural cell injury in Alzheimer is had to significant protective effect, can significantly improve behavioristics's obstacle of Alzheimer.
The object of this invention is to provide the new purposes in preparation control Alzheimer medicine, stilbene glucoside can be applicable to preparation for the health product or the medicine that improve Alzheimer cognitive function.The dosage form that stilbene glucoside and pharmaceutically acceptable salt thereof, ester or sugar and excipient etc. can be prepared into is the pharmaceutically acceptable dosage forms such as tablet, capsule, injection, granule.Show that this compound is with a wide range of applications for the preparation of control Alzheimer medicine.Above-mentioned health product and medicine can be used for delaying and improve cognitive decrease relevant disease as the disease of Alzheimer, improve old people's physical constitution and quality of life.
Accompanying drawing explanation
Fig. 1 is the search strategy figure of Normal group mice, this group mice can rely on spatial cues to find platform, in the search of target quadrant, also frequently pass through original platform district for a long time, its movement locus concentrates on target quadrant, be trend formula, between search concealment plateau, at target quadrant, stopped for 53.1% time (and at offside quadrant, not stopping), 5 times, spanning platform district.
Fig. 2 is the search strategy figure of model group mice, this group Mus is more swum around pool wall, range of activity is large, less trip is near original platform, movement locus is random mode, at target quadrant, stop 32.6% time (and having stopped for 21.5% time at offside quadrant), there is no spanning platform district.
Fig. 3 is the search strategy figure of TSG intervention group mice, this group Mus also shows certain search strategy, range of activity concentrates on target quadrant and passes through original platform position, its movement locus is also obvious trend formula, at target quadrant, 41.8% time (and having stopped for 12.0% time at offside quadrant), 1 time, spanning platform district have been stopped.
Fig. 4 is three groups of experiment mice Hippocampal CA 1 apoptosis rate histogram analysis, and ★ represents and matched group comparison in the drawings,
p< 0.01; ▲ represent and model group comparison
p< 0.05.
Fig. 5 is the mRNA relative expression quantity electrophoresis pattern of three groups of experiment mice Hippocampus position Fas antiapoptotic factors.
Fig. 6 is the mRNA relative expression quantity electrophoresis pattern of three groups of experiment mice Hippocampus position Fas-L antiapoptotic factors.
Fig. 7 is the electrophoresis pattern of the albumen relative expression quantity of three groups of experiment mice Hippocampus position Fas/Fas-L antiapoptotic factors.
The specific embodiment
Below in conjunction with specific embodiment, further describe the present invention, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these modifications and replacement all fall within the scope of protection of the present invention.
embodiment 1
Animal grouping and intervention: 3 60 of monthly age APP695V717I transgenic mices, purchased from Institute of Experimental Animals, Chinese Academy of Medical Sciences's (licence numbering: SCKK 20080013), body weight (30 ± 4.5) g, male and female are not limit, with the monthly age with 30 of the C57BL/6J mices of background as blank group.The animal applications table of random number choosing is divided into groups, be divided into matched group, model group, stilbene glucoside (TSG) and organize each 30.Blank group, model group gavage liquid are normal saline, and stilbene glucoside group gavage liquid is stilbene glucoside suspension.Each treated animal starts front 3 d in experiment and starts administration above, every day gavage 1 time, continuous 3 weeks, animal gavage amount press 100mg/kg.d calculate (in early stage preliminary experiment to memory improvement the most significantly in dose concentration).The each group of laggard row behavioristics test in 3 weeks, then puts to death mice and gets hippocampal tissue, for extracting endoplasmic reticulum albumen and organizing RNA.
Main agents and medicine: Fas/FasL primary antibodie is purchased from Stressgen company; Primer designed, designed, synthetic by Shanghai Hua Da gene company limited; Trizol, Taq enzyme, reverse transcriptase are purchased from MBI company.Stilbene glucoside is from Radix Polygoni Multiflori, to extract the dry powder separating, and content provides for medicament chamber of 72%(Lanzhou General Hospital of Lanzhou Military Command), during experiment, water is dissolved as the concentrated solution of 100 mg/ml.
test example 1, the improvement effect of stilbene glucoside to model mouse cognitive competence
One, test objective
Observe the impact of stilbene glucoside on each treated animal Mus cognitive competence.
Two, test method
Adopt Morris water maze test, Morris water maze main body is diameter 150cm, the circular stainless steel water of the black pond of high 50cm, and depth of water 30cm, water temperature keeps (22 ± 1) ℃; On pool wall, indicate 4 place of entry, thus pond is divided into 4 quadrants, using first quartile center as target quadrant, a circular escape platform (black platform diameter is 9cm, high 28cm) of hiding is placed in waters, center, and platform is lower than water surface 2cm; Experimental session water maze pool wall labelling and ambient room internal reference thing remain unchanged as space with reference to clue, for mice locating platform, camera head be housed directly over water maze and be connected with computer, by image acquisition and analytical system software (SLY-WMS2.1), synchronously recording mouse movement track in good time.
Three, result of the test
The test of Morris water maze laboratory shows, under A β toxic action, the learning and memory of model mouse, spatial orientation, working memory ability obviously decline, and show as escape latency in the test of Morris water maze and extend, swim total distance increase and the minimizing of spanning platform number of times etc.; After TSG intervenes, model mouse is hidden shortening incubation period, and swimming distance shortens, and spanning platform number of times increases, and illustrates that TSG improves model mouse learning and memory, spatial orientation, work and study ability, has cerebral protection.(in Table 1, Fig. 1-3)
Table 1 is the contrasts in the test of Morris water maze laboratory of three groups of experiment mices:
Note: with matched group comparison:
* p< 0.05; With model group comparison:
△ p< 0.05
test example 2,the effect of stilbene glucoside to model mouse cerebral circulation function
One, test objective
Observe the impact of stilbene glucoside on each treated animal rat cerebral cortex blood circulation.
Two, test method
Application laser-Doppler blood perfusion imager, light source is the chloro-Ne laser of 2 mW, wavelength 632.8 nm, probe PF403.Support fixing optical fiber probe, is close to by probe the cerebral tissue cortex epidural of causing injury in advance, middle 1% the agar solution that fully covers, and cerebral blood flow (rCBF) when monitoring is not caused injury, measures 10 min, Perosoft software automatic analysis result.
Three, result of the test
The more equal not statistically significant of cerebral blood flow before the modeling of each group Mus (
p> 0.05).Stilbene glucoside group after modeling and model group and matched group relatively cerebral blood flow all obviously reduce, but after stilbene glucoside is intervened, cerebral blood flow obviously increases compared with model group, have significant difference (
p< 0.01), in Table 2.
Table 2 is that three groups of experiment mice local cerebral cortex blood flows change relatively:
Note: with matched group comparison:
* p< 0.05; With model group comparison:
△ p< 0.05
test example 3,the expression impact of stilbene glucoside on apoptosis rate and Fas and Fas-L
One, test objective
Observe the intervention effect of stilbene glucoside to regulation and control model mouse apoptosis rate and antiapoptotic factors Fas and Fas-L expression.
Two, test method
The detection of apoptosis rate: adopt Roche Holding Ag's original position apoptosis detection kit to detect, method is TUNEL method, respectively organizes changes of cell apoptosis trend, the positive apoptotic cell of brown color cell with Olympus microscopic examination, negative without colour developing, count at random positive, negative cells in 10 visuals field.Under light microscopic, calculate apoptotic index (Apoptosis Index, AI), computational methods: every random two sections of animal, 1mm2 region is observed respectively in every section in Hippocampal CA 1, calculate respectively each district apoptosis cell and total cell number.AI=apoptosis cell/total cell number × 100/%.
The mrna expression of antiapoptotic factors Fas and Fas-L: adopt RT-polymerase chain reaction (RT-PCR) to detect, according to Medline gene library designed, designed primer.Product is through agarose gel electrophoresis, and under ultraviolet delineascope, observed result is as follows, and takes pictures:
Genes of interest Fas (349bp), forward primer: 5 '-GTGAAACCGACAACAACTGCT-3 ', downstream primer: 5 '-CAAGGCTCAAGGATGTCTTCA-3 ';
Genes of interest Fas-L (400bp), forward primer: 5 '-TTGGAATGGGGTTAGGAATGTA-3 ', downstream primer: 5 '-TTCTCCTCCATTAGCACCAGAT-3 ';
Internal reference β-actin (100bp), forward primer: 5 '-CGTTGACATCCGTAAAGACCTCTA-3 ', downstream primer: 5 '-TAAAACGCAGCTCAGTAACAGTCCG-3 '.
The protein expression of antiapoptotic factors Fas and Fas-L: with immunoblotting (Western blot) detection, density－gradient centrifuga－tion method extracts albumen, hippocampal tissue is transferred in homogenizer, add lysate homogenate, centrifugal 10 min(2400 r/min, radius 13.5cm), get supernatant, continue centrifugal 15 min(rotating speed 12000 r/min, radius 13.5cm), get supernatant, centrifugal 30 min(15000 r/min again, radius 13.5cm), add lysate and protease inhibitor, with two Kui Lin formic acid (BCA) protein determination kits mensuration protein concentrations; Sample and isopyknic sample-loading buffer mix, boil degeneration, with the separation of gather-acrylamide gel electrophoresis (SDS-PAGE) of 10% sodium lauryl sulphate, transfer protein is to nitrocellulose filter, 5% defatted milk powder sealing, hatches with primary antibodie, adds horseradish peroxidase-labeled two to resist and hatches, ECL test kit carries out chemiluminescence detection, the processing of JS-300 gel images instrument scanning analysis.
Three, result of the test
The apoptosis rate of each group Mus Hippocampal CA 1 is measured: from table 3, and with matched group comparison, all significantly increases of the neuronal apoptosis index of model group and TSG group (
p< 0.01); With model group comparison, the apoptotic index of TSG group significantly reduce (
p< 0.01), in Table 3, Fig. 4.
Table 3 is three groups of experiment mice Hippocampal CA 1 apoptosis rate comparisons:
Note: with matched group comparison:
* p< 0.05; With model group comparison:
△ p< 0.05
The mRNA of cell Fas, Fas-L expresses: RT-PCR product, through agarose gel electrophoresis, has been amplified respectively to 349bp (Fas) and 400bp (Fas-L) two bands.The mrna expression that further statistical description is respectively organized hippocampus of mice Fas, Fas-L has significant difference, relatively finding between two in group:, with matched group comparison, Fas, the Fas-L mRNA of model group and TSG group expresses all significantly to be increased (
p< 0.01); With model group comparison, all minimizings of mRNA expression of the Fas of TSG group and Fas-L (
p< 0.01), have significant difference (
p< 0.01).In Table 4, Fig. 5-6.
Table 4 is the mrna expression analysis of three groups of experiment mice Hippocampus position Fas/Fas-L:
Note: with matched group comparison:
* p< 0.05; With model group comparison:
△ p< 0.05
The protein expression situation of Hippocampus Fas, Fas-L: adopt Western blotting methods analyst, show that in hippocampal tissue, Fas, Fas-L albumen show as single band, molecular weight is 43kDa left and right, and the performance of β-actin albumen is single band, and expression is basically identical.Between each group of statistical description, the protein expression of Mus Hippocampus Fas, Fas-L has significant difference, in group, relatively finds between two: compared with matched group, the Fas of model group, Fas-L expressing quantity obviously increase (
p< 0.05); TSG group, compared with model group, is starkly lower than the expression of model group, but its expression is lower than matched group, all have the significance difference opposite sex (
p< 0.05), there is statistical significance.In Table 5, Fig. 7.
Table 5 is three groups of experiment mice Hippocampus position Fas/Fas-L protein expression comparisons:
Note: with matched group comparison:
* p< 0.05; With model group comparison:
△ p< 0.05
test example 4,the inhibitory action of stilbene glucoside to model mouse excitatory amino acid
One, test objective
Observe the impact of stilbene glucoside on each treated animal Mus excitatory amino acid.
Two, test method
The mensuration of excitatory amino acid-glutamic acid in cerebral tissue (Glu), aspartic acid (Asp) content: laboratory animal is after 21 days, get after 10 mice By Sodium Pentobarbitals for every group, in ice bath, broken end is got brain, prepare cerebral hippocampal tissue (title weight in wet base) homogenate, after centrifugation, get supernatant HPLC Fluorometric assay glutamic acid, aspartate content.
Three, result of the test
Glutamic acid and the aspartic acid concentration of matched group phase when each do not have significant change, and model group glutamic acid and aspartic acid concentration raise, with matched group relatively have significant difference (
p< 0.01), TSG group in glutamic acid and aspartic acid concentration higher than matched group (P < 0.01), with model group comparison glutamic acid and aspartate content be starkly lower than model group (
p< 0.01), in Table 6.
Table 6 is three groups of experiment mice excitatory amino acid concentration contrasts:
Note: with matched group comparison:
* p< 0.05; With model group comparison:
△ p< 0.05.
Claims (2)
1. the new purposes of stilbene glucoside in preparation control Alzheimer medicine, it is characterized in that stilbene glucoside prevents and/or treats by cerebral circulation insufficiency of function in preparation, the overexpression of apoptosis factor Fas/FasL, excitatory amino acid level increases the purposes in health product or the medicine of caused cognitive disorder disease Alzheimer.
2. according to the purposes of claim 1, it is characterized in that: the dosage form that stilbene glucoside and pharmaceutically acceptable salt thereof, ester or sugar and excipient can be prepared into is tablet or for capsule or for injection or for granule.
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| CN107753492A (en) * | 2017-10-25 | 2018-03-06 | 安徽古尔特科技有限公司 | Stibene-glucoside reduces the New function of the expression of protein kinase N 1 |
| CN107875160A (en) * | 2017-10-25 | 2018-04-06 | 安徽古尔特科技有限公司 | Stibene-glucoside reduces the New function of DNA methylation enzyme 3a expressions |
| CN116751237A (en) * | 2023-05-17 | 2023-09-15 | 遵义医科大学第五附属(珠海)医院 | Mitochondrial targeting stilbene glucoside derivative and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107753492A (en) * | 2017-10-25 | 2018-03-06 | 安徽古尔特科技有限公司 | Stibene-glucoside reduces the New function of the expression of protein kinase N 1 |
| CN107875160A (en) * | 2017-10-25 | 2018-04-06 | 安徽古尔特科技有限公司 | Stibene-glucoside reduces the New function of DNA methylation enzyme 3a expressions |
| CN107875160B (en) * | 2017-10-25 | 2021-04-16 | 安徽古尔特科技有限公司 | Application of stilbene glucoside in preparing DNMT3A reduced expression reagent |
| CN116751237A (en) * | 2023-05-17 | 2023-09-15 | 遵义医科大学第五附属(珠海)医院 | Mitochondrial targeting stilbene glucoside derivative and preparation method and application thereof |
| CN116751237B (en) * | 2023-05-17 | 2023-12-05 | 遵义医科大学第五附属(珠海)医院 | Mitochondrial targeting stilbene glucoside derivative and preparation method and application thereof |
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Application publication date: 20140430 |