CN110507663A - Application of the Ganglioside GM3 in preparation treatment atherosclerosis drug - Google Patents
Application of the Ganglioside GM3 in preparation treatment atherosclerosis drug Download PDFInfo
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- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 title claims abstract description 55
- 239000003814 drug Substances 0.000 title claims abstract description 38
- 229940079593 drug Drugs 0.000 title claims abstract description 28
- 201000001320 Atherosclerosis Diseases 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 30
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 24
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 239000002552 dosage form Substances 0.000 claims description 2
- 150000002270 gangliosides Chemical class 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 25
- 230000000879 anti-atherosclerotic effect Effects 0.000 abstract description 11
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- 102000013918 Apolipoproteins E Human genes 0.000 description 12
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- 210000000709 aorta Anatomy 0.000 description 12
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 9
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- 208000024891 symptom Diseases 0.000 description 7
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- 108010028554 LDL Cholesterol Proteins 0.000 description 6
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- 102000007330 LDL Lipoproteins Human genes 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 3
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- 230000036523 atherogenesis Effects 0.000 description 2
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- 210000001539 phagocyte Anatomy 0.000 description 2
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- 230000002792 vascular Effects 0.000 description 2
- WZUVPPKBWHMQCE-XJKSGUPXSA-N (+)-haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
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- 235000012000 cholesterol Nutrition 0.000 description 1
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- 229930182470 glycoside Natural products 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention provides a kind of application of Ganglioside GM3 in treatment cardiovascular and cerebrovascular diseases medicament, belong to cardiovascular disease drug efficacy study technical field.For Ganglioside GM3 in the application in treatment cardiovascular and cerebrovascular diseases medicament, the cardiovascular and cerebrovascular disease is atherosclerosis.It is using a effective amount of Ganglioside GM3 as the effective component in the drug of preparation treatment cardiovascular and cerebrovascular disease or pharmaceutical composition the present invention also provides a kind of drug for treating cardiovascular and cerebrovascular disease or pharmaceutical composition.The present invention specifies drug effect of the GM3 in terms of antiatherosclerosis, a kind of new medicament selection is provided for treatment cardiovascular disease atherosclerosis disease especially therein, it is proved through experiment in vitro of the invention and zoopery level, Ganglioside GM3 truly has effect on antiatherosclerosis, thus, Ganglioside GM3 is used for the treatment of cardiovascular disease especially atherosclerosis disease, there is important researching value and potential applicability in clinical practice.
Description
Technical field
The invention belongs to cardiovascular disease drug efficacy study technical fields, and in particular to Ganglioside GM3 is delaying or controlling
The effect in cardiovascular disease especially vascular atherosclerosis disease is treated, it is outstanding to can be applied to preparation treatment cardiovascular disease
It is the drug in vascular atherosclerosis disease.
Background technique
Arteriosclerosis (Arteriosclerosis) gradually increases in China in recent years, it has also become the master of the elderly's death
One of reason is wanted, and still in rising trend.Atherosclerosis (Atherosclerosis) be in arteriosclerosis it is common most
Important one kind can lead to a variety of diseases or clinical symptoms, wherein it is most known, most importantly cause myocardial infarction, hat
The generation of the illnesss such as heart trouble and apoplexy, thus it may be said that atherosclerosis is the root of many important common diseases or death.
Therefore, it finds prevention, diagnose and delay or treat the effective ways of atherosclerosis and drug is of great significance.Also,
As China progresses into aging society, between the following 10-30, this disease, which is likely to rise to important society, is asked
Topic, thus be also the critical issue that there is an urgent need to solve early.
The formation and development of atherosclerosis is a slow, long-term process, involves a variety of serum lipoproteins, more
Kind cell (including vascular endothelial cell, macrophage, smooth muscle cell and lymphocyte etc.) and different kinds of molecules, mechanism are abnormal
The formation of complexity, especially macrophage inner lipid precipitating and endangium atherosclerotic plaque is atherosclerosis
Main feature.It is numerous the study found that there is the aggregation of a large amount of Ganglioside GM3s in artery plaque region, in atherosclerosis
GM3 content is more times of normal blood vessel in patch, and many documents show that GM3 influences intravascular cortex integrality and infiltration
Property, there are also document report GM3 to influence the cells rows such as the adherency, proliferation and migration of tumour cell, fibroblast, epidermal cell etc.
For, but still do not know how GM3 influences atherogenesis and progression of the disease, what plays the role of, more not by GM3
Development is treatment or the research of atherosclerosis disease drug is delayed to report.
Summary of the invention
The purpose of the present invention is to provide a kind of potential new drug of antiatherosclerosis disease or new medicine selections.
The present invention provides a kind of application of Ganglioside GM3 in treatment cardiovascular and cerebrovascular diseases medicament.
Further, the Ganglioside GM3 is in the application in treatment cardiovascular and cerebrovascular diseases medicament, the heart and brain blood
Pipe disease is atherosclerosis.
It is by a effective amount of nerve the present invention also provides a kind of drug for treating cardiovascular and cerebrovascular disease or pharmaceutical composition
Glycosides rouge GM3 is saved as the effective component in the drug or pharmaceutical composition of preparation treatment cardiovascular and cerebrovascular disease.
In the drug or pharmaceutical composition of above-mentioned treatment cardiovascular and cerebrovascular disease, in addition to Ganglioside GM3 as effectively at
/ outer, it can also add pharmaceutically acceptable ingredient and/or carrier.
The drug or pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease including the above-mentioned Ganglioside GM3 including effective component
It can be prepared into pharmaceutically acceptable dosage form according to existing pharmaceutical technology, with clinically acceptable administration mode application.
In the drug or pharmaceutical composition of above-mentioned treatment cardiovascular and cerebrovascular disease, the cardiovascular and cerebrovascular disease is Atherosclerosis
Change.
It should be noted that " effective quantity " as described herein, which refers to, takes metapedes to alleviate treated disease to a certain extent
At least one pharmaceutical quantities of one or more symptoms of disease or illness.Its result can for sign, symptom or the cause of disease abatement and/
Alleviate or biosystem any other needed for variation.
It should be noted that " treatment " as described herein refers to alleviation, mitigation or improvement, cures disease or condition symptoms,
Alleviate, mitigate or improve, cure the potential metabolism reason for leading to symptom, inhibits disease or illness, such as prevent disease or illness
Development, alleviate disease or illness, be that disease or illness improve, alleviate the symptom as caused by disease or illness, or stop disease
The symptom of disease or illness.
Basic principle of the invention:
GM3 is delivered medicine to ApoE by tail vein injection mode by the present invention-/-C57BL/6 mouse detects GM3 to drink high in fat
The influence for eating modeling atherosclerosis, specifies the drug effect of GM3 antiatherosclerosis；It is further tested by In vitro cell experiment
Demonstrate,prove the effect of GM3 antiatherosclerosis.
The present invention specifies drug effect of the GM3 in terms of antiatherosclerosis, for treatment cardiovascular and cerebrovascular disease especially its
In atherosclerosis disease provide a kind of new medicament selection, demonstrate,proved through experiment in vitro of the invention and zoopery level
Bright, Ganglioside GM3 truly has effect on antiatherosclerosis, thus, Ganglioside GM3 is used for cardiovascular and cerebrovascular disease
The treatment of disease especially atherosclerosis disease, has important researching value and potential applicability in clinical practice.
Detailed description of the invention
The detection of the atherosclerotic plaque of Fig. 1 mouse aorta pectoralis.Aorta pectoralis is by longitudinally slit, exposure bleeding
On the inside of pipe, patch with oil red O stain (red), the quantitative analysis of patch (*, p < 0.05, by Low dose, Middle dose,
High dose is compared with Model group；##, p < 0.001, by Model compared with Control group).
The detection of the atherosclerotic plaque of Fig. 2 mouse aorta root.Use oil red O and haematoxylin dyeing, (A figure)
The display diagram of each group sample, quantitative analysis (*, the p < 0.05, by Low dose, Middle dose, High dose of (B) patch
Compared with Model group；##, p < 0.001, by Model compared with Control group).
Fig. 3: GM3 inhibits lipid precipitation/foamed of macrophages in vitro RAW264.7.(A) sky without OxLDL stimulation
The oil red O dyestuff that the macrophage of white control group is not red-dyed, cell almost do not generate fat drips；(B) it is pierced by Ox-LDL
Swash but the Macrophage Surface part of the positive controls without drug-treated is coloured, generates the fat drips of certain amount, Ox-
LDL is induction of the preliminary lipid precipitation/foamed of macrophage；(C-E) after various concentration GM3 pretreatment, Ox~LDL induction
Macrophage lipid precipitating degree make moderate progress, increase with concentration, improve degree it is better, illustrate that GM3 is able to suppress body
Lipid precipitation/foamed of outer macrophage.(F) quantitative analysis of fat drips area ratio, it was demonstrated that high concentration GM3 can significantly inhibit huge
The foamed of phagocyte RAW264.7.
Specific embodiment
Combined with specific embodiments below, the present invention is further described.
1. external source GM3 of example inhibits the ApoE of feeding high in fat-/-The formation of C57BL/6 rat aorta atherosis.
Use the ApoE of feeding high in fat-/-Male C57BL/6 mouse is as atherosclerosis mode mouse.Experiment is divided into 5
A group (every group of 6 mouse), it is respectively as follows: Control group (the normal ApoE without feeding high in fat-/-Mouse), Model group (injection
The ApoE of the feeding high in fat of physiological saline-/-Mouse), High dose group (tail vein injection high dose GM3 4mg/kg/3d),
Middle dose group (tail vein injection middle dosage GM3 1mg/kg/3d), Low dose group (tail vein injection low dosage GM3
0.4mg/kg/3d), continuous medication 8 weeks while feeding high in fat.
(1) lipids detection.Mouse blood sample (allow before sampling mouse fasting 12 hours) is taken after medication 8 weeks；3000rpm
It is centrifuged 10 minutes acquisition serum samples；It is measured with automatic clinical chemistry analyzer (Beckman Coulter AU480) total in serum
Cholesterol (TC), triglycerides (TG), highdensity lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-
C content).
Lipid of mice content after the administration of 1. various concentration GM3 tail vein of table
TG: total triglycerides；TC: total cholesterol；LDL-C: low density lipoprotein cholesterol；HDL-C: high-density lipoprotein
Cholesterol.Significant difference: *, p < 0.05, * *, P < 0.001 by Low dose, Middle dose, High dose with
Model group compares；▲, p < 0.05, ▲ ▲, P < 0.001 is by Model compared with Control group.
(table 1) as the result is shown, with the normal ApoE without feeding high in fat-/-Mouse is compared, the ApoE of feeding high in fat-/-Mouse
GC, TC, LDL-C and HDL-C level significantly increase, show that after feeding high in fat, lipid of mice increases, at the beginning of indicating modeling
It walks successfully.With the ApoE of feeding high in fat-/-Mouse is compared, and after various concentration GM3 medication, GC, TC, LDL-C and HDL-C are horizontal
It is gradually reduced, and GC, TC, LDL-C and HDL-C level increase with GM3 administration concentration and declines more obvious, wherein High
The decline degree of dose group is maximum, and significant difference is presented.This result, which reflects GM3, has effects that blood lipid is inhibited to increase,
Reflect the potential of its antiatherosclerosis indirectly.
(2) inner wall fat drips/patch quantitative detection of overall length aorta.After medication 8 weeks, take mouse overall length aorta (from
Aorta heel is to abdominal aorta, until ilium is divided to go out), 3 hours are fixed with 4% paraformaldehyde；The careful adipose tissue for rejecting periphery,
It splits longitudinal direction；It is dyed at room temperature in propylene glycol 0.5 hour with oil red O；After being cleaned 2-3 times with 60% propylene glycol, it will split
Arteries on the inside of be layered on glass slide upward, covering covered makes blood vessel be sufficiently spread out, take pictures, and patch is in scarlet
Color carries out quantitative analysis later.
(Fig. 1) as the result is shown, the normal ApoE without feeding high in fat-/-The aorta pectoralis of mouse is athero- almost without artery
Hardening spot, and the ApoE of feeding high in fat-/-There is a large amount of red patch (the i.e. artery congee of oil red O coloring on the aorta pectoralis of mouse
Sample plaque) (A figure), quantitative comparison is in significant difference (B figure), illustrates the Atherosclerosis Model success structure of mouse
It builds.After various concentration GM3 administration, red plaque area is gradually reduced, and is increased with administration concentration and is reduced more obvious, wherein
Significant difference is presented with High dose group in Middle dose compared with Model group, it was demonstrated that GM3 has antiatherosclerosis
Effectiveness.
(3) imaging of aorta petal position atherosclerotic plaque and quantitative.After medication 8 weeks, being connected to for mouse is taken
The heart of the arch of aorta；Frozen section organizes freezing mixture to embed with OCT；8 are cut using freezing-microtome (Leica CM1520)
The serial section of μ m thick；15 minutes are fixed with 95% ethyl alcohol；It takes pictures and divides after being dyed according to a conventional method with oil red O and hematoxylin
Analysis.
(Fig. 2) as the result is shown, the normal ApoE without feeding high in fat-/-It is only non-on the inside of the blood vessel of the aorta petal of mouse
Often small atherosclerotic plaque, and the ApoE of feeding high in fat-/-There is very thick red on the inside of the blood vessel of the aortic root of mouse
Patch (i.e. the atherosclerotic plaque of oil red O coloring) (figure A), quantitative comparison are presented significant difference (figure B), illustrate again
The Atherosclerosis Model of mouse successfully constructs.After various concentration GM3 administration, red plaque thickness and area gradually subtract
It is small, it is increased with administration concentration and reduces more obvious, wherein High dose group has most thin thickness or the smallest area, with
Model group further proves that GM3 has the effectiveness of antiatherosclerosis compared to significant difference is presented.
The lipid precipitation (or foamed) of example 2.GM3 inhibition macrophages in vitro.
This part cell experiment is divided into following 5 groups: (1) blank control group: the mouse of no any stimulation or processing
RAW264.7 macrophage；(2) positive controls: through the small of 80um/ml oxidative low density lipoprotein (Ox-LDL) stimulation 6h
Mouse RAW264.7 macrophage；(3) experimental group 1: after 1 μ g/ml GM3 handles mouse RAW264.7 macrophage 6h, then with 80
The cell 6h of μ g/ml Ox-LDL stimulation；(4) experimental group 2: mouse RAW264.7 macrophage 6h is handled through 10 μ g/ml GM3
Afterwards, then with 80um/ml Ox-LDL the cell 6h stimulated；(5) experimental group 3: huge through 40 μ g/ml GM3 processing mouse RAW264.7
After phagocyte 6h, then the cell 6h stimulated with 80um/ml Ox-LDL；The above processing stimulates under the conditions of 5%CO2,37 DEG C
Incubator in carry out, fix 20 minutes with 4% paraformaldehyde at room temperature later, phosphate buffer clean 2 times, with 60%
Isopropanol is handled 1-2 minutes；After phosphate buffer cleaning removes extra isopropanol, 20 points are dyed at room temperature with oil red O
Clock, then 30 seconds are handled twice with 60% isopropanol；After phosphate buffer cleaning removes extra isopropanol, it is inverted with fluorescence
Microscope (Nikon LH-M100CB) is imaged.
(Fig. 3) as the result is shown, the oil red O that the macrophage of the blank control group without ox-LDL stimulation is not red-dyed
Dyestuff (Fig. 3 A), illustrates that lipid precipitation does not occur for cell；And pass through Ox-LDL stimulation but the positive controls without drug-treated
Macrophage in by largely colour (Fig. 3 B), illustrate Ox-LDL induction of the lipid precipitation or foamed of macrophage；By
After various concentration GM3 pretreatment, the degree of the macrophage lipid precipitating of Ox-LDL induction makes moderate progress (Fig. 3 C-3E), with
Concentration increases, and improvement degree is better (Fig. 3 E), illustrates that GM3 is able to suppress the lipid precipitation (or foamed) of macrophages in vitro.
For quantitative analytical data (Fig. 3 F) as it can be seen that High dose group is compared with Model group, plaque area is smaller, and significant difference is presented,
Disclose the effect of GM3 inhibits the lipid precipitation of macrophage.The lipid precipitation step of macrophage is atherogenesis
With the committed step of development, therefore further prove GM3 have antiatherosclerosis effectiveness.
The above only expresses the preferred embodiment of the present invention, and the description thereof is more specific and detailed, but can not be because
This and be interpreted as limitations on the scope of the patent of the present invention.It should be pointed out that for those of ordinary skill in the art, In
Under the premise of not departing from present inventive concept, several deformations can also be made, improves and substitutes, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (6)
1. application of the Ganglioside GM3 in treatment cardiovascular and cerebrovascular diseases medicament.
2. a kind of Ganglioside GM3 according to claim 1 treatment cardiovascular and cerebrovascular diseases medicament in application in,
It is characterized in that, the cardiovascular and cerebrovascular disease is atherosclerosis.
3. a kind of drug for treating cardiovascular and cerebrovascular disease or pharmaceutical composition, which is characterized in that be by a effective amount of ganglioside
Rouge GM3 is as the effective component in the drug or pharmaceutical composition of preparation treatment cardiovascular and cerebrovascular disease.
4. a kind of drug for treating cardiovascular and cerebrovascular disease according to claim 3 or pharmaceutical composition, which is characterized in that institute
It states in drug or pharmaceutical composition other than Ganglioside GM3 is as effective component, can also add pharmaceutically acceptable
Ingredient and/or carrier.
5. a kind of drug for treating cardiovascular and cerebrovascular disease according to claim 3 or pharmaceutical composition, which is characterized in that institute
It states drug or pharmaceutical composition includes effective component Ganglioside GM3, pharmacy can be prepared into according to existing pharmaceutical technology
Upper acceptable dosage form, with clinically acceptable administration mode application.
6. according to the drug or pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease of the claim 3-5 described in any one, feature
It is, the cardiovascular and cerebrovascular disease is atherosclerosis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111407768A (en) * | 2020-05-15 | 2020-07-14 | 内蒙古自治区中医药研究所 | Application of composition in nerve injury protection field |
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|---|---|---|---|---|
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| WO2000035932A1 (en) * | 1998-12-16 | 2000-06-22 | Fidia S.P.A. | Process for the preparation of ganglioside gm3 by acid hydrolysis of ganglioside inner esters and its use in the pharmaceutical field |
| TW200843786A (en) * | 2007-03-20 | 2008-11-16 | Univ Osaka | Prophylactic and/or therapeutic agent for cardiac infarction |
-
2019
- 2019-08-07 CN CN201910727986.5A patent/CN110507663A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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