CN108210504A - The application of sulphation galactooligosacchari(es and pharmaceutical composition - Google Patents
The application of sulphation galactooligosacchari(es and pharmaceutical composition Download PDFInfo
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- CN108210504A CN108210504A CN201711439601.2A CN201711439601A CN108210504A CN 108210504 A CN108210504 A CN 108210504A CN 201711439601 A CN201711439601 A CN 201711439601A CN 108210504 A CN108210504 A CN 108210504A
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- galactooligosacchari
- sulphation
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Classifications
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- 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
- A61K31/7024—Esters of saccharides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to biomedicine fields, and in particular to a kind of application of oligosaccharides in Parkinson disease is prevented and treated.The oligosaccharides mainly alternately connects the oligosaccharides formed by 6 sulfate of α L galactolipins of the β D galactolipins of 3 connections and 4 connections; the degree of polymerization is 2 10; its is safe; there is significant neuroprotection to Parkinson's disease, can be used for preparing drug, health products and the special medicine purposes formula food of prevention and treatment Parkinson disease.
Description
Technical field
The present invention relates to biomedicine fields, and in particular to sulphation galactooligosacchari(es are in Parkinson disease is prevented and treated
Application.
Background technology
With the increase year by year of average human life, the world is just stepping into the global aging epoch.The nerve related with the age
Degenerative disorders are consequently increased, and in terms of central nervous system, are mainly shown as that excited and process of inhibition weakens, cerebral function
It reduces, failure of memory and forfeiture, exacerbation of the progressive decline of identification function and emotionally disturbed etc. then occurs.
Parkinson's disease (Parkinson ' s disease, PD) is a kind of nerveous system for being mainly in 50 years old or more the middle-aged and the old
System degenerative disorders.For PD using dyskinesia as main performance, typical pathologic change is that nigrostriatal dopamine serotonergic neuron becomes
Property or death, lead to the Clinical symptoms such as postural balance obstacle, splinting, static tremor, bradykinesia.This kind of disease disability rate
Height, the course of disease are long, white elephant are brought to patient and its family, and with the increase of aging of population, the quantity of PD patient
In increasing trend, therefore, the prevention problem of PD is extremely urgent.At present, lead to the concrete reason that dopamine neuron damages also not
Determine, but more and more studies have shown that is excessively generated by oxidative stress, immune inflammatory factor, mitochondrial respiratory chain obstacle and
Apoptosis caused by ubiquitin degradation system disorders etc. takes part in the generation and/or development of PD.Parkinson's disease is to patient, family and society
All bring huge pressure so that the treatment of the neurodegenerative diseases such as numerous concerns, Parkinson's disease is given to it in the whole world
Drug research becomes an important topic in gerontology field.
In recent years, Carbohydrate drugs are from the aspect of its drug effect and safety, and development trend is gradually from the research to polysaccharide
Go to the research to oligosaccharide and oligosaccharides.Oligosaccharides has huge demand space in medical health field.Oligosaccharide kind medicines structure
Uniform, quality controllable, mechanism of action is clear and definite, has become one of main direction of Carbohydrate drugs.Ocean institute of Chinese Academy of Sciences Zhang Quanbin
Deng reported mannoglucan aldehydic acid oligosaccharides prepare treat or prevent Parkinson's disease in terms of have more significant act on；
Chinese Marine University has found that the oligomannuronic acid HS971 tools that reducing end is carboxyl are significantly improved memory
With anti-senile dementia effect.
This patent, which reports a kind of sulphation galactooligosacchari(es, has significantly Parkinson's disease in cell and zoopery
Therapeutic effect can be applied to Parkinson's disease prevention and treatment.
Invention content
The purpose of the present invention is to provide a kind of application of sulphation galactooligosacchari(es in Parkinson disease is prevented and treated,
Sulphation galactooligosacchari(es can be used in protection nerve cell, the drug or product that prevent and treat Parkinson disease.
To achieve the above object, the technical solution adopted by the present invention is：
A kind of application of sulphation galactooligosacchari(es in Parkinson disease is treated, the oligosaccharides refer to that the degree of polymerization is 2-
10, the sulphation galactooligosacchari(es alternately connected by the α-L- galactolipin -6- sulfates that the β-D- galactolipins of 3- connections are connected with 4-.
The drug is includes sulphation galactooligosacchari(es and the medicine of other pharmaceutically acceptable carriers and/or excipient
Compositions.
Carrier includes sodium alginate micro ball, liposome etc..
Excipient：Such as mannitol, magnesium stearate, starch, cyclodextrin.
The dosage form of the drug is injection, oral preparation or local administration preparation.
The present invention sulphation galactooligosacchari(es anti-apoptotic and adjust PI3K/Akt signal paths in terms of carried out deeply and
Comprehensive research finds that sulphation galactooligosacchari(es have protective effect, i.e. sulphation galactooligosacchari(es to the MPTP neurotrosises induced
The application in preventing and treating nervous system disease agent can prepared.
The sulphation galactooligosacchari(es can be applicable to the medicine for preparing prevention and/or treatment Parkinson disease as active ingredient
Advantages of the present invention in object, health food or special medicine purposes formula food or functional food：
1st, compared with the drug of existing anti-neurodegenerative disease, sulphation galactooligosacchari(es have good bio-compatible
Property, it can take for a long time, and without obvious toxic-side effects in the range of pharmaceutical dosage.
2nd, product of the present invention has many advantages, such as toxic side effect is small, safe and effective, has in terms of Parkinson's disease is prevented
Wide development prospect.
Description of the drawings
The HPLC analysis of spectra of Fig. 1 sulphation galactooligosacchari(es.
Influence of Fig. 2 sulphations galactooligosacchari(es to PC12 neural cell activities.
Fig. 3 sulphations galactooligosacchari(es are on the ethological influence of PD Mice Mices.
Influence of Fig. 4 sulphations galactooligosacchari(es to PD mouse DA, 5-HT and its metabolite.
Influence of Fig. 5 sulphations galactooligosacchari(es to PD mouse cell apoptosis.
Influence of Fig. 6 sulphations galactooligosacchari(es to PD mouse PI3K/Akt signal paths.
The influence that Fig. 7 sulphations galactooligosacchari(es express PD mouse NGF/TrkA.
Influence of Fig. 8 sulphations galactooligosacchari(es to PD mouse TH, DAT and DRD2.
Influence of Fig. 9 sulphations galactooligosacchari(es to PD mouse MAO-B and α-synuclein.
Figure 10 sulphations galactooligosacchari(es are to PD mouse TNF-α, the influence of IL-1 β and GFAP.
Influence of Figure 11 sulphations galactooligosacchari(es to PD mouse dopaminergic neurons.
Specific embodiment
The present invention will be specifically described by embodiment below.One skilled in the art will recognize that these embodiments are
It is illustratively rather than restricted.These embodiments will not be with any side
Formula limits the scope of the invention.
Embodiment 1：The preparation of sulphation galactooligosacchari(es
100g her millet straws add to the water of its 40 times of quality, 120 DEG C of extraction 4h, after filtering with 90 DEG C of hot water injections twice, conjunction
And filtrate, it dialyses after being concentrated into the 1/6 of original volume, the liquid after dialysis is again concentrated to the 1/12 of original volume.Then body is added in
The ethyl alcohol of product concentration 90%, makes ethyl alcohol final volume a concentration of 75%.Centrifuged after standing overnight, lower sediment with it is water-soluble go out after, it is cold
Dry, as galactan crude extract is lyophilized.It above-mentioned polysaccharide is dissolved in water is configured to the solution of mass concentration 2.5% and add 4mol/L sulphur
The final concentration of 0.5mol/L of acid solution is stirred to react 3h in 80 DEG C, then adds in saturation barium hydroxide and is neutralized to neutrality, centrifuges
Supernatant, supernatant use molecular cut off to dialyse for the bag filter of 2000 dalton, collect dialysis permeate, are concentrated and dried
Sulphation galactooligosacchari(es are obtained afterwards, and attached drawing 1 is the degree of polymerization analysis of spectra of sample, it can be seen that sulphation galactooligosacchari(es mainly include
The oligosaccharides eluted peak of 9 degree of polymerization, degree of polymerization 2-10 carry out ESI-MS analyses, it can be seen that sulphation gala to sample
Oligosaccharides is few for the sulphation gala that the α-L- galactolipin -6- sulfates that the β-D- galactolipins of 3- connections are connected with 4- alternately connect
Sugar, degree of polymerization 2-10.
1 sulphation galactooligosacchari(es composition analysis of table
Embodiment 2：Influence of the sulphation galactooligosacchari(es to 6-OHDA induction PC12 cells
Sulphation galactooligosacchari(es of the present embodiment obtained by using embodiment 1.Oligosaccharides with aqua formal layout, liquid configuration
Concrete operations are as follows：(1) 40.0mg oligosaccharides accurately is weighed, be dissolved in 1mL 0.01M phosphate buffers (PH7.2-7.4)；(2)
Processing is filtered to aforementioned liquid with 0.22 μm of the pin type filter in aperture, obtains storing liquid for sterile oligosaccharides；It (3) will be above-mentioned
After storing liquid packing, in -80 DEG C of preservations, in following embodiment.
Primary operational is as follows：
The present invention has studied the nerve cell that sulphation galactooligosacchari(es damage 6-OHDA using cell survival rate as index
The protective effect of PC12 cells.
Material：Phaeochromocytoma cells strain PC12 cells, using containing 5% fetal calf serum, 10% horse
The sugared culture solution of the DMEM high of serum, 100U/mL penicillin and 100U/mL streptomysins is placed in 37 DEG C, in the incubator containing 5%CO2
Culture.
Method：Experiment is divided into control group, 6-OHDA damages group, sulphation galactooligosacchari(es positive controls and sulphation gala
Oligosaccharides administration group, oligosaccharide sample concentration for the treatment of are respectively adopted 50,100 and 200 μ g/mL, every group of 6 holes, 37 DEG C, cultivate containing 5%CO2
Be incubated in case it is adherent for 24 hours after, sulphation galactooligosacchari(es administration processing 12h, then 75 μM of 6-OHDA processing for 24 hours, adds in 10 μ L
CKK-8 solution, 37 DEG C of incubation 40min, OD value at 490nm is measured with microplate reader (Diagnostic Pasteur LP400)
(OD)。
Fig. 2 is result of the sulphation galactooligosacchari(es to the protective effect of the 6-OHDA nerve cells damaged.Said determination knot
Fruit is prompted, and 6-OHDA is (48.54 ± 4.43) % to the damage ratio of cell.The sulphation galactooligosacchari(es of test lure 6-OHDA
The neural cell injury led has apparent repair, and cell viability, which has, to have clear improvement, and system goes out good nerve and protects
Shield acts on.
Embodiment 3：Influence of the sulphation galactooligosacchari(es to MPTP induction PD mouse
Sulphation galactooligosacchari(es of the present embodiment obtained by using embodiment 1.MPTP is a kind of fat-soluble neurotoxin, can
MPP+ is converted into through monoamine oxidase B (MAO-B) to pass through blood-brain barrier, inhibits mitochondrial respiratory after the intake of DA transporters
Chain complex I and then damage DA serotonergic neurons are current widely used Parkinson's models.
Primary operational is as follows：
Oligosaccharides is administered in the form of aqua, and the concrete operations of liquid configuration are as follows：(1) 40.0mg oligosaccharides accurately is weighed, be dissolved in
In 150ml physiological saline；(2) processing is filtered to aforementioned liquid with the pin type filter in 0.22 μm of aperture, it is sterile to obtain
Oligosaccharides stores liquid；(3) after above-mentioned storage liquid is dispensed, in -80 DEG C of preservations, in following embodiment.
C57BL/6 mouse (weight：20 ± 2g, 8 week old or so)：SPF grades of mouse adapt to environment after a week, are weighed simultaneously
It is randomly divided into 5 groups, i.e., control group, model group, sulphation galactooligosacchari(es are low, high (25,50mg/kg) 2 dosage groups, positive control
Medicine Madopar (70mg/kg) group.In addition to control group, continuous 7 days of mouse peritoneal injection (20mg/kg mouse weights), control group is given
Give the same dose of physiological saline.Then, sulphation galactooligosacchari(es are low, high (25,50mg/kg) group gives 25,50mg/kg abdominal cavities
Injection 7 days, Madopar group (70mg/kg) give intraperitoneal injection 7 days, and model group and control group give the same dose of physiology salts
Water.This experiment carried out behaviouristics detection respectively at the 14th day and the 21st day.
(1) Behaviors survey：
Grasping clubglass test：Grasping clubglass test：One 50 centimeter lengths, a diameter of 1 centimetre of vertical rod are taken, an orange is placed on top
Shape body, rod are wrapped in Anti-skid adhesive tape, and mouse is head-up placed on to ball top, and record mouse is completely downward from top dome end to head
Spent time is to land the time (T- between total time-consuming used in incubation period (T-turn) and being climbed to mouse to bar bottom end hind leg
total).Every mouse carries out 3 measure every time, takes its average value.
Suspension experiment:A coarse electric wire is taken to hang over mouse fore paw is horizontal above, two rear solid ends can tangle 3 points of note, a rear solid end
2 points of note can be tangled, two pawls cannot tangle 1 point of note.Every mouse carries out 3 measure every time, takes its average value.
Spacious field is tested：Mouse is placed in the plastic box of 44*44cm, puts a camera shooting for carrying writing function above
Machine records the action trail in mouse 5min.
(2) HPLC combined with electrochemical detector (HPLC-ECD) method is to DA, NE, 5-HT in mouse striaturn and its metabolite
Dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) have carried out calculating and statistical analysis.
(3) after completing Animal Behavior Science observation, each group takes 4, and 10% chloraldurate is anaesthetized, physiological saline more than+4%
Brain is taken after polyformaldehyde perfusion, and 24 hours are fixed in 4% paraformaldehyde, goes in 20%, 30% sucrose solution and is dehydrated successively,
Continuous coronal frozen section is done, piece is 16 μm thick.With reference to routine immunization group method, the change of Bcl-2, Bax, pPI3K, pAkt are detected
Change situation.(4) 5 mouse striatum revealeds are taken, albumen are extracted with protein lysate, with Western blot protein immunoblots
Method detection Bcl-2, Bax, Cytc, cleaved-caspase-3, PARP, TH, DRD2, TNF-, IL-1, pPI3K, PI3K,
PAkt, Akt, β-actin expressing quantities.
(5) 5 mouse striatum revealeds are taken, using Enzyme-linked Immunosorbent Assay (ELISA) method measure MAO-B and α-
The expression of synuclein.
Fig. 3 the result shows that, mouse starts to occur static tremor after MPTP processing, movement is reduced, the PD samples fortune of delay of response
Dynamic obstacle performance, occur individually hind leg open, the changes such as perpendicular hair, and sulphation galactooligosacchari(es are in 25mg/kg and 50mg/kg pair
The behavior disorder of MPTP inductions significantly improves effect.
Fig. 4 the result shows that, MPTP processing after mouse DA contents reduce, (DOPAC+HVA/DA) ratio raising.DA metabolism speed
Rate is speeded, and metabolite increases, when being more common in DA serotonergic neuron Incomplete injuries.Sulphation galactooligosacchari(es reduce (HVA+
DOPAC the ratio of)/DA illustrates that it can reduce DA metabolic turnover rates, protects DA serotonergic neurons.Meanwhile sulphation galactooligosacchari(es
Also increase the content of 5-HT and its metabolite HIAA, but to the content of NE without significant change.
The results show that MPTP processing causes to promote antiapoptotic factors Bax raisings, suppression antiapoptotic factors Bcl-2 is reduced, is swashed simultaneously Fig. 5
Lived caspase-3 and PARP.After the effect of sulphation galactooligosacchari(es, it is suppressed that the ratio of Bax/Bcl-2, while lower
The expression of caspase-3 and PARP shows that sulphation galactooligosacchari(es can significantly inhibit the generation of Apoptosis of MPTP mouse.
Fig. 6 is the results show that MPTP mouse phosphorylation PI3K, Akt and GSK3 β expression quantity reduces, and is manifested with control mice
Work property significant difference.After the processing of sulphation galactooligosacchari(es, the expression quantity of phosphorylation PI3K, Akt and GSK3 β are significantly improved,
Show that sulphation galactooligosacchari(es adjust PI3K/Akt signal paths, have protective effect to dopamine neuron.
Fig. 7 is the results show that MPTP mouse NGF and TrkA phosphorylation level reduce, and are counted with control mice in conspicuousness
Learn difference.After the processing of sulphation galactooligosacchari(es, NGF and TrkA phosphorylations are significantly improved, show that sulphation galactooligosacchari(es are adjusted
PI3K/Akt signal paths have protective effect to dopamine neuron.
Fig. 8 the result shows that, be injected intraperitoneally MPTP after, mouse striaturn TH and DAT protein expression is significantly reduced compared with control group,
After successive administration 7 days, sulphation galactooligosacchari(es administration group TH and DAT expression quantity is than MPTP model group animal showed increaseds, through system
Count difference significance.Equally, sulphation galactooligosacchari(es significantly improve the expression quantity of DRD2.
Oneself can lead to the raising of MAO-B levels and the aggregation of α-synuclein albumen some researches show that MPTP, so as to send out
Wave cytotoxic effect.Fig. 9 the result shows that, caused by sulphation galactooligosacchari(es can significantly inhibit MPTP α-synuclein accumulate
With the overexpression of MAO-B.
Figure 10 is the results show that TNF-α, IL-1 β and GFAP are shown compared with saline control group in MPTP mouse striaturns
Raising is write, and the intraperitoneal injection of 25mg/kg and 50mg/kg sulphations galactooligosacchari(es can significantly inhibit MPTP mouse inflammatory factors
Release, as a result with statistical significance.
Figure 11 the result shows that, be injected intraperitoneally MPTP after, Nissl neuronal cells largely reduce, with saline control group
Compared in notable statistics difference.Sulphation galactooligosacchari(es group cellular morphology tends to be normal, and structural integrity, number is significantly more than
MPTP groups.
Claims (8)
1. the application of sulphation galactooligosacchari(es, it is characterised in that：The sulphation galactooligosacchari(es can be applicable to as active ingredient
Prepare drug, health food or the special medicine purposes formula food of prevention and/or treatment Parkinson disease or functional food
In product.
2. application according to claim 1, it is characterised in that：
The sulphation galactooligosacchari(es have following feature：
(1) composition sugar：Sulphation galactooligosacchari(es；
(2) α-L- galactolipins that the β-D- galactolipin -6- sulfates of 3- connections are connected with 4- are alternately formed by connecting；
(3) the oligosaccharides degree of polymerization：2-10.
3. application according to claim 1, it is characterised in that：The drug is comprising sulphation galactooligosacchari(es and other
The pharmaceutical composition of pharmaceutically acceptable carrier and/or excipient.
4. the application according to claim 1 or 3, it is characterised in that：The dosage form of the drug for injection, oral preparation or
Local administration preparation.
5. application according to claim 1, it is characterised in that：The sulphation galactooligosacchari(es can effectively inhibit Parkinson
Sick α-increase of core synapsin expression and the overexpression of MAO-B.
6. application according to claim 1, it is characterised in that：The sulphation galactooligosacchari(es can effectively adjust PI3K/
Akt/Bcl-2 signal paths inhibit dopaminergic apoptotic neurons, promote the growth of neuron.
7. a kind of pharmaceutical composition, it is characterised in that：Using sulphation galactooligosacchari(es as active ingredient, wherein also added with other
Pharmaceutically acceptable carrier and/or excipient form pharmaceutical composition.
8. pharmaceutical composition according to claim 7, it is characterised in that：The dosage form of the drug is injection, oral preparation
Or local administration preparation.
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