CN103800348B - Application of mannose glucuronic acid oligosaccharide in preparation of medicine and/or healthcare product for treating or preventing Parkinson's disease and/or senile dementia - Google Patents

Application of mannose glucuronic acid oligosaccharide in preparation of medicine and/or healthcare product for treating or preventing Parkinson's disease and/or senile dementia Download PDF

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CN103800348B
CN103800348B CN201410092395.2A CN201410092395A CN103800348B CN 103800348 B CN103800348 B CN 103800348B CN 201410092395 A CN201410092395 A CN 201410092395A CN 103800348 B CN103800348 B CN 103800348B
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acid oligosaccharide
glucuronic acid
oligosaccharide
mannose
medicine
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CN103800348A (en
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张全斌
金维华
张文静
王晶
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Institute of Oceanology of CAS
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Abstract

The invention relates to an application of a mannose glucuronic acid oligosaccharide in preparation of a medicine and/or healthcare product for treating or preventing Parkinson's disease and/or senile dementia. The mannose glucuronic acid oligosaccharide is formed by 2- linked mannose and 4- linked glucuronic acid or salt thereof through being connected alternatively, has significant neuroprotective effect to senile dementia and Parkinson's disease, and can be used for the preparation of medicines and healthcare products for preventing and treating neurodegenerative diseases.

Description

The application of mannoglucan aldehydic acid oligosaccharide in preparation treatment or prevention parkinson disease and/or medicine for senile dementia and/or health product
Technical field
The invention belongs to biomedicine field, relate to the application of mannoglucan aldehydic acid oligosaccharide in treatment parkinson disease and medicine for senile dementia.
Background technology
Along with the increase year by year of average human life, the world is just stepping into the global aging epoch.The neurodegenerative disease relevant with the age also increases thereupon, in central nervous system, main manifestations weakens with process of inhibition for excited, and brain function reduces, hypomnesis and forfeiture, occur that the Progressive symmetric erythrokeratodermia of recognition function goes down and the increasing the weight of of emotionally disturbed subsequently.Parkinson disease are also known as Parkinsonism, it is the common central nervous system degenerative disease of middle-aged and elderly people, Parkinsonian major pathologic features is after the cell generation pathologic because being arranged in midbrain position " black substance " changes, the synthesis of dopamine reduces, suppress the function of acetylcholine to reduce, then the excitation of acetylcholine strengthens relatively.Unbalance result just there is " Parkinsonism " in both.Update shows, in state-owned 1,700,000 Parkinsonians, wherein in the crowd of more than 55 years old, every 100 people just have 1 parkinson patient, estimate annual newly-increased parkinson patient about 100,000 people.Parkinson disease all bring huge pressure to patient, family and society, make the whole world give numerous concerns to it, the important topic that the research of Parkinsonian medicine becomes in geriatrics field.
Alzheimer (Alzheimer's Disease) i.e. so-called senile dementia, also known as stages alzheimer's disease.Be the lethal neurodegenerative diseases of a kind of Progressive symmetric erythrokeratodermia development, clinical manifestation is cognitive and memory function constantly worsens, and activity of daily living Progressive symmetric erythrokeratodermia goes down, and has various neuropsychic symptom and behavior disorder.According to the display of the Chinese Alzheimer association announcement survey result of 2011, the whole world 3,650 ten thousand people that have an appointment suffer from dementia, and within every 7 seconds, just having a people to suffer from, this is sick, and mean survival time (MST) only has 5.9 years, is to threaten one of aged health " four large killers ".
In recent years, Carbohydrate drugs is from the viewpoint of its drug effect and safety, and its development trend is gradually from the research forwarded to the research of polysaccharide oligosaccharide and oligosaccharide.Oligosaccharide has huge demand space at medical health field.Oligosaccharide kind medicines structure is homogeneous, quality controllable, and mechanism of action is clear and definite, one of main direction becoming Carbohydrate drugs.Chinese Marine University has reported that reducing end is that the OM HS971 of carboxyl has significant Improving memory and anti-senile dementia effect, intends the prevention and therapy being used for senile dementia clinically.
This patent reports the mannoglucan aldehydic acid oligosaccharide be made up of mannose and glucuronic acid and has significant therapeutic effect to parkinson disease and senile dementia tool in cell and zoopery, can be applied to the prevention and therapy of parkinson disease and senile dementia.
Summary of the invention
The application in prevention and therapy anti-parkinson drug or medicine for senile dementia and health product prepared by mannoglucan aldehydic acid oligosaccharide.Described manna glucuronic acid oligosaccharide has following feature:
(1) composition sugar: mannose and glucuronic acid or its salt;
(2) glucuronic acid that the mannose that 2-connects is connected with 4-or its salt alternately connect;
(3) its structural formula is following general expression (I) or (II)
In formula, R is the inorganic salts such as H or Na, K, and n is the integer between 0-8
In formula, R is the inorganic salts such as H or Na, K, and n is the integer between 0-8
(II)
Described medicine is the pharmaceutical composition containing mannoglucan aldehydic acid oligosaccharide and pharmaceutically acceptable carrier and/or excipient.
Carrier comprises sodium alginate micro ball, liposome etc.
Excipient: as mannitol, magnesium stearate, starch, cyclodextrin etc.
The dosage form of described medicine is injection, oral formulations or local administration preparation.
Tool of the present invention has the following advantages:
Mannoglucan aldehydic acid oligosaccharide has preventive and therapeutic action to parkinson disease and senile dementia, and toxic and side effects is little, safe and effective, may be used for medicine and the health product of preparing treatment parkinson disease and senile dementia.
Accompanying drawing explanation
The gel chromatography figure of ethanol eluent in the preparation process of Fig. 1 oligosaccharide;
ESI-MS and the HPLC figure of Fig. 2 mannoglucan aldehydic acid oligosaccharide G1-G4; A is G4; B is G3; C is G2; D is G1;
The hydrogen spectrum of Fig. 3 G2;
The carbon spectrum of Fig. 4 G2;
The two-dimentional HMBC spectrogram of Fig. 5 G2;
The two-dimentional hsqc spectrum figure of Fig. 6 G2;
The two-dimentional TOCSY spectrogram of Fig. 7 G2;
The hydrogen spectrum of Fig. 8 G3;
The carbon spectrum of Fig. 9 G3;
The hydrogen spectrum of Figure 10 G4;
The carbon spectrum of Figure 11 G4;
Figure 12 mannoglucan aldehydic acid oligosaccharide G2 is on the errors number of dementia mice step-through test and preclinical impact;
Figure 13 mannoglucan aldehydic acid oligosaccharide G2 is on the errors number of dementia mice water maze step-through test and preclinical impact;
Figure 14 mannoglucan aldehydic acid oligosaccharide G2 is on the impact of dementia mice Hippocampal Acetylcholine transferase active;
Figure 15 mannoglucan aldehydic acid oligosaccharide G2 is on the impact of dementia mice Hippocampal Acetylcholine esterase active.
Detailed description of the invention
By embodiment, the present invention is specifically described below, but the present invention has more than and is limited to following case study on implementation scope.
The preparation of embodiment 1 mannoglucan aldehydic acid oligosaccharide
Extract 3 hours at dry Thallus Laminariae (Thallus Eckloniae) being adopted the distilled water 100 DEG C of 30 times of quality, extracting solution is through filtering, and after concentrated, adding ethanol to final concentration is 75% precipitation, leaves standstill 12 h before harvest precipitations, sinks to and obtain laminarin through vacuum drying.Laminarin sample being dissolved in mass concentration is (solid-liquid ratio is 60mg/mL) reflux 5 hours in the sulfuric acid solution of 4%, PH=6-7 is neutralized to barium hydroxide, centrifugal, supernatant concentration is to 1/5th of initial volume, activated carbon column chromatography on concentrated solution, first balance with distilled water, then 50%-90% ethanol gradient elution is used, 50%-90% ethanol elution is concentrated into 1/5th of initial volume, boil off ethanol, directly go up Bio-gel P4 column chromatography, separation obtains six components (Fig. 1), ESI-MS and HPLC analysis (Fig. 2) is carried out to collecting the sample obtained above.NMR(Fig. 3-11) result confirms the structure of oligosaccharide further.Result shows, and G1-G4 is respectively mannoglucan aldehydic acid eight sugar, six sugar, tetrose and disaccharide.Its structure all meets the structural formula shown in figure below:
Wherein G1 is mannoglucan aldehydic acid eight sugar, n=3 in formula
G2 is mannoglucan aldehydic acid six sugar, n=2 in formula
G3 is mannoglucan aldehydic acid tetrose, n=1 in formula
G4 is mannoglucan aldehydic acid disaccharide, n=0 in formula
Embodiment 2: mannoglucan aldehydic acid oligosaccharide is to MPP +the protective effect of the neurocyte of damage
Neurotoxin MPTP is widely used in the research of parkinson disease (PD), and the MPTP entered in human body is changed into MPP by monoamine oxidase-B +, suppress the NADH CoQ reductase (composite I) of mitochondrial electron transport chain, thus ATP in cell is reduced, oxygen-derived free radicals is formed, and starts apoptosis, finally causes cell death.PC12 cell derived rat adrenal medulla pheochromocytoma, is widely used in the in vitro study of nervous system disease, is widely used in Parkinsonian research.Because cultured cells strain does not exist monoamine oxidase, MAO, so directly add MPP +, simulation MPTP causes Parkinsonian cell model.The present invention is index with cell survival rate, have studied mannuronic acid oligosaccharide to MPP +the protective effect of the neurocyte PC12 cell of damage, treats Parkinsonian probability to inquire into mannuronic acid oligosaccharide.
Material: people's neuroblastoma cells strain PC12 cell is purchased from Chinese Academy of Sciences's Shanghai biochemistry and Institute of Cell Biology.Adopt the high sugared culture fluid (Invitrogen) of DMEM containing 10% hyclone, 100U/mL penicillin and 100U/mL streptomycin, be placed in 37 DEG C, containing 5%CO 2incubator in cultivate.Mannuronic acid oligosaccharide adopts sample prepared by embodiment 1.
Method: test is divided into matched group, MPP +damage group, each oligosaccharide sample to normal cell processed group and each oligosaccharide sample to MPP +damage PC12 cytosis group, oligosaccharide sample concentration for the treatment of adopts 10,100 and 1000 μ g/ml respectively, often organizes 8 holes, 37 DEG C, containing 5%CO 2fresh medium 180 μ L is changed after hatching 24h and 48h in incubator, add 20mL MTT (5mg/mL, Sigma), 200 μ L dimethyl sulfoxide (DMSO are added after 4h, Sigma), jolting 10 minutes, measures 550nm place optical density value (OD) by microplate reader (Diagnostic Pasteur LP400).
Table 1 is the result of each oligosaccharide to the protective effect of the neurocyte that MPP+ damages.MT reconnaissance T measurement result is pointed out, and MPP+ is (49.50 ± 5.48) % to the damage ratio of cell.Four mannoglucan aldehydic acid oligosaccharide of test all have obvious repair to the neural cell injury of MPP+ induction, and cell viability has and all has clear improvement, and system goes out good neuroprotective.PC12 cell is the neuroblastoma cells strain of DA energy, can represent the various physiological characteristicies of substantia nigra of midbrain district DA serotonergic neuron well, therefore be widely used in Parkinsonian research.Each mannuronic acid oligosaccharide can protect PC12 cell to avoid MPP +damage, illustrates that it has neurocyte protection effect, may be used for Parkinsonian prevention and therapy.
Table 1 mannoglucan aldehydic acid oligosaccharide is to MPP +the neuroprotective of the PC12 cell of damage
Note: MPP +be (49.50 ± 5.48) % to the damage ratio of PC cell
Embodiment 3 mannoglucan aldehydic acid oligosaccharide is to the protective effect of the neuroblastoma strain SH-SY5Y that beta amyloid peptide damages
Material: SH-SY5Y cell strain; A β 25-35segment is synthesized by the Capital University of Medical Sciences, high performance liquid chromatography purification, purity more than 98%, serum-free MEM wiring solution-forming, considers film sucking filtration ,-20 DEG C of preservations for 0.22 μm.Mannuronic acid oligosaccharide adopts sample prepared by embodiment 1.
Test method: cell culture condition is add 10% hyclone (Hyclone, SH30070.03), 15mmol.L in MEM (Gibco BRL, 41500-067) culture medium -1hEPES (DNN company), penicillin 1x10 5iU.L -1, streptomycin 1x10 5iU.L -1, 5%CO 2, 37 DEG C, change weekly liquid twice, go down to posterity once.
MTT metabolic rate measure: by SY5Y cell with density for 1 × 10 3individual cell is inoculated in 96 orifice plates (Costar product), is divided into matched group, A β after 3 days 25-35group and A β 25-35+ P2 group (10,40,80 μ g/ml), A β 25-35+ each oligosaccharide (10,100,1000 μ g/ml) medicine group, often organizes 8 holes.Inoculate latter 24 hours every holes and add MTT (5mg/ml) 20 μ l, hatch 4 hours for 37 DEG C, sucking-off culture fluid, every hole adds DMSO200 μ l, jolting 10 minutes, measures 550nm place optical density value (OD) by microplate reader (Diagnostic Pasteur LP400).
Result: as shown in table 1, mannuronic acid oligosaccharide G1-G4 all significantly can resist 20 μMs of A β when three concentration 25-35toxicity, improves cultured cell MTT metabolic rate, and strengthens gradually along with sample concentration increases its activity, and result shows that mannuronic acid oligosaccharide can resist A β by neuroprotective cell SY5Y 25-35toxicity, has significant neuroprotective.Neuronal apoptosis plays a part very important in neural cell injury, and medicine stops it to further develop by intervening apoptotic process, plays a protective role to neurocyte.SH-SY5Y cell derived is in the neuroblastoma of people, and its physiology and morphology function is similar to normal neurons, tapered, and has obvious aixs cylinder, is the current good a kind of cell of Studies On Neuronal function in the world.Mannuronic acid oligosaccharide has neuroprotective to SY5Y cell, shows that mannuronic acid oligosaccharide may be used for the treatment of nervous system disease as parkinson disease and alzheimer disease.
Table 2 mannoglucan aldehydic acid oligosaccharide is to the neuroprotective of the SH-SY5Y cell that A β damages
Note: A β is (62.45 ± 6.58) % to the damage ratio of cell
Embodiment 4: mannuronic acid oligosaccharide G2 is to the effect of senile dementia
Laboratory animal: Kunming mouse.Before the test, the male KM mice making average weight be about 22g freely obtains feedstuff and water one week to adapt to laboratory environment.
Material: mannoglucan aldehydic acid oligosaccharide G2, prepares in embodiment 1.
A β 1-40available from Sigma, is dissolved in physiological saline solution, is made into 1mg/ml concentration, and sealing is placed in 37 DEG C of incubators 7 days makes it cohesion.
Test method: after mice adapts to one week, weighed and be divided into 5 groups at random, i.e. matched group, model group, mannoglucan aldehydic acid oligosaccharide G2 basic, normal, high (25,50,100mg/kg) three dosage groups, neat (2.5mg/kg) group of positive control drug hydrochloric acid Donna piperazine.Except matched group, to mice one-sided intracerebral ventricle injection A β 1-40.With reference to Maurice method, after chloral hydrate anesthesia, ventriculus dexter cerebri location (A:-2mm; L:2mm; H:-4mm), vertical skull inserting needle 3mm, slowly injection 3 μ l/ A β only 1-40, matched group is the sterile saline of equivalent.
Animal starts to give relative medicine in second day after operation, dosage 0.5ml/20g, and matched group, model group gavage normal saline, and every day 1 time, continuously to testing end.
(1) mice keeps away dark test
From A β 1-40within after modeling the 9th day, carry out keeping away dark test.This is kept away concealed installation and puts and be divided into bright (25 × 25 × 16cm) dark (24 × 20 × 15cm) two compartments, between be connected by an arched door (8.9 × 11.4cm), door can be shut as required by experimenter or open.Compartment floor is rustless steel fence (3.175mm).The fence floor of side, darkroom and stimulator are connected, and can shock by electricity, and side, bright room is not then connected with stimulator, therefore does not have electric current to pass through.Mice is put into bright room, after 10s, the door between light and shade room is opened.After mice (extremity) enters darkroom completely, immediately middle door is shut, and give once shock by electricity (electric current is 0.6mA).Allow mice stop 10s in darkroom, mice is put back in cage.After electricity irritation trains 24 hours, mice is put back to bright room, middle door is opened, and in record 5min, mice enters number of times and the incubation period in darkroom.
(2) rat/mouse labyrinth experiment
From A β 1-40within after modeling the 12nd day, carry out water maze test, five days by a definite date.This labyrinth has 5 cecums, and labyrinth is divided into two parts by test first day one block of black plastic plate, and mice is swum in the part only containing a cecum; Test second day, reset the position of plastic plate, mice is swum in the part containing three cecums; Test and removed plastic plate to the 5th day on the 3rd day, make mice covering the race.Record the errors number of its incubation period finding platform and arrival cecum respectively.
(3) cortex acetylcholinesterase (AChE) and acetylcholine transferase (ChAT) determination of activity
After Behavior test terminates, mice broken end gets brain, peels off hippocampal tissue rapidly, make 10% tissue homogenate with the normal saline of pre-cooling in ice bath.According to the operation of test kit description, the acetylcholinesterase and the acetylcholine transferase that measure this tissue are active.
Result
Mice keeps away dark test
1) as seen from Figure 12, A β model group is compared with matched group, and mice significantly shortens incubation period, errors number showed increased (p<0.05).Three dosage group incubation periods of mannoglucan aldehydic acid oligosaccharide G2 and errors number all comparatively A β model group have clear improvement, and it is suitable together that it acts on positive control drug hydrochloric acid Donna piperazine.
2) rat/mouse labyrinth test
As seen from Figure 13, model group is compared with matched group, and mice is found the incubation period of platform and obviously extends (p<0.05) through the errors number of cecum, shows A β 1-40one-sided intracerebroventricular causes mice Model of Dementia and is successfully established.Along with the prolongation of training time, mice incubation period and errors number shorten gradually.From the 3rd day, A β 1-40compared with three dosage groups of one-sided intracerebroventricular model group and matched group and mannuronic acid oligosaccharide G2, mouse wrong times showed increased, wherein the mannoglucan aldehydic acid oligosaccharide G2 high concentration group mice incubation period of remarkable shortening compared with model group.Train the 4th day, the middle and high dosage group of matched group and mannoglucan aldehydic acid oligosaccharide G2 significantly shortens incubation period compared with model group, and positive control drug hydrochloric acid Donna piperazine is neat not effective, shows that G2 is soon effective.Train the 5th day, three dosage groups of mannoglucan aldehydic acid oligosaccharide G2 are compared with model group with neat group of hydrochloric acid Donna piperazine, and the incubation period of mice obviously shortens and obviously reduces with errors number.
3) Hippocampal Acetylcholine esterase and acetylcholine transferase activity
Acetylcholinesterase and acetylcholine transferase are catabolic enzyme and the synzyme of acetylcholine respectively, and both regulate the content of acetylcholine in brain jointly.As shown in figure 14, in hippocampal tissue, hydrochloric acid Donna piperazine is organized and three dosage groups of mannoglucan aldehydic acid oligosaccharide G2 and A β together 1-40one-sided intracerebroventricular model group is compared acetylcholine transferase activity and is raised, but does not have significance.Matched group, neat group of hydrochloric acid Donna piperazine and mannoglucan aldehydic acid oligosaccharide G2 tri-dosage groups are compared with model group as shown in figure 15, acetylcholine esterase active significantly reduces, and what deserves to be explained is that front two groups of acetylcholine esterase actives are lower than matched group by about 50%, in explanation, the mannoglucan aldehydic acid oligosaccharide G2 of dosage and hydrochloric acid Donna piperazine significantly can both suppress the decomposition of hipocampal ACh together, thus improve the content of hipocampal ACh.This may be that mannoglucan aldehydic acid oligosaccharide G2 improves A β 1-40one-sided intracerebroventricular causes one of approach of AD symptom.
Conclusion: mannoglucan aldehydic acid oligosaccharide G2 can A β 1-40the behavioral indexes of the mice of damage, improves the memory of mice, reduces errors number.Improve acetylcholine transferase active, reduce acetylcholine esterase active.There is significant anti-senile dementia effect.
The foregoing describe specific embodiments of the invention, so and be not used to limit the present invention, those skilled in the art can not depart from improvement and the change of scope and spirit to embodiment disclosed herein.

Claims (4)

1. the application in the medicine and/or health product treating and/or preventing parkinson disease and/or senile dementia prepared by manna glucuronic acid oligosaccharide; Described its structural formula of manna glucuronic acid oligosaccharide is one in following general expression (I) or (II) or two kinds;
In formula, R is one or two or more kinds in H, Na or K, and n is the integer between 0-8
In formula, R is one or two or more kinds in H, Na or K, and n is the integer between 0-8
(II)。
2. application according to claim 1, is characterized in that:
Described manna glucuronic acid oligosaccharide has following feature:
(1) composition sugar: mannose and glucuronic acid or its salt;
(2) glucuronic acid that the mannose that 2-connects is connected with 4-or its salt alternately connect.
3. application according to claim 1, is characterized in that: described medicine is the pharmaceutical composition comprising mannoglucan aldehydic acid oligosaccharide and other pharmaceutically acceptable carrier and/or excipient.
4. application according to claim 1, is characterized in that: the dosage form of described medicine is injection, oral formulations or local administration preparation.
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