CN103342758A - Low molecular weight chondroitin sulfate and application thereof in preparation of anti-alzheimer disease medicine - Google Patents
Low molecular weight chondroitin sulfate and application thereof in preparation of anti-alzheimer disease medicine Download PDFInfo
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- CN103342758A CN103342758A CN2013102845205A CN201310284520A CN103342758A CN 103342758 A CN103342758 A CN 103342758A CN 2013102845205 A CN2013102845205 A CN 2013102845205A CN 201310284520 A CN201310284520 A CN 201310284520A CN 103342758 A CN103342758 A CN 103342758A
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Abstract
The invention discloses a low molecular weight chondroitin sulfate which is prepared by a preparation method comprising the following steps of: oxidizing and degrading raw chondroitin sulfate obtained from shark cartilage; and intercepting through an ultrafiltration membrane to obtain the low molecular weight chondroitin sulfate with molecular weight less than 5,000 daltons. The oxidization and degradation process includes: processing the chondroitin sulfate through hydrogen peroxide for 8 to 12 hours; and reacting at temperature of 60 to 70 DEG C. The low molecular weight chondroitin sulfate can be used as a candidate active ingredient for resisting alzheimer disease, and can be used for preparing medicines for treating, reducing or preventing nervous system relevant to cognitive decline. The first study result shows that the chondroitin sulfate with relatively low molecular weight has inhibition to nerve cell toxicity generated under the induction of Abeta after being degraded; and micromolecular polysaccharide can easily pass through a blood brain barrier, so that the low molecular weight chondroitin sulfate can easily act on the brain hippocampus related to learning and memory, and as a result, the study is of great significance.
Description
Technical field
The present invention relates to low-molecular weight chondroitin sulfate and the application in the medicine of preparation anti-Alzheimer disease thereof, belong to pharmaceutical field.
Background technology
Senile dementia (Alzheimer ' s disease, AD), namely alzheimer's disease occurs in senium and presenium, is a kind of primary neurological encephalopathy (HIE) of main performance with the damage in learning and memory.Along with social population's aging, its sickness rate raises just year by year.Amyloid (Amyloid-beta, A β) is AD important pathological molecule.Under pathological conditions, A β produces in a large number, make a large amount of A β form the amyloid fibril of high polymeric form, and gathering produces neurocyte toxicity, cause neurocyte to be lost, and then the formation senile plaque, show as learning and memory function decline and dull-witted, so the neurotoxicity of A β may be one of major reason that causes AD.At present, be the gathering that concentrates on the formation that suppresses A β peptide, antagonism A β of the drug development of target spot, suppress the neurotoxic injury due to the A β or accelerate degraded and the removing of A β with A β.Therefore the medicine that acts on A β fibril has good prospect to treatment AD.
Chondroitin sulfate (CS) can promote the growth of tire mouse cerebral neuron and induce most of neural length that increases cynapse.CS can reduce effectively the beta induced generation of A neuronal cell line and former generation neuronic neurotoxic effect, CS-A can suppress and postpone A β and form, CS-B suppresses A β
1-42The SH-SY5Y apoptosis of inducing reduces A β and causes neurotoxicity.From 14d tire mouse akrencephalon, extract the proliferation function that the CS-D, the CS-E that obtain have the relevant neural stem cell/precursor cell of potential promotion fibroblast growth factor-2 (FGF-2).CS sulfation monose and disaccharide can suppress the short fibril formation effect of endogenous glycosaminoglycan in conjunction with the A beta molecule by competitiveness, illustrate that they may be that the endogenous glycosaminoglycan is induced the inhibitor that produces A β formation.In addition, discover that derivative low molecular weight heparin with the heparin of CS structural similitude can reduce A β and accumulate and A β in brain
25-35The neurocyte toxic action of inducing.
The present invention utilizes the effect of the neurocyte toxicity of the beta induced generation of inhibition A that chondroitin sulfate has, the low-molecular weight chondroitin sulfate that obtains in the hope of deriving (LMWCS) has the effect of anti-AD too, this research lays the foundation for the research and development of anti-AD medicine, has bigger theory significance and prospect should be arranged.
Summary of the invention
At above-mentioned prior art, the invention provides a kind of low-molecular weight chondroitin sulfate (LMWCS), and preparation method thereof, with and application in anti-senile dementia disease.
The present invention is achieved by the following technical solutions:
A kind of low-molecular weight chondroitin sulfate (LMWCS), obtain by following preparation method: derive from the chondroitin sulfate raw material (Mw:10000～30000 dalton) of shark suft bone through after the oxidative degradation, obtain molecular weight less than 5000 daltonian low-molecular weight chondroitin sulfates after holding back with ultra-filtration membrane; Described oxidative degradation process is: handle chondroitin sulfate with hydrogen peroxide, the treatment time is 8～12 hours, and temperature of reaction is 60～70 ℃.
Preferably, being to use the 30%(percent by volume) hydrogen peroxide handles chondroitin sulfate, and every 3g chondroitin sulfate is with 30% hydrogen peroxide of 8～12ml.
The described chondroitin sulfate raw material that derives from shark suft bone is natural original chondroitin sulfate, namely directly extract in the animal body obtain, without the chondroitin sulfate of degraded.
Low-molecular weight chondroitin sulfate of the present invention confirms by experiment, has the provide protection to Model of Dementia due to the amyloid-beta (A β), can effectively suppress PC12 and SH-SY5Y neurocyte toxic action that A β causes, and can suppress the nerve cell apoptosis of the beta induced generation of A, and memory and space exploration ability to the senile dementia model mice due to the A β have significant improvement effect, and the beta induced superoxide-dismutase (SOD) of inhibition A, Selenoperoxidase (GSH-px), acetylcholine transferase enzyme activities such as (ChAT) and raising mda (MDA), the content of acetylcholinesterase (AChE), utilize Electronic Speculum, circular dichroism spectrometry research low-molecular weight chondroitin sulfate is to the direct influence of A β filament structure, the result shows that low-molecular weight chondroitin sulfate has direct repression to the neurocyte toxicity of the beta induced generation of A, illustrate that low-molecular weight chondroitin sulfate has therapeutic action to alzheimer's disease, therefore, low-molecular weight chondroitin sulfate of the present invention can be used for the treatment of, improve or the relevant nervous system disorders of prevention cognitive function decline, can be used as a kind of candidate's activeconstituents of anti-Alzheimer disease, for the preparation for the treatment of, improve or prevent the medicine of the relevant nervous system disorders of cognitive function decline; The relevant nervous system disorders of described cognitive function decline is the dementia that alzheimer's disease, vascular dementia, mild cognitive damage and other oxidative stresss participate in.
The present invention is that to study degraded back first inhibited to the neurocyte toxicity of the beta induced generation of A than the chondroitin sulfate of small molecular weight, because micromolecular polysaccharide is easier to pass through hemato encephalic barrier, the easier relevant cerebral hippocampus district of learning and memory that acts on, therefore research of the present invention has great importance.
Description of drawings
Fig. 1 is the restraining effect of the neurocyte toxicity of the beta induced generation of the A of LMWCS.
Fig. 2 is the restraining effect of the nerve cell apoptosis of the beta induced generation of the A of LMWCS, and A-F and a-f are respectively the apoptosis result of PC12 and SH-SY5Y cell, wherein (A, a) control group, (B, b) A β
25-35Model group, (C-E, c-e) each dosage treatment group of LMWCS.
Fig. 3 has the improvement effect for memory and the space exploration ability that the A β of LMWCS causes the senile dementia model mice, (A) mouse seeks the platform time in latent period, (B) mouse seeks the distance of platform, (C) mouse is explored the time that arrives original platform in the experiment for the first time, hunting time in the target quadrant during (D) mouse is explored and tests.
Fig. 4 is the influence that the A β of LMWCS causes the oxidative stress enzyme activity of senile dementia model mice, (A) superoxide dismutase activity, (B) glutathione peroxidase activity, (C) mda content.
Fig. 5 is the influence that the A β of LMWCS causes the central cholinergic system vigor of senile dementia model mice, (A) acetylcholinesterase vigor, (B) acetylcholine transferase vigor.
Fig. 6 is the restraining effect that the A β of LMWCS fibril forms, and (A-C) is respectively final concentration 10 μ MA β
1-40, 10 μ M A β
1-40+ 50 μ g/mLLMWCS, 10 μ MA β
1-40Hatch 24hr for+50 μ g/mLCS37 ℃, (D-F) be respectively final concentration 10 μ M A β
1-40, 10 μ MA β
1-40+ 50 μ g/mLLMWCS, 10 μ MA β
1-40Hatch 48hr for+50 μ g/mLCS37 ℃.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Experimental technique among the embodiment if no special instructions, is ordinary method.
The preparation of embodiment 1LMWCS
Molecular weight is 10000～30000 daltonian shark chondroitine raw material 3g, is dissolved in the 50ml ultrapure water magnetic agitation dissolving of heating, control temperature to 65 ℃ adds the 30%(percent by volume) hydrogen peroxide 10ml, about control pH5.0, react after 10 hours and stop, add 95% ethanol of 6 times of volumes, leave standstill 10min, place, abandon supernatant, the precipitation that obtains is with 95% washing with alcohol 3 times, and drying obtains sample.Sample is held back with the ultra-filtration membrane of molecular weight 5000, and drying obtains the product low-molecular weight chondroitin sulfate, measures this product molecular-weight average (Mr) less than 5000 through the multiple angle laser light scattering instrument.
The bioactivity research of embodiment 2LMWCS
Investigate the neurocyte toxic action that LMWCS suppresses the beta induced generation of A: not add A β
25-35The negative contrast of cell viability, adopt mtt assay to investigate the toxic action that LMWCS suppresses the neurocyte of the beta induced generation of A, concrete implementation step is as follows:
The frozen storing liquid of rat pheochromocyte oncocyte (PC12) and neuroblastoma cell (SH-SY5Y) is melted in 37 ℃ of water-baths fast, the centrifugal 5min of 1000r/min, abandon supernatant, sedimentation cell is resuspended and blow and beat mixing gently with nutrient solution, form cell suspension, on cell counting count board, carry out cell counting, be inoculated in then in the culturing bottle, place CO
2Constant incubator (5%CO
2, 37 ℃) and cultivate 24h, change liquid, changed liquid once in later per 2～3 days.When treating that cell grows to the fusion state, cell cleans twice with PBS, adds 0.25% trypsinase, 1～2mL then, observes under inverted microscope, treat that the intercellular substance increases, cell retraction becomes bowlder, immediately with the trypsinase sucking-off or outwell, adds the nutrient solution that contains 10% foetal calf serum and stops digestion, blow and beat cell on bottle wall repeatedly with the elbow suction pipe, make most of cell detachment form cell suspension, under inverted microscope, count, then with 10
5/ mL density is inoculated in the new culturing bottle, and constant incubator continues to cultivate.
Adopt mtt assay to measure the neurocyte toxicity that LMWCS suppresses the beta induced generation of A.Collect the logarithmic phase cell, adjusting concentration of cell suspension is 0.5 * 10
4/ hole is divided in 96 orifice plates, and every hole 200 μ L place 37 ℃, 5%CO
2CO
2Cultivate in the constant incubator and make cell attachment; The adding medicine (LMWCS establishes 3 concentration gradients: 50 μ g/mL, 100 μ g/mL, 200 μ g/mL, with the substratum dilution, each concentration is established 3 parallel holes), continue to cultivate 24h; Add A β
25-35(30 μ M) cultivates 24h again; The careful supernatant of drawing, the PBS washing, recentrifuge is abandoned supernatant, adds 200 μ L fresh cultures; Every hole adds MTT solution 5 μ L, and 37 ℃ are continued to stop cultivating behind the cultivation 2h, add 150 μ LDMSO and measure each hole absorbancy (A in wavelength 570nm place with enzyme-linked immunosorbent assay instrument
570) value, and calculate its survival rate: survival rate=(experimental group A
570/ control group A
570) * 100%.Repeated experiments six times is averaged.
PC12 and the Cytotoxic restraining effect of SH-SY5Y of the beta induced generation of the A of different concns LMWCS are seen Fig. 1, the result shows that PC12 and the SH-SY5Y cytotoxicity of the beta induced generation of the A of LMWCS have the obvious suppression effect, increase restraining effect enhancing along with concentration, has concentration dependent, when concentration increased to 200 μ g/mL, cell survival rate reached 84.78% and 81.64% respectively.
Embodiment 3LMWCS suppresses apoptosis research
Adopt AnnexinV-FITC/PI pair to dye method, flow cytometer has detected the restraining effect of the apoptosis of the beta induced PC12 of the A of LMWCS and SH-SY5Y cell.Concrete dosing experimental technique behind the collecting cell, adds AnnexinV(5 μ L with example 1) and PI(10 μ L), detect with streaming.Calculate the apoptotic cell rate, apoptotic cell rate=(the early stage cell of apoptosis+apoptosis cell in late period)/total cell * 100%.Repeated experiments three times is averaged.
PC12 and the apoptotic restraining effect of SH-SY5Y of the beta induced generation of the A of different concns LMWCS are seen Fig. 2, the result shows that PC12 and the SH-SY5Y apoptosis of the beta induced generation of the A of LMWCS have the obvious suppression effect, increase restraining effect enhancing along with concentration has concentration dependent.
The A β of embodiment 4LMWCS causes memory and the space exploration capability study of senile dementia model mice
1. laboratory animal and reagent
Laboratory animal: male Balb/c mouse, body weight 18-22g is provided by Shandong University's Experimental Animal Center, production licence number is the SCXK(Shandong) 20090001, occulting light is according to 12h:12h, and ad lib is drunk water.
Reagent: A β
1-40, Sigma company; Huperzine A-Zhulin Antun, Tailong Pharmaceutical Co., Ltd., Henan; MDA, SOD, GSH-PX, Na
+/ K
+-ATPase, AchE, ChAT detection kit, bio-engineering corporation is built up in Nanjing.
2. condensed state A β
1-40Preparation
With 0.1mgA β
1-40Be dissolved in the 0.1mL sterile saline, concentration is about 0.23mmol/L.Sealing is placed in 37 ℃ of cell culture incubators hatches 7d, makes it become the A β of condensed state
1-40, be placed in 4 ℃ of refrigerators standby.
3 mouse AD Modellings, administration and test
Mouse weighed and be 6 groups at random, be respectively sham operated rats (Vehicle), A β model group (Model), positive control Huperzine A-Zhulin Antun group (HBY), LMWCS low (50mg/kg), in (150mg/kg), high (450mg/kg) dosage group.Vehicle group, Model group give distilled water 10ml/kg.
Mouse stomach is after one week, and except Sham group mouse, other group mouse carry out intracerebroventricular injection A β
1-40Modeling.Also make improvements slightly with reference to the Maurice method, behind 0.2mL0.4% vetanarcol anesthetized mice, mouse is fixed on the stereotaxic apparatus, crown portion skin is cut off in the alcohol swab wiping, exposes bregma.Employing ventriculus dexter cerebri location, bregma left and right sides 1.0mm, 0.5mm backward, the degree of depth be the downward 2.5mm of skull surface place (AP ,-0.5mm, ML, ± 1.0mm, DV ,-2.5mm)
[11], every little injection 3 μ l aggegation attitude A β
1-40, microsyringe is extracted sterilization back skin suture behind the constant speed injection 3min, let the acupuncture needle remain at a certain point 5min.Sham group mouse is injected 3 μ L stroke-physiological saline solution.Begin to be administered to the water maze end of test (EOT) behind the 24hr, the mouse broken end is got brain, isolate cortex and hippocampus, carry out homogenate in the ice bath, 3000rpm, 15min carries out SOD, GSH-PX, Na with test kit behind the absorption supernatant
+/ K
+-ATPase and MDA assay, and the active detection of ChAT, AChE.
4. result
As seen from Figure 3, the Model group is compared with the Vehicle group, and obviously prolong (p＜0.05) latent period that mouse seeks platform, illustrates that the one-sided intracerebroventricular of A β causes the mouse Model of Dementia and successfully sets up.Along with the prolongation of mouse water maze training time, constantly shorten the latent period of mouse.Compare with the Vehicle group, the prolongation of latency of Model group mouse, each administration group is sought platform and is all organized shortening (p＜0.05) than Model latent period in the experiment.Behind the water maze training 5d, remove the laggard row space of platform and explore experiment, the Model group is compared with the Vehicle group, the time that arrives for the first time the original platform position obviously prolongs, and obviously shorten (p＜0.05) residence time in the target quadrant, and LMWCS administration group and Model group is compared, the time that mouse arrives the original platform position for the first time shorten and in the target quadrant residence time obviously prolong (p＜0.05).
Found out by Fig. 4, SOD, GSH-px vigor all significantly are lower than the Vehicle group in Model group mouse brain cortex and the hippocampus, MDA content is higher than Vehicle group (p＜0.05), and demonstrating the interior antioxidase activity of Model group mouse brain has downtrending, and change has taken place the level of oxidative stress.Give LMWCS after three weeks; the oxidative stress level all improves in each dosage group mouse brain; SOD in mouse brain cortex and the hippocampus, GSH-px vigor are better than the Model group; and MDA content obviously increases (p＜0.05); point out LMWCS can improve in the mouse brain oxidative stress level thus and reduce the free radical damage degree, be conducive to protect the mouse brain tissue to avoid oxidative damage.
Found out that by Fig. 5 Model group mouse brain cortex and hippocampus ChAT activity are starkly lower than Vehicle group (p＜0.05), Ach synthesis rate and content in the prompting Model group mouse brain may descend, and the cholinergic system function reduces.HBY group and the LMWCS group mouse ChAT activity of pallium and hippocampus behind drug treatment all increases the wherein active significantly enhancing (p＜0.05) of the middle and high dosage group of Huperzine A-Zhulin Antun group and LMWCS.Model group AchE activity is compared raising (p＜0.05) with the Vehicle group, show that A β may make the active raising of AchE in the mouse brain, the Huperzine A-Zhulin Antun group can make active obviously reduce (p＜0.05) of the AchE of cortex and hippocampus, each dosage group of LMWCS is compared with the Model group can reduce the AchE activity, and prompting LMWCS may influence the AchE activity.
The influence of the A β of embodiment 5LMWCS filament structure
Get A β
1-40, add LMWCS(100 μ g/mL respectively) and CS(100 μ g/mL), make the final concentration of A β reach 100 μ M, the blank group is the A β of 100 μ M
1-40Sample is placed 37 ℃ then and hatch, respectively at 24, the 48hr sampling carries out the electron microscopic observation experiment, sample drop is added on the copper mesh of 200 order Formvar-bag quilt, 25 ℃ of dry 1min are with 2% phospho-wolframic acid negative staining, A β
1-40The fibril form adopts the JEM-1200EX transmission electron microscope observing.The result as shown in Figure 6.
As shown in Figure 6, A β can form fibril at 24hr, but at 48hr, fibril is assembled more obvious, and the filamentous cloud cluster obviously increases, yet adds LMWCS in A β solution, and it is thinner that fibril becomes, and the fibril amount is few.Add CS in A β solution, fibril forms and is less than the fibril number that simple A beta peptide aggregation produces.
Claims (6)
1. low-molecular weight chondroitin sulfate, it is characterized in that: obtain by following preparation method: derive from the chondroitin sulfate raw material of shark suft bone through after the oxidative degradation, obtain molecular weight less than 5000 daltonian low-molecular weight chondroitin sulfates after holding back with ultra-filtration membrane; Described oxidative degradation process is: handle chondroitin sulfate with hydrogen peroxide, the treatment time is 8～12 hours, and temperature of reaction is 60～70 ℃.
2. a kind of low-molecular weight chondroitin sulfate according to claim 1 is characterized in that: be to handle chondroitin sulfate with 30% hydrogen peroxide, every 3g chondroitin sulfate is with 30% hydrogen peroxide of 8～12ml.
3. the preparation method of claim 1 or 2 described a kind of low-molecular weight chondroitin sulfates, it is characterized in that: derive from the chondroitin sulfate raw material of shark suft bone through after the oxidative degradation, obtain molecular weight less than 5000 daltonian low-molecular weight chondroitin sulfates after holding back with ultra-filtration membrane; Described oxidative degradation process is: handle chondroitin sulfate with hydrogen peroxide, the treatment time is 8～12 hours, and temperature of reaction is 60～70 ℃.
4. preparation method according to claim 3 is characterized in that: be to handle chondroitin sulfate with 30% hydrogen peroxide, every 3g chondroitin sulfate is with 30% hydrogen peroxide of 8～12ml.
5. claim 1 or the 2 described a kind of low-molecular weight chondroitin sulfates application in the medicine of the relevant nervous system disorders of preparation treatment, improvement or the decline of prevention cognitive function.
6. application according to claim 5 is characterized in that: the relevant nervous system disorders of described cognitive function decline comprises the dementia that alzheimer's disease, vascular dementia, mild cognitive damage and other oxidative stresss participate in.
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| CN104004114A (en) * | 2014-06-06 | 2014-08-27 | 嘉兴纽迪康生物科技有限公司 | Preparation method of low-molecular-weight chondroitin sulfate |
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| CN108484795A (en) * | 2018-04-28 | 2018-09-04 | 泰山医学院 | Chondroitin sulfate lithium and its preparation method and application |
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