CN106474101A - Application of the Galangin in treatment diabetes mellitus encephalopathy medicine - Google Patents
Application of the Galangin in treatment diabetes mellitus encephalopathy medicine Download PDFInfo
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- CN106474101A CN106474101A CN201510336309.2A CN201510336309A CN106474101A CN 106474101 A CN106474101 A CN 106474101A CN 201510336309 A CN201510336309 A CN 201510336309A CN 106474101 A CN106474101 A CN 106474101A
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- galangin
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Abstract
The present invention relates to the new pharmacological action of Galangin, the i.e. preventive and therapeutic action to diabetes mellitus encephalopathy.Galangin is obviously improved the Cognitive function damage that diabetes cause, and significantly reduces intracerebral advanced glycation end products（AGEs）Level, significantly increases intracerebral beta amyloid precursor protein β position lyases 1（BACE1）Activity and expression, significantly reduce intracerebral interleukin 1 β（IL‑1β）And tumor necrosis factor α（TNF‑α）Level, dramatically increases intracerebral reduced glutathione（GSH）Level；Dramatically increase superoxide dismutase in serum（SOD）Activity, GSH level etc. are acted on.Galangin can be used for the prevention and treatment of the diabetic complications such as diabetes mellitus encephalopathy.
Description
Technical field
The present invention relates to the preventive and therapeutic effect of the new pharmacological action of Galangin and its mechanism of action, especially Galangin to diabetes mellitus encephalopathy.
Background technology
Diabetes mellitus encephalopathy（diabetic
Encephalopathy, DE）Refer to diabetes（Diabetes mellitus, DM）The moral function disorder disease with hypophrenia and cerebral nerve physiology and structural change as principal character of the progressive generation of prolonged illness patient, is diabetes modal complication in central nervous system.Under diabetic disease states, the structural change of brain is mainly hippocampus and cortical atrophy, and function changes and is mainly Cognitive function damage, and substantial amounts of research report has affirmed the fact that diabetes cause cognition dysfunction.In 2006, buzzword diabetes cognition dysfunction（diabetes-associated cognitive decline,DACD）Proposition further enhancing understanding of the people to this dysfunction, and become the focus of diabetes mellitus encephalopathy research.Existing about 3.47 hundred million adult's having diabetes in the whole world according to estimates, wherein 40% lives in the nations of China and India.Extensive epidemiological investigation and shown based on the perspective study of epidemiology survey：Diabetes are age-related decrease of cognitive function and dull-witted hazards, and with respect to ND, the speed of decrease of cognitive function increased 1.5-2.0 times in diabetic；Similarly, for Alzheimer disease (Alzheimer's disease, AD)
The incidence of disease, DM patient is 2 times of non-DM patient.Most results of study show that diabetes mellitus encephalopathy is a kind of process of brain accelerated ageing, thus foreign scholar de la Monte SM seminar proposes the viewpoint that AD is III type DM.Therefore, diabetes mellitus encephalopathy is becoming one of important research topic of this century whole world the world of medicine.
Galangin, another name：Galangin；3,5,7- trihydroxyflavones, English name Galangin, be primarily present in zingiberaceous plant and propolis, it is known that its there is antiviral antitumor action.Structure is as follows：
Content of the invention
1. goal of the invention
It is an object of the invention to be found that the new pharmacological action of Galangin, i.e. preventive and therapeutic effect of the Galangin to diabetes mellitus encephalopathy.In fact, the present invention relates to preventive and therapeutic effect and its possible mechanism of action of the Galangin to diabetes Cognitive function damage.
2. technical scheme
Galangin has preventive and therapeutic effect to diabetic complications such as diabetes mellitus encephalopathies, and the learning and remembering ability infringement tool that especially Galangin causes to diabetes improves significantly；Galangin be by reduce beta amyloid precursor protein β-position lyases 1（BACE1）Function, suppression advanced glycation endoproducts（AGEs/RAGE）Axle, anti-inflammatory, anti-oxidation stress etc. realize above-mentioned effect.
3. beneficial effect
Above pharmacological tests show that the present invention has advantages below：
（1）The present invention is found that new pharmacological action and new medical usage to Galangin, has opened up a new application.
（2）Present invention demonstrates that Galangin preventing and treating diabetes mellitus encephalopathy pharmacological effect is good, effect is strong, imply that good prospect in medicine.
（3）In Morris water maze test, Galangin can obviously reduce the escape latency of DM rat, increase platform traversing times and the percentage of the time of staying in platform place quadrant, illustrate that Galangin has the learning and remembering ability for being obviously improved DM rat.
（4）Present invention demonstrates that Galangin has the effect for substantially reducing AGEs level in DM rat hippocampus, illustrate that Galangin can substantially suppress AGEs/RAGE axle mediating proteins saccharification.
（5）Present invention demonstrates that Galangin has and BACE1 activity, the effect of expression in DM rat cerebral cortex is significantly reduced, prompt Galangin and can obviously reduce the generation of intracerebral nerve cell toxic agent A β and its damage of Central nervous system.
（6）Galangin substantially reduces IL-1 β and TNF-α level in DM rat hippocampus, shows that Galangin has powerful antiinflammatory action.
（7）Galangin substantially increases GSH level in serum, strengthens SOD in serum
The effect of activity, shows that Galangin has very strong antioxidation.
Description of the drawings
Hereinafter, embodiment of the present invention is described in detail in conjunction with accompanying drawing, wherein：
Impact of Fig. 1 Galangin to the training DM rat escape latency of 1 day and 4 days
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05.
Impact of Fig. 2 Galangin to DM rat platform traversing times
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05, * *P<0.01.
Impact of Fig. 3 Galangin to the time of staying of DM rat platform place quadrant
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05.
Impact of Fig. 4 Galangin to DM rat fasting blood-glucose
Note：Compare with Normal group,P<0.01；
Fig. 5 Galangin is in DM rat hippocampus
The impact of AGEs content
Note：Compare with Normal group,P<0.01；Compare with model group, * *P<0.01.
Fig. 6 Galangin is in DM rat cerebral cortex
The impact of BACE1 activity
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05.
Fig. 7 Galangin is in DM rat cerebral cortex
The impact of BACE1 protein expression
Note：Compare with Normal group,P<0.01；Compare with model group, * *P<0.01.
Impact of Fig. 8 Galangin to IL-1 β level in DM rat hippocampus
Note：Compare with Normal group,P<0.01；Compare with model group, * *P<0.01.
Impact of Fig. 9 Galangin to TNF-α level in DM rat hippocampus
Note：Compare with Normal group,P<0.01；Compare with model group, * *P<0.01.
Figure 10 Galangin is to SOD in DM rat blood serum
The impact of activity
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05, * *P<0.01.
Figure 11 Galangin is to GSH in DM rat blood serum
The impact of level
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05.
Specific embodiment
Following examples are that the present invention is further illustrated, but never limit the scope of the present invention.The present invention is further elaborated on referring to embodiment, it should be appreciated to those skilled in the art that the present invention is not limited to these embodiments and the preparation method for using.And, those skilled in the art can carry out equivalent, combination, improvement according to description of the invention or modify to the present invention, but these are intended to be included in the scope of the present invention.
Embodiment
1
：Galangin pair
DM
The impact of Cognition Function in Rats
1 materials and methods
1.1 Experimental Animals Male SD strain rats, 8-9 week old, 190-220g, Hainan Medical College's Experimental Animal Center.
1.2 medicines are purchased from upper Hiroad standing grain medical sci-tech Development Co., Ltd with reagent Galangin（HPLC purity>98%）, STZ
Purchased from sigma company, glucose testing kit builds up Bioengineering Research Institute purchased from Nanjing.
1.3 method
1.3.1 model foundation male SD Rat Fast can't help more than water 12h, inject STZ by 55mg/kg disposable celiac（0.1mol/L sodium citrate buffer solution, pH4.4 are dissolved in before use）Carry out modeling, after modeling three days, socket of the eye veniplex takes blood about 0.2ml, and 25 DEG C, 3000rpm centrifugation 10min separate serum.Fasting blood-glucose is detected with glucose kit（FBG）, FBG value is taken more than 250mg/dl (13.9mmol/L) and less than 600mg/dl（33.3mmol/L）Rat as successful diabetes rat.
1.3.2 it is grouped and successful for modeling diabetes rat is randomly divided into 3 groups according to blood glucose value by administration, respectively diabetic model group, Galangin high and low dose group, per 10 rat of group.One group Normal group is separately set, per 10 rats of group.Galangin high and low dose group presses 15,30mg/kg respectively
Gavage（By 10ml/kg volume）Give Galangin（Suspension is made with water）, once a day, continuous 9 weeks.Normal group and model group are to same volume physiological saline.Monitor a body weight weekly, administered volume is adjusted, monthly monitor a fasting blood-glucose.
1.3.3, after index determining is administered 8 weeks, each group rat carries out Morris water maze test, observational learning, memory function, the percentage of the escape latency, platform traversing times and the time of staying in platform place quadrant of record rat.Afterwards, each group rat femoral vein takes blood, separately serum, and Cord blood is standby；At once put to death, brain is taken, separate hippocampus and cortex, -80 DEG C of preservations.
1.4 multigroup are compared and adopt one-way analysis of variance, and comparing between two groups carries out statistical analysis using t inspection,P<0.05 represents that difference is statistically significant.
2 results
2.1 Galangins learn to DM rat, the impact of memory function
In the test of Morris water maze, compare with normal rats, in the training of 5 days, the escape latency of DM rat is all dramatically increased（P<0.01）, platform traversing times（P<0.01）And the percentage in the time of staying of platform place quadrant is substantially reduced（P<0.01）.Galangin low dosage is in the escape latency for significantly reducing DM rat on the 5th day of training（P<0.05）, high dose all significantly reduced the escape latency of DM rat at the 1st, 4 days（P<0.05）；Galangin high and low dose can all be significantly increased to the percentage of the time of staying of platform place quadrant（P<0.05 orP<0.01）, and only high dose dramatically increases platform traversing times（P<0.05）.As a result Fig. 1, Fig. 2, Fig. 3 are seen.
Impact of 2.2 Galangins to DM rat blood sugar and body weight
In whole experiment process, the FBG of DM rat is constantly in high-level state, is significantly higher than normal rat（P<0.01）.After DM rat gives Galangin high and low dose 4 and 9 weeks, FBG is still within high-level state, compares with non-administration DM rat, no difference of science of statistics（See Fig. 4）.After administration is started, the body weight of DM rat is substantially less than the body weight of normal rat（P<0.01）, Galangin high dose administration 5 and 9 weeks after, dramatically increase the body weight of DM rat（P<0.05）, other body weight of two dosage all to DM rat during being administered do not make significant difference（It is shown in Table 4）.
Impact of 1 Galangin of table to DM rat body weight
Note：Compare with Normal group,P<0.01；Compare with model group, *P<0.05.
Embodiment
2
：Galangin pair
DM
In rat hippocampus
AGEs
The impact of level
1 materials and methods
1.1 animals used as test are with embodiment 1.
1.2 medicines are purchased from the U.S. with the anti-RAGE antibody of reagent rabbit
Santa Cruz company, the anti-GAPDH antibody of rabbit are purchased from Bioworld company of the U.S., and NTx enzyme is purchased from sigma company of the U.S., and alkaline phosphatase two is anti-, phenylmethyl sulfonylfluoride（PMSF）With
BCA protein testing cassete is purchased from the green skies biotech firm in Jiangsu, Na3VO4Chinese medicines group is purchased from NaF（Shanghai）Chemical reagent Co., Ltd.
1.3 method
Fluorescence spectrophotometry detects AGEs level.The hippocampus sample that will be preserved, by 10 times amount after weighing（w/v）Add the PBS of 100mM（pH7.4）Buffer solution, ultrasound homogenate at 4 DEG C.Homogenate 10000rpm centrifugation at 4 DEG C
After 15min, supernatant is used for total protein content and other indexs of correlation are determined.Precipitation being taken, being washed 3 times with distilled water, chloroform/methanol (1 is added in precipitation:1) 1.0ml, shaken overnight.Add methanol/water (4:1) 0.5ml, 4000rpm centrifugation 5min at 4 DEG C.Precipitation is with methyl alcohol
1.0ml is washed 2 times, and distilled water is washed 2 times, then with pH7.5,0.02mol/LHepes buffer solution（Contain
0.1mol/L CaCl2）Wash 2 times.At being deposited in 4 DEG C in 1.0ml Hepes buffer solution overnight.Centrifugation removes buffer solution, and particle is suspended in
1.0ml enzyme containing NTx（290U）Hepes buffer solution in, add toluene and each 2.0 μ l of chloroform.With the blank tube containing only Hepes buffer solution and clostridiopetidase A as standard, 37 DEG C of vibrations
24h, digestive juice is centrifuged, and leaves and takes supernatant.With the fluorescence intensity in fluorescence spectrophotometry detection supernatant（The content of reflection AGEs）, excitation wavelength is 370nm, and absorbing wavelength is 440nm.The content of AGEs with
U/mg hippocampal protein represents.
2 results
In DM rat hippocampus, AGEs content is dramatically increased, statistically significant with the comparison in normal rat hippocampus（P<0.01）.Galangin high dose can significantly reduce the AGEs content in DM rat hippocampus（P<0.01）, as a result see Fig. 5.
Embodiment
3
：Galangin pair
DM
In rat cerebral cortex
BACE1
Activity, protein expression and
mRNA
The impact of level
1 materials and methods
1.1 animals used as test are with embodiment 1.
1.2 medicines and reagent
The anti-BACE1 antibody of rabbit is purchased from abcam company of Britain, and the anti-GAPDH antibody of rabbit is purchased from Bioworld company of the U.S., the artificial synthesized fluorogenic substrate of BACE1（Article No. ES004）Purchased from the U.S.
R＆D System company.Rat Bace1 and β-actin primer are synthesized by Shanghai Sheng Gong bio-engineering corporation, and TRIzol is purchased from Invitrogen Chinese companies.
1.3 method
1.3.1 BACE1 determination of activity
Fluorescence spectrophotometry BACE1 activity.The brain cortex homogenate liquid prepared when AGEs level is determined, is centrifuged the sample of the supernatant as BACE1 determination of activity of gained.BCA
After method determines total protein concentration, 50-70 μ g albumen is added in 100 μ l reaction systems of final concentration of 10 μM of fluorogenic substrate, reacts 10 min at 37 DEG C, add 20
μ l dimethyl sulfoxide (DMSO)（DMSO）Terminating reaction, determines the fluorescence intensity of reaction system using fluorescent instrument（FSU）, reflection BACE1 activity.BACE1
The size of activity is expressed as the percentage of normal group product formation.
1.3.2 BACE1 protein expression is determined
Western blotting method determines BACE1 protein expression.The brain cortex tissue slurries that packing is preserved are taken, sample, transferring film is separated by electrophoresis（Nitrocellulose filter）, film is washed, closing, an anti-reflective are answered, and two anti-reflective are answered, and colour developing scans or takes pictures, the change of Image J software analysis protein expression level.Using GAPDH as internal reference.
1.4 statistical procedures are with embodiment 1.
2 results
2.1 Galangins are in DM rat cerebral cortex
The impact of BACE1 activity
In DM rat cerebral cortex, BACE1 activity is dramatically increased, and is normal rat corticocerebral 129%, more statistically significant between two groups（P<0.05）；Galangin can significantly reduce DM
BACE1 activity in rat cerebral cortex（P<0.05）, as a result see Fig. 6.
2.2 Galangins are in DM rat cerebral cortex
The impact of BACE1 protein expression
In DM rat cerebral cortex, the relative expression of BACE1 albumen dramatically increases, statistically significant with the comparison in normal rat cerebral cortex（P<0.01）；Galangin can be significantly reduced in DM rat cerebral cortex
BACE1 protein expression（P<0.01）, as a result see Fig. 7.
Embodiment
4
：Galangin pair
DM
In rat hippocampus
IL-1
β
With
TNF-
α
The impact of level
1 materials and methods
1.1 animals used as test are with embodiment 1.
1.2 medicines are purchased from Shanghai Excell Biology Product Co., Ltd. with the ELISA kit of reagent IL-1 β and TNF-α, and BCA protein testing cassete is purchased from the green skies biotech firm in Jiangsu.
1.3 method
Enzyme Linked Immunoadsorbent Assay（ELISA）Method determines IL-1 β and TNF-α level.The sample of BACE1 determination of activity is taken, determines IL-1 β and TNF-α level in hippocampus.IL-1 β and TNF-α level determination are carried out in strict accordance with the operating procedure of respective kit.
1.4 statistical procedures are with embodiment 1.
2 results
In DM rat hippocampus, IL-1 β and TNF-α level are dramatically increased, and than increased 2.9 times and 48.6% respectively in normal rat hippocampus, are compared all statistically significant between two groups（AllP<0.01）.The basic, normal, high dosage of Galangin can all significantly reduce the IL-1 β in DM rat hippocampus and TNF-α level（AllP<0.01）, as a result see Fig. 8, Fig. 9.
Embodiment
5
：Galangin pair
DM
In rat blood serum
SOD
Activity and
GSH
The impact of level
1 materials and methods
1.1 animals used as test are with embodiment 1.
1.2 medicine and reagent SOD and
GSH kit builds up Bioengineering Research Institute purchased from Nanjing.
1.3 method
Spectrophotometry SOD activity and GSH level.Go bail for the serum sample that deposits, SOD activity and GSH level is determined, is carried out in strict accordance with the operating procedure of respective kit.
1.4 statistical procedures are with embodiment 1.
2 results
In DM rat blood serum SOD activity and
GSH level is significantly reduced, and than reducing 16.2% and 38.4% respectively in normal rabbit serum, is compared all statistically significant between two groups（AllP<0.01）；Galangin high and low dose can all significantly increase the SOD activity in DM rat blood serum（P<0.05 orP<0.01）；Galangin high dose can dramatically increase the GSH level in DM rat blood serum（P<0.05）, as a result see Figure 10, Figure 11.
Finally be necessary described herein be：Above example is served only for being described in more detail technical scheme; it is not intended that limiting the scope of the invention, those skilled in the art belongs to protection scope of the present invention according to some nonessential modifications and adaptations that the above of the present invention is made.
Claims (2)
1. preventive and therapeutic effect of the Galangin to diabetes mellitus encephalopathy etc..
2. the learning and remembering ability infringement tool that Galangin causes to diabetes improves significantly.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1453286A (en) * | 2002-03-28 | 2003-11-05 | 科学与工业研究委员会 | 8-(C-beta-D-glycopyranyl)-7,3',4'-trihydroxyflavone, its separating process, medical composition and used for medicine for diabets |
| WO2006001665A1 (en) * | 2004-06-28 | 2006-01-05 | Seoul National University Industry Foundation | Composition for preventing or treating acute or chronic degenerative brain diseases including flavonoid derivatives |
| CN104270945A (en) * | 2012-03-19 | 2015-01-07 | 巴克老龄化研究所 | APP specific BACE inhibitors (ASBIS) and uses thereof |
| CN104800200A (en) * | 2014-01-23 | 2015-07-29 | 上海中医药大学 | Medical uses of galangin |
-
2015
- 2015-06-17 CN CN201510336309.2A patent/CN106474101A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1453286A (en) * | 2002-03-28 | 2003-11-05 | 科学与工业研究委员会 | 8-(C-beta-D-glycopyranyl)-7,3',4'-trihydroxyflavone, its separating process, medical composition and used for medicine for diabets |
| WO2006001665A1 (en) * | 2004-06-28 | 2006-01-05 | Seoul National University Industry Foundation | Composition for preventing or treating acute or chronic degenerative brain diseases including flavonoid derivatives |
| CN104270945A (en) * | 2012-03-19 | 2015-01-07 | 巴克老龄化研究所 | APP specific BACE inhibitors (ASBIS) and uses thereof |
| CN104800200A (en) * | 2014-01-23 | 2015-07-29 | 上海中医药大学 | Medical uses of galangin |
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