CN108785301A - The application of naringenin and its derivative in preventing alzheimer disease - Google Patents
The application of naringenin and its derivative in preventing alzheimer disease Download PDFInfo
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- CN108785301A CN108785301A CN201811042921.9A CN201811042921A CN108785301A CN 108785301 A CN108785301 A CN 108785301A CN 201811042921 A CN201811042921 A CN 201811042921A CN 108785301 A CN108785301 A CN 108785301A
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- naringenin
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- alzheimer disease
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The invention discloses the application of naringenin and its derivative in preventing alzheimer disease.After naringenin is become alkali metal salt such as naringenin sodium/potassium by the present invention, water solubility promotes 1000 times or more, and the assimilation effect of naringenin sodium/potassium is significantly improved compared with naringenin, so that active drug concentration liter in vivo.Zoopery surface, naringenin sodium/potassium is as drug or food additives for treating alzheimer disease or other cognitive disorder diseases.
Description
Technical field
The present invention relates to field of medicaments, specifically relate to the application of naringenin and its derivative in preventing alzheimer disease.
Background technology
Alzheimer disease (Alzheimer ' s disease, AD) is commonly called as senile dementia, is that one kind is recognized with progressive
Dysfunction and learning and memory damage the neurodegenerative disease being characterized.In dull-witted class disease, AD is most important disease
Type.According to demographic prediction, to the year two thousand fifty, global AD patient's number will be more than 100,000,000, this will greatly reduce correlation
The quality of life of crowd, and increase the burden of entire society.Due to the complexity of the AD state of an illness, pathogenesis is still not clear, and faces
Effective therapy is there is no on bed.Therefore, the drug of research and development effectively prevention AD is still current problem urgently to be resolved hurrily.
At present in clinical test, many is directed to the antibody drug of A beta hypothesis just in progress like a raging fire, but very much
Experiment all count out one after another, it is likely that the reason of be that antibody drug target spot is single, administration time is too late, and causes strong
Neuroinflammation.
On the contrary, the traditional Chinese medicine ingredient of the more effects of some multiple target points but can be without any confusion in the clinical test of prevention AD
Progress, this has prompted the huge Development volue of traditional Chinese medicine.What Chinese culture was known as dietotherapy says prevalence, with traditional Chinese medicine or food
Object extract, which prevents AD, has higher feasibility.
It is rich in flavone compound, the wherein pericarp of citrus fruit in the food such as white phoenix dish, Buckwheat Flower, citrus fruit
In be rich in naringenin.Pharmacologically, naringenin (Formulas I) has the effects that antibacterial, anti-inflammatory, anticancer, spasmolysis and cholagogic.But shaddock ped
Element haves the shortcomings that be insoluble in water and bioavilability is low, limits its use.
" Supercritical anti-solvent prepares naringenin/hydroxy propyl-Beta-ring to the patent of invention of Publication No. CN 106265596A
The method of dextrin microcapsules " disclose it is a kind of using hydroxypropyl-β-cyclodextrin to naringenin carry out solubilising, solubilizing effect can
Reach 30g/L, solubilizing effect is relatively good.Although this method solves the solubility of naringenin, but its bioavilability
It is unclear；And the drug absorption effect and application effect of naringenin/hydroxypropyl-β-cyclodextrin microcapsules are indefinite.
Invention content
The technical problem to be solved in the present invention naringenin is insoluble in water and the low disadvantage of bioavilability, and naringenin is changed
At naringenin derivative, such as naringenin sodium/potassium, its solubility is improved, and by naringenin derivative in prevention alzheimer
Application in disease.Naringenin sodium/potassium is equipped with to the composition of pharmaceutically acceptable auxiliary material composition, can be used for preventing the seas A Erzi
Silent disease.Prevention includes the morbidity for postponing alzheimer disease, treatment progressive cognition dysfunction, improves ability of learning and memory.
The derivative of naringenin is that the derivative of naringenin is alkali metal salt.The alkali metal salt includes lithium, sodium, potassium, rubidium, cesium salt,
It is preferred that sodium and sylvite.
Alkali metal salt is prepared using the following method：The naringenin aqueous slkali of 0.05~0.12M of proper volume is dissolved,
Then pH is titrated to as 8.5~9.5 to get naringenin alkali metal salt.Naringenin and its derivative are being prepared for preventing A Er
Application in the drug of Zi Haimo diseases.The prevention includes the morbidity for postponing alzheimer disease, treatment progressive cognitive function
Obstacle improves ability of learning and memory.Naringenin and its alkali metal salt that derivative is naringenin.Alkali metal include lithium, sodium, potassium,
Rubidium, cesium salt.
At room temperature, naringenin is practically insoluble in water, and concentration is less than 20mg/L, even if forming naringenin triethylamine salt chemical combination
Object, concentration can only also arrive 400mg/L.
Naringenin is dissolved with the sodium hydroxide or potassium hydroxide of 0.05~0.12M of proper volume, then with being titrated to pH
For 9.0 to get naringenin sodium/potassium.Titration with hydrochloric acid can be used, naringenin can also be made to be changed into organic salt shape with pH adjusting agent
Formula.
At room temperature, when being dissolved naringenin with NaOH aqueous solutions, solubility is more than 20g/L, titration with hydrochloric acid is then used, by pH
Value is titrated to 9 or so, obtains pH value and is titrated to 9 or so, the naringenin sodium water solution of a concentration of 20g/L, than the dissolving of naringenin
Degree at least 1000 times of raising, it is 50 times higher than naringenin triethylamine salt.According to each phenolic hydroxyl group potentiometric analysis of naringenin, the shaddock ped of formation
Plain sodium structural formula is as shown in Figure 1, the H of 7 upper hydroxyls is replaced by alkali metal atom.
Naringenin alkali metal salt is equipped with pharmaceutically acceptable auxiliary material, including solvent, propellant, solubilizer, cosolvent,
Emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant,
Corrigent, suspending agent, coating material, aromatic, anti-binder, integrated agent, penetration enhancer, pH adjusting agent, delays preservative
Electuary, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agents, moisturizer, absorbent, diluent, flocculation
Agent and deflocculant, filter aid, release retarding agent etc..
The advantageous effect that is reached of the present invention is：Naringenin is become naringenin alkali metal salt by the present invention, and water solubility carries
1000 times or more are risen, the assimilation effect of naringenin alkali metal salt is significantly improved compared with naringenin, so that active drug is dense in vivo
Degree rises.Zoopery surface, naringenin alkali metal salt as drug or food additives for treat alzheimer disease or its
Its cognitive disorder disease.
Description of the drawings
Attached drawing is used to provide further understanding of the present invention, and a part for constitution instruction, the reality with the present invention
It applies example to be used to explain the present invention together, not be construed as limiting the invention.In the accompanying drawings：
Fig. 1 is the structural formula of naringenin sodium；
Fig. 2 is the experimental result of naringenin sodium enhancing microglia phagocytosis amyloid protein；
Fig. 3 is experimental result of the mouse model verification naringenin sodium to the preventive and therapeutic effect of AD.
Specific implementation mode
Hereinafter, preferred embodiments of the present invention will be described, it should be understood that preferred embodiment described herein is only used
In the description and interpretation present invention, it is not intended to limit the present invention.
Embodiment
At room temperature, naringenin is dissolved with the NaOH aqueous solutions of 100mM, solubility is more than 20g/L, is then dripped with hydrochloric acid
It is fixed, pH value is titrated to 9 or so, pH value is obtained and is titrated to 9 or so, the naringenin sodium water solution of a concentration of 20g/L.
Use alzheimer disease model mice for research object, mouse instructions of taking is：Na-Nar is stored up with drinking water
After liquid dilutes 50 times, the drinking-water of mouse is replaced.
Naringenin sodium enhances microglia phagocytosis amyloid protein experiment：
It is swallowed using primary microglia and removes oligomerization amyloid A β1-42(AD markers) is model.
Naringenin sodium liquid storage is spare after being filtered with 0.22 μm of filter.
Primary microglia is first planted in 24 orifice plates for being placed with cell climbing sheet, with final concentration of 20 μM of shaddock after 12h
Skin element sodium (liquid storage molar concentration is 73.5mM) first pre-processes 1h, and the amyloid A β of FITC labels is then added1-42, reaction
Cell is cleaned with precooling PBS buffer solution 3 times, remove the amyloid protein not swallowed, then fixed with 4% formalin after 6h
Cell, then marking microglia by immunofluorescence dyeing, (immunofluorescence dyeing step is：1. 500 μ l 0.5%
Triton X-100 are incubated at room temperature 20min permeable membranes；2. PBS is washed 3 times, 2min/ times；3. 500 μ l, 5% fetal calf serum room temperatures are closed
1h；4. rabbit-anti microglia molecular labeling Iba1 antibody 1:400 dilutions, are then added on cell climbing sheet, 4 degree of overnight incubations；
5. washing cell 5 times, 2min/ times with PBS；6. the goat antirabbit secondary antibody 1 that TRITC is marked:400 dilutions, are then added to cell and climb
On piece is incubated at room temperature 1h；7. washing cell 3 times, 2min/ times with PBS；8. by nucleus dyestuff DAPI with 1:1000 dilutions, then
It is added on cell climbing sheet, is incubated at room temperature 10min；9. washing cell 3 times, 2min/ times with PBS；10. the anti-fluorescent quenching envelopes of 20 μ l are added dropwise
On tablet to glass slide, cell climbing sheet is carefully taken out with tweezers then, is tipped upside down on glass slide, with highlighted nail sheet for oil seal),
Observation and Image Acquisition are carried out with laser confocal microscope again, carries out image analysis with Image J, the results are shown in Figure 2.By
The result of Fig. 2 is it is found that naringenin sodium can increase the clearance rate of intracerebral amyloid protein；Inhibit microglia M1 activation.
Mouse model verifies preventive and therapeutic effect of the naringenin sodium to AD
It is model that 5xFAD transgenic mices (AD model mices), which are respectively adopted,.
5xFAD transgenic mices are acute AD models, and pathological characters just occur in mouse two or three months, 4 months big in mouse
When be administered, successive administration three months.Pass through the Spatial memory ability of determined with Morris water mouse, simulation naringenin sodium (Na-
Nar) to the therapeutic effect of AD.As a result, it has been found that Na-Nar can significantly improve the Spatial memory ability of AD model mices, it is right
AD has apparent preventive and therapeutic action.The results are shown in Figure 3.
Water maze laboratory：Water maze is mainly made of a round stainless steel pond, a diameter of 120cm, escape platform
A diameter of 10cm injects after water, and adding titanium dioxide or milk keeps water opaque, and platform is hidden in underwater 1cm and (is fixed
It is intermediate in one of artificial ready-portioned four quadrants).Pond depth 60cm, edge set four mouse and enter water starting point
(East, West, South, North), and the object of patch different shape and color gives mouse space orientation to provide visual cues on wall.In experiment
Water temperature is maintained at 22 ± 1 DEG C, and position of platform, visual cues position etc. remain unchanged in whole experiment process.Mouse in experiment
After being put into pond, be connected to mouse under computer camera start recording found in water maze hide platform swimming incubation period,
Distance and path.Training twice, 1 minute every time, for finding the mouse of platform, allows it to stay on platform after 30 seconds to mouse daily
Labyrinth is taken out, next training is carried out again after two hours of resting；For can not find the mouse of platform, it is channeled on platform,
It is equally taken out after 30 on platform, next training is carried out again after two hours of resting.It is continuous to instruct according to the training of mouse
Practice 4-6 days, and last time training terminate 24 hours after detect mouse memory capability (platform is taken away, allows mouse in labyrinth
Time etc. that is middle freely to explore 1 minute, recording and analyzing the number of mouse spanning platform position, stay in platform place quadrant).
In experiment, every group of 9-16 mouse.The results are shown in Figure 3, it is seen that naringenin sodium significantly improves Model of Dementia mouse learning cognition
Ability.
Finally it should be noted that：The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention,
Although the present invention is described in detail referring to the foregoing embodiments, for those skilled in the art, still may be used
With technical scheme described in the above embodiments is modified or equivalent replacement of some of the technical features.
All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in the present invention's
Within protection domain.
Claims (9)
1. a kind of composition, which is characterized in that include the naringenin and its derivative for preventing alzheimer disease.
2. composition as described in claim 1, which is characterized in that it is described prevention include delay alzheimer disease morbidity,
It treats progressive cognition dysfunction, improve ability of learning and memory.
3. composition as claimed in claim 1 or 2, which is characterized in that the derivative of naringenin is that the derivative of naringenin is
Alkali metal salt.
4. composition as claimed in claim 3, which is characterized in that the alkali metal salt is lithium, sodium, potassium, rubidium, caesium.
5. composition as claimed in claim 4, which is characterized in that alkali metal salt is prepared using the following method：
The naringenin lye of 0.05~0.12M of proper volume is dissolved, is then titrated to pH as 8.5~9.5 to get naringenin
Alkali metal derivant.
6. the application of naringenin and its derivative in preparing the drug for preventing alzheimer disease.
7. application according to claim 6, which is characterized in that it is described prevention include delay alzheimer disease morbidity,
It treats progressive cognition dysfunction, improve ability of learning and memory.
8. application according to claim 6, which is characterized in that the naringenin and its derivative is the alkali gold of naringenin
Belong to salt.
9. application according to claim 6, which is characterized in that the alkali metal includes lithium, sodium, potassium, rubidium, caesium.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811042921.9A CN108785301A (en) | 2018-09-05 | 2018-09-05 | The application of naringenin and its derivative in preventing alzheimer disease |
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| CN201811042921.9A CN108785301A (en) | 2018-09-05 | 2018-09-05 | The application of naringenin and its derivative in preventing alzheimer disease |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113679712A (en) * | 2021-10-13 | 2021-11-23 | 广东海洋大学 | Application of naringenin in preparing promoter for promoting M1 microglia to polarize to M2 |
| CN113713025A (en) * | 2021-10-18 | 2021-11-30 | 浙江海洋大学 | Granule for preventing Alzheimer's disease and preparation thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555793A (en) * | 2004-01-08 | 2004-12-22 | 中山大学 | Naringin and its salt used for preparing cough suppressing phlegm tramsforming medicine |
| CN1864675A (en) * | 2006-02-06 | 2006-11-22 | 中国人民解放军第二军医大学 | Use of naringenin and derivative in preparation of product for resisting cardiovascular and cerebrovascular disease |
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2018
- 2018-09-05 CN CN201811042921.9A patent/CN108785301A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555793A (en) * | 2004-01-08 | 2004-12-22 | 中山大学 | Naringin and its salt used for preparing cough suppressing phlegm tramsforming medicine |
| CN1864675A (en) * | 2006-02-06 | 2006-11-22 | 中国人民解放军第二军医大学 | Use of naringenin and derivative in preparation of product for resisting cardiovascular and cerebrovascular disease |
Non-Patent Citations (3)
| Title |
|---|
| SAEED GHOFRANI等: "Naringenin improves learning and memory in an Alzheimer"s disease rat model: Insights into the underlying mechanisms", 《EUROPEAN JOURNAL OF PHARMACOLOGY》 * |
| 杨文青 等: "柚皮素改善阿尔茨海默病模型大鼠的认知能力及其机制研究", 《中草药》 * |
| 马晶 等: "柚皮素对阿尔茨海默病模型大鼠学习记忆能力的影响", 《中药材》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113679712A (en) * | 2021-10-13 | 2021-11-23 | 广东海洋大学 | Application of naringenin in preparing promoter for promoting M1 microglia to polarize to M2 |
| CN113713025A (en) * | 2021-10-18 | 2021-11-30 | 浙江海洋大学 | Granule for preventing Alzheimer's disease and preparation thereof |
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Application publication date: 20181113 |