CN107648209A - A kind of application of compound in terms of improving cognition and memory ability and reducing senile plaque expelling - Google Patents
A kind of application of compound in terms of improving cognition and memory ability and reducing senile plaque expelling Download PDFInfo
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- CN107648209A CN107648209A CN201710848946.7A CN201710848946A CN107648209A CN 107648209 A CN107648209 A CN 107648209A CN 201710848946 A CN201710848946 A CN 201710848946A CN 107648209 A CN107648209 A CN 107648209A
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- hispolon
- alzheimer
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Abstract
The invention discloses applications of the Hispolon in terms of improving cognition and memory ability and reducing senile plaque expelling.Alzheimer's disease (Alzheimer ' s disease, AD it is) a kind of nerve degenerative diseases using nerve cell fibre matting, amyloid beta (A β) plaque deposition and decrease of cognitive function as pathological characters, it is considered as one of key link of AD morbidities that wherein the extracellular toxicity of aβ protein, which is built up,.Present invention discover that Hispolon can improve the spatial memory learning ability of AD mouse and can substantially remove the amyloid plaques in APP/PS1 double transgenic AD model mice cerebral tissues, this explanation Hispolon can be applied to the treatment and related drugs research and development of Alzheimer's disease.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, in particular it relates to which Hispolon prepares the medicine for the treatment of Alzheimer's disease
In application.
Background technology
Alzheimer's disease (Alzheimer ' s disease, AD) is also known as alzheimer's disease, and clinical manifestation is psychomotor
Exception, aphasis, cognition and memory capability decline, it is that a kind of common generation is failed in elderly population progressive nervous function
Disease.According to《World's Alzheimer's disease report in 2009》Report, untill the year two thousand fifty, suffering from the sick number will increase sharply extremely
1.5 hundred million[1]。
What the pathogenesis on AD was presently the most widely accepted is sunk with the oligomer and fibroid of amyloid beta
Form sediment and be formed as the A β theories of mark[2].Under normal physiological, by amyloid beta-protein precursor (beta amyloid precursor
Protein, APP) the A β generation shearing enzyme hydrolysis through β and γ and come and degraded be in poised state.Under pathological conditions, APP
There is exception in metabolism, and A β generations drastically increase, and accumulate in intracerebral due to that can not be removed in time, the formation of toxicity oligomer makes
Nerve cell fibre matting, astroglia and microglia hyperplasia simultaneously discharge inflammatory factor (such as TNF-α, IL-6, IL-
2) cause cascade reaction, A β generation can be strengthened again in turn[3], trigger nerve degenerative diseases.Therefore, A β in brain are removed
Be accumulated as to treat the disease important channel[4]。
Treatment AD specific drug clinically there is no to occur at present.Existing treatment AD medicine is such as：Cholinesterase suppresses
Agent Doneppezil Hydrochloride, nonsteroidal anti-inflammatory drug aspirin, calcium antagonist Nimodipine etc. can only slow down AD Development process, change
Kind symptom, can not prevent disease development.Based on A beta hypothesises, beta-secretase and gamma-secretase inhibitors are designed to reduce A β generation,
But reduce adjoint larger side effect of secretase itself；The design such as immunization therapy, A β antibody, polypeptide is in itself for antibody and more
How by blood-brain barrier, effectively accumulation and toxic side effect are a challenge again for treatment Alzheimer's disease to peptide in the brain.
Epidemiological study finds that the active skull cap components of some water fruits and vegetables and Chinese herbal medicine can reduce AD morbidities
Relative risk[5].Curcumin can suppress the cumulative in vitro of aβ protein and can remove the shape reduction A β oligomerizations of the big intracerebral senile plaque expelling of AD mouse
The toxic action of thing[6].Another major polyphenolic constitutent resveratrol for finding grape seed extract etc. can also suppress Tg2576A β and tire out
Ponding is put down, and improves its impaired memory function[7].These evidences all show, suppress the small molecule chemical combination that A β built up and reduced its toxicity
The exploitation of thing can turn into promising AD Therapy studies direction.
Hispolon (chemical name 6- (3,4-dihydroxyphenyl) -4-hydroxyhexa-3,5-dien-2-one,
Molecular formula C12H12O4) it is the active component extracted from Phellinus.Until 2017, Hispolon monomer functionals are studied and reported
Literature search there are about 65, majority research concentrates on Hispolon as a kind of mushroom extract in potential anticarcinogen object space
The exploration of the signal path in face, research related to Alzheimer's disease Hispolon have no any report.The present invention is formed sediment with AD
Effects of the Hispolon in terms of AD treatments is carried out from animal organ and animal integral level based on powder sample albumen hypothesis
Systematic research.
Bibliography
1.World Alzheimer’s Report 2009.Martin Prince.Jim Jackson et al.2009
2.Hardy J,Selkoe DJ.The amyloid hypothesis ofAlzheimer’s disease:
progress andproblems on the roadto therapeutics.Science.2002:297:353-356
3.Mehlhorn G,Holborn M,et al.Induction of cytokines in glial cells
surrounding cortical beta-amyloid plaques in transgenic Tg2576mice with
Alzheimer pathology,Int J Dev Neurosci.200018(4-5):423-31
4.Wang J,Ho L,et al.(2006a)Moderate consumption of Cabernet Sauvignon
attenuate A beta neuropathology in a mouse model of Alzheimer’s disease.FASE
BJ20:2313-2320
5.Assuncao M,Santos Marques MJ,et al.Green tea averts age-dependent
decline of hippoca-mpal signaling systens related to antioxidant defenses and
survival.Free Radic Biol Med.2010.48:831-838
6.Venus Singh Mithu,Bidyut Sarkar,et al.Curcumin alters the salt
bridge-contain-ing turn region in amyloid beta1-42 aggregates.JBC.2014.289
(16):11122-11131
7.Liu P,kEMPER LJ,et al.Grape seed polyphenolic extract specifically
decreases Aβ56in the brains of Tg2576mice.J Alzheimer Dis.2011.26(4):657-66
The content of the invention
1st, applications of the Hispolon in the medicine for preparing treatment Alzheimer's disease
2nd, applications of the Hispolon in the medicine for treating A amyloid betas deposition disease in brain is prepared
3rd, compared with prior art, the beneficial effects of the present invention are：The present invention is using the hypothesis of AD amyloids as base
Plinth, systematic research is carried out from histoorgan to animal integral level to effects of the Hispolon in terms of AD treatments.Card
Real Hispolon can be to A beta monomers polymerization and the A β to Alzheimer's disease APP/PS1 double transgenic AD mouse B6C3-Tg
The formation of amyloid beta deposition has obvious inhibitory action, and can significantly improve AD ability of learning and memory in mice.
4th, the present invention uses animal model of the APP/PS1 bi-transgenic mices as Hispolon to senile dementia curative effect,
Fed for a long time by gastric infusion mode, and determine Hispolon to the elimination effect of aβ protein senile plaque expelling in AD mouse brains and
Improvement in terms of its learning and memory function.
Brief description of the drawings：
Fig. 1 is that Hispolon tests knot with APP/PS1 transgenic mice Y labyrinth error rates and Morris water maze incubation periods
Fruit
Fig. 2 be Hispolon and APP/PS1 transgenic mices the preclinical change of Morris water mazes experiment in 6 days and
The incubation period result of four different quadrants
Fig. 3 is that the Morris water maze space exploration experiment mices of Hispolon and APP/PS1 transgenic mices are virtually put down
Platform traversing times, target quadrant residence time and target quadrant advance distance result
Fig. 4 is Hispolon to the thioflavin S coloration results of the senile plaque expelling of APP/PS1 transgenic mices and quantization
Fig. 5 is Hispolon and the senile plaque expelling of APP/PS1 transgenic mices congo red staining result and quantization
Embodiment：
Below in conjunction with the accompanying drawings, the substantive content of the present invention is further illustrated with embodiments of the invention, but not with this
To limit the present invention.For the technical field of the invention those of ordinary skill, the premise of present inventive concept is not being departed from
Under, some simple deductions can also be made and replaced, should all be considered as belonging to protection scope of the present invention.
Behaviors surveys of the embodiment 1Hispolon to APP/PS1 transgenic mices
The present invention tests the wild type (WT) used and is purchased from Nanjing University's pattern with APP/PS1 bi-transgenic mices and moves
Thing research institute, and the PCR method provided in strict accordance with supplier is identified murine genes.By August age APP/PS1 transgenosis
Mouse is set to Hispolon administration groups, Aricept administration group, saline control group 1, separately set one group of WT wild-type mice as
Control group 2, continue gastric infusion 2 months.
Y maze experiments set three outward appearance identical black bar shapeds long-armed, are combined in Y-shaped, three long-armed marks be A,
B, C, mouse are put into from A arms, during acting on one's own if from it is another it is long-armed turn back if be designated as mistake, such as ABA, BCB etc., occur
During mistake, then recalculated using the arm as starting point, such as ABACBABCBA.Every mouse experiment duration 8 minutes, when experiment finishes,
Cleaning Y labyrinths are simultaneously disinfected in alcohol, and next mouse experiment is carried out after drying.
Morris water maze laboratories, two days Mice water maze training stages (not record data), mouse is divided towards pool wall
Pond is not respectively put into from 4 place of entry (quadrant), platform is hidden under water at 1cm, and water temperature is kept for 23 DEG C, and training continues 2 points
Clock, if mouse failed to find platform in 2 minutes, by its with tool guides to hiding platform and stop 20 seconds, Ran Houjin
Row is trained next time.Experimental stage, experiment was carried out continuously 6 days since the 3rd day, experiment 1 time daily of every mouse, during experiment,
Mouse is respectively put into pond towards pool wall from 4 place of entry (quadrant), record mouse is from water is entered to finding and stop under water
The time required to hiding platform, as incubation period.Platform is removed within 8th day, every mouse is under the distalmost end of original platform position
Water, free swimming 2 minutes, time, the number of spanning platform and the path that animal is swum in target quadrant (platform region)
It will be kept track of and analyzed by microcam Deng major parameter.
Experimental result statistics is shown in that accompanying drawing 1 is left, and wild mouse (WT) accuracy is 85% or so, the AD mouse of gavage physiological saline
Y maze experiments accuracy only have about 68%, Hispolon treat 2 months after after, the Y of AD mouse fan's accuracy substantially rises, and says
Bright Hispolon can improve AD mouse cognition and memory abilities, possess as the potentiality of Alzheimer's disease prevention and treatment medicine.
Morris water maze laboratories result find, Hispolon treatment after, AD mouse find platform incubation period it is obvious under
Drop, compared to wild mouse (WT) and AD gavages physiological saline group (Control), therapeutic effect close to 50% or so (Fig. 1 right sides),
Training result after four regions (quadrant) put into mouse can see, and AD Hispolon treats mouse at different four
The incubation period for putting into quadrant all substantially shortens (Fig. 2 is right), and training experiment since the 3rd day, dive by Hispolon groups treatment AD mouse
The volt phase is gradually reduced, and during by the 6th day, averagely only 47 seconds or so (Fig. 2 is left), after removing platform, it is real that mouse carries out orientation navigation
Test, as a result find no matter Hipolon treatment groups AD mouse are passing through the number of virtual platform, or in the target quadrant residence time
There is obviously improvement (Fig. 3) with the distance of advance, and Comparatively speaking, improvement effect of the Aricept medicine group to AD mouse symptoms
Fruit is limited.In summary behaviouristics result, which can be seen that Hispolon, can significantly improve the learning and memory ability of AD mouse,
Show that Hsipolon can be applied to the research and development of Alzheimer's disease prevention and treatment medicine.
The Pathological experiment that embodiment 2Hispolon is acted on APP/PS1 transgenic mices cerebral tissue
After the anesthesia of the yellow Jackets of 10 monthly age AD mouse 0.4%, blood is taken by irrigating atrium, 4% paraformaldehyde heart fills
Stream carries out whole body and fixed, and takes brain tissue to weigh, and half brain, which is put into 4% paraformaldehyde solution, to be used to do histopathology, and another half loads
- 80 DEG C of cryopreservation tube is preserved for biochemical analysis.Cut into slices after cured piece of embedding of brain tissue that 4% paraformaldehyde is fixed, pass through thioflavin
S, it is Congo red that cerebral cortex and hippocampus deposition patch are dyed.Pathological image passes through digital microscope and fluorescence microscope
Obtain and carry out quantitative analysis.
Brain tissue thioflavin S is dyed with congo red staining result as shown in Figure 4, Figure 5, Hispolon treatment groups either skin
Floor area or hippocampus, its dye A β deposit patch quantity compared to the control group A D mouse of only gavage physiological saline for,
Obvious reduction is showed, and there is statistical significance, and Aricept medicine group does not have then to AD murine brain plaque depositions
It is significant to change, show that Hipolon can suppress deposition of the aβ protein in brain tissue, prevent available in Alzheimer's disease
With the research and development of medicine.
Claims (5)
1. a kind of compound Hispolon of protection is in terms of improving Alzheimer's disease cognition and memory ability and reducing senile plaque expelling
Using.
A kind of 2. applications of the compound Hispolon of protection in the research and development of Alzheimer's disease related drugs.
3. protection compound Hispolon builds up the treatment effect in terms of forming the Alzheimer's disease of senile plaque expelling in suppression aβ protein
It should be researched and developed with related drugs.
4. compound Hispolon is protected to improve the Alzheimer's disease response to treatment and Related Drug of cognition and memory impairment
Thing is researched and developed.
5. protect molecule knots of the compound Hispolon and the like in Alzheimer's disease treatment and medicament research and development application
Structure basis, protects effect of the Hispolon molecular structure in Alzheimer's disease therapeutic action and medicament research and development.
Hispolon also known as CTK8G0190 or OR107820 or 6- (3,4-dihydroxyphenyl) -4-hydroxyhexa-3,5-
Dien-2-one, international Compound Identification InChI=1S/C12H12O4/c1-8 (13) 6-10 (14) 4-2-9-3-5-11 (15)
12 (16) 7-9/h2-7,14-16H, 1H3, molecular weight 220.224g/mol.Meanwhile protection has Hispolon similar structures
Application of the compound molecule in the treatment and medicament research and development of Alzheimer's disease.With Hispolon similar structures compound point
Two oxygen atom spacing are 2.78A on sub- dihydroxyphenyl, are simply replaced for three oh groups of Hispolon molecules
Change or increase and decrease its long-chain the similar compound that the change of structure caused by group-CH2- is formed, be regarded as the present invention
Protection domain.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109999179A (en) * | 2019-05-08 | 2019-07-12 | 山东省分析测试中心 | Low dosage interleukin-22 is used to prepare the application in treatment Alzheimer disease drugs |
| CN112041025A (en) * | 2019-06-17 | 2020-12-04 | 浙江莱恩海思医疗科技有限公司 | Light therapy device and light therapy apparatus for head irradiation and treatment method thereof |
Citations (1)
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| KR20170045053A (en) * | 2015-10-16 | 2017-04-26 | 가톨릭대학교 산학협력단 | Ethyl acetate extracts from Phellinus linteus fruiting bodies having neuroprotective effect and pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising the same |
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2017
- 2017-09-20 CN CN201710848946.7A patent/CN107648209A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20170045053A (en) * | 2015-10-16 | 2017-04-26 | 가톨릭대학교 산학협력단 | Ethyl acetate extracts from Phellinus linteus fruiting bodies having neuroprotective effect and pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising the same |
Non-Patent Citations (1)
| Title |
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| 姜招峰主编: "《阿尔茨海默病发病机理及其相关生物活性物质研究》", 30 June 2016, 中国轻工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109999179A (en) * | 2019-05-08 | 2019-07-12 | 山东省分析测试中心 | Low dosage interleukin-22 is used to prepare the application in treatment Alzheimer disease drugs |
| CN112041025A (en) * | 2019-06-17 | 2020-12-04 | 浙江莱恩海思医疗科技有限公司 | Light therapy device and light therapy apparatus for head irradiation and treatment method thereof |
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