CN105712966B - A kind of phenol boheic acid element and its preparation method and application - Google Patents
A kind of phenol boheic acid element and its preparation method and application Download PDFInfo
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- CN105712966B CN105712966B CN201610045855.5A CN201610045855A CN105712966B CN 105712966 B CN105712966 B CN 105712966B CN 201610045855 A CN201610045855 A CN 201610045855A CN 105712966 B CN105712966 B CN 105712966B
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- C07—ORGANIC CHEMISTRY
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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Abstract
The present invention relates to a kind of phenol boheic acid elements and its preparation method and application；Five mMs of dihydromyricetins are added to 20 ml methanols to dissolve 30 minutes, the solution of dissolving is placed into ice bank, by 5.5 mMs of piperidines, it is titrated in the presence of 10 DEG C of argon gas into dihydromyricetin methanol solution, placement makes it in 20 minutes, and the reaction was complete, is then vacuumizing, to reduce 20% time concentration of reaction solution of air pressure, after filtering, phenol boheic acid element can be obtained by washing three times with methanol；Medicine available for Alzheimer's disease dementia and other nerves/nervous system progressive degeneration lesion；Phenol boheic acid element is the potential compound of effective prevention and treatment Alzheimer's dementia disease；Anxiety disorder, cognitive disorder, sleep-disorder, the cognition for causing or occurring due to various reasons, the hypofunction symptom of the other forms of study/memory capability can be effectively improved；Its structural formula is as follows：
Description
Technical field
The present invention relates to a kind of phenol boheic acid element and preparation method thereof, available for Alzheimer's disease (also alzheimer '
Silent disease) dementia and other nerves/nervous system progressive degeneration lesion medicine.
Background technology
The whole world has 36,000,000 people to live in the pain of Alzheimer's disease at present.Have in the world 1/9th years
There is dementia symptom in age in the people of over-65s, and in 2013, the social economical burden related with Alzheimer disease was more than
2000200000000000 U.S. dollars, Alzheimer disease are most common dementias, account for the 50% to 75% of total dementia, with
The increase ratio at age also increases.It is reported according to the World Health Organization 2013, the whole world has more than 85 years old old man of 25%-50%
Suffer from Alzheimer disease.People was more than 60 years old, and senile dementia (mainly containing Alzheimer's disease) is in low/medium income area
Number be booming income area twice.The warp of burden on society that these Alzheimer diseases are formed in the world at present
Cost of helping is more than annual 200400000000 U.S. dollar.It is unofficial to nurse (45%) and formal Social Nursing in high-income countries
(40%) cost being in the great majority, and direct medical cost accounts for (15%), mainly due to not effective drug.In low income
With medium inclined low income country, cannot be nursed with senile dementia, patients of senile dementia is futureless, and
And it can not survive.Chinese population accounts for a quarter of total world population, is a middle income country.It is after the U.S.
Two big aging countries.Therefore, it is the task of top priority that entire China, which needs the product of Kang Aercihaimoshi diseases/senile dementia,.
WHO Report says, to the year two thousand fifty, the growth of Alzheimer disease number will be present double.Low/medium
The people that there are 71% over-65s in income country will be lived in Alzheimer's disease pain.In addition, dementia research is small
Group to Latin America, Asia and the Caribbean 20 low or middle income country aging aspects research shows that, have three points
Two dementia case be happened at these developing countries, but current data, which only have 10%, is produced in these countries and regions
Raw.In fact in low income country, it is estimated to be the incidence of higher senile dementia.According to the Center for Disease Control
(2013) report, compared to diabetes, cancer, the decline of the death rate of heart disease and stroke, Alzheimer disease
The death rate but dramatically increases, the reason is that due to lacking effective drug therapy.Therefore, Alzheimer disease is identified at present
For " century disease ".Low income country more needs the drug of Alzheimer disease.Countries in the world fabric study is
One kind, which can be found, can fight Alzheimer disease therapy.By 2012, more than the clinic of 1000 unit organizations
Experiment or carrying out, and Alzheimer disease is treated, but the result is that undesirable and unknown with finding method.
Up to the present, existing therapy can only temporarily improve symptom, but all be unable to the progress of reverse disease and prevention A Erci
The generation of the silent dementia in sea.It is nearest the study found that the exploitations of various confrontation Alzheimer disease drugs are concentrated mainly on
Excessive beta amyloid albumen precipitation (A β) is reduced, and the clinical trial for reducing the treatment of beta amyloid albumen precipitation all has failed.
This illustrates that excessive beta amyloid albumen precipitation is a kind of phenomenon in the pathological change of Alzheimer disease, it is not
It is the key that generation, therapeutic effect target spot.And the mechanism or unknown that Alzheimer disease is caused to be in progress." beta amyloid
Albumen precipitation " is Alzheimer disease pathogenic factor or only a byproduct of Alzheimer disease is unclear
Chu.
Other than the onset theory of excessive beta amyloid albumen precipitation, acetylcholine is theoretical, and calcium metabolism is theoretical, peroxide
Change theoretical etc. and relative drug to use, all do not obtain the result of clinical accreditation.Middle rivastigmine, cholinesterase suppression
The 4 beta 2 subunit types of nAChR α of preparation and varenicline are studied in the administration of Alzheimer disease patient
In compared with placebo, the daily routines of administered patient and cognitive ability are presented with slightly improving or without improvement.In Memantine
In the system evaluation of safety, Memantine on probation goes the mild cognition impairment for the treatment of Alzheimer disease, but result
Display and placebo compare, and Memantine is there is no the mild cognition impairment and cognitive function for improving patient, and it has
Increase the risk of gastrointestinal lesions.
Invention content
The object of the present invention is to provide a kind of phenol boheic acid element and preparation method thereof, for Alzheimer's disease (also Ah
Er Cihaimo diseases) dementia and other nerves/nervous system progressive degeneration lesion medicine.
Phenol boheic acid of the present invention is plain (PDTOP), is the flavone compound being synthesized.Also known as phenol dihydro is yellow
Keto-alcohol, English：Piperidinium2,3-dihydroxy-5- ((2R, 3R) -3,5,7-trihydroxy-4-oxochroman-
2-yl)phendate)
The preparation method of phenol boheic acid element of the present invention：
Five mMs of (5mmol, 1.6g) dihydromyricetins are added to 20 ml methanols to dissolve 30 minutes, by the molten of dissolving
Liquid is placed into ice bank, with 5.5 mMs of piperidines, is titrated in the presence of -10 DEG C of argon gas into dihydro
Myricetin methanol solution, placing makes it in 20 minutes the reaction was complete, then, in low-voltage vacuum concentration of reaction solution,
After filtering, phenol boheic acid element (~2g) can be obtained by washing three times with methanol.
The preparation method of dihydromyricetin：
Toxifolin dihydro quercetin normal-temperature reaction in the presence of flavones hydroxylase and flavones monoxidase, becomes dihydro poplar
Syphilis.
The preparation of phenol boheic acid element：
Dihydromyricetin category flavone compound, is present in the flower, leaf, fruit of many plants, is mostly deposited in the form of glycosides
Such as rutin (rutin sophorin), quercitin, Hyperoside etc..
The source of dihydromyricetin can be the natural product from Raisin Tree Seed, vine tea, Cuculidae flower class and conifer leaf/seed
Middle extraction or synthesis.Two methods have formed large-scale production pattern in China.But due to the susceptible of illumination
The characteristics of property and solubility are low so that dihydromyricetin is limited on using, and medicinal effects also can there are unstable.
Alzheimer's dementia disease (AD) is that neural progressive degenerative disease becomes, and the sufferer of Alzheimer's disease is in addition to recognizing
Know/learning ability decline, Spirit nerve symptoms of disease, as anxiety and epileptic attack are all seen in Alzheimer disease patient respectively
To up to 70% and 17%, this shows the interneural transfer function barrier of CNS inhibition nerve-gamma amino butyric acid (GABARs)
Hinder, and this be also gamma amino butyric acid participate in Alzheimer disease morbidity mechanism evidence.Phenol boheic acid element is
A kind of phenol flavones object of synthesis is the conditioning agent of gamma amino butyric acid.The effect of phenol boheic acid element and current dihydromyricetin
The effect of Memantine (30 mg kg day) clinically used is compared, to the gene of Alzheimer's dementia disease
Transformation (Tg2576) four monthly age mouse gives plain (0.5 mg kg day) the 3 months oral medications of phenol boheic acid.This A Erci
Extra large Mo Shi dementias sample diseased mice has been proved to, and is growing up after (6 monthly age), can gradually generate Alzheimer's dementia
Beta amyloid albumen precipitation (A β) in the cranial nerve that disease has, the Alzheimer's dementias such as cognitive ability and learning disability
Disease sample pathophysiological change.Start monthly once to be tested after administration, to observe phenol boheic acid element at any time to alzheimer '
The preventive and therapeutic action of Mo Shi dementias morbidity.Compare and dihydromyricetin, behavioral experiment are observed the results show that phenol boheic acid
The mouse of element administration changes in the case of the genetic modification for having Alzheimer's dementia disease without there is apparent cognitive ability
Become, the neurological susceptibility of anxiety increase and epileptic attack do not occur.Pathologically, phenol boheic acid element is apparent reduces β shallow lakes in cranial nerve
Powdered protein precipitates.From the electro physiology (patch-clamp) of Alzheimer's dementia disease mouse (August age) hippocampal dentate neuron
Record shows that the frequency of natural electric current release (mIPSC) and amplitude are reduced after the inhibitory synapse of gamma amino butyric acid mediation, are dashed forward
It maintains that electric current (synaptic tonic current) is inhibited to reduce between touching.And phenol boheic acid element take, Alzheimers
The electric current of gamma amino butyric acid-mediation on dementia mouse hippocampal dentate neuron is effectively obtained recovery.Quantitative analysis is shown
Show, neuroceptor nebulin (gephyrin) and adjust gamma amino butyric acid receptor Synaptic formation and gamma amino butyric acid
The anchorin of receptor postsynaptic plasticity, in Alzheimer's dementia disease mouse intracerebral, nebulin be reduced to 50% hereinafter,
Particularly hippocampus and cortex.The treatment of phenol boheic acid element effectively restores nebulin gephyrin levels.Also, by phenol
Boheic acid element gives, and beta amyloid albumen precipitation significantly reduces in cranial nerve.These results indicate that phenol boheic acid element gives not
Skill and cognitive ability damage can only be improved, alleviate melancholy, the pathological change of Alzheimer's dementia disease is reversed to include subtracting
The beta amyloid albumen precipitation that increases less and stop or progressive europathology reversed change, restore gephyrin levels and
Restore transmission and the functionality of gamma amino butyric acid system.Importantly, phenol boheic acid element can be to there is potential alzheimer '
The organism of Mo Shi dementia gene alterations has prevention effect.The present invention proves that the action target spot of phenol boheic acid element is nerve
The protein such as gephyrin of connection and repair is played in system.Phenol boheic acid element is a kind of very potential and future treatment
The drug candidate of Alzheimer's dementia disease.
So far, difficult limitation of the research pathogenetic to Alzheimer's disease with modeling, it is impossible to carry out
Human trial.Transgene mouse model is by technological transformation, has beta amyloid albumen precipitation and carries one or several mutation
Familial Alzheimer disease gene overexpression and generate.Although these models cannot replicate the A Er of the mankind completely
Thatch sea Mo's disease, but scientific circles' accreditation has been obtained, they can be provided valuable is crazy about for providing Alzheimers
It stays the evidence of the pathogenesis of disease and carries out the test of drug development to detect the therapeutic effect of drug.
People's research shows that, cognition/memory and the forfeiture of learning ability, with Spirit nerve symptoms of disease, such as anxiety and epilepsy
Deng, in Alzheimer disease patient respectively be up to 70% and 17%.The function that this prompting gamma amino butyric acid can be transmitted
Obstacle.Gamma amino butyric acid is the vital neurotransmitter for participating in adjusting necessary normal cognition function.Its gamma
The loss of aminobutyric acid cynapse and the gamma amino butyric acid synaptic activity of exception lead to the cognition of Alzheimer disease patient
Defect is related.However, pathogenesis is unclear.
Gephyrin is the key that the nebulin after inhibitory synapse.Gephyrin is a kind of polymer scaffolding protein,
Function forms tufted for guiding gamma amino butyric acid receptor after nerve synapse and inhibits site, and anchor gamma amino butyric acid receptor
In the position of postsynaptic membrane.Gephyrin genes remove and removal experiment shows that gamma amino butyric acid subtracts in postsynaptic membrane aggregation
It is few, with conductive impairment between gamma amino butyric acid cynapse.Therefore, the gephyrin of normal quality and quantity is to maintaining gamma amino
The function of being conducted between butyric acid cynapse is vital.Although however, there is report to point out gephyrin in Alzheimer
Disease is reduced, but its pathogenesis and pathological effect are unclear.
The synthetic method of dihydromyricetin has been ripe and has been that diversified technology is present in raw material supply industry.But
It is that dihydromyricetin whether naturally extract or synthesis all has to the neurological susceptibility of illumination and high temperature, is dropped after there is illumination
Low ingredient easily decomposes, and should not preserve for a long time.As medicinal, effect can reduce；In addition the water solubility of dihydromyricetin is more low asks
The presence of topic, is limited to pharmaceutical dosage form.Synthesizing phenol boheic acid element, can not only greatly improve as medicinal dihydromyricetin
The stability of plain ingredient, and can significantly improve as medicinal effect effect.The present invention is not only limited to dihydromyricetin,
To other there is mutually isostructural flavone compound to have applicability.Synthesized surely according to the characteristic of different flavone compounds
Fixed, efficient dihydromyricetin, dihydromyricetin can be that synthesis can also be extracted from vine tea.Two methods China
Through forming large-scale production pattern.But due to the neurological susceptibility and unstability to illumination so that dihydromyricetin is in use
It is limited in power effect, medicinal effects are also unstable.The invention, which has, increases dihydromyricetin original structure stability
Add, while at least five times or more can be improved in itself than dihydromyricetin as medicinal effect effect.Thus method, Ke Yikai
Dihydromyricetin is opened up as medicinal prospect of the application.
Phenol boheic acid element of the present invention is used for Alzheimer's disease dementia and its nerve/nervous system progressive
The medicine of degeneration lesion, for treatment effective quantity for 0.1-1000 mg kg of body weight, preferably 0.5-500 milligram/public affairs
Jin weight, even more preferably about 0.5-10 mg kg of body weight, most preferably from about 0.5-5 mg kg of body weight (subject).
Can to be further understood to the present invention, with reference to attached drawing, wherein：
1) phenol boheic acid element is administered three months in 4 monthly age transgenosis (Tg2576) Alzheimer disease mouse models
Afterwards, exploration/locomitivity is improved, reduces the sensibility (Fig. 3) of anxiety degree and convulsive seizure.
We compared with the wild-type mice of age-matched, give phenol boheic acid element three to Alzheimer disease mouse
After a month, the Behavioral change influence on Alzheimer disease is tested.Mouse is divided into three groups：(1) hero of wild type (weight)
Property mouse (2% sucrose, oral medication), the Alzheimer disease mouse (2% sucrose, oral medication) of (2) and (3)
Alzheimer disease adds in phenol boheic acid plain (2% sucrose of 0.5 milligram/kg of PDTOP phenol boheic acid element), respectively.3
After moon treatment, mouse has carried out inspection and behavioural analysis.
Locomotor activity measures.One of the parameter of move distance as quantization locomotor activity (Figure 1A).Control mice has run 891
± 59 centimetres/5 minutes.The distance of Alzheimer disease mouse race 275 ± 12 centimetres/5 minutes, and give phenol boheic acid element
The distance of running of the Alzheimer disease mouse for the treatment of is increased to 609 ± 101 centimetres/5 minutes.Control mice shows frequency
Numerous exploratory behaviour (22.5 ± 3.4 times) has inquired into the center 2.0 ± 0.6 times in open zone, and the center that rests on is 0.1 ± 0.1 minute
(Figure 1B, Fig. 1 C and Fig. 1 D).Alzheimer disease mouse performance exploratory behaviour 12.7 ± 2.3 times, explores Opening field
The center of (0.2 ± 0.1 time), the center that rests on are only 0.02 ± 0.01 minute.Phenol boheic acid extract for treating Alzheimer
Disease mouse increases exploratory behaviour (18.1 ± 2.0 times), explores Opening field (1.3 ± 2.0 times), and it is 0.12 to rest on centre time
± 0.03 point.The result shows that reducing exploration/autonomic activities in Alzheimer disease mouse model, exploring ability reduces.Often
Day, oral phenol boheic acid was plain, and 4 monthly age transgenosis Alzheimer disease mouse is made not to be further development of Alzheimer
Dementia maintains autonomic activities, Exploratory behavior ability.
The Elevated plus-maze (three E of figure) that anxiety is measured.Time of the control group in enclosed area is 48.5 ± 7.5% Hes
32.6 ± 3.2%.Significantly shorten the Ming Shi areas residence time in dementia mice, and be obviously prolonged in the darkroom area residence time.Dull-witted+
The time of phenol boheic acid element mice spent is identical with control group.
Reduce exploration/autonomic activities in Alzheimer disease mouse model, exploring ability reduces.Oral phenol daily
Boheic acid extract for treating Alzheimer disease mouse improves autonomic activities, improves Exploratory behavior ability.
The Elevated plus-maze (Fig. 1 E) that anxiety is measured.Time of the control group in enclosed area is 48.5 ± 7.5% Hes
32.6 ± 3.2%.Significantly shorten the Ming Shi areas residence time in dementia mice, and be obviously prolonged in the darkroom area residence time.Dull-witted+
The time of PDTOP mice spents is identical with control group.
It is frightened with pentylenetetrazol (Pentylenetetrazol, PTZ) induction twitch in the neurological susceptibility detection of convulsion with unconsciousness breaking-out
It faints.Fig. 2 F signal convulsion with unconsciousness breaking-out duration.The PTZ induction convulsive seizure duration of control group is 1.5 ± 0.6 points
Clock, in Alzheimer disease group, the PTZ induction convulsive seizure duration is 5.0 ± 0.8 minutes.Dementia+phenol boheic acid element
PTZ induction the convulsive seizure duration be 2.0 ± 0.5 minutes.These results indicate that not to the April of phenol boheic acid element
Age transgenosis Alzheimer disease mouse with advancing age, is developed into Alzheimer disease, display trip
For defect, the neurological susceptibility of twitch uneasy and occurred frequently.And it is three months plain to phenol boheic acid, prevent the hair of Alzheimer disease
Disease does not show the developmental disorder of CNS inhibition nerve-gamma amino butyric acid receptor system, the convulsions that do not have a convulsion disease
Shape.
2) the oral identification for significantly improving Alzheimer's disease animal model of phenol boheic acid element and situated leaning and memory
Ability (Fig. 2)
Mouse is randomly divided into 4 groups：(1) treatment of wild type (control) the male mice oral medication of 2% sucrose；(2)
Add oral medication of the 0.5 mg/kg phenol boheic acid element in 2% sucrose in the male mice of wild type (administration control), daily
It is administered once；(3) Alzheimer's disease dementia mice with the oral medication of 2% sucrose, is administered once a day；(4) A Er
Ci Haimo diseases dementia mice adds the plain 0.5 mg/kg weight of phenol boheic acid in 2% sucrose, is administered once a day；(5) dementia
Mouse adds 2 mg/kg weight of dihydromyricetin in 2% sucrose, it is administered once a day；And Alzheimer's disease dementia mice
It is administered orally, is administered once a day to the Memantine of 30 mg/kg weight.By trimestral treatment, the cognition of mouse is remembered
Recall, carry out test with new object identification and (Fig. 2A) is evaluated.Wild type control group is used to explore the time (ORI=of new object
68.9 ± 6.8%).51.2 ± 3.6% are reduced in Alzheimer's disease dementia mice.The wild type of phenol boheic acid element processing is small
The recognition capability of mouse performance is identical to wild type control group.It is shown in plain (PDTOP) mouse of Alzheimer disease+phenol boheic acid
It writes and improves new object identification ability (ORI=67.8 ± 6.6%).Although with Alzheimer disease+dihydromyricetin (DHM)
Mouse, which significantly improves new object identification ability, does not have intentional significant difference, but the recovery of the cognitive ability of PDTOP administration groups is more
Significantly.The Alzheimer disease mouse of Memantine treatment shows with same age control group Alzheimer disease mouse
Improvement is not recognized, but with the control group of same age relatively without remarkable result.
Then, we have evaluated continuity and novel object recognition capability are tested (Fig. 2 B).Compared with wild type control group, Ah
Er Cihaimo dementia mouse show the reduction (42.2 ± 2.6%) of RI.The treatment of phenol boheic acid element has reversed alzheimer '
The reduction of the RI of silent dementia mouse, and show that significant episodic memory improves.And the Alzheimer of Memantine treatment is crazy about
Slow-witted disease mouse in the improvement that cognitive ability is relatively shown with cotemporary Alzheimer disease mouse, but with wild type pair
According to group compared to no remarkable result.
Computational methods：Object identifying index (ORI) and discrimination index (RI) are calculated (ORI) according to the following formula；Index=
(TN-TF/ (TN+TF), wherein, TF and TN represent object or background (TF times) and new object or context (TN) known to exploration.
Statistical analysis experiment is examined with unidirectional ANOVA and Tukey.
This group of experimental result is shown：
I) plain (PDTOP) the 0.5 mg/kg administration of phenol boheic acid and 2 mg/kg of dihydromyricetin (DHM) are administered
Effect compares, can generate it is stronger prevention 4 monthly age transgenosis Alzheimer disease mouse be not further development of Ah
The effect of Er Cihaimo dementias.
II) plain (PDTOP) the 0.5 mg/kg administration of phenol boheic acid can prevent 4 monthly age transgenosis Alzheimers
Disease mouse is not further development of Alzheimer disease, does not occur knowing ability reduction.And with reversing cognitive ability
Reduction effect.
3) phenol boheic acid element significantly reduces accumulation (Fig. 3) of the A β plaque block in hippocampal gyrus in Alzheimer disease mouse.
Research has shown that beta amyloid albumen precipitation includes beta amyloid albumen in Alzheimer disease mouse model and sinks
Shallow lake patch, which exists, gradually to be accumulated.Phenol boheic acid element 3 months oral medications after, glial fibrillary acid protein (GFAP), the mankind by
The protein of GFAP coded by said gene.The expression of GFAP is collectively referred to as astroglia astroglia in central nervous system
In cell, there are the brain and spinal cord of characteristic astroglia.It takes part in many important central nervous system processes, including
Cell communication and the function of blood-brain barrier.
GFAP is related to accumulation of the beta amyloid albumen precipitation patch in the hippocampal gyrus of Alzheimer's disease.Therefore, we make
The variation of GFAP in the animal of Alzheimer's disease (Fig. 3) is determined with immunoassay.Control group (control by wild type, sucrose
Treat), Alzheimer disease (AD) (sucrose therapy) and Alzheimer disease receive PDTOP treatment groups (AD+
PDTOP 0.5mg/kg), male, the mouse at 4 months big ages.Daily oral medication three months.After three months, all animals
Brain take out carry out GFAP detections.
Fig. 3 A-C show the immunoreactivity of GFAP in the slice from three groups of hippocampus.We analyze the close of polymorphic layer (PL)
Degree.Compared with control group (Fig. 3 A), PL density is dramatically increased in AD groups (Fig. 3 B).In addition, Fig. 3 B displays increase A β plaque block (such as arrow
Head is directed toward).And after phenol boheic acid plain (PDTOP) treatment, relative density (ROD) reduces, and both A β plaque block was reduced in AD+PDTOP groups
(Fig. 3 C).Fig. 3 D show the result of relative density.This illustrates that aquation boheic acid element can reduce A β plaque block and play " the work of street cleaner
With ".
The Alzheimer's disease mouse of Fig. 3 E-G displays solubility and insoluble A β 1-40 and A β 1-42 are in full intracerebral
Level is measured with ELISA method.Fig. 3 E and Fig. 3 F show the horizontal measuring method of cortex beta amyloid albumen precipitation.Phenol boheic acid extract for treating
Reduce water solubility A β 1-42 (89.2 ± 7.8 and 143.1 ± 24.1 untreated Alzheimer's disease mouse) and insoluble A β
1-42 (209.1 ± 55.0 and 453.6 ± 147.3 untreated Alzheimer's disease mouse).Hippocampus A β levels measure (figure
3G), phenol boheic acid extract for treating reduces water solubility A β 1-40 (830.3 ± 27.4 and 1150.0 ± 191.8) and insoluble A β 1-40
The level of (4095.3 ± 1079.4 and 6729.6 ± 1620).
This result shows that, it is small can to prevent 4 monthly age transgenosis Alzheimer diseases for oral phenol boheic acid element daily
Mouse is not further development of Alzheimer disease, the possibility that prevention A β 1-40 and A β 1-42 are generated.
4) Nervous toxicity reaction (Fig. 4) caused by phenol boheic acid element can reduce excessive glutamic neuron.
Glutamate receptor (nmda receptor) is depended in hippocampus long memory.Glutamate receptor be calcium ion permeability by
Body.Excessive activation glutamic acid releases the flow of calcium ions excessive by generation is known from experience, so as to induce the various of Alzheimer disease
Pathological change.A β peptide can combine and activate glutamate receptor.Make during this investigation it turned out, we test excessive glutamic neuron
Effect of the aquation boheic acid element in hippocampus is recorded with electro physiology recording technique.
Under isoflurane anesthesia, surgical thread is retained under the both sides of rat carotid artery rat.It fully recovers by two days, greatly
Mouse is caused short wink cerebral ischemia, is at once closed head outer skin layer by bracing wire 10 minutes.Fig. 4 shows that phenol boheic acid element can be with dosage
Reduce to dependence excessive glutamic neuron.Hippocampal neuron whole-cell voltage-clamp system is in -70mV.Fig. 4 A are shown from hippocampus
The record of dentate fascia neuron.Phenol boheic acid element perfusion (0 → 0.01 → 0.03 → 0.1 micromole) generate dose-dependently and
MEPSC amplitudes (Fig. 4 B), frequency (Fig. 4 E) and total electrical charge transfer (Fig. 4 F) are significantly reduced, and phenol boheic acid element is had no effect on from right
According to a group neurons of rats activity (Fig. 4 C-D).
This explanation, phenol boheic acid element can reduce nerve caused by the excessive glutamic neuron occurred after Cranial nerve injury as birth trauma
Poison reaction, so as to play the role of protecting cranial nerve.And the phenol boheic acid element dosage for inhibiting Nervous toxicity reaction can be played
30 times are reduced than the dihydromyricetin dosage that we deliver in the past.
5) treatment of phenol boheic acid element can repair the gamma amino butyric acid nerve conduction that Alzheimer's disease mouse is damaged
System disorders (Fig. 5)
The behavior expression observed in four monthly age of Alzheimer's disease mouse male female model prompts gamma amino butyric acid
Receptor suppression system is damaged.In order to test this possibility, gamma is assessed on the dentation nerve cell that we return in cerebral hippocampal
The dynamics of natural electric current release (mIPSC) and the amplitude of inhibition electric current after the inhibitory synapse of aminobutyric acid mediation, to A Er
The prevention and treatment effect of Ci Haimo disease mouse is assessed.In order to confirm that the preventive effect of phenol boheic acid element and treatment are imitated
Fruit, to all four monthly ages, male female Alzheimer's disease mouse is grouped for we.Control group, Alzheimer disease
Group, Alzheimer disease give phenol boheic acid element (+PDTOP2 months 2 months dull-witted, 0.5 mg/kg of body after developing 2 months groups
Weight), the therapeutic effect of phenol boheic acid element is tested with this；It is (silly to the plain group in April of phenol boheic acid simultaneously with dementia development group in April
Stay 2 months+PDTOP2 months), the prevention effect of phenol boheic acid element is tested with this.
Fig. 5 A show whole-cell recording technique (voltage clamp is at -70 millivolts).Fig. 5 B show that the mIPSCs of four groups of overlappings compares：
Compare mouse, dull-witted, dementia+DHM and dementia+PDTOP (with reference to diagram).The dynamic variation that Fig. 5 C are summary mIPSCs compares.
The dynamics of the mIPSCs of the DG nerve cells of dull-witted mouse has change.The dull-witted group in April (AD4m) of frequency of electric current is generated in Fig. 5 C
Continue development damage, frequency compared with 2 months group (AD2m) it is lower.And phenol boheic acid plain April is given simultaneously having developed dementia pathology in April
(AD+P), phenol boheic acid element significantly inhibits the development of dull-witted pathology.And phenol tea is given after dull-witted pathology having developed 2 months
Sour element 2 months
(AD2m+P2m), developed dull-witted pathology is reversed.Electric current raising speed each group does not have difference.Current amplitude
AD2m and AD4m groups have apparent reduction, and giving phenol boheic acid element can prevent and reverse damage.Current slow (neuroceptor
Channel closing velocity) there is apparent reduce to maintain the exploitation of neuroceptor channel in AD2m and AD4m groups, and give phenol boheic acid element
It can prevent and reverse damage.
These results further prove, the treatment of phenol boheic acid element, can not only restore the gamma amino fourth of hippocampal neuron
The function of acid acceptor.And it can prevent in the presence of having potential Alzheimer's disease gene, preventing gamma aminobutyric acid
Receptor is injury-free.And it is also importantly, the effect of phenol boheic acid element does not have the notable difference of male and female gender.
6) Gephyrin levels Alzheimer's disease mouse intracerebral decline 50% hereinafter, and phenol boheic acid element control
It is horizontal (Fig. 6) that treatment can restore Gephyrin.
Gephyrin is key scaffold albumen tissue, is related to inhibition of the gamma amino butyric acid receptor clustering in synapses
Postsynaptic receptor density.Gephyrin not only has the structure function of gamma amino butyric acid energy synaptic sites, but also for cynapse
The vital effect of dynamics.Therefore, we have studied the protein levels of gephyrin and gamma amino butyric acid receptor y 2
Subunit receives phenol boheic acid element and controls in hippocampus and cortex (together) in control group, Alzheimer's disease group and Alzheimer's disease
The mouse for the treatment of group.
Immunoassay shows that (Fig. 6 A) has dropped 50% to Alzheimer's disease mouse gephyrin levels compared with the control
Below.1.5 months after phenol boheic acid element (0.5 mg kg of body weight) treatment, gephyrin horizontal components restored, through 3 months water
After changing boheic acid extract for treating, gephyrin is restored to control level (Fig. 6 B).It is reduced in Alzheimer's disease mouse
Gephyrin levels may cause gamma amino butyric acid function of receptors to be damaged.Gamma amino butyric acid receptor plays in neurotransmission
The decrease of synapses of effect.As a result, the synaptic contact between losing nerve, nerve signal cannot transmit, particularly brain
The nerve synapse reduction of hippocampal gyrus can directly affect cognition and memory.In addition the animal of these nerve damages shows to lack and visit
Rope/motor activity ability, anxiety, the neurological susceptibility of epileptic attack increase.Phenol boheic acid extract for treating effectively restores gephyrin's
Level, also, increase with the level of gephyrin, in cognition and memory test is measured, Alzheimer's disease mouse has
The improvement of apparent cognition and memory ability.Here it is phenol boheic acid element can reverse the pathological change of Alzheimer disease and then
Improve cognition and memory, improve the mechanism that study reaches therapeutic effect.
7) pharmacokinetics of phenol boheic acid element and logical more blood-brain barriers (Fig. 7)
In order to be best understood from the potentiality to be exploited of phenol boheic acid element, we and the pharmacokinetics and energy of Pyrogentisinic Acid's boheic acid element
No logical more blood-brain barriers are determined (Fig. 7, MS-HPLC).Fig. 7 is shown the result is that testing white mouse (weight 240 ± 20 from male
Gram) obtain.As shown in the figure, it is divided into five dosage groups (n=8/ groups).First day, after taking orally phenol boheic acid element to animal, 15
Point, 30 points, 1 hour, 4 hours and 8 hour time point blood samplings take serum, test phenol boheic acid cellulose content (Fig. 7 A).Again the 14th
My god, experiment and dosage are repeated, to observe whether animal body generates drug resistance (tolerance) property (Fig. 7 B).
This group can generate phenol boheic acid element concentration liter in dose-dependent haematologic it is demonstrated experimentally that the administration of phenol boheic acid element
It is high.Pharmacokinetics show phenol boheic acid element maximum concentration and plateau value more than 25.0 mgs/kg.Do not find animal body
Pyrogentisinic Acid's boheic acid element generates drug resistance.In addition, the phenol boheic acid element also surveyed after oral administration can be within 3 minutes by blood brain screen
Hinder (Fig. 7 C).
Summary：
1) phenol boheic acid element (0.5 mg/kg, oral three months or more) for Alzheimer's disease animal take orally to
Medicine makes 4 monthly age transgenosis Alzheimer disease mouse not be further development of Alzheimer disease, maintains certainly
Main activity, Exploratory behavior ability.
2) phenol boheic acid plain (0.5 mg/kg, more than trimestral oral medication) prevents 4 monthly age transgenosis A Er
Ci Haimo dementias mouse is not further development of Alzheimer disease, is allowed to Alzheimer disease do not occur
Common anxiety symptom.
1) and 2) 3) in, phenol boheic acid element and dihydromyricetin compare, phenol boheic acid element show significant prevention and
Therapeutic effect, 5 times of dosage is less than dihydromyricetin, and 5 times of effect or more is better than dihydromyricetin.
4) phenol boheic acid plain (0.5 mg/kg) is compared with Memantine (dose indicatings of 30 mg/kg FDA), to subtracting
Few amyloid protein-β (A β) peptide has the effect of more notable and effective；
5) phenol boheic acid element can be reduced directly and inhibit the excessive release of the excessive glutamate caused by nerve damage
And neurotoxicity caused by release；
6) since phenol boheic acid is known as the effect of significantly effective, amyloid protein-β (A β) peptide, phenol boheic acid element are reduced
The secondary senile dementia of identification and learning and memory impairment can be improved, it is important that phenol boheic acid element has preventive effect.
7) neuron loss caused by the excitotoxicity of glutamate-induced can be reduced due to phenol boheic acid element.
8) animal body is not caused to generate drug resistance after the administration of phenol boheic acid element.
9) phenol boheic acid element concentration in dosage dependence blood can be generated after the administration of phenol boheic acid element to change.
10) it runs through blood-brain barrier after phenol boheic acid element is orally available and then reaches action target spot, and without gender gap
It is different.
11) phenol boheic acid element is in human volunteer, hence it is evident that improves cognitive power and memory capability
More than summary, phenol boheic acid element is that having for an effective prevention and treatment Alzheimer's dementia disease newly is latent
The new compound of power.Phenol boheic acid element can also be effectively improved anxiety disorder, cognitive disorder, sleep-disorder, due to various reasons
The cognition for causing or occurring, the hypofunction symptom of the other forms of study/memory capability.
Description of the drawings
Fig. 1 phenol boheic acid influences experiment to the Behavioral change of Alzheimer disease.
A long ranges/5 minutes；B explores frequency；C exploring abilities；D stops the field time；E explores labyrinth ability；F twitches
The convulsive attack duration；
Fig. 2 phenol boheic acid elements take orally the identification for improving Alzheimer's disease animal model and situated leaning and memory capability pair
According to the facts test.
A is tested and is evaluated with new object identification；B continuitys test novel object recognition capability；
Fig. 3 phenol boheic acid elements reduce A β plaque block in AD animals and are tested in the accumulation of hippocampal gyrus.
A-C shows the immunoreactivity of GFAP in the slice from three groups of hippocampus；
D shows the result of relative density；
The Alzheimer's disease mouse of E-G displays solubility and insoluble A β 1-40 and A β 1-42 are in the level of full intracerebral
It is measured with ELISA method；
Fig. 4 phenol boheic acids element reduces Nervous toxicity reaction experiment caused by excessive glutamic neuron.
A shows the record from hippocampal dentate neuron；B phenol boheic acid element perfusions (0 → 0.01 → 0.03 → 0.1 μM)
It generates dose-dependently and significantly reduces mEPSC amplitudes；E frequencies；F total electrical charges shift；
The activity of C-D neurons of rats；
Fig. 5 phenol boheic acids extract for treating repairs the gamma amino butyric acid nerve conduction system barrier that Alzheimer's disease mouse is damaged
Hinder experiment.
A shows whole-cell recording technique (voltage clamp is at -70 millivolts)；B shows that the mIPSCs of four groups of overlappings compares：
Mouse is compareed, dull-witted, dementia+DHM and dementia+PDTOP；The dynamic variation of C summaries mIPSCs compares；
The treatment of Fig. 6 phenol boheic acid element restores the experiment of Gephyrin levels.
A Alzheimer's disease mouse gephyrin levels are compared with the control；B gephyrin are restored to control level；
The pharmacokinetics of Fig. 7 phenol boheic acid element and logical more blood-brain barrier determination experiments.
The 1st day PDTOP dosage of A measures；The 14th day dosage of B measures；
Result after Fig. 8 volunteer's use.
The intelligence test standard (Chinese translation) promulgated in Fig. 9 U.S. alzheimer's disease association website.
Specific embodiment
Embodiment 1
Five mMs of (5mmol, 1.6g) dihydromyricetins of synthesis are added to 20 ml methanols and dissolve 30 minutes, will dissolve
Solution be placed into ice bank.With 5.5 mMs of piperidines (0.47 g/l), titrated in the presence of -10 DEG C of argon gas into dihydro poplar
Syphilis methanol solution, placement makes it in 20 minutes, and the reaction was complete.Then, it (vacuumizes, to reduce air pressure about 20%) under low pressure
Concentration of reaction solution, after filtering, phenol boheic acid element (~2g) can be obtained by washing three times with methanol.
Embodiment 2
500 grams of dihydromyricetins are added to 6.25 liters of methanol to dissolve 30 minutes, the solution of dissolving is placed into ice bank.With
103.8 g/l of piperidines is titrated in the presence of -10 DEG C of argon gas into dihydromyricetin methanol solution, and placing 20 minutes makes its reaction
Completely.Then, it (vacuumizes under low pressure, to reduce air pressure about 20%) concentration of reaction solution, after filtering, is washed three times with methanol
It is plain (about 625 grams) that phenol boheic acid can be obtained.
Embodiment 3
5000 grams of dihydromyricetins are added to 62.5 liters of methanol to dissolve 30 minutes, the solution of dissolving is placed into ice bank.
It with 1038 g/l of piperidines, is titrated in the presence of -10 DEG C of argon gas into dihydromyricetin methanol solution, placing makes it anti-for 20 minutes
It should be complete.Then, it (vacuumizes under low pressure, to reduce air pressure about 20%) concentration of reaction solution, after filtering, three is washed with methanol
It is plain (about 6250 grams) all over phenol boheic acid can be obtained.
Embodiment 4
Volunteer (26 people) is that the damage of intelligence cognitive ability or diagnosis caused by hospital diagnosis has various illness have A Er
The patient of Zi Haimo diseases takes the other drugs person of being not affected significantly.First, these patients have been carried out by U.S.'s alzheimer
What the intelligence test (Fig. 9) promulgated in disease association website take preceding test (medication time 0) record is average.Often
Two weeks retest is primary.Full marks are 30 points.Subject age took orally from 60 to 90 years old prepared by embodiment 1 once a day
Phenol boheic acid element, take intelligence cognitive ability after two months and be obviously improved.Drug withdrawal also has no that symptom rebounds.And without gender
Difference.
Effective quantity for the treatment of is 0.1 mg kg of body weight (subject).
Embodiment 5
Volunteer (260 people) is that the damage of intelligence cognitive ability or diagnosis caused by hospital diagnosis has various illness have A Er
The patient of Zi Haimo diseases takes the other drugs person of being not affected significantly.First, these patients have been carried out by U.S.'s alzheimer
What the intelligence test (Fig. 9) promulgated in disease association website take preceding test (medication time 0) record is average.Often
Two weeks retest is primary.Full marks are 30 points.Subject age took orally from 60 to 90 years old prepared by embodiment 2 once a day
Phenol boheic acid element, take intelligence cognitive ability after two months and be obviously improved.Drug withdrawal also has no that symptom rebounds.And without gender
Difference.
Effective quantity for the treatment of is 5 mg kg of body weight (subject).
Embodiment 6
Volunteer (260 people) is that the damage of intelligence cognitive ability or diagnosis caused by hospital diagnosis has various illness have A Er
The patient of Zi Haimo diseases takes the other drugs person of being not affected significantly.First, these patients have been carried out by U.S.'s alzheimer
What the intelligence test (Fig. 9) promulgated in disease association website take preceding test (medication time 0) record is average.Often
Two weeks retest is primary.Full marks are 30 points.Subject age took orally from 60 to 90 years old prepared by embodiment 2 once a day
Phenol boheic acid element, take intelligence cognitive ability after two months and be obviously improved.Drug withdrawal also has no that symptom rebounds.And without gender
Difference.
Effective quantity for the treatment of is 10 mg kg of body weight.
Embodiment 7
Volunteer (260 people) is that the damage of intelligence cognitive ability or diagnosis caused by hospital diagnosis has various illness have A Er
The patient of Zi Haimo diseases takes the other drugs person of being not affected significantly.First, these patients have been carried out by U.S.'s alzheimer
What the intelligence test (Fig. 9) promulgated in disease association website take preceding test (medication time 0) record is average.Often
Two weeks retest is primary.Full marks are 30 points.Subject age took orally from 60 to 90 years old prepared by embodiment 2 once a day
Phenol boheic acid element, take intelligence cognitive ability after two months and be obviously improved.Drug withdrawal also has no that symptom rebounds.And without gender
Difference.
An effective quantity for treatment is 0.5 mg kg of body weight (subject).
Embodiment 8
Volunteer (26 people) is that the damage of intelligence cognitive ability or diagnosis caused by hospital diagnosis has various illness have A Er
The patient of Zi Haimo diseases takes the other drugs person of being not affected significantly.First, these patients have been carried out by U.S.'s alzheimer
What the intelligence test (Fig. 9) promulgated in disease association website take preceding test (medication time 0) record is average.Often
Two weeks retest is primary.Full marks are 30 points.Subject age took orally from 60 to 90 years old prepared by embodiment 3 once a day
Phenol boheic acid element, take intelligence cognitive ability after two months and be obviously improved.Drug withdrawal also has no that symptom rebounds.And without gender
Difference.
An effective quantity for treatment is 500 mg kg of body weight.
Embodiment 9
Volunteer (26 people) is that the damage of intelligence cognitive ability or diagnosis caused by hospital diagnosis has various illness have A Er
The patient of Zi Haimo diseases takes the other drugs person of being not affected significantly.First, these patients have been carried out by U.S.'s alzheimer
What the intelligence test (Fig. 9) promulgated in disease association website take preceding test (medication time 0) record is average.Often
Two weeks retest is primary.Full marks are 30 points.Subject age took orally from 60 to 90 years old prepared by embodiment 3 once a day
Phenol boheic acid element, take intelligence cognitive ability after two months and be obviously improved.Drug withdrawal also has no that symptom rebounds.And without gender
Difference.
An effective quantity for treatment is 1000 mg kg of body weight.
Claims (5)
1. a kind of application of phenol boheic acid element, it is characterised in that：
Its plain structural formula of the phenol boheic acid is：
The preparation method of the phenol boheic acid element is：
Five mMs of dihydromyricetins are added to 20 ml methanols to dissolve 30 minutes, the solution of dissolving is placed into ice bank, it will
5.5 mMs of piperidines is titrated in the presence of -10 DEG C of argon gas into dihydromyricetin methanol solution, and placing 20 minutes makes its reaction
Completely, it is then vacuumizing, to reduce 20% time concentration of reaction solution of air pressure, after filtering, washing three times with methanol can obtain
Phenol boheic acid element；
The application of the phenol boheic acid element：It is moved back for Alzheimer's disease dementia and its nerve/nervous system progressive
Change the medicine of lesion.
2. the application of phenol boheic acid element according to claim 1, it is characterised in that：For Alzheimer's disease dementia
And its medicine of nerve/nervous system progressive degeneration lesion, for treatment an effective quantity for 0.1-1000 milligrams/
Kg body weight, daily sooner or later or be administered after meal in the morning, afternoon and evening.
3. the application of phenol boheic acid element according to claim 1, it is characterised in that：For Alzheimer's disease dementia
And its medicine of nerve/nervous system progressive degeneration lesion, for treatment an effective quantity for 0.5-500 milligrams/
Kg body weight.
4. the application of phenol boheic acid element according to claim 1, it is characterised in that：For Alzheimer's disease dementia
And its medicine of nerve/nervous system progressive degeneration lesion, an effective quantity for treatment are 0.5-10 milligrams/public affairs
Jin weight.
5. the application of phenol boheic acid element according to claim 1, it is characterised in that：For Alzheimer's disease dementia
And its medicine of nerve/nervous system progressive degeneration lesion, an effective quantity for treatment are 0.5-5 milligrams/public affairs
Jin weight.
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