CN109453159A - A kind of Rhizoma valerianae latifoliae extract monomeric compound is preparing the application in anti-AD drug - Google Patents
A kind of Rhizoma valerianae latifoliae extract monomeric compound is preparing the application in anti-AD drug Download PDFInfo
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Abstract
The invention belongs to technical field of traditional Chinese medicines, there is provided a kind of Rhizoma valerianae latifoliae extract monomeric compound and its application in the drug of preparation treatment alzheimer's disease, and in particular to a kind of application of Rhizoma valerianae latifoliae extract monomeric compound in the drug of preparation treatment alzheimer's disease.With the compound effects in alzheimer's disease Caenorhabditis elegans pathological model in the present invention, the result shows that: Rhizoma valerianae latifoliae extract monomeric compound has significant therapeutic effect to the Caenorhabditis elegans for suffering from alzheimer's disease, shows the paralysis phenotype for significantly delaying alzheimer's disease Caenorhabditis elegans.Simultaneously compared with jatamans valeriana rhizome water extract, compound antiparalytic effect is significantly improved, and has higher medical value.Rhizoma valerianae latifoliae extract monomeric compound provided by the invention has the potentiality of anti-alzheimer's disease, can apply in the drug of preparation treatment alzheimer's disease.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicines, a kind of Rhizoma valerianae latifoliae extract monomeric compound is provided and its in treatment A Erzi
Application in the drug of the silent disease in sea.
Background technique
Alzheimer's disease (Alzheimer's disease, AD) is one kind with progressive cognitive disorder and memory impairment
Based on nervous system degenerative disease, be senile dementia one of the most common type form.Clinically with memory disorders, aphasia,
Agnosia, the damage of visual space technical ability, execution dysfunction and the performance of the generalized dementias such as personality and behavior change are characterized.Silly
Proportion is more than 75% in slow-witted patient.With the aggravation of China's aging degree, AD can become the master for influencing senior health and fitness
One of disease is wanted, being effectively prevented and treated AD becomes another key subjects of the pendulum in face of us.
Amyloid beta deposition (aβ protein) and neurofibrillary tangles are the two big key pathological features of AD.Modern medicine
Years of researches have been carried out to the pathogenesis of AD, but due to its cause of disease complexity, the pathogenesis of the disease is still indefinite so far,
" A β cascades hypothesis " is currently by one of well accepted mechanism of scientific circles.The theory thinks the A β of abnormal deposition in brain in patients
By a series of cascade reactions such as radical reaction, Mitochondrial oxidative damage and inflammatory reaction, mind is directly or indirectly acted on
Through member and Deiter's cells, neuronal function exception or dead is eventually led to, causes cognitive impairment and amnesia, finally
Cause dementia.Currently, A amyloid beta is one of the target of the anti-AD drug of screening the most generally acknowledged.
The AD cause of disease is complicated, the course of disease is very long and morbidity link is more, needs Long-term taking medicine, the sea anti-A Erzi listed at present
Silent medicine has acetylcholinesterase inhibitor (such as galanthamine) and N-methyl-D-aspartate receptor (nmda receptor) antagonism
Agent (such as Memantine), but said medicine is expensive, illusion after medication, misunderstanding, dizziness, headache and the side effects such as tired are aobvious
It writes, and only for illness, rather than is directed to the cause of disease.Therefore, the anti-AD drug clinically applied at present can only be controlled but cannot be reversed
Conditions of patients.In such situations, it is found that more efficiently anti-AD drug is extremely urgent.
Caenorhabditis elegans (Caenorhabditis elegans) be a highly useful multifunctional drug screening and
The research platform of mechanism of drug action.Its cheap, easily culture；Generation cycle is short, offspring's number is more, while can get a large amount of backgrounds
Consistent individual is guaranteed experimental repeatability and is tested using large sample size, to exclude the influence of individual difference；With it is high
Biology is highly conserved in terms of gene and molecular pathway (Kaletta and Hengartner, 2006).It is as one from thin
Born of the same parents' levels in vitro drug is just sieved to a bridge of horizontal drug secondary screening in Mice Body, the increasingly favor by pharmacy man.People
Source Caenorhabditis elegans AD pathological model is by source of people A β1-42Gene is transferred to Myosin promoter downstream and is temperature controlled
Expression, which can be in 15 DEG C of normal growths, when being transferred under the conditions of 25 DEG C, A β1-42It expresses and tired in its intramuscular
Product, causes nematode to lose locomitivity and benumb.Test medicine, which is added, can delay muscular paralysis phenotype, and result is with muscular paralysis
The percentage that nematode population accounts for tested nematode population quantity indicates.It is higher that nematode ratio is not benumbed, and the anti-AD effect of drug is more significant.
This model early have been used for anti-AD disease mechanism and anti-AD drug and candidate study on mechanism (Link, 1995；
2001)。
Epilepsy medicine (Dianxianning) is the traditional Chinese medicine compound prescription in China.Researches show that epilepsy medicine (Dianxianning)s can improve the AD sample symptom of AD nematode paralysis
With 5-HT sensibility.Epilepsy medicine (Dianxianning) significantly reduces A beta oligomers content, to reduce A β toxicity, and improves anti-stress ability, protects
Influence (Zhi et al., 2017) of the nematode from oxidative stress.Jatamans valeriana rhizome equally has as the monarch drug in a prescription in epilepsy medicine (Dianxianning) compound
Such effect.Therefore, explore and find that the anti-AD effective component of jatamans valeriana rhizome is imperative.
The present invention tests Rhizoma valerianae latifoliae extract monomeric compound using Caenorhabditis elegans AD pathological model, finds
The compound can dose-dependently slow down Caenorhabditis elegans AD pathological characters.Therefore, the present invention now provides a kind of spider
Fragrant extract monomeric compound and its application in the drug of preparation treatment alzheimer's disease.
Bibliography
Kaletta T,Hengartner MO.Finding function in novel targets:C.elegans
as a model organism.Nat Rev Drug Discov 2006,5:387e398.
Link CD.Expression of human beta-amyloid peptide in transgenic
Caenorhabditis elegans.Proc Natl Acad Sci USA 1995,92:9368e9372.
Link CD.Transgenic invertebrate models of age-associated
neurodegenerative diseases.Mech Ageing Dev 2001,122:1639e1649.
Zhi D,Wang D,Yang W,et al.Dianxianning improved amyloidβ-induced
pathological characteristics partially through DAF-2/DAF-16insulin like
pathway in transgenic C.elegans[J].Sci Rep,2017,7(1):11408.
Summary of the invention
It is an object of the present invention to provide a kind of medical compounds, and in particular to a kind of Rhizoma valerianae latifoliae extract monomeric compound and its
Application in the drug of preparation treatment alzheimer's disease.
Rhizoma valerianae latifoliae extract monomeric compound shown in following formula (1) or its pharmaceutically acceptable salt:
If pharmaceutically acceptable carrier and/or auxiliary material is added in formula (1) compound or its pharmaceutically acceptable salt,
Creme, capsule, tablet, granule, solution, powder, any dosage form of suspension is made.
Compound or its pharmaceutically acceptable salt as described in formula (1) is in preparation treatment Alzheimer disease drug
Using.
If formula (1) compound or its pharmaceutically acceptable salt are effective component in preparation treatment alzheimer's disease
Application in drug.
The present invention is tested using Caenorhabditis elegans as alzheimer's disease pathological model, the results showed that the monomer
Compound has significant therapeutic effect to AD Caenorhabditis elegans.It shows to the excessive table of AD Caenorhabditis elegans intramuscular A β
There is significant inhibiting effect up to caused paralysis phenotype, it can significantly delay the fiber crops of alzheimer's disease Caenorhabditis elegans
Numbness phenotype.Compared with jatamans valeriana rhizome water extract, antiparalytic effect significantly improves the compound simultaneously, has higher medical value.Cause
This, Rhizoma valerianae latifoliae extract monomeric compound provided by the invention has the potentiality of anti-AD, can answer in the drug of preparation treatment AD
With.
Specific embodiment
Technical solution of the present invention is described in further detail combined with specific embodiments below, but protection scope of the present invention is not
It is confined to as described below.
The extracting method of embodiment one, Rhizoma valerianae latifoliae extract monomeric compound
The dried roots (20.0kg) for taking jatamans valeriana rhizome (Valeriana jatamansi) are impregnated after crushing with 95% ethyl alcohol
Four times, seven days every time, obtain the total medicinal extract 1332g of ethyl alcohol.It is suspended in the distilled water of 1.5L, then uses ethyl acetate respectively
(EtOAc) it is extracted four times with n-butanol (n-BuOH), obtains acetic acid ethyl ester extract 409g.Acetic acid ethyl ester extract silicagel column
Chromatography, mobile phase are petroleum ether-acetone (40:1,20:1,10:1,5:1,2:1,1:1), recycle the exhibition of TLC thin-layer chromatography
It opens, merges similar portion, finally obtain 6 parts.
The part 10:1 (20.0g) is taken to separate using silica gel column chromatography, with chlorofonn-ethylacetate 100:1 elution, such as formula (1)
The compound (60mg).
Embodiment two, jatamans valeriana rhizome delay the muscular paralysis of AD Caenorhabditis elegans
1. biomaterial
(1) AD nematode strain CL4176 is purchased from Caenorhabditis Genetics Center (CGC)；For transgenosis product
Mankind A β expresses in 25 DEG C of temperature-induced lower muscle specifics in system1-42, A β1-42Assemble in musculature, eventually leads to nematode fiber crops
Numbness, the present embodiment is using caenorhabditis elegan CL4176 strain as the pathological model for screening anti-AD drug.
(2) Escherichia coli OP50 (uracil leaky mutant) is purchased from Caenorhabditis Genetics Center
(CGC), as the food of Caenorhabditis elegans.
2. reagent
(1) solid NGM (Nematode Growth Medium) medium component and production (being upgraded to example with 1):
| Ingredient | Content |
| NaCl | 3.00g |
| K2HPO4 | 2.34g |
| KH2PO4 | 17.23g |
| Peptone | 2.50g |
| Agar | 17.00g |
| Supplement H2O is extremely | 1000mL |
After solid NGM culture medium prepares, high-pressure constant temp sterilizing 20min, is added 5mg/ under aseptic operating platform at 121 DEG C
ML cholesterol 1mL, 1M MgSO4 1mL,1M CaCl21mL shakes up, and pours into sterilized 9cm culture plate, about 20mL/ plate while hot.
It stands and waits culture medium solidification, it is spare.
(2) M9 formula of liquid
| Ingredient | Content |
| Na2HPO4 | 6.00g |
| KH2PO4 | 3.00g |
| NaCl | 5.00g |
| 1M MgSO4 | 1.00mL |
| Supplement H2O is extremely | 1000mL |
(3) preparation of lysate: 1:1 is mixed by volume for 6.4%NaClO solution and 1M NaOH solution.
3. preparing the NGM plate of jatamans valeriana rhizome
(1) mother liquid medicine is prepared:
A: weighing jatamans valeriana rhizome 1.42g, adds water 100ml, and 100 DEG C of water mention 30 minutes, and extracting solution is taken to be settled to 100ml, prepares
14.2mg/ml medical fluid is spare.
B: taking A liquid 25mL, is settled to 100ml, and gradient dilution prepares 3.55mg/ml medical fluid.
C: taking B liquid 25mL, is settled to 100ml, and gradient dilution prepares 0.8875mg/ml medical fluid.
(2) the NGM plate containing jatamans valeriana rhizome is configured:
Corresponding NGM culture medium is added in 14.2mg/ml, 3.55mg/ml, 0.8875mg/ml jatamans valeriana rhizome decocting liquid respectively
In, a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices.
10 times of dilutions of the final concentration of initial mother liquor of jatamans valeriana rhizome.
It finally, is 1.42mg/ml, 0.355mg/ml, 0.08875mg/ml containing compound concentration in NGM plate
It stands and waits culture medium solidification.Food of the even spread Escherichia coli OP50 as nematode on culture medium.
4. implementation steps
(1) culture of nematode:
Nematode is connect on the solid NGM plate for being coated with Escherichia coli OP50, is subsequently placed in 16 DEG C of incubator and cultivates, when
Synchronizing is handled when nematode grows to adult.
(2) nematode synchronizes:
It selects containing a large amount of adults and the NGM culture medium that there are part line eggs to hatch, with M9 liquid by nematode from training
It supports and is swept away on base, is transferred in centrifuge tube, standing makes nematode free settling to tube bottom, abandons supernatant.How much sight worm amount is to centrifugation
Lysate is added in pipe, is vibrated 5-7 minutes on whirlpool misfortune blender, stops being vortexed when nematode complete rupture, and be sub-packed in
In 1.5mL centrifuge tube, line eggs are washed three times with M9 solution.
(3) effect of the jatamans valeriana rhizome water extract to Caenorhabditis elegans CL4176
The line eggs being sub-packed in centrifuge tube after synchronization are transferred to and is coated with OP50 and mixes various concentration jatamans valeriana rhizome
The NGM culture dish of water extract and it is coated with OP50 and added in the NGM culture dish (blank control) with the isometric sterile water of drug,
60 nematodes of each culture dish, for three culture dishes of each drug concentration as in parallel, 16 DEG C are cultivated 3 days to the L3 phase.
In order to make nematode express A β, L3 phase nematode is turned to induce at 25 DEG C, nematode paralysis item is started counting after 34h
Number.Every two hours count once, until all nematodes are all benumbed, i.e., when carrying out mechanical stimulus nematode body using platinum filament, nematode
Only head is movable.Experimental result is shown in Table 1.
Therapeutic effect result of the 1 various concentration jatamans valeriana rhizome of table to AD nematode
Note: a, b, c indicate P < 0.05, have significant difference.
PT50 is that paralysis nematode accounts for the time used when tested nematode population half.Experimental data is expressed as PT50 ± standard
Poor (SD).The last one time point nematode of tested experimental group paralysis percentage reaches 50%.
The time that Of control is equal to when the tested nematode 75% of processing group is benumbed subtracts time difference when 25% paralysis
Time when benumbing divided by control group nematode 75% subtracts time difference when 25% paralysis, finally multiplied by 100%.Test number
According to being expressed as Of control ± standard deviation (SD).Data markers have different letters then to mean significant difference, P in each experiment
<0.05。
The experimental results showed that AD nematode muscular paralysis can be being postponed using the jatamans valeriana rhizome water extract in the present embodiment
Half paralysis time (PT50).In terms of of control (%) value, 1420 μ g/ml groups can significantly delay nematode rate of paralysis, but
It is to need under very high concentration, jatamans valeriana rhizome water extract can just play significant drug effect.
Delay to embodiment three, Rhizoma valerianae latifoliae extract monomeric compound dose-dependant the muscular paralysis of AD Caenorhabditis elegans
1. biomaterial
(1) AD nematode strain CL4176 is purchased from Caenorhabditis Genetics Center (CGC)；For transgenosis product
Mankind A β expresses in 25 DEG C of temperature-induced lower muscle specifics in system1-42, A β1-42Assemble in musculature, eventually leads to nematode fiber crops
Numbness, the present embodiment is using caenorhabditis elegan CL4176 strain as the pathological model for screening anti-AD drug.
(2) Escherichia coli OP50 (uracil leaky mutant) is purchased from Caenorhabditis Genetics Center
(CGC), as the food of Caenorhabditis elegans.
2. reagent
(1) solid NGM (Nematode Growth Medium) medium component and production (being upgraded to example with 1):
| Ingredient | Content |
| NaCl | 3.00g |
| K2HPO4 | 2.34g |
| KH2PO4 | 17.23g |
| Peptone | 2.50g |
| Agar | 17.00g |
| Supplement H2O is extremely | 1000mL |
After solid NGM culture medium prepares, high-pressure constant temp sterilizing 20min, is added 5mg/ under aseptic operating platform at 121 DEG C
ML cholesterol 1mL, 1M MgSO4 1mL,1M CaCl21mL shakes up, and pours into sterilized 9cm culture plate, about 20mL/ plate while hot.
It stands and waits culture medium solidification, it is spare.
(2) M9 formula of liquid
| Ingredient | Content |
| Na2HPO4 | 6.00g |
| KH2PO4 | 3.00g |
| NaCl | 5.00g |
| 1M MgSO4 | 1.00mL |
| Supplement H2O is extremely | 1000mL |
(3) preparation of lysate: 1:1 is mixed by volume for 6.4%NaClO solution and 1M NaOH solution.
3. preparing the NGM plate of monomeric compound
(1) mother liquid medicine is prepared:
A: weighing Rhizoma valerianae latifoliae extract monomeric compound monomer 1.4mg, adds 30.4 μ L of dimethyl sulfoxide (DMSO), prepares
100mM (46mg/ml) medical fluid is spare.
B: taking 10 μ L of A liquid, and gradient dilution prepares 10mM (4.6mg/ml) 4600 μ g/ml medical fluid.
C: taking 10 μ L of B liquid, and gradient dilution prepares 1mM (0.46mg/ml) 46 μ g/ml medical fluid.
(2) the NGM plate containing monomeric compound is configured:
100mM, 10mM, 1mM liquid are added in corresponding NGM culture medium respectively, a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices.
1000 times of dilutions of the final concentration of initial mother liquor of Rhizoma valerianae latifoliae extract monomeric compound.
It finally, is 100 μM, 10 μM, 1 μM containing compound concentration in NGM plate
It stands and waits culture medium solidification.Food of the even spread Escherichia coli OP50 as nematode on culture medium.
4. implementation steps
(1) culture of nematode:
Nematode is connect on the solid NGM plate for being coated with Escherichia coli OP50, is subsequently placed in 16 DEG C of incubator and cultivates, when
Synchronizing is handled when nematode grows to adult.
(2) nematode synchronizes:
It selects containing a large amount of adults and the NGM culture medium that there are part line eggs to hatch, with M9 liquid by nematode from training
It supports and is swept away on base, is transferred in centrifuge tube, standing makes nematode free settling to tube bottom, abandons supernatant.How much sight worm amount is to centrifugation
Lysate is added in pipe, is vibrated on whirlpool misfortune blender and stops within 5-7 minutes being vortexed when nematode complete rupture, and be sub-packed in
In 1.5mL centrifuge tube, line eggs are washed three times with M9 solution.
(4) effect of the Rhizoma valerianae latifoliae extract monomeric compound to Caenorhabditis elegans CL4176
The line eggs being sub-packed in centrifuge tube after synchronization are transferred to and is coated with OP50 and mixes various concentration jatamans valeriana rhizome
The NGM culture dish of extract monomeric compound and it is coated with OP50 and added with the NGM culture dish (blank with the isometric DMSO of drug
Control) in, 60 nematodes of each culture dish, for three culture dishes of each drug concentration as in parallel, 16 DEG C are cultivated 3 days to the L3 phase.
In order to make nematode express A β, L3 phase nematode is turned to induce at 25 DEG C, nematode paralysis item is started counting after 34h
Number.Every two hours count once, until all nematodes are all benumbed, i.e., when carrying out mechanical stimulus nematode body using platinum filament, nematode
Only head is movable.Experimental result is shown in Table 2.
Therapeutic effect result of the 2 various concentration Rhizoma valerianae latifoliae extract monomeric compound of table to AD nematode
Note: a, b, c indicate P < 0.05, have significant difference.
PT50 is that paralysis nematode accounts for the time used when tested nematode population half.Experimental data is expressed as PT50 ± standard
Poor (SD).The last one time point nematode of tested experimental group paralysis percentage reaches 50%.
The time that Of control is equal to when the tested nematode 75% of processing group is benumbed subtracts time difference when 25% paralysis
Time when benumbing divided by control group nematode 75% subtracts time difference when 25% paralysis, finally multiplied by 100%.Test number
According to being expressed as Of control ± standard deviation (SD).Data markers have different letters then to mean significant difference, P in each experiment
<0.05。
The experimental results showed that significant using the Rhizoma valerianae latifoliae extract monomeric compound (as described in formula 1) in the present embodiment
It postpones AD nematode muscular paralysis half paralysis time (PT50).In terms of of control (%) value, 46 μ g/ml groups can significantly delay
Nematode rate of paralysis.Compared with jatamans valeriana rhizome water extract, in same drug concentration, the compound antiparalytic effect significantly at
Increase again, there is higher medical value.
Delay to example IV, Rhizoma valerianae latifoliae extract monomeric compound dose-dependant the muscular paralysis of AD Caenorhabditis elegans
It is operated with embodiment three, the results are shown in Table 3.
Therapeutic effect result of the 3 various concentration jatamans valeriana rhizome monomeric compound of table to AD nematode
Note: a, b, c indicate P < 0.05, have significant difference.
PT50 is that paralysis nematode accounts for the time used when tested nematode population half.Experimental data is expressed as PT50 ± standard
Poor (SD).The last one time point nematode of tested experimental group paralysis percentage reaches 50%.
The time that Of control is equal to when the tested nematode 75% of processing group is benumbed subtracts time difference when 25% paralysis
Time when benumbing divided by control group nematode 75% subtracts time difference when 25% paralysis, finally multiplied by 100%.Test number
According to being expressed as Of control ± standard deviation (SD).Data markers have different letters then to mean significant difference, P in each experiment
<0.05。
The experimental results showed that significant using the Rhizoma valerianae latifoliae extract monomeric compound (as described in formula 1) in the present embodiment
It postpones AD nematode muscular paralysis half paralysis time (PT50).In terms of of control (%) value, 46 μ g/ml groups can significantly delay
Nematode rate of paralysis.Compared with jatamans valeriana rhizome water extract, in same drug concentration, the compound antiparalytic effect significantly at
Increase again, there is higher medical value.
Claims (4)
1. Rhizoma valerianae latifoliae extract monomeric compound shown in following formula (I) or its pharmaceutically acceptable salt:
2. compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that: the compound or its medicine
Pharmaceutically acceptable carrier and/or auxiliary material is added in acceptable salt on, is made creme, capsule, tablet, and granule is molten
Liquor, powder, any dosage form of suspension.
3. application of the compound as described in claim 1 in preparation treatment Alzheimer disease drug.
4. compound as described in claim 1 is application of the effective component in preparation treatment Alzheimer disease drug.
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