CN105943545A - Medicine composition and application thereof for treating memory disorder - Google Patents
Medicine composition and application thereof for treating memory disorder Download PDFInfo
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- CN105943545A CN105943545A CN201610145986.0A CN201610145986A CN105943545A CN 105943545 A CN105943545 A CN 105943545A CN 201610145986 A CN201610145986 A CN 201610145986A CN 105943545 A CN105943545 A CN 105943545A
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- ginsenoside
- luteolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract
The invention relates to a medicine composition which includes a component (a): one or more ginsenoside monomers and a component (b): luteolin or an analogue thereof as active components, wherein the ginsenoside monomers are selected from ginsenoside Rg1, Rb1, Rg3, Rg5, Rd, Rh1, Rh3 and Re. The luteolin analogue is selected from apigenin, kaempferol, quercetin, myricetin, isorhamnetin and glucosides thereof. Compared with single active component, the medicine composition has a better effect of treating memory disorder and is reduced in usage amount of the active components. The medicine composition can be used for treating the memory disorder caused by dementia, cerebral trauma or cerebral stress.
Description
Technical field
The invention belongs to the field of Chinese medicines, be specifically related to a kind of pharmaceutical composition, its comprise luteolin or its analog with
And ginsenoside is as active component；Further relate to said composition for improving amnemonic purposes.
Background technology
Dysmnesia refer to that individual is in and a kind of can not remember or memory information or the state of technical ability, and clinical manifestation is memory
Weaken, forget, paramnesia, fabricate and cryptomnesia etc..Clinically, dysmnesia are the syndromes that numerous disease may occur in which, main
Dementia to be had (including the polytypes such as senile dementia, vascular dementia, dementia with Lewy body), Alzheimer, cerebral trauma or
Dysmnesia etc. caused by stress.Dementia refers to chronic acquired Progressive symmetric erythrokeratodermia syndrome of intelligent disorder, clinically with slowly appearance
Hypophrenia is principal character, and hypomnesis is its core symptom, dysmnesia occurs in early days.Along with adding of aged tendency of population
Speed, the sickness rate of senile dementia is consequently increased, it has also become cause old people dead after tumor, heart disease, cerebrovascular
The fourth-largest cause of disease.Alzheimer's disease (AD) is the neurodegenerative diseases of a kind of Progressive symmetric erythrokeratodermia development, and its Clinical symptoms is
Dysmnesia, aphasia, apraxia, agnosia, visual space dysfunction etc., the intelligence hypomnesis that particularly Progressive symmetric erythrokeratodermia increases the weight of.β-shallow lake
Generation, accumulation and the toxic action of powder sample peptide (β-amyloid peptide, A β) are considered as AD principle pathological mechanism.A β's
Accumulation can activate microglia and astrocyte, causes body response to oxidative stress, produces substantial amounts of reactive oxygen species
(ROS) and active nitrogen free radical (RNS), ROS and RNS is active peroxide, and substantial amounts of accumulation can cause neuron to aoxidize
System and antioxidant system unbalance, and inflammatory mediator release can be induced to increase, further result in cell injury, wither at neuron
Play an important role during dying.
Owing to the amnemonic cause of disease is complicated, morbidity link is more, and western medicine dysmnesia effect is poor up to now,
Patient often has marked difference to the reaction of some certain drug, and drug resistance and side effect easily occurs.And in motherland's traditional medicine
Natural drug there is too many levels, multi-level, the action character of Mutiple Targets, it can overcome the disadvantages that the above-mentioned deficiency of Western medicine.
Radix Ginseng is a kind of at the widely used conventional medicament of Asian countries, has nootropic effect.The main one-tenth of Radix Ginseng
Divide ginsenoside, there is multiple pharmacological effect, particularly can hypermnesis and cognitive function.Wherein, ginsenoside
Rg1, Rb1, Rg3, Rg5, Rd, Rh1, Rh3 and Re etc. are the main components that Radix Ginseng plays nootropic effect.There are some researches show, Radix Ginseng
Saponin Rg1 and Rb1 all can promote children's Mus body development, and contribute to the adult rear diving tower of mice and keep away dark Memory acquisition process.
Ginsenoside Rg1 mainly improves learning and memory function by affecting learning and memory coherent signal approach.Rg1 can be by induction
C-fos gene expression, increases Hippocampus cAMP level, improves ability of learning and memory (Liu and Zhang, 1996).Rg1 can carry
Choline acetyltransterase and the expression of tyrosine kinase mRNA and hippocampal neural somatomedin mRNA water in high Basal Forebrain of Rats
Flat (Salim et al, 1997).Ginsenoside Rg1 improves middle age learning and memory of little mouse by increasing P-AKT and BDNF level
Ability (Zhu et al, 2015).Rg1 can reduce Hippocampus A β 1-40 content, and may raise BDNF level by PKA-CREB,
Thus improve SAMP8 learning and memory of little mouse function (Shi et al, 2010).Note is significantly improved relative to above-mentioned each ginsenoside
The effect recalled, its fancy price constrains being widely used of they.
Flavone, is a class polyphenolic substance, is widely present in plant, and have pharmacological action widely.The most prominent
Go out is its antioxidation, and the particularly antioxidation of polyhydroxy flavone is higher.Additionally, flavone compound to study,
Memory and nervous functional defects have Beneficial Effect (Jeremy P.E.Spencer, 2008).Luteolin (5,7,3 ', 4 '-four
Flavonol), kaempferol (3,5,7,4 '-kaempferol), Quercetin (Quercetin), ampelopsin
(dihydromyricetin), isorhamnetin (3,5,7,4 '-tetrahydroxy-3 '-methoxy flavone) etc. are all polyhydroxys
The representative compound of base flavone, they structures are similar, wide material sources.Structural analysis and biological study to luteolin
All it turned out it and have significant antioxidation, oxidant can be alleviated and damage (Dajas that radical pair cell causes
Et al, 2003；Seelinger et al, 2008).Luteolin is played by the generation of suppression ROS and proinflammatory inflammation factor
To A β25-35The protective effect (Wang and Gao, 2015) of the neuronal damage of induction.Luteolin may be by strengthening mice
The antioxidant activity of cerebral tissue has improvement result to the behavior depression of chronic unpredictability gentleness Stress Depression Model mice
(Liu et al, 2013).Research proves that luteolin suppresses neurocyte by PI3K-Akt-NF-κ B-ERK signal path
Oxidative stress (Zhou et al, 2011).Apigenin (Apigenin) and luteolin the most extremely phase
Seemingly, and there is similar antioxidation, improving studing ability, the amnemonic effect of improvement.Other polyhydroxy flavone
Compound, also has similar effect such as kaempferol, Quercetin, ampelopsin, isorhamnetin etc..
Ginsenoside monomer the most is not applied in combination to improve note by prior art with luteolin or its analog
Recall the relevant report of obstacle.Present inventor have unexpectedly discovered that, the combination of two kinds of active component is relative to single-activity
Composition has the effect preferably improving memory, can be used for treating dysmnesia, and can reduce the consumption of ginsenoside, has
Potential economic and social benefit.
Summary of the invention
One aspect of the present invention provides a kind of pharmaceutical composition, its comprise one or more ginsenoside monomers of component (a) with
And component (b) luteolin or its analog are as active component, wherein said ginsenoside monomer selected from ginsenoside Rg1,
Rb1, Rg3, Rg5, Rd, Rh1, Rh3 and Re, described luteolin be similar to thing selected from apigenin, kaempferol, Quercetin, ampelopsin,
Isorhamnetin and glucosides thereof；And wherein component (a) is 1: 50 to 10: 1 with the weight ratio of component (b).
In preferred embodiment, component (a) is the one in ginsenoside Rg1, Rb1, Rg3, Rd, Rh1 and Re or many
Kind, such as two kinds, three kinds, four kinds, five kinds or six kinds；It is highly preferred that component (a) be ginsenoside Rg1, Rb1, Rg3, Rd, Rh1 and
One or both in Re；It is more preferred still that component (a) is ginsenoside Rg1 or Rb1 or the mixture of the two；Most preferably,
Component (a) is ginsenoside Rg1.
When the mixture that component (a) is multiple ginsenoside monomer, each ginsenoside monomer can be with any possible
Ratio exists.Especially, when during component (a) is ginsenoside Rg1, Rb1, Rg3, Rd, Rh1 and Re two kinds (as Radix Ginseng
During the mixture of saponin Rg1 and Rb1), two kinds of components can exist with any possible ratio, and such as 100: 1 to 1: 100, excellent
Select 50: 1 to 1: 50, more preferably 25: 1 to 1: 25, most preferably 10: 1 to 1: 10, such as 1: 1.
In preferred embodiments, component (b) is luteolin, apigenin, kaempferol, Quercetin, ampelopsin and different
One or more in rhamnetin, such as two kinds, three kinds, four kinds, five kinds or six kinds；It is highly preferred that component (b) be luteolin,
One or both in apigenin, kaempferol, Quercetin, ampelopsin and isorhamnetin；It is more preferred still that component (b) is sweet-scented osmanthus
Grass element or apigenin or the mixture of the two；Most preferably, component (b) is luteolin.Component (b) can be also luteoloside
The glucosides such as (i.e. luteolin 7-O-glucoside), apiin.
Multiple mixing in component (b) is luteolin, apigenin, kaempferol, Quercetin, ampelopsin and isorhamnetin
During compound, the most each component can exist with any possible ratio.Especially, when component (b) be luteolin, apigenin,
(as during for the mixture of luteolin and apigenin) during in kaempferol, Quercetin, ampelopsin and isorhamnetin two kinds, two kinds
Component can exist with any possible ratio, and such as 100: 1 to 1: 100, preferably 50: 1 to 1: 50, more preferably 25: 1 to 1:
25, most preferably 10: 1 to 1: 10, such as 1: 1.
In preferred embodiments, component (a) is 1: 50 to 1: 20 with the weight ratio of component (b), more preferably 1: 45 to 1
: 25, even more preferably from 1: 40 to 1: 30, even more preferably 1: 30,1: 31,1: 32,1: 33,1: 34,1: 35,1: 36,1: 37,1:
38,1: 39 or 1: 40.
In preferred embodiments, component (a) is 1: 1 to 10: 1 with the weight ratio of component (b), more preferably 1: 1 to 8:
1, even more preferably from 1: 1 to 5: 1, even more preferably 1: 1 to 3: 1, most preferably 1: 1,1.5: 1,2: 1,2.1: 1,2.2: 1,2.3: 1,
2.4: 1,2.5: 1,2.6: 1,2.7: 1,2.8: 1,2.9: 1 or 3: 1.
In preferred embodiments, the pharmaceutical composition of the present invention comprises component (a) ginsenoside Rg1 or Rb1 or two
The mixture of person and component (b) luteolin or apigenin or the mixture of the two are as active component, and wherein component (a)
It is 1: 50 to 1: 20 or 1: 1 to 10: 1, preferably 1: 40 to 1: 30 or 1: 1 to 5: 1 with the weight ratio of component (b).
In preferred embodiments, the pharmaceutical composition of the present invention comprises component (a) ginsenoside Rg1 and component
B () luteolin is as active component, and wherein component (a) is 1: 50 to 1: 20 or 1: 1 to 10 with the weight ratio of component (b):
1, preferably 1: 45 to 1: 25 or 1: 1 to 8: 1, more preferably 1: 40 to 1: 30 or 1: 1 to 5: 1.
In preferred embodiments, the pharmaceutical composition of the present invention comprises component (a) ginsenoside Rg1 and component
B () luteolin is as active component, and wherein component (a) is 1: 1 to 3: 1 with the weight ratio of component (b).
The pharmaceutical composition of the present invention can make pharmaceutically suitably preparation with pharmaceutically acceptable excipient, as made
Piece agent, capsule, granule, injection, oral liquid, suspensoid, microsphere, liposome etc..
Another aspect of the present invention provides the pharmaceutical composition of the present invention for preparing the use improving amnemonic medicine
On the way.
In preferred embodiments, described dysmnesia are dull-witted (as senile dementia, vascular dementia and Louis body are silly
Stay) dysmnesia that cause, the dysmnesia that Alzheimer causes, and cerebral trauma, cerebral ischemia maybe stress cause
Dysmnesia；The dysmnesia that more preferably Alzheimer causes, and the dysmnesia that cerebral trauma or oxidative stress cause.
In the present invention, statement " comprising component (a) and component (b) as active component " means the medicine in the present invention
In compositions, active component is made up of component (a) and component (b), does not contains other unspecified active component.
Accompanying drawing explanation
The impact (A reality platform quadrant time ratio, B speed) on explorative experiment of the monomer of Fig. 1 various dose；
The monomer of Fig. 2 various dose is on keeping away the dark impact (A errors number, B place of safety time) learning the stage；
On the impact keeping away the dark consolidation phase, (A enters dark incubation period to the monomer of Fig. 3 various dose, and B errors number, during C place of safety
Between)；
Scopolamine model mice is worn the impact of platform number of times by the various combination of Fig. 4 two monomer；
The impact on the scopolamine model mice reality platform quadrant swim time of the various combination of Fig. 5 two monomer；
Scopolamine model mice is worn the impact of platform number of times by the combination of Fig. 6 two monomer；And
The combination of Fig. 7 two monomer impact on the scopolamine model mice reality platform quadrant swim time.
Detailed description of the invention
Below by embodiment, as a example by luteolin and ginsenoside Rg1, the invention will be further described.Should manage
Solving, embodiments of the invention are for the present invention rather than limitation of the present invention are described.Essence according to the present invention
The simple modifications carrying out the present invention broadly falls into claimed scope.
Additionally, in the present invention, term " monomer " means the purest single compound, as HPLC purity is more than
80%, preferably greater than 90%, do not contain the composition of the pharmacological action affecting this active component, but allow to contain the miscellaneous of acceptable amount
Matter.In the present invention, d represents that sky, h represent hour, and min represents minute, and s represents the second.
Embodiment 1: luteolin and ginsenoside Rg1 improve the determination of the effective dosage ranges of learning and memory
Determine that luteolin and ginsenoside Rg1 improve the effective dosage ranges of learning and memory function by the present embodiment.
1 test material
Animal: male ICR Mus, about body weight 20g (n=108), is purchased from Beijing Bioisystech Co., Ltd of dimension tonneau China,
Credit number is SCXK (capital) 2012-0001.
Medicine: ginsenoside Rg1, white crystalline powder, purity is more than 99%, lot number 150629；Luteolin, faint yellow
Powder, purity is more than 98%, lot number 150703；All it is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd.Donepezil, is purchased from
Defend material (Chinese) pharmaceutcal corporation, Ltd, lot number 1407016；Scopolamine, is purchased from sigma company.
2 test methods
First on the basis of literature survey, determine the two respective high, medium and low dosage of monomer.Then mice is divided at random
It it is 9 groups: matched group (C), scopolamine model group (S), donepezil group (D), luteolin low dose group (LL, 20mg/kg
BW), dosage group (LM, 60mg/kg BW), luteolin high dose group (LH, 180mg/kg BW), ginsenoside in luteolin
Dosage group (GM, 15mg/kg BW) and ginsenoside Rg1's height agent in Rg1 low dose group (GL, 5mg/kg BW), ginsenoside Rg1
Amount group (GH, 45mg/kg BW).Luteolin, ginsenoside Rg1 and donepezil are all dissolved in 0.5%CMC-Na solution, all
Using gastric infusion (0.1ml/10g), matched group and model group give 0.5%CMC-Na, every day 1 time.Successive administration 3 Zhou Houkai
Beginning Behaviors survey (water maze and keep away dark).1h before Behaviors survey, each group continuation relative medicine gavage.30min before experiment,
In addition to matched group intraperitoneal injection of saline, other organizes equal lumbar injection scopolamine, and volume injected is 0.1ml/10g.According to
Behavioristics's result determines that two monomers each improve the effective dosage ranges of learning and memory function.
Water maze laboratory totally 6 days, first 5 days is experiment of surely navigating, and last 1 day is explorative experiment.Step-through test totally 2 days, the 1st day
For acquisition model, the 2nd day for consolidating pattern.
3 result of the tests
(1) luteolin of various dose and ginsenoside Rg1's impact preclinical on scopolamine Mice water maze
Table 1: fixed boat is tested preclinical impact by the monomer of various dose
Remarks: #P ＜ 0.05, ##P ＜ 0.01, compared with matched group；* P ＜ 0.05, * * P ＜ 0.01, with S group (i.e. east Liang
Henbane alkali model group) compare；Additionally, in all forms and accompanying drawing of the application, symbol #, ##, * and * * is respectively provided with above-mentioned phase
Same implication.
After can be seen that lumbar injection scopolamine in table, mice significantly extends incubation period model group.Three various dose
Luteolin process after, mice shorter latencies (wherein luteolin 60mg/kg and 180mg/kg there were significant differences)；Three
After the ginsenoside Rg1 of various dose processes, mice also shortens (wherein ginsenoside Rg1 15mg/kg and 45mg/kg incubation period
There were significant differences).
(2) impact that scopolamine model mice water maze is explored by the luteolin of various dose and ginsenoside Rg1
In explorative experiment, scopolamine model mice substantially reduces at the swimming time of real platform quadrant.Various dose
After luteolin and ginsenoside Rg1 process, mice dramatically increases (multiple doses of two kinds of monomers at the swimming time of real platform quadrant
Amount group all has significant difference).Each group mice swimming rate is not significantly different from.
Table 2: the monomer of the various dose impact on explorative experiment
(3) scopolamine model mice is kept away the dark impact learnt by luteolin and the ginsenoside Rg1 of various dose
In keeping away dark study, the errors number of scopolamine model mice increases (P ＜ 0.01), and the place of safety time reduces (P
＜ 0.01).After two kinds of monomers process, the errors number of mice all reduces that (each dosage group of two kinds of monomers all has significance poor
Different), the place of safety time increases (in luteolin, dosage group and ginsenoside Rg1's high dose group have significant difference).
Table 3: the monomer of various dose is on keeping away the dark impact learning the stage
| Group | Dosage (mg/kg) | Errors number (secondary) | Place of safety time (s) |
| C | 4.72±0.61 | 288.33±1.67 | |
| S | 1 | 17.34±1.34## | 162.48±9.23## |
| D | 5 | 12.00±1.55* | 241.32±16.70** |
| LL | 20 | 12.84±1.36* | 184.28±16.07 |
| LM | 60 | 11.75±1.13** | 224.21±12.47** |
| LH | 180 | 11.88±0.92** | 216.25±17.72* |
| GL | 5 | 12.25±1.31* | 196.25±14.96 |
| GM | 15 | 12.34±1.18* | 180.36±19.43 |
| GH | 45 | 11.38±1.56* | 213.42±10.24** |
(4) scopolamine model mice is kept away the dark impact consolidated by luteolin and the ginsenoside Rg1 of various dose
In keeping away dark consolidation, the shorter latencies (P ＜ 0.01) of scopolamine model mice, errors number increases (P ＜
0.01), the place of safety time reduces (P ＜ 0.01).After two kinds of monomers process, the prolongation of latency of mice (two kinds of monomers multiple
Dosage group all has significant difference), errors number all reduces (each dosage group of two kinds of monomers all has significant difference), place of safety
Time increases (the middle and high dosage of luteolin and the high dose group of Rg1 have significant difference).
Table 4: the monomer of the various dose impact on keeping away the dark consolidation phase
Conclusion combines water maze and step-through test result, and luteolin is in the range of 20-180mg/kg, ginsenoside Rg1
In the range of 5-45mg/kg, the learning and memory function of mice all there is improvement result.
Embodiment 2: luteolin and the combination of ginsenoside Rg1
Multiple combinations of two monomers are obtained by uniform Design.Uniform Design is a kind of multifactor design efficient, quick
Analysis method, number theory is combined by it with multivariate statistical method, utilizes uniform designs table, makes each experimental factor and level in test
In the range of reasonably arranged, reach to use less testing site, it is thus achieved that the purpose of more information.Uniform Design is to utilize uniformly
Design table arranges test, and uniform designs table is formulated according to mathematical theory, meets uniformly dispersing principle.I.e. uniform Design is only examined
Consider " uniformly dispersing " of testing site, and do not considered " the most comparable ", thus test number (TN) can have been greatly reduced.Each uniformly set
Meter table all has one and uses table, indicates how to select suitable row from uniform designs table, and be made up of these row
The uniformity (representing with homogeneity deviation D, D is the least, and the uniformity is the best) of testing program.
Typically 6 dosage (i.e. level) are set in the effective dosage ranges of each medicine (i.e. factor), uniformly set
Meter.Table 5 is 4 factor 6 horizontal homogeneous design U6 *(64), table 6 is uniform designs table U6 *(64) use table.
Table 5:4 factor 6 horizontal homogeneous design table U6 *(64)
Table 6: uniform designs table U6 *(64) use table
In the present invention, using luteolin and ginsenoside Rg1 as the factor of investigation, each factor arranges 6 water
Flat, then obtain 6 compatible combination by uniform Design.The setting of each factor level depends on effective agent that previous experiments determines
Weight range (luteolin 20-180mg/kg, ginsenoside Rg1 5-45mg/kg).In view of the present embodiment is two factor six levels
Test, after consulting table 5 and table 6, uses the 1st row in table 5 and the 3rd row.Table 7 is the setting of two factors each 6 levels, table 8
For according to U6 *(64) combination of two monomers that obtains after uniform Design.
The setting of table 7: two factor each 6 levels
| Level | Factor (ginsenoside Rg1, mg/kg) | Factor (luteolin, mg/kg) |
| 1 | A1(2.5) | B1(15) |
| 2 | A2(12) | B2(50) |
| 3 | A3(21.5) | B3(85) |
| 4 | A4(31) | B4(120) |
| 5 | A5(40.5) | B5(155) |
| 6 | A6(50) | B6(190) |
Table 8: according to U6 *(64) combination of two monomers that obtains after uniform Design
The combination of embodiment 3: two monomer improves the effect of learning and memory function
1 test material
Animal: male ICR mouse (n=108), purchased from Beijing Bioisystech Co., Ltd of dimension tonneau China, credit number is
SCXK (capital) 2012-0001.
Medicine: ginsenoside Rg1, white crystalline powder, purity is more than 99%, lot number 150629；Luteolin, faint yellow
Powder, purity is more than 98%, lot number 150703；All it is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd.Donepezil, is purchased from
Defend material (Chinese) pharmaceutcal corporation, Ltd, lot number 1407016；Scopolamine, is purchased from sigma company.
2 test methods
According to the modular design pharmacological experiment obtained in embodiment 2, use scopolamine pharmacological model.Animal is divided at random
Be 9 groups: matched group (Con), scopolamine model group (Sco), donepezil group (Don), combine one group (50:120), combination two
Group (40.5:15), combine three groups (31:155), combine four groups (21.5:50), combine five groups (12:190), combine six groups (2.5:
85), often 12 are organized.Medication is with embodiment 1, and relative medicine starts Behavior test after processing 3 weeks.Employing water maze is examined
Survey learning and memory function.
3 result of the tests
The impact that scopolamine model mice water maze is explored by the various combination of two monomers
The wearing platform number of times and reduce at the swimming time of real platform quadrant of scopolamine model group mice.Six test group
Conjunction there are three combinations make wearing platform number of times and increasing at the swimming time of real platform quadrant of mice, there is compared with model group system
Difference learned by meter, they be respectively 50 (G): 120 (L) (i.e. the weight ratio of ginsenoside Rg1 and luteolin is 1: 2.4), 40.5
(G): 15 (L) (i.e. ginsenoside Rg1 is 2.7: 1 with the weight ratio of luteolin) and 2.5 (G): 85 (L) (i.e. ginsenoside Rg1
It is 1: 34 with the weight ratio of luteolin).
Scopolamine model mice is worn platform number of times and the shadow of real platform quadrant swim time by the various combination of table 9: two monomer
Ring
| Group | Wear platform number of times (secondary) | Real platform quadrant time ratio (%) |
| Con | 1.63±0.54 | 35.60±3.30 |
| Sco | 0.25±0.17# | 21.25±2.88## |
| Don | 1.63±0.60* | 28.90±1.78* |
| 50:120 | 1.56±0.59* | 29.62±1.64* |
| 40.5:15 | 2.28±0.47** | 28.59±1.64* |
| 31:155 | 0.88±0.62 | 21.20±4.09 |
| 21.5:50 | 0.56±0.45 | 30.53±5.01 |
| 12:190 | 0.58±0.30 | 26.16±3.03 |
| 2.5:85 | 3.72±0.36** | 34.96±1.46** |
Conclusion ginsenoside Rg1 and luteolin have significantly after combining with the ratio of 1: 2.4,2.7: 1 and 1: 34
Improve the effect of scopolamine model mice learning memory disorder.
The combination of embodiment 4: two monomer improves the pharmacodynamics checking of learning and memory function
The combination of the present embodiment two monomers to obtaining in embodiment 3 carries out pharmacodynamics checking.
1 test material
Animal: male ICR mouse (n=66), purchased from Beijing Bioisystech Co., Ltd of dimension tonneau China, credit number is
SCXK (capital) 2012-0001.
Medicine: ginsenoside Rg1, white crystalline powder, purity is more than 99%, lot number 150629；Luteolin, faint yellow
Powder, purity is more than 98%, lot number 150703；All it is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd.Donepezil, is purchased from
Defend material (Chinese) pharmaceutcal corporation, Ltd, lot number 1407016；Scopolamine, is purchased from sigma company.
2 test methods
According to the modular design pharmacological evaluation obtained in embodiment 3, use scopolamine pharmacological model.Animal is randomly divided into
6 groups: matched group [Con], model group [Sco], donepezil group [Don], combination group ([G:L (2.5:85)], i.e. ginsenoside
The weight ratio of Rg1 and luteolin is 1: 34), ginsenoside Rg1's group (2.5mg/kg) [G (2.5)], luteolin group (85mg/
Kg) [L (85)], often group 11.Medication is with embodiment 1, and relative medicine starts Behavior test after processing 3 weeks.Use water
Maze method detection learning and memory function.
3 result of the tests
The impact that scopolamine model mice water maze is explored by the combination of two monomers
The wearing platform number of times and substantially reduce at the swimming time of real platform quadrant of scopolamine model group mice.It is used alone
What luteolin or ginsenoside Rg1 all can increase model mice wears platform number of times and the swimming time at real platform quadrant thereof.Combination
What group can dramatically increase model mice wears platform number of times and the swimming time at real platform quadrant thereof.Combination group is relative to single medicine group
Have and significantly preferably improve effect.Wherein, G:L (2.5:85) group is worn platform number of times effect and is significantly stronger than G (2.5) group (P ＜
0.05)；The real platform quadrant time percent effect of G:L (2.5:85) group is significantly stronger than G (2.5) group (P ＜ 0.05).
Scopolamine model mice is worn platform number of times and real platform quadrant swim time by the combination of table 10: two monomer
| Group | Wear platform number of times (secondary) | Real platform quadrant time ratio (%) |
| Con | 2.75±0.46 | 36.80±2.00 |
| Sco | 1.00±0.29## | 23.50±0.60## |
| Don | 2.45±0.34** | 32.30±3.00** |
| G:L (2.5:85) | 2.38±0.19** | 32.70±2.60** |
| G(2.5) | 1.70±0.16* | 25.20±2.10 |
| L(85) | 1.88±0.23* | 27.40±1.60* |
Conclusion ginsenoside Rg1 and luteolin are really significantly improved Rhizoma Scopoliae Japonicae after combining with the weight ratio of 1: 34
The effect of alkali model mice learning memory disorder, and its action effect is significantly better than single medicine.
Claims (10)
1. a pharmaceutical composition, its comprise one or more ginsenoside monomers of component (a) and component (b) luteolin or
Its analog as active component, wherein said ginsenoside monomer selected from ginsenoside Rg1 and Rb1, Rg3, Rg5, Rd, Rh1,
Rh3 and Re, described luteolin is similar to thing selected from apigenin, kaempferol, Quercetin, ampelopsin, isorhamnetin and glucosides thereof；And
Wherein component (a) is 1: 50 to 10: 1 with the weight ratio of component (b).
2. the pharmaceutical composition of claim 1, during wherein component (a) is ginsenoside Rg1, Rb1, Rg3, Rd, Rh1 and Re
Plant or multiple；It is highly preferred that component (a) is one or both in ginsenoside Rg1, Rb1, Rg3, Rd, Rh1 and Re；The most more
Preferably, component (a) is ginsenoside Rg1 or Rb1 or the mixture of the two；Most preferably, component (a) is ginsenoside Rg1.
3. the pharmaceutical composition of claim 1, wherein component (b) is luteolin, apigenin, kaempferol, Quercetin, ampelopsin
With one or more in isorhamnetin；It is highly preferred that component (b) is luteolin, apigenin, kaempferol, Quercetin, Fructus Myricae rubrae
Element and isorhamnetin in one or both；It is more preferred still that component (b) is luteolin or apigenin or the mixing of the two
Thing；Most preferably, component (b) is luteolin.
4. the pharmaceutical composition any one of claim 1-3, wherein component (a) is 1: 50 to 1 with the weight ratio of component (b):
20, more preferably 1: 45 to 1: 25, even more preferably from 1: 40 to 1: 30, even more preferably 1: 30,1: 31,1: 32,1: 33,1: 34,1:
35,1: 36,1: 37,1: 38,1: 39 or 1: 40.
5. the pharmaceutical composition any one of claim 1-3, wherein component (a) is 1: 1 to 10 with the weight ratio of component (b):
1, more preferably 1: 1 to 8: 1, even more preferably from 1: 1 to 5: 1, even more preferably 1: 1 to 3: 1, most preferably 1: 1,1.5: 1,2: 1,2.1:
1,2.2: 1,2.3: 1,2.4: 1,2.5: 1,2.7: 1,2.8: 1,2.9: 1 or 3: 1.
6. the pharmaceutical composition of claim 1, it comprises component (a) ginsenoside Rg1 or Rb1 or the mixture of the two and group
Point (b) luteolin or apigenin or the mixture of the two are as active component, and the weight of wherein component (a) and component (b)
Ratio is 1: 50 to 1: 20 or 1: 1 to 10: 1, preferably 1: 45 to 1: 25 or 1: 1 to 8: 1, more preferably 1: 40 to 1: 30 or 1: 1 to 5:
1。
7. the pharmaceutical composition of claim 1, it comprises component (a) ginsenoside Rg1 and component (b) luteolin as work
Property composition, and the weight ratio of wherein component (a) and component (b) is 1: 50 to 1: 20 or 1: 1 to 10: 1, preferably 1: 45 to 1: 25 or
1: 1 to 8: 1, more preferably 1: 40 to 1: 30 or 1: 1 to 5: 1.
8. the pharmaceutical composition any one of claim 1-3, it is made according to a conventional method with pharmaceutically acceptable excipient
Tablet, capsule, granule, oral liquid, suspensoid, injection, microsphere, liposome.
9. the pharmaceutical composition any one of claim 1-8 is for preparing the purposes improving amnemonic medicine.
10. the purposes of claim 9, wherein said dysmnesia are dull-witted (as senile dementia, vascular dementia and Louis body are silly
Slow-witted) dysmnesia that cause, the dysmnesia that Alzheimer causes, and the note that cerebral trauma, cerebral ischemia maybe stress cause
Recall obstacle；It is preferably the dysmnesia that Alzheimer causes, and the dysmnesia that cerebral trauma or oxidative stress cause.
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| CN114259486A (en) * | 2020-09-16 | 2022-04-01 | 香港科技大学 | Application of luteolin and pharmaceutical composition thereof |
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