CN109758464B - Application of Vietnam ginsenoside R4 in preparation neurodegenerative disease therapeutic agent - Google Patents
Application of Vietnam ginsenoside R4 in preparation neurodegenerative disease therapeutic agent Download PDFInfo
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Abstract
The present invention provides application of Vietnam ginsenoside R4 in preparation neurodegenerative disease therapeutic agent, especially preparing the application in Antiparkison Drugs.In the present invention, by designing external Parkinson's model, it is put forward for the first time and confirms that Vietnam ginsenoside R4 can reduce cellular damage, by inhibiting the oxidative stress and regulating cell apoptosis of cell, to play anti-Parkinson effect.Thus, the present invention provides using Vietnam ginsenoside R4 as the application of the effective therapeutic agent of Parkinson disease, provide the foundation to develop and expanding the medicinal application of Vietnam ginsenoside R4.
Description
Technical field
The present invention relates to drug fields, control in particular to Vietnam ginsenoside R4 in preparation neurodegenerative disease
The application in drug is treated, is especially preparing the application in Antiparkison Drugs.
Background technique
Neurodegenerative disease is central nervous system generation function barrier caused by the forfeiture due to neuron or myelin
A kind of disease hindered, is mainly in person in middle and old age's period.Alzheimer's disease, Parkinson's disease, hungtington's chorea etc. compare
Common neurodegenerative disease.
Parkinson's disease (Parkinson's disease, PD) is to betide ranking in elderly population to be only second to the sea A Erzi
The neurodegenerative disease of silent disease, reason are the dead selectivity of dopaminergic neuron in black substance or missing and cell
The formation of interior Louis's corpusculum.The Clinical symptoms of PD disease shows as being slow in action, posture gait disorder, static tremor, flesh
Tetanic, paces towing etc., partially may occur in which the symptoms such as cognitive disorder, depressed, lather.These non-motor symptoms will be into
The pain of one step making patients, influences the life quality of patient.
The cause of disease of Parkinson's disease is unclear, but a large amount of evidences show many factors involved in its pathogenic process, including thin
Born of the same parents' apoptosis, aging, autoimmunity, noxious material, oxidative stress and geographical environment.Wherein, degeneration of dopaminergic neurons is most
Whole common pathway is oxidative stress, and oxidative stress is the imbalance of generation and the elimination of oxygen radical in organism or cell, is led
Cause reactive active oxygen (reactive oxygen species, ROS) and reactive active nitrogen (reactive nitrogen
Species, RNS) in vivo accumulation it is excessive caused by oxidative damage.Wherein, ROS can cause protein denaturation, lipid peroxy
Change and gene mutation, eventually lead to neural cell injury and apoptosis.The disease incidence of PD is that China is in trend is risen year by year at present
The main bugbear one of urgently to be resolved to the whole world.Therefore, the importance that anti-Parkinson drug is develop and useedd is self-evident.
Vietnam ginsenoside R4 is a kind of saponins compound extracted from folium panacis japonici cum caule.Ginsenoside has a variety of pharmacology
Learn activity, such as anti-oxidant, anti-aging, reducing blood lipid, the hair improve immunity, inhibit ischemical reperfusion injury, reducing inflammatory reaction
It is raw.Vietnam ginsenoside R4 belongs to one of saponin(e active component, but can Vietnam ginsenoside R4 to the mind of PD disease injury
There is neuroprotection through member, at present both at home and abroad there is not yet relevant report.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of Vietnam's ginsenoside R4 in preparation neurodegenerative disease medicine
Application in object.
The second object of the present invention is to provide a kind of pharmaceutical composition for neurodegenerative disease treatment.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
Application of Vietnam ginsenoside R4 in preparation neurodegenerative disease therapeutic agent.
Meanwhile the present invention also provides a kind of pharmaceutical composition for neurodegenerative disease treatment, the medicine groups
Closing includes Vietnam's ginsenoside R4 in object.
Compared with prior art, the invention has the benefit that
1) it in the present invention, by designing external Parkinson's model, is put forward for the first time and confirms that Vietnam ginsenoside R4 can
Cellular damage is reduced, by inhibiting the oxidative stress and regulating cell apoptosis of cell, to play anti-Parkinson effect.
Thus, the present invention provides using Vietnam ginsenoside R4 as the application of the effective therapeutic agent of Parkinson disease, to develop and expanding
The medicinal application of big Vietnam ginsenoside R4 provides the foundation.
2) pathogenesis of Parkinson disease is still not clear at present, present invention discover that Apoptosis and oxidative stress and pa gold
The generation of gloomy disease is closely related, the meaning of primary study Apoptosis and oxidative stress of the present invention in Parkinson disease,
On the basis of using PC12 cell as model, ROS, the expression quantity of Bax, Caspase-3 are analyzed, and use the Vietnamese of various concentration
Ginseng saponin(e R4 is acted on Parkinson's model, studies the dependency relationships between its neuroprotection and its concentration, is pa gold
Effective drug concentration is screened in the treatment of gloomy disease, and finds for the drug of anti-Parkinson and provide new research think of with preparation
Road.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is toxicity data of Vietnam's ginsenoside R4 for normal PC12 cell；
Fig. 2 is protective effect of Vietnam's ginsenoside R4 to the 6-OHDA PC12 cell induced；
Fig. 3 is the metamorphosis figure that Vietnam's ginsenoside R4 acts on PC12 cell after 6-OHDA induction；Wherein, (a) just
Normal control group, (b) 6-OHDA processing group, (c) 100 μm of R4+250 μm of 6-OHDA groups；
Fig. 4 is influence of Vietnam's ginsenoside R4 to the 6-OHDA PC12 apoptosis rate induced；
Fig. 5 is the influence that Vietnam's ginsenoside R4 causes oxidative stress to 6-OHDA；
Fig. 6 is the influence that Vietnam's ginsenoside R4 causes NF- κ B expression quantity to 6-OHDA；
Fig. 7 is the influence of Vietnam's ginsenoside R4 Bax and Caspase-3 expressing quantity intracellular to PC12.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Although some researches show that the saponins compounds such as ginsenoside Rg1, Re and F1 have certain anti-Parkinson's disease
Effect, however, especially it is in the neurodegenerative diseases such as Parkinson's disease for the medicinal study of Vietnam ginsenoside R4
Effect, there are no relevant research reports.In view of in the research blank of Vietnam's ginsenoside R4 medicinal applications, spy proposes this hair
It is bright.
It is to carry out neurodegenerative disease, especially Parkinson using Vietnam ginsenoside R4 as effective substance in the present invention
The applied experiments of disease treatment, and it is experimentally confirmed the potential medical value that Vietnam ginsenoside R4 has anti-Parkinson's disease.
Specifically, in the present invention, the structure of Vietnam ginsenoside R4 are as follows:
It in the present invention, tests and finds through cell guidance model, Vietnam ginsenoside R4 has effects that anti-Parkinson's disease.More
Southern ginsenoside R4 can by reduce by cellular damage caused by Parkinson's disease (especially for as caused by Parkinson's disease by
Damaging cell has neuroprotective function), and inhibit by the cellular oxidation caused by Parkinson's disease stress, and reduce by Parkinson
Caused by disease the effects of cell death, the pharmacologic action for the treatment of of Parkinson disease is played.
Further, experimental study also found, Vietnam ginsenoside R4 also has the NF- for inhibiting to be caused by Parkinson's disease
κ B p65 enters nuclear expression, and inhibits the effect by the Parkinson's disease Caspase-3 protein expression caused and Bax gene expression
Fruit, this is expected to the new point of penetration for becoming Parkinson disease treatment.
Pharmacologic action based on Vietnam ginsenoside R4 in treatment of Parkinson disease, the present invention also provides a kind of nerves to move back
Row disease treatment pharmaceutical composition, especially treatment of Parkinson disease pharmaceutical composition.
Specifically, pharmaceutical composition provided by the present invention except comprising Vietnam ginsenoside R4 as functional mass in addition to, also
Including pharmaceutically acceptable auxiliary material.In order to reach combination therapy effect, pharmaceutical composition of the present invention can also include removing Vietnam
The second pharmic function component outside ginsenoside R4.
It in certain embodiments of the present invention, can also will include Vietnamese for the ease of the application of pharmaceutical composition
The pharmaceutical composition of ginseng saponin(e R4 is prepared into different pharmaceutical dosage forms, especially oral agents and injection；
In currently preferred some embodiments, the oral agents include: tablet, granule, dripping pill, soft capsule,
Suspending agent, at least one of solution and syrup；
Wherein, for solid orally ingestibles such as tablet, granular-grade, dripping pill and soft capsules, in addition to including Vietnam's ginseng
Saponin(e R4 as effective substance outside, can also include: comprising at least one inert pharmaceutically acceptable auxiliaries, the auxiliary material a) filler or
Incremental agent, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive, such as carboxy methyl cellulose, algae
Hydrochlorate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) moisturizer, such as glycerol, d) disintegrating agent, such as fine jade
Rouge, calcium carbonate, potato or tapioca, alginic acid, silicate and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorb plus
Fast agent, such as quaternary ammonium compound, g) wetting agent, such as cetanol and glycerin monostearate, h) absorbent, such as kaolin and
Bentonite and i) lubricant, such as talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate, and its
Mixture；
For suspending agent, the liquid oral medicines such as solution and syrup, in addition to making comprising Vietnam ginsenoside R4
It can also include at least one inert diluent commonly used in the art, such as water or other solvents, solubilizer outside for effective substance
And emulsifier, such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Ergol, propylene glycol, 1,3- fourth two
Alcohol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil),
Glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan aliphatic ester and its mixture；And wetting agent, emulsifier and
The auxiliary materials such as suspending agent, sweetener, flavoring agent and aromatic.
In currently preferred some embodiments, the injection includes: freeze dried powder, and solution type injection agent mixes
Outstanding at least one of type injection and emulsion-type injection；
Wherein, for freeze dried powder, in addition to comprising Vietnam ginsenoside R4 as effective substance other than, also at least contain one
The common freeze-drying excipients of kind, such as: the carbohydrates such as glucose, lactose, the polyalcohols such as mannitol, sorbierite, glycine, paddy ammonia
Excipients are lyophilized in the amino acids such as acid, the macromoleculars class such as the inorganic salts such as sodium chloride, potassium chloride, calcium chloride and gelatin.
Wherein, for solution type injection agent, the liquid injections agent such as suspension injection and emulsion-type injection is removed
Comprising south ginsenoside R4 as effective substance outside, also at least contain a kind of dispersing agent or the auxiliary materials such as wetting agent and suspending agent.
In following specific embodiment, the present invention passes through following experiments have shown that Vietnam ginsenoside R4 (lower abbreviation R4) is right
Parkinson's disease (lower abbreviation PD) has preferable neuroprotection, and a variety of Pathologic changes of PD can be effectively relieved:
It is comprehensive that Parkinson's sample is generated using 6- hydroxyl dopamine (lower abbreviation 6-OHDA) induction PC12 cell design in vitro
Disease.By detection PC12 cell survival rate, cellular morphology observation, Apoptosis-Related Factors expression, oxidative stress relevant parameter are measured,
Research finds that R4 pretreatment has been obviously reduced the neurotoxicity and Apoptosis that 6-OHDA is induced in PC12 cell.Pass through
The expression quantity of western blot technology detection nuclear factor NF- κ B p65.6-OHDA is drawn in addition, exploring R4 by this method
The influence that the rush antiapoptotic factors Bax and apoptosis risen executes PROTEIN C aspase-3 expression is finally studied discovery R4 and is mediated by NF- κ B
Apoptosis pathway play neuroprotection.
Wherein, R4 used extracts separation for patent applicant from folium panacis japonici cum caule and obtains, and structure is given by nuclear magnetic resonance technique
Confirmation is given, is numbered with commercially available CAS are as follows: the commodity of 156009-80-2 are consistent with nuclear-magnetism result.
In following each group experiment, all data are all made of SPSS ver.19.0 software and carry out statistical analysis.Data with
Mean+SD (x ± s) indicates.It is experimental group and control group, experimental group using one-way analysis of variance and t check analysis
Difference between experimental group.As p < 0.05, it is believed that difference has conspicuousness.
1 mtt assay of embodiment detects R4 for the toxic effect of normal PC12 cell
Experimental material: pheochromocytoma PC12 is purchased from American Type Culture Collecti (ATCC)
Experimental procedure: will be digested in the PC12 cell of logarithmic phase with 0.25% pancreas enzyme -EDTA, after be added and be aided with
The DMEM in high glucose culture medium of 10% fetal calf serum, 5% horse serum, 100 μ g/mL streptomysins and 100units/mL penicillin will
Cell is blown and beaten to individual cells；After resuspension, with 3 × 105Cell/mL is inoculated in 96- plate, is carried out according to different experimental groups
Agent-feeding treatment.Wherein, blank group is free from the DMEM complete medium of PC12 cell；Control group has been free from R4 and 6-OHDA
Cell culture fluid；Experimental group is the cell culture fluid for being separately added into 6.25,12.5,25,50,100,200 μM of R4.
Each group culture solution is in CO2Incubator culture absorbs cell culture fluid for 24 hours, with vacuum pressure pump, is added with final concentration
For the 100 μ L of MTT stock solution of 0.5mg/mL, continue to be put into CO2After incubator is incubated for 4h, isometric MTT terminate liquid is added, after
After continuous culture 16-20h, using microplate reader in wavelength is the absorbance that every hole is measured at 550nm, and calculates cell according to formula
Survival rate.Calculation formula are as follows:
Cell survival rate=(AExperimental group-ABlank group)/(AControl group-ABlank group) × 100%, A is that Detection wavelength is extinction at 550nm
Degree.
Experimental result as shown in Figure 1, by Fig. 1 result it is found that 6.25-200 μM R4 handle cell after, cell survival rate
92% or more, illustrate R4 to PC12 cell there are no significant toxicity.
2 mtt assay of embodiment detects influence of the R4 to the 6-OHDA PC12 cell viability induced
Experimental procedure: by the cell in logarithmic phase with 3 × 105Cell/mL is inoculated in 96- plate, and culture is for 24 hours.If
Vertical control group, blank group, 250 μM of 6-OHDA processing groups, 250 μM of 6-OHDA+25 μM of R4 processing groups, 250 μM of 6-OHDA+50
μM R4 processing group, 6-OHDA+100 μM of R4 processing group.The R4 pretreatment 30min of various concentration is first added in experimental group, then
250 μM of 6-OHDA processing is added for 24 hours.Every group of cell survival rate is measured using mtt assay, specific steps are as described in Example 1.
Experimental result is as shown in Fig. 2, as shown in Figure 2,6-OHDA processing group cell survival rate is 58.76%, compared to 6-
The cell survival rate of OHDA processing group, the R4 pretreated group of various concentration obviously rises, and respectively reaches 70.81%, 78.74% He
80.88%, and there is concentration dependant sexual intercourse.It can be seen that R4 pretreatment can substantially reduce cell mortality.
Influence of 3 R4 of embodiment to the 6-OHDA PC12 cellular morphology induced
Experimental procedure: using the PC12 cellular morphology of scanning electron microscope (SEM) observation 6-OHDA induction, cell grouping
Setting: Normal group, 250 μM of 6-OHDA processing groups, 250 μM of 6-OHDA+25 μM of R4 processing groups, 250 μM of 6-OHDA+50
μM R4 processing group, 250 μM of 6-OHDA+100 μM of R4 processing groups.Cell drug after treatment, it is solid with 2.5% glutaraldehyde
Determine the fixed cell of liquid, be incubated for 1h in the incubator, with PBS solution washing cell 3 times, each 5min, finally using 30%,
50%, 70%, 90%, 100% ethanol gradient elution washes cell 2 times, each 5min.The cell handled well is taken, and in the secure execution mode (sem
Observe its cellular morphology.
Experimental result as shown in Figure 3, by Fig. 3 (a) (Normal group) result it is found that normal PC12 cell have it is prominent
It rises, it is tightly attached to each other between cell, form network-like structure；Meanwhile by Fig. 3 (b) (6-OHDA processing group) result it is found that
After 6-OHDA is handled, cell process disappears, and becomes independent individual cells；Further, by (100 μm R4+250 μm of Fig. 3 (c)
6-OHDA group) it is found that after R4 medical preconditioning, cell state is very significantly improved result.It can be seen that R4 is to impaired PC12
Cell has apparent neuroprotective function.
Influence of 4 R4 of embodiment to the 6-OHDA PC12 Apoptosis induced
Experimental procedure: by the PC12 cell in logarithmic growth phase with 3 × 105The hole cells/ is inoculated in 6 orifice plates, drug
Treatment process is as described in Example 3.After drug-treated, the cell in every hole is subjected to pancreatin digestion, at room temperature with 1800rpm from
Heart speed collects PC12 cell after being centrifuged 3min.Then cell is resuspended with 1 × binding buffer of 100 μ l, is added
Annexin V-FITC and PI be protected from light incubation, after 15min, the PBS of 400 μ l are added, is carried out in 1h using flow cytometer
Detection.Finally handled using flow cytometry software FlowJo.
As a result see Fig. 4, by Fig. 4 result it is found that the apoptosis rate of Normal group cell be 7.35%, 6-OHDA induction after,
Cell damage, apoptosis rate are increased to 36.97%, and after giving drug R4 pretreatment, the apoptosis rate of cell is dense as R4 is added
The increase of degree and reduce, it is respectively 25 that concentration, which is added, as R4, and at 50,100 μM, the apoptosis rate of cell is reduced respectively to 33%,
22.6%, 16.2%.It can be seen that R4 can obviously reduce the apoptosis rate of impaired PC12 cell.
5 R4 of embodiment causes the influence of oxidative stress to 6-OHDA induction PC12 cell
Oxidative stress refer to organism or into the cell by external irritant when, intracorporal active oxygen radical ROS and RNS exists
Internal excess accumulation, the horizontal decline of antioxidant system defence, it is impaired to eventually lead to in-vivo tissue.Therefore, ROS can be with bidirectional modulation
Apoptosis and cell Proliferation, there is inner links between cell signalling and ROS.Contained by ROS in measurement cell body
Amount, and then investigate the influence that R4 causes oxidative stress to 6-OHDA induction PC12 cell.
Different experiments group is set according to 3 method of embodiment, and carries out drug-treated respectively, then utilizes DCFH-DA fluorescence
It is horizontal that decoration method detects intracellular ROS under flow cytometer.As a result as shown in Figure 5.By Fig. 5 result it is found that with normal right
It is compared according to group, the ROS average fluorescent strength of the independent processing group of 6-OHDA is 3.595 times of control group.When total with R4 and 6-OHDA
After processing, the intracorporal ROS level of cell reduces, respectively 2.989 times, 2.111 times and 1.703 times, it is seen that ROS is in vivo
The neuroprotection of dynamic equilibrium and R4 have important contact.
6 R4 of embodiment causes the influence of the NF- κ B of PC12 cell to 6-OHDA
Drug-treated process and its grouping situation such as embodiment 3 are described in detail.Cell after treatment uses nucleoprotein/born of the same parents
After starching Protein Extraction Reagent kit extraction Nuclear extract, Bradford method quantifies albumen, and it is thin that western blot surveys it
The accumulation of NF- κ B subunit p65 in karyon.
For experimental result as shown in fig. 6, by Fig. 6 result it is found that in Normal group, the expression quantity of NF- κ B p65 is lower,
But after 6-OHDA induction PC12 cell, the accumulation of NF- κ B p65 be increased significantly in nucleus, illustrate that 6-OHDA can cause
The core of NF- κ B shifts.After various concentration R4 pretreatment, core shifting phenomena is obviously reduced, and has dose-dependent relationship.Cause
This, R4 is able to suppress the effect that the NF- κ B p65 as caused by 6-OHDA enters nuclear expression.
Influence of 7 R4 of embodiment to Bax the and Caspase-3 protein expression of PC12 cell
Detect the situation of change of intracellular Bax and Caspase-3 expressing quantity using western blot technology, and with
β-actin is used as standard internal reference albumen.In numerous apoptosis genes, the expression of Bcl-2 family is to Apoptosis to Guan Chong
It wants, is of great significance wherein promoting apoptogene Bax and anti-apoptotic Bcl-2 to whether determining cell occurs apoptosis.Caspase grades
Connection reaction is the foundation stone of Apoptosis, and Caspase activates a specific signal system, leads to core shrinkage and DNA fragmentation, finally
Control the occurrence and development of Apoptosis.
Drug-treated process and its grouping situation such as embodiment 3 are described in detail.It is total that cell extraction cell is collected after drug-treated
Albumen detects Bax the and Caspase-3 expressing quantity of cell at western blot.
For experimental result as shown in fig. 7, by Fig. 7 result it is found that after 6-OHDA inducing cell, intracellular apoptosis executes albumen
Caspase-3 and rush apoptogene Bax expression quantity obviously rise, and after giving R4 pretreatment, the two expression quantity decreases,
And tool and concentration dependant sexual intercourse, R4 concentration is higher, and the expression quantity of Caspase-3 and Bax restore higher.By as above testing
As a result it is known that R4 is the expression quantity by lowering Bax and Caspase-3 protein, and then regulating cell apoptosis, performance are refreshing
Through protective effect.
As the experimental result of embodiment 1-7 as above it is found that R4 can reduce the accumulation of ROS caused by 6-OHDA, reduce
Response to oxidative stress.After being pre-processed with R4, apoptosis rate is reduced, and the behavior that core displacement occurs for NF- κ B is reduced, more
Add and is able to verify that Parkinson's model that R4 PC12 cell induced for 6-OHDA generates has significant neuroprotection, and
The apoptotic response that NF- κ B is mediated takes part in the neuroprotection of R4, and this is also that R4 is mentioned as the application of anti-PD therapeutic agent
Theoretical foundation is supplied.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (3)
1. application of Vietnam ginsenoside R4 in preparation neurodegenerative disease therapeutic agent, the neurodegenerative disease are
Parkinson's disease.
2. application according to claim 1, which is characterized in that Vietnam ginsenoside R4 is reduced in preparation by Parkinson's disease institute
Lead to the application in cellular damage drug；
And/or application of Vietnam ginsenoside R4 caused by preparation inhibits by Parkinson's disease in oxidative stress drug；
And/or application of Vietnam ginsenoside R4 caused by preparation is reduced by Parkinson's disease in cell death drug.
3. application according to claim 1, which is characterized in that Vietnam ginsenoside R4 inhibits in preparation by Parkinson's disease institute
The NF- κ B p65 of initiation enters the application in nuclear expression drug；
And/or Vietnam ginsenoside R4 preparation inhibit the Caspase-3 protein expression caused by Parkinson's disease and
Application in Bax gene expression drug.
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