CN109498768A - Application of the palace of the Qing Dynasty Shoutao pills in preparation treatment improvement decrease of memory, amnesia, cognitive disorder drug - Google Patents
Application of the palace of the Qing Dynasty Shoutao pills in preparation treatment improvement decrease of memory, amnesia, cognitive disorder drug Download PDFInfo
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Abstract
Improve the present invention provides a kind of palace of the Qing Dynasty Shoutao pills in preparation treatment and recall power decline, amnesia, the application in cognitive disorder drug, belongs to technical field of traditional Chinese medicines.The present invention is by 3 kinds of quasi- old cognitive disorder animal model, that is, natural aging mices, APP/PS1 bi-transgenic mice, SAMP8 Senescence-accelerated Mouse's, the effect and mechanism that palace of the Qing Dynasty Shoutao pills intervene learning and memory are observed using technology and methods, subordinate act, central neurotransmitter, relevant enzyme and other biochemical indicators, histocyte morphology etc. such as Morris water maze, ELISA, HE dyeing.
Description
Technical field
The present invention relates to technical field of traditional Chinese medicines is belonged to, specifically palace of the Qing Dynasty Shoutao pills improve decrease of memory, amnesia, cognition barrier
The new application hindered.
Background technique
Aging is the affirmative risk factor of old cognitive disorder.With advancing age, the illness rate of old cognitive disorder
In increasing trend.The old cognitive disorder course of disease is long, pathogenic factor is more, pathomechanism is complicated and influences each other, and primary and secondary cause and effect is still not
It is clear, it blocks a certain pathologic process without taking into account other merely, good therapeutic effect may not necessarily be generated, therefore clinic is controlled at present
It treats and applies several chemicals simultaneously often.But the effect is unsatisfactory for this treatment method, and side effect is larger.
Summary of the invention
In view of this, the present invention is intended to provide a kind of palace of the Qing Dynasty Shoutao pills improve decrease of memory, amnesia, cognitive disorder it is new
Purposes.
Palace of the Qing Dynasty Shoutao pills are adjusting maincenter AChE vigor, adjust maincenter key neurotransmitter ACh and generate, discharge and degrade,
So as to improve central cholinergic system function, improve decrease of memory, amnesia, cognitive disorder new application；
Palace of the Qing Dynasty Shoutao pills improve maincenter NE, 5-HT energy in the intake and katabolism for adjusting monoamine neurotransmitters
The function of system, so as to improve decrease of memory, amnesia, cognitive disorder new application；
Palace of the Qing Dynasty Shoutao pills are improving the anti-oxidant ability with removing free radical of body, mitigate Cell membrane lipids peroxidating, protect
Protect nerve cell, restore corresponding brain function, so as to improve decrease of memory, amnesia, cognitive disorder new application；
Palace of the Qing Dynasty Shoutao pills are delaying or are reducing the apoptosis of crucial brain area neuron, losing, and protect its structure and function, thus
Easyization cynapse transmitting, improve decrease of memory, amnesia, cognitive disorder new application.
Compared with the existing technology, present invention has the advantage that
(1) (natural aging mice, APP/PS1 double transgenic are small by 3 kinds of quasi- old cognitive disorder animal models by the present invention
Mouse, SAMP8 Senescence-accelerated Mouse's), using Morris water maze, ELISA, HE dye etc. technology and methods, subordinate act, in
Pivot neurotransmitter, relevant enzyme and other biochemical indicators, histocyte morphology etc. observe palace of the Qing Dynasty Shoutao pills intervention study note
The effect and mechanism recalled.
(2) pharmacodynamics and Study on mechanism the result shows that, palace of the Qing Dynasty Shoutao pills may decline memory of the elder, is strong
Forget, cognitive disorder etc. has improvement and therapeutic effect, this effect may be by following multiple target spots and link realizes:
1. adjusting maincenter AChE vigor, adjusts maincenter key neurotransmitter ACh and generate, discharge and degrade, so as to improve in
Pivot Cholinergic improves study, memory function；
2. adjusting the intake and katabolism of monoamine neurotransmitters, improve the function of maincenter NE, 5-HT energy system,
To help to improve study, memory function；
3. significantly improving the anti-oxidant ability with removing free radical of body, mitigate Cell membrane lipids peroxidating, protection nerve
Cell restores corresponding brain function, to facilitate anti-aging, improve memory capability, prevent or delay pathologic process；
4. delaying or reducing the apoptosis of crucial brain area neuron, lose, its structure and function is protected, is passed to easily change cynapse
It passs, improves and remember relevant brain function.
(3) compared with donepezil, Ginkgo Leaf Agent, palace of the Qing Dynasty Shoutao pills show different drug effect and mechanism in our current research.
The effect of palace of the Qing Dynasty Shoutao pills improvement learning and memory no significant difference, part test result compared with donepezil are better than Jenner
It is more；And palace of the Qing Dynasty Shoutao pills are adjusting the effect of maincenter ACh energy system function, anti-oxidant aspect more compared with donepezil, Ginkgo Leaf Agent
Significantly.As a result also prompt, in terms of improving mild cognitive impairment, the selection of the prescription thinking and dosage of palace of the Qing Dynasty Shoutao pills be it is reasonable and
Effectively.
(4) maincenter AChE vigor table of the palace of the Qing Dynasty Shoutao pills to APP/PS1 bi-transgenic mice and SAMP8 Senescence-accelerated Mouse's
Reveal significant humidification, completely contradicts with donepezil, Ginkgo Leaf Agent.Meanwhile palace of the Qing Dynasty Shoutao pills can significantly increase APP/PS1
Bi-transgenic mice maincenter ACh is horizontal.In view of the inevitable defect of existing AChEI, palace of the Qing Dynasty Shoutao pills are to this of AChE
Action character may make it obtain bigger clinical efficacy.
(5) palace of the Qing Dynasty Shoutao pills may adjust NE, 5-HT energy system activity by adjusting horizontal play of maincenter NE, 5-HT
Effect.Cognitive process, palace of the Qing Dynasty Shoutao pills are participated in view of influencing each other and (relying on and enhance) between cholinergic and monoaminergic system
The effect for improving learning and memory may have certain be associated with the intake and degradation etc. for intervening monoamine transmitters.
(6) palace of the Qing Dynasty Shoutao pills as compound, are formed by plurality of Chinese compatibility, and every taste Chinese medicine is also by multiple group of effective components
It may be different effective components in different flavour of a drug by influencing each other (such as collaboration, antagonism, instead at, final pharmacodynamics effect
Assistant), by system complex multiple under different body conditions adjust after and it is reflected a kind of whole, macroscopical as a result,
This is very different in the mode of action and action approach of human body with single chemical component.This multiple target point of palace of the Qing Dynasty Shoutao pills,
The action character of too many levels, fully demonstrated Chinese medicine Multiple components influence each other, co-therapies disease the characteristics of, it is possible to
Under the premise of paying close attention to patient's entirety problem, reducing toxic side effect to the greatest extent, achieve the purpose that more effectively to improve cognitive disorder.
Detailed description of the invention
Influence (the 1-5 days) of the palace of the Qing Dynasty Fig. 1 Shoutao pills to natural aging mice swimming path length.
Influence (the 1-5 days) of the palace of the Qing Dynasty Fig. 2 Shoutao pills to natural aging mice swimming escape latency.
Influence (the 6th day) note of the palace of the Qing Dynasty Fig. 3 Shoutao pills to natural aging mice swimming path length: 1. young controls；
2.11 moon age group；3. palace of the Qing Dynasty Shoutao pills large dosage group；4. palace of the Qing Dynasty Shoutao pills small dose group；5. how much dose group of Jenner；6. Jenner
More small dose groups；7. donepezil group.Compared with Normal group: #P < 0.05；Compared with model group: * P < 0.05, * * P <
0.01。
Influence (the 6th day) note of the palace of the Qing Dynasty Fig. 4 Shoutao pills to natural aging mice swimming escape latency: 1. young controls
Group；2.11 moon age group；3. palace of the Qing Dynasty Shoutao pills large dosage group；4. palace of the Qing Dynasty Shoutao pills small dose group；5. how much dose group of Jenner；6. gold medal
Receive more small dose groups；7. donepezil group.Compared with Normal group: #P < 0.05；Compared with model group: * P < 0.05, * * P <
0.01。
Influence of the Fig. 5 to natural aging mice model maincenter ACh content.
Influence of the Fig. 6 to natural aging mice model maincenter NE level.
Influence of the Fig. 7 to natural aging mice model maincenter 5-HT level.
Influence of the Fig. 8 to natural aging mice model maincenter AChE vigor.
Influence of the Fig. 9 to natural aging mice model maincenter SOD vigor.
Influence of the Figure 10 to natural aging mice model maincenter MDA content.
The area Figure 11 natural aging mice model maincenter CA1 histomorphological changes (HE dyeing, × 200).
Influence (the 1-4 days) of the palace of the Qing Dynasty Figure 12 Shoutao pills to APP/PS1 transgenic mice swimming path length.
Influence (the 1-4 days) of the palace of the Qing Dynasty Figure 13 Shoutao pills to APP/PS1 transgenic mice escape latency.
Influence (the 5th day) note of the palace of the Qing Dynasty Figure 14 Shoutao pills to APP/PS1 transgenic mice swimming path length: 1. brood lifes
Non-transgenic group；2.APP/PS1 double transgenic group；3. palace of the Qing Dynasty Shoutao pills large dosage group；4. palace of the Qing Dynasty Shoutao pills small dose group；5. gold medal
Receive multiple groups；6. donepezil group.Compared with Normal group: #P < 0.05；Compared with model group: P < 0.05 *.
Influence (the 5th day) note of the palace of the Qing Dynasty Figure 15 Shoutao pills to APP/PS1 transgenic mice escape latency: 1. brood lifes are non-
Transgenosis group；2.APP/PS1 double transgenic group；3. palace of the Qing Dynasty Shoutao pills large dosage group；4. palace of the Qing Dynasty Shoutao pills small dose group；5. gold medal
Receive multiple groups；6. donepezil group.Compared with Normal group: #P < 0.05；Compared with model group: P < 0.05 *.
Influence of the Figure 16 to APP/PS1 double transgenic mouse model maincenter ACh level.
Influence of the Figure 17 to APP/PS1 double transgenic mouse model maincenter NE level.
Influence of the Figure 18 to APP/PS1 double transgenic mouse model maincenter 5-HT level.
Influence of the Figure 19 to APP/PS1 double transgenic mouse model maincenter AChE vigor.
Influence of the Figure 20 to APP/PS1 double transgenic mouse model maincenter SOD vigor.
Influence of the Figure 21 to APP/PS1 double transgenic mouse model maincenter MDA content.
The area Figure 22 APP/PS1 bi-transgenic mice maincenter CA1 histomorphological changes (HE dyeing, × 200).
Influence (the 1-4 days) of the palace of the Qing Dynasty Figure 23 Shoutao pills to SAMP8 mouse swimming path length.
Influence (the 1-4 days) of the palace of the Qing Dynasty Figure 24 Shoutao pills to SAMP8 mouse escape latency.
Influence (the 5th day) note of the palace of the Qing Dynasty Figure 25 Shoutao pills to SAMP8 mouse swimming path length: 1. brood raw non-transgenics
Group；2. APP/PS1 double transgenic group；3. palace of the Qing Dynasty Shoutao pills large dosage group；4. palace of the Qing Dynasty Shoutao pills small dose group；5. Jenner's multiple groups；
6. donepezil group.Compared with Normal group: ##P < 0.01；Compared with model group: P < 0.01 * P < 0.05, * *.
Influence (the 5th day) note of the palace of the Qing Dynasty Figure 26 Shoutao pills to SAMP8 mouse escape latency: 1. brood raw non-transgenics
Group；2.APP/PS1 double transgenic group；3. palace of the Qing Dynasty Shoutao pills large dosage group；4. palace of the Qing Dynasty Shoutao pills small dose group；5. Jenner's multiple groups；
6. donepezil group.Compared with Normal group: #P < 0.05；Compared with model group: P < 0.01 * P < 0.05, * *.
Influence of the Figure 27 to SAMP8 mouse model maincenter ACh content.
Influence of the Figure 28 to SAMP8 mouse model maincenter NE content.
Influence of the Figure 29 to SAMP8 mouse model maincenter 5-HT level.
Influence of the Figure 30 to SAMP8 mouse model maincenter AChE vigor.
Influence of the Figure 31 to SAMP8 mouse model maincenter SOD vigor.
Influence of the Figure 32 to SAMP8 mouse model maincenter MDA content.
The CA 1 Zone of Hippocampus in Mouse Figure 33 SAMP8 histocyte morphological change (HE dyeing, × 200).
Specific embodiment
Influence and Mechanism Study of 1 palace of the Qing Dynasty Shoutao pills to natural aging mice ability of learning and memory
1.1 drugs and reagent
Palace of the Qing Dynasty Shoutao pills bulk pharmaceutical chemicals coarse powder, new medicine company is mentioned up to Ren Tang pharmaceutical factory in Tianjin, lot number: P004；Ginkgo leaf extracts
Object piece (standard Ginkgo biloda extract EGb 761, trade name: Ginkgo Leaf Agent), Dr Willmar Schwabe, lot number: 4181212；
Donepezil (Aricept): the packing of material (China) pharmaceutcal corporation, Ltd is defended in 10mg, the manufacture of French Peizer PGM company.Administration
Dosage is according to clinical, experiment document report and this room previous experiments result.
ACh, AChE enzyme-linked immunologic detecting kit: Bioengineering Research Institute is built up in Nanjing, lot number: 20150625,
20151023；MDA, SOD, protein assay kit: Bioengineering Research Institute is built up in Nanjing, lot number: 20150707,
20150706；Bioengineering Research Institute is built up in NE, 5-HT enzyme-linked immunologic detecting kit, Nanjing.Lot number: 20151118.
1.2 animals and grouping
57 mouse of natural aging mice MODEL C, 11 monthly ages, male.Purchased from Institute of Experimental Animals, Chinese Academy of Medical Sciences.
Quality certification number: SCXK (capital) 2011-0004.6 groups are randomly divided into, i.e. age group in March (seven young controls), age group in November is (close old
Year control group), donepezil group, Ginkgo Leaf Agent (EGb 761) large dosage of group, Ginkgo Leaf Agent (EGb 761) small dose group, palace of the Qing Dynasty peach offered as a birthday present
Ball 3.6g/kg group, palace of the Qing Dynasty Shoutao pills 1.8g/kg group.
All animal feedings and experiment are by " experimental animal feeding and guide for use " (China Academy of TCM Xiyuan doctor
Institute) it carries out.
1.3 instruments and equipment
Morris water maze: it is purchased from institute of Materia Medica,Chinese Academy of Medical Sciences；Full-automatic microplate reader: BioTeK company, beauty
State；Optical microscopy: BH-2 type, Olympus company, Japan；Pathologic image analysis instrument: HPIAS-1000 type, Zhong Ke company, in
State；Automation-tissue-dehydrating machine: TP1010 type；Tissue embedding machine: ZMN-7803 type；Rotary microtome: AS325 type, Shando
Company, Britain.
1.4 test method
1.4.1 to the influence of mouse Spatial memory ability
Before formal experiment, mouse is trained 1 time daily, continuous training 5 days.During trained and formal experiment, labyrinth External reference
Object remains unchanged.Training the previous day, by mouse head body portion stained yellow, to form sharp contrast with water, being easy to record a video is
System acquisition monitoring.Training Day by mouse towards pool wall into the water, training its find platform.Training time 120s.In 120s not
The person that finds platform, is led to platform, is allowed to 30s on standing table, generates memory.Formal experiment in 6th day, automatic video recording record system
System record mouse finds the time (swimming continuance time) of platform, swimming path length, while in determining search strategy, all quadrants
Swimming time and path etc..
1.4.2 to the influence of mouse cholinergic, monoaminergic nerve mediator and relevant enzyme
Sacrificed by decapitation after mouse administration, takes out rapidly maincenter on ice platform, weighs, and liquid nitrogen is rapidly frozen, -80 DEG C of preservations.It presses
Kit specification detects the content of ACh, AChE, NE and 5-HT in mouse maincenter.
1.4.3 to the influence of anti-oxidative ability of mice
Mouse sacrificed by decapitation, takes out rapidly maincenter on ice platform, the physiological saline cleaning of pre-cooling, after weighing plus physiological saline system
Standby 10% brain homogenate, -20 DEG C of preservations.By the activity and MDA content of SOD in each kit specification detection mouse maincenter.
1.4.4 to the influence of mouse tissue cytomorphology
Mouse broken end takes brain, sets fixed in 10% formalin, conventional to be dehydrated, waxdip, paraffin embedding, serial section, piece
It is 5 μm thick, the dyeing of Hematoxylin-eosin (hematoxylin-eosin, HE) method.Slice is randomly selected, observation is taken pictures, to brain skin
Layer, hippocampus carry out pathologic examination.
1.5 statistical analysis
Pharmacodynamic experiment counts special-purpose software with SPSS11.0, using One-Way ANOVA statistical method.Experimental result
With It indicates.P < 0.05 is statistically significant.
1.6 test result
1.6.1 to the influence of natural aging mice Spatial memory ability
Compared with young control, November, swimming continuance time of the age group mouse in Morris water maze (was escaped latent
Phase), swimming path length have it is significant extend (P < 0.05), search strategy is mostly marginal mode or random mode.Palace of the Qing Dynasty Shoutao pills are given
Medicine (3.6g/kg and 1.8g/kg) is after 9 weeks, swimming continuance time, path length and November age group ratio of the mouse in water maze
It is more obviously shortened (P < 0.05), search strategy significantly improves, mostly trend formula, even it is linear；Compared with age group in November,
Positive drug donepezil, the swimming continuance time of Ginkgo Leaf Agent 0.24g/kg, 0.12g/kg group mouse, path length obviously contract
Short (P < 0.05~0.01), search strategy is mostly linear, marginal mode and tends to formula；With donepezil, Ginkgo Leaf Agent 0.24g/kg
And 0.12g/kg group is compared, the main Swimming Achievements of water maze of palace of the Qing Dynasty Shoutao pills 3.6g/kg group mouse be not significantly different (P >
0.05).It the results are shown in Table 1, Fig. 1~4.
Influence (6th day) of the table 1 to natural aging mice model space ability of learning and memory
Note: #P < 0.05 compared with age group in March；P < 0.01 * P < 0.05 compared with age group in November, * *.
1.6.2 to the influence of cholinergic, monoaminergic nerve mediator and relevant enzyme
(1) to the influence of maincenter ACh level
Compared with young control, November, age group mouse maincenter ACh level had a decreasing trend, but not statistically significant (P >
0.05).After being administered 9 weeks, compared with age group mouse in November, positive drug donepezil and Ginkgo Leaf Agent, each dosage group of palace of the Qing Dynasty Shoutao pills
Mouse maincenter ACh content is without significant changes (P > 0.05)；Positive drug Jenner's multiple groups mouse maincenter ACh content have it is raised become
Gesture, but there was no significant difference (P > 0.05).It the results are shown in Table 2, Fig. 5.
Influence of the table 2 to natural aging mice model maincenter ACh content
(2) to the influence of monoamine neurotransmitters NE level
Compared with young control, the horizontal significantly raising (P < 0.05) of age group mouse maincenter NE in November.After being administered 8 weeks, with 3
Month age group mouse is compared, positive drug Ginkgo Leaf Agent 0.12g/kg group, palace of the Qing Dynasty Shoutao pills 3.6g/kg, 1.8g/kg group mouse maincenter NE water
Average significant raising (P < 0.05~0.01), and compared with age group mouse in November, palace of the Qing Dynasty Shoutao pills 1.6g/kg group mouse maincenter
The horizontal significant raising (P < 0.05) of NE；Positive drug donepezil and Ginkgo Leaf Agent's 0.24g/kg group mouse maincenter NE level have reduction
Trend, but there was no significant difference (P > 0.05).It the results are shown in Table 3, Fig. 6.
Influence of the table 3 to natural aging mice model maincenter NE levelUnit: μ g/L
Note: #P < 0.05 compared with sham-operation group, ##P < 0.01；P < 0.05 * compared with model group.
(3) to the influence of maincenter 5-HT level
Compared with young control, November, age group mouse maincenter 5-HT content was without significant changes (P > 0.05).Administration 9 weeks
Afterwards, compared with age group mouse in November, palace of the Qing Dynasty Shoutao pills 3.6g/kg group mouse maincenter 5-HT level significantly reduces (P < 0.05), sun
Property medicine donepezil and Jenner's multiple groups mouse are then without significant difference (P > 0.05).It the results are shown in Table 4, Fig. 7.
Influence of the table 4 to natural aging mice model maincenter 5-HT level
Note: P < 0.05 * compared with age group in November.
(4) to the influence of maincenter AChE vigor
Compared with young control, age group mouse maincenter AChE vigor in November significantly reduces (P < 0.05).After being administered 9 weeks,
Compared with age group mouse in November, positive drug donepezil group mouse maincenter AChE vigor has raising trend, but not statistically significant
(P > 0.05), Ginkgo Leaf Agent, palace of the Qing Dynasty Shoutao pills group mouse maincenter AChE vigor are without significant changes (P > 0.05).It the results are shown in Table 5, figure
8。
Influence of the table 5 to natural aging mice model maincenter AChE vigor
(5) to the influence of maincenter SOD vigor
Compared with young control, November, age group mouse maincenter SOD vigor was without significant changes (P > 0.05).After being administered 9 weeks,
Compared with age group mouse in November, positive drug donepezil, Ginkgo Leaf Agent and each administration group mouse maincenter SOD vigor of palace of the Qing Dynasty Shoutao pills
Without significant changes (P > 0.05).It the results are shown in Table 6, Fig. 9.
Influence of the table 6 to natural aging mice model maincenter SOD vigor
(6) to the influence of maincenter MDA content
Compared with young control, November, age group mouse maincenter MDA content was without significant changes (P > 0.05).After being administered 9 weeks,
Compared with age group mouse in November, positive drug donepezil, Ginkgo Leaf Agent 0.24g/kg, Ginkgo Leaf Agent 0.12g/kg, palace of the Qing Dynasty Shoutao pills
Each administration group mouse maincenter MDA content of 1.8g/kg, palace of the Qing Dynasty Shoutao pills 3.6g/kg has downward trend, wherein palace of the Qing Dynasty Shoutao pills
1.8g/kg group mouse MDA content, which significantly reduces (P < 0.05), the results are shown in Table 7, Figure 10.
Influence of the table 7 to natural aging mice model maincenter MDA content
Note: P < 0.05 * compared with age group in November.
(7) on the morphologic influence of hippocampal tissue
Under light microscopic as it can be seen that young control CA 1 Zone of Hippocampus in Mouse pyramidal cell dense arrangement, it is offline neat bright on cell
Aobvious, cell is plentiful；Nuclear membrane understands that kernel is high-visible.The arrangement of age group in November CA 1 Zone of Hippocampus in Mouse pyramidal cell is more loose,
The number of plies is reduced, and part eucaryotic cell structure is imperfect, it is seen that a few cell is lost；The shrinkage of respective cells core, deep dye, it is triangular in shape.With
November, age group was compared, in positive drug donepezil, Ginkgo Leaf Agent 0.24g/kg and palace of the Qing Dynasty Shoutao pills 3.6g/kg, 1.8g/kg group mouse
Pivot pyramidal cell level is relatively clear, and cellular morphology is improved in varying degrees；Karyopycnosis, deep dye degree mitigate.Wherein Ginkgo Leaf Agent
It is preferable with palace of the Qing Dynasty Shoutao pills 3.6g/kg group cell state.The result is shown in Figure 11.
Influence and Mechanism Study of 2 palace of the Qing Dynasty Shoutao pills to APP/PS1 double transgenic mouse model ability of learning and memory
2.1 drugs and reagent
Palace of the Qing Dynasty Shoutao pills bulk pharmaceutical chemicals coarse powder, new medicine company is mentioned up to Ren Tang pharmaceutical factory in Tianjin, lot number: P004；Ginkgo leaf extracts
Object piece (standard Ginkgo biloda extract EGb 761, trade name: Ginkgo Leaf Agent), Dr Willmar Schwabe, lot number: 4181212；
Donepezil (Aricept): the packing of material (China) pharmaceutcal corporation, Ltd is defended in 10mg, the manufacture of French Peizer PGM company.Administration
Dosage is according to clinical, experiment document report and this room previous experiments result.
ACh, AChE enzyme-linked immunologic detecting kit: Bioengineering Research Institute is built up in Nanjing, lot number: 20150625,
20151023；MDA, SOD, protein assay kit: Bioengineering Research Institute is built up in Nanjing, lot number: 20150707,
20150706；Bioengineering Research Institute is built up in NE, 5-HT enzyme-linked immunologic detecting kit, Nanjing.Lot number: 20151118.
2.2 animals and grouping
APP/PS1 bi-transgenic mice September age, half male and half female.Purchased from Institute of Experimental Animals, Chinese Academy of Medical Sciences.With
Machine is divided into 6 groups, i.e. non-transgenic group, blank group, donepezil group, Ginkgo Leaf Agent (EGb 761) group, palace of the Qing Dynasty Shoutao pills 3.6g/kg
Group, palace of the Qing Dynasty Shoutao pills 1.8g/kg group.
All animal feedings and experiment are by " experimental animal feeding and guide for use " (China Academy of TCM Xiyuan doctor
Institute) it carries out.
2.3 instruments and equipment
Morris water maze video tracking analysis system 2.0 is purchased from Chengdu TME Technology Co., Ltd.；Full-automatic enzyme mark
Instrument: BioTeK company, the U.S.；Optical microscopy: BH-2 type, Olympus company, Japan；Pathologic image analysis instrument: HPIAS-
1000 types, Zhong Ke company, China；Automation-tissue-dehydrating machine: TP1010 type；Tissue embedding machine: ZMN-7803 type；Rotation slice
Machine: AS325 type, Shando company, Britain.
2.4 test method
2.4.1 to the influence of mouse Spatial memory ability
Before formal experiment, mouse is trained 1 time daily, continuous training 4 days.During trained and formal experiment, labyrinth External reference
Object remains unchanged.Training the previous day, by mouse head body portion stained yellow, to form sharp contrast with water, being easy to record a video is
System acquisition monitoring.Training Day by mouse towards pool wall into the water, training its find platform.Training time 120s.In 120s not
The person that finds platform, is led to platform, is allowed to 30s on standing table, generates memory.Formal experiment in 5th day, automatic video recording record system
System record mouse finds the time (swimming continuance time) of platform, swimming path length, while in determining search strategy, all quadrants
Swimming time and path etc..
2.4.2 to the influence of mouse cholinergic, monoaminergic nerve mediator and relevant enzyme
Sacrificed by decapitation after mouse administration, takes out rapidly maincenter on ice platform, weighs, and liquid nitrogen is rapidly frozen, -80 DEG C of preservations.It presses
Kit specification detects the content of ACh, AChE, NE and 5-HT in mouse maincenter.
2.4.3 to the influence of anti-oxidative ability of mice
Mouse sacrificed by decapitation, takes out rapidly maincenter on ice platform, the physiological saline cleaning of pre-cooling, after weighing plus physiological saline system
Standby 10% brain homogenate, -20 DEG C of preservations.By the activity and MDA content of SOD in each kit specification detection mouse maincenter.
2.4.4 to the influence of mouse tissue cytomorphology
Mouse broken end takes brain, sets fixed in 10% formalin, conventional to be dehydrated, waxdip, paraffin embedding, serial section, piece
It is 5 μm thick, the dyeing of Hematoxylin-eosin (hematoxylin-eosin, HE) method.Slice is randomly selected, observation is taken pictures, to brain skin
Layer, hippocampus carry out pathologic examination.
2.5 statistical analysis
Pharmacodynamic experiment counts special-purpose software with SPSS11.0, using One-Way ANOVA statistical method.Experimental result
With It indicates.P < 0.05 is statistically significant.
2.6 test result
2.6.1 to the influence of APP/PS1 double transgenic mouse model Spatial memory ability
Compared with brood raw non-transgenic group mouse, swimming of the blank group transgenic mice in Morris water maze continues
Time, swimming path length have significant extension (P < 0.05), and search strategy is mostly marginal mode and random mode.With blank group ratio
Compared with (3.6g/kg) is administered after 8 weeks in palace of the Qing Dynasty Shoutao pills, and swimming continuance time of the mouse in water maze has shortening trend but without aobvious
It writes sex differernce (P>0.05), swimming path length and the obvious shortening (P<0.05) of blank group, search strategy is mostly trend formula；
Comparison medicine donepezil, the swimming continuance time of palace of the Qing Dynasty Shoutao pills (1.8g/kg) group mouse, swimming path length significantly shorten
There is trend formula in (P < 0.05), search strategy.It the results are shown in Table 8, Figure 12~15.
Influence of the table 8 to APP/PS1 double transgenic mouse model Spatial memory ability
Note: #P < 0.05 compared with non-transgenic group；P < 0.05 * compared with blank group.
2.6.2 to the influence of cholinergic, monoaminergic nerve mediator and relevant enzyme
(1) to the influence of maincenter ACh level
Compared with brood raw non-transgenic group, blank group transgenic mice maincenter ACh level significantly reduces (P < 0.05).It gives
After medicine 8 weeks, compared with blank group transgenic mice, the horizontal significantly raising of palace of the Qing Dynasty Shoutao pills 3.6g/kg group mouse ACh (P <
0.05)；Positive drug donepezil, Jenner's multiple groups mouse maincenter ACh content have raised trend, but there was no significant difference (P >
0.05).It the results are shown in Table 9, Figure 16.
Influence of the table 9 to APP/PS1 double transgenic mouse model maincenter ACh level
Note: #P < 0.05 compared with non-transgenic group；P < 0.05 * compared with transgenosis group.
(2) to the influence of monoamine neurotransmitters NE level
Compared with brood raw non-transgenic group, blank group transgenic mice maincenter NE level has decreasing trend, but without statistics
It learns meaning (P > 0.05).After being administered 8 weeks, compared with blank group transgenic mice, palace of the Qing Dynasty Shoutao pills 1.8g/kg group mouse NE water
Head up display, which writes, increases (P < 0.01)；Positive drug donepezil, Jenner's multiple groups are without significant changes (P > 0.05).It the results are shown in Table 10, figure
17。
Influence of the table 10 to APP/PS1 bi-transgenic mice maincenter NE level
Note: P < 0.01 * * compared with transgenosis group.
(3) to the influence of maincenter 5-HT level
Compared with brood raw non-transgenic group, blank group transgenic mice maincenter 5-HT level without significant changes (P >
0.05).After being administered 8 weeks, compared with brood raw non-transgenic group, palace of the Qing Dynasty Shoutao pills 3.6g/kg group significantly reduces (P < 0.01)；With
Blank group transgenic mice compares, and after palace of the Qing Dynasty Shoutao pills 3.6g/kg is administered 8 weeks, mouse 5-HT level significantly reduces (P < 0.05)；
Positive drug donepezil, Jenner's multiple groups mouse maincenter NE level have the tendency that reduction, but there was no significant difference (P > 0.05).Knot
Fruit is shown in Table 11, Figure 18.
Influence of the table 11 to APP/PS1 double transgenic mouse model maincenter 5-HT level
Note: ##P < 0.01 compared with non-transgenic group；P < 0.05 * compared with transgenosis group.
(4) to the influence of maincenter AChE vigor
Compared with brood raw non-transgenic group, blank group transgenic mice maincenter AChE vigor without significant changes (P >
0.05).After being administered 8 weeks, palace of the Qing Dynasty Shoutao pills 3.6g/kg group mouse maincenter AChE vigor and brood raw non-transgenic group, blank group
The more equal very significant of mouse increases (P < 0.01), and palace of the Qing Dynasty Shoutao pills 1.8g/kg and positive drug donepezil, Jenner's multiple groups are small
Mouse maincenter AChE vigor is without significant changes (P > 0.05).It the results are shown in Table 12, Figure 19.
Influence of the table 12 to APP/PS1 double transgenic mouse model maincenter AChE vigor
Note: ##P < 0.01 compared with non-transgenic group；P < 0.01 * * compared with transgenosis group.
(5) to the influence of maincenter SOD vigor
Compared with brood raw non-transgenic group, blank group transgenic mice maincenter SOD vigor is remarkably decreased (P > 0.01).It gives
After medicine 8 weeks, compared with brood raw non-transgenic group, palace of the Qing Dynasty Shoutao pills 3.6g/kg maincenter SOD vigor significantly increases (P < 0.01)；
Compared with blank group transgenic mice, positive drug Ginkgo Leaf Agent, palace of the Qing Dynasty Shoutao pills 3.6g/kg and 1.8g/kg group mouse maincenter SOD are living
Power is significantly raised (P<0.01), and positive drug donepezil group mouse maincenter SOD vigor is without significant changes (P>0.05).As a result see
Table 13, Figure 20.
Influence of the table 13 to APP/PS1 double transgenic mouse model maincenter SOD vigor
Note: ##P < 0.01 compared with non-transgenic group；P < 0.01 * * compared with transgenosis group.
(6) to the influence of maincenter MDA content
Compared with brood raw non-transgenic group, blank group transgenic mice maincenter MDA content is without significant changes (P > 0.05).
After being administered 8 weeks, compared with brood raw non-transgenic group, naive mice, positive drug donepezil, Ginkgo Leaf Agent and palace of the Qing Dynasty peach offered as a birthday present
Ball 3.6g/kg, 1.8g/kg group mouse maincenter MDA content is without significant changes (P > 0.05).It the results are shown in Table 14, Figure 21.
Influence of the table 14 to APP/PS1 double transgenic mouse model maincenter MDA content
(7) on the morphologic influence of hippocampal tissue
Under light microscopic as it can be seen that non-transgenic group CA 1 Zone of Hippocampus in Mouse pyramidal cell dense arrangement, it is offline neat bright on cell
Aobvious, cell is plentiful；Nuclear membrane understands that kernel is high-visible.The arrangement of APP/PS1 double transgenic group CA 1 Zone of Hippocampus in Mouse pyramidal cell
More loose, the number of plies is reduced, and part eucaryotic cell structure is imperfect, it is seen that a few cell is lost；The shrinkage of respective cells core, deep dye are in
Triangle.Compared with transgenosis group mouse, positive drug donepezil, Ginkgo Leaf Agent and palace of the Qing Dynasty Shoutao pills 3.6g/kg, 1.8g/kg group
Mouse maincenter pyramidal cell level is relatively neat, clear, and cellular morphology is improved in varying degrees；Karyopycnosis, deep dye degree mitigate.Its
Middle donepezil and palace of the Qing Dynasty Shoutao pills 3.6g/kg group cell integrality become apparent compared with the improvement of other administration groups.As a result see figure
22。
Influence and Mechanism Study of 3 palace of the Qing Dynasty Shoutao pills to SAMP8 mouse model ability of learning and memory
3.1 drugs and reagent
Palace of the Qing Dynasty Shoutao pills bulk pharmaceutical chemicals coarse powder, new medicine company is mentioned up to Ren Tang pharmaceutical factory in Tianjin, lot number: P004；Ginkgo leaf extracts
Object piece (standard Ginkgo biloda extract EGb 761, trade name: Ginkgo Leaf Agent), Dr Willmar Schwabe, lot number: 4181212；
Donepezil (Aricept): the packing of material (China) pharmaceutcal corporation, Ltd is defended in 10mg, the manufacture of French Peizer PGM company.Administration
Dosage is according to clinical, experiment document report and this room previous experiments result.
ACh, AChE enzyme-linked immunologic detecting kit: Bioengineering Research Institute is built up in Nanjing, lot number: 20150625,
20151023；MDA, SOD, protein assay kit: Bioengineering Research Institute is built up in Nanjing, lot number: 20150707,
20150706；Bioengineering Research Institute is built up in NE, 5-HT enzyme-linked immunologic detecting kit, Nanjing.Lot number: 20151118.
3.2 animals and grouping
SAMP8 mouse September age, half male and half female.Purchased from Institute of Experimental Animals, Chinese Academy of Medical Sciences.6 groups are randomly divided into,
That is SAMR group, SAMP8 group, donepezil group, Ginkgo Leaf Agent (EGb 761) group, palace of the Qing Dynasty Shoutao pills 3.6g/kg group, palace of the Qing Dynasty Shoutao pills
1.8g/kg group.
All animal feedings and experiment are by " experimental animal feeding and guide for use " (China Academy of TCM Xiyuan doctor
Institute) it carries out.
3.3 instruments and equipment
Morris water maze video tracking analysis system 2.0 is purchased from Chengdu TME Technology Co., Ltd.；Full-automatic enzyme mark
Instrument: BioTeK company, the U.S.；Optical microscopy: BH-2 type, Olympus company, Japan；Pathologic image analysis instrument: HPIAS-
1000 types, Zhong Ke company, China；Automation-tissue-dehydrating machine: TP1010 type；Tissue embedding machine: ZMN-7803 type；Rotation slice
Machine: AS325 type, Shando company, Britain.
3.4. test method
3.4.1 to the influence of mouse Spatial memory ability
Before formal experiment, mouse is trained 1 time daily, continuous training 4 days.During trained and formal experiment, labyrinth External reference
Object remains unchanged.Training the previous day, by mouse head body portion stained yellow, to form sharp contrast with water, being easy to record a video is
System acquisition monitoring.Training Day by mouse towards pool wall into the water, training its find platform.Training time 120s.In 120s not
The person that finds platform, is led to platform, is allowed to 30s on standing table, generates memory.Formal experiment in 5th day, automatic video recording record system
System record mouse finds the time (swimming continuance time) of platform, swimming path length, while in determining search strategy, all quadrants
Swimming time and path etc..
3.4.2 to the influence of mouse cholinergic, monoaminergic nerve mediator and relevant enzyme
Sacrificed by decapitation after mouse administration, takes out rapidly maincenter on ice platform, weighs, and liquid nitrogen is rapidly frozen, -80 DEG C of preservations.It presses
Kit specification detects the content of ACh, AChE, NE and 5-HT in mouse maincenter.
3.4.3 to the influence of anti-oxidative ability of mice
Mouse sacrificed by decapitation, takes out rapidly maincenter on ice platform, the physiological saline cleaning of pre-cooling, after weighing plus physiological saline system
Standby 10% brain homogenate, -20 DEG C of preservations.By the activity and MDA content of SOD in each kit specification detection mouse maincenter.
3.4.4 to the influence of mouse tissue cytomorphology
Mouse broken end takes brain, sets fixed in 10% formalin, conventional to be dehydrated, waxdip, paraffin embedding, serial section, piece
It is 5 μm thick, the dyeing of Hematoxylin-eosin (hematoxylin-eosin, HE) method.Slice is randomly selected, observation is taken pictures, to brain skin
Layer, hippocampus carry out pathologic examination.
3.5 statistical analysis
Pharmacodynamic experiment counts special-purpose software with SPSS11.0, using One-Way ANOVA statistical method.Experimental result
With It indicates.P < 0.05 is statistically significant.
3.6 test result
3.6.1 to the influence of SAMP8 mouse model Spatial memory ability
Compared with SAMR group mouse, swimming continuance time, swimming path length of the SAMP8 group mouse in Morris water maze
Degree significantly extends (P < 0.05~0.01), and search strategy is mostly marginal mode and random mode.Compared with SAMP8 group, palace of the Qing Dynasty peach offered as a birthday present
(3.6g/kg, 1.8g/kg) is administered after 8 weeks in ball, swimming continuance time, path length and SAMP8 group of the mouse in water maze
It is more obviously shortened (P < 0.05~0.01), search strategy is mostly trend formula, even linear；Comparison medicine donepezil and
The swimming continuance time of Jenner multiple groups mouse significantly shortens (P < 0.05~0.01), and trend formula, even straight occurs in search strategy
Wire type, but path length nothing of swimming significantly changes (P > 0.05).It the results are shown in Table 15, Figure 23~26.
Influence of the table 15 to SAMP8 mouse model Spatial memory ability
Note: #P < 0.05 compared with SAMR group, ##P < 0.01；P < 0.01 * P < 0.05 compared with SAMP8 group, * *.
3.6.2 to the influence of cholinergic, monoaminergic nerve mediator and relevant enzyme
(1) to the influence of maincenter ACh level
Compared with SAMR group mouse, SAMP8 group mouse maincenter ACh content has a decreasing trend, but not statistically significant (P >
0.05).After being administered 8 weeks, compared with SAMR, SAMP8 group, the horizontal significantly raising of positive drug donepezil group mouse maincenter ACh (P <
0.05~0.01)；Positive drug Ginkgo Leaf Agent, palace of the Qing Dynasty Shoutao pills (3.6g/kg, 1.8g/kg) group mouse maincenter ACh content become without significant
Change (P > 0.05).It the results are shown in Table 17, Figure 27.
Influence of the table 17 to SAMP8 mouse model maincenter ACh level
Note: #P < 0.05 compared with SAMR group；P < 0.01 * * compared with SAMP8 group.
(2) to the influence of monoamine neurotransmitters NE level
Compared with SAMR group mouse, the horizontal extremely significant reduction (P < 0.01) of SAMP8 group mouse maincenter NE.After being administered 8 weeks, with
SAMP8 group mouse is compared, the extremely significant raising (P < 0.01) of donepezil, Jenner multiple groups mouse NE level；Palace of the Qing Dynasty Shoutao pills
(3.6g/kg, 1.8g/kg) organizes the horizontal extremely significant reduction (P < 0.01) of mouse NE.It the results are shown in Table 18, Figure 28.
Influence of the table 18 to SAMP8 mouse maincenter NE level
Note: ##P < 0.01 compared with SAMR group；P < 0.01 * * compared with SAMP8 group.
(3) to the influence of maincenter 5-HT level
Compared with SAMR group mouse, SAMP8 group mouse maincenter 5-HT level is without significant changes (P > 0.05).After being administered 8 weeks,
Compared with SAMR group mouse, positive drug donepezil, Ginkgo Leaf Agent, each administration group mouse maincenter 5-HT level nothing of palace of the Qing Dynasty Shoutao pills
Significant difference (P > 0.05).It the results are shown in Table 19, Figure 29.
Influence of the table 19 to SAMP8 mouse model maincenter 5-HT level
(4) to the influence of maincenter AChE vigor
Compared with SAMR group mouse, the extremely significant raising (P > 0.01) of SAMP8 group mouse maincenter AChE vigor.After being administered 8 weeks,
Compared with SAMP8 group, positive drug donepezil, Jenner's multiple groups mouse maincenter AChE vigor are substantially reduced (P < 0.05)；The palace of the Qing Dynasty longevity
Peach ball (3.6g/kg, 1.8g/kg) organizes the extremely significant raising (P < 0.01) of mouse maincenter AChE vigor.It the results are shown in Table 20, Figure 30.
Influence of the table 20 to SAMP8 mouse model maincenter AChE vigor
Note: ##P < 0.01 compared with SAMR group；P < 0.01 * P < 0.05 compared with SAMP8 group, * *.
(5) to the influence of maincenter SOD vigor
Compared with SAMR group mouse, SAMP8 group mouse maincenter SOD vigor is without significant changes (P > 0.05).After being administered 8 weeks,
Compared with SAMP8 group mouse, positive drug donepezil, Jenner's multiple groups mouse maincenter SOD vigor without significant changes (P > 0.05),
Palace of the Qing Dynasty Shoutao pills (3.6g/kg) group mouse maincenter SOD vigor has raising trend, but there was no significant difference；With SAMR, SAMP8 group
Mouse is compared, and palace of the Qing Dynasty Shoutao pills (1.8g/kg) organize mouse maincenter SOD vigor and significantly increase (P < 0.05).It the results are shown in Table 21, figure
31。
Influence of the table 21 to SAMP8 mouse model maincenter SOD vigor
Note: #P < 0.05 compared with SAMR group；P < 0.05 * compared with SAMP8 group.
(6) to the influence of maincenter MDA content
Compared with SAMR group mouse, mouse maincenter MDA content is organized without significant change (P > 0.05).After being administered 8 weeks, with SAMR
Group compares, and positive drug donepezil group mouse maincenter MDA content significantly reduces (P < 0.05)；Compared with SAMP8 group mouse, the palace of the Qing Dynasty
Shoutao pills (1.8g/kg), donepezil, Jenner's multiple groups mouse maincenter MDA content have the tendency that reduction, but there was no significant difference
(P>0.05).It the results are shown in Table 22, Figure 32.
Influence of the table 7 to SAMP8 mouse model maincenter MDA content
Note: #P < 0.05 compared with SAMR group.
(7) on the morphologic influence of hippocampal tissue
Under light microscopic as it can be seen that SAMR group CA 1 Zone of Hippocampus in Mouse pyramidal cell dense arrangement, it is offline neat obvious on cell, carefully
Born of the same parents are plentiful；Nuclear membrane understands that kernel is high-visible.SAMP8 group mouse pyramidal cell obviously arranges loose, and part eucaryotic cell structure is endless
It is whole；The shrinkage of a few cell core, deep dye, it is triangular in shape；The clearly visible neuron loss in the area CA1.Compared with SAMP8 group, positive drug
Donepezil, Ginkgo Leaf Agent and each administration group hippocampus of mice pyramidal cell level of palace of the Qing Dynasty Shoutao pills are more visible, and cell arrangement is closer,
Cellular morphology is improved in varying degrees.Wherein Ginkgo Leaf Agent and palace of the Qing Dynasty Shoutao pills 3.6g/kg group effect are preferable.As a result see Figure 33.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (4)
1. palace of the Qing Dynasty Shoutao pills improve in preparation treatment recalls power decline, amnesia, the application in cognitive disorder drug.
2. palace of the Qing Dynasty Shoutao pills, by the intake and katabolism of adjusting monoamine neurotransmitters, improve maincenter in preparation treatment
The function of NE, 5-HT energy system, so as to improve the application in decrease of memory, amnesia, cognitive disorder drug.
3. palace of the Qing Dynasty Shoutao pills treat anti-oxidant by raising body and remove the ability of free radical in preparation, mitigation Cell membrane lipids
Peroxidating protects nerve cell, restores corresponding brain function, so as to improve answering in decrease of memory, amnesia, cognitive disorder drug
With.
4. palace of the Qing Dynasty Shoutao pills, by delaying or reducing the apoptosis of crucial brain area neuron, lose, protect its structure in preparation treatment
And function improves decrease of memory, amnesia, the application in cognitive disorder drug to easily change cynapse transmitting.
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| CN115887593A (en) * | 2022-11-22 | 2023-04-04 | 津药达仁堂集团股份有限公司达仁堂制药厂 | Application of Qinggong Shoutao pills in preparation of autoimmune regulation medicine |
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|---|---|---|---|---|
| CN102048990A (en) * | 2009-11-03 | 2011-05-11 | 天津中新药业集团股份有限公司达仁堂制药厂 | Quality control method for Chinese medicinal preparation Qinggong Shoutao pills |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102048990A (en) * | 2009-11-03 | 2011-05-11 | 天津中新药业集团股份有限公司达仁堂制药厂 | Quality control method for Chinese medicinal preparation Qinggong Shoutao pills |
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| 丛伟红: "老年抑郁共病老年性痴呆及古方清宫寿桃丸的相关研究", 《第二届国际抑郁共病暨第十二届中国中西医结合基础理论学术研讨会论文集》 * |
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| CN115887593A (en) * | 2022-11-22 | 2023-04-04 | 津药达仁堂集团股份有限公司达仁堂制药厂 | Application of Qinggong Shoutao pills in preparation of autoimmune regulation medicine |
| CN115887593B (en) * | 2022-11-22 | 2024-03-26 | 津药达仁堂集团股份有限公司达仁堂制药厂 | Application of qinggongshou peach pill in preparing medicine for regulating autoimmune property |
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