CN103181928B - Salicylic acid glucosides methyl is in prevention and/or the application for the treatment of Alzheimer - Google Patents
Salicylic acid glucosides methyl is in prevention and/or the application for the treatment of Alzheimer Download PDFInfo
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- CN103181928B CN103181928B CN201110448676.3A CN201110448676A CN103181928B CN 103181928 B CN103181928 B CN 103181928B CN 201110448676 A CN201110448676 A CN 201110448676A CN 103181928 B CN103181928 B CN 103181928B
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Abstract
The invention discloses class salicylic acid glucosides methyl compound as shown in logical formula (I) and isomer thereof the application in preparation prevention and/or treatment Alzheimer.
Description
Technical field
The present invention relates to salicylic acid glucosides methyl compound and isomer thereof preparation prevention and/or treatment Ah
Application in Alzheimer's disease；Belong to pharmaceutical technology field.
Background technology
Along with the quickening of China's the aging process of the society, aging population quantity is continuously increased.According to statistics, cut-off is extremely
The year two thousand twenty, China's aging level is up to 17.17%, and various senile disease patient numbers are the most in rising trend.?
Developed country, senile dementia becomes the fourth-largest dead killer being only second to cardiovascular diseases, cancer, apoplexy.
The specific medicament not yet having senile dementia prevention and cure at present is available, has therefore developed targeting, side effect
Little, can effectively control and the medicine of reverse disease is imperative.
Chinese invention patent application (denomination of invention: " and salicylic acid glucosides methyl compound, its synthetic method with
Purposes ", application number: 200910082224.0；Publication number CN101863934A；Publication date 2010-10-20 :)
In disclose a class salicylic acid glucosides methyl compound, disclose this compounds prepare antipyretic, antiinflammatory and
Application in analgesic.Application in its preparation prevention and/or treatment Alzheimer disease drugs is not disclosed.
Morris water maze laboratory and mice step-through test are to evaluate medicine senile dementia, particularly Alzheimer
One of important experiment that disease model learning and memory of little mouse improves.
Summary of the invention
The technical problem to be solved in the present invention is to provide the new prevention of a class and/or the medicine for the treatment of Alzheimer
Thing.
Specifically, described medicine is the salicylic acid glucosides methyl compound as shown in logical formula (I) and different
Structure body
R is selected from lactose, maltose.
Methyl salicylate lactoside, compound numbers DL0309
Methyl salicylate maltoside
In Morris water maze laboratory, mice escape latency is gradually shortened with the increase of frequency of training.With vacation
Operation group is compared, and A β group mice escape latency is obviously prolonged, and the escape latency that DL0309 respectively organizes is all
2 days and the 5th day have shortened, have had significant difference.Meanwhile, DL0309 is to mice swimming distance (centimetre)
Impact the most clearly, learning and memory the 1-5 days, compare with A β model group, treatment group swimming distance
All having substantially shortening, high dose group effect becomes apparent from.Illustrate that DL0309 is to Senlie dementia model mice study note
Recall the effect of being significantly improved.
In mice step-through test, compared with sham operated rats, the incubation period of A β model group mice substantially shortens.
DL0309 each treatment group is compared with A β model group, and incubation period is obviously prolonged.Illustrate that DL0309 is to senile dementia
Model mice learning and memory is significantly improved effect.
Term and abbreviation:
Sham: sham operated rats
Detailed description of the invention
Embodiment 1. salicylic acid glucosides methyl (DL0309) improves mice Alzheimer learning and memory Morris water
Maze experiment
Morris water maze laboratory be drug evaluation Senlie dementia model learning and memory of little mouse improve important experiment it
One.
1. laboratory animal, instrument and medicine and reagent
Male mice in kunming, body weight 18-22g, Chinese Academy of Medical Sciences's Institute of Botany provide.Freely take the photograph
Food drinking-water, room temperature 23-27 DEG C, relative humidity 55-65%, aeration-drying, peace and quiet, 12 hours periodicity of illuminations.
Step-through test device is provided by institute of Materia Medica,Chinese Academy of Medical Sciences.A β needed for modeling1-42, positive drug Ah Si
Woods is purchased from Sigma company.
2. experimental design and animal packet
Experimental design: laboratory animal operation is forward and backward conventional raises, and room temperature keeps 23～25 DEG C, ad lib, enters
Water.Laboratory animal is randomly divided into sham operated rats, model group, positive drug group, treatment (high, medium and low dosage)
Group, laboratory animal treatment group intracerebroventricular injection A β1-42Manufacture Alzheimer disease model, sham operated rats injection physiology
Saline, performs the operation and starts the last week to be administered, and Post operation continues to be administered 2 weeks for second day.
Animal is grouped: mice operation consent carries out random packet；
Coagulation state A β1-42Preparation: by A β1-42It is dissolved in physiological saline solution, is configured to the storing solution of 1mM,
It is placed in CO2Incubator is hatched 96h, makes the A β of coagulation state1-42；
Sham operated rats (sham group), intracerebroventricular injection physiological saline solution, Post operation 24h gavage gives physiology
Saline；
Model group, intracerebroventricular injection aseptic 9nmol A β1-42, Post operation 24h gavage gives normal saline；
DL0309 treatment group, intracerebroventricular injection aseptic 9nmol A β1-42, Post operation 24h gastric infusion, continuously
Being administered 2 weeks, DL0309 pharmaceutical quantities is 75mg/kg, 150mg/kg, 300mg/kg；
Aspirin positive drug group, intracerebroventricular injection aseptic 9nmol A β1-42, Post operation 24h gastric infusion,
Successive administration 2 weeks, dosage is 100mg/kg.
(note: medicine and positive control drug all configure with normal saline.)
3.Aβ1-42Intracerebroventricular injection causes the preparation of Alzheimer mouse model
With 0.4% pentobarbital sodium anesthetized mice, mice is fixed on position finder, cuts off head skin, wine
Essence cotton rub is wiped, and exposes bregma.Employing ventriculus dexter cerebri positions, and from bregma backward 0.2～0.5mm, opens by sagittal suture
At 1.0mm, it is the body surface of tricorn.Wearing an aperture with microsyringe in this position, the degree of depth is cranium
At bone surface downward 2.5～3mm, every mice injects 3 μ l A β with 2 μ l/min constant speed1-42(3μmol/L).Raw
Reason saline group mice is injected 3 μ l normal saline and replaces A β1-42.Postoperative 24h starts to give respectively Drug therapy, presses
Every day every mice 0.1ml medicinal liquid gavage, saline control group is 0.1ml normal saline.
4.Morris water maze laboratory
Mice Spatial memory ability is detected by Morris water maze video frequency following system, this system by
Round pool, automatic camera and analysis system composition.Experiment is carried out under quiet environment, position, pond, light source
Position and each experimental site of experimenter keep the experiment condition such as constant all to keep constant.Mice swimming pond is average
Being divided into four quadrants (NE, NW, SE, SW), platform is put in SE quadrant central authorities, diameter 80cm, the depth of water
25cm, the water surface is higher than half space about 1cm, and water temperature controls at 22 ± 2 DEG C.Each group mice is trained 2 times every day,
Totally 5 days.During 1d training, selective calling platform opposite and adjacent quadrants are location into the pool, and mice is placed in quadrant edge
At 1/2 radian, head enters water towards pool wall, in recording 60 seconds mice find platform required time (i.e. escape latency,
Escape latency) and swimming distance (cm).The person that do not found platform through 60 seconds, is led to platform, is put
Putting 15 seconds, guide it to learn, escape latency is recorded as 60 seconds.Repeats to operate as above, by each group for 2-5 days
Mice escape latency and swimming distance of the 2-5 days in Morris water maze is tested are learned as weighing its space
The index of habit ability.
5. result
Two-way analysis of variance result shows, mice escape latency is gradually shortened with the increase of frequency of training.With
Sham operated rats is compared, and A β group mice escape latency is obviously prolonged, and is shown in Table 1,##P ＜ 0.01vs.sham), DL0309
The escape latency of each group has all shortened at the 2nd day and the 5th day, have significant difference (*P ＜ 0.05,**P ＜ 0.01,***P ＜ 0.001vs.A β).Meanwhile, DL0309 on mice swimming distance (centimetre) impact also
Clearly, being shown in Table 2, learning and memory the 1-5 days, compare with A β model group, treatment group swimming distance is all
Having substantially shortening, high dose group effect becomes apparent from.
The table 1DL0309 impact on learning and memory of little mouse water maze laboratory escape latency
Note: data carries out variance analysis, with mean ± SEM, n=10,##P ＜ 0.01vs. sham operated rats,*P ＜ 0.05,**P ＜ 0.01,***P ＜ 0.001vs.A β model group.
The table 2DL0309 impact on learning and memory of little mouse water maze laboratory swimming time
Note: data carries out variance analysis, with mean ± SEM, n=10, ##P ＜ 0.01vs sham operated rats,*P ＜ 0.05,**P ＜ 0.01,***P ＜ 0.001vs.A β
Model group.
Embodiment 2. salicylic acid glucosides methyl (DL0309) improves mice Alzheimer learning and memory step-through test
Mice step-through test is the important experiment side investigating senile dementia, particularly Alzheimer learning and memory
One of method.
1. laboratory animal, instrument and medicine and reagent
Male mice in kunming, body weight 18-22g, Chinese Academy of Medical Sciences's Institute of Botany provide.Freely take the photograph
Food drinking-water, room temperature 23-27 DEG C, relative humidity 55-65%, aeration-drying, peace and quiet, 12 hours periodicity of illuminations.
Step-through test device is provided by institute of Materia Medica,Chinese Academy of Medical Sciences.A β needed for modeling1-42, positive drug Ah Si
Woods is purchased from Sigma company.
2. experimental design and animal packet
Experimental design: laboratory animal operation is forward and backward conventional raises, and room temperature keeps 23～25 DEG C, ad lib, enters
Water.Laboratory animal is randomly divided into sham operated rats, model group, positive drug group, treatment (high, medium and low dosage)
Group, laboratory animal treatment group intracerebroventricular injection A β1-42Manufacture Alzheimer disease model, sham operated rats injection physiology
Saline, performs the operation and starts the last week to be administered, and Post operation continues to be administered 2 weeks for second day.
Animal is grouped: mice operation consent carries out random packet；
Coagulation state A β1-42Preparation: by A β1-42It is dissolved in physiological saline solution, is configured to the storing solution of 1mM,
It is placed in CO2Incubator is hatched 96h, makes the A β of coagulation state1-42；
Sham operated rats (sham group), intracerebroventricular injection physiological saline solution, Post operation 24h gavage gives physiology
Saline；
Model group: intracerebroventricular injection aseptic 9nmol A β1-42, Post operation 24h gavage gives normal saline；
DL0309 treatment group: intracerebroventricular injection aseptic 9nmol A β1-42, Post operation 24h gastric infusion, continuously
Being administered 2 weeks, DL0309 pharmaceutical quantities is 75mg/kg, 150mg/kg, 300mg/kg；
Aspirin positive drug group: intracerebroventricular injection aseptic 9nmol A β1-42, Post operation 24h gastric infusion,
Successive administration 2 weeks, dosage is 100mg/kg.
(note: reactive compound and positive control drug all configure with normal saline.)
3.Aβ1-42Intracerebroventricular injection causes the preparation of Alzheimer mouse model
With 0.4% pentobarbital sodium anesthetized mice, mice is fixed on position finder, cuts off head skin, wine
Essence cotton rub is wiped, and exposes bregma.Employing ventriculus dexter cerebri positions, and from bregma backward 0.2～0.5mm, opens by sagittal suture
At 1.0mm, it is the body surface of tricorn.Wearing an aperture with microsyringe in this position, the degree of depth is cranium
At bone surface downward 2.5～3mm, every mice injects 3 μ l A β with 2 μ l/min constant speed1-42(3μmol/L).Raw
Reason saline group mice is injected 3 μ l normal saline and replaces A β1-42.Postoperative 24h starts to give respectively Drug therapy, presses
Every day every mice 0.1ml medicinal liquid gavage, saline control group is 0.1ml normal saline.
4. step-through test
Step-through test device is divided into light and shade two Room, has the circular hole of an a diameter of 3cm size, at the bottom of darkroom between two Room
Portion's copper grid connect electricity.First mice is put into during training in reaction chamber adaptation 3min, then darkroom base copper grid lead to 40V,
50Hz alternating current.Mice is put into bright room back to hole, and mice enters darkroom and is then shocked by electricity.Keep away dark during training
Incubation period is discarded more than 180s person.Again mice is put into after 24h bright room, enters for the first time in record 5min
Enter the time (incubation period) in darkroom.If mice is still introduced into darkroom during 5min, it is designated as 300s incubation period.
5. result
Compared with sham operated rats, the incubation period of A β model group mice substantially shortens, and is shown in Table 3,#P ＜ 0.01vs. does evil through another person
Art group).Reactive compound each treatment group compared with A β model group, be obviously prolonged incubation period (*P ＜ 0.01,**P ＜ 0.05
Vs.A β model group).
The table 3.DL0309 impact on learning and memory of little mouse swimming step-through test latent time
Claims (1)
1. salicylic acid glucosides methyl compound and isomer thereof as shown in logical formula (I) treat Alzheimer in preparation
Application in medicine
R is selected from lactose, maltose.
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| CN108239126B (en) * | 2016-12-26 | 2021-07-06 | 中国医学科学院药物研究所 | Salicylic acid methyl ester lactoside crystal III type solid matter, preparation method, composition and application thereof |
| CN112915109B (en) * | 2021-01-21 | 2023-03-24 | 吉林省农业科学院 | Application of lactobacillus plantarum DP189 in preparation of medicine for preventing and/or treating Alzheimer disease |
| CN112915108B (en) * | 2021-01-21 | 2022-08-02 | 吉林省农业科学院 | Application of bacillus coagulans JA845 in preparation of medicines for preventing and/or treating Alzheimer disease |
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| CN101863934A (en) * | 2009-04-20 | 2010-10-20 | 中国医学科学院药物研究所 | Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof |
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| CN101863934A (en) * | 2009-04-20 | 2010-10-20 | 中国医学科学院药物研究所 | Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof |
Non-Patent Citations (1)
| Title |
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| NSAIDs and Alzheimer’s disease: how far to generalise from trials?;John CS Breitner;《THE LANCET Neurology》;20030930;第2卷;最左栏最后一段 * |
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