CN110721190A - Medicine for preventing and treating senile dementia - Google Patents
Medicine for preventing and treating senile dementia Download PDFInfo
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- CN110721190A CN110721190A CN201911148473.5A CN201911148473A CN110721190A CN 110721190 A CN110721190 A CN 110721190A CN 201911148473 A CN201911148473 A CN 201911148473A CN 110721190 A CN110721190 A CN 110721190A
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- 150000001875 compounds Chemical class 0.000 claims abstract description 49
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- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a medicine for preventing and treating senile dementia. The research of the invention shows that the compound shown in the formula I can inhibit the activity of acetylcholinesterase and butyrylcholinesterase and can protect nerve cells. Therefore, the compound can be used for preparing food and/or medicines for treating and/or preventing senile dementia. The compound is derived from medicinal fungus inonotus obliquus, has small side effect, and shows no physiological toxicity after being perfused by 10 times of dosage.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a medicine for preventing and treating senile dementia.
Background
With the progress of society and the improvement of living standard of people, the service life of people is longer and longer. However, the incidence of some high-grade diseases such as neurodegenerative diseases is also increasing year by year. Senile dementia, also known as Alzheimer's Disease (AD), is one of the degenerative diseases, which is mainly manifested by deterioration of brain function, such as decline in learning and memory, impairment of visual spatial function (a condition in which patients are prone to getting lost), and transformation of characters (apathy or dysphoria). With the increasing life expectancy of humans, AD has become one of the leading causes of death in developed countries. In developing countries, as the population ages, the proportion of AD patients also increases year by year, placing a great burden on the families and society. The main purposes of the drug therapy are to delay or prevent the worsening of dementia, improve the daily living ability of patients and reduce complications, thereby improving the quality of life and prolonging the survival time. The medicines used for treatment at present are mainly cholinesterase inhibitors, such as donepezil hydrochloride, tacrine, rivastigmine and the like. Although effective, these drugs have great side effects. For example, tacrine is a non-selective reversible choline enzyme inhibitor, which can penetrate through a blood brain barrier to enter the brain after being taken orally, and has obvious effect on treating or delaying the disease condition. But the bioavailability is low, the individual absorption difference is large, the curative effect fluctuation is large, the toxicity of the medicine is large, and some patients cannot accept effective treatment dose.
The separation and purification of compounds from Chinese medicinal materials has been successful in the treatment of senile dementia. For example, huperzine A is an alkaloid extracted from huperzine serrate of family huperziaceae, is a reversible cholinesterase inhibitor, has effects of promoting memory reproduction and enhancing memory retention, and has high oral activity, long action time and little side effect.
Inonotus obliquus (Fr) Pilat, also called Inonotus obliquus, is mainly grown under the bark of white birch, silver birch, elm and alder, or under the bark of living tree or on the withered trunk of felled tree. Research shows that the composition has the effects of treating gastrointestinal diseases, helping tumor recovery, resisting oxidation, reducing high blood pressure, high blood fat and high blood sugar and the like. However, no effect on the prevention and treatment of AD has been found yet.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a drug for preventing and treating senile dementia, wherein the compound of formula I is derived from medicinal fungus inonotus obliquus, can effectively inhibit key enzymes, protect nerve cells, improve memory of model animals, has an effect of preventing and treating senile dementia, and has good safety.
The invention provides an application of a compound shown in a formula I in preparation of an acetylcholinesterase and/or butyrylcholinesterase activity inhibitor;
the invention also provides the use of a compound of formula I for the preparation of a formulation for protecting neuronal cells;
in embodiments of the invention, the protecting the neural cell is protecting the neural cell under oxidative conditions.
In a particular embodiment, the oxidation is hydrogen peroxide induced oxidation.
In an embodiment of the invention, the neural cell is a human bone marrow neuroblast.
In particular embodiments, the compounds of formula I are used to demonstrate activity in human bone marrow neuroblastoma cells. The specific cell line is SH-SY 5Y.
The invention also provides application of the compound in the formula I in preparing a medicament for preventing and/or treating Alzheimer's disease;
in the present invention, the prevention and/or treatment includes improvement of learning ability.
The improvement of learning ability comprises the improvement of animal positioning navigation ability and/or the improvement of animal space exploration ability. In the present invention, the animal used to verify the efficacy of the compound of formula I is a mouse, in particular a rat.
In the embodiment of the invention, the Alzheimer's disease is Alzheimer's disease caused by oxidation.
In some embodiments, the oxidation-induced alzheimer's disease is alzheimer's disease caused by D-galactose.
The invention also provides a medicament for preventing and treating Alzheimer's disease, which comprises a compound shown in the formula I;
in the invention, the preparation method of the compound of the formula I comprises the following steps:
step 1: pulverizing Fuscoporia obliqua fruiting body, extracting with ethanol water solution with volume fraction of not less than 95% for 3 times, filtering the obtained extract, mixing, and concentrating to obtain extract A;
step 2: adding water into the extract A to prepare suspension, sequentially extracting with petroleum ether and ethyl acetate, and concentrating the ethyl acetate extract to prepare an extract B;
and step 3: passing the extract B through a reduced pressure column, and performing gradient elution by using a mixed solution of petroleum ether and ethyl acetate and a mixed solution of chloroform and methanol to obtain 20 fractions which are marked as Fr.1-Fr.20;
and 4, step 4: combining Fr.6 and Fr.7, passing through a reverse phase column, and performing gradient elution by using 50-100% methanol aqueous solution to obtain 25 flow portions which are marked as Fr. (6, 7) -1-Fr. (6, 7) -25;
and 5: from Fr. (6, 7) -22, through a common silica gel column, the mixture was purified by mixing with petroleum ether: gradient elution is carried out on the mixed solution of ethyl acetate to obtain 17 parts, which are marked as Fr (6, 7) -22-1-Fr (6, 7) -22-17;
step 6: and (5) combining the Fr. (6, 7) -22-13-Fr. (6, 7) -22-14, and crystallizing to obtain the compound of the formula I.
In the invention, the medicine also comprises pharmaceutically acceptable auxiliary materials.
The pharmaceutically acceptable adjuvants comprise one or more of fruit powder, edible essence, sweetener, sour agent, bulking agent, lubricant, antiseptic, suspending agent, edible pigment, diluent, emulsifier, disintegrating agent or plasticizer.
Preferably, the medicament is an oral formulation. Preferably, the dosage form is tablet, capsule, pill, granule, decoction, ointment, distillate, oral liquid, drop pill or syrup.
More preferably, the capsule is a hard capsule or a soft capsule. More preferably, the tablet is an oral tablet or buccal tablet. More preferably, oral tablets refer to tablets intended for oral administration, most of which are those in which the drug is absorbed through the gastrointestinal tract to act, and some of which are those in which the drug is locally present in the gastrointestinal tract. In some embodiments provided herein, the oral tablet is a compressed tablet, a dispersible tablet, an effervescent tablet, a chewable tablet, a coated tablet, or a sustained release tablet.
The invention also provides a method for treating Alzheimer's disease, which is to administer the medicament.
The research of the invention shows that the compound shown in the formula I can inhibit the activity of acetylcholinesterase and butyrylcholinesterase and can protect nerve cells. Therefore, the compound can be used for preparing food and/or medicines for treating and/or preventing senile dementia. The compound is derived from medicinal fungus inonotus obliquus, has small side effect, and shows no physiological toxicity after being perfused by 10 times of dosage.
Detailed Description
The invention provides a medicine for preventing and treating senile dementia, and a person skilled in the art can use the contents to reference the text and properly improve the process parameters to realize the purpose. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The test materials adopted by the invention are all common commercial products and can be purchased in the market.
The invention is further illustrated by the following examples:
examples
1. Preparation of the Compounds
Pulverizing Inonotus obliquus fruiting body into powder, extracting with 95% ethanol water solution for 3 times, filtering the obtained extractive solution, mixing, and concentrating to obtain extract. Adding water, stirring to obtain suspension, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, and extracting the extractive layers until the extractive solution is colorless. Evaporating and concentrating each extraction layer to prepare extract for later use.
Taking ethyl acetate layer extract, passing through a reduced pressure column (silica gel H), adopting petroleum ether: ethyl acetate (1:0 → 1:1) → chloroform: methanol (20:1 → 0:1) system gradient elution, and the fractions obtained are respectively concentrated and combined on a plate to obtain 20 fractions (Fr.1-Fr.20).
From these, Fr.6 and Fr.7 were combined (17.086g) and passed through a reverse phase column and eluted with a gradient of 50% to 100% methanol in water to give 25 fractions (Fr. (6, 7) -1-Fr. (6, 7) -25). Fr. (6, 7) -22 was passed through a general silica gel column (petroleum ether: ethyl acetate: 100:1 to 4:1) to obtain 17 fractions (Fr. (6, 7) -22-1 to Fr. (6, 7) -22-17). Wherein (Fr. (6, 7) -22-13-Fr. (6, 7) -22-14) are combined and washed to obtain the compound shown in the formula I:
2. inhibition of key enzymes of alzheimer's disease by compounds of formula I
2.1 inhibitory Activity of Compounds on Acetylcholinesterase
Preparing a sample solution to be detected: 675 mu L of prepared PBS solution (pH is 8.0) is taken to be placed in an EP tube, after a compound to be detected is dissolved in DMSO (the concentration is 1mM), 45 mu L of the solution is taken to be added into the EP tube, finally 90 mu L of 0.2U/mL acetylcholinesterase solution is absorbed, shaking is carried out, and 180 mu L of the uniformly mixed solution to be detected is respectively taken 4 times to be placed in a 96-well plate; (negative and blank: 675. mu.L of the prepared PBS solution was put in an EP tube, 45. mu.L of the DMSO solution was put in the EP tube, 90. mu.L of the acetylcholinesterase solution was finally aspirated, shaken up, and 180. mu.L of the well-mixed solution to be assayed was put in a 96-well plate 4 times each time)
After the 96-well plate was left at 37 ℃ for 15 minutes, 20. mu.L (10mM) AICI (iodothioacetyl choline) + 10. mu.L (2mM) DTNB (5,5' -dithio-bis-2-nitrobenzoic acid)) of the substrate was added to each group; (blank: Add 10. mu.L PBS + 10. mu.L (1mM) DTNB) solution)
After the 96-well plate was left at 37 ℃ for 30 minutes, the OD value absorbance of each well was measured at a wavelength of 412nm with a microplate reader.
The inhibitory activity of the compound on acetylcholinesterase is calculated according to the following formula:
inhibition rate (OD)DMSO-ODSample (A))/(ODDMSO-ODPBS)×100％
After the compound is diluted by several times of gradients, the inhibition rate of acetylcholinesterase of samples with different concentrations is detected by the same detection method, and the IC50 value of the sample is calculated by utilizing GraphPad Prism 7 software.
2.2 inhibitory Activity of Compounds on butyrylcholinesterase
The preparation and detection methods of the sample solution to be detected and the calculation method of the enzyme activity are the same as the above, and the acetylcholinesterase is changed into butyrylcholinesterase.
As shown in Table 1, the compounds have inhibitory activities to both acetylcholinesterase and butyrylcholinesterase to some extent, and among them, Compound 2 has the strongest inhibitory activity.
Inhibitory Activity of the Compounds of Table 1 on Acetylcholinesterase and Butyrylcholinesterase
3. Neuroprotective detection method
SH-SY5Y (human bone marrow neuroblastoma cell line) cells were selected and inoculated on a 96-well flat-bottomed cell culture plate at 100. mu.L concentration of 5X 104cells/mL, cultured at 37 ℃ in 5% CO2Adding 100 μ L of prepared compound solution to be tested (final concentration 40 μ M) after 24H under the condition of humidity above 90%, culturing under the condition, adding 50 μ L of diluted H after 5H2O2(final concentration: 1000. mu.M) solution, 20. mu.L of 5mg/mL MTT solution was added to each well after 3 hours, the supernatant was aspirated after 4 hours of reaction, and 100. mu.L DMSO was added to each well to dissolve it sufficiently. Measuring and recording the absorbance of each hole under the 490nm wavelength of a microplate reader, and calculating the growth inhibition rate of the tumor cells according to the following formula. The control group is indomethacin, the negative control group is DMSO, and the test compound is half-diluted for 6 concentration gradients. The concentration of the test compound is shown on the abscissa and the inhibition ratio is shown on the ordinate, andplotting IC of test Compounds50The value is obtained. The results are shown in Table 2, the compound can promote the proliferation of SH-SY5Y nerve cells, and the effect is obviously better than that of positive control vitamin E.
TABLE 2 protection of SH-SY5Y by compounds
Morris Water maze experiment
70 SPF grade healthy adult SD rats, with body mass (220+20) g, half male and half female, were purchased from the laboratory animal center, university of Hainan medical college. After 1 week of standard acclimatization, the Morris water maze test culling response was either too slow (no platform found within 2 min) or sensitive (platform found within 10 s) rats selected 50 rats were randomly divided into a blank group, a model group, a compound lower and higher 2 dose group and a positive drug tacrine control group, 10 rats each.
The groups were treated as follows:
model group: injecting D-galactose 120mg/kg into abdominal cavity of rat once a day for 6 weeks continuously to construct dementia model;
blank group: injecting equal amount of physiological saline into the rat subcutaneously;
tacrine group: rats were injected intraperitoneally with 120mg/kg of D-galactose once a day for 6 consecutive weeks. Performing intragastric administration on tacrine group from the first day, wherein the doses are 1 time/d and 5mg/kg, and the continuous period is 8 weeks;
low dose group of compounds of formula I: rats were injected intraperitoneally with 120mg/kg of D-galactose once a day for 6 consecutive weeks. Gavage 50mg/kg of compound from the first day, 1 time/day for 8 weeks;
a high dose group of compounds of formula I: rats were injected intraperitoneally with 120mg/kg of D-galactose once a day for 6 consecutive weeks. Gavage 72mg/kg of compound starting on day one 1/d for 8 weeks;
the groups were fed normal diet, and in order to maintain the experimental conditions consistent, both the blank and model groups were gavaged with an equal dose of isotonic saline (equal to the dose of the compound gavage solution) daily for 8 weeks.
After 8 weeks of treatment, a water maze experiment was performed, which consisted of two major parts, a circular pool (diameter 120cm, height 50cm) and a platform (movable position, diameter 10cm, height 22 cm). The outer surface of the water pool is provided with a support and shading cloth is arranged outside the support to prevent interference of external light, personnel and the like. The temperature of water in the water pool rises to about 23 ℃, the platform is placed in the center of a quadrant of the circular water pool, and the water level is 1cm higher than that of the platform. The placing positions of space reference objects such as articles and the like are kept fixed in the testing process so as to eliminate interference factors.
① location navigation experiment (place navigation) is used for reflecting the learning ability of the rat, training the rat for 5 consecutive days, keeping the fixed reference object around the water pool unchanged, putting the rat into the water pool from four water entry points of the water pool in the northeast, southeast, northwest and southwest every day, the rat can not face the platform, the computer automatically stores the time for the rat to climb up the platform, namely the Escape Latency (EL), if the rat does not find the platform within one minute, the rat is induced to climb up the platform by a stick type object, and the rat has two minutes of rest time in the middle of continuous swimming.
② spatial Probe test the sixth day of the experiment the memory ability of the rat was removed from the platform, the rat was returned to the pool from the original platform position, and the number of platforms the rat crossed was recorded (we should keep dark and quiet the reference position unchanged during the behavioural test)
The results are shown in table 3, the escape latency of rats becomes shorter and shorter with the training time, and the escape latency of rats on the fourth and fifth days of the localized voyage experiment is significantly lower in both tacrine and compound dose groups than in the model group. The number of platform crossings by rats in the tacrine group and each dose group of compound was also significantly higher on day six than in the model group. The three compounds are shown to enhance the learning and memory ability of rats.
Table 3 effect of compounds on escape latency and number of platform crossings in rats: (
n＝10)
Significant differences from the model group, p <0.05
5. Safety test
The compound is administrated to mice once, the dose is 720mg/kg, and the compound has no influence on diet and behavior, so the compound has little acute toxicity and is safe to take orally. The rats in the administration group had good hair luster and mental state, were fed with water normally, and began to increase body weight continuously after one week of administration. Indicating that the three compounds can be safely used within the effective dosage range.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Claims (10)
1. The use of a compound of formula I for the preparation of an inhibitor of acetylcholinesterase and/or butyrylcholinesterase activity;
2. the use of a compound of formula I for the preparation of a preparation for protecting neuronal cells;
3. the use of claim 2, wherein the protecting of the neural cell is protecting the neural cell under oxidative conditions.
4. The use of claim 2 or 3, wherein the neural cell is a human bone marrow neuroblast.
5. The application of the compound in the formula I in preparing the medicine for preventing and/or treating the Alzheimer disease;
6. use according to claim 5, wherein the prevention and/or treatment comprises an improvement in learning ability.
7. The use according to claim 6, wherein said improving learning capabilities comprises improving positioning voyage capabilities and/or improving space exploration capabilities.
8. The use according to any one of claims 5 to 7, wherein the Alzheimer's disease is oxidation-induced Alzheimer's disease.
9. Use according to claim 8, wherein the oxidation is caused by D-galactose.
10. A medicament for preventing and treating Alzheimer's disease, which is characterized by comprising a compound shown in a formula I;
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| CN112972654A (en) * | 2021-03-05 | 2021-06-18 | 温州医科大学慈溪生物医药研究院 | Application of FGF21 in preparation of medicine for treating cranial nerve injury |
| CN113956320A (en) * | 2021-10-22 | 2022-01-21 | 中国热带农业科学院热带生物技术研究所 | Triterpenoid compound with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities and preparation method and application thereof |
| CN116983316A (en) * | 2023-08-31 | 2023-11-03 | 广东海洋大学 | Application of inonotus obliquus Kong Junchun in preparation of medicines for preventing or treating intestinal injury |
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| WO2019129249A1 (en) * | 2017-12-29 | 2019-07-04 | 上海蓝木化工有限公司 | Triterpenoid-containing pharmaceutical composition and use thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112972654A (en) * | 2021-03-05 | 2021-06-18 | 温州医科大学慈溪生物医药研究院 | Application of FGF21 in preparation of medicine for treating cranial nerve injury |
| CN112972654B (en) * | 2021-03-05 | 2022-07-01 | 温州医科大学慈溪生物医药研究院 | Application of FGF21 in preparation of medicine for treating cranial nerve injury |
| CN113956320A (en) * | 2021-10-22 | 2022-01-21 | 中国热带农业科学院热带生物技术研究所 | Triterpenoid compound with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities and preparation method and application thereof |
| CN113956320B (en) * | 2021-10-22 | 2022-12-30 | 中国热带农业科学院热带生物技术研究所 | Triterpenoid compound with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities and preparation method and application thereof |
| CN116983316A (en) * | 2023-08-31 | 2023-11-03 | 广东海洋大学 | Application of inonotus obliquus Kong Junchun in preparation of medicines for preventing or treating intestinal injury |
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