CN114652712B - Application of kadsura pepper quinuclidine in preparation of medicine for preventing and treating senile dementia - Google Patents

Application of kadsura pepper quinuclidine in preparation of medicine for preventing and treating senile dementia Download PDF

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CN114652712B
CN114652712B CN202210296382.1A CN202210296382A CN114652712B CN 114652712 B CN114652712 B CN 114652712B CN 202210296382 A CN202210296382 A CN 202210296382A CN 114652712 B CN114652712 B CN 114652712B
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kadsura pepper
quinuclidine
dichloromethane
kadsura
abeta
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CN114652712A (en
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陈辉
曾梦楠
朱莹
郭宇涵
孙彦君
李孟
薛贵民
冯卫生
郑晓珂
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Henan University of Traditional Chinese Medicine HUTCM
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms

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Abstract

The invention discloses application of kadsura pepper quinuclidine in preparing medicaments for preventing and treating senile dementia, and the invention discovers that the kadsura pepper quinuclidine is relative to Abeta for the first time through experimental research 25‑35 The induced PC-12 cell injury has obvious protective effect, and can play a role by enhancing autophagy level of cells, and further experiments in animals prove that the kadsura pepper quinuclidinol can obviously improve Abeta 25‑35 Inducing cognitive function of mice and improving pathological changes of brain, and can be conveniently prepared into various pharmaceutical dosage forms, thereby being convenient for clinical use and being used for preventing and treating senile dementia.

Description

Application of kadsura pepper quinuclidine in preparation of medicine for preventing and treating senile dementia
Technical Field
The invention relates to the technical field of medicines, in particular to application of kadsura pepper stem quinine in preparation of medicines for preventing and treating senile dementia.
Background
Senile dementia, also called Alzheimer's Disease (AD for short), is a neurodegenerative Disease mainly represented by chronic progressive memory and cognitive function impairment, the pathogenesis of which is hidden and irreversible, with gradual loss of memory and mental behavior changes, and serious ones even lose life self-care ability. With the increasing global aging trend, AD patients have proliferated and now become a further disease that severely threatens the health of the elderly following cardiovascular disease, cancer and stroke. At present, cholinesterase inhibitors (such as donepezil) and N-methyl-D-aspartate receptor antagonists (such as memantine) are commonly used as main therapeutic drugs in clinic, but the drugs can only be used for improving and relieving symptoms, can not radically cure the disease, and have certain side effects at different degrees. Therefore, the research and development of the safe and effective novel AD therapeutic drug has important significance.
The kadsura pepper-seed alcohol (D-31) is a natural product separated from kadsura pepper (Piper Kadsura Ohwi) of piperaceae and has a large content, and literature researches show that the kadsura pepper-seed alcohol has a certain anti-inflammatory and PAF antagonistic activity, but no report on prevention or treatment of senile dementia by the kadsura pepper-seed alcohol is found in the prior art.
Disclosure of Invention
Aiming at the situation, the invention aims to solve the defects of the prior art and provides the application of the kadsura pepper quinuclidine in preparing the medicine for preventing and treating the senile dementia, which can effectively solve the medicine problem of the senile dementia.
The technical scheme is that the structural formula of the kadsura pepper quinuclidine is shown as the general formula (I):
the application of the kadsura pepper quinuclidine shown in the general formula (I) and pharmaceutically acceptable salts and isotope labels thereof in medicaments for preventing and/or treating Alzheimer's disease.
The medicine containing the kadsura pepper-seed-quinuclidine as shown in the general formula (I) comprises pure optical isomers and/or racemates and pharmaceutically acceptable salts thereof and is applied to medicines for preventing and/or treating Alzheimer disease.
The kadsura pepper quinuclidine shown in the general formula (I) and a pharmaceutically acceptable carrier are prepared into one of tablets, capsules, injections, powder injections, granules, powder, pills, fat emulsion, microcapsules, dripping pills, ointments, sustained release agents or quick release control dosage forms.
The preparation method of the kadsura pepper quinuclidine shown in the general formula (I) comprises the following steps:
1) Pulverizing the dried kadsura pepper stem medicinal material, performing cold leaching extraction with 2-5 times of dichloromethane for 24 hours each time, extracting for 3 times, and concentrating the extracting solution under reduced pressure to obtain dichloromethane part extractum;
2) Mixing the dichloromethane part total extractum with 100-200 mesh silica gel in the same amount, and sequentially mixing the dichloromethane part total extractum with 100 volume ratio: 0. 100:2, 100:3, 100:4, 100:5, 100:10, 100:20, 100:50, 100:100, 100:200, 0:100 petroleum ether-acetone mixed solvent gradient elution, wherein each 500mL is a fraction, the fractions are concentrated under reduced pressure, the same fractions are combined according to the thin layer detection condition, 13 components (Fr.1-13) are obtained through co-separation, a large amount of crystalline solid in the component Fr.7 is separated out, and dichloromethane and methanol are used for repeatedly washing, so that the kadsura pepper stem quinuclidine is obtained.
The kadsura pepper quinuclidinol of the invention is relative to Abeta 25-35 The induced PC-12 cell injury has obvious protective effect, and can play a role by enhancing autophagy level of cells, and further experiments in animals prove that the kadsura pepper quinuclidinol can obviously improve Abeta 25-35 Induces cognitive function in mice and improves pathological changes in the brain. Therefore, the invention discloses the application of the kadsura pepper quinuclidine in preparing the medicine for preventing and treating the AD disease for the first time, and opens up a new application of the kadsura pepper quinuclidine.
Drawings
FIG. 1 shows the detection of the pair Abeta by the cell immunofluorescence method of the invention 25-35 Induction of LC in PC-12 cells 3 The effect of protein B expression levels (compared to group M, * P<0.05 sum ** P<0.01)。
FIG. 2 shows the pair of Abeta of kadsura pepper-flow 25-35 Inducing cognitive function in mice and improving brain pathology experimental results (compared to group M, * P<0.05 sum ** P<0.01)。
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples.
Example 1
In the specific implementation of the invention, the preparation method of the kadsura pepper-seed alcohol comprises the following steps:
1) Crushing 5kg of dried kadsura pepper stem medicinal materials, and carrying out cold leaching extraction with 2-5 times of dichloromethane for 24 hours each time for 3 times. Concentrating the extracting solution under reduced pressure to obtain 85g of dichloromethane part extractum;
2) Mixing the dichloromethane part total extractum with 100-200 mesh silica gel in the same amount, and sequentially mixing the dichloromethane part total extractum with 100 volume ratio: 0. 100:2, 100:3, 100:4, 100:5, 100:10, 100:20, 100:50, 100:100, 100:200, 0:100, wherein each 500mL of petroleum ether-acetone mixed solvent is a flow part, the flow parts are decompressed and concentrated, the same flow parts are combined according to the thin layer detection condition, 13 components of Fr.1-13 are obtained through separation, a large amount of crystalline solid is separated out from the component Fr.7, and dichloromethane and methanol are used for repeatedly washing, so that 2.28g of kadsura pepper stem quinine is obtained.
The foregoing description of the preferred embodiments of the present invention is provided for the purpose of illustration, and is not intended to limit the scope of the invention in any way, since various modifications, equivalents, improvements and/or the like may be made thereto without departing from the spirit and scope of the invention.
The kadsura pepper quinuclidinol of the invention is relative to Abeta 25-35 The induced PC-12 cell injury has obvious protective effect, and can play a role by enhancing autophagy level of cells, and further experiments in animals prove that the kadsura pepper quinuclidinol can obviously improve Abeta 25-35 Inducing cognitive function and improving pathological changes of brain of mice, and related experimental data are as follows:
1. spectral data of the kadsura pepper quinuclidine of the present invention:
molecular formula C 21 H 22 O 5 CAS registry number 28178-92-9. 1 H NMR(CDCl 3 ,500MHz)δ H 6.92(1H,s,H-7),6.78～6.74(3H,m,H-2,5,6),6.13(1H,s,H-2′),5.94(2H,s,O-CH 2 -O),5.88(1H,m,J＝15.6,6.6,H-8′),5.81(1H,s,H-5′),5.10(2H,m,H-9′),3.78(3H,s,4′-OCH 3 ),3.23(3H,s,3′-OCH 3 ),3.12(2H,m,H-7′),1.64(3H,s,H-9)； 13 C NMR(CDCl 3 ,125MHz)δ C 187.2(C-7′),172.4(C-4′),147.5(C-3),146.4(C-4),141.3(C-2′),139.8(C-1′),135.1(C-8′),132.9(C-1),131.6(C-7),127.2(C-8),123.1(C-6),117.2(C-9′),109.4(C-5),108.2(C-2),105.8(C-5′),101.1(O-CH 2 -O),80.0(C-3′),56.3(4′-OCH 3 ),52.6(3′-OCH 3 ),32.9(C-7′),14.2(C-9).
2. MTT method for detecting kadsura pepper quinuclidinol to Abeta 25-35 Protective Activity of induced PC-12 cell injury:
(1) Thawing PC-12 cells frozen by liquid nitrogen in a water bath at 37deg.C to ice water coexistence state, immediately centrifuging at 1000rpm for 5min, discarding supernatant, transferring cells into a culture dish containing 1640 medium containing 10% FBS (100 kU/L for both green and streptomycin), and adding 5% CO 2 Culturing in a constant temperature incubator at 37 ℃ until the cells grow to 80-90% of a dish for digestion and passage. Fresh medium was changed every 48 hours.
(2) PC-12 cells were placed at 37℃with 5% CO 2 Culturing in incubator to logarithmic phase, and culturing at cell density of 2X10 4 Inoculating into 96-well plate, dividing into normal group (Con) and model group (Abeta after 24 hr 25-35 M, 20. Mu.M), dosing group (Fengtonqual, D-31, set up 4 dose groups of 1. Mu.M, 5. Mu.M, 10. Mu.M and 20. Mu.M), after 24h incubation, 20. Mu.L of MTT solution (5 mg/mL) was added per well, incubation was continued for 4h, medium was carefully aspirated, 150. Mu.L of DMSO was added per well, and shaking was performed for 10min to complete dissolution. The absorbance (OD) of each well was measured at 490nm by a microplate reader, and the cell viability was calculated. The results are shown in Table 1.
(3) Statistical analysis
Experimental data in mean ± standard deviationIt shows that SPSS20.0 was used for statistical analysis. The comparison between groups used One-Way analysis of variance (One-Way ANOVA). P in comparison with the model group<0.05 shows significant difference, P<0.01 indicates a very significant difference.
TABLE 1 Fengteng quinine vs. Abeta 25-35 Influence of induced PC-12 cell injury
Group of Dosage (mu M) Cell viability
Normal group (Con) --- 1.000±0.026 **
Model group (M) --- 0.723±0.015
Fengteng quinine group (D-31) 1 0.762±0.007 *
Fengteng quinine group (D-31) 5 0.828±0.005 **
Fengteng quinine group (D-31) 10 0.892±0.012 **
Fengteng quinine group (D-31) 20 0.920±0.018 **
Experimental results: the results are shown in Table 1, and compared with the normal group, Aβ 25-35 Model group cell viability was significantly reduced (P)<0.01 After the administration, the kadsura pepper quinuclidinol group (D-31) can obviously improve the PC-12 cell activity (P) compared with a model group at the concentration of 1-20 mu M<0.05 or P<0.01 And the obvious dose-effect relationship is shown.
3. Detection of kadsura pepper quinuclidinol to Abeta by using cell immunofluorescence technology 25-35 Effects of induction of PC-12 cell autophagy proteins:
PC-12 cells were placed at 37℃with 5% CO 2 Culturing in incubator to logarithmic phase, and culturing at cell density of 3×10 4 Inoculating into 96-well plate, dividing into normal group (Con) and model group (Abeta after 24 hr 25-35 M) and administration group (10μm+Abeta 25-35 The culture is continued for 24 hours. 200. Mu.L of 4% paraformaldehyde was added and the mixture was fixed at room temperature for 15min and washed twice with cold PBS. The samples were washed 3 times with PBS containing 0.25% Triton X-100 for 5min each. Following incubation of the cells in 2% BSA in PBST for 30min, the blocking solution was removed and primary antibody LC diluted with 2% BSA in PBST 3 B at 4℃overnight; recovering primary antibody, washing cells with PBS for 3 times and 5min each time, and incubating with 2% BSA-containing PBST diluted rabbit secondary antibody (1:1000) and mouse secondary antibody (1:500) at room temperature in dark place for 1h; the secondary antibody solution was recovered, the cells were washed 3 times with PBS, 5min each time, cells were incubated with DAPI (nucleus-stained) for 5min, PBST was washed 1 time, PBS was washed 1 time, and fluorescence intensity was detected and analyzed by Operetta CLS, and the results are shown in FIG. 1.
The experimental results show that: LC (liquid Crystal) device 3 B is used as a marker protein of autophagy and can reflect the level of autophagy. As shown in FIG. 1, LC in model group (M) cells compared to normal group (CON) 3 B protein expression level was significantly reduced (P<0.01 For example), LC in cells of the administration group after the intervention of kadsura pepper-quinol (D-31) compared to the model group 3 B protein expression level was significantly increased (P<0.01). The results show that the kadsura pepper quinuclidinol can obviously enhance the Abeta 25-35 Induces autophagy levels in PC-12 cells.
4. Kadsura pepper quinuclidinol pair A beta 25-35 Experimental study to induce cognitive function in mice and improve brain pathology:
(1) Preparation of animal models
Will Aβ 25–35 The powder was formulated at 1mMAβ 25–35 The solution was incubated in an incubator at 37℃for 7 days in the absence of light for further aging and diluted to 300. Mu.M with sterile physiological saline immediately prior to the experiment. Mice were anesthetized with isoflurane gas and fixed to the mice plates. The microinjection needle is positioned at the position 2mm behind the bregma point, the right 2.2mm and the lower 1.5mm, and after the needle is inserted, the microinjection needle stays in the brain of the mouse for 5min and then uniformly injects 2.5 mu L of the injection needle containing Abeta 25–35 The normal saline is kept in place for 5min after injection, and then the needle is pulled out. After molding, the materials are fed in an ultra-clean bench with sterile water and sterile feed for one week, and then transferred to the outside of the ultra-clean bench for feeding.
(2) Grouping and administration
40 7-week-old male Kunming mice were randomly assigned to the normal group (Con), model group (M), donepezil group (Don), and kadsura pepper-quinol group (Fut), 10 each. Intra-brain injection of Abeta in mice of each group except the normal group 25–35 And (5) performing molding. Each group of mice was kept at 12/12h light/dark cycle, fed and drinking water freely. Donepezil (10 mg/kg/D) and kadsura alcohol (D-31) (10 mg/kg/D) were administered by gavage for 5 weeks after 1 week of molding recovery. The general condition of mice throughout the experiment was observed and relevant behavioral index detection was performed 4 weeks after dosing.
(3) New object identification experiment
New object recognition experiments are a test method for evaluating the learning and memory abilities of mice based on the innate characteristics of rodents. In this experiment, we put two identical objects A1 and A2 at the left and right ends of the square area, respectively, then we put the mouse at equidistant positions from each object, and record the number of times of exploring a new object within 5min (1 time when both feet touch the new object). After 24h, A2 was changed to another new object B, and the number of times of exploring object A1 and new object B in 5min was again recorded. 5A beta 1-40 、Aβ 1-42 P-Tau content detection
Cutting Hippocampus, adding PBS at a weight-to-volume ratio of 1:9, grinding, homogenizing, centrifuging at 5000 Xg for 10min, collecting supernatant, and detecting Abeta according to the operation requirement of the kit 1-40 、Aβ 1-42 Content of p-Tau.
(4) Hematoxylin-eosin (HE) staining
Mouse brain tissue was fixed in 10% neutral formalin, dehydrated stepwise with ethanol, paraffin-embedded in 4 μm sections, fixed, conventional HE stained, and histopathological observed under light microscope (. Times.400).
(5) Experimental results
The experimental results showed that in the new object recognition experiment (FIG. 2, A/B), the model group mice had significantly lower likes and dislikes indexes for the new objects than the normal group (P<0.01 After the drug administration is finished, the preference and aversion indexes of mice of the positive drug group (Don) and the kapok alcohol group (D-31) to new objects are obviously increased, which indicates that the kapok alcohol can obviously improve Abeta 25-35 Inducing memory impairment in mice.
HE staining results showed (FIG. 2, C), the cells in the hippocampus of the normal mice were aligned neatly and tightly, the nuclei were complete and clearly visible, and the staining was uniform; compared with the normal group, the hippocampal cell arrangement of the mice in the model group is disordered, the cell nucleus is atrophic, the cell gap is enlarged, the cell layer is incomplete, and the Abeta plaque is deposited; after the drug stem is given, the cell damage of the hippocampus of the mouse is obviously improved, the number of ordered cell layers of cell arrangement is increased, and the Abeta plaque is reduced.
ELISA kit results showed (FIG. 2, D/E/F) that mice in the model group had Abeta in the brain compared to the normal group 1-42 、Aβ 1-40 The level of P-Tau was significantly elevated (P<0.01 or P<0.05 A) is provided; administering drug dry prognosis, mice brain Aβ compared to model group 1-42 、Aβ 1-40 And P-Tau levels were significantly reduced (P<0.01 or P<0.05). The results show that the kadsura pepper quinuclidinol can obviously enhance Abeta 25-35 Inducing cognitive function in mice and improving pathological changes in the brain.
The experimental results show that the kadsura pepper quinuclidinol is relative to Abeta 25-35 The induced PC-12 cell damage model and the neurodegenerative diseases represented by the mouse model have remarkable improvement effect, so that the method can be used for treating or preventing the neurodegenerative diseases, especially senile dementia, and more preferably AD diseases.
Chemically, kadsura pepper-quinuclidine has a completely different chemical structure and framework type from current clinical AD therapeutics. Therefore, the invention provides a new structure type for developing new medicines for preventing and treating AD diseases, and has good development and application prospects.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention explores a new medical application of the kadsura pepper quinuclidine, exploits a new application field of the kadsura pepper quinuclidine, and provides application of the kadsura pepper quinuclidine in preparing medicaments for preventing and treating AD diseases.
2. The kadsura pepper quinuclidine is rich in source, low in cost, simple in preparation process, capable of being made into oral preparations, injections, tablets and the like, and convenient to use.
3. Through in vivo and in vitro experimental researches, the product of the product, namely the kadsura pepper quinuclidinol, is found to be A beta 25-35 The induced PC-12 cell injury has obvious protective effect and can obviously improve Abeta 25-35 Inducing the cognitive function of mice and improving the pathological changes of brain, can be effectively used as a medicament for preventing and treating AD, has different chemical structure types from the prior clinical AD therapeutic medicament, provides a new structure type for developing a new AD therapeutic medicament, and has great development and application prospects.

Claims (2)

1. An application of kadsura pepper quinuclidine and its isotope labels in the prevention and/or treatment of senile dementia,
2. the method for preparing the kadsura pepper-quinuclidine alcohol represented by the general formula (I) as claimed in claim 1, which is characterized by comprising the following steps:
1) Pulverizing the dried kadsura pepper stem medicinal material, performing cold leaching extraction with 2-5 times of dichloromethane for 24 hours each time, extracting for 3 times, and concentrating the extracting solution under reduced pressure to obtain dichloromethane part extractum;
2) Mixing the dichloromethane part total extractum with 100-200 mesh silica gel in the same amount, and sequentially mixing the dichloromethane part total extractum with 100 volume ratio: 0. 100:2, 100:3, 100:4, 100:5, 100:10, 100:20, 100:50, 100:100, 100:200, 0:100 petroleum ether-acetone mixed solvent gradient elution, wherein each 500mL is a fraction, the fractions are concentrated under reduced pressure, the same fractions are combined according to the thin layer detection condition, fr.1-13 components are obtained through co-separation, a large amount of crystalline solid is separated out from the Fr.7, and dichloromethane and methanol are used for repeatedly washing, so that the kadsura pepper stem quinuclidine is obtained.
CN202210296382.1A 2022-03-24 2022-03-24 Application of kadsura pepper quinuclidine in preparation of medicine for preventing and treating senile dementia Active CN114652712B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101036639A (en) * 2007-04-18 2007-09-19 山东大学齐鲁医院 Application of piperlonguminine and dihydropiperlonguminine in the preparation of the medicine for curing senile dementia
CN101642465A (en) * 2009-07-31 2010-02-10 暨南大学 Application of Kadsura heteroclite (Roxb.) Craib polysaccharide of Guangdong province for preparing medicaments for preventing and/or treating senile dementia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101036639A (en) * 2007-04-18 2007-09-19 山东大学齐鲁医院 Application of piperlonguminine and dihydropiperlonguminine in the preparation of the medicine for curing senile dementia
CN101642465A (en) * 2009-07-31 2010-02-10 暨南大学 Application of Kadsura heteroclite (Roxb.) Craib polysaccharide of Guangdong province for preparing medicaments for preventing and/or treating senile dementia

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