CN117281820A - New application of gastrodin - Google Patents
New application of gastrodin Download PDFInfo
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- CN117281820A CN117281820A CN202311480935.XA CN202311480935A CN117281820A CN 117281820 A CN117281820 A CN 117281820A CN 202311480935 A CN202311480935 A CN 202311480935A CN 117281820 A CN117281820 A CN 117281820A
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- gastrodin
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- PUQSUZTXKPLAPR-UJPOAAIJSA-N Gastrodin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(CO)C=C1 PUQSUZTXKPLAPR-UJPOAAIJSA-N 0.000 title claims abstract description 101
- PUQSUZTXKPLAPR-KSSYENDESA-N 4-(beta-D-Glucopyranosyloxy) benzyl alcohol Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1)c1ccc(CO)cc1 PUQSUZTXKPLAPR-KSSYENDESA-N 0.000 title claims abstract description 88
- 229930193974 gastrodin Natural products 0.000 title claims abstract description 88
- PUQSUZTXKPLAPR-NZEXEKPDSA-N helicidol Natural products O([C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](CO)O1)c1ccc(CO)cc1 PUQSUZTXKPLAPR-NZEXEKPDSA-N 0.000 title claims abstract description 88
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- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- 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
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The application discloses a new application of gastrodin, which is characterized in that the application analyzes the action mode of gastrodin and E3 ubiquitin ligase FBXO15 after docking; study the influence of gastrodin on the BEND.3 transport, barrier function and P-gp expression of Abeta 40-induced mouse brain microvascular endothelial cells, and simultaneously carry out gene silencing on P-gp, verify that the gastrodin interferes with the transport and barrier function of cells by improving the expression of P-gp, and reveal that the gastrodin can reduce the deposition of Abeta 40 by influencing the expression and transport of P-gp; the gastrodin can improve learning and memory disorder of AD model mice, improve P-gp expression and reduce Abeta 40 deposition, and the content proves that the gastrodin can mediate P-gp to play a role in reducing Abeta 40 deposition so as to relieve or treat Alzheimer disease.
Description
Technical Field
The application relates to the technical field of medicines, in particular to a new application of gastrodin.
Background
Alzheimer's Disease (AD) is a progressive neurodegenerative disease with hidden onset and is characterized clinically by generalized dementia such as memory impairment, aphasia, disuse, disbelief, impairment of vision space skills, executive dysfunction, and personality and behavioral changes. As the global population ages, the incidence of AD tends to rise year by year. AD has become a fatal disease that endangers human health at position 4 following cardiovascular and cerebrovascular diseases and tumors due to the lack of effective therapies. Therefore, finding effective drugs for preventing and treating AD has become a problem to be solved in life sciences.
AD has two major neuropathological features: extracellular amyloid plaques formed by beta-amyloid (aβ) and intracellular neurofibrillary tangles (NFT) aggregated by hyperphosphorylated tau. According to the amyloid hypothesis, the deposition of aβ in the brain is a major cause of AD pathogenesis, and metabolic abnormalities of aβ lead to increased production thereof, triggering tau hyperphosphorylation, neuronal damage, oxidative stress, etc., and ultimately leading to impairment of cognitive function. Therefore, clearing aβ deposits in the brain to reduce the progression of AD is an important strategy to prevent and treat this disease.
Clearing Abeta deposition in brain and relieving or treating nervous system degeneration diseases characterized by beta amyloid deposition in intracranial microvasculature.
Gastrodin (chemical name 4-hydroxymethylbenzene-beta-D glucopyranoside), molecular formula C 13 H 18 O 7 Is the monomer with the highest active ingredient content in the dry root tuber extract of Gastrodia elata (Gastrodia elata BL.) belonging to Orchidaceae.
Studies have shown that ubiquitination of P-glycopin (P-gp) in the blood brain barrier results in reduced ability of P-gp to transport Abeta 40, and accumulation of Abeta 40 exacerbates AD progression.
Disclosure of Invention
The invention aims to provide a new application of gastrodin.
First, the application of gastrodin or pharmaceutically acceptable salt thereof in preparing medicines for preventing, relieving or treating Alzheimer's disease and/or amyloid beta neuritis; and/or, gastrodin or pharmaceutically acceptable salt thereof in the prevention, alleviation or treatment of Alzheimer's disease and/or amyloid beta neuritis; the Alzheimer's disease is aggravated by the continued deposition of Abeta 40.
Specifically, gastrodin can improve the spatial memory capacity of AD patients, inhibit the ubiquitination degradation of P-gp of AD patients and improve the expression level of the gastrodin. Gastrodin can reduce accumulation of Abeta 40 to exert AD resisting effect.
Second, the application of gastrodin or pharmaceutically acceptable salt thereof in preparing products for inhibiting ubiquitination degradation of P-glycinin or improving P-glycinin protein expression; and/or the number of the groups of groups,
application of gastrodin or pharmaceutically acceptable salt thereof in inhibiting ubiquitination degradation of P-glycin or improving P-glycin protein expression.
Third, the use of gastrodin or a pharmaceutically acceptable salt thereof in the manufacture of a product for reducing aβ40 levels; and/or, the use of gastrodin or a pharmaceutically acceptable salt thereof for reducing the level of aβ40.
Preferably, the P-Glycoprotein, A beta 40 is in vivo or in vitro; the in vivo is cortex, hippocampus or plasma, and the in vitro is in vitro cell.
Fourth, the use of gastrodin or a pharmaceutically acceptable salt thereof for the preparation of a product that binds to E3 ubiquitin-protein ligase FBXO 15; and/or the number of the groups of groups,
use of gastrodin or a pharmaceutically acceptable salt thereof in combination with E3 ubiquitin-protein ligase FBXO 15.
Preferably, the gastrodin forms hydrophobic interactions with PRO-220, ARG-248, LEU-168, VAL-369, ILE-193, ILE-240 amino acids of the FBXO15 protein pocket; and/or, the gastrodin forms hydrogen bond interaction with TYR-368, ASP-394 and TYR-392 amino acids of the FBXO15 protein.
Preferably, the E3 ubiquitin-protein ligase FBXO15 is in vivo or in vitro; preferably, the body comprises the brain or blood; in vitro is the mouse brain microvascular endothelial cells induced by Abeta 40.
Preferably, the product is a pharmaceutical.
The invention analyzes the action mode of gastrodin and E3 ubiquitin ligase FBXO15 after docking; study the influence of gastrodin on the BEND.3 transport, barrier function and P-gp expression of Abeta 40-induced mouse brain microvascular endothelial cells, and simultaneously carry out gene silencing on P-gp, verify that the gastrodin interferes with the transport and barrier function of cells by improving the expression of P-gp, and reveal that the gastrodin can reduce the deposition of Abeta 40 by influencing the expression and transport of P-gp; the gastrodin can improve learning and memory disorder of AD model mice, improve P-gp expression and reduce Abeta 40 deposition, and the content proves that the gastrodin can mediate P-gp to play a role in reducing Abeta 40 deposition so as to relieve or treat Alzheimer disease.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiments of the application and together with the description serve to explain the application and do not constitute an undue limitation to the application. In the drawings:
FIG. 1 is a lentiviral vector;
FIG. 2 shows an optimized gastrodin structure;
fig. 3 shows the molecular docking results of gastrodin and FBXO 15;
FIG. 4 is the effect of gastrodin on Abeta 40 induced BEND.3 cells;
FIG. 5 is a graph showing example results of gastrodin increasing P-gp expression and decreasing P-gp and FBXO15 binding levels;
FIG. 6 is a graph showing example results of inhibition of P-gp ubiquitination by gastrodin;
FIG. 7 shows that gastrodin reduces the expression of Abeta 40 by P-gp;
FIG. 8AD mouse water maze test;
FIG. 9 shows P-gp expression and ubiquitination levels in the cortex and hippocampus of AD mice after gastrodin application;
figure 10 shows aβ deposition at various sites in AD mice following gastrodin application.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved by the present application more clear, the present application is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the present application.
Preparation method and transfection of shRNA-P-gp lentivirus:
1. construction of lentiviral recombinant plasmids
1) According to RNAi sequence design principle, designing target sequence for target gene P-gp sequence, synthesizing DNA sequence containing target and enzyme cutting site, dissolving the synthesized primer dry powder in annealing buffer solution, water-bathing at 90 deg.C for 15min, naturally cooling to room temperature.
2) Enzyme cutting and recovering shRNA vector (figure 1);
3) The shRNA carrier is connected with the primer;
4) Transferring the connection product into the prepared bacterial competent cells for transformation;
5) Preparing recombinant plasmids;
6) Positive clones were identified by sequencing.
Coding sequence of final shRNA
5'-CCGGGCCCTGGCAAAGCATTTGTATCTCGAGATACAAATGCTTTGCCAGGGCTTTTTG-3' (SEQ ID NO: 1) is inserted between the cleavage sites of the lentiviral vector, and the insert sequence in the recombinant clone is completely consistent with the designed oligo sequence through comparison, so as to obtain the shRNA-P-gp plasmid.
5'-CCGGCAACAAGATGAAGAGCACCAACTCGAGTTGGTGCTCTTCATCTTGTTGTTTTTG-3' (SEQ ID NO: 2) was inserted between the cleavage sites of the lentiviral vector to obtain a shRNA-NC control plasmid.
2. Lentivirus packaging and titer detection
3 plasmids (20. Mu.g of vector plasmid, 15. Mu.g of pHelper1.0 vector plasmid and 10. Mu.g of pHelper 2.0 vector plasmid) in the course of packaging lentiviruses were subjected to high-purity endotoxin-free extraction according to the experiment, 293T cells in the exponential growth phase were co-transfected, virus stock was collected, concentrated by ultrafiltration, and virus titer was detected by RT-PCR.
3. Transfection
Lentiviral transfection: 24h to 24 wells before transfectionPlating 0.5X10 per well in the plate 5 BEND.3 cells, 37℃CO 2 The cells were cultured overnight in an incubator at a concentration of 5%. Serum-free medium and Polybrene were mixed to a final concentration of 8. Mu.g/ml. The medium in the 24-well plate was replaced with 0.5ml Polybrene-medium mixture per well, a corresponding volume of lentivirus was added to each well according to MOI value, after overnight incubation, the medium was removed and 1ml of complete medium was added to each well, at 37 ℃, CO 2 Culturing was continued in an incubator at a concentration of 5%. After transfection, western blot experiments were used to verify transfection efficiency.
EXAMPLE 1 Gastrodin and FBXO15 molecular Butt-joint procedure
It was found that ubiquitination of P-Glycoprotein (P-gp) (Access: AAA 59575.1) in the blood-brain barrier results in a reduced ability of P-gp to transport Abeta 40, while Abeta 40 accumulation exacerbates AD progression. Screening researches are carried out on ubiquitin related proteins, and the gastrodin can be combined with E3 ubiquitin-protein ligase FBXO15 to inhibit the ubiquitination of P-gp, so that the path proves that the gastrodin is a compound with the activity of resisting Alzheimer disease. The specific implementation process is as follows:
related proteins involved in the ubiquitin coupling pathway are searched in a Uniprot database (https:// www.uniprot.org/keywords/KW-0833), and molecular docking is sequentially carried out on the related proteins with gastrodin, so that the gastrodin can be well combined with target protein E3 ubiquitin-protein ligase FBXO15 (the amino acid sequence of which is shown as SEQ ID NO: 3). The specific process and results are as follows:
1.1 preparation of Gastrodin Compound Structure
The structure of the compound Gastrodin of the present butt joint is obtained from the PubCHem database https:// pubchem.ncbi.n.lm.gov/, and then Chem3D software is imported to perform optimization and energy minimization by using an MM2 module, and the compound Gastrodin structure is saved as an sdf format file to be used as a ligand molecule of molecular butt joint (figure 2).
1.2 preparation of target protein Structure
The structure of the FBXO15 (ID: AF-Q9QZN 0-F1) protein is from the UniProt database https:// www.uniprot.org/uniprotkb/Q9QZN0/, the protein structure is processed on the Maestro11.9 platform, the protein is processed with Schrodinger's Protein Preparation Wizard, the water of crystallization is removed, the missing hydrogen atoms are added, and the missing bond information is repaired, the missing peptide is repaired, and finally the protein is subjected to energy minimization and geometry optimization.
1.3 molecular docking
The molecular docking is handled and optimized byThe Glide module in Maestro software is complete. Protein processing utilized Protein Preparation Wizard modules. The receptors were pre-treated, optimized and minimized (constraint minimization using OPLS3e force field). The compound structure was prepared according to the default settings of the LigPrep module. During screening in a Glide module, the prepared receptor is introduced, the docking site (x= -2.53, y= -12.34, z= -7.05) is predicted according to the structural characteristics of the protein, and the docking box is set as +.>Finally, molecular docking and screening were performed by standard precision methods (Standard Precision, SP).
1.4 Butt joint results screening and analysis
Analyzing the action mode of the compound and the target protein to obtain the action condition of the compound and the protein residue, such as generated hydrogen bond action, pi-pi interaction, hydrophobic interaction and the like, and referring to the butt joint scoring of the compound to explain the compound binding mechanism.
The molecular docking result of gastrodin and target protein FBXO15 is shown in figure 3, the binding energy is-7.01 kcal/mol, and the gastrodin and target protein FBXO15 are well combined. The gastrodin can form strong hydrophobic interaction with PRO-220, ARG-248, LEU-168, VAL-369, ILE-193 and ILE-240 amino acids of the FBXO15 protein pocket, and particularly the ARG-248 can form a cation-pi conjugated interaction with the benzene ring of the gastrodin, thereby having important effect on stabilizing molecules; in addition, gastrodin can also form strong hydrogen bond interactions with TYR-368, ASP-394 and TYR-392 amino acids of FBXO15 protein, and the hydrogen bonds have important contributions to small molecules in the anchoring protein site.
Example 2 Effect of gastrodin on Aβ40-induced BEND.3 cell Barrier function and P-gp expression
2.1 test group setup
And (3) cells: mouse brain microvascular endothelial cell bEND.3
Experimental grouping: normal group, aβ40 group, high dose of gastrodin+aβ40 group, medium dose of gastrodin+aβ40 group, low dose of gastrodin+aβ40 group.
The treatment method comprises the following steps: normal groups of BEND3 cells were cultured for 30h using normal medium; after the Aβ40 group BEND3 cells are cultured for 6 hours by using the Aβ40 containing 100nM, the normal culture medium is replaced for continuous culture for 24 hours; after 6h of culturing the Gastrodin+Aβ40 group BEND3 cells with Aβ40 of 100nM, the culture medium containing different concentrations of Gastrodin was changed to continue the culture for 24h.
2.2 detection index
WB detects the expression level of P-gp protein; co-ip detected binding levels in each of the groups of FBXO15 and P-gp proteins; co-ip was tested for ubiquitination levels of the P-gp proteins of each group using 150nM MG132 treatment simultaneously with each of the above groups; TEER test endothelial cell resistance values of each group; the Fluorescein-supported dextran experiment examined cell permeabilities of each group.
2.3 test results
The results of the study of the effect of gastrodin on Abeta 40-induced brain microvascular endothelial cell BEND.3 barrier function and P-gp expression in mice are shown in FIGS. 4-6. Compared with the A beta 40 group, the P-gp expression and the cell resistance value of the gastrodin-high dose (81 mu M) +A beta 40 group and the gastrodin-medium dose (27 mu M) +A beta 40 group are increased, and the cell permeability is reduced; the levels of binding of FBXO15 and P-gp in three groups, gastrodin-high dose + aβ40 group, gastrodin-medium dose + aβ40 group and gastrodin-low dose (9 μm) +aβ40 group, exhibited a different degree of reduction, a reduction in the level of ubiquitination of P-gp, the most pronounced reduction in the high dose group and the second in the medium dose group. The result shows that the gastrodin can inhibit the ubiquitination degradation of P-gp and improve the expression of P-gp.
EXAMPLE 3 Gastrodin interferes with cell transport and Barrier function by affecting the expression of P-gp protein
3.1 test group
And (3) cells: mouse brain microvascular endothelial cells BEND.3
Experimental grouping: Aβ40+shRNA-NC group, Aβ40+shRNA-P-gp group, gastrodin optimal dose (81. Mu.M) +Aβ40+shRNA-NC group, gastrodin optimal dose (81. Mu.M) +Aβ40+shRNA-P-gp group.
Remarks: shRNA-P-gp is lentivirus
The treatment method comprises the following steps: bend.3 transfected shRNA-NC and shRNA-P-gp, respectively, followed by dosing treatment as described above.
3.2 detection index
Detecting the transport activity of cells by using an NBD-CSA fluorescent experiment; immunofluorescence (IF) was used to detect aβ40 deposition in each group of cells.
3.3 test results
After the P-gp is subjected to gene silencing, the construction of a virus vector is slowed down by gene knockout and a transfection experiment is completed, and the Abeta 40 deposition condition in mouse brain microvascular endothelial cells BEND.3 is detected. As shown in fig. 7, shRNA-P-gp group aβ40 expression increased and shRNA-nc+gastrodin group aβ40 expression decreased compared to shRNA-NC (normal) group; compared with the shRNA-P-gp group, the shRNA-P-gp+gastrodin group A beta 40 expression is reduced; compared with the shRNA-NC+gastrodin group, the shRNA-P-gp+gastrodin group A beta 40 expression is increased. The results indicate that gastrodin can reduce Abeta 40 deposition by improving P-gp expression.
Example 4 Water maze experiment to examine behavioral changes in mice of each group
4.1 test group
Animals: APP/PS1 mice (9 weeks old); male, 25g or so.
Experimental grouping: C56/BL6, APP/PS1 group, APP/PS1 group+Gastrodin (60 mg/kg), APP/PS1 group+Gastrodin (90 mg/kg), APP/PS1 group+Gastrodin (150 mg/kg); each group n=6.
The treatment method comprises the following steps: APP/PS1 group mice were given double distilled water following 3 weeks of gavage; APP/PS1 group
Gastrodin (60 mg/kg) was administered to mice in the +Gastrodin (60 mg/kg) group by gavage for 3 weeks; the mice were sacrificed for material sampling after the behavioral testing 12h after the last dose.
4.2 index detection: the water maze test detects the behavioral changes (one time point) of each group of mice.
4.3 test results
The results of the water maze test for the behavioral changes of each group of mice are shown in fig. 8. Compared with the C56/BL6 group, the number of times of crossing the platform area, the target quadrant time duty ratio and the total swimming distance in 1min of the APP/PS1 group mouse water maze experiment are all reduced, and the latency time for finding the platform for the first time is increased. Compared with the APP/PS1 group, the APP/PS 1+gastrodin (60 mg/kg) group, the APP/PS 1+gastrodin (90 mg/kg) group and the APP/PS 1+gastrodin (150 mg/kg) group have the advantages that the time of crossing the platform area and the target quadrant time ratio in 1min of the mouse water maze experiment are increased, and the latency time for finding the platform for the first time is reduced; the total swimming distance of mice in the APP/PS 1+gastrodin (90 mg/kg) group and the APP/PS 1+gastrodin (150 mg/kg) group is increased. The result shows that the gastrodin can improve the spatial memory capacity of the AD mice.
EXAMPLE 5 AD mice cortex and hippocampal P-gp expression and ubiquitination levels after Gastrodin application
5.1 test group: same as 4.1
5.2 detection index
After the behaviours are finished, the mouse materials are sacrificed, and the expression condition of the P-gp protein in the cortex and the hippocampus of each group of mice is detected by WB; after the behavioural is finished, the mouse materials are sacrificed, and Co-ip is used for detecting the combination condition of P-gp and FBXO15 proteins in cerebral cortex and hippocampus of each group of mice, and the ubiquitination level of the P-gp proteins;
5.3 test results
The results of AD mouse cortex and hippocampal P-gp expression and ubiquitination levels after gastrodin application are shown in figure 9. Compared to the C56/BL6 group, the APP/PS1 group had an increased level of cortex, hippocampal FBXO15 and P-gp binding and an increased level of ubiquitination of P-gp. Compared with the APP/PS1 group, the gastrodin (60 mg/kg), the gastrodin (90 mg/kg) and the gastrodin (150 mg/kg) groups have the advantages that the binding levels of the human cortex, the sea horse FBXO15 and the P-gp are reduced in different degrees, the ubiquitination level of the P-gp is reduced in different degrees, the reduction of the high-dose group is most obvious, and the medium-dose group is second. The result shows that the gastrodin can inhibit the ubiquitination degradation of P-gp and improve the expression level of the P-gp.
EXAMPLE 6 deposition of Abeta at various sites in AD mice after Gastrodine application
6.1 test group: same as 4.1
6.2 detection index
After the behavioural is finished, the mice are sacrificed to obtain materials, and the IF detects the deposition conditions of the cortex, the hippocampus Aβ40 and the Aβ42 of each group of mice; after the behaviours are finished, the mice are sacrificed to obtain materials, and ELISA is used for detecting the expression conditions of cortex, hippocampus, blood plasma Aβ40 and Aβ42 of each group of mice.
6.3 test results
The deposition of Abeta at each site of AD mice after gastrodin application is shown in figure 10. Aβ40 and Aβ42 expression was elevated in the cortex, hippocampus and plasma of the APP/PS1 group compared to the C56/BL6 group. The APP/PS 1+gastrodin (60 mg/kg), APP/PS 1+gastrodin (90 mg/kg) and APP/PS 1+gastrodin (150 mg/kg) groups showed reduced expression of Abeta 40, abeta 42 in the cortex, hippocampus and plasma of mice as compared to the APP/PS1 group. The result shows that the gastrodin can reduce the deposition of Abeta in the cortex, the hippocampus and the blood plasma of the AD mice, thereby slowing down the development of the AD.
The technical scheme of the invention can prove that the gastrodin can improve the expression of P-gp through a ubiquitination-protease system, reduce the accumulation of Abeta 40 and play an anti-AD role, and the clear action mechanism is helpful for the market new application of the gastrodin and the research and development of anti-AD drugs.
The invention and its embodiments have been described above with no limitation, and the actual construction is not limited to the embodiments of the invention as shown in the drawings. In summary, if one of ordinary skill in the art is informed by this disclosure, a structural manner and an embodiment similar to the technical solution should not be creatively devised without departing from the gist of the present invention.
Claims (8)
1. The application of gastrodin or pharmaceutically acceptable salt thereof in preparing medicines for preventing, relieving or treating Alzheimer's disease and/or amyloid beta neuritis; and/or, gastrodin or pharmaceutically acceptable salt thereof in the prevention, alleviation or treatment of Alzheimer's disease and/or amyloid beta neuritis; the Alzheimer's disease is aggravated by the continued deposition of Abeta 40.
2. Application of gastrodin or pharmaceutically acceptable salt thereof in preparing products for inhibiting ubiquitination degradation of P-glycin or improving expression of P-glycin protein; and/or the number of the groups of groups,
application of gastrodin or pharmaceutically acceptable salt thereof in inhibiting ubiquitination degradation of P-glycin or improving P-glycin protein expression.
3. Application of gastrodin or pharmaceutically acceptable salt thereof in preparing products for reducing A beta 40 level; and/or, the use of gastrodin or a pharmaceutically acceptable salt thereof for reducing the level of aβ40.
4. The use according to claim 2 or 3, wherein the P-Glycoprotein, A beta 40 is in vivo or in vitro; the in vivo is cortex, hippocampus or plasma, and the in vitro is in vitro cell.
5. Use of gastrodin or a pharmaceutically acceptable salt thereof for the preparation of a product for binding to E3 ubiquitin-protein ligase FBXO 15; and/or the number of the groups of groups,
use of gastrodin or a pharmaceutically acceptable salt thereof in combination with E3 ubiquitin-protein ligase FBXO 15.
6. The use according to claim 5, wherein the gastrodin forms a hydrophobic interaction with amino acids PRO-220, ARG-248, LEU-168, VAL-369, ILE-193, ILE-240 of the FBXO15 protein pocket; and/or, the gastrodin forms hydrogen bond interaction with TYR-368, ASP-394 and TYR-392 amino acids of the FBXO15 protein.
7. The use according to claim 5 or 6, wherein E3 ubiquitin-protein ligase FBXO15 is in vivo or in vitro; preferably, the body comprises the brain or blood; in vitro is the mouse brain microvascular endothelial cells induced by Abeta 40.
8. The use according to any one of claims 2-7, wherein the product is a medicament.
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