CN114432320A - Application of arjunolic acid in product for preventing or treating neuroinflammation - Google Patents
Application of arjunolic acid in product for preventing or treating neuroinflammation Download PDFInfo
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- CN114432320A CN114432320A CN202210224857.6A CN202210224857A CN114432320A CN 114432320 A CN114432320 A CN 114432320A CN 202210224857 A CN202210224857 A CN 202210224857A CN 114432320 A CN114432320 A CN 114432320A
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- neuroinflammation
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- A—HUMAN NECESSITIES
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- 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
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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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Abstract
The invention relates to an application of arjunolic acid in preparing a product for preventing or treating neuroinflammation or acute and chronic central nerve degenerative diseases caused by neuroinflammation; the neuroinflammation is lipopolysaccharide-induced neuromicroglial cell inflammation. The acute and chronic central neurodegenerative diseases comprise: alzheimer's disease, Parkinson's disease, multiple sclerosis and Huntington's chorea. Pharmacological experiments prove that the arjunolic acid has obvious neuroinflammation inhibition activity and can be used for preparing medicines for preventing or treating neuroinflammation and related diseases, so the arjunolic acid has higher clinical application value and development prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of arjunolic acid in a product for preventing or treating neuroinflammation.
Background
A great deal of research shows that the occurrence and the development of acute and chronic neurodegenerative diseases are closely related to neuroinflammation in the brain. Neuroinflammation is a major disease of various neurodegenerative diseases including Alzheimer's Disease (AD) and Parkinson's Disease (PD)And (4) physical characteristics. The inflammation-mediated neurodegenerative disease is mainly the activation of microglia followed by the release of a series of inflammatory factors, such as Nitric Oxide (NO), prostaglandin E2 (PGE)2) Interleukins (ILs), tumor necrosis factor (TNF-. alpha.), and the like.
Lipopolysaccharide (LPS) is a classical substance widely used to activate microglia. LPS induces BV2 microglia, activating mitogen-activated protein kinase (MAPKs) and nuclear transcription factor-kB (NF-kB) signal transduction pathways. MAPK pathway proteins mainly comprise ERK, p38 and JNK, and under the stimulation condition, the MAPK pathway proteins are phosphorylated and activate NF-kB pathway, and meanwhile, the expression of ILs and TNF-alpha is promoted. NF-kB is a protein complex for controlling DNA transcription, after being activated, IkB-alpha in cytoplasm is phosphorylated and degraded, and p65 protein enters nucleus to be combined with DNA, thereby promoting inflammatory factors NO and PGE2IL-6 and TNF-alpha.
It has been found that inhibition of the neuroinflammatory response can attenuate neuronal disease in damaged brain regions or delay the progression of neurodegenerative disease. Therefore, the search and research of the neuroinflammation inhibitor in the brain have important significance for developing novel medicaments for treating various acute and chronic neurodegenerative diseases.
The arjunolic acid can be extracted from the plants, the plants can be recycled for many times, the economic benefit is improved, the environment is protected, and the monomer compound product is stable and easy to store. The arjunolic acid is derived from parts of plants of Lagerstroemia of Lythraceae, and can also be separated from plants such as fructus Chebulae and caulis Akebiae. The arjunolic acid has various biological activities, such as oxidation resistance, antibiosis, heart protection, liver protection, important function in the aspects of peroxidation resistance and the like. Arjunolic acid has an important role in maintaining the levels of various antioxidant enzymes, such as superoxide dismutase (SOD), Catalase (CAT), glutathione-S-transferase (GST), Glutathione Reductase (GR) and glutathione peroxidase (GPx), cellular metabolite levels, reduced Glutathione (GSH), oxidized glutathione (GSSG), thereby reducing oxidative stress, and its protective effects on the liver, pancreas and kidney are also key characteristics of arjunolic acid. Therefore, arjunolic acid has the potential of treating various diseases.
Disclosure of Invention
The invention provides an application of arjunolic acid in a product for preventing or treating neuroinflammation, the arjunolic acid can inhibit neuroinflammation activity, and can be used for preparing a product for preventing or treating neuroinflammation and related diseases thereof, so the arjunolic acid has higher clinical application value and development prospect.
The technical scheme adopted by the invention is as follows: application of arjunolic acid in preparing products for preventing or treating neuroinflammation or acute and chronic central nerve degenerative diseases caused by neuroinflammation.
The application of the arjunolic acid provided by the invention comprises two aspects: 1) the application of the compound in preparing products for preventing or treating neuroinflammation; 2) the application of the compound in preparing products for preventing or treating acute and chronic neurodegenerative diseases caused by neuroinflammation; particularly shown in the micro glial Nitric Oxide (NO) induced by arjunolic acid to Lipopolysaccharide (LPS), prostaglandin E2 (PGE)2) The release of tumor necrosis factor alpha (TNF-alpha) and interleukin 6(IL-6) has obvious inhibiting effect, and the inhibition of LPS-induced microglia inflammation pathways including MAPKs and NF-kB pathways shows that the arjunolic acid has obvious neuroinflammation inhibiting activity. Also includes the application of the product which is prepared by taking arjunolic acid as an effective component and is used for preventing or treating acute and chronic neurodegenerative diseases caused by neuroinflammation.
Preferably, the constitutional formula of the arjunolic acid is shown as a formula,
preferably, the neuroinflammation is lipopolysaccharide-induced neuromicroglial inflammation.
Preferably, the acute and chronic central neurodegenerative diseases include: alzheimer's disease, Parkinson's disease, multiple sclerosis and Huntington's chorea.
Preferably, the medicament is for reducing the expression of inflammatory factors.
Preferably, the medicament is for reducing the expression of inflammatory signalling pathways.
Preferably, the inflammatory factor comprises any one or a combination of NO, PGE2, IL-6 and TNF-alpha.
Preferably, the inflammatory signaling pathway is MAPK and/or NF- κ B. The MAPKs include p38, JNK and ERK. The NF- κ B comprises an I κ B- α protein and p 65.
The experimental result shows that arjunolic acid induces nitrogen monoxide (NO) and prostaglandin E2 (PGE) on Lipopolysaccharide (LPS) induced microglia cells2) The release of tumor necrosis factor alpha (TNF-alpha) and interleukin 6(IL-6) has obvious inhibition effect, the inhibition of LPS-induced microglial cell inflammation pathways including MAPKs and NF-kB pathways shows that the arjunolic acid has obvious neuroinflammation inhibition activity, can reduce the expression level of NO, PGE2, IL-6 and TNF-alpha protein in hippocampal tissues and cerebral cortex, simultaneously can reduce the expression level of MAPK protein and/or NF-kB protein, can effectively inhibit microglial cell activation and inflammatory factor secretion, control neuroinflammation reaction, relieve the neuron damage caused by subsequent inflammatory factors, improve the cognitive function, memory disorder and motor coordination capacity of brain tissues, and the arjunolic acid is applied to the preparation of medicaments and/or health care products and/or food for preventing or treating neuroinflammation or acute and chronic central neurodegenerative diseases caused by neuroinflammation, has good application value and development prospect.
Preferably, the product is a medicament or health product.
Preferably, the dosage form of the medicine or the health care product is tablets, capsules, granules, pills, suspending agents, dispersing agents, syrups or injections. The drug for inhibiting neuroinflammation and the drug for preventing or treating acute or chronic neurodegenerative diseases caused by neuroinflammation in the present invention can be introduced into the body such as muscle, intradermal, subcutaneous, vein, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc. The medicines in the above various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
Compared with the prior art, pharmacological experiments prove that the arjunolic acid has obvious neuroinflammation inhibition activity and can be used for preparing medicines for preventing or treating neuroinflammation and related diseases, so the arjunolic acid has higher clinical application value and development prospect.
Drawings
FIG. 1 is a graph of the effect of arjunolic acid (B4) on BV2 cell survival;
FIG. 2 is a graph of the effect of arjunolic acid on LPS-induced microglial inflammatory cell levels; wherein a is the influence of arjunolic acid on the NO level of LPS induced microglia; b is the influence of arjunolic acid on the level of LPS-induced microglial cell TNF-alpha; c is the influence of arjunolic acid on the level of LPS-induced microglia IL-6; d is the influence of arjunolic acid on the LPS induced microglial cell PGE2 level;
FIG. 3 is the effect of arjunolic acid on LPS-induced microglial MAPK protein expression; wherein a is expression of p38 level induced by LPS; b is expression of LPS induced microglia JNK level; c is expression of LPS induced microglia ERK level; d is a graph of the comparative effect of the expression of p38, JNK and ERK levels after LPS induction and the expression of arjunolic acid and p38, JNK and ERK levels of LPS-induced microglia cells;
FIG. 4 shows the effect of arjunolic acid on LPS-induced microglial cell NF- κ B protein expression; wherein a is the expression of the level of LPS-induced microglia IkappaB-alpha protein; b is expression of LPS-induced microglia p65 level; c is a graph of the effect of Terminalia arjuna acid on the expression of LPS-induced microglial I kappa B-alpha protein and p 65;
in fig. 1 to 4, B4 represents arjunolic acid; "#" or "+" is less than 0.05 for P value, "# #" or "+" is less than 0.01 for P value, and three "# # ####" or "+" is less than 0.001 for P value; "#" is compared to the control group, "#" is compared to the LPS group;
FIG. 5 shows the compound arjunolic acid (B4)1H-NMR (400MHz) spectrogram, and determination solvent is deuterated methanol (CD)3OD);
FIG. 6 shows the compound arjunolic acid (B4)13C-NMR (100MHz) spectrum, determination solvent is deuterated methanol (CD)3OD)。
Detailed Description
For the purpose of enhancing the understanding of the present invention, the present invention will be described in further detail with reference to the accompanying drawings and examples, which are provided for the purpose of illustration only and are not intended to limit the scope of the present invention.
Example (b): the application of arjunolic acid in preparing products for preventing or treating neuroinflammation or acute and chronic central nerve degenerative diseases caused by neuroinflammation; the constitutional formula of the arjunolic acid is shown as a formula,
the neuroinflammation is lipopolysaccharide-induced neuromicroglial cell inflammation. The acute and chronic central neurodegenerative diseases comprise: alzheimer's disease, Parkinson's disease, multiple sclerosis and Huntington's chorea. The medicament is used for reducing the expression of inflammatory factors. The inflammatory factors include any one or more of NO, PGE2, IL-6 and TNF-alpha in combination. Tumor necrosis factor (TNF- α), which is mainly produced by activated monocytes/macrophages, can kill and inhibit tumor cells, promote neutrophil phagocytosis, counteract fever caused by infection, induce acute phase protein synthesis of hepatocytes, promote differentiation of myeloid leukemia cells into macrophages, promote cell proliferation and differentiation, is an important inflammatory factor, and is involved in pathological injury of certain autoimmune diseases. The medicament is for reducing the expression of inflammatory signaling pathways. The inflammation signal pathway is MAPK and/or NF-kB. The MAPKs include p38, JNK and ERK.
Reflux-extracting fructus Akebiae (3kg) with 70% ethanol for 3 times for 2 hr, mixing extractive solutions, concentrating, and drying to obtain crude extract 220 g. Dispersing the crude extract in 1L distilled water, transferring to a separating funnel, adding equal volume of n-hexane, extracting for 3 times, combining the extracts, concentrating and drying to obtain n-hexane fraction. According to the above method, dichloromethane, ethyl acetate and n-butanol are sequentially extracted to obtain dichloromethane fraction, ethyl acetate fraction and n-butanol fraction. Taking 15g of dichloromethane part, and sequentially separating with forward silica gel, Sephadex LH-20, and ODS column chromatography to obtain compound arjunolic acid (B4). The compound arjunolic acid (B4) has the structure channel1H,13The C-NMR measurement was analytically confirmed by comparison with the literature (see FIGS. 5 and 6).
The raw materials and reagents used in the present invention are commercially available.
Specifically, the effect of arjunolic acid on LPS-induced release of microglial inflammatory factors. Wherein, the cell strain: microglial cell strain BV 2; medicine preparation: LPS; arjunolic acid (B4); the method comprises the following specific steps:
(1) culture of microglia strain BV2 and determination of cell survival rate
Cells were cultured in RMPI medium (containing 10% fetal calf serum, 100U penicillin and 100U streptomycin), 37 ℃ and 5% CO2Culturing under the condition. BV2 cells were planted in 96-well plates, and after the cells were attached to the wall, arjunolic acid was added, and an equal volume of RMPI medium was added to the control group, each group had 6 wells, and incubated for 24 h. MTT solution with a final mass concentration of 0.5mg/mL is added, the culture is continued for 3 hours, the supernatant is aspirated off, 150. mu.L of dimethyl sulfoxide solution (DMSO) is added to each well, and the absorbance value is detected at 540nm after complete dissolution. The effect of arjunolic acid (B4) on BV2 cell survival is shown in figure 1.
(2) Inflammatory factors (NO, PGE)2IL-6, TNF-alpha) assay
Adjusting the cell suspension to 1X 106and/mL, added to a 24-well culture plate. Adding arjunolic acid after cell adherence, adding equal volume of RMPI culture medium into control group with 3 holes per group, culturing for 4 hr, adding LPS final substance except for control groupThe concentration was 1. mu.g/mL, and the culture was continued for 24 hours to collect the supernatant. Detection of NO concentration by Griess method: 50 μ L of the cell culture supernatant was added to a 96-well plate, 50 μ L of Griess reagent was added thereto, the reaction was carried out at room temperature for 15min, and the absorbance at 540nm was measured using a microplate reader. Detection of PGE in supernatants by ELISA2IL-6 and TNF-alpha contents are respectively detected according to the ELISA detection kit instruction.
As can be seen from FIG. 2, NO and PGE were observed after LPS induction2The concentrations of TNF-alpha and IL-6 are obviously increased, and the concentration of NO and PGE of arjunolic acid is obviously reduced2IL-6 and TNF-alpha levels.
Specifically, the arjunolic acid influences LPS-induced microglial inflammation pathways MAPK and NF-kB. Wherein, the cell strain: microglial cell strain BV 2; medicine preparation: LPS; arjunolic acid; the method comprises the following steps: the Western blot method comprises the following specific steps:
adjusting the cell suspension to 1X 106and/mL, added to 6-well plates. After the cells are attached to the wall, arjunolic acid is added, an equal volume of RMPI culture medium is added into a control group, and after the cells are cultured for 4 hours, LPS is added into the cells except the control group, wherein the final mass concentration of the LPS is 1 mu g/mL. MAPK protein is extracted after the cells are cultured for 1h, and the ratio of the protein extracting solution as lysate to the mixed solution of protease and phosphatase inhibitor is 100: 3. NF- κ B protein was extracted after 0.5h of cell culture using a Nuclear extraction kit, methods referred to product instructions. Loading 30 mu g of protein of each sample, applying 7.5-12% SDS-PAGE concentrated gel and separating gel to carry out 120V vertical electrophoresis, transferring 45V membranes, sealing 5% skimmed milk powder solution at room temperature for 1h, incubating with primary anti-solution overnight at 4 ℃, washing with 0.05% Tween-20TBS solution, incubating with secondary antibody solution at room temperature for 1h, and developing with ECL after washing.
As can be seen from fig. 3, fig. 3a to c show that after LPS induction, MAPKs including p38, JNK and ERK level expression is significantly increased, and as can be seen from fig. 3d, arjunolic acid can significantly reduce p38, ERK and JNK expression.
As can be seen from FIG. 4, after LPS induction, phosphorylation levels of I kappa B-alpha protein and p65 are remarkably increased, and as can be seen from FIG. 4c, arjunolic acid inhibits I kappa B-alpha phosphorylation, so that total protein expression of I kappa B-alpha is increased, and phosphorylation expression of p65 is inhibited.
The experimental results are as follows: the arjunolic acid can obviously inhibit LPS-induced microglial inflammation channels including MAPKs channels and NF-kB channels.
In conclusion, the arjunolic acid of the invention can be used for preventing or treating neuroinflammation and neurodegenerative diseases.
It is obvious to those skilled in the art that the present invention is not limited to the above embodiments, and it is within the scope of the present invention to adopt various insubstantial modifications of the method concept and technical scheme of the present invention, or to directly apply the concept and technical scheme of the present invention to other occasions without modification.
Claims (10)
1. Application of arjunolic acid in preparing products for preventing or treating neuroinflammation or acute and chronic central nerve degenerative diseases caused by neuroinflammation.
3. the use according to claim 1, wherein the neuroinflammation is lipopolysaccharide-induced neuromicroglial inflammation.
4. The use of claim 1, wherein the acute or chronic neurodegenerative disease comprises: alzheimer's disease, Parkinson's disease, multiple sclerosis and Huntington's chorea.
5. The use according to claim 1, wherein the medicament is for reducing the expression of an inflammatory factor.
6. The use according to claim 1, wherein the medicament is for reducing the expression of inflammatory signaling pathways.
7. The use of claim 5, wherein the inflammatory factor comprises any one or more of NO, PGE2, IL-6, and TNF- α in combination.
8. The use according to claim 6, wherein the inflammatory signaling pathway is MAPK and/or NF- κ B.
9. The use according to claim 1, wherein the product is a pharmaceutical or nutraceutical product.
10. The use according to claim 9, wherein the pharmaceutical or nutraceutical is in the form of tablets or capsules or granules or pills or suspensions or dispersions or syrups or injections.
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