CN116712420A - Application of Zanthoxylum bungeanum amide in preparation of medicine for treating multiple sclerosis - Google Patents
Application of Zanthoxylum bungeanum amide in preparation of medicine for treating multiple sclerosis Download PDFInfo
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- CN116712420A CN116712420A CN202310612908.7A CN202310612908A CN116712420A CN 116712420 A CN116712420 A CN 116712420A CN 202310612908 A CN202310612908 A CN 202310612908A CN 116712420 A CN116712420 A CN 116712420A
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- sanshool
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- multiple sclerosis
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- amide
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- 239000003814 drug Substances 0.000 title claims abstract description 35
- 150000001408 amides Chemical class 0.000 title claims abstract description 20
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- 238000002360 preparation method Methods 0.000 title claims description 13
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- 229920001144 Hydroxy alpha sanshool Polymers 0.000 claims abstract description 30
- LHFKHAVGGJJQFF-UEOYEZOQSA-N Hydroxy-alpha-sanshool Chemical group C\C=C\C=C\C=C/CC\C=C\C(=O)NCC(C)(C)O LHFKHAVGGJJQFF-UEOYEZOQSA-N 0.000 claims abstract description 30
- LHFKHAVGGJJQFF-UMYNZBAMSA-N (2e,6e,8e,10e)-n-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide Chemical compound C\C=C\C=C\C=C\CC\C=C\C(=O)NCC(C)(C)O LHFKHAVGGJJQFF-UMYNZBAMSA-N 0.000 claims abstract description 25
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- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses application of Zanthoxylum bungeanum amide in preparing a medicament for treating multiple sclerosis. The Zanthoxylum bungeanum amide is selected from hydroxy-alpha-sanshool and hydroxy-beta-sanshool. The research results of the invention show that the hydroxy-alpha-sanshool and/or the hydroxy-beta-sanshool have good therapeutic effect on experimental autoimmune encephalomyelitis mouse models. Compared with the model group, the drug intervention can obviously improve the nerve dysfunction and disability degree of mice, delay clinical symptoms, relieve spinal tissue inflammation, regulate immune function and show good treatment effect. The invention can provide a new medicine for treating the multiple sclerosis.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of Zanthoxylum bungeanum amide in preparation of a medicine for treating multiple sclerosis.
Background
Multiple sclerosis (multiple sclerosis, MS) is an autoimmune disease characterized mainly by inflammatory demyelinating lesions of the central nervous system, and is mainly manifested by vision loss, multiple vision, limb sensory disorder, limb movement disorder, bladder dysfunction, etc. The disease has multiple time and space, is well developed in young and middle-aged people, and has become the most common cause of permanent disability of young adults except wounds. Currently, there is no unified, effective treatment for multiple sclerosis. Corticosteroids such as prednisone are commonly used in clinic to relieve acute-phase symptoms, medicines for preventing immune system from attacking myelin sheath such as interferon beta, glatiramer acetate, natalizumab, fingolimod and the like are adopted to reduce the future recurrence times, and other medicines for relieving or controlling specific symptoms are used to improve survival conditions. Corticosteroids can shorten the period of onset, but have obvious side effects and are not suitable for long-term use. Immunomodulators such as interferon-beta and natalizumab are expensive, are susceptible to tolerance when used for a long term against a single target drug, and increase the risk of progressive multifocal leukoencephalopathy. The traditional Chinese medicine has the effects of less adverse reaction, multiple targets, multiple ways and system regulation, and has unique advantages in the treatment of multiple sclerosis. Therefore, the safe and effective medicine for treating the multiple sclerosis, which has small toxic and side effects, is found to have important significance from the traditional Chinese medicine treasury.
Disclosure of Invention
The invention aims to provide an application of Zanthoxylum bungeanum amide in preparing a medicament for treating multiple sclerosis.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the invention provides the use of a zanthoxylum bungeanum amide for the manufacture of a medicament for the treatment of multiple sclerosis.
The Zanthoxylum amides are selected from the group consisting of hydroxy-alpha-sanshool, hydroxy-beta-sanshool (ref: jingjin Luo, jingxuan Ke, xiaoyan Hou, shanshan Li, qingying Luo, hejun Wu, guanghui Shen, zhiqing Zhang, composition, structure and flavor mechanism of numbing substances in Chinese prickly ash in the genus Zanthoxylum: A review, food Chemistry,2022,373 (Pt B): 131454.).
The structure of the hydroxy-alpha-sanshool is as follows:
the structure of the hydroxy-beta-sanshool is as follows:
the medicine for treating the multiple sclerosis refers to Zanthoxylum bungeanum amide as the only active ingredient.
The medicament for treating the multiple sclerosis is in the form of capsules, tablets, granules, solutions, suspensions, emulsions or syrups.
The administration mode of the medicine for treating the multiple sclerosis is oral.
By adopting the technical scheme, the invention has the following advantages and beneficial effects:
the research results of the invention show that the hydroxy-alpha-sanshool and/or the hydroxy-beta-sanshool have good therapeutic effect on Experimental Autoimmune Encephalomyelitis (EAE) mouse models. Compared with the model group, the drug intervention can obviously improve the nerve dysfunction and disability degree of mice, delay clinical symptoms, reduce spinal tissue inflammation and show good treatment effect. The invention can provide a new medicine for treating the multiple sclerosis.
The invention carries out systematic chemical research on the amide components of the Zanthoxylum plant, separates a large amount of amide compounds and carries out extensive activity research. Experiments show that the hydroxy-alpha-sanshool and/or the hydroxy-beta-sanshool have good effect of resisting multiple sclerosis, can develop new application, and show great clinical application value.
The animal efficacy experiment proves that the hydroxyl-alpha-sanshool and/or hydroxyl-beta-sanshool of the zanthoxylum bungeanum amide substances can effectively improve the nerve function, relieve the symptoms of paralysis, disability and the like, inhibit spinal tissue inflammation and further achieve the aim of treating multiple sclerosis. The hydroxyl-alpha-sanshool and/or hydroxyl-beta-sanshool are wide in source, can provide a new medicine for treating multiple sclerosis, and have great clinical application value.
Drawings
FIG. 1 is a schematic representation of the effect of hydroxy-alpha-sanshool treatment on the clinical symptoms of EAE multiple sclerosis mice model.
FIG. 2 is a schematic representation of the effect of hydroxy- α -sanshool treatment on spinal cord tissue inflammation in a mice model of EAE multiple sclerosis.
FIG. 3 is a graphical representation of the effect of hydroxy-alpha-sanshool tablet treatment on the clinical symptoms of EAE multiple sclerosis mouse model.
FIG. 4 is a graphical representation of the effect of hydroxy-alpha-sanshool tablet treatment on spinal cord tissue inflammation in a mouse model of EAE multiple sclerosis.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
Example 1
Establishment of multiple sclerosis mouse model and drug administration intervention
The Experimental Autoimmune Encephalomyelitis (EAE) mouse model is a common classical model for multiple sclerosis studies, approaching the key pathological features of immune inflammation and demyelination associated with the disease. The present invention uses MOG/Freund's complete adjuvant/pertussis toxin to induce the model.
Building and grouping EAE mouse models: after 1 week of adaptive feeding, C57BL/6 male mice were randomized into Normal (Normal), model (Model), hydroxy- α -sanshool low dose (HASL, 10 mg/kg), hydroxy- α -sanshool high dose (HASH, 20 mg/kg), hydroxy- β -sanshool low dose (HBSL, 10 mg/kg), and hydroxy- β -sanshool high dose (HBSH, 20 mg/kg), each group of 10 animals. Except for the normal group, the other groups were subcutaneously injected with 50 uL/dot (MOG-containing) of antigen emulsion at four points on both sides of the spinal column of the back of the mouse 35-55 250. Mu.g, inactivated Mycobacterium tuberculosis H37RA 800. Mu.g, PBS 100. Mu.L, freund's complete adjuvant 100. Mu.L); the mice were intraperitoneally injected with 100 μl (500 ng/mouse) of pertussis toxin 30min after the antigen emulsion injection and the following day, respectively. Each administration group was filled with the corresponding drug at the first day of molding, the administration volume was 10mL/kg, 1 time a day, and the normal group and the model group were filled with distilled water at the same volume for 4 weeks continuously. During the experiment, observing the morbidity of the mice at fixed time in the morning and scoring the neural function by adopting a KONO' S scoring method; and finally, the coordination and balance of the mice are evaluated by using a speed-changing rotating rod fatigue tester in three days. After the end of the experiment, mice were sacrificed, spinal cord tissues of each group of mice were removed, and interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-17A (IL-17A) levels were detected by ELISA kit protocol.
The results were analyzed as follows:
FIG. 1 is a schematic representation of the effect of hydroxy-alpha-sanshool treatment on the clinical symptoms of EAE multiple sclerosis mice model. Wherein A is a schematic of the clinical scoring results of KONO' S. In the experimental process, the normal group mice have good growth condition, active diet and bright fur, and are free from abnormality; the model group mice begin to be easy to irritate on the 4 th day, and begin to be continuously ill on the 8 th day of the experiment, and the model group mice are presented with symptoms such as limb weakness, lameness, paralysis and the like; mice in each administration group show symptoms related to diseases such as tail weakness, lameness and the like at 12 days, and compared with a model group, the mice have obvious effects on resisting EAE induction and delaying clinical symptoms and reducing clinical scores through the intervention of hydroxy-alpha-sanshool and hydroxy-beta-sanshool (10, 20 mg/kg).
The coordination and balance of mice were checked by using a rotating rod, and the retention time of mice was recorded, as shown in fig. 1B, which is a schematic diagram of the results at rod time, and the results show that the average of mice in the model group was significantly reduced (p < 0.01), and that after oral administration of hydroxy-alpha-sanshool, hydroxy-beta-sanshool (10, 20 mg/kg), limb movement balance dysfunction caused by EAE (p <0.05 or p < 0.01) was significantly improved.
IFN-gamma, IL-17A and TNF-alpha are common pro-inflammatory cytokines in the body. The results are shown in FIG. 2, and FIG. 2 is a schematic diagram showing the effect of hydroxy-alpha-sanshool and hydroxy-beta-sanshool treatment on spinal cord tissue inflammation in mice model of EAE multiple sclerosis. Wherein, A is the schematic diagram of the effect result of hydroxyl-alpha-sanshool and hydroxyl-beta-sanshool on the spinal cord tissue inflammation IFN-gamma of the EAE multiple sclerosis mouse model, B is the schematic diagram of the effect result of hydroxyl-alpha-sanshool and hydroxyl-beta-sanshool on the spinal cord tissue inflammation IL-17A of the EAE multiple sclerosis mouse model, and C is the schematic diagram of the effect result of hydroxyl-alpha-sanshool and hydroxyl-beta-sanshool on the spinal cord tissue inflammation TNF-alpha of the EAE multiple sclerosis mouse model. IFN-gamma, IL-17A, increases blood brain barrier permeability, and is involved in the pathogenesis of multiple sclerosis; TNF- α and its soluble receptors are involved in the disability, progression of disability and clinical manifestations of multiple sclerosis. The results of ELISA method for determining the content of the three in spinal cord tissue show that compared with normal mice, the levels of IFN-gamma, IL-17A and TNF-alpha in spinal cord tissue of model mice are obviously increased (p < 0.01), and the levels of inflammatory factors in tissues of mice with low and high doses of medicines are obviously reduced (p <0.05 or p < 0.01), which indicates that hydroxy-alpha-sanshool and hydroxy-beta-sanshool have better effects in inhibiting spinal immune inflammation.
In conclusion, the hydroxy-alpha-sanshool and/or the hydroxy-beta-sanshool can inhibit spinal cord inflammation, obviously improve the nerve function and the overall functional state of an EAE model mouse, inhibit the occurrence and the development of multiple sclerosis, and have great potential for becoming a drug for treating multiple sclerosis.
Example 2
Preparation of tablets:
hydroxy-alpha-sanshool or hydroxy-beta-sanshool 5g
Lactose 42g
Corn starch 12g
Magnesium stearate 1g
The preparation method comprises the following steps: mixing hydroxy-alpha-sanshool or hydroxy-beta-sanshool, lactose and corn starch, wetting with 20mL water, sieving the mixture, drying at 55deg.C, sieving again, adding magnesium stearate, mixing, sieving, and tabletting with single punch. Each tablet weighs 300mg, and the content of the hydroxy-alpha-sanshool or the hydroxy-beta-sanshool is 25mg.
Pharmacodynamic experiments on tablets:
building and grouping EAE mouse models: after 1 week of C57BL/6 male mice were acclimatized, they were randomly assigned to Normal (Normal), model (Model), hydroxy- α -sanshool (HAST, 48 mg/kg), hydroxy- β -sanshool (HBST, 48 mg/kg) and 10 animals per group. Except for the normal group, the other groups were subcutaneously injected with 50 uL/dot (MOG-containing) of antigen emulsion at four points on both sides of the spinal column of the back of the mouse 35-55 250. Mu.g, inactivated Mycobacterium tuberculosis H37RA 800. Mu.g, PBS 100. Mu.L, freund's complete adjuvant 100. Mu.L); the mice were intraperitoneally injected with 100 μl (500 ng/mouse) of pertussis toxin 30min after the antigen emulsion injection and the following day, respectively. Each administration group was filled with the corresponding drug at the first day of molding, the administration volume was 10mL/kg, 1 time a day, and the normal group and the model group were filled with distilled water at the same volume for 4 weeks continuously. During the experiment, observing the morbidity of the mice at fixed time in the morning and scoring the neural function by adopting a KONO' S scoring method; and finally, the coordination and balance of the mice are evaluated by using a speed-changing rotating rod fatigue tester in three days. After the end of the experiment, mice were sacrificed, spinal cord tissues of each group of mice were removed, and IFN-. Gamma., TNF-. Alpha., IL-17A levels were detected by ELISA kit according to the instructions.
The results are shown in FIG. 3, and FIG. 3 is a schematic diagram showing the effect of hydroxy-alpha-sanshool tablets, hydroxy-beta-sanshool tablet treatment on the clinical symptoms of EAE multiple sclerosis mice model. Wherein A is a schematic of the clinical scoring results of KONO' S. In the experimental process, the normal group mice have good growth condition, bright fur and normal activity; the model group mice begin to be easy to irritate on the 5 th day, and begin to be developed successively on the 8 th day of the experiment, and the model group mice are represented by symptoms such as tail weakness, hindlimb trawling, limb paralysis and the like; mice in each administration group show symptoms related to diseases such as tail weakness, lameness and the like at 12 days, and compared with a model group, the mice have obvious effects on resisting EAE induction, delaying clinical symptoms and reducing clinical scores through the intervention of the hydroxy-alpha-sanshool tablet and the hydroxy-beta-sanshool tablet. The coordination and balance of mice were tested using a rotating rod, and the residence maintenance time of mice was recorded, as shown in fig. 3B, and the average in-rod time of mice in the model group was significantly reduced (p < 0.01), and after the gastric lavage of the hydroxy-alpha-sanshool tablet and the hydroxy-beta-sanshool tablet, the limb movement balance dysfunction caused by EAE was significantly improved (p < 0.01).
The results are shown in FIG. 4, and FIG. 4 is a graph showing the effect of hydroxy-alpha-sanshool tablets, hydroxy-beta-sanshool tablet treatment on spinal cord tissue inflammation in mice model of EAE multiple sclerosis. Wherein, A is the schematic diagram of the effect result of the gastric lavage hydroxyl-alpha-sanshool tablet and the hydroxyl-beta-sanshool tablet on the spinal cord tissue inflammation IFN-gamma of the EAE multiple sclerosis mouse model, B is the schematic diagram of the effect result of the gastric lavage hydroxyl-alpha-sanshool tablet and the hydroxyl-beta-sanshool tablet on the spinal cord tissue inflammation IL-17A of the EAE multiple sclerosis mouse model, and C is the schematic diagram of the effect result of the gastric lavage hydroxyl-alpha-sanshool tablet and the hydroxyl-beta-sanshool tablet on the spinal cord tissue inflammation TNF-alpha of the EAE multiple sclerosis mouse model. The results show that compared with the normal mice, the levels of IFN-gamma, IL-17A and TNF-alpha in spinal cord tissues of the mice in the model group are obviously increased (p < 0.01), the levels of the inflammatory factors in the tissues of the mice filled with the gastric hydroxyl-alpha-sanshool tablets and the hydroxyl-beta-sanshool tablets are obviously reduced (p <0.05 or p < 0.01), and the hydroxyl-alpha-sanshool tablets and the hydroxyl-beta-sanshool tablets are suggested to have better effects in inhibiting spinal immune inflammation.
The results show that the hydroxyl-alpha-sanshool tablet and the hydroxyl-beta-sanshool tablet can reduce the incidence of multiple sclerosis, improve spinal cord tissue inflammation and have good therapeutic effect on the disease.
Example 3
Preparation of oral suspension:
hydroxy-alpha-sanshool or hydroxy-beta-sanshool 6g
Citric acid 1g
Glycerol 20mL
Tween-80 2mL
Pregelatinized starch 0.2g
Sodium benzoate 0.2g
Xanthan gum 0.5g
Purified water was added to 200mL.
The preparation method comprises the following steps: adding tween-80 and glycerol into hydroxy-alpha-sanshool or hydroxy-beta-sanshool, mixing thoroughly, adding pregelatinized starch, xanthan gum, sodium benzoate and citric acid under stirring, adding water to 200mL, stirring to disperse thoroughly, and obtaining oral suspension.
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.
Claims (7)
1. Application of Zanthoxylum bungeanum amide in preparing medicine for treating multiple sclerosis is provided.
2. Use of Zanthoxylum bungeanum amide according to claim 1 for the preparation of a medicament for the treatment of multiple sclerosis, characterized in that said Zanthoxylum amide is selected from the group consisting of hydroxy- α -sanshool, hydroxy- β -sanshool.
3. Use of Zanthoxylum bungeanum amide according to claim 2 for the preparation of a medicament for the treatment of multiple sclerosis, characterized in that the hydroxy- α -sanshool has the structure:
4. use of Zanthoxylum bungeanum amide according to claim 2 for the preparation of a medicament for the treatment of multiple sclerosis, characterized in that the hydroxy- β -sanshool has the structure:
5. use of Zanthoxylum bungeanum amide according to claim 1 for the preparation of a medicament for the treatment of multiple sclerosis, characterized in that said medicament for the treatment of multiple sclerosis refers to Zanthoxylum amide as sole active ingredient.
6. Use of Zanthoxylum bungeanum amide according to claim 1 for the preparation of a medicament for the treatment of multiple sclerosis, characterized in that the medicament for the treatment of multiple sclerosis is in the form of a capsule, a tablet, a granule, a solution, a suspension, an emulsion or a syrup.
7. Use of Zanthoxylum bungeanum amide according to claim 1 for the preparation of a medicament for the treatment of multiple sclerosis, characterized in that the administration of said medicament for the treatment of multiple sclerosis is oral.
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