CN113181182A - Application of pseudolycorine in preparation of medicine for preventing and/or treating multiple sclerosis - Google Patents
Application of pseudolycorine in preparation of medicine for preventing and/or treating multiple sclerosis Download PDFInfo
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- CN113181182A CN113181182A CN202110621558.1A CN202110621558A CN113181182A CN 113181182 A CN113181182 A CN 113181182A CN 202110621558 A CN202110621558 A CN 202110621558A CN 113181182 A CN113181182 A CN 113181182A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Abstract
The invention provides application of pseudolycorine or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating multiple sclerosis. The invention proves that the pseudolycorine hydrochloride can effectively prevent and improve the occurrence and development of autoimmune encephalomyelitis and obviously lighten the demyelinating injury of spinal white matter and the inflammatory infiltration of central nervous system lymphocytes by inhibiting the differentiation and the amplification of pathogenic Th17 cells at the focal positions of peripheral immune organs and central nervous system and the secretion of inflammatory cytokines through an ideal animal model of human multiple sclerosis, namely an autoimmune encephalomyelitis whole animal disease model induced by myelin oligodendrocyte glycoprotein (35-55 segments).
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of pseudolycorine or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating multiple sclerosis.
Background
Multiple Sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination, a central nervous system involvement, manifested primarily by recurrent episodes of vision loss, diplopia, acrosomatic or movement disorders, ataxia, bladder or rectal dysfunction. The disease is the second leading cause of permanent disability of adults except for trauma, and is easy to cause large social and economic burden. Recent statistics in 2020 indicate that the incidence of multiple sclerosis in adults in our country is 0.235/10 million per year. The mouse autoimmune encephalomyelitis (EAE) whole animal disease model is an ideal animal model for researching human multiple sclerosis, has important significance in the research of clinical neuroimmunology, and provides a reliable basis for the new treatment of the disease or the screening of new drugs.
Although the pathogenesis of multiple sclerosis is not completely understood at present, recent studies have found that autoantigen-specific Th17 cells play a crucial role in the development of the disease. IL-17 secreted by Th17 cells can affect the functions of endothelial cells, epithelial cells, fibroblasts, myeloid cells, microglia and other cells, and promote the secretory expression of various inflammatory mediators, including IL-8, CXCL1, CXCL6, IL-1 beta, IL-6, TNF-alpha, GM-CSF, MIP-2, nitric oxide, neurotrophic factors, adhesion molecules and the like. In addition, IL-17 is also a key factor for Th17 cells to migrate across the blood brain barrier by inducing the expression of MMP-3 and CCR 6. The development of a therapeutic drug for autoimmune encephalomyelitis (namely multiple sclerosis) by aiming at the differentiation and the amplification of Th17 cells and taking the cell function as a target point also becomes a hot spot of the research and the development of a new drug for the autoimmune disease of the central nervous system.
Pseudo-lycorine hydrochloride (Pseudolycorine) is an extract of lycoris radiata or lycoris aurea bulb in lycoris family, and the previous research shows that the small molecular compound has obvious antiviral, antileukemia and antiparasitic activities and has killing effect on a plurality of solid tumor cells with apoptosis resistance. The structural analogues of pseudolycorine hydrochloride, such as lycorine, have been found to act on intracellular signal targets such as Reactive Oxygen Species (ROS) and Jak-Stat, key molecules of the cell signal transmission have a key regulation effect on the activation and function of immune cells, but the regulation of the immune activity of the pseudolycorine hydrochloride and the effect in autoimmune diseases.
At present, the effect of pseudolycorine hydrochloride in multiple sclerosis is not reported at home and abroad, and the structural formula of the pseudolycorine hydrochloride (C13H20CINO4) is as follows:
disclosure of Invention
In order to solve the problems, the invention provides application of pseudolycorine or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating multiple sclerosis.
Further, the pharmaceutically acceptable salt thereof is pseudolycorine hydrochloride.
Further, the medicament is a medicament for alleviating the degree of inflammatory infiltration of lymphocytes in the spinal cord.
Further, the drug is a drug that reduces the demyelinating area of the spinal cord.
Further, the drug is a drug that inhibits Th17 cells.
Still further, the medicament is a medicament for inhibiting spinal cord Th17 cell differentiation and expansion and/or peripheral blood Th17 cell-associated inflammatory cytokine secretion; the related inflammatory cytokines include but are not limited to IL-6, IL-23, IL-17A.
Furthermore, the medicine takes pseudolycorine or medicinal salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials or auxiliary ingredients are added to prepare a common preparation.
Further, the preparation is in the form of oral preparation or injection.
Further, the oral preparation includes but is not limited to tablets, granules, capsules, pills, powders, suspensions or solutions.
The pseudolycorine or the medicinal salt thereof is used for preparing the medicine for preventing and/or treating the multiple sclerosis, and the autoimmune encephalomyelitis integral animal disease model induced by Myelin Oligodendrocyte Glycoprotein (MOG) (35-55 segments) which is an ideal animal model of the human multiple sclerosis proves that the pseudolycorine hydrochloride can effectively prevent and improve the occurrence and development of the autoimmune encephalomyelitis by inhibiting the differentiation and the amplification of pathogenic Th17 cells at the focus parts of peripheral immune organs and central nervous system and the secretion of inflammatory cytokines, thereby obviously relieving the demyelinating injury of the spinal white matter and the inflammatory infiltration of lymphocytes of the central nervous system. Based on the above, the pseudolycorine hydrochloride can be used for preparing a medicine for preventing and treating multiple sclerosis, is a natural small molecular compound which has huge clinical application potential and can be used for treating autoimmune diseases of the central nervous system.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 Pseudolycorine hydrochloride reduces clinical disease activity scores in mice modelled by EAE
FIG. 2 shows that pseudolycorine hydrochloride can reduce the degree of spinal cord lymphocyte infiltration of mice molded by EAE
FIG. 3 Pseudolycorine hydrochloride can reduce spinal cord demyelination in mice molded with EAE
FIG. 4 shows that pseudolycorine hydrochloride can reduce the infiltration degree of Th17 cells in spinal cord of mice molded with EAE
FIG. 5 Pseudolycorine hydrochloride can reduce Th 17-related inflammatory cytokine concentration in peripheral blood of mice model of EAE
Detailed Description
Example 1 Effect of Pseudolycorine hydrochloride on autoimmune encephalomyelitis Whole animal disease model
The following animal protocol was approved by the institutional animal care and use committee and the ethical committee on laboratory animals. Experimental data were statistically analyzed using GraphPad Prism 6.0 software. The measurement data are expressed in x + -s, and t-test is applied to analyze the difference between the two groups; one-way variance (ANOVA), combined with Bonferroni, was applied to analyze differences between groups, and the specific experimental methods and results were as follows:
1. pseudolycorine hydrochloride: obtained by purchasing a commercially available product;
2. establishment of mouse EAE model
(1)MOG35-55Dissolving the (myelin oligodendrocyte glycoprotein 35-55 fragment) polypeptide freeze-dried powder in PBS to prepare a solution with the final concentration of 2 mg/mL;
(2)MOG35-55the polypeptide solution is prepared by the following steps of 1: 1 proportion and complete Freund's adjuvant (4mg/mL tuberculin), emulsifying and homogenizing to prepare EAE-inducing antigen emulsion;
(3) 2% sodium pentobarbital is used for anesthetizing 8-12-week-old female C57BL/6 mice (50mg/kg), and then antigen emulsion is injected subcutaneously at multiple points (s.c.) around the spinal column of the back of each group of mice, wherein the injection dose of each mouse is 200 mu L;
(4) mice were given an intraperitoneal injection (i.p.) of pertussis toxin 200 ng/mouse on the day of immunization, i.e., at 0 and 48 hours, respectively;
3. experiment grouping
27 EAE molding mice were randomly divided into a solvent (physiological saline) control group, a pseudolycorine hydrochloride group of 40mg/kg and a tacrolimus positive control group, from the 0 th day of primary immunization, the pseudolycorine hydrochloride and tacrolimus were administered by intraperitoneal injection (i.p.) for 18 consecutive days, and the control group was injected with the same amount of solvent. Animals were sacrificed on day 20 after molding immunization and pathological sampling was performed.
4. Clinical disease activity score
Benson scoring criteria: 0 minute: no symptoms are caused; 1 minute: the tail tension disappears, and mild gait is clumsy; and 2, dividing: the two hind limbs are weak and can recover after being turned over passively; and 3, dividing: double hind limb paralysis cannot be recovered after passive turning over, but can be moved after stimulation is given; and 4, dividing: double hind limb paralysis, forelimb paralysis or weakened muscle strength with urinary incontinence; and 5, dividing: moribund status or death. Clinical scoring clinical assessment of EAE severity was performed blindly, with 2 persons per day at least 1 time at the same time, according to the Benson scoring criteria. Benson score, with symptoms between the two criteria, calculated as. + -. 0.5.
5. Staining of common pathological tissues
(1) After anesthetizing the mice with 2% sodium pentobarbital (50mg/kg), the mice were perfused with physiological saline and 4% paraformaldehyde; the lumbar enlargement section of the spinal cord is taken out and placed in 4% paraformaldehyde for overnight fixation at 4 ℃. After the material is fixed, the graded ethanol solution is dehydrated; adding ethanol, xylene and xylene for transparency. After clearing, the tissues were embedded in paraffin and the embedded tissues were sectioned (8 μm).
(2) Dewaxing the slices by dimethylbenzene, and adding graded ethanol for rehydration; performing hematoxylin/eosin (HE) staining after rehydration; and (5) sealing and storing neutral gum after dyeing is finished.
(3) The step of dyeing, dewaxing and rehydration by Locker Fast Blue (LFB) is the same as the step of dyeing by HE; after LFB dyeing, 0.05% lithium carbonate solution is differentiated, after graded ethanol rinsing, xylene rinsing is carried out, after dyeing, neutral gum sealing is carried out, and microscopic examination is carried out.
6. Frozen section immunofluorescence detection
After anesthetizing the mice with 2% sodium pentobarbital (50mg/kg), the mice were perfused with physiological saline and 4% paraformaldehyde; taking out the spinal cord lumbar enlargement segment, placing the spinal cord lumbar enlargement segment in 4% paraformaldehyde, and fixing the spinal cord lumbar enlargement segment at 4 ℃ overnight; dehydrating 30% sucrose, and embedding with embedding medium; after embedding, frozen sections (20 μm) were taken. The frozen section is blocked by PBS containing 10% mouse serum, incubated with rabbit anti-mouse IL-17A and rat anti-mouse CD4 antibody, washed, incubated with fluorescence labeled secondary antibody, blocked and examined by fluorescence microscope.
7. Enzyme linked immunosorbent assay (ELISA) detection
The concentrations of IL-6, IL-23 and IL-17A in mouse serum are detected by adopting a corresponding cytokine ELISA detection kit.
8. Results of the experiment
(1) From MOG35-55The results of the clinical disease activity scores of the mice of the different treatment groups according to the Benson score criteria are shown in FIG. 1, starting on day 1 and ending on day 20 of the polypeptide immunization of C57BL/6 mice.
As can be seen from FIG. 1, the EAE-modeled mice of the 40mg/kg pseudolycorine hydrochloride group had a significant decrease in clinical disease activity score (p <0.05) from day 13 compared to the solvent control group, indicating that the disease condition of the EAE-modeled mice of the group was significantly alleviated from day 13; the clinical disease activity score of the EAE model-making mice of the 1mg/kg tacrolimus positive control group is obviously reduced (p is less than 0.05) from the 14 th day, which indicates that the disease of the EAE model-making mice is obviously relieved from the 14 th day.
Tacrolimus also plays a positive role in treating autoimmune diseases such as Atopic Dermatitis (AD), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and the like as a powerful immunosuppressant, and test results prove that pseudolycorine hydrochloride shows similar effect to tacrolimus when the pseudolycorine hydrochloride is used for intervening in the treatment of EAE, thereby indicating that the pseudolycorine hydrochloride can be applied to the preparation of the medicine for treating autoimmune encephalomyelitis/multiple sclerosis.
(2) The spinal cord lymphocyte infiltration condition of each group of mice is detected by HE staining, and the inflammatory infiltration area of HE staining pathological sections is semi-quantitatively analyzed by Image-Pro Plus Image analysis software, and the result is shown in figure 2.
As can be seen from fig. 2: compared with a solvent control group, the inflammatory infiltration area of the spinal cord of the EAE molding mice of the 40mg/kg pseudolycorine hydrochloride group is obviously reduced (p is less than 0.05), which indicates that the inflammatory infiltration degree of lymphocytes in the spinal cord of the EAE molding mice of the group is relieved; the results of the 1mg/kg tacrolimus positive control group were similar to the 40mg/kg pseudolycorine hydrochloride group.
(3) Spinal cord demyelination was detected by LFB staining in each group of mice and semi-quantitative analysis of demyelinated area of LFB stained pathological sections was performed using Image-Pro Plus Image analysis software, and the results are shown in fig. 3.
As can be seen from fig. 3: compared with the solvent control group, the demyelinating area of the spinal cord of the EAE modeling mice of the 40mg/kg pseudolycorine hydrochloride group is obviously reduced (p is less than 0.05), which indicates that the demyelinating degree of the white matter of the spinal cord of the EAE modeling mice is relieved; the results of the 1mg/kg tacrolimus positive control group were similar to the 40mg/kg pseudolycorine hydrochloride group.
(4) Expression of Th17 cells in spinal cords of mice in each group was detected by immunofluorescence staining, and Image-Pro Plus Image analysis software was used to analyze CD4 cells per unit area of frozen spinal cord sections of mice in each group+IL-17A+The cell number was semi-quantitatively analyzed, and the results are shown in FIG. 4.
As can be seen from fig. 4: compared with solvent control group, the unit area CD4 of the spinal cord of mice molded by EAE of pseudolycorine hydrochloride group of 40mg/kg+IL-17A+The number of cells is obviously reduced (p)<0.05), which indicates that the infiltration degree of Th17 cells in spinal cord of the group of mice with EAE molding is obviously reduced; the results of the 1mg/kg tacrolimus positive control group were similar to the 40mg/kg pseudolycorine hydrochloride group.
(5) The concentration of Th17 cell-associated inflammatory cytokines in peripheral blood of each group of mice was measured by ELISA, and the results are shown in FIG. 5.
As can be seen from fig. 5: compared with a solvent control group, the concentrations of IL-6, IL-23 and IL-17A in peripheral blood of mice molded by EAE of the pseudolycorine hydrochloride group at 40mg/kg are obviously reduced (p is less than 0.05). The expression level of a key inflammatory cytokine IL-17A is reduced, which indicates that the Th17 cytopathogenicity of the group of EAE modeling mice is reduced; the expression level of IL-6 and IL-23 is reduced, which shows that the differentiation and survival ability of Th17 cells are also reduced; the results of the 1mg/kg tacrolimus positive control group were similar to the 40mg/kg pseudolycorine hydrochloride group.
In conclusion, the invention proves that the pseudolycorine hydrochloride can effectively prevent and improve the occurrence and development of the autoimmune encephalomyelitis and obviously relieve the demyelination injury of spinal white matter and the inflammatory infiltration of central nervous system lymphocytes through an autoimmune encephalomyelitis whole animal disease model, can be used for preparing the medicine for preventing and treating the multiple sclerosis, and is a natural small molecular compound with huge clinical application potential.
Claims (10)
1. Use of pseudolycorine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of multiple sclerosis.
2. Use according to claim 1, characterized in that: the pharmaceutically acceptable salt thereof is pseudolycorine hydrochloride.
3. Use according to claim 1, characterized in that: the medicament is a medicament for relieving the inflammatory infiltration degree of lymphocytes in the spinal cord.
4. Use according to claim 1, characterized in that: the medicament is a medicament that reduces the demyelinating area of the spinal cord.
5. Use according to claim 1, characterized in that: the drug is a drug that inhibits Th17 cells.
6. Use according to claim 5, characterized in that: the medicine is used for inhibiting spinal cord Th17 cell differentiation and expansion and/or peripheral blood Th17 cell-related inflammatory cytokine secretion.
7. Use according to claim 6, characterized in that: the related inflammatory cytokines include but are not limited to IL-6, IL-23, IL-17A.
8. Use according to any one of claims 1 to 7, characterized in that: the medicine is prepared into a common preparation by taking pseudolycorine or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
9. Use according to claim 8, characterized in that: the preparation is in the form of oral preparation or injection.
10. Use according to claim 9, characterized in that: the oral preparation comprises but is not limited to tablets, granules, capsules, pills, powder, suspension or solution.
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Non-Patent Citations (2)
| Title |
|---|
| GAN ZHANG等: "Pseudolycorine Chloride Ameliorates Th17-cell-mediated CNS Autoimmunity by Restraining MDSCs Expansion", 《RESEARCH SQUARE》 * |
| 吴利红等: "伪石蒜碱抑制活化T细胞增殖与功能的机制研究", 《中国现代应用药学》 * |
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