Application of docosapentaenoic acid in preparation of medicine for preventing and / or treating systemic lupus erythematosus

Abstract

The invention discloses application of docosapentaenoic acid or medicinal salt thereof in preparation of a medicine for preventing and / or treating systemic lupus erythematosus. The invention aims to provide novel application of docosapentaenoic acid in treatment of systemic lupus erythematosus. In view of various immune abnormalities existing in the systemic lupus erythematosus morbidity process, the docosapentaenoic acid has potential application value in the field of systemic lupus erythematosus treatment due to the effects of regulating immune cell functions and improving immune microenvironment.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to application of docosapentaenoic acid or a pharmaceutical salt thereof in preparation of a medicine for preventing and / or treating systemic lupus erythematosus. BACKGROUND

[0002] Docosapentaenoic acid belongs to the organic compounds of polyunsaturated fatty acids, and is a fatty acid molecule with unique physiological functions. In the body, docosapentaenoic acid is a prolonged metabolic product of EPA and is an intermediate product of EPA and DHA. It exhibits certain effects in maintaining cardiovascular health, improving nervous system function, and reducing inflammatory response.

[0003] Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve multiple systems and organs of the body, mainly including skin, kidney, blood system, cardiovascular system, etc. There are multiple immune abnormalities in the body of patients with systemic lupus erythematosus, including DC cell migration defects, Treg cell functional abnormalities, and Th1 cell overactivation, etc. These abnormalities interact with each other, leading to the occurrence and development of the disease. The pathogenesis has not been fully understood, and it may be related to multiple factors such as genetics, autoimmune disorders, environment, and infection. The drugs currently used in the clinical treatment of systemic lupus erythematosus mainly include glucocorticoids, antimalarials, immunosuppressive agents, and biological agents, which are mainly used to inhibit inflammatory response, reduce autoantibodies, relieve immune response, and control disease progression, etc. The existing treatment methods can relieve symptoms to a certain extent, but have many limitations, such as large side effects of immunosuppressive agents and antibody biological agents, increased risk of infection and tumor by long-term use, and easy recurrence after drug withdrawal, etc.

[0004] At present, there is no literature report about the activity and mechanism of docosapentaenoic acid or its pharmaceutical salt against systemic lupus erythematosus. SUMMARY

[0005] The application aims to provide application of docosapentaenoic acid or its pharmaceutical salt in preparation of a medicine for preventing and / or treating systemic lupus erythematosus.

[0006] In order to achieve the above-mentioned purpose, the technical scheme adopted by the application is as follows:

[0007] In a first aspect of the application, application of docosapentaenoic acid or its pharmaceutical salt in preparation of a medicine for preventing and / or treating systemic lupus erythematosus is provided.

[0008] The all-cis-7,10,13,16,19-docosapentaenoic acid (DPA) has a CAS: 24880-45-3.

[0009] The drug for preventing and / or treating systemic lupus erythematosus is made of all-cis-7,10,13,16,19-docosapentaenoic acid or a pharmaceutically acceptable salt thereof as a sole active ingredient.

[0010] The pharmaceutically acceptable salt is a salt of all-cis-7,10,13,16,19-docosapentaenoic acid with sodium hydroxide, sodium carbonate, potassium hydroxide, calcium hydroxide, calcium chloride, magnesium oxide, magnesium hydroxide.

[0011] In a second aspect of the present application, a pharmaceutical preparation is provided, which is made of all-cis-7,10,13,16,19-docosapentaenoic acid or a pharmaceutically acceptable salt thereof and a medically acceptable auxiliary.

[0012] The pharmaceutical preparation has a dosage form selected from the group consisting of a suspension, a granule, a capsule, a tablet, a powder, an emulsion, a solution, a dripping pill, an injection, a suppository, an enema, an aerosol, a patch, and a drop.

[0013] The pharmaceutical preparation is administered orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, sublingually, transdermally, or rectally.

[0014] In a third aspect of the present application, a pharmaceutical composition is provided, which is made of all-cis-7,10,13,16,19-docosapentaenoic acid or a pharmaceutically acceptable salt thereof and another drug for treating systemic lupus erythematosus.

[0015] The other drug for treating systemic lupus erythematosus is selected from the group consisting of a non-steroidal anti-inflammatory drug, an antimalarial drug, a glucocorticoid, an immunosuppressant, and a biological agent.

[0016] The present application can inhibit the excessive immune response of a patient with systemic lupus erythematosus, restore the accumulation of thymic migratory peripheral dendritic cells and the generation of Treg cells, inhibit the excessive activation of Th1 cells, rebuild the central tolerance of systemic lupus erythematosus, inhibit tissue inflammation and damage, promote the restoration of central immune tolerance of systemic lupus erythematosus, and effectively relieve the symptoms of systemic lupus erythematosus.

[0017] Thanks to the above technical solutions, the present application has the following advantages and beneficial effects:

[0018] The docosapentaenoic acid can play a role in multiple key links in the pathogenesis of systemic lupus erythematosus, restore the aggregation of thymic migratory peripheral dendritic cells (Dendritic cell, DC) and Treg cell generation, restore thymic DC migration defects and inhibit Th1 cell overactivation, and other mechanisms, rebuild the central tolerance of systemic lupus erythematosus and inhibit tissue inflammation and damage, promote the recovery of central immune tolerance of systemic lupus erythematosus, and effectively relieve the symptoms of systemic lupus erythematosus. And the source of docosapentaenoic acid is relatively extensive, the preparation cost is low, and the safety is high, and there is no obvious toxic and side effects, which provides a new and more potential drug selection for the prevention and / or treatment of SLE.

[0019] The present application aims to provide a new use of docosapentaenoic acid in the treatment of systemic lupus erythematosus. In view of the various immune abnormalities in the pathogenesis of systemic lupus erythematosus, the role of docosapentaenoic acid in regulating immune cell function and improving immune microenvironment makes it have potential application value in the field of systemic lupus erythematosus treatment.

[0020] The docosapentaenoic acid provided by the present application can reduce the level of autoimmune antibodies and kidney C3c complement deposition, inhibit the excessive immune response of systemic lupus erythematosus patients, restore the aggregation of thymic migratory peripheral dendritic cells and Treg cell generation, reduce the kidney inflammation caused by lupus, and inhibit the proportion of Th1 cells in the spleen and lymph nodes. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 The results of the influence of docosapentaenoic acid on the thymic dendritic cells of systemic lupus erythematosus mice are shown in the figure.

[0022] Figure 2 The results of the influence of docosapentaenoic acid on the migration ability of thymic dendritic cells of systemic lupus erythematosus mice are shown in the figure.

[0023] Figure 3 The results of the influence of docosapentaenoic acid on the proportion of Treg cells in the thymus of systemic lupus erythematosus mice are shown in the figure.

[0024] Figure 4 The results of the influence of docosapentaenoic acid on the pathological damage and inflammatory response of systemic lupus erythematosus mice are shown in the figure.

[0025] Figure 5 The results of the influence of docosapentaenoic acid on the proportion of thymic dendritic cells of systemic lupus erythematosus mice are shown in the figure.

[0026] Figure 6 The results of the influence of docosapentaenoic acid on the migration function of thymic dendritic cells of systemic lupus erythematosus mice are shown in the figure.

[0027] Figure 7This is a schematic diagram showing the effect of DPA treatment on Treg cells in mice with systemic lupus erythematosus.

[0028] Figure 8 This is a schematic diagram showing the effect of DPA treatment on Th1 cells in mice with systemic lupus erythematosus. Detailed Implementation

[0029] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0030] Example 1

[0031] Changes in migratory dendritic cells and Treg cells in systemic lupus erythematosus (SLE) mice and control mice (Ctrl).

[0032] Eight-week-old female C57 / BL6 mice were randomly divided into two groups according to their body weight: a control group (Ctrl) and a model group (SLE). A systemic lupus erythematosus (SLE) mouse model was established according to the literature (Suppression of Autoimmunity and Renal Disease in Pristane-Induced Lupus by Myeloperoxidase. Arthritis Rheumatol. 2015 Jul;67(7):1868-80.). Mice in the control group were injected intraperitoneally with 0.5 mL of physiological saline, while mice in the model group were injected intraperitoneally with 0.5 mL of styrannol (Sigma). Four months later, skin lesions, urinary protein, and autoantibodies were detected, confirming the successful establishment of the SLE mouse model. Mice were euthanized by cervical dislocation, and thymus tissue was collected. The proportions of DC cell subsets (XCR1+SIRPα+cDC1 and XCR1-SIRPα+cDC2) and regulatory T cells (Tregs) were detected by flow cytometry and other methods.

[0033] Flow cytometry results as follows Figure 1 As shown, Figure 1 This diagram illustrates the changes in thymic dendritic cells in mice with systemic lupus erythematosus (SLE). Figure A shows the flow cytometry results of the cDC1 to cDC2 ratio in the thymus of SLE mice. As can be seen, the proportion of XCR1-SIRPα+cDC2 in the thymus of the model group mice was significantly lower than that in the control group, indicating a significant decrease in the number of migratory cDC2 cells in the thymus of SLE mice. Figure B shows the corresponding statistical results from A. The results shown are mean ± standard deviation (n=5~7).

[0034] Flow cytometry results are shown in Figure 2 , and Figure 2 is a schematic diagram of the change in the migration ability of the dendritic cells of the thymus of the systemic lupus erythematosus mice. In the diagram, A is a schematic diagram of the flow cytometry detection results of the proportion of CCR2+cDC2 in the thymus of the systemic lupus erythematosus mice. As can be seen from the diagram, the proportion of CCR2+cDC2 in the thymus of the model group mice is significantly lower than that of the control group, that is, the homing of CCR2-mediated cDC2 to the thymus is impaired in the systemic lupus erythematosus mice; B is a schematic diagram of the corresponding statistical results in A. The results shown in the diagram are the mean ± standard deviation (n = 4-5).

[0035] Flow cytometry results are shown in Figure 3 , and Figure 3 is a schematic diagram of the change in the proportion of Treg cells in the thymus of the systemic lupus erythematosus mice. In the diagram, A is a schematic diagram of the flow cytometry detection results of the proportion of Treg in the thymus of the systemic lupus erythematosus mice. As can be seen from the diagram, the proportion of Treg cells in the thymus of the model group mice is significantly lower than that of the control group, that is, the generation and development of Treg are defective in the systemic lupus erythematosus mice, and the central immune tolerance is impaired; B is a schematic diagram of the corresponding statistical results in A. The results shown in the diagram are the mean ± standard deviation (n = 3-6).

[0036] In summary, the migration of cDC2 to the thymus is selectively impaired in the systemic lupus erythematosus mice, leading to defective generation and development of Treg, decreased immune suppression function, and impaired central immune tolerance.

[0037] Example 2

[0038] Effect of docosapentaenoic acid (DPA) on systemic lupus erythematosus mouse model

[0039] Normal 13-week-old MRL mice were used as the control group (Ctrl), and spontaneous systemic lupus erythematosus mice MRL / lpr were randomly divided into three groups, namely the control group, the model group (MRL / lpr Ctrl) and the administration group (MRL / lpr DPA). The control group and the model group were fed with normal saline (100 mg / kg / day) every day, and the administration group was fed with DPA (100 mg / kg / day) every day. After 6 weeks of treatment, the control group, the model group and the administration group mice were sacrificed by cervical dislocation, and the mouse serum samples were collected for detection of autoimmune antibody levels; the mouse kidney tissues were taken for detection of kidney C3c complement deposition; at the same time, the thymus (Thymus), spleen (Spleen) and lymph node (LN) tissues were taken, and DC cells, Treg cells and Th1 cells were detected by flow cytometry and other methods.

[0040] The results of the detection of the self-antibody, the kidney self-antibody deposition and the kidney HE staining are shown in Figure 4 Figure 4 The results of the DPA treatment on the pathological damage and inflammatory response of the SLE mice are shown in the figure. A is a statistical diagram of the detection results of the SLE self-antibody of the DPA treatment (n=5). As can be seen from the figure, the SLE self-antibody level of the administration group is lower than that of the model group, that is, the DPA supplement can reduce the SLE self-antibody level of the mice and improve the inflammatory level of the mice. B is a diagram of the immunofluorescence detection results of the DPA treatment on the kidney self-antibody deposition of the SLE mice. As can be seen from the figure, the kidney self-antibody deposition of the administration group is less than that of the model group, and the DPA supplement can reduce the kidney self-antibody deposition of the SLE mice and relieve the kidney damage. C is a diagram of the HE staining detection results of the DPA treatment on the kidney pathology of the SLE mice. As can be seen from the figure, compared with the normal kidney of the control group, the inflammatory cell infiltration of the SLE kidney of the administration group is significantly reduced, and the glomerular swelling is obviously improved. Therefore, the DPA can reduce the overall inflammatory response by reducing the SLE self-antibody level of the mice, reduce the kidney self-antibody deposition to reduce the antibody-mediated kidney damage, and significantly improve the pathological state of the kidney tissue, thereby playing an anti-inflammatory and kidney protection role in the disease progression of the SLE mice.

[0041] The flow cytometry results are shown in Figure 5 Figure 5 The results of the DPA treatment on the proportion of the thymus dendritic cells of the SLE mice are shown in the figure. A is a diagram of the flow cytometry detection results of the DPA treatment on the proportion of the thymus cDC1 and cDC2. As can be seen from the figure, the proportion of the SIRPα+cDC2 of the administration group is significantly higher than that of the model group, that is, the DPA supplement can increase the proportion of the migratory dendritic cells, that is, the SIRPα+cDC2, in the thymus of the SLE mice. B is a diagram of the corresponding statistical results of A. The results shown in the figure are the mean value ± standard deviation (n=3).

[0042] The flow cytometry results are shown in Figure 6 Figure 6 ​​​Figure 8 is a schematic diagram of the effect of DPA treatment on the migration function of thymic dendritic cells in SLE mice. A is a schematic diagram of the flow cytometry detection result of the effect of DPA treatment on the proportion of CCR2+cDC2 in the thymus. As can be seen from the figure, the expression level of CCR2+cDC2 in the model group is lower than that in the control group, and the expression level of CCR2+cDC2 in the administration group is significantly higher than that in the model group, that is, the expression of CCR2 of cDC2 in SLE mice is inhibited, and the selective impairment of the migration of cDC2 to the thymus exists, and the expression of CCR2 of cDC2 in SLE mice is enhanced by DPA, and the migration ability of cDC2 to the thymus is restored; B is a schematic diagram of the corresponding statistical result in A. The results shown in the figure are mean ± standard deviation (n=3).

[0043] The flow cytometry results are shown in Figure 7 , Figure 7 Figure 9 is a schematic diagram of the effect of DPA treatment on Treg cells in SLE mice. A is a schematic diagram of the flow cytometry detection result of the effect of DPA treatment on the proportion of Treg in the thymus and spleen. As can be seen from the figure, the proportion of Treg in the thymus and spleen in the administration group is higher than that in the model group, that is, DPA can rebuild the cDC2-Treg tolerance microenvironment of the thymus of SLE mice, rescue the development of Treg, and promote the recovery of central immune tolerance; B is a schematic diagram of the corresponding statistical result in A. The results shown in the figure are mean ± standard deviation (n=3).

[0044] The flow cytometry results are shown in Figure 8 , Figure 8 Figure 10 is a schematic diagram of the effect of DPA treatment on Th1 cells in SLE mice. A is a schematic diagram of the flow cytometry detection result of the effect of DPA treatment on the proportion of Th1 cells in the spleen and lymph node. As can be seen from the figure, the proportion of Th1 cells in the administration group is lower than that in the model group, that is, DPA can inhibit the excessive activation of peripheral Th1 cells in SLE mice, and reduce the level of inflammation; B is a schematic diagram of the corresponding statistical result in A. The results shown in the figure are mean ± standard deviation (n=3-5).

[0045] In summary, DPA can improve the immune disorder state of SLE mice through multiple immune regulation mechanisms: on the one hand, DPA can significantly increase the proportion of SIRPα+cDC2 in the thymus of mice, up-regulate the expression level of CCR2 on the surface of cDC2, thereby restore the impaired selective migration of cDC2 to the thymus, and rebuild the balance of dendritic cell subsets in the thymus; on the other hand, DPA can increase the proportion of Treg cells in the thymus and spleen, help to rebuild the thymic cDC2-Treg tolerant microenvironment, rescue the development of Treg cells, and further promote the recovery of central immune tolerance. Therefore, DPA can not only directly alleviate the inflammatory damage and renal pathological changes of SLE mice, but also can improve the immune imbalance related to the disease from the immune tolerance mechanism by regulating dendritic cell migration and Treg cell development, so as to achieve the purpose of treating the disease.

[0046] The above merely describes the preferred embodiments of the present application and is not intended to limit the present application in any form. Although the present application has been disclosed as above with the preferred embodiments, it is not intended to limit the present application, and any skilled person in the art can make some changes or modifications to the above-mentioned technical content without departing from the technical solution of the present application, and any simple modification, equivalent change and modification of the above-mentioned embodiments according to the technical essence of the present application are still within the scope of the present application.

Claims

1. The use of a docosapentaenoic acid or its pharmaceutical salt in the preparation of drugs for the prevention and / or treatment of systemic lupus erythematosus.

2. The application according to claim 1, characterized in that, The drug for the prevention and / or treatment of systemic lupus erythematosus uses docosapentaenoic acid (DEA) or its pharmaceutical salt as the sole active ingredient.

3. The application according to claim 1, characterized in that, The medicinal salt is a salt formed by docosapentaenoic acid with the following substances: sodium hydroxide, sodium carbonate, potassium hydroxide, calcium hydroxide, calcium chloride, magnesium oxide, and magnesium hydroxide.

4. A pharmaceutical preparation, characterized in that, It is made from docosapentaenoic acid or its pharmaceutical salt and medically acceptable excipients.

5. The pharmaceutical preparation according to claim 4, characterized in that, The dosage form of the pharmaceutical preparation is selected from suspensions, granules, capsules, tablets, powders, emulsions, solutions, pellets, injections, suppositories, enemas, aerosols, patches, or drops.

6. The pharmaceutical preparation according to claim 4, characterized in that, The drug formulation can be administered orally, intravenously, via intraperitoneal injection, intramuscular injection, subcutaneously, via sublingual injection, via transdermal administration, or via rectal suppository.

7. A pharmaceutical composition, characterized in that, It is made from docosapentaenoic acid or its pharmaceutical salt and other drugs for treating systemic lupus erythematosus.

8. The pharmaceutical composition according to claim 7, characterized in that, The other drugs for treating systemic lupus erythematosus are selected from nonsteroidal anti-inflammatory drugs, antimalarial drugs, glucocorticoids, immunosuppressants, and biological agents.

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