CN111214478B

CN111214478B - Use of friedel-crafts glycosides in preparing medicine for treating and/or preventing synovial membrane related diseases

Info

Publication number: CN111214478B
Application number: CN202010111771.3A
Authority: CN
Inventors: 王�华; 张海严; 戴好富; 曾祥周; 胡爱华; 王皓; 樊凯
Original assignee: Hainan Medical College
Current assignee: Hainan Medical College
Priority date: 2020-02-24
Filing date: 2020-02-24
Publication date: 2023-08-08
Anticipated expiration: 2040-02-24
Also published as: CN111214478A

Abstract

The invention discloses an application of a friedel-crafts glycoside in preparing a medicament for treating and/or preventing synovial membrane related diseases, and experiments prove that a cardiac glycoside compound friedel-crafts glycoside can weaken joint synovial membrane inflammation and M1 type macrophage polarization in a synovial membrane, so that OA disease process and cartilage injury of a mouse model mouse induced by joint cavity collagenase injection are delayed. The invention provides a phenomenon and a molecular mechanism for treating OA and OA synovitis by FGS, and provides a new idea for clinically treating OA and OA synovitis.

Description

Use of friedel-crafts glycosides in preparing medicine for treating and/or preventing synovial membrane related diseases

Technical Field

The invention belongs to the technical field of medicines, and relates to application of freude glycoside in preparation of medicines for treating and/or preventing synovial membrane related diseases.

Background

Synovitis is an inflammatory disorder that occurs in the synovial tissue within the joint, and therefore, all synovial lesions occur at the joint site. The synovium can be divided into two layers, namely a synovial inner layer (i.e. a surface layer) which is thinner and is close to the joint cavity and a synovial lower layer, wherein the surface layer is provided with 2-3 layers of cells, and two types of cells can be confirmed under an electron microscope, but no obvious boundary exists between the two types of cells, namely macrophage-like synovial cells and fibroblast-like synovial cells. During synovitis, the number of macrophages increases dramatically. This massive growth results in part from the original macrophages in the synovium escaping the apoptotic pathway, but more from the infiltrating macrophages during blood circulation. Macrophages are a highly variable cell that, in response to the difference in its microenvironment, has two major polarized forms, M1 and M2. M1 type macrophages produce a variety of pro-inflammatory cytokines such as IL-6 and TNF-a, etc., activating inflammatory responses and articular cartilage degradation.

Osteoarthritis (OA) is the most common joint disease in the elderly population worldwide, with the specific list of OA being about 10% in men and up to 18% in women for people over 60 years old. Up to now, about 2.42 million of patients with OA worldwide have become an important cause of affecting the quality of life of the elderly population. The main clinical manifestation of the disease is pain and gradual loss of function. Because the pathogenesis is not completely understood, clinical treatment is mainly pain relief and advanced joint replacement. Because patients are mostly elderly, and the operation may cause adverse consequences and the service life of the prosthesis is limited, the clinical application of the joint replacement operation has a certain limitation. Thus, early prevention and treatment of OA and related pathogenesis studies are particularly important. OA was once thought to be a purely mechanical cartilage degenerative disease, and to date, it has been clearly understood that OA is a complex disease involving the whole joint, with clinical symptoms mainly manifested by progressive degradation of articular cartilage and synovial inflammation. Accumulation of a large number of M1 type macrophages in OA synovial tissue is positively correlated with cartilage damage and disease severity, and attenuation of M1 type polarization of macrophages in synovial tissue delays disease progression.

Frugoside (FGS) is a cardiac glycoside compound isolated and extracted from Calotropis gigantea (Calotropis gigantean L.) and has the following structure:

as early as 19 th century, cardiac glycosides have been widely used for the treatment of cardiac insufficiency. With the deep research, the anti-tumor effect of the cardiac glycoside drug is also discovered. Studies have shown that FGS has similar tumor cytotoxicity and cell line selectivity as commonly used cardiac glycosides (e.g., digoxin and ouabain). The most interesting thing occurred in 1967, lancaster and Vegad reported for the first time the anti-inflammatory activity of ouabain. A great deal of researches prove that the cardiac glycoside compounds can reduce inflammation through various acute or chronic animal inflammation models, such as acute inflammation induced by infection, chronic inflammation caused by autoimmune diseases, neuritis, cystic fibrosis and the like. However, no report has been made so far on the treatment of OA and OA-related synovitis by cardiac glycoside compounds.

Disclosure of Invention

The invention aims to develop a medicament for treating and/or preventing synovial membrane related diseases.

The invention aims at realizing the following technical scheme:

use of a friedel-crafts glycoside for the preparation of a medicament for the treatment and/or prevention of synovitis.

A pharmaceutical composition for the treatment and/or prevention of synovitis, said pharmaceutical composition comprising as active substance a friedel-crafts glycoside.

Use of a friedel-crafts glycoside for the preparation of a medicament for the treatment and/or prevention of synovitis-related osteoarthritis.

A pharmaceutical composition for the treatment and/or prevention of synovitis-related osteoarthritis, comprising as active substance freude glycoside.

Use of a friedel-crafts glycoside for the preparation of a medicament for reducing the polarization of M1 type macrophages.

A pharmaceutical composition for attenuating polarization of M1 type macrophages, the pharmaceutical composition comprising, as an active substance, a friedel-crafts glycoside.

The beneficial effects of the invention are as follows: the cardiac glycoside compound FGS can weaken the inflammation of joint synovium and polarization of M1 type macrophages in the synovium; thereby delaying the OA disease process and cartilage injury of mice with the model of mouse OA (collagenase induced osteoarthritis, CIOA) induced by the injection of collagenase into the joint cavity. The invention provides a phenomenon and a molecular mechanism for treating OA and OA synovitis by FGS, and provides a new idea for clinically treating OA and OA synovitis.

Drawings

FIG. 1 is a graph showing changes in synovial inflammation after 1 week, 3 weeks and 6 weeks of FGS (0.2 mg/kg) injection into the right knee joint cavity of CIOA mice;

FIG. 2 is a graph showing changes in knee joint cartilage after 1 week, 3 weeks and 6 weeks of FGS (0.2 mg/kg) injection into the right knee joint cavity of CIOA mice;

FIG. 3 shows changes in joint synovial membrane M1 type macrophages after 1 week, 3 weeks and 6 weeks of FGS (0.2 mg/kg) injection into the right knee joint cavity of CIOA mice.

Detailed Description

The technical scheme of the present invention will be further described with reference to specific embodiments and drawings, but it should be understood that the scope of the present invention is not limited by the specific embodiments.

(1) Establishment of therapeutic action of FGS on CIOA mice

A. C57BL/6 male mice of 10-12 weeks old were purchased from Guangdong province medical laboratory animal center, and the joint cavity was injected with collagenase to induce experimental mouse OA model (CIOA), and FGS (0.2 mg/kg) was injected into the same joint cavity twice a week 3 days after molding. The experiments were divided into sham surgery group, CIOA group and cioa+fgs group.

B. Experimental mice were isolated from knee joint tissue samples 1 week (early OA), 3 weeks (mid OA) and 6 weeks (late OA) after FGS injection, respectively, and then paraffin-embedded and sectioned for later study.

C. HE staining of tissue specimens to observe the histological changes of synovium and evaluate the therapeutic effect of FGS on synovitis (fig. 1), demonstrating that FGS can attenuate joint synovitis;

D. safranin O-fast green staining of tissue specimens to observe histological changes in articular cartilage and matrix and scoring (fig. 2), demonstrating that FGS can delay OA disease progression and cartilage damage;

(2) FGS can weaken polarization of M1 type macrophage

The joint cavity of the CIOA mouse is injected with FGS, and immune tissue fluorescence staining proves that FGS can reduce the positive cell number proportion of iNOS (M1 type macrophage marker) in the inner layer of the sliding film of the CIOA mouse (figure 3), and the FGS can weaken the polarization of M1 type macrophages.

In conclusion, the cardiac glycoside compound FGS can weaken the polarization of M1 type macrophages in joint synovial membrane inflammation and synovial membrane; thereby delaying the OA disease process and cartilage injury of the CIOA mice. The invention provides a phenomenon and a molecular mechanism for treating OA and OA synovitis by FGS, and provides a new idea for clinically treating OA and OA synovitis.

The foregoing is merely a specific embodiment of the present invention and not all embodiments, and any equivalent modifications of the technical solution of the present invention that will be obvious to those skilled in the art from reading the present specification are intended to be encompassed by the claims of the present invention.

Claims

1. Use of a friedel-crafts glycoside in the manufacture of a medicament for the treatment of osteoarthritis.

2. Use of a frei glycoside in the manufacture of a medicament for the treatment of osteoarthritis-associated synovitis.