New application of inflammasome inhibitor CY-09 in treatment of post-myocardial infarction inflammation and ventricular remodeling

Abstract

The invention relates to a novel application of an inflammasome inhibitor CY-09, in particular to an application of the inflammasome inhibitor CY-09 in preparing a medicine for treating inflammation after myocardial infarction and ventricular remodeling. Experimental results show that the inflammasome inhibitor CY-09 can significantly reduce the tissue inflammation level, improve the cardiac function of mice after myocardial infarction and reverse ventricular fibrosis. Therefore, CY-09 can be used for preparing medicines for treating inflammation after myocardial infarction and ventricular remodeling.

Description

Technical Field

[0001] The present invention relates to an application technology of an inflammasome inhibitor CY-09 for preparing a medicine for treating inflammation after myocardial infarction and ventricular remodeling, belonging to the field of biotechnology and new medical technology. Background Art

[0002] Myocardial infarction (MI) is the leading cause of death among residents worldwide. Post-MI maladaptive ventricular remodeling and subsequent heart failure are the biggest clinical challenges. Studies have shown that inflammation plays a key role in this process. Immune inflammatory disorders such as abnormal immune activation, impaired inflammatory suppression, and inflammatory spatial disorder interfere with the repair process, ultimately leading to adverse remodeling of the infarcted heart. After myocardial infarction, damaged cardiomyocytes release a variety of inflammatory mediators, activating the innate immune system and inflammasomes. In recent years, the role of NLRP3 inflammasome in post-MI immune inflammatory disorders and ventricular remodeling has attracted widespread attention. NLRP3 inflammasome is a multiprotein complex including pro-caspase1, ASC, and NLRP3. Activated NLRP3 inflammasome can cleave inactive pro-IL-18 and pro-IL-1β through caspase1 to generate active IL-18 and IL-1β. These cytokines play an important role in post-MI inflammatory response and ventricular remodeling.

[0003] Despite the diversity of treatments after myocardial infarction, effective drugs targeting inflammation are still limited. Although relevant drug research has been widely carried out, the efficacy has not achieved ideal results, and existing treatment options often lack direct intervention methods targeting inflammasomes. Although some drugs have shown potential in reducing inflammation and improving cardiac function, they do not specifically target NLRP3 inflammasomes.

[0004] Recent reports have shown that the inflammasome inhibitor CY-09 has a selective and direct effect on the NLRP3 inflammasome. Its molecular formula is C 19 H 12 F3NO3S2, the structural formula is as follows:

[0006] It has been shown to effectively reduce the myocardial infarction area in myocardial ischemia-reperfusion model mice and significantly alleviate myocardial ischemia / reperfusion injury (Xie D, Guo H, Li M, et al. Splenic monocytes mediateinflammatory response and exacerbate myocardial ischemia / reperfusion injuryin a mitochondrial cell-free DNA-TLR9-NLRP3-dependent fashion. Basic ResCardiol. 2023;118(1):44.). The invention patents with publication numbers CN111419842A and CN112245427A respectively disclose the important role of CY-09 in the treatment of non-alcoholic fatty liver disease and artificial joint wear particle-induced osteolysis, but its role in NLRP3 inflammasome-mediated inflammation and ventricular remodeling after myocardial infarction is still unclear. Therefore, this study is expected to expand the clinical application of CY-09. Summary of the invention

[0007] Technical problem: The purpose of the present invention is to provide a new use of the inflammasome inhibitor CY-09, specifically the use of the inflammasome inhibitor CY-09 in the preparation of a drug for treating inflammation and ventricular remodeling after myocardial infarction. According to the further characteristics of the use described in the present invention, the prepared drug includes: a therapeutically effective dose of the inflammasome inhibitor CY-09, and a pharmaceutically acceptable excipient.

[0008] Technical solution: The present invention simulates the effect of inflammasome inhibitor CY-09 in treating ventricular remodeling after myocardial infarction in a mouse model. The inventor constructed a mouse model of myocardial infarction: C57BL / 6J mice aged 6-8 weeks, and established a myocardial infarction model by ligating the left coronary artery. CY-09 treatment was implemented before the establishment of the myocardial infarction model: 30 minutes before modeling, the mice were intraperitoneally injected with CY-09 solution at a dose of 2 mg / kg. The CY-09 solution is a mixture of dimethyl sulfoxide (DMSO) and corn oil (volume ratio 1:9).

[0009] Beneficial effects: The experimental results of the present invention show that the inflammasome inhibitor CY-09 can significantly improve the cardiac function of rats, reduce ventricular remodeling, and reduce the degree of myocardial fibrosis. Therefore, the present invention suggests that the inflammasome inhibitor CY-09 can be used to prepare drugs for treating inflammation and ventricular remodeling after myocardial infarction. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The flowchart of the experiment using CY-09 to treat myocardial infarction (MI) mice in the present invention.

[0011] Figure 2 These are the results of immunoblotting analysis of the NLRP3 signaling pathway in the myocardial tissue of mice in the control group and CY-09 group in Example 1.

[0012] Figure 3 This is the qRT-PCR analysis of the expression of pro-inflammatory genes in the myocardial tissue of mice in the control group and CY-09 group in Example 1.

[0013] Figure 4 Representative cardiac ultrasound images of the control group and MI mice injected with CY-09 in Example 1, as well as changes in cardiac function parameters at different time points.

[0014] Figure 5 Representative images of HE staining of myocardial tissue sections of the control group and MI mice injected with CY-09 in Example 1. DETAILED DESCRIPTION

[0015] The present invention is described in detail below through specific implementation modes in conjunction with the attached drawings. Example

[0016] like Figure 1 As shown, the experimental process of using CY-09 to treat myocardial infarction (MI) mice in the present invention includes model establishment, intervention and detection steps.

[0017] 1. Preparation of Myocardial Infarction (MI) Animal Model Thirty male C57BL / 6J mice aged 6-8 weeks, weighing approximately 20-25 grams, were used to establish a myocardial infarction model by ligating the left coronary artery. After the mice were anesthetized, the heart was exposed by sternotomy and the proximal end of the left coronary artery was ligated. After the model was successfully established, the chest cavity was immediately sutured and the mice were returned to a normal environment.

[0018] 2. Group Intervention Before the MI model was established, mice were randomly divided into two groups, with 15 mice in each group: (1) Control group (15 rats): 30 minutes before model establishment, a mixture of dimethyl sulfoxide (DMSO) and corn oil (volume ratio 1:9) was intraperitoneally injected at a dose of 4 mL / kg.

[0019] (2) CY-09 group (15 rats): CY-09 solution was injected 30 minutes before model establishment. The dose of CY-09 solution was 4 mL / kg (i.e., 2 mg / kg), and the solution was prepared as a mixture of DMSO and corn oil (volume ratio 1:9).

[0020] All mice underwent echocardiography to detect cardiac function on days 1, 3, 7, and 28 after the model was established. Ten mice in each group were randomly killed on day 3 after the model was established for tissue immunoblotting, qRT-PCR, and HE staining of myocardial tissue sections. On day 28 after the model was established, the remaining mice were killed for Masson staining of myocardial tissue sections.

[0021] 3. Experimental Results On the third day after the start of treatment, myocardial tissue samples were collected and the expression of proteins related to the NLRP3 signaling pathway was analyzed by immunoblotting. Figure 2 The results showed that CY-09 significantly inhibited the activation of the NLRP3 signaling pathway, indicating that it has a significant effect in intervening in myocardial inflammation.

[0022] On the third day after the start of treatment, qRT-PCR was used to detect the expression levels of pro-inflammatory genes (such as IL-1β, IL-6, and IL-18) in myocardial tissue. Figure 3 The experimental results showed that CY-09 significantly inhibited the expression level of pro-inflammatory genes, demonstrating its excellent anti-inflammatory effect.

[0023] On the third day after the start of treatment, HE staining was performed on myocardial tissue to evaluate the infiltration of inflammatory cells. Figure 5 The results showed that CY-09 significantly reduced the number of inflammatory cells in the infarct area, further confirming its efficacy in inflammation.

[0024] The cardiac function of the mice was evaluated by cardiac ultrasound on days 1, 3, 7, and 28 after the start of treatment. Figure 4 The data showed that the left ventricular ejection fraction (LVEF) of mice in the CY-09 treatment group was significantly increased at each time point, and the cardiac shortening fraction (FS) was also significantly higher than that in the control group, while the left ventricular internal diameter (LVIDs and LVIDd) was significantly lower than that in the control group.

[0025] On the 28th day after the start of treatment, Masson staining of myocardial tissue was performed to further evaluate ventricular fibrosis. The results showed that CY-09 significantly reversed ventricular fibrosis, reduced the area of ​​fibrosis, and increased ventricular wall thickness, further supporting its effectiveness in improving ventricular remodeling.

[0026] The above experimental results show that the inflammasome inhibitor CY-09 has a significant cardioprotective effect, can effectively inhibit the NLRP3 signaling pathway, reduce the level of inflammation in myocardial tissue, improve cardiac function, and significantly reverse ventricular fibrosis and remodeling. Therefore, CY-09 has potential application prospects in the treatment of post-myocardial infarction inflammation and ventricular remodeling.

Claims

1. Application of inflammasome inhibitor CY-09 for the preparation of drugs for the treatment of post-myocardial infarction inflammation and ventricular remodeling.

2. A pharmaceutical composition for treating inflammation and ventricular remodeling after myocardial infarction, characterized in that: It comprises a therapeutic dose of the inflammasome inhibitor CY-09 and pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claim 2, characterized in that Dosage forms include, but are not limited to, tablets, capsules, injections, and microcapsules.

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