Application of cinnamic acid in preparation of medicine for preventing or treating myocardial infarction chronic-stage pathological injury

Abstract

The invention discloses application of cinnamic acid in preparation of a medicine for preventing or treating myocardial infarction chronic-stage pathological injury, and relates to the technical field of medicines. A coronary artery ligation animal model is used for simulating a chronic-stage pathological injury process after myocardial infarction, the cinnamic acid is subjected to gavage intervention, and various detection methods are used for evaluating the intervention effect of the cinnamic acid, so that the cinnamic acid is proved to have a remarkable curative effect on chronic-stage myocardial fibrosis, ventricular remodeling and heart failure after myocardial infarction for the first time; the invention further provides the application of the cinnamic acid in preparation of the medicine for preventing or treating myocardial infarction chronic-stage pathological injury, and compared with previous researches, the application range of the cinnamic acid is expanded, so that the application research of the cinnamic acid and the research and development of the medicine for myocardial infarction are both of great significance to application research of the cinnamic acid and research and development of the medicine for myocardial infarction.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to the use of cinnamic acid in the preparation of medicaments for the prevention or treatment of pathological damage in the chronic phase of myocardial infarction. Background Technology

[0002] The course of myocardial infarction is usually clearly divided into acute, subacute, and chronic phases by clinical guidelines and textbooks. Acute phase: refers to the period from several hours to one week after onset, characterized by myocardial ischemia and necrosis and severe inflammatory response; Subacute phase: refers to the period from one week to several weeks after onset, during which necrotic myocardium begins to be absorbed and scar tissue begins to form; Chronic phase: usually refers to the period after onset (generally ≥4 weeks), at which time myocardial necrosis has stabilized, and the main pathological changes are myocardial fibrosis, ventricular remodeling, and other persistent damage.

[0003] Cinnamic acid (CA) is an important natural active ingredient in traditional Chinese medicines such as cinnamon. Current research shows that cinnamic acid has antibacterial, anti-inflammatory, and antioxidant effects, and has significant therapeutic advantages in the treatment of tumors, metabolic diseases, nervous system diseases, liver and kidney damage, and cardiovascular diseases. In current research on cinnamic acid intervention in cardiovascular diseases, the models used include: (1) Transverse Aortic Constriction (TAC) model, a model of myocardial hypertrophy and heart failure caused by pressure overload, simulating the disease process of hypertensive heart disease and aortic stenosis; (2) Angiotensin II-induced hypertensive myocardial hypertrophy model; (3) Isoproterenol-induced myocardial ischemia model, a model that stimulates β1 receptors to cause cardiac overload, triggering myocardial necrosis, oxidative stress and inflammatory response, simulating the disease process of acute myocardial injury and ischemia-reperfusion injury; (4) Streptozotocin-induced diabetic cardiomyopathy, simulating heart disease and injury in the process of diabetes. (5) A model of cardiac disease and injury induced by obesity / hyperlipidemia induced by a high-fat diet. (6) A coronary artery occlusion-reperfusion model to simulate the pathological process of cardiac injury caused by ischemia-hypoxia during the acute phase of myocardial infarction and reperfusion. In summary, cinnamic acid has a good therapeutic effect on myocardial hypertrophy, heart failure, acute myocardial injury, myocardial ischemia, diabetes-related cardiac injury, obesity / hyperlipidemia-related cardiac injury, and ischemia-reperfusion injury during the acute phase of myocardial infarction simulated by the above models.

[0004] However, current research on cinnamic acid in the treatment of myocardial infarction only focuses on the damage caused by ischemia, hypoxia, inflammatory response and reperfusion during the acute or subacute phase of myocardial infarction, and does not evaluate the efficacy in correcting chronic fibrotic changes, ventricular remodeling and ischemic-hypoxic microenvironment after myocardial infarction.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The purpose of this invention is to provide the use of cinnamic acid in the preparation of medicaments for the prevention or treatment of pathological damage in the chronic phase of myocardial infarction.

[0007] This invention is implemented as follows: In a first aspect, the present invention provides the use of cinnamic acid in the preparation of medicaments for the prevention or treatment of pathological damage in the chronic phase of myocardial infarction.

[0008] In an optional implementation, the pathological damage of the chronic phase of myocardial infarction includes at least one of chronic myocardial fibrosis, ventricular remodeling, and heart failure in the late stage of myocardial infarction.

[0009] In an alternative embodiment, the cinnamic acid can prevent or treat chronic pathological damage from myocardial infarction by improving fibrosis.

[0010] In an optional embodiment, the cinnamic acid prevents or treats chronic pathological damage from myocardial infarction by increasing left ventricular ejection fraction and left ventricular fractional shortening, and decreasing left ventricular end-diastolic volume and left ventricular end-systolic volume.

[0011] In optional embodiments, the cinnamic acid can be administered orally or by gavage.

[0012] In an optional embodiment, the dosage of oral administration or gavage administration is 120-300 mg / kg; In an optional embodiment, the drug for preventing or treating chronic pathological damage from myocardial infarction uses cinnamic acid as the sole active ingredient or one of the active ingredients.

[0013] In an optional embodiment, the drug for preventing or treating pathological damage in the chronic phase of myocardial infarction is a suspension of sodium cellulose and cinnamic acid, wherein the content of cinnamic acid is 33.6~84 mg / mL.

[0014] In an optional embodiment, the drug may further include pharmaceutically acceptable excipients, carriers, or diluents; And / or, the dosage form of the drug is a tablet, pill, capsule, granule, suspension, drop pill, oral liquid preparation, injection, powder for injection, aerosol, suppository or subcutaneous dosage form.

[0015] Secondly, the present invention provides the use of cinnamic acid in the preparation of a drug for improving the microenvironment of ischemia and hypoxia in the chronic phase of myocardial infarction.

[0016] The present invention has the following beneficial effects: This invention simulates the chronic pathological damage process after myocardial infarction using an animal model with coronary artery ligation. Cinnamic acid was administered via gavage, and its intervention effect was evaluated using various detection methods. For the first time, this invention demonstrates that cinnamic acid exhibits significant efficacy in treating chronic myocardial fibrosis, ventricular remodeling, and heart failure after myocardial infarction. Furthermore, it proposes the application of cinnamic acid in the preparation of drugs for the prevention or treatment of chronic pathological damage after myocardial infarction. Compared with previous studies, this invention expands the application scope of cinnamic acid, which is of great significance for the application research of cinnamic acid and the development of drugs for myocardial infarction. Attached Figure Description

[0017] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram of animal modeling and drug administration for myocardial infarction provided by the present invention; Figure 2 The images show schematic diagrams of cardiac ultrasound at various stages of the myocardial infarction mouse model provided by this invention, where *, **, and *** represent P<0.05, P<0.01, and P<0.001 respectively compared to Sham. Figure 3 The diagram illustrates the efficacy evaluation of cinnamic acid provided by this invention, where *** indicates P < 0.001 compared to Sham, and # indicates P < 0.05 compared to MI; Figure 4 This is a schematic diagram comparing the therapeutic effects of cinnamic acid and cinnamon provided by the present invention, wherein *** indicates P<0.001 compared with Sham, and # indicates P<0.05 compared with MI. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0020] Cinnamic acid, as a natural product and a major active ingredient in traditional Chinese medicine, has advantages in its broad therapeutic range, high safety, low price (making it cost-effective), and improved adherence to long-term use. These advantages offer greater potential for its application in the prevention and treatment of chronic diseases or in the chronic recovery process of acute illnesses. Therefore, research on the preventive and therapeutic effects of cinnamic acid on myocardial fibrosis, ventricular remodeling, and heart failure during the chronic phase of myocardial infarction, as well as its role in improving the ischemic and hypoxic microenvironment, is of great value.

[0021] This invention simulates the chronic pathological damage process after myocardial infarction using an animal model with coronary artery ligation, intervenes with cinnamic acid by gavage, and evaluates the intervention effect of cinnamic acid using various detection methods. For the first time, it has demonstrated the therapeutic effect of cinnamic acid on chronic myocardial fibrosis, ventricular remodeling, and heart failure after myocardial infarction.

[0022] Specifically, the present invention provides the use of cinnamic acid in the preparation of medicaments for the prevention or treatment of pathological damage in the chronic phase of myocardial infarction.

[0023] Among them, pathological damage in the chronic phase of myocardial infarction includes at least one of chronic myocardial fibrosis, ventricular remodeling, and heart failure in the late stage of myocardial infarction.

[0024] It's important to note that the core function of drugs in the acute and subacute phases of myocardial infarction is "anti-inflammation," while in the chronic phase, their core function is to improve fibrosis and the ischemic-hypoxic microenvironment. Therefore, their mechanisms are completely different. Cinnamic acid prevents or treats pathological damage in the chronic phase of myocardial infarction by improving fibrosis.

[0025] Cinnamic acid can prevent or treat chronic pathological damage from myocardial infarction by increasing left ventricular ejection fraction and left ventricular fractional shortening, and decreasing left ventricular end-diastolic volume and left ventricular end-systolic volume.

[0026] Cinnamic acid efficacy validation models include, but are not limited to, chronic phase myocardial infarction models constructed by left anterior descending coronary artery ligation, coronary artery ligation models, or coronary artery occlusion-reperfusion models. Other chemical or physical methods can also be used to induce chronic phase myocardial infarction models.

[0027] Cinnamic acid can be administered via methods including, but not limited to, oral administration and gavage. The dosage for oral or gavage administration is 120-300 mg / kg.

[0028] The drug used to prevent or treat pathological damage in the chronic phase of myocardial infarction is a suspension of sodium cellulose and cinnamic acid. In this invention, the purchased cinnamic acid has a purity of 99.5%. It is administered after being suspended in 0.5% sodium cellulose. The dosage and corresponding body weight are calculated according to the above-mentioned oral or gavage administration dosage. The content of cinnamic acid in the drug used to prevent or treat pathological damage in the chronic phase of myocardial infarction is 33.6~84 mg / mL.

[0029] Drugs used to prevent or treat pathological damage in the chronic phase of myocardial infarction use cinnamic acid as the sole active ingredient or one of the active ingredients. That is, cinnamic acid can be formulated as a single drug or as an active ingredient in drug preparations. Drugs also include pharmaceutically acceptable excipients, carriers, or diluents. Dosage forms include tablets, pills, capsules, granules, suspensions, drop pills, oral liquid preparations, injections, powder for injection, aerosols, suppositories, or subcutaneous dosage forms.

[0030] Furthermore, this invention also provides the use of cinnamic acid in the preparation of medicaments for improving the ischemic and hypoxic microenvironment in the chronic phase of myocardial infarction.

[0031] "Improving the microenvironment of ischemia and hypoxia in the chronic phase of myocardial infarction" refers to the targeted relief of the abnormal microenvironment of "insufficient blood perfusion and lack of oxygen supply" in the local myocardium during the chronic phase of myocardial infarction (usually ≥4 weeks). By improving blood supply, optimizing metabolism, or protecting damaged myocardial cells, it breaks the vicious cycle of "ischemia and hypoxia → further deterioration of myocardial function → aggravation of microcirculatory disorders", thereby delaying pathological progression and protecting cardiac function.

[0032] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0033] Example 1 (1) Constructing an animal model of myocardial infarction ( Figure 1 ): Mice (C57BL / 6J, male, 6-8 weeks old, weighing approximately 22g) were divided into a myocardial infarction model group (MI) and a sham-operated group. In the MI group, myocardial ischemia and necrosis were induced by ligation of the left anterior descending coronary artery; while in the sham-operated group, the same anesthesia, thoracotomy, and coronary artery exposure procedures were performed, but the blood vessels were not ligated (or only briefly separated and sutured), ensuring that the myocardium was not damaged by ischemia.

[0034] The specific procedures are as follows: Mice in the myocardial infarction model group (MI) and the sham operation group (Sham) were placed in induction chambers and induced with 4-5% isoflurane, followed by continuous anesthesia with 1.5-2% isoflurane via a face mask. An incision was made in the left 3rd-4th intercostal space. The muscle tissue was bluntly dissected to expose the ribs, which were then cut. The thoracic cavity was carefully opened to expose the heart, and the left anterior descending coronary artery was located. In the MI group, the left anterior descending coronary artery was ligated using non-absorbable sutures. Successful ligation was indicated by pale discoloration of the distal myocardium and ST-segment elevation on the electrocardiogram. The left anterior descending coronary artery was not ligated in the sham operation group (Sham). The muscles and skin were sutured layer by layer. Mice were kept warm post-operatively until full recovery. An echocardiogram was performed one week post-operation to determine if there was cardiac injury during the acute phase of myocardial infarction. Another echocardiogram was performed four weeks post-operation to determine if there was cardiac injury during the chronic phase of myocardial infarction and to assess the success of the model.

[0035] This invention uses left anterior descending coronary artery ligation for myocardial infarction modeling. Compared with previous left anterior descending coronary artery occlusion-reperfusion models, it better simulates the entire pathological process of myocardial infarction, including the acute phase, subacute phase (healing phase), and chronic phase (old myocardial infarction). Figure 2 (echocardiography at various stages in a mouse model of myocardial infarction). Figure 2 As shown, in the acute phase (1 week) and subacute phase (4 weeks), compared with the sham surgery group, the left ventricular ejection fraction (LVEF) of the myocardial infarction model group (MI) was significantly lower, and the LVEF of the myocardial infarction model group was basically below 50%, suggesting possible heart failure; the left ventricular fractional shortening (LVFS) was significantly reduced, suggesting cardiac systolic dysfunction in the MI group; the left ventricular end-diastolic volume (LVEDV) was significantly increased; the left ventricular end-systolic volume (LVESV) was significantly increased, and a stable chronic phase myocardial infarction injury model was formed after 4 weeks.

[0036] (2) Grouping and administration: Four weeks after surgery, echocardiography was used to assess the modeling status. Except for the sham surgery group, the mice that successfully developed the model were randomly divided into a myocardial infarction model group (MI), a low-dose cinnamic acid group (CA-L), and a high-dose cinnamic acid group (CA-H), with 6 mice in each group.

[0037] The sham surgery group and the myocardial infarction model group (MI) were given the same volume (0.1 mL / animal / day) of 0.5% sodium carboxymethyl cellulose by gavage for 2 weeks.

[0038] The low-dose cinnamic acid group (CA-L) and the high-dose cinnamic acid group (CA-H) were administered cinnamic acid via gavage. Cinnamic acid powder was added to 0.5% sodium carboxymethyl cellulose to prepare a suspension, and the model animals were administered the suspension via gavage at doses of 120 mg / kg / day and 300 mg / kg / day (0.1 mL / animal / day) for 2 weeks.

[0039] (3) Evaluation of efficacy: After the gavage treatment period, cardiac ultrasound was performed to assess cardiac function; after anesthesia, the animal's heart was dissected for direct observation; the myocardial infarction lesion area was collected for electron microscopy and other biochemical index detection; serum was collected for biological index detection; cardiac tissue sections were sectioned and subjected to various pathological staining to observe pathological changes, fibrosis, etc.; cardiac tissue sections were subjected to immunohistochemistry or immunofluorescence staining for various biomarkers.

[0040] (4) Data analysis: After two weeks of intervention with cinnamic acid via gavage, the efficacy was evaluated. Figure 3 The results indicated that, in the chronic phase of myocardial infarction, the MI group had significantly larger infarct foci compared to the sham surgery group. Figure 3 In the MI group (CA-L and CA-H), the lesion size was significantly reduced in both the low-dose cinnamic acid group and the high-dose cinnamic acid group. Compared with the Sham group, the heart-to-body weight ratio was significantly increased in the MI group; compared with the MI group, the heart-to-body weight ratio was significantly decreased in both the low-dose cinnamic acid group (CA-L) and the high-dose cinnamic acid group (CA-H). Figure 3 (B)

[0041] Echocardiography revealed that compared to the Sham group, the MI group exhibited significant cardiac dysfunction, with significantly decreased LVEF and LVFS, and significantly increased LVEDV and LVESV. Compared to the MI group, the low-dose cinnamic acid group (CA-L) and the high-dose cinnamic acid group (CA-H) showed significantly improved cardiac function, with significantly increased LVEF and LVFS, and significantly decreased LVESV. The CA-H group also showed a significantly decreased LVEDV. Figure 3 (C). The above results indicate that cinnamic acid is significantly effective in intervening in the pathological changes of chronic myocardial infarction, including myocardial fibrosis, ventricular remodeling, and heart failure.

[0042] Example 2: Comparative Experiment on the Therapeutic Effects of Cinnamon and Cinnamic Acid Since cinnamic acid is an important active ingredient in the traditional Chinese medicine cinnamon, and compound prescriptions containing cinnamon are widely used in clinical practice for cardiovascular diseases, this experimental case further compares the efficacy of cinnamon (pinyin: Rougui, Latin name: Cinnanmomi Cortex) and the low-dose cinnamic acid group (CA-L). The specific procedures are as follows: (1) Constructing an animal model of myocardial infarction: Mice (C57BL / 6J, male, 6-8 weeks old, weighing approximately 22g) were divided into a myocardial infarction model group (MI) and a sham-operated group. In the MI group, myocardial ischemia and necrosis were induced by ligation of the left anterior descending coronary artery; while in the sham-operated group, the same anesthesia, thoracotomy, and coronary artery exposure procedures were performed, but the blood vessels were not ligated (or only briefly separated and sutured), ensuring that the myocardium was not damaged by ischemia.

[0043] The specific procedures were as follows: Mice in the myocardial infarction model group (MI) and the sham operation group (Sham) were placed in induction chambers and induced with 4-5% isoflurane, followed by continuous anesthesia with 1.5-2% isoflurane maintained via a face mask. An incision was made in the left 3rd-4th intercostal space. The muscle tissue was bluntly dissected to expose the ribs, which were then cut. The thoracic cavity was carefully opened to expose the heart, and the left anterior descending coronary artery was located. In the MI group, the left anterior descending coronary artery was ligated using non-absorbable sutures. Successful ligation was indicated by pale discoloration of the distal myocardium and ST-segment elevation on the electrocardiogram. In the sham operation group (Sham), the left anterior descending coronary artery was not ligated. The muscles and skin were sutured layer by layer. Mice were kept warm post-operatively until full recovery.

[0044] (2) Grouping and administration: In the fourth week after surgery, except for the sham surgery group, the other mice that successfully developed the model were randomly divided into the myocardial infarction model group (MI), the low-dose cinnamic acid group (CA-L), and the cinnamon group (Rougui), with 6 mice in each group.

[0045] The sham surgery group and the myocardial infarction model group (MI) were given the same volume (0.1 mL / animal / day) of 0.5% sodium carboxymethyl cellulose by gavage for 2 weeks.

[0046] The low-dose cinnamic acid group (CA-L) was given cinnamic acid by gavage. Cinnamic acid powder was added to 0.5% sodium carboxymethyl cellulose to prepare a suspension, and the model animals were gavaged at 120 mg / kg / day (0.1 mL / animal / day) for 2 weeks.

[0047] The Rougui group was prepared by mixing cinnamon granules with 0.5% sodium carboxymethyl cellulose to form a suspension, and the model animals were subjected to gavage intervention at a rate of 4 g / kg / day (0.1 mL / animal) for 2 weeks.

[0048] (3) Evaluation of efficacy: After the gavage dry procedure is completed, an echocardiogram is performed to assess cardiac function.

[0049] (4) Data analysis: Please see Figure 4Echocardiography results showed that, compared with the Sham group, the MI group had significant cardiac dysfunction, with significantly decreased LVEF and LVFS, and significantly increased LVEDV and LVESV. Compared with the myocardial infarction model group (MI), the low-dose cinnamic acid group (CA-L) showed significantly improved cardiac function, with significantly increased LVEF and LVFS, and significantly decreased LVESV. Compared with the MI group, although the LVEF and LVFS in the cinnamon group (Rougui) showed an increasing trend, there was no significant difference; although LVEDV and LVESV also showed a decreasing trend, there was no significant difference, indicating that the cinnamon group did not significantly improve cardiac function.

[0050] The above results indicate that although cinnamic acid is one of the main active components of cinnamon, it exhibits an independent and superior therapeutic advantage over cinnamon as a whole in its intervention effect on the chronic phase of myocardial infarction. The lack of significant improvement in chronic phase damage from cinnamon may be because the anti-inflammatory and antioxidant effects of cinnamon tend to exert their therapeutic advantage more readily in the acute phase, while the chronic phase is not the optimal window for its efficacy.

[0051] In summary, this invention simulates the chronic pathological damage process after myocardial infarction using an animal model with coronary artery ligation. Cinnamic acid was administered via gavage, and its intervention effect was evaluated using various detection methods. This invention is the first to demonstrate that cinnamic acid exhibits significant efficacy in treating chronic myocardial fibrosis, ventricular remodeling, and heart failure after myocardial infarction. Furthermore, it proposes the application of cinnamic acid in the preparation of drugs for the prevention or treatment of chronic pathological damage after myocardial infarction. Compared with previous studies, this invention expands the application scope of cinnamic acid, which is of great significance for the application research of cinnamic acid and the development of drugs for myocardial infarction.

[0052] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The application of cinnamic acid in the preparation of drugs for the prevention or treatment of pathological damage in the chronic phase of myocardial infarction.

2. The application according to claim 1, characterized in that, The pathological damage in the chronic phase of myocardial infarction includes at least one of chronic myocardial fibrosis, ventricular remodeling, and heart failure in the late stage of myocardial infarction.

3. The application according to claim 1, characterized in that, The cinnamic acid is said to prevent or treat chronic pathological damage from myocardial infarction by improving fibrosis.

4. The application according to claim 1, characterized in that, The cinnamic acid prevents or treats chronic functional impairment of myocardial infarction by increasing left ventricular ejection fraction and left ventricular fractional shortening, and decreasing left ventricular end-diastolic volume and left ventricular end-systolic volume.

5. The application according to claim 1, characterized in that, The administration methods of cinnamic acid include oral administration and gavage administration.

6. The application according to claim 5, characterized in that, The dosage for oral administration or gavage administration is 120-300 mg / kg.

7. The application according to claim 1, characterized in that, The drug used to prevent or treat pathological damage in the chronic phase of myocardial infarction has cinnamic acid as its sole active ingredient or one of its active ingredients.

8. The application according to claim 1, characterized in that, The drug used to prevent or treat pathological damage in the chronic phase of myocardial infarction is a suspension of sodium cellulose and cinnamic acid, wherein the content of cinnamic acid is 33.6~84 mg / mL.

9. The application according to claim 1, characterized in that, The drugs used to prevent or treat pathological damage in the chronic phase of myocardial infarction also include pharmaceutically acceptable excipients, carriers or diluents; And / or, the dosage form of the drug for preventing or treating pathological damage in the chronic phase of myocardial infarction is a tablet, pill, capsule, granule, suspension, drop pill, oral liquid preparation, injection, powder for injection, aerosol, suppository or subcutaneous dosage form.

10. Application of cinnamic acid in the preparation of drugs for improving the microenvironment of ischemia and hypoxia in the chronic phase of myocardial infarction.

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