Application of ginseng epoxy alkynol in preparation of medicine for treating myocardial infarction

Abstract

The invention belongs to the technical field of new application of medicines, and provides application of ginseng epoxy alkynol in preparation of medicines for treating myocardial infarction. The ginseng epoxy alkynol can protect the process of lesion and myocardial infarction caused by left anterior descending branch ligation of the heart to a certain extent, reduce the degree of myocardial fibrosis, reduce the infarction area, relieve ventricular wall tumors, effectively reduce the degree of myocardial infarction and relieve myocardial ischemia after myocardial infarction. The compound has a wide application prospect in treatment of myocardial infarction, especially acute myocardial infarction.

Description

Technical Field

[0001] The invention belongs to the technical field of new drug applications, and provides application of ginseng epoxyalkynol in preparing drugs for treating myocardial infarction. Background Art

[0002] Coronary heart disease is one of the main causes of myocardial infarction. Due to the stenosis or occlusion of the coronary arteries and insufficient blood supply, patients with coronary heart disease are prone to myocardial ischemia and hypoxia. Prolonged or severe ischemia and hypoxia may lead to myocardial cell death, and then cause myocardial infarction (heart attack). Myocardial infarction (MI) is a common pathological phenomenon in clinical medicine. Its fundamental problem lies in the sharp reduction or interruption of blood supply to the heart, which leads to damage to the myocardial tissue. This disease may cause serious complications such as heart failure, arrhythmia, cardiogenic shock and even cardiac arrest, and is a late manifestation of coronary artery disease. Tracing its roots, most cases of myocardial infarction are closely related to coronary heart disease, especially when rupture of atherosclerotic plaques leads to complete blockage of the coronary arteries, which often becomes a direct cause of myocardial infarction.

[0003] Studies have shown that Chinese medicine has shown significant effects in the prevention and treatment of myocardial infarction. For example, curcumin, with its anti-inflammatory properties, can effectively prevent the occurrence of myocardial infarction, reduce the area of ​​infarction, and inhibit the proliferation of perivascular fibrous tissue and apoptosis of myocardial cells. Wang Yong et al. pointed out in their study "The Effect of Curcumin on Cell Apoptosis and Cardiac Function after Myocardial Infarction in Rats" that curcumin can inhibit apoptosis of myocardial cells after myocardial infarction, improve ventricular remodeling and cardiac dysfunction after myocardial infarction, and its effect is positively correlated with the dose.

[0004] In addition, the combined use of Tanshinone IIA and Puerarin also showed significant therapeutic potential. According to Chinese invention patent CN110693889B, the Chinese medicine composition can inhibit the infiltration of inflammatory cells, improve cardiac function, improve hemodynamics, reduce the destruction of myocardial cells, alleviate the damage of myocardial cells caused by acute myocardial ischemia, inhibit the process of myocardial fibrosis and ventricular remodeling, and promote the recovery and improvement of cardiac function after myocardial ischemia. These studies provide strong support for the application of Chinese medicine in the prevention and treatment of myocardial infarction.

[0005] Panaxydol (PND) is a polyacetylene compound, a class of long-chain fatty compounds with seventeen carbon atoms, which has two conjugated alkynyl groups in its structural skeleton. Studies have shown that Panaxydol has anti-inflammatory effects, anti-platelet aggregation and inhibition of cell oxidase, but the specific application and effect of Panaxydol in the treatment of myocardial infarction need further study. Summary of the invention

[0006] The inventors of the present invention discovered that ginseng epoxy alkynol has a protective effect on myocardial infarction, provided a use of ginseng epoxy alkynol in the preparation of a drug for treating myocardial infarction, and expanded the application of ginseng epoxy alkynol in disease treatment.

[0007] The technical solution of the present invention is as follows:

[0008] The invention provides use of ginseng epoxy alkynol in preparing a medicine for treating myocardial infarction.

[0009] Furthermore, the myocardial infarction is acute myocardial infarction.

[0010] Furthermore, the myocardial infarction is caused by coronary heart disease.

[0011] Furthermore, the coronary heart disease is caused by rupture of atherosclerotic plaques.

[0012] Furthermore, the ginseng epoxyalkynol can treat myocardial infarction by protecting the tissue pathological changes caused by ligation of the left anterior descending branch of the heart, slowing down the progression of myocardial infarction, reducing the severity of myocardial infarction, reducing the degree of myocardial fibrosis, reducing the infarct area, alleviating ventricular aneurysm and / or alleviating myocardial ischemia after myocardial infarction.

[0013] Furthermore, the drug also includes pharmaceutically acceptable excipients, and its dosage form includes oral preparations or injections.

[0014] Furthermore, the oral preparation includes any one of tablets, granules, capsules, oral liquids and suspensions.

[0015] Furthermore, the dosage of the ginseng epoxy alkynol is 10-100 mg / kg.

[0016] Preferably, the dosage of ginseng epoxyalkynol is 10-50 mg / kg.

[0017] More preferably, the dosage of ginseng epoxyalkynol is 20 mg / kg.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The ginseng epoxy alkynol of the present invention can protect the histopathological changes caused by the ligation of the left anterior descending branch of the heart to a certain extent, effectively slow down the myocardial infarction process caused by the ligation, reduce the degree of myocardial fibrosis, reduce the infarct area, relieve ventricular aneurysm, effectively reduce the degree of myocardial infarction, and relieve the myocardial ischemia after myocardial infarction. In addition, the dosage of ginseng epoxy alkynol in the treatment of myocardial infarction is lower than that of the positive control drug enalapril maleate. Therefore, the application of ginseng epoxy alkynol in the treatment of myocardial infarction (MI) has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The results of pathological changes in cardiac tissues of rats in each group;

[0021] Figure 2 The heart weight index results of rats in each group (compared with the sham operation group, #### p<0.0001, with significant difference; compared with the model group, **** p<0.0001, *** p<0.001, * p<0.05, significant difference);

[0022] Figure 3 Masson staining images of the hearts of rats in each group;

[0023] Figure 4 The results of collagen deposition in each group of rats on the degree of fibrosis (compared with the sham operation group, #### p<0.0001, with significant difference; compared with the model group, **** p<0.0001, *** p<0.001, ** p<0.01, significant difference). DETAILED DESCRIPTION

[0024] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited.

[0025] Example 1: Study on the application of ginseng epoxyalkynol in treating myocardial infarction

[0026] (1) Establishment of myocardial infarction rat model

[0027] After the rats were fed with basic feed in the SPF animal room for 7 days, the animal model was prepared: 1% sodium pentobarbital (50 mg / kg) was used for intraperitoneal anesthesia of the rats. After waiting for 5 minutes, the rats were pinched at the tip and root of the tail to observe if the rats had no reaction. After the rats were in anesthetized state, tracheal intubation was performed and assisted ventilation was performed with a small animal ventilator. The ventilator respiratory rate was 80, the respiratory ratio was 1:2, the tidal volume was 7, and the air pressure was 0. The thoracotomy was performed at the 4th intercostal space on the left side of the rats, the pericardium was torn open, the myocardium was exposed, and the left anterior descending branch of the heart coronary artery was permanently ligated with a circular non-invasive suture needle 5-0 silk thread 2 mm below the left atrial appendage and the pulmonary artery cone. Finally, the rats with successful modeling were randomly divided into groups for subsequent drug administration experiments.

[0028] (2) Grouping and drug administration

[0029] Rats were randomly divided into sham operation group, model group, enalapril group and low, medium and high dose groups of ginseng epoxy alkynol (1mg / kg PND group, 2mg / kg PND group and 5mg / kg PND group), with 9 rats in each group. The 1mg / kg PND group, 2mg / kg PND group and 5mg / kg PND group were given corresponding doses of ginseng epoxy alkynol, the enalapril group was given 5mg / kg of enalapril maleate, and the sham operation group and the model group were gavaged with pure water; after modeling, gavage was continued for 4 weeks, and the organs were taken and stored at -80℃ for subsequent experiments.

[0030] (3) Pathological changes of myocardial infarction tissue

[0031] The results are as follows Figure 1 As shown in the figure, the hearts of rats in the sham operation group were full and regular in shape, usually in the shape of an inverted cone. The ventricular wall thickness was uniform, the myocardium had good elasticity, the surface was smooth, and the color was ruddy.

[0032] The model group rats had significant changes in the shape of their hearts. The tissue in the infarcted area shrank and collapsed, turned pale and bloodless, and adhered to the surrounding fat. The myocardium in the infarcted area became thinner, and a significant infarcted area may appear in the left ventricle. The heart was generally large and irregular in shape. Fibrosis, hypertrophy, and remodeling occurred in the heart.

[0033] The overall morphology of the heart in the enalapril group may gradually return to normal or remain stable, and the smoothness of the heart surface improves as scar tissue is formed and repaired. The infarct area shrinks, and the color gradually changes from pale or khaki to light red.

[0034] The overall morphology and surface smoothness of the hearts of rats in the low-dose group of ginseng epoxyalkynol: Compared with the model group, the area of ​​myocardial injury began to show improvement in the edges, the overall appearance changed, and the smoothness of the heart surface improved; Infarction focus: The area of ​​the infarction focus was reduced, but not as obvious as the improvement in the medium and high doses, and gradually turned into light white.

[0035] The overall morphology and surface smoothness of the hearts of rats in the medium-dose group of ginseng epoxyalkynol: Compared with the model group, the area of ​​myocardial injury began to show improvement in the edges, the overall appearance changed significantly, and the smoothness of the heart surface improved; Infarction focus: The area of ​​the infarction focus was reduced and gradually turned into light white.

[0036] The overall morphology and surface smoothness of the heart of rats in the high-dose group of ginseng epoxyalkynol: Compared with the model group, the overall appearance of the heart tended to be normal, and the smoothness of the heart surface was improved; Infarction focus: The area of ​​the infarction focus was reduced and gradually turned into light red.

[0037] It can be seen that ginseng epoxyalkynol has a significant improvement effect on cardiac tissue lesions caused by left anterior descending branch ligation, such as myocardial infarction, myocardial fibrosis, hypertrophy and remodeling.

[0038] (4) Heart mass index

[0039] After continuous oral administration for 4 weeks, the rats in each group were weighed (BW), anesthetized with 1% pentobarbital, and the animals were killed to collect heart tissues. The heart weight (HW) of the rats in each group was weighed, and the heart weight index (HWI) was calculated by the ratio of heart weight (HW) to body weight (BW), that is, HWI = HW / BW × 100%, which was used to quantify the size or weight of the heart relative to the whole body weight and evaluate the heart function and pathological state. The results are shown in Figure 2 .

[0040] like Figure 2 As shown in the results, compared with the sham operation group, the heart weight index of the rats in the model group increased significantly (p < 0.0001); compared with the model group, the heart weight index of the rats in the positive drug enalapril group decreased significantly (p < 0.0001); after the administration of low, medium and high doses of ginseng epoxy alkynol, the heart weight index of the rats showed a downward trend, and the low, medium and high doses of ginseng epoxy alkynol groups showed significant differences (p < 0.05, p < 0.001, p < 0.0001, respectively). Since the heart weight index is negatively correlated with cardiac function, that is, the larger the heart weight index, the worse the heart function. It can be seen that ginseng epoxy alkynol can significantly reduce the heart weight index after myocardial infarction, reduce the burden on the heart, and have a protective effect on the heart, showing its positive role in improving cardiac function and relieving symptoms related to myocardial infarction.

[0041] (5) Histological examination

[0042] Four weeks after administration, the animals were anesthetized, and the intact heart tissue was collected and fixed in 4% paraformaldehyde overnight, embedded in paraffin, sliced, stained with prepared hematoxylin for 3 minutes, washed with tap water, differentiated with differentiation solution for 3 seconds, rinsed with tap water, and then blued with blueing solution. After rinsing with tap water, it was stained with Ponceau acid fuchsin staining solution for 8 minutes, rinsed with tap water, soaked in phosphomolybdic acid for 3 minutes, and then directly stained with aniline blue for 3 minutes; soaked in 1% glacial acetic acid for 1 minute, dehydrated, and sealed, examined under a microscope, and image acquisition and analysis.

[0043] The results are as follows Figure 3 As shown in the figure, compared with the sham operation group, in the model group, the myocardial cells in the infarct area lost their function due to ischemic necrosis, and the fibroblasts proliferated and activated, resulting in the massive synthesis and deposition of collagen fibers, showing a clear blue color. The Masson staining results showed that a large amount of collagen fibers were deposited in the model group; compared with the model group, the blue color in the infarct area was significantly reduced in the Masson staining results of the low, medium, and high dose groups of ginseng epoxyalkynol, indicating that the damaged tissue can be repaired after administration, and the deposition of collagen fibers is significantly reduced. In addition, the red area of ​​the muscle fibers in the infarct area can usually reflect the overall structure and functional state of the myocardial tissue. In the model group, the muscle fibers in the infarct area were broken or degenerated due to ischemic necrosis, resulting in a disordered structure in the red area, while the red area structure in the enalapril group and the low, medium, and high dose groups of ginseng epoxyalkynol was more orderly.

[0044] (6) Determination of myocardial collagen volume fraction

[0045] After Masson staining, collagen fibers appear blue, muscle fibers appear red, and cell nuclei appear blue-black. Image J image analysis software was used to perform semi-quantitative analysis of the deposition of myocardial collagen fibers. By measuring the ratio of collagen area to total myocardial area in the infarcted area, the myocardial collagen volume fraction (CVF) was calculated, that is, CVF = myocardial collagen area / total myocardial tissue area × 100%, in order to objectively evaluate the deposition of collagen fibers. The results are shown in Figure 2. Figure 4 shown.

[0046] Depend on Figure 4 It can be seen that compared with the sham operation group, the myocardial collagen volume fraction in the model group increased, and there was a significant difference (p < 0.0001); compared with the model group, the low, medium and high dose groups of ginseng epoxy alkynol were significantly reduced (p < 0.001, p < 0.0001, p < 0.0001, respectively), and each dose group was better than the positive drug enalapril group. The above results show that ginseng epoxy alkynol can significantly reduce the degree of collagen deposition after myocardial infarction, thereby improving the condition of myocardial fibrosis caused by myocardial infarction.

[0047] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. Use of ginseng epoxyalkynol in the preparation of drugs for treating myocardial infarction.

2. The use according to claim 1, characterized in that The myocardial infarction is acute myocardial infarction.

3. The use according to claim 1, characterized in that The myocardial infarction is caused by coronary heart disease.

4. The use according to claim 3, characterized in that The coronary heart disease is caused by rupture of atherosclerotic plaques.

5. The use according to claim 1, characterized in that: The ginseng epoxyalkynol treats myocardial infarction by protecting the tissue pathological changes caused by ligation of the left anterior descending branch of the heart, slowing down the progression of myocardial infarction, reducing the degree of myocardial infarction, reducing the degree of myocardial fibrosis, reducing the infarct area, alleviating ventricular aneurysm and / or alleviating myocardial ischemia after myocardial infarction.

6. The use according to claim 1, characterized in that: The drug also includes pharmaceutically acceptable excipients, and its dosage form includes oral preparations or injections; wherein the oral preparations include any one of tablets, granules, capsules, oral liquids and suspensions.

7. The use according to claim 1, characterized in that The dosage of the ginseng epoxy alkynol is 10-100 mg / kg.

8. The use according to claim 7, characterized in that The dosage of the ginseng epoxyalkynol is 10-50 mg / kg.

9. The use according to claim 8, characterized in that The dosage of the ginseng epoxyalkynol is 20 mg / kg.

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