Use of norellipine in the preparation of a medicament for treating myocardial ischemia reperfusion injury

Abstract

The application discloses application of norisoboldine or a pharmaceutically acceptable salt, a polymorph or a solvate thereof in preparation of a drug for preventing or treating myocardial ischemia-reperfusion injury. It is found that the compound can rapidly target ischemia-reperfusion damaged myocardial cells, inhibit ROS / MDA oxidative stress, quench inflammation storm, and reversely change mitochondrial membrane potential collapse, down-regulate pro-apoptotic protein Bax and up-regulate anti-apoptotic protein Bcl-2, and then inhibit Caspase 3 cleavage, thereby effectively blocking a lethal apoptosis network of myocardial cells from the source. The drug can significantly improve the survival rate of myocardial cells and reduce the myocardial infarction area, and provides a multi-target, mechanism clear new candidate drug for clinical prevention and treatment of acute cardiovascular critical illness.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of norisobordine in the preparation of drugs for treating myocardial ischemia-reperfusion injury. Background Technology

[0002] Acute myocardial infarction (AMI) is a cardiovascular emergency with extremely high morbidity and mortality worldwide. Currently, the most effective means of saving the lives of AMI patients and reducing the infarct size in clinical practice is to implement reperfusion therapy as early as possible, including thrombolytic therapy, percutaneous coronary intervention, and coronary artery bypass grafting. However, during the process of restoring blood supply to the ischemic myocardium, further progressive damage to the structure and function of cardiomyocytes often occurs, leading to serious arrhythmias, myocardial stunning, and even irreversible myocardial cell death. This clinical phenomenon is known as myocardial ischemia-reperfusion (I / R) injury. Myocardial I / R injury not only diminishes the benefits of reperfusion therapy but is also a key factor leading to long-term heart failure in patients.

[0003] With the development of molecular cardiology, those skilled in the art have gradually realized that myocardial I / R injury is a complex pathological cascade reaction triggered by multiple factors and intertwined with multiple pathways, among which oxidative stress, inflammatory storm and mitochondrial-dependent apoptosis are the core links that drive the deterioration of myocardial injury. First, reperfusion triggers a burst of reactive oxygen species (ROS), leading to the depletion of endogenous antioxidant systems such as superoxide dismutase (SOD), resulting in lipid peroxidation (elevated MDA levels) and direct damage to cardiomyocyte membrane structure. Second, ischemia-reperfusion strongly activates the local immune inflammatory response in the myocardium, prompting the massive release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18), forming an inflammatory storm and exacerbating microvascular microcirculatory disturbances. Finally, severe oxidative stress and inflammatory toxicity attack the "energy factory" of cardiomyocytes—mitochondria—leading to mitochondrial membrane potential (MMP) depolarization and functional collapse, which in turn promotes the upregulation of pro-apoptotic proteins (such as Bax) and the downregulation of anti-apoptotic proteins (such as Bcl-2), ultimately activating the cascade cleavage of the core executive protein Caspase-3, leading to irreversible apoptosis of cardiomyocytes.

[0004] Most existing cardiovascular drugs in clinical practice can only target a single target (such as simple vasodilation or simple anticoagulation), and cannot simultaneously intervene in the complex "oxidation-inflammation-apoptosis" network in the process of myocardial I / R injury. Therefore, there is an urgent need in this field to find a new type of drug that can block the above-mentioned pathological cascade reactions at multiple targets and through multiple pathways, thereby effectively reducing myocardial I / R injury.

[0005] Norisopolidine (NOR) is a major isoquinoline alkaloid active ingredient extracted and isolated from the dried tuberous root of Lindera strychnifolia, a traditional Chinese medicine.

[0006] In existing pharmaceutical literature and patent disclosures, those skilled in the art have significant limitations in their understanding of the pharmacological activity of NOR. Currently, the vast majority of research and application development for this monomer focuses on chronic autoimmune diseases and bone metabolism disorders. For example, existing technologies have disclosed that NOR can treat rheumatoid arthritis by inhibiting osteoclast differentiation or improve ulcerative colitis by modulating the intestinal immune barrier. In these chronic disease models, it mainly plays a basic immunomodulatory role. Although there are some reports on the use of traditional Chinese medicine compound formulas or crude extracts containing Lindera strychnifolia for the treatment of myocardial infarction or hypertrophic cardiomyopathy, these existing technologies all rely on the macroscopic synergistic effect of multi-component mixtures and are often aimed at chronic structural heart disease or simple ischemic phases. Existing technologies have not disclosed that a specific component of Lindera strychnifolia plays a dominant role in this process, and there has been no research or disclosure on the relationship between NOR and anti-myocardial I / R injury treatment. Summary of the Invention

[0007] This invention provides the application of norisobordine in the preparation of drugs for treating myocardial ischemia-reperfusion injury. This application enables the drug prepared with norisobordine to take effect rapidly within the extreme stress window of acute ischemia-reperfusion injury, lasting from tens to hundreds of minutes. It allows the target of norisobordine to precisely cross over from chronic local diseases of peripheral synovium or intestinal tissue in existing technologies to rapid targeted intervention in cardiomyocytes. Furthermore, it solves the technical problem of existing clinical prevention and treatment drugs for MIRI using single antioxidants or single anti-inflammatory drugs, which "treat the symptoms but not the root cause, and cannot block the apoptosis cascade." It achieves the simultaneous inhibition of local myocardial inflammatory storms (TNF-α, IL-1β, IL-18) while simultaneously clearing reactive oxygen species (ROS) and downregulating oxidative stress (MDA, SOD), and ultimately severing the mitochondrial dysfunction and apoptosis network caused by upstream oxidative / inflammatory toxicity. This maximizes cardiomyocyte survival (MTT), reduces cytotoxicity (LDH), and minimizes the area of ​​acute myocardial infarction (TTC).

[0008] To achieve the above objectives, the present invention provides the following technical solution: The use of norisoboridine or its pharmaceutically acceptable salts, polymorphs, and solvates in the preparation of drugs for the treatment or prevention of myocardial ischemia-reperfusion injury.

[0009] Preferably, the dosage form of the drug is one or more of the following: injection solution, lyophilized powder for injection, intravenous drip solution, nanoparticles, liposomes or polymer micelles.

[0010] Preferably, the drug is a pharmaceutical composition comprising norisoboline and at least one conventional cardiovascular emergency medication.

[0011] Preferably, the conventional cardiovascular emergency medications include one or more of beta-blockers, ACE inhibitors, antiplatelet aggregation drugs, or edaravone.

[0012] Preferably, the myocardial ischemia-reperfusion injury includes: injury caused by percutaneous coronary intervention for acute myocardial infarction, injury caused by coronary artery bypass grafting, and secondary myocardial injury caused by thrombolytic therapy or heart transplantation.

[0013] Preferably, the norisoboridine inhibits cardiomyocyte apoptosis by specifically reversing mitochondrial membrane potential collapse, downregulating the pro-apoptotic protein Bax and upregulating the anti-apoptotic protein Bcl-2, thereby inhibiting Caspase 3 cleavage.

[0014] Preferably, the norisobordine can also inhibit ROS / MDA oxidative stress and calm the TNF-α / IL-1β / IL-18 cytokine storm.

[0015] Preferably, the monomer purity of the norisoboridine is greater than or equal to 98%.

[0016] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention discloses for the first time a novel application of norisoporin in the treatment of myocardial ischemia-reperfusion injury; 2. Experiments have confirmed that norepinephrine, at the macroscopic in vivo level, can be administered via intraperitoneal injection to significantly reduce the infarct area, improve histopathological damage, and reverse the gold standard indicators of myocardial injury, thus building a strong preventive protective barrier for the heart. 3. Norisopolidine achieves extremely high therapeutic rescue and toxicity inhibition effects at the cellular level, mainly manifested in improving cell survival rate and maintaining cell membrane integrity; 4. Norisoboridine constructs a dual upstream blocking barrier of "antioxidant-anti-inflammatory", which plays a role in effectively resisting oxidative stress and calming local inflammatory storms in the myocardium; 5. Norisopolidine reverses mitochondrial-dependent apoptosis by stabilizing mitochondrial function and blocking core apoptosis in cardiomyocytes.

[0017] Other features and advantages of this disclosure will become clear from the following detailed description of exemplary embodiments with reference to the accompanying drawings. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments or related technologies of this disclosure, the accompanying drawings used in the description of the embodiments or related technologies will be briefly introduced below. Obviously, the accompanying drawings described below are only embodiments of this disclosure. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0019] Figure 1 This is a comparison chart of MTT detection results from the present invention; Figure 2 This is a comparison chart of lactate dehydrogenase (LDH) release at the cellular level according to the present invention. Figure 3 This is an immunofluorescence imaging image of the intracellular reactive oxygen species (ROS) level detected by the DCFH-DA fluorescent probe method of this invention. Figure 4 This is a bar chart showing the DCFH-DA detection results of the present invention; Figure 5 This is a bar chart showing the detection of malondialdehyde (MDA) content at the cellular level according to the present invention. Figure 6 This is a bar chart showing the detection of superoxide dismutase (SOD) content at the cellular level according to the present invention. Figure 7 This is a bar chart showing the detection of the pro-inflammatory cytokine TNF-α content in this invention. Figure 8 This is a bar chart showing the detection of the pro-inflammatory cytokine IL-1β content in this invention. Figure 9 This is a bar chart showing the detection of the pro-inflammatory cytokine IL-18 content in this invention. Figure 10 This is a fluorescence image of mitochondrial membrane potential detection using JC-1 staining according to the present invention; Figure 11 This is a quantitative statistical bar chart of the fluorescence spectrum of mitochondrial membrane potential detection using the JC-1 of this invention; Figure 12 This is a Western blot image of protein immunoblotting at the cell level, as presented in this invention. Figure 13 This is a bar chart showing the quantitative statistical analysis of the pro-apoptotic protein Bax at the cellular level in this invention. Figure 14 This is a bar chart showing the quantitative statistical analysis of the anti-apoptotic protein Bcl-2 at the cellular level in this invention. Figure 15 This is a bar chart showing the quantitative statistical analysis of the cellular-level execution protein cleaved-Caspase 3 in this invention. Figure 16 This is a diagram showing the results of the TTC staining experiment of this invention; Figure 17 This is a comparison chart of the infarct area in this invention; Figure 18 This is a comparative diagram of the HE staining experiment of this invention; Figure 19 This is a comparison chart of serum creatine kinase isoenzyme (CK-MB) levels according to the present invention. Figure 20 This is a comparison chart of serum cardiac troponin I (cTnI) levels according to the present invention. Figure 21 This is a comparison chart of lactate dehydrogenase (LDH) release levels at the animal level in this invention. Figure 22 This is a bar chart showing the detection of malondialdehyde (MDA) content in animals according to the present invention. Figure 23 This is a bar chart showing the detection of superoxide dismutase (SOD) content in animals according to the present invention. Figure 24 This is an immunoblot image of protein detection at the animal level according to the present invention; Figure 25 This is a bar chart showing the quantitative statistical analysis of the pro-apoptotic protein Bax at the animal level in this invention. Figure 26 This is a bar chart showing the quantitative statistical analysis of the anti-apoptotic protein Bcl-2 at the animal level in this invention. Figure 27 This is a bar chart showing the quantitative statistical analysis of cleaved-Caspase 3, the protein used in the animal assay of this invention. Detailed Implementation

[0020] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] Please see Figure 1-27 This invention provides a technical solution: the application of norisobordine in the preparation of drugs for treating myocardial ischemia-reperfusion injury.

[0022] Statistical analysis explanation: All experimental data in the following embodiments and figures of this invention are expressed as mean ± standard deviation (Mean ± SD). Comparisons among multiple groups were performed using one-way ANOVA, combined with Tukey's test for statistical analysis. P A difference of <0.05 is considered statistically significant; when PWhen < 0.01, the difference is considered highly statistically significant; when P A value < 0.001 is considered statistically significant. In the figures below, # indicates a comparison with the normal control group (Control / Sham group). P < 0.05, ## indicates P < 0.01, ### indicates P < 0.001; * indicates compared to the model group (H / R or I / R group). P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001. Example 1: In vitro cell-level experiments with norisopolidine: Step 1 (Hypoxia Modeling): H9c2 cardiomyocytes in the logarithmic growth phase were harvested, and their original culture medium was replaced with a sugar-free medium containing only 2% serum. The cell culture plate was then placed in a specially designed hypoxia chamber, along with an anaerobic bag and an anaerobic indicator to strictly ensure a physically hypoxic microenvironment. The sealed hypoxia chamber was then placed in a 37°C incubator for hypoxia treatment, precisely simulating the myocardial "ischemia" period.

[0023] Step Two (Reoxygenation and Drug Administration): After modeling, remove the cells, discard the sugar-free culture medium, and restore the normal high-glucose complete culture medium to simulate "reperfusion". During this critical window period, add norisoboridine to the culture medium at a final concentration of 3 μM or 10 μM, and place the cells in a conventional incubator for continued reoxygenation.

[0024] The survival rate of cardiomyocytes was determined by MTT assay, and a comparison chart of MTT assay results was created by comparing the results with those of the blank control group and the hypoxia / reoxygenation (H / R) group. Figure 1 It can be seen that the drug prepared by norisoboridine of the present invention can effectively increase the survival rate of myocardial cells damaged by hypoxia and reoxygenation.

[0025] Similarly, the concentration of lactate dehydrogenase (LDH) in the cell supernatant of each group was measured to obtain a comparison chart of LDH release at the cell level. Figure 2 As can be seen, the drug prepared by norisobordine of the present invention can significantly reduce the release of lactate dehydrogenase, proving that it can directly counteract acute cytotoxicity caused by reoxygenation and better maintain the integrity of the cell membrane.

[0026] The above experiments confirm that even after H9c2 cardiomyocytes have undergone strict physical hypoxia (2% glucose-free serum, anaerobic bag microenvironment), administration of 3μM or 10μM norisoporin during the reoxygenation (reperfusion) period can still exert a powerful therapeutic effect, demonstrating that norisoporin has extremely high therapeutic rescue and toxicity inhibition at the cellular level.

[0027] Reactive oxygen species (ROS) were detected in each group of cells, and immunofluorescence imaging maps of intracellular ROS levels based on the DCFH-DA fluorescent probe method were obtained. Figure 3 ), and obtained a bar chart comparing the DCFH-DA detection results ( Figure 4 Simultaneously, the levels of malondialdehyde (MDA), a lipid peroxidation marker, were detected in each group of cells. Figure 5 The content of superoxide dismutase (SOD) and ( Figure 6 ).

[0028] Through the above three sets of tests Figures 3-6 It is evident that norisobordine significantly scavenged reactive oxygen species (ROS) bursts within cardiomyocytes, substantially reduced the level of malondialdehyde (MDA), a lipid peroxidation marker, and significantly restored the endogenous antioxidant activity of superoxide dismutase (SOD). This demonstrates that the drug of the present invention possesses potent antioxidant stress resistance.

[0029] Simultaneously, the release of the core pro-inflammatory cytokines TNF-α, IL-1β, and IL-18 in each of the above cell groups was detected, and a comparison chart of the corresponding pro-inflammatory cytokine contents was obtained. Figure 7 , Figure 8 , Figure 9 It is evident that the drug prepared by norisoporin can specifically inhibit the severe inflammatory cascade response induced by ischemia-reperfusion, significantly downregulate the release of core pro-inflammatory cytokines TNF-α, IL-1β and IL-18, and reduce the damage of inflammation to the myocardial environment.

[0030] Based on the above test results Figures 3-6 and Figures 7-9 It is known that the drug prepared from norisobordine has a strong antioxidant stress effect and can calm the local inflammatory storm in the myocardium, thus constructing a dual upstream blocking barrier of "antioxidant-anti-inflammatory" for myocardial cells.

[0031] Simultaneously, JC-1 fluorescent probe detection was performed on each of the above groups of cells, and fluorescence images of mitochondrial membrane potential detection stained with JC-1 were obtained. Figure 10 ) and quantitative statistical bar chart of JC-1 mitochondrial membrane potential detection fluorescence map ( Figure 11It is evident that the drug of the present invention significantly inhibits hypoxia / reoxygenation-induced mitochondrial membrane potential collapse and significantly reverses ischemia-reperfusion-induced mitochondrial membrane potential (MMP) damage.

[0032] Simultaneously, Western blotting was performed on the cells in each group to obtain Western blotting images. Figure 12 ) and quantitative statistical bar charts of pro-apoptotic protein Bax, anti-apoptotic protein Bcl-2, and executive protein cleaved-Caspase3, respectively ( Figure 13 , Figure 14 , Figure 15 As can be seen, the drug of the present invention significantly downregulates the expression of the pro-apoptotic protein Bax, upregulates the expression of the anti-apoptotic protein Bcl-2, and inhibits the activation of the executive protein cleaved-Caspase 3, thereby blocking the core apoptosis process of cardiomyocytes.

[0033] The results of JC-1 fluorescent probe detection and protein immunoblotting show that the drug norisoporin can reverse mitochondrial-dependent apoptosis, fundamentally blocking the irreversible death of cardiomyocytes, which is reflected in the dramatic increase in the survival rate of H9c2 cells in the MTT assay in vitro. Example 1:

[0034] In vivo animal studies of norisoboridine: Step 1 (Prophylactic Administration): SD rats were used as test subjects. Thirty minutes before the myocardial ischemia modeling surgery, the rats were administered norepinephrine via intraperitoneal injection (ip) at a dose of 15 mg / kg or 30 mg / kg.

[0035] Step 2 (In vivo modeling and reperfusion): 30 minutes after drug administration, SD rats were anesthetized and intubated. The left anterior descending coronary artery (LAD) was ligated by opening the chest to induce acute myocardial ischemia. After the set ischemia time, the ligation was loosened to restore blood flow and induce reperfusion injury.

[0036] The infarct area was observed and compared using TTC staining experiments. The TTC staining results for the normal control group (Sham), the ischemia / reperfusion group (I / R), and the NOR 30 mg / kg group are shown below. Figure 16 Comparison of infarct area between the normal control group (Sham), the ischemia / reperfusion group (I / R), and the NOR 15mg / kg group, see [image / image]. Figure 17 Therefore, the drug prepared by norisoporin of the present invention can greatly reduce the area of ​​irreversible myocardial necrosis caused by ischemia-reperfusion.

[0037] HE staining experiments were performed on the normal control group (Sham), the ischemia / reperfusion group (I / R), and the NOR 15 mg / kg and NOR 30 mg / kg groups. Comparative images of HE staining experiments were obtained (see...). Figure 18 It can be seen that the drug prepared by norisoboridine of the present invention effectively reduces myocardial fiber breakage, disordered arrangement and severe interstitial edema.

[0038] As above, the gold standard for reversing myocardial injury was measured in the normal control group (Sham), the ischemia / reperfusion group (I / R), and the NOR 15 mg / kg and NOR 30 mg / kg groups. Specifically, the levels of serum creatine kinase isoenzyme (CK-MB) and cardiac troponin I (cTnI) were measured, resulting in a comparison chart of serum creatine kinase isoenzyme (CK-MB) levels. Figure 19 Comparison of the levels of ) and cardiac troponin I (cTnI) () Figure 20 ).

[0039] In the same cell-level experiment, the concentration of lactate dehydrogenase (LDH) in the supernatant of cardiomyocytes in each group was measured, and a comparison chart of LDH release at the animal level was obtained. Figure 21 ).

[0040] The above in vivo animal experiments have demonstrated that intraperitoneal injection of norisoporin at a dose of 15 mg / kg or 30 mg / kg 30 minutes before the onset of myocardial ischemia can build a strong preventive protective barrier for the heart, achieving effective prevention and substantial rescue of myocardial tissue.

[0041] At the same cellular level, the levels of malondialdehyde (MDA), a lipid peroxidation marker, were detected in the above groups of cardiomyocytes in animal studies. Figure 22 The content of superoxide dismutase (SOD) and ( Figure 23 ).

[0042] At the same cellular level, Western blotting was performed on the above groups of cardiomyocytes at the animal level to obtain Western blotting maps. Figure 24 ) and quantitative statistical bar charts of pro-apoptotic protein Bax, anti-apoptotic protein Bcl-2, and executive protein cleaved-Caspase 3, respectively ( Figure 25 , Figure 26 , Figure 27 This also proves that the drug of the present invention blocks the core apoptosis process of cardiomyocytes.

[0043] Based on the above experimental results, the drug prepared by norisopordine of this invention can: 1. Eliminate reactive oxygen species and block the cascade amplification of inflammation: After targeting damaged myocardial tissue, norisobordine directly intervened in the sources of oxidative stress. Detection results confirmed that it significantly reduced intracellular ROS levels and malondialdehyde (MDA) content in tissues, and restored superoxide dismutase (SOD) activity. Simultaneously, it specifically inhibited immune-mediated microenvironment deterioration, significantly downregulating the release of pro-inflammatory factors TNF-α, IL-1β, and IL-18. This demonstrated that norepinephrine (NOR) effectively maintained the integrity of myocardial cell membrane structure, as evidenced by a significant reduction in lactate dehydrogenase (LDH) release in cell culture supernatant in vitro.

[0044] 2. Protects mitochondrial function and reverses apoptosis: Norisoperidine directly protects mitochondrial function in cardiomyocytes. JC-1 assays showed that it significantly inhibited hypoxia / reoxygenation-induced mitochondrial membrane potential collapse. Western blotting further confirmed that 3, 10 μM (in vitro) or 15, 30 mg / kg (in vivo) of norisoperidine significantly upregulated the expression of the anti-apoptotic protein Bcl-2, downregulated the expression of the pro-apoptotic protein Bax, and significantly reduced the cleavage of the core executive protein cleaved-Caspase 3. NOR fundamentally blocks irreversible cardiomyocyte death, as evidenced by a dramatic increase in H9c2 cell viability in in vitro MTT assays.

[0045] 3. Rescue of cardiac tissue structure and improvement of myocardial enzyme levels: TTC staining confirmed a statistically significant reduction in the area of ​​myocardial infarction; HE staining confirmed a significant improvement in myocardial fiber rupture and interstitial edema; and the concentrations of the gold standard markers of myocardial injury (CK-MB, cTnI) in peripheral serum were significantly reduced, fully demonstrating its extremely high clinical translational value.

[0046] The above experiments at the cellular and animal levels demonstrate that the application of the drug of this invention primarily addresses two core technical issues: 1. Overcome the technical limitation that norisopolidine is only applicable to chronic, local immune / bone and joint diseases, and solve the technical problem of its difficulty in achieving targeted and rapid intervention in acute cardiovascular emergencies.

[0047] This invention aims to overcome the biases of existing technologies and address the question of whether norisoporin can rapidly take effect within the extreme stress window of acute ischemia-reperfusion lasting tens to hundreds of minutes. This invention focuses on precisely targeting cardiomyocytes, moving beyond peripheral synovial or intestinal tissues, and addressing how to specifically stabilize the mitochondrial membrane potential (MMP) of cardiomyocytes using this compound, and potently intervene in the core lethal apoptosis network dominated by Bax / Bcl-2 / cleaved-Caspase 3, thereby providing a new rescue strategy for acute lethal myocardial injury.

[0048] 2. To overcome the shortcomings of existing MIRI clinical prevention and treatment drugs, namely "single target and weak defense," and to solve the technical problem of how to achieve multidimensional closed-loop protection of "antioxidation-anti-inflammation-anti-mitochondrial apoptosis" using a single drug component. This invention aims to solve the technical problem that existing single antioxidants or single anti-inflammatory drugs "treat the symptoms but not the root cause and cannot block the apoptosis cascade reaction." This invention is committed to clarifying the multi-target synergistic pharmacological mechanism of norisoboridine, that is, how to use a single effective component to simultaneously inhibit the local inflammatory storm in the myocardium (TNF-α, IL-1β, IL-18) while clearing reactive oxygen species (ROS) and downregulating oxidative stress (MDA, SOD) at the source, and ultimately sever the mitochondrial functional collapse and apoptosis network caused by upstream oxidative / inflammatory toxicity, thereby maximizing cardiomyocyte survival (MTT), reducing cytotoxicity (LDH), and shrinking the acute myocardial infarction area (TTC).

[0049] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. The use of norisoporin or its pharmaceutically acceptable salts, polymorphs, and solvates in the preparation of drugs for the treatment or prevention of myocardial ischemia-reperfusion injury.

2. The application according to claim 1, characterized in that: The dosage form of the drug is one or more of the following: injection solution, lyophilized powder for injection, intravenous drip solution, nanoparticles, liposomes, or polymer micelles.

3. The application according to claim 1, characterized in that: The drug is a pharmaceutical composition comprising norisobordine and at least one commonly used cardiovascular emergency medication.

4. The application according to claim 3, characterized in that: The commonly used cardiovascular emergency medications include one or more of the following: beta-blockers, ACE inhibitors, antiplatelet aggregation drugs, or edaravone.

5. The application according to claim 1, characterized in that: The myocardial ischemia-reperfusion injury includes: injury caused by percutaneous coronary intervention for acute myocardial infarction, injury caused by coronary artery bypass grafting, and secondary myocardial injury caused by thrombolytic therapy or heart transplantation.

6. The application according to claim 1, characterized in that: The norisoboridine inhibits cardiomyocyte apoptosis by specifically reversing mitochondrial membrane potential collapse, downregulating the pro-apoptotic protein Bax and upregulating the anti-apoptotic protein Bcl-2, thereby inhibiting Caspase 3 cleavage.

7. The application according to claim 1 or 6, characterized in that: The aforementioned norisobordine can also inhibit ROS / MDA oxidative stress and calm the TNF-α / IL-1β / IL-18 cytokine storm.

8. The application according to claim 1, characterized in that: The monomer purity of the norisoboridine is greater than or equal to 98%.

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