CN117462538A - Application of flavonoid compounds in myocardial ischemia reperfusion injury - Google Patents
Application of flavonoid compounds in myocardial ischemia reperfusion injury Download PDFInfo
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- CN117462538A CN117462538A CN202311723606.3A CN202311723606A CN117462538A CN 117462538 A CN117462538 A CN 117462538A CN 202311723606 A CN202311723606 A CN 202311723606A CN 117462538 A CN117462538 A CN 117462538A
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- reperfusion injury
- myocardial ischemia
- ischemia reperfusion
- acid
- myocardial
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
Abstract
The application of flavonoids compounds in myocardial ischemia reperfusion injury is provided. The invention provides application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for preventing and treating myocardial ischemia reperfusion injury:wherein the R is 1 Selected from hydrogen or methoxy, said R 2 Selected from hydroxy or methoxy, said R 3 Selected from hydrogen or hydroxy. The flavonoid compound can reduce myocardial tissue infarction, improve cardiac function and protect rat myocardial ischemia reperfusion injury.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to medical application of flavonoid compounds.
Background
After partial or complete acute occlusion of the coronary arteries, and after a certain period of time, the ischemic myocardium is restored to normal perfusion, but the tissue damage is rather progressive and aggravated, and secondary damage is brought to the patient, called myocardial ischemia reperfusion injury (Myocardial ischemia-reperfusion injury, MIRI). Partial myocardial necrosis, increased inflammatory factors, severe cytokine oxidation, and other physiological responses after MIRI will result in poor therapeutic effect and poor prognosis. Several major mechanisms responsible for myocardial reperfusion injury, such as calcium overload, rapid pH correction, and reactive oxygen species production, are now well established, which can lead to mitochondrial damage leading to myocardial cell necrosis or apoptosis. After myocardial cell death, the heart begins to repair itself, and then inflammatory cells begin to infiltrate the heart and clear away the dead myocardial cells, thereby causing an increase in the number of cell necrosis, exacerbating symptoms and complications of myocardial ischemia-related diseases. Myocardial ischemia reperfusion injury has now become one of the main causes of cardiovascular diseases affecting the therapeutic effect of ischemic diseases.
The current methods for clinically treating myocardial ischemia reperfusion injury are five methods, namely hyperbaric oxygen therapy, application of cardiac Fang Lina peptide, novel anti-diabetic myocardial protectant, polarized fluid therapy and cryotherapy. The mechanism of action of these five therapies is to reduce reperfusion injury by reducing infarct size. Research shows that myocardial ischemia reperfusion injury may be closely related to oxidative stress, intracellular calcium overload, myocardial cell damage, glucose metabolism blocking and the like, so that the pathogenesis can be used as a potential therapeutic target point of myocardial ischemia reperfusion injury clinical diseases, and the occurrence of injury is reduced or the injury which has already occurred is relieved through instruments, medicines and the like. However, there is currently no clinically effective therapeutic agent for MIRI. Therefore, the development of drugs or treatments that safely and effectively reduce MIRI injury has become a critical issue to be addressed.
Disclosure of Invention
The invention aims to provide medical application of flavonoid compounds.
In particular, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of myocardial ischemia reperfusion injury:
wherein the R is 1 Selected from hydrogen or methoxy, said R 2 Selected from hydroxy or methoxy, said R 3 Selected from hydrogen or hydroxy.
In a preferred embodiment, the compound of formula (I) is selected from:
in another preferred embodiment, the compound or pharmaceutically acceptable salt thereof is used as the sole active ingredient in the preparation of medicaments for preventing and treating myocardial ischemia reperfusion injury 。
Details of the various aspects of the invention will be described in detail in subsequent sections. The features, objects, and advantages of the invention will be apparent from the description, and from the claims.
Drawings
FIG. 1 cytotoxicity pattern of homoplantagin, salicifolicin, farnesin, geraniin, apigenin, luteolin, eupatorium flavone, demethoxycodone.
FIG. 2 effects of homoplantain, salicifolicin, farnesin, geraniin, apigenin, luteolin, eupatorium flavone, demethoxycodone, metoprolol, esmolol and rosiglitazone on related myocardial enzyme markers such as LDH, CPK, tn at the cellular level. (note: in comparison with the blank control group, # P＜0.05， ## p is less than 0.01; compared with the I/R group, P<0.05，**P<0.01)。
Detailed Description
The invention relates to the treatment/prevention effect of a natural flavonoid compound on myocardial ischemia reperfusion injury. The compound is a 5, 7-dihydroxyl natural flavonoid compound. The compound has the effect of obviously relieving myocardial ischemia reperfusion injury. Cell experiments prove that the medicine also has better safety and good prospect of patent medicine. Animal experiments further prove that the compounds can relieve myocardial ischemia reperfusion injury.
The structural formula of the 5, 7-dihydroxyl natural flavonoid compound is as follows:
wherein the R is 1 Selected from hydrogen or methoxy, said R 2 Selected from hydroxy or methoxy, said R 3 Selected from hydrogen radicals or hydroxy radicals 。
Specifically, the present invention provides the following compounds:
TABLE 1
The invention also includes all pharmaceutically acceptable salts of the compounds described above. These salts may be formed by positively charged moieties (amine groups) of the compound with negatively charged (e.g., hydrochloric acid) of opposite electrical properties; including but not limited to salts with: hydrochloric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfurous acid, nitric acid, carbonic acid, boric acid, selenious acid, phosphomolybdic acid, phosphorous acid, citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid, D-lactic acid, L-lactic acid, DL-lactic acid, oxalic acid, sulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, tartaric acid, malonic acid, succinic acid, fumaric acid, citric acid, benzoic acid, or substituted benzoic acid.
The flavonoid compounds of the invention can be purchased through commercial paths, and the purity of the flavonoid compounds meets the medicinal standard.
The flavonoid compound has the following advantages:
(1) The activity is strong: the medicines have stronger effect of relieving myocardial ischemia reperfusion injury at the cellular level and the animal level and are obviously stronger than the current clinical common medicines of esmolol and metoprolol;
(2) The safety is high: the medicine has no obvious toxic and side effect at the cellular level, and LD thereof 50 >Within 50 μm concentration, it is a relatively safe drug candidate.
The flavonoid compounds of the present invention may be used alone or in the form of a pharmaceutical composition. The pharmaceutical composition comprises the flavonoid compound of the invention as an active ingredient and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition of the present invention contains 0.1 to 99.9% by weight of the flavonoid of the present invention as an active ingredient. The pharmaceutically acceptable carrier does not destroy the pharmaceutical activity of the flavonoid compound, and the effective dosage of the flavonoid compound can play the role of the drug carrier, so that the dosage of the flavonoid compound is nontoxic to human bodies.
The pharmaceutically acceptable carrier includes, but is not limited to: soft phospholipids, aluminum stearate, aluminum oxide, ion exchange materials, self emulsifying drug delivery systems, tween or other surfactants, serum proteins, buffer substances such as phosphates, glycine, sorbic acid, water, salts, electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, magnesium silicate, saturated fatty acid partial glyceride mixtures and the like.
Other commonly used pharmaceutical excipients such as binders (e.g. microcrystalline cellulose), fillers (e.g. starch, glucose, lactose anhydrous and lactose beads), disintegrants (e.g. crospvp, croscarmellose sodium, low substituted hydroxypropylcellulose), lubricants (e.g. magnesium stearate) and absorption promoters, adsorption carriers, fragrances, sweeteners, excipients, diluents, wetting agents, etc.
The flavonoid compounds of the present invention and pharmaceutical compositions thereof may be prepared according to conventional methods in the art and may be administered by enteral or parenteral or topical routes. The oral preparation comprises capsule, tablet, oral liquid, granule, pill, powder, pellet, paste, etc.; parenteral formulations include injection solutions and the like; topical formulations include creams, patches, ointments, sprays and the like. Preferably an oral formulation.
The flavonoid compounds and the pharmaceutical compositions thereof of the present invention may be administered orally, sublingually, intramuscularly or subcutaneously, intravenously, urethrally, vaginally, etc.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. All percentages, ratios, proportions, or parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this patent specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
Example one flavonoid cytotoxicity test of the present invention
In order to detect whether homoplantain, salicifolicin, farnesin, geraniin, apigenin, luteolin, eupatorium flavone and demethoxy procyanidin have an effect on cell viability, we performed an evaluation of the cell activity to ensure that the compound obtains more realistic data at the cell level.
[ Experimental materials ]
HEK293 cells, DMEM medium, fetal bovine serum, penicillin-streptomycin, homoplantagin, salamandelic flavin, farnesin, diosmetin. Apigenin, luteolin, eupatorium adenophorum flavone, demethoxyprocyanidin dimethyl sulfoxide, and CCK-8 reagent.
Experimental procedures
(1) HEK293 cells were cultured in a incubator at 37℃with a carbon dioxide concentration of 5% and the medium was DMEM medium (10% foetal calf serum and 1% diabody were added to DMEM medium).
(2) HEK293 cells were grown at 5X 10 when the cell state was stable 3 Density of individual cells/wells was seeded in 96-well plates;
(3) Incubation was performed for 48 hours after addition of the different compounds;
(4) Then 20 mu L of CCK-8 reagent is added, and after incubation is carried out for 30 minutes, the mixture is put into a microplate reader for detection, and the detection condition is set to absorbance detection, and the wavelength is 450nm.
[ experimental results ]
As shown in figure 1, when the medicine is 20 mu M, the survival rate of HEK293 cells is more than 90%, which indicates that the flavonoid compounds have better safety.
Example II study of the Effect of the flavonoid Compounds of the invention on myocardial enzyme markers related to LDH, CPK, tn and the like
In order to verify whether the flavonoid compound can relieve myocardial ischemia reperfusion injury at the cellular level, the invention further detects the effects of homoplantain, salicifolium, farnesoid, geraniin, apigenin, luteolin, eupatorium flavone, demethoxyccornflower flavone, and related myocardial enzyme markers such as LDH, CPK, tn after myocardial ischemia reperfusion injury by clinically treating common medicines such as metoprolol, esmolol and rosiglitazone at the cellular level.
[ Experimental materials ]
H9C2 cells, DMEM medium, hypoxic medium, fetal bovine serum, CCK-8 kit, rat Lactate Dehydrogenase (LDH) enzyme-linked immunoassay EILISA kit, rat phosphocreatine kinase (CPK) enzyme-linked immunoassay ELISA kit, rat troponin (Tn) enzyme-linked immunoassay ELISA kit, homoplantain, salamandelic flavin, farnesin, geraniin, apigenin, luteolin, eupatorin, demethoxyprocyanidin, metoprolol, esmolol, rosiglitazone, dimethyl sulfoxide.
Experimental procedures
(1) Cell culture and grouping
H9C2 cells were cultured in a constant temperature incubator at 37℃with a carbon dioxide concentration of 5% and a DMEM medium (10% fetal bovine serum and 1% diabody were added to the DMEM medium). H9C2 cells are planted in a 96-well plate, after the cell adhesion is stable, the cells are randomly divided into a blank group, an I/R group and an I/R+homoplantain group, wherein the I/R+Liuzhan Huang Suzu group, the I/R+farnesin group, the I/R+Pelargonin group, the I/R+apigenin group, the I/R+Oleacetin group, the I/R+herba Lycopi flavone group, the I/R+demethoxycornflower flavone group, the I/R+metoprolol group, the I/R+esmolol group and the I/R+rosiglitazone group, and the drug concentration is 20 mu M after drug addition treatment is carried out for 48 hours.
(2) Construction of MIRI model
Before the hypoxia experiment starts, the culture medium of each group is replaced by a hypoxia culture medium, a nitrogen incubator is opened, when the oxygen content is lower than 1.2%, cells are put into the incubator and timing is started, after about 3 hours, the cells are taken out, after the hypoxia culture medium is replaced by a complete culture medium, the cells are put into a constant temperature of 37 ℃ and 5% CO 2 Reoxygenation is carried out for 30min in an incubator.
(3) Cell activity and Lactate Dehydrogenase (LDH), phosphocreatine kinase (CPK), troponin (Tn) assays
After reoxygenation for 30min, the supernatants of each group were aspirated and tested for Lactate Dehydrogenase (LDH), phosphocreatine kinase (CPK), troponin (Tn) using ELISA kit. The cell viability assay was then performed by adding CCK-8 reagent to the cell wells.
[ experimental results ]
As shown in FIG. 2, the cell activity of the I/R group is reduced and the activity of the myocardial enzyme markers related to LDH, CPK, tn and the like is increased compared with that of the blank group, which indicates that the membrane formation is successful; compared with the I/R group, the cell activity of each flavonoid group is increased, the activity of related myocardial enzyme markers such as LDH, CPK, tn is reduced, and the activity of related myocardial enzyme markers of metoprolol, esmolol and rosiglitazone groups is obviously higher than that of the flavonoid group, which shows that compared with the metoprolol, esmolol and rosiglitazone, the flavonoid compound has stronger MIRI relieving effect at the cell level.
Example III Effect verification of flavonoid Compounds of the invention on MIRI rat models
To verify whether the flavonoid compounds of the present invention are able to alleviate the symptoms associated with MIRI rats, their therapeutic effect on MIRI rats was further examined.
[ Experimental materials ]
Healthy SD rats, homoplantagin, salamandelic flavin, farnesin, geraniin, apigenin, luteolin, eupatorium flavone, desmethoxycornflower Huang Tongmei tollol, esmolol, rosiglitazone, uratam, physiological saline.
Experimental procedures
(1) SD rat film
Injecting uratam for anesthesia in the abdominal cavity, and recording a limb two-lead electrocardiogram; the middle of the trachea is cut open and connected with a breathing machine; immediately after the chest cavity is opened between the third rib and the fourth rib to expose the heart, the respirator is opened, and parameters are set: respiratory rate 70 times/min, tidal volume 20mL/kg, respiratory ratio 1:1, a step of; after stabilizing for 5min, opening pericardium, and clamping coronary artery at the position of about 2mm of lower edge of left auricle, wherein ST elevation or T wave high rise of electrocardiograph is used for indicating myocardial ischemia; after 30min of occlusion, the arterial occlusion is released to restore blood perfusion, and the elevated ST segment is lowered or the T wave with high rise is restored to indicate that the myocardial reperfusion is successful; SD rats were randomly divided into blank, I/R, I/R+homoplantain, I/R+Liuzhan Huang Suzu, I/R+farnesin, I/R+Pelargoniin, I/R+apigenin, I/R+luteolin, I/R+herba Lycopi flavone, I/R+demethoxyprocyanidin, I/R+metoprolol, I/R+esmolol, I/R+rosiglitazone; the flavone compound administration concentration is 150mg/kg, the metoprolol administration concentration is 10mg/kg, the esmolol administration concentration is 10mg/kg, and the rosiglitazone administration concentration is 6mg/kg. Another 16 rats were used as a sham surgical group, which performed a surgical procedure, and the rest of the procedure was identical to the test group except that the coronary arteries were not occluded.
(2) Determination of the heart/body Mass ratio
After 4 weeks of administration treatment, the weights of the rats in each group were weighed, the heart tissue was removed by opening the chest after the anesthesia by intraperitoneal injection of urateine, the weights were weighed after washing with physiological saline, and then the heart/body mass ratio was calculated.
(3) Determination of myocardial infarction area
After weighing heart tissue, freezing for 30min at-20 ℃, cutting into slices of 1mm, placing in a 1% TTC solution, incubating for 15min at 37 ℃ in dark, and calculating myocardial infarction area by using a BI-2000 medical image analysis system, wherein normal tissue is red and a infarct area is grey.
(4) Determination of AST, CK, LDH content and T-AOC level in serum
After 4 weeks of drug administration treatment, blood was taken through the abdominal aorta before taking the heart tissue, the upper serum was taken after centrifugation at 1500rpm for 10min, then the AST, CK, LDH content was determined by a full-automatic biochemical detector according to the kit operating method steps, and the T-AOC level in the serum was determined by an ultraviolet-visible spectrophotometer.
[ experimental results ]
As shown in tables 1 and 2, compared with the sham operation group, the heart/body mass ratio of the rat in the I/R group was significantly increased, the heart/body mass ratio of the rat with myocardial ischemia reperfusion injury in each drug group was significantly decreased after 4 weeks of drug treatment, and the myocardial tissue infarct area of the rat was significantly decreased as compared with the I/R group, wherein the effect of the flavonoid group was significantly better than that of the metoprolol, esmolol, rosiglitazone group. Furthermore, the AST, CK, LDH content in the serum of group I/R rats was significantly increased and T-AOC was significantly decreased compared to sham groups; after 4 weeks of drug treatment, the content of AST, CPK, LDH in serum of rats with myocardial ischemia reperfusion injury is obviously reduced, the T-AOC level is obviously increased, and compared with metoprolol, esmolol and rosiglitazone, the flavonoid compound has better effect. The flavonoid compound disclosed by the invention can reduce myocardial tissue infarction, improve cardiac function and protect rat myocardial ischemia reperfusion injury.
TABLE 1 Change of heart/body Mass ratio and myocardial tissue infarct size for groups of rats
TABLE 2 variation of AST, CPK, LDH content and T-AOC levels in serum from various groups of rats
The various aspects of the invention have been described above. It will be understood, however, that equivalent changes and modifications may be made thereto by those skilled in the art without departing from the spirit of the invention, which changes and modifications likewise fall within the scope of the claims of the present application.
Claims (3)
1. Use of a compound of formula (i) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and treatment of myocardial ischemia reperfusion injury:
wherein the R is 1 Selected from hydrogen or methoxy, said R 2 Selected from hydroxy or methoxy, said R 3 Selected from hydrogen or hydroxy.
2. The use according to claim 1, wherein the compound of formula (i) is selected from:
3. the use according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof is used as the sole active ingredient in the manufacture of a medicament for the prevention and treatment of myocardial ischemia reperfusion injury.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN118359663A (en) * | 2024-04-26 | 2024-07-19 | 西安交通大学医学院第一附属医院 | Mitochondrial targeting genistein derivative and application thereof in preparation of medicines for resisting myocardial ischemia reperfusion injury |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN118359663A (en) * | 2024-04-26 | 2024-07-19 | 西安交通大学医学院第一附属医院 | Mitochondrial targeting genistein derivative and application thereof in preparation of medicines for resisting myocardial ischemia reperfusion injury |
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