CN106913565B - Application of liquiritigenin M in preparing medicine for treating and/or preventing thrombotic diseases - Google Patents
Application of liquiritigenin M in preparing medicine for treating and/or preventing thrombotic diseases Download PDFInfo
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Abstract
The invention discloses an application of liquiritigenin M in preparing a medicament for treating and/or preventing thrombotic diseases. Experiments show that the liquiritigenin M can obviously reduce the weight of arteriovenous bypass thrombus and obviously improve the levels of NO, cGMP and PGI2 in the plasma of a thrombus rat in vivo; the liquiritin M can inhibit platelet aggregation by influencing NO/cGMP metabolic pathway and changing PGI2 level; in addition, the liquiritigenin M can remarkably reduce the cerebral edema caused by cerebral thrombosis, reduce the content of MDA in brain tissues and increase the activity of SOD; the compound is proved to have certain antioxidant activity and obvious protective effect on cerebral thrombosis. Therefore, the liquiritigenin M has the function and value of treating thrombotic diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of liquiritigenin M in preparing a medicine for treating thrombotic diseases.
Background
The thrombosis embolism disease is a disease which seriously harms the health of middle-aged and elderly people AT present, has high morbidity and high lethality rate, thrombosis is a complex process with multi-factor participation and gradual development, blood is abnormally coagulated due to activation of platelets and activated blood coagulation factors under a flowing state, the thrombosis plays a role in promoting the occurrence and development of cardiovascular and cerebrovascular diseases and is also one of main causes of death and disability, conditions of the thrombosis include vascular intimal injury, change of a blood flow state and increase of blood coagulability, therefore, platelet function inhibition and blood coagulation prevention can prevent thrombosis, and more platelet and antithrombin drugs such as a platelet cyclooxygenase inhibitor aspirin, a platelet inner ring nucleotide inhibitor dipyridamole, an Adenosine Diphosphate (ADP) receptor antagonist clopidogrel, heparin of antithrombin Ш (AT Ш), warfarin and the like are clinically applied.
Glycyrrhiza glabra Radix et Rhizoma, which is the dried root and rhizome of Glycyrrhiza uralensis Fisch, Glycyrrhiza inflata Bat or Glycyrrhiza glabra L, is a commonly used Chinese medicine. Recent researches show that flavonoid components contained in liquorice have strong effects of resisting oxidation and atherosclerosis, reducing blood fat, reducing blood pressure and the like.
Gancaonin M (Gancaonin M, C)21H20O5CAS number: 129145-51-3) is flavonoid component in Glycyrrhrizae radix, and its structural formula is shown in formula I:
few reports about the pharmacological research of the liquiritigenin M exist, and the application of the liquiritigenin M in preparing the medicines for treating the thrombotic diseases is not reported yet.
Disclosure of Invention
The invention aims to find a natural extracted medicine capable of preventing and/or treating thrombotic diseases from traditional Chinese medicines. The invention surprisingly discovers that the liquiritigenin M extracted from liquorice can obviously inhibit the formation of rat carotid and arteriovenous bypass thrombosis, has certain antioxidant activity and has obvious protective effect on cerebral thrombosis.
In view of the above, the invention provides an application of glycyronine M in preparing a medicament for treating and/or preventing thrombotic diseases.
Further, the thrombotic disease is arteriovenous bypass thrombosis.
Further, the thrombotic disease is cerebral thrombosis.
The invention also provides a medicament prepared from the liquiritigenin M for treating and/or preventing thrombotic diseases, which is characterized by also comprising pharmaceutically acceptable auxiliary materials.
Specifically, the dosage form of the medicine is an oral administration dosage form, an injection administration dosage form or an external administration preparation.
Further, the oral administration dosage form is tablets, capsules, granules, pills, oral liquid, soft extracts, suspending agents, dispersing agents or syrups.
The injection administration preparation is injection liquid or powder injection for injection.
The external administration preparation is suppository, patch or gel.
Preferably, the dose of the liquiritigenin M of the oral administration dosage form is 16 mg/kg-d through dose conversion-1～64mg/kg·d-1. More preferably, the dose of said glycyronin M is 32 mg/kg-d-1～64mg/kg·d-1。
The liquiritigenin M is purchased from Shanghai leaf Biotechnology Co., Ltd, a product number of 129145-51-3. The liquiritigenin M can obviously reduce the weight of arteriovenous bypass thrombus in vivo and obviously improve the levels of NO, cGMP and PGI2 in the plasma of a thrombus rat; the liquiritin M is shown to inhibit platelet aggregation by influencing NO/cGMP metabolic pathway and changing PGI2 level.
In addition, the liquiritigenin M can remarkably reduce the cerebral edema caused by cerebral thrombosis, reduce the content of MDA in brain tissues and increase the activity of SOD; the compound is proved to have certain antioxidant activity and obvious protective effect on cerebral thrombosis.
Detailed Description
As mentioned above, the present invention aims to provide the application of the liquiritin M in the preparation of the drugs for treating and/or preventing thrombotic diseases. The following will specifically describe the contents of the experiment.
It is specifically noted that similar alternatives and modifications will be apparent to those skilled in the art, which are also intended to be included within the present invention. It will be apparent to those skilled in the art that the techniques of the present invention may be implemented and applied by modifying or appropriately combining the methods and applications described herein without departing from the spirit, scope, and content of the present invention.
If the specific conditions are not indicated, the method is carried out according to the conventional conditions or the conditions suggested by manufacturers, and the used raw material medicines or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.
Effect of Licorice root Ning M on experimental thrombosis resistant model rat
1 materials of the experiment
60 clean-grade SD rats, male, with the body mass of about 180-; PGI2, cGMP and NO kits were purchased from Nanjing institute of bioengineering; the other reagents are domestic analytical purifiers.
2 method of experiment
2.1 Experimental grouping and modeling
After one week of regular feeding, 60 SD rats were randomized into 5 groups: normal control group, model group, low, medium and high dose drug group, each group has 12 drugs. The medicine composition is infused with the Gancaoganning M according to the body mass standards of 100, 200 and 400mg/kg, and the normal control group and the model group are infused with the same amount of normal saline for 1 time every day for 2 weeks continuously. 60 rats were taken 1h after the last administration for carotid and arteriovenous bypass thrombosis experiments. The rats are anesthetized (30-40 mg/kg of sodium pentobarbital, i.p.), the right common carotid artery and the left external jugular vein are separated, a silk thread with the length of 6cm is placed at the middle section of a polyethylene tube, and the polyethylene tube is filled with heparin normal saline solution (50U/mL). After one end of the polyethylene tube is inserted into the left external jugular vein, heparin (50U/mL) is accurately injected into the polyethylene tube for anticoagulation, then the other end of the polyethylene tube is inserted into the right common carotid artery, the artery clamp is opened, blood flows from the right common carotid artery to the polyethylene tube and returns to the left external jugular vein, the blood flow is interrupted after the blood flow is opened for 15min, the silk thread is rapidly taken out and weighed, and the weight of the silk thread is subtracted from the total weight to obtain the weight of the thrombus. And calculating the thrombus inhibition rate.
The thrombus inhibition rate (%) is (wet weight of thrombus in model group-wet weight of thrombus in drug group)/wet weight of thrombus in model group × 100%
2.2 determination of plasma levels of NO, cGMP, PGI2
60 rats in a carotid and arteriovenous bypass thrombosis experiment are taken, 1mL of blood is taken from inferior vena cava, and EDTA is used for anticoagulation. cGMP and PGI2 were assayed by radioimmunoassay and NO was determined spectrophotometrically according to the kit instructions.
2.3 statistical analysis
Data results obtained are mean ± sd
Showing that SPSS16.0 software is used for statistical analysis, single-factor analysis of variance is adopted for comparison among groups, and the t test among groups shows that P is less than 0.05, so that the difference is significant.
3 results of the experiment
3.1 Effect of Licorice M on arteriovenous bypass Thrombus model
As shown in Table 2, the normal control group had no thrombosis. Compared with the model group, the thrombus weight of each dose group of the liquiritin M is obviously reduced (P <0.01), and the dose dependence is realized.
TABLE 2 inhibition of arteriovenous bypass thrombosis by Liquirinin M
P <0.05, P <0.01 compared to model group.
3.2 Effect of Glycyrrhizine M on levels of NO, cGMP, PGI2 in rat plasma
Table 3 shows that, compared with the model group, each dose group of glycyrrhizin M significantly increased the level of NO, PGI2 (P <0.05 or P <0.01) in plasma, and was dose-dependent, and that, except for the glycyrrhizin M low dose group, the cGMP level (P <0.01) in plasma was significantly increased compared with the model group.
TABLE 3 Effect of Glycyrrhizin M on levels of NO, cGMP, PGI2 in rat plasma
Compared with the normal control group,##P<0.01; comparison with model group<0.05,**P<0.01.
Experiments prove that the compound can obviously inhibit the formation of rat carotid and arteriovenous bypass thrombus and improve the levels of NO, cGMP and PGI2, thereby providing experimental basis for the development of the ganciclovir M for clinical medicines.
The thrombus formed by rat carotid artery and vein bypass is platelet thrombus and is caused by the aggregation of platelets adhered to the silk thread, and the formed thrombus structure is similar to white thrombus in the artery and is closer to pathological conditions. The ginkgo leaf extract can effectively inhibit the formation of the thrombus, and the mechanism of inhibiting the thrombus formation is probably related to the inhibition of platelet aggregation.
NO, cGMP, PGI2 are known to be involved in thrombus formation. NO is a messenger molecule with platelet aggregation inhibiting, platelet and blood cell adhesion inhibiting effects. The action mechanism is that cGMP in blood platelet is increased through NO/cGMP metabolic pathway, and contractile protein is regulated through the second messenger function of cGMPPhosphorylation level and intracellular Ca2+The level is reduced, inhibiting platelet aggregation and reducing thrombus formation. In addition, NO can simultaneously increase the PGI2 level, and the mechanism is more complex. Prostacyclin (PGI2) has a protective effect in the cardiovascular system, expands blood vessels, inhibits platelet aggregation, and antagonistically reduces thromboxane TXA2, the most potent known platelet aggregation agent. The ratio of PGI2 to TXA2 is critical for the stabilization and regulation of the physiological functions of the cardiovascular system. The experiment proves that the ganciclovir M can simultaneously increase the levels of NO, cGMP and PGI2, inhibit platelet aggregation by influencing the NO/cGMP metabolic pathway and changing the level of PGI2, and generate the thrombolytic effect.
In conclusion, it is possible that the action of liconine M against thrombus and the inhibition of platelet aggregation is one of the mechanisms of antithrombotic action.
Effect of Erliconing M on Experimental cerebral thrombosis model
1 materials of the experiment
60 clean male SD rats with the body mass of about 180-220g are purchased from Beijing Witonglihua laboratory animal technology GmbH; a superoxide dismutase (SOD) and Malondialdehyde (MDA) determination kit, which is purchased from Nanjing to build a bioengineering institute; the other reagents are domestic analytical purifiers.
2 method of experiment
2.1 establishment and grouping of Experimental cerebral thrombosis models
60 healthy male SD rats are randomly divided into 5 groups, namely a normal control group, a model group, a low-dose drug group, a medium-dose drug group and a high-dose drug group, and each group comprises 12 drugs. The medicine composition is infused with the Gancaoganning M according to the quality standards of 100, 200 and 400mg/kg, and the normal control group and the model group are infused with the same amount of physiological saline. Each group of rats was administered by gavage for 2 weeks 1 time per day (1mL/100 g). The rat cerebral thrombosis model was replicated 1h after the last dose according to literature methods. After 5min, injecting 0.5% Evans blue solution into the right common carotid artery according to the mass of a rat of 5 mL/kg; and then, after 5min, the head is rapidly cut off and the patient is killed, and the left and right hemispheres of the brain are taken out and are called the wet weight of the brain. Brain tissue was homogenized at 5mL per gram (0.5% Na)2SO4: acetone ═ 3: 7) homogenizing, transferring into test tube, sealing, and standing at 4 deg.C for 60min, centrifuging at 3000r/min for 10min, collecting supernatant, and measuring absorbance (A) at 620 nm. Evans blue content is expressed as the ratio of the optical density of the embolized hemisphere (right infarct zone, left control zone) to its brain weight.
2.2 detection of Right side brain index and brain Water content of cerebral thrombosis rat
Grouping and administrating 60 healthy male SD rats according to 2.1, copying a cerebral thrombosis model, opening the cranium after 3h, taking brain tissue, sucking redundant blood, weighing left and right cerebral hemispheres, and calculating right cerebral index and brain water content (brain dry weight is baked to constant weight at 110 ℃).
Right brain index (right wet weight of brain x 100/body mass)
The water content of the right brain is (weight of right brain wet-dry weight of right brain)/weight of right brain wet x 100%
2.3 detection of SOD and MDA content in cerebral tissue of cerebral ischemia rat
Grouping and administrating 60 healthy male SD rats according to 2.1, copying a cerebral thrombosis model, opening cranium after 3h, taking out brain tissue, adding physiological saline into the right cerebral hemisphere, grinding into 10% brain tissue homogenate, centrifuging at 3000r/min for 15min, taking supernatant, storing at-20 ℃, and measuring SOD and MDA according to the kit specification.
2.4 statistical analysis
Data results obtained are mean ± sd
Showing that SPSS16.0 software is used for statistical analysis, single-factor analysis of variance is adopted for comparison among groups, and the t test among groups shows that P is less than 0.05, so that the difference is significant.
3 results of the experiment
3.1 Effect of Licorice M on Evans blue content in rat cerebral infarction area
As shown in Table 4, after the thrombus-inducing agent was injected into the right common carotid artery of the SD rat in the model group, the vascular permeability of the right cerebral hemisphere was increased, evans blue was increased to reach the brain tissue through the blood vessel, and blue staining was not observed in the left hemisphere. The glycyrone M can reduce the evans blue staining degree (P <0.05 or P <0.01) of the right cerebral hemisphere of the rat dose-dependently.
TABLE 4 Effect of Licorice M on Evans blue content in rat cerebral infarction area
Compared with the normal control group,##P<0.01; comparison with model group<0.05,**P<0.01
3.2 Effect of Licorice M on cerebral thrombosis rat brain index and brain Water content
After 3 hours of injecting and ligating a thrombus inducer into the right common carotid artery of a normal SD rat, the right cerebral index, the brain water content and the weight ratio of right/left cerebral hemispheres are all obviously increased; ganciclovir M can dose-dependently alleviate cerebral edema in rats caused by thrombosis-inducing agents, reduce the water content of the right brain and the weight ratio of the right/left hemisphere (see table 5).
TABLE 5 Effect of Licorice M on cerebral thrombosis cerebral edema
Compared with the normal control group,##P<0.01; comparison with model group<0.05,**P<0.01.
3.3 Effect of Licorice M on SOD and MDA in rat brain tissue
After the right common carotid artery is ligated and thrombus inducer is given to normal rats, the MDA content in the right brain tissue can be increased, and the SOD activity is reduced; the liquiritin M can reduce the content of MDA in brain tissues and increase the activity of SOD, and partial liquiritin M has statistical differences, and the results are shown in table 6.
TABLE 6 Effect of Licorice M on SOD and MDA in cerebral thrombosis rat brain tissue
Compared with the normal control group,##P<0.01; comparison with model group<0.05,**P<0.01.
More and more evidence shows that when cerebral ischemia and hypoxia occur, ATP in the brain is exhausted, so that the normal metabolic pathway of brain cells is damaged, and free radicals in the body are generated in a large quantity. SOD is the most main substance for eliminating free radicals in vivo, and during acute onset of ischemic cerebrovascular disease, SOD activity is reduced, and scavenging ability for oxygen free radicals is reduced. The accumulation of free radicals in large quantities destroys the integrity of the nerve cell membrane, and causes cerebral edema and other complications. The experimental result shows that the liquiritin M can obviously reduce the evans blue staining and the cerebral edema degree caused by cerebral thrombosis, and can reduce the MDA content in brain tissues and increase the SOD activity. The research results show that the liquiritigenin M has certain antioxidant activity and has obvious protective effect on cerebral thrombosis.
On the basis of the experiment, the invention also provides a medicament prepared from the liquiritigenin M for treating and/or preventing thrombotic diseases, and is characterized in that the medicament also comprises pharmaceutically acceptable auxiliary materials.
Specifically, the dosage form of the medicine is an oral administration dosage form, an injection administration dosage form or an external administration preparation.
Further, the oral administration dosage form is tablets, capsules, granules, pills, oral liquid, soft extracts, suspending agents, dispersing agents or syrups. The injection administration preparation is injection liquid or powder injection for injection; the external administration preparation is suppository, patch or gel.
The selection of the types and the ranges of the preparation auxiliary materials and the preparation of the preparation can be realized according to the conventional means in the field. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.
The experimental results show that all the doses of the liquiritigenin M have good treatment or prevention effects on the artery and vein bypass thrombosis or the cerebral thrombosis and have dose dependence. Wherein, the medium-dose group and the high-dose group have particularly prominent effect on thrombus and can comprehensively improve all thrombus index parameters. More preferably, when the dose is 400mg/kg d-1When the composition is used, the weight of the rat arteriovenous bypass thrombus is reduced most obviously, the levels of NO, cGMP and PGI2 in the plasma of the thrombus rat are improved obviously, the cerebral edema caused by cerebral thrombosis is greatly reduced, the content of MDA in brain tissues can be reduced, and the SOD activity is increased. The result shows that the liquiritin M can inhibit platelet aggregation by influencing NO/cGMP metabolic pathway and changing PGI2 level, and the antioxidant activity of the compound also has obvious protective effect on cerebral thrombosis.
Claims (5)
1. Application of glycyronin M in preparing medicine for treating and/or preventing thrombotic diseases.
2. The use according to claim 1, wherein the thrombotic disorder is an arteriovenous bypass thrombus.
3. The use according to claim 1, wherein the thrombotic disorder is cerebral thrombosis.
4. The use according to any one of claims 1 to 3, wherein the medicament is in the form of an oral, injectable or topical formulation.
5. The use according to claim 4,
the oral administration dosage form is tablets, capsules, granules, pills, oral liquid, soft extract, suspending agent, dispersing agent or syrup;
the injection administration preparation is injection liquid or powder injection for injection;
the external administration preparation is suppository, patch or gel.
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Non-Patent Citations (4)
| Title |
|---|
| A multiplex approach for the UPLC-PDA-MS/MS data: analysis of licorice;Min He等;《Analytical Methods》;20141231;第6卷;2239-2246 * |
| Structures of five new prenylated flavonoids, gancaonins L, M, N, O, and P from aerial parts of Glycyrrhiza uralensis;Toshio Fukai等;《Heterocycles》;19901231;第31卷(第2期);373-382 * |
| 甘草总黄酮对大鼠血栓形成和凝血时间的影响;杨玉梅等;《包头医学院学报》;20031231;第19卷(第2期);90-91 * |
| 甘草抗动脉粥样硬化和抗血栓形成研究进展;张明发、沈雅琴;《西北药学杂志》;20110630;第26卷(第3期);222-226 * |
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