CN117752649A - Application of sanggenon C in preparation of platelet aggregation and thrombosis resisting medicine - Google Patents
Application of sanggenon C in preparation of platelet aggregation and thrombosis resisting medicine Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new application of sanggenon C, in particular to an application of sanggenon C in preparing an anti-platelet aggregation and anti-thrombosis drug. The invention discovers that the sanggenon C can obviously inhibit the platelet aggregation activity induced by different inducers in vitro: in an in vivo thrombus model experiment, the sanggenon C can well inhibit FeCl 3 Induced carotid thrombosis in mice and carrageenan-induced thrombosis in the tail of mice. It was also found that the sanggenon C of the present invention did not show a significant bleeding tendency. The utility model shows that the sanggenon C is expected to play a certain positive role in the prevention and treatment of thrombotic diseases as an anti-platelet aggregation and anti-thrombosis drug.
Description
Technical Field
The invention relates to a new application of sanggenon C, in particular to an application of sanggenon C in preparing an anti-platelet aggregation and anti-thrombosis drug.
Background
Thrombotic diseases refer to ischemic changes and dysfunction diseases of tissues and organs caused by two pathological processes of thrombosis and thromboembolism, and are becoming the biggest killers for human health. In China, the number of deaths caused by cardiovascular diseases exceeds 40% of the total number of deaths, and the deaths are the main cause of urban and rural residents. When vascular endothelium is diseased or damaged, platelets are activated within seconds and accumulate around the damaged site. Arterial thrombosis caused by excessive activation and aggregation of platelets is an important cause of high incidence of such diseases, so that the function of platelets is important for the occurrence of thrombotic diseases.
According to the influencing factors of thrombosis, the anti-platelet drugs can prevent and treat thrombosis by preventing adhesion, aggregation and release of platelets, thereby reducing the occurrence of thrombotic diseases. Thus, antiplatelet agents are undoubtedly important clinical agents for the treatment of thrombotic disorders, and in theory, all signal molecules involved in platelet activation are likely to be potential targets for antiplatelet agents. The drugs used at present mainly comprise aspirin, P2Y12 receptor antagonists, glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists, protease activated receptor (PAR 1) antagonists and the like. Although antiplatelet drugs have been available that reduce the occurrence of thrombotic disorders to some extent, bleeding side effects are not negligible. Therefore, a novel target for targeted treatment of thrombotic diseases and overcoming the defects of the traditional medicines is sought, and the development of novel small molecular compounds with anti-platelet aggregation and anti-thrombosis activity has important research value and social significance.
The mulberry bark is dry root bark of Morus alba L. The Moraceae plant, has cold nature, sweet taste, and lung meridian tropism, has the effects of purging lung, relieving asthma, inducing diuresis and detumescence, and is mainly used for clinically treating lung heat asthma and cough. Morgandone C (sanggenon C) is a flavonoid extracted from cortex Mori. Researches show that the sanggenon C as one of the active ingredients of the mulberry bark flavonoids has pharmacological activities in various aspects such as lung protection, anti-tumor, heart protection, liver protection, nerve protection, osteoporosis resistance, enzyme inhibition, anti-inflammatory, antioxidation and the like, and has potential value as a clinical medicine. However, no related study and report on the influence of sanggenon C on platelet function and thrombotic diseases exist at present.
Disclosure of Invention
The invention aims to: the invention aims to provide a new application of sanggenon C in preparing an anti-platelet aggregation and anti-thrombosis drug so as to expand the application range of sanggenon C.
The technical scheme is as follows:
use of sanggenon C in the manufacture of a medicament for use as a sanggenon C as a vertebrate orphan kinase inhibitor (VLK), said sanggenon C having the chemical structural formula:
application of sanggenon C in preparing medicine for treating or preventing thrombosis is provided.
Application of sanggenon C in preparing medicine for treating or preventing platelet aggregation is provided.
Further, when applied as an anti-platelet aggregation drug, the final concentration of the sanguisorbanone C in the system is 10-100 mu M.
Further, when the mulberry root-ketone C is used as an antithrombotic drug, the final concentration of the mulberry root-ketone C in the system is 10-60mg/kg.
The invention provides application of sanggenon C in preparing a medicament for treating and/or preventing thrombosis.
The application is characterized in that the sanggenon C and pharmaceutically acceptable auxiliary materials form a preparation.
The application is characterized in that the dosage form of the sanggenon C is oral administration dosage form, transdermal administration dosage form, inhalant and injection.
The use is characterized in that the oral administration dosage form is a tablet, a capsule, a pill or an emulsion. The VLK small molecule inhibitor has antithrombotic activity, and can break the blank that no VLK inhibitor is applied to platelet aggregation resistance and thrombosis resistance at present.
The invention has the following advantages and beneficial effects:
the sanggenon C related to the invention is discovered to be a VLK inhibitor for the first time, can obviously inhibit thrombin and collagen-induced mouse platelet aggregation, has platelet aggregation resisting activity, and the inhibition effect is concentration-dependent.
According to the prior art, antithrombotic drugs mainly comprise anticoagulants, antiplatelet drugs and fibrinolytic drugs, are main drugs for preventing and treating thrombotic diseases, such as aspirin, and adverse reactions of the antithrombotic drugs are bleeding phenomena, such as subcutaneous bleeding, digestive tract bleeding and intracranial bleeding, which can cause death or disability, so that the antithrombotic drugs cannot be taken for a long time for patients with cerebral infarction and the like, and the conditions of the patients are possibly aggravated. Therefore, the search for drugs that do not exhibit bleeding while resisting thrombosis has been a technical challenge in the art. The invention discovers that the sanggenon C has antithrombotic activity, can effectively inhibit FeCl 3-induced carotid thrombosis and carrageenan-induced tail thrombosis of mice, and has no obvious bleeding risk.
Therefore, the invention provides a new thought and a research basis for developing a novel medicament for the excessive activation of blood platelets and/or the prevention and treatment of thrombotic diseases.
Drawings
FIG. 1 is a schematic diagram showing the results of inhibition of thrombin-induced murine platelet aggregation by sanguisorba ketone C in example 1;
FIG. 2 is a graph showing the results of inhibition of collagen-induced murine platelet aggregation by sanguisorbanone C in example 1;
FIG. 3 is a graph showing the measurement of the inhibition of carrageenan-induced thrombosis and thrombus length in mice by sanguisorba C in example 2;
FIG. 4 is a statistical graph of inhibition of carrageenan-induced mouse tail thrombosis and thrombus length by sanguisorba ketone C in example 2;
FIG. 5 is a schematic representation of the inhibition of FeCl by sanguisorbanone C in example 3 3 Inducing carotid thrombosis and blood flow cut-off time observation results of the mice;
FIG. 6 is a schematic representation of the inhibition of FeCl by sanguisorbanone C in example 3 3 Inducing carotid thrombosis and blood flow cut-off time statistics of the mice;
FIG. 7 is a schematic representation of the inhibition of FeCl by sanguisorbanone C in example 3 3 Inducing carotid thrombosis and blood flow velocity statistics of the mice;
FIG. 8 is a graph showing the statistics of sanguisorbanone C in example 4 on bleeding time in tail-biting experiments of mice;
FIG. 9 is a graph showing the results of the inhibitory activity of sanguisorbanone C on VLK at various concentrations in example 5.
Detailed Description
Morgandone C was purchased from Meilin under the designation S916374.
EXAMPLE 1 influence of sanggenon C on thrombin and collagen-induced murine platelet aggregation
The experimental method comprises the following steps: drawing abdominal aortic blood of rats, taking sodium citrate as an anticoagulant according to the ratio of 1: and 9 proportion anticoagulated rat arterial blood. The upper Platelet Rich Plasma (PRP) was collected by centrifugation at 800rpm for 15min at room temperature, the upper Platelet Rich Plasma (PRP) was collected by centrifugation at 800rpm for 15min again, the platelet rich plasma was pooled twice, the remaining plasma was centrifuged at 3000rpm for 10min at room temperature, and the upper Platelet Poor Plasma (PPP) was collected. The combined PRPs were centrifuged again at 800rpm at room temperature for 10min to remove residual white blood cells and red blood cells as much as possible. Counting the number of PRP platelets with a platelet counter, and adjusting the number of PRP platelets by PPP to about 2X 10 8 /mL。
The platelet aggregation instrument was turned on 30 minutes before the experiment, and after the platelet aggregation instrument was preheated to 37 ℃, the optical path detection was performed on several channels with double distilled water. 320 μl PRP was added to the collection tube, morgandone C was added at final concentrations of 10 μM, 33 μM, 100 μM, and incubated at 37deg.C with stirring at 600rpm for 10min. The instrument was zeroed with PPP to adjust the baseline, and after the baseline remained stable, collagen or thrombin was added at a final agonist concentration of 25. Mu.g/mL or 5U/mL to detect platelet aggregation. The platelet aggregation level was recorded by a platelet aggregation meter for 5-10min, and the maximum aggregation level (MA) of platelets during aggregation was recorded.
Experimental results: as shown in FIGS. 1 and 2, 10. Mu.M, 33. Mu.M, and 100. Mu.M of sanguisorba ketone C inhibited thrombin-and collagen-induced platelet aggregation in rat platelets, and the inhibition was concentration-dependent.
EXAMPLE 2 Morgandone C inhibits carrageenan-induced mouse tail thrombosis
The experimental method comprises the following steps: carrageenan induced thrombosis model experiments. The tested animals are ICR male mice, and are fed in separate cages before experiments in clean animal experiments of animal centers of university of Chinese medical science. The mice to be tested are divided into 5 groups of model group, aspirin group, high, medium and low doses of the compound of the invention, and the like, and 8 mice in each group. The administration dosage is respectively model group of edible oil containing 5% DMSO, aspirin group is 60mg/kg, the high, medium and low dosages of the compound are respectively 60mg/kg,20mg/kg and 6mg/kg, the compound is dissolved by DMSO, and the edible oil is diluted to prepare emulsion containing 5% DMSO. The administration time is that of the administration in advance, the administration mode is that of the administration by gastric lavage, 50mg/kg carrageenan solution is injected into the abdominal cavity after 1 hour of gastric lavage, and the mice are placed in the environment of 15 ℃ for low temperature feeding for 24 hours. After successful molding, the thrombus length at the tail of the mice was measured. The measured values are expressed as mean ± standard error of the mean of each set of independent experiments. The inter-group analysis employed one-factor analysis of variance, with p <0.05 considered statistically significant.
Experimental results: the compounds of the present invention inhibit carrageenan-induced thrombosis in the tail of mice. Wherein, as shown in fig. 3 and 4, the average thrombus length of the model group is 6.98+/-0.14 cm, which indicates that the carrageenan-induced mouse tail thrombus model is successfully constructed. The average thrombus length of the positive medicine aspirin group is 3.49+/-0.31 cm. The average thrombus length of the high, medium and low dose groups of the compound is 3.86+/-0.17 cm, 4.4+/-0.46 cm and 4.91+/-0.51 cm respectively. The compounds significantly reduced the length of thrombus compared to the model group, indicating that the compounds have an inhibitory effect on thrombus formation and have a significant dose dependence.
EXAMPLE 3 inhibition of FeCl by sanggenon C 3 Induction of carotid thrombosis in mice
The experimental method comprises the following steps: feCl 3 And (3) inducing a carotid artery thrombosis model experiment of the mice. The tested animals are ICR male mice, and are fed in separate cages before experiments in clean animal experiments of animal centers of university of Chinese medical science. The mice to be tested are divided into 5 groups of model group, aspirin group, high, medium and low doses of the compound of the invention, and the like, and 6 mice in each group. The administration dose is respectively model group of edible oil containing 5% DMSO, aspirin group is 60mg/kg, the compound high, medium and low doses are respectively 60mg/kg,20mg/kg,6mg/kg, the compound is dissolved by DMSO, and the edible oil is diluted to prepare the compound containing 5% DEmulsion of MSO. The administration time is the administration in advance, the administration mode is the stomach irrigation, and the mould is made after 1 hour of stomach irrigation. The molding method comprises anesthetizing a test mouse with 10% chloral hydrate, incising neck skin of the mouse along the longitudinal line of the cervical midline with sterilizing equipment, separating muscle tissue with surgical forceps, exposing trachea, separating lateral carotid artery about 3cm, separating carotid artery from surrounding tissue with plastic film, protecting surrounding vascular tissue, and sucking 7.5% FeCl 3 A small filter paper sheet of the solution is clung to the carotid artery, and after applying the paper sheet for 2min, the blood vessel is imaged under a moorFLPI-2 laser speckle blood flow imager. One angiogram was taken every minute, each mouse was sacrificed thirty minutes after taking, blood flow per minute was analyzed with mfpi 2 software while counting the time of disappearance of blood flow, and raw data was analyzed using GraphPad Prism 6.0 software. The measured values are expressed as mean ± standard error of the mean of each set of independent experiments. The inter-group analysis adopts single factor analysis of variance, p<0.05 is considered statistically significant.
Experimental results: the compound can inhibit FeCl 3 Inducing carotid thrombosis in mice. As shown in fig. 5 and 6, the mean time of blood flow disappearance of the model group is 6.17+/-0.7 min, the mean time of blood flow disappearance of the positive medicine aspirin group is 22.67+/-1.23 min, and the mean time of blood flow disappearance of the compound high, medium and low dose groups is 18+/-1.71 min, 11.83+/-0.6 min and 6.67+/-0.56 min respectively. The positive drug and the compound can significantly extend the time to disappearance of blood flow compared to the model group, the compound having a pronounced dose dependence. As shown in fig. 7, the compounds significantly reduced the blood flow reduction rate compared to the model group.
Example 4 mulberenone C had no significant risk of bleeding.
The experimental method comprises the following steps: tail breaking experiment. The tested animals are ICR male mice, and are fed in separate cages before experiments in clean animal experiments of animal centers of university of Chinese medical science. The mice to be tested are divided into 5 groups of model group, aspirin group, high, medium and low doses of the compound of the invention, and the like, and 6 mice in each group. The administration dose is respectively model group of edible oil containing 5% DMSO, aspirin group is 60mg/kg, and the compound has high, medium and low doses respectively
60mg/kg,20mg/kg,6mg/kg, the compound used was dissolved in DMSO and diluted with edible oil to make an emulsion containing 5% DMSO. The administration time is the administration in advance, and the administration mode is gastric lavage. 1 hour after administration, the mice were placed on a holder to prevent the tail from being disturbed, a culture dish filled with physiological saline was prepared, tail-breaking treatment was performed at the 2mm position of the tail tip of the mice, the tail-breaking position was placed in the culture dish, and the time was counted from the outflow of blood until the blood flow was stopped, and the time was counted, and the raw data were analyzed by GraphPad Prism 6.0 software. The measured values are expressed as mean ± standard error of the mean of each set of independent experiments. The inter-group analysis employed one-factor analysis of variance, with p <0.05 considered statistically significant.
Experimental results: the compounds of the present invention have no significant risk of bleeding. As shown in FIG. 8, the average bleeding time of the tail of the mice in the model group is 93+/-10.29 s, the average bleeding time of the high, medium and low dose groups of the compound of the invention is 256+/-31.64 s, and the average bleeding time of the mice in the model group is 107+/-10.15 s, 100+/-6.95 s and 97.5+/-7.16 s respectively. Aspirin has a significant risk of bleeding compared to the model group, while the compound group showed no significant difference in bleeding time from the model group, indicating that the compound had no effect on clotting function in mice and no significant risk of bleeding.
Example 5 sanggenon C is a vertebrate autism kinase inhibitor.
The experimental method comprises the following steps: mu.L of 3.75. Mu.M purified VLK protein was taken, 1. Mu.L of sanguisorbanone C diluted in a gradient with Tris-HCl pH=7 buffer solution at a maximum concentration of 1mM was added, and the mixture was stirred and stirred well and incubated at room temperature (25 ℃) for 1h. mu.L of 1.44mM reaction substrate and 2. Mu.L of 17.88. Mu.MATP were added, and the mixture was thoroughly mixed and reacted at 37℃for 10 minutes. Adding detection reagent of the same system, mixing thoroughly, reacting at room temperature (25deg.C) for 10min, and measuring its chemiluminescence intensity. The inhibition (%) was calculated as follows: inhibition ratio (%) = [1- (RLU [ background group ] -RLU [ experimental group ])/(RLU [ control group ] -RLU [ model group ]) ] ×100%.
Experimental results: the compound of the invention dose-dependently inhibits the activity of vertebrate autism kinase, and the half inhibition rate is 7.7 mu M. As shown in fig. 9, the compounds of the present invention can inhibit VLK activity.
Claims (6)
1. The application of sanggenon C in preparing a medicament which is taken as sanggenon C and is a vertebrate autism kinase inhibitor, wherein the chemical structural formula of the sanggenon C is as follows:
2. application of sanggenon C in preparing medicine for treating or preventing thrombosis is provided.
3. Application of sanggenon C in preparing medicine for treating or preventing platelet aggregation is provided.
4. The use according to any one of claims 1-3, wherein sanguisorbanone C is formulated with pharmaceutically acceptable excipients.
5. The use according to claim 4, wherein the dosage form of sanggenon C is an oral dosage form, a transdermal dosage form, an inhalant, an injection.
6. The use according to claim 5, wherein the oral administration form is a tablet, capsule, pill or emulsion.
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