CN117243949A - Application of wedelolactone in preparation of medicine for treating cerebral ischemia reperfusion injury - Google Patents
Application of wedelolactone in preparation of medicine for treating cerebral ischemia reperfusion injury Download PDFInfo
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- wedelolactone
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- reperfusion injury
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Classifications
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- 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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
Abstract
The invention belongs to the technical field of cerebrovascular diseases, and relates to application of wedelolactone in preparing a medicament for treating cerebral ischemia reperfusion injury, and experiments are carried out by establishing a mouse cerebral ischemia reperfusion model, so that the wedelolactone can obviously reduce cerebral infarction volume, promote cerebral blood flow and improve nerve dysfunction after cerebral ischemia, and the wedelolactone can be used for improving cerebral ischemia reperfusion injury, so that reliable experimental data and theoretical basis are provided for developing application of wedelolactone in treating cerebral vascular diseases.
Description
Technical field:
the invention belongs to the technical field of cerebrovascular diseases, and relates to application of wedelolactone in preparation of a drug for treating cerebral ischemia reperfusion injury.
The background technology is as follows:
cerebral stroke is the second leading cause of death and first leading cause of disability worldwide, with ischemic stroke being the most common type, accounting for about 85%. Ischemic stroke is mainly caused by insufficient blood supply to brain tissues or is completely blocked. Secondary brain injury is the main cause of exacerbation of the condition after cerebral ischemia, and is caused by a series of complex and multi-link pathogenesis, mainly comprising excitatory amino acid toxicity, free radical generation, calcium overload, inflammation, oxidative stress and neuronal apoptosis. Currently, treatment of stroke is focused mainly on reducing neuronal cell death. Although this approach has been validated for experimental stroke, clinical trials have shown that none of the neuroprotective drugs tested have achieved effective clinical efficacy in the treatment of acute stroke. Therefore, finding drugs that might interfere with the pathophysiological mechanisms of ischemic stroke is a reliable way to ameliorate ischemic brain injury.
Wedelolactone is a furanocoumarin small molecular compound extracted from eclipta, and has chemical name of 7-methoxy-5, 11, 12-trihydroxy coumarin, molecular weight of 314.25, and molecular formula of C16H10O7. Studies have proved that wedelolactone has the effects of resisting inflammation, resisting pulmonary fibrosis, promoting fat browning, resisting oxidation, protecting liver and the like. For example, chinese patent CN201910142049.3 discloses the use of wedelolactone in the manufacture of a medicament for the treatment of fungal keratitis, and proposes that wedelolactone has a therapeutic effect on fungal keratitis under in vivo and in vitro conditions; under in vitro conditions, the influence of wedelolactone on IL-1 beta secretion is studied by adopting a human macrophage model stimulated by aspergillus fumigatus; under in vivo conditions, a C57BL/6 mouse fungal keratitis model is adopted, and the influence of wedelolactone on clinical scores, pathological changes, caspase-1 signal paths and interleukin 1 beta secretion of the cornea of the model mouse is studied. In addition, the application of wedelolactone combined with natamycin in preparing medicines for treating fungal keratitis is also provided. Chinese patent CN202210752882.1 discloses application of wedelolactone in preparation of products for promoting embryo development, and belongs to the technical field of animal medicines. The wedelolactone is applied to the preparation of medicines for promoting embryo development, and can improve embryo development due to the functions of enhancing blastocyst development and resisting oxidization, inhibiting autophagy and the like; by adding wedelolactone into an in vitro culture medium, the wedelolactone can promote the parthenogenesis of oocytes to a blastula stage after parthenogenesis, weaken the expression of autophagy in development, improve the antioxidation function of embryos and the formation rate of blastula, thereby enhancing the development capacity of pig embryos and inhibiting the problems of oxidative stress and transitional autophagy generated in the in vitro development process. In recent years, more and more researches show that wedelolactone has the advantages of reducing the occurrence of tumors from the inducement aspect by reducing obesity on one hand, and has remarkable anti-tumor activity in various types of tumors on the other hand, and the mechanism of action of wedelolactone mainly plays a role in exerting stronger anti-cancer activity by inhibiting cell proliferation, inducing apoptosis, blocking cell cycle, inhibiting migration invasion, increasing chemotherapy sensitivity and other approaches. For example, chinese patent CN201810746471.5 discloses a research method for applying wedelolactone in preparing products for treating lung cancer, researches the influence of wedelolactone on the activity, cycle and apoptosis of non-small cell lung cancer A549 cells and the intervention effect on the expression of p-Caspase3, p53, p-STAT1 and STAT1 genes of the cells, discusses the anti-tumor effect of wedelolactone on the A549 cells and the mechanism thereof, and provides a theoretical basis for the mechanism research of treating the non-small cell lung cancer by traditional Chinese medicines in the future. Although the prior art has some application researches on wedelolactone, further development of new application thereof is also very necessary. At present, research reports on wedelolactone against ischemic cerebral apoplexy are not found.
The invention comprises the following steps:
the invention aims to overcome the defects in the prior art, provides application of wedelolactone in preparing a medicament for treating cerebral ischemia reperfusion injury, and develops a new application of wedelolactone.
In order to achieve the above purpose, the invention provides an application of wedelolactone in preparing a medicament for treating cerebral ischemia reperfusion injury, wherein a cerebral ischemia reperfusion animal model is established through a middle artery embolism model (Middle cerebral artery occlusion, MCAO) of a mouse, and behaviours, dead brain stems and cerebral blood flow are observed; compared with the model group, the cerebral infarction volume of the mice in the experimental group is obviously reduced, the nerve function is obviously improved, and the cerebral blood flow is obviously improved, which shows that wedelolactone can obviously reduce cerebral ischemia reperfusion injury of the mice and improve nerve dysfunction after cerebral ischemia.
The wedelolactone provided by the invention is a monomer drug and is purchased from Shanghai Rong medical science and technology development Co. The chemical structural formula of wedelolactone is as follows:
compared with the prior art, the wedelolactone is used for treating cerebral ischemia reperfusion injury for the first time, and experiments are carried out by establishing a mouse cerebral ischemia reperfusion model, so that experimental results show that the wedelolactone can obviously reduce cerebral infarction volume, promote cerebral blood flow and improve nerve dysfunction after cerebral ischemia, and the wedelolactone can be used for improving cerebral ischemia reperfusion injury, thereby providing reliable experimental data and theoretical basis for developing the application of the wedelolactone in treating cerebrovascular diseases.
Description of the drawings:
fig. 1 is a schematic diagram of experimental results of the influence of wedelolactone on cerebral blood flow of mice with cerebral ischemia reperfusion injury, wherein A is a laser Doppler blood flow meter image and B is a cerebral blood flow histogram.
Fig. 2 is a schematic diagram of experimental results of the effect of wedelolactone on the behavioral score of mice with cerebral ischemia reperfusion injury according to the present invention, wherein # represents p <0.01 compared with Sham group and x represents p <0.01 compared with MCAO/R group.
Fig. 3 is a schematic diagram of experimental results of the influence of wedelolactone on cerebral infarction volume of mice with cerebral ischemia reperfusion injury, wherein A is a TTC stained brain slice diagram, and B is a cerebral infarction volume histogram.
The specific embodiment is as follows:
the invention will now be described in further detail with reference to the following examples in conjunction with the accompanying drawings.
Example 1.
The embodiment relates to an experiment for influencing the cerebral ischemia reperfusion injury cerebral infarction volume of mice by wedelolactone, which comprises the following steps:
(1) Experimental animals: healthy male C57 mice, 23 g-25 g, are provided by Jinan Pengyue laboratory animal breeding Limited company, purchased 1 week before the experiment, placed in SPF-class animal laboratory at the temperature (25-27) DEG C, and fed with water.
(2) Experimental medicine: wedelolactone was purchased from Shanghai Roxb pharmaceutical technology development Co. When in use, the sodium carboxymethyl cellulose is added into boiling water, the mass concentration of the sodium carboxymethyl cellulose is 0.5 percent, the stirring is continued, after the sodium carboxymethyl cellulose is dissolved and the room temperature is restored, the wedelolactone is added into the mixture, the stirring is continued, and the ultrasonic treatment is carried out until the wedelolactone is fully dissolved before each use.
(3) Construction of MCAO/R mouse brain ischemia reperfusion injury animal model
1) Mice were randomly divided into 3 groups, one group being a Sham surgery group (Sham group), 6; one group was model group (MCAO/R group, 6) and one group was model+dosing group (wil group, 12). Model group and model + dosing group a model of focal cerebral ischemia/reperfusion injury in mice was prepared using middle cerebral artery occlusion surgery. Before operation, selecting a bolt line with a corresponding model according to the weight of the mouse, and blackening the non-spherical end of the bolt line by using a black waterproof marker pen so as to be convenient for searching the bolt line during later bolt line pulling. Mouse intraperitoneal injection of ketamine (80 mg kg) -1 ) And tolylthiazide (10 mg.kg) -1 ) Anesthesia. The mouse is fixed on a mouse operating table in a supine position, the alcohol cotton ball disinfects the neck, and the skin is cut off by surgical scissors in the middle of the neck. The forceps delaminate the tissue layer by layer, separating the left Common Carotid Artery (CCA), the External Carotid Artery (ECA), and the Internal Carotid Artery (ICA) in sequence. Cutting a wedge-shaped small opening at the ECA, inserting an MCAO model bolt line, and lightly pushing the bolt line to enter the internal carotid artery until the bolt line is inserted into the Middle Cerebral Artery (MCA) starting point to cause the blood flow supply disorder of the MCA; after ischemia for 2 hours, slowly pulling out the thrombus line to carry out blood flow reperfusion for 22 hours; iodophor disinfection, aseptic surgical suture wound suturing, tail vein tramadol (2.5 mg kg) -1 ) To reduce postoperative pain. Sham mice used the same surgical procedure described above, but did not block MCA. All post-operative experimental animals were placed on a heating pad to maintain body temperature at 37±0.5 ℃ until the mice wake up.
2) Laser Doppler blood flow monitor for monitoring cerebral blood flow of mice
Whether the cerebral ischemia reperfusion injury model is successful or not is usually monitored by using a laser Doppler blood flow instrument for the cerebral blood flow change of the mice. The specific operation is as follows: placing the anesthetized mice in a tray, sterilizing hair and skin at the top of the heads of the mice by alcohol, cutting off the skin at the top of the heads of the mice by surgical scissors, cleaning the hair remained at the cutting-off position of the heads by cotton balls dipped with physiological saline, and observing cerebral blood flow under the cameras of a laser Doppler blood flow instrument at the heads of the mice. The evaluation criteria are: the mice were considered successful in terms of cerebral blood flow that fell below 40-30% of pre-ischemic.
(3) Randomly dividing the model after molding and the administration group mice into 2 groups, wherein 6 groups are respectively wedelolactone low-dose and high-dose groups, and wedelolactone low-dose groups (WEL 40 mg/kg), and after molding, each mouse is administered with wedelolactone 40mg per kilogram of body weight and continuously lavage for 7 days; wedelolactone high dose group (WEL 80 mg/kg), wedelolactone 80 mg/kg per kg body weight was administered to each mouse after molding, followed by gastric administration for 7 days. The model group was given the same volume of physiological saline after molding.
(4) Influence of wedelolactone on brain blood flow in MCAO/R mice
After 7 days of administration, each group of mice was anesthetized, placed in a tray, the top skin of the mice was cut by surgical scissors, the hair remaining at the head-cut position was cleaned with a cotton ball dipped with physiological saline, and the heads of the mice were photographed under a laser Doppler blood flow meter camera to observe blood flow. The results are shown in FIG. 1.
As can be seen from FIG. 1, the model group (MCAO/R) mice had significantly reduced cerebral blood flow to 40-30% of pre-ischemic compared to the Sham group, and the modeling was considered successful. Further observing the change of wedelolactone with different dosages on cerebral blood flow, the result shows that the low-dosage and high-dosage therapeutic administration of wedelolactone can obviously increase the cerebral blood flow of mice for 7 days, which indicates that wedelolactone plays a key role in restoring cerebral blood flow of mice.
(5) Influence of wedelolactone on cerebral ischemia reperfusion nerve function injury in mice
All mice were scored neuro-behaviourally 7 days after dosing according to Longa scale 5 scoring method, the results are shown in figure 2.
Table 1Longa class 5 scoring method
As can be seen from fig. 2, the mice of the middle and high dose wedelolactone groups have lower neuro-behavioral scores compared with the model group, which indicates that the administration of wedelolactone for 7 days with low and high dose treatment can significantly reduce the neuro-functional scores and improve the neuro-dysfunction of the mice. Figure 2 is counted using a one-way anova, # represents p <0.01 compared to Sham group and x represents p <0.01 compared to MCAO/R group.
(6) Influence of wedelolactone on cerebral ischemia reperfusion injury cerebral infarction volume of mice
After 7 days of administration, mice were sacrificed and brain tissue was immediately removed and placed in a-80 ℃ freezer. Placing 2% TTC (2, 3, 5-triphenyltetrazolium chloride) aqueous solution in a 37 ℃ incubator, preheating for 15min in advance, and cutting frozen brain tissue into 6 slices with the thickness of 2mm; sequentially placing the cut brain slices into TTC preheated by a incubator at 37 ℃ for shading and dyeing for 15min; and (3) putting the dyed brain slices into 4% paraformaldehyde for fixation overnight, and sequentially arranging the fixed brain slices on black background filter paper and taking pictures by a digital camera. Cerebral infarction volume= (sum of ischemic side areas)/(sum of whole brain areas) ×brain sheet thickness×100%. The results are shown in FIG. 3.
As can be seen from fig. 3, compared with the model group, wedelolactone can significantly reduce the cerebral infarction volume caused by ischemia reperfusion of mice in 7 days of treatment administration of the low-dose group and the high-dose group, which indicates that wedelolactone plays a significant role in improving the cerebral infarction volume of mice.
Claims (1)
1. The application of wedelolactone in preparing the medicine for treating cerebral ischemia reperfusion injury is characterized in that wedelolactone can reduce the cerebral infarction volume of a model mouse with ischemia reperfusion injury, improve cerebral blood flow and improve nerve dysfunction after cerebral ischemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311460445.3A CN117243949A (en) | 2023-11-06 | 2023-11-06 | Application of wedelolactone in preparation of medicine for treating cerebral ischemia reperfusion injury |
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| CN202311460445.3A CN117243949A (en) | 2023-11-06 | 2023-11-06 | Application of wedelolactone in preparation of medicine for treating cerebral ischemia reperfusion injury |
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