CN115444850A - Application of tenuigenin in preparation of medicine for treating cerebral arterial thrombosis - Google Patents
Application of tenuigenin in preparation of medicine for treating cerebral arterial thrombosis Download PDFInfo
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- CN115444850A CN115444850A CN202110639290.4A CN202110639290A CN115444850A CN 115444850 A CN115444850 A CN 115444850A CN 202110639290 A CN202110639290 A CN 202110639290A CN 115444850 A CN115444850 A CN 115444850A
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- tenuigenin
- ischemic stroke
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- 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 relates to application of tenuigenin in preparation of a medicine for treating cerebral arterial thrombosis. The invention researches the influence of the tenuigenin on the cerebral infarction volume, the brain tissue water content and the nerve function of a rat model with ischemic stroke, and finds that the tenuigenin can effectively reduce the cerebral infarction and the cerebral edema degree and improve the nerve function. Meanwhile, the effects of the tenuigenin and the ginkgo biloba extract are compared, and the improvement effect of the tenuigenin on the ischemic stroke is found to be obviously better than that of the ginkgo biloba extract. The results show that the tenuigenin has important application value in the clinical treatment of the ischemic stroke, and can be used for preparing an experimental reagent for researching the pathophysiological mechanism of the ischemic stroke.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of tenuigenin in preparation of medicines for treating cerebral arterial thrombosis.
Background
Ischemic stroke is a cerebrovascular accident caused by the reduction or interruption of local blood supply of brain tissues, and ischemic tissues can show symptoms of neurological impairment in corresponding areas, so that a series of complex biochemical molecule cascade reactions are triggered, such as energy metabolism disorder, excitotoxic glutamate signal pathway activation, free radical reaction and the like. These changes trigger a series of inflammatory cascades associated with apoptotic necrosis that result in the destruction of cellular integrity, ultimately manifested as impairment of neuronal function.
Polygala tenuifolia sapogenin (Tenuigenin) molecular formula C 30 H 45 ClO 6 Molecular weight 537.13. Modern pharmacological studies prove that the tenuigenin has multiple biological effects of resisting inflammation, resisting oxidation, nourishing nerves, treating acute lung injury and the like. Such as the literature (Pi Ting, xue Xiaoyan, lin Lianfeng, etc.. Polygala tenuifolia sapogenin has nutrition effect on cortical neurons of newborn rats. Chinese journal of pharmacology and toxicology 2011,25 (1): 40-43) discloses that Polygala tenuifolia sapogenin can promote the survival of SD rat cortical neurons in 24h newborn in vitro and can promote the growth of cortical neuron processes; literature (Hu Liyun, tan Jiaying, zhu Hui Wo, etc.. Polygalaxgenin protects hippocampal neurons in rats with acute cerebral hemorrhage [ J]The journal of international pathological science and clinic, 2018,038 (006): 1139-1145) discloses that tenuigenin has protective effects on acute cerebral hemorrhage (ICH) hippocampal neurons, possibly associated with reducing cerebral edema and regulating Bax, bcl-2, tgf-beta 1 and VEGF protein expression levels.
However, the report of polygala tenuifolia sapogenin for treating ischemic stroke is not seen at present.
Disclosure of Invention
The invention aims to provide a new application of polygala tenuifolia sapogenin aiming at the defects in the prior art.
In a first aspect, the invention provides an application of tenuigenin in preparing a medicine for treating cerebral arterial thrombosis.
As a preferred example of the invention, the medicament takes the tenuigenin as the only active ingredient.
As another preferred embodiment of the invention, the medicament further comprises other active ingredients capable of treating ischemic stroke.
As another preferred embodiment of the present invention, the treatment of ischemic stroke refers to reduction of cerebral infarction volume.
As another preferred embodiment of the present invention, the treatment of ischemic stroke refers to the reduction of cerebral edema.
As another preferable example of the present invention, the medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier is selected from the group consisting of a cosolvent, an emulsifier, an excipient, a filler, a binder, a humectant, a disintegrant, an absorption enhancer, and a colorant.
In a second aspect, the invention provides the use of tenuigenin in the preparation of an agent for reducing the cerebral infarction volume, the degree of cerebral edema or improving neurological function in an animal model of ischemic stroke.
As a preferable example of the invention, the agent takes the tenuigenin as the only active ingredient.
As another preferred example of the invention, the test agent further comprises other active ingredients capable of reducing the cerebral infarction volume, the cerebral edema degree or improving the nerve function of the animal model of ischemic stroke.
Herein, the "drug" refers to a substance used for the prevention, treatment and diagnosis of diseases. The experimental reagent refers to pure chemicals used for realizing chemical reactions, analytical assays, research and test, teaching experiments and chemical formulas.
The invention has the advantages that:
1. the invention researches the influence of the tenuigenin on the cerebral infarction volume, the brain tissue water content and the nerve function of a rat model with ischemic stroke, and finds that the tenuigenin can effectively reduce the cerebral infarction and the cerebral edema degree and improve the nerve function. Meanwhile, the effects of the tenuigenin and the ginkgo biloba extract are compared, and the therapeutic effect of the tenuigenin on the ischemic stroke is found to be obviously better than that of the ginkgo biloba extract. The results show that the tenuigenin has important application value in the clinical treatment of the ischemic stroke.
2. The pathophysiological processes of ischemic stroke are very complex, and the relationship between the pathogenesis and different damage mechanisms is unknown. The polygala tenuifolia sapogenin is found to have remarkable improvement effect on the cerebral infarction volume, the brain tissue water content and the nerve function of a rat model with the ischemic stroke, so that the polygala tenuifolia sapogenin can be used as an experimental reagent to research the pathophysiological process of the ischemic stroke and explore the relationship among different injuries so as to guide the scientific treatment of the disease, and targeted measures are taken aiming at different links so as to reduce the disability and fatality rates.
Drawings
Figure 1 brain ischemia 3 hours, each group of rats neural function score statistical map (n = 6).
Fig. 2 brain ischemia for 3 hours, statistical water content of rat brain tissue for each group (n = 6).
Fig. 3 is a statistical graph of the cerebral infarction volume of rats in each group with 3 hours of cerebral ischemia, bright red color of normal tissue and white color of infarct site (n = 6).
Detailed Description
The following detailed description of the present invention will be made with reference to the accompanying drawings.
Example 1
1. Purpose of experiment
The improvement effect of Tenuigenin (TEN) and Ginkgo Biloba Extract (GBE) on ischemic stroke is researched.
2. Experimental materials
2.1 Experimental animals
Healthy SPF-grade SD male rats aged 9-11 weeks and weighing 250-290g were purchased from Shanghai Spiker laboratory animals, inc. The feeding and experimental procedures comply with relevant working practice regulations of the animal ethics committee (animal ethics committee review approval number: r 20160302).
2.2 reagents and consumables
Polygala tenuifolia sapogenin (shanghai hanxiang biotechnology limited), ginkgo biloba extract (synfei geen technology limited), chloral hydrate (national drug group), TTC stain (beijing west dense technology limited), MCAO silica gel thread plug (A4) (beijing west dense technology limited), carotid injection syringe (beijing west dense technology limited), stainless steel brain slicing blade (beijing west dense technology limited).
2.3 instrumentation
Stainless steel brain slicing die (Beijing Western Density technology Co., ltd.), blank fixing binding plate (Beijing Western Density technology Co., ltd.), oven (Shanghai constant technology Co., ltd.), electronic balance (METTLER TOLEDO, switzerland), and surgical instrument (department of medical instrument wholesale).
3. Experimental method
3.1 Experimental groups
Male SD rats with SPF grade weight of 250-290g were selected and randomly divided into 4 groups, namely a sham operation group (S group), a model group (I/R group), a carotid perfusion TEN injection 6mg/kg group, and a carotid perfusion GBE injection 6mg/kg group.
3.2 modeling
Referring to the MCAO model method established by Longa et al, the Common Carotid Artery (CCA) on the right side of the rat is exposed, the Y point of the vascular bifurcation is found, ligation is performed at a position 2-3cm below the Y point of the common carotid artery, the Internal Carotid Artery (ICA) and the External Carotid Artery (ECA) are isolated at this position, and the ECA is ligated while threading below the ICA for standby. A small hole is pricked at a position which is about 4mm away from a Y point on the CCA, a thread plug is inserted from the pricked position of the CCA to approach the ICA of the brain, and the insertion depth is about 19 +/-0.5 mm. The cable through the ICA was tied, the outer skin of the rat was sutured, and the exposed cable plugs were marked. After the thread plug stays in the blood vessel for 90min, the thread plug with the mark is gently pulled out for 1-2cm, and reperfusion is recovered. The body temperature of the rat is maintained at 37-37.5 ℃ during the operation process, and the rat is raised in a single cage after awakening. The sham group only performed the model preparation procedure, and the wire emboli did not enter the cerebral vessels.
3.3 modes of administration
After model building, rats were randomly and evenly grouped. A single carotid dose was administered 3h after ischemia. The dosage of the medicine is as follows: 6mg/kg TEN. The method comprises the following specific steps: polygalaxgenin (TEN) was formulated in sterile normal saline, and 15. Mu.l 1% NaOH was added per mg TEN to increase its solubility, with a drug concentration of 3.3mg/ml. 10% chloral hydrate (0.3-0.4 ml/kg) was injected intraperitoneally for anesthesia. Fixing a rat, separating a common carotid artery, an internal carotid artery and an external carotid artery, straightening a marking line of the common carotid artery, repeating the modeling process, threading the internal carotid artery and the external carotid artery for standby, carefully cutting off a ligature of the internal carotid artery, and completely pulling out the remaining ligature. The hole is pricked again at the position 1cm away from the Y point of the common carotid artery, then the tip of the syringe catheter which sucks the medicine is inserted into the internal carotid artery through the hole, and the medicine is administrated at the uniform speed of 0.05 mL/min. After the administration, the internal carotid artery was ligated, and the rats were kept warm until they recovered, and were raised in a single cage. The GBE group was given 6mg/kg GBE in the same manner. Model group rats were injected with the corresponding volume of sterile saline and 1% NaOH in the carotid artery.
3.4 neurological Scoring
Rats were evaluated for neurological function 24h post-surgery using the Garcia method. The Garcia method is evaluated from 6 aspects of rat motor behavior, and the scoring criteria are detailed in the table below, with a total score of 18, with rats scoring less with greater degree of injury and vice versa. The specific method is as follows:
3.5 brain tissue Water content measurement
After 24h of MCAO model ischemia, rats were anesthetized with 10% chloral hydrate (0.3-0.4 ml/kg), intact brain tissue was taken, wet weight of brain was quickly weighed, and then placed in a drying oven (100 ± 2) ° c, and dry weight of brain was weighed after 24 h. The water content of the brain tissue was calculated according to the formula and compared for each experimental group.
Calculating the formula: brain tissue water content (%) = (wet brain weight-dry brain weight)/wet brain weight × 100%.
3.6 2,3,5-Triphenyltetrazole chloride (TTC) staining of rat cerebral infarction sites
Narcotizing MCAO rat with 10% chloral hydrate (0.3-0.4 ml/kg), collecting intact brain tissue, cutting brain slices with thickness of 2mm uniformly and continuously along the coronal plane of the brain tissue, quickly placing into a glass dish containing TTC with concentration of 2% for dyeing, incubating in a constant temperature water bath at 37 deg.C in dark for 30min, arranging the brain slices orderly, and taking pictures for storage. In the brain slice stained with TTC, the rose-red area is normal brain tissue, and the white area is the cerebral infarction area. Calculating and counting by using Image J software to obtain the infarct area of each rat coronal brain slice, expressing the infarct degree by using the proportion of the infarct volume to the whole brain volume, and comparing with each experimental group.
Calculating the formula: infarct volume = infarct area x 2mm.
Infarct volume percentage = (brain necrotic tissue volume/whole brain tissue volume) × 100%.
3.9 data analysis
Experimental data are expressed as mean ± s.e.m, and n represents the number of samples. Statistical analysis GraphPad Prism software was used. The difference between the two groups was compared by t-test. The size of the difference between groups was analyzed by One-way ANOVA, a One-way analysis of variance method. P <0.05, P <0.01, P <0.001, were the most significant statistical differences.
4. Results of the experiment
4.1 neurological Scoring
6mg/kg TEN significantly improved the neurological score compared to the model group and Ginkgo biloba leaf extract (P <0.001, P-Ap-0.05), as shown in FIG. 1.
4.2 brain tissue Water content measurement
6mg/kg TEN reduced the degree of cerebral edema compared to the model group and Ginkgo biloba leaf extract (P <0.01, P < -0.05), as shown in FIG. 2.
4.3 rat cerebral infarction volume measurement
The 6mg/kg TEN drug group was able to reduce cerebral infarct volume (P <0.001, P < -0.05) compared to the model group and ginkgo biloba extract. See fig. 3.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (10)
1. Application of tenuigenin in preparing medicine for treating cerebral arterial thrombosis is provided.
2. The use according to claim 1, wherein the medicament comprises tenuigenin as the sole active ingredient.
3. The use according to claim 1, wherein the medicament further comprises other active ingredients capable of treating ischemic stroke.
4. The use according to claim 1, wherein the treatment of ischemic stroke is a reduction in cerebral infarct volume.
5. The use of claim 1, wherein the treatment of ischemic stroke is a reduction in cerebral edema.
6. The use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier.
7. The use according to claim 6, wherein the pharmaceutically acceptable carrier is selected from the group consisting of co-solvents, emulsifiers, excipients, fillers, binders, humectants, disintegrants, absorption enhancers and colorants.
8. The tenuigenin is applied to preparing an experimental reagent for reducing the cerebral infarction volume and the cerebral edema degree of an animal model of ischemic stroke or improving the nerve function.
9. The use of claim 8, wherein the test agent comprises tenuigenin as the only active ingredient.
10. The use of claim 8, wherein the test agent further comprises other active ingredients capable of reducing the cerebral infarction volume, the degree of cerebral edema or improving neurological function of an animal model of ischemic stroke.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110787174A (en) * | 2019-10-30 | 2020-02-14 | 吉林化工学院 | Application of polygala tenuifolia saponin and brain protection medicine |
| CN113350357A (en) * | 2020-03-05 | 2021-09-07 | 上海市普陀区中心医院 | Application of composition of hydroxysafflor yellow A and polygala tenuifolia sapogenin in preparation of medicine for treating ischemic stroke |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110787174A (en) * | 2019-10-30 | 2020-02-14 | 吉林化工学院 | Application of polygala tenuifolia saponin and brain protection medicine |
| CN113350357A (en) * | 2020-03-05 | 2021-09-07 | 上海市普陀区中心医院 | Application of composition of hydroxysafflor yellow A and polygala tenuifolia sapogenin in preparation of medicine for treating ischemic stroke |
Non-Patent Citations (1)
| Title |
|---|
| 朱小青等: "Effects of Senegenin against Hypoxia/Reoxygenation-Induced Injury in PC12 Cells", CHIN J INTEGR MED, vol. 22, no. 5, pages 353, XP035989405, DOI: 10.1007/s11655-015-2091-8 * |
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