阅读说明：本技术 格兰地新或其可药用盐的新应用 (New application of gladioxin or pharmaceutically acceptable salt thereof ) 是由 何源峰 叶文才 柴玉爽 师蕾 朱启亮 范春林 宁娜 曾瑚瑚 耿春贤 苏碧茹 张春 于 2020-06-04 设计创作，主要内容包括：本发明提供一种格兰地新和/或其可药用盐的新应用,主要是将格兰地新和/或其可药用盐用于制备预防或者治疗脑血管疾病药物。本发明基于构建的细胞模型,验证了格兰地新和/或其可药用盐能够保护脑神经元,有效避免神经元数量和/或活力降低,以及保护神经元功能学形态免受损伤,这说明,格兰地新和/或其可药用盐能够用来有效防治脑血管疾病。(The invention provides a new application of glatiramer and/or a pharmaceutically acceptable salt thereof, which is mainly used for preparing a medicament for preventing or treating cerebrovascular diseases. The invention verifies that the glatiramer and/or the pharmaceutically acceptable salt thereof can protect brain neurons, effectively avoid the reduction of the number and/or the activity of the neurons, and protect the functional morphology of the neurons from being damaged based on the constructed cell model, which shows that the glatiramer and/or the pharmaceutically acceptable salt thereof can be used for effectively preventing and treating cerebrovascular diseases.)

1. The application of gladioxin or/and pharmaceutically acceptable salts thereof in preparing medicaments for preventing or/and treating cerebrovascular diseases.

2. The use according to claim 1, wherein the cerebrovascular disease is a cerebrovascular disease caused by brain neuron damage.

3. The use of claim 2, wherein the brain neurons are functionally morphologically impaired.

4. The use of claim 2, wherein the brain neurons are reduced in number or/and viability.

5. The use according to any one of claims 2 to 4, wherein the damage is damage caused by hypoxia of the brain.

6. The use of any one of claims 2 to 4, wherein the injury is an injury caused by cerebral ischemia.

7. The use according to any one of claims 2 to 4, wherein the injury is an injury caused by cerebral thrombosis.

8. The use of any one of claims 2 to 4, wherein the brain neurons are brain cortical neurons.

9. The use according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt is a water-soluble salt of glandide.

10. The use according to any one of claims 1 to 4, wherein the medicament comprises gladiolide or/and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Technical Field

The invention relates to the technical field of medicines, in particular to a new application of gladiolide or a pharmaceutically acceptable salt thereof.

Background

With the improvement of living standard and the acceleration of life rhythm, cardiovascular and cerebrovascular diseases become the first killer threatening the health and longevity of middle-aged and elderly people. Among them, cerebrovascular disease is one of three causes of death in humans, and has the characteristics of high morbidity, high mortality and high recurrence rate. According to statistics, 50-70% of patients with cerebrovascular diseases remain serious disabilities, including a series of symptoms such as physical dysfunction, visual and auditory loss, cognitive function reduction and the like, and great pain, huge mental stress and heavy burden are brought to individuals, families and society. Therefore, the enhancement of the prevention and treatment of cerebrovascular diseases has a positive effect on the improvement of the health level and the quality of life of human beings.

Groindigine (also known as greenish berberine, corydalis tetradehydrocheilanthifoline) is derived from plants such as Coptis chinensis Franch of Ranunculaceae and Thalictrum foeniculum, and isoquinoline alkaloids belonging to protoberberine type alkaloids like berberine, and is yellow crystalline powder with molecular formula C₁₉H₁₆NO₄ ⁺The structural formula is as follows:

gladiolide has antiinflammatory, analgesic, blood pressure lowering, antioxidant, topoisomerase inhibiting and blood sugar lowering effects.

Disclosure of Invention

Based on the above, the main object of the present invention is to provide a new application of gladiodine and/or its pharmaceutically acceptable salts, mainly in the preparation of drugs for preventing or/and treating cerebrovascular diseases.

The purpose of the invention is mainly realized by the following technical scheme:

the application of gladioxin or/and pharmaceutically acceptable salts thereof in preparing medicaments for preventing or/and treating cerebrovascular diseases.

In some of these embodiments, the cerebrovascular disease is a cerebrovascular disease caused by brain neuron damage.

In some of these embodiments, the brain neurons are functionally morphologically impaired.

In some of these embodiments, the number of dendrites of the brain neurons is decreased.

In some of these embodiments, the brain neurons have reduced dendritic length.

In some of these embodiments, the brain neurons are reduced in number or/and viability.

In some of these embodiments, the injury is due to cerebral hypoxia.

In some of these embodiments, the injury is an injury caused by cerebral ischemia.

In some of these embodiments, the injury is an injury caused by cerebral thrombosis.

In some of these embodiments, the brain neurons are brain cortical neurons.

In some of these embodiments, the pharmaceutically acceptable salt is a water-soluble salt of glandinew.

In some of these embodiments, the glandinew water soluble salt is glandinew sulfate, glandinew stearate, glandinew monthly silicate, or glandinew hydrochloride.

In some of these embodiments, the medicament comprises gladiolide or/and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the dosage form of the medicament is tablets, pills, granules, dripping pills, capsules, oral liquid, injection, freeze-dried powder injection for injection, eye drops, ointments, sprays, ointments or suppositories.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a new application of glatiramer and/or a pharmaceutically acceptable salt thereof, and mainly relates to the application of glatiramer and/or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating cerebrovascular diseases. The invention verifies that the glatiramer and/or the pharmaceutically acceptable salt thereof can protect brain neurons, effectively avoid the reduction of the number and/or the activity of the neurons, and protect the functional morphology of the neurons from being damaged based on the constructed biological model, which shows that the glatiramer and/or the pharmaceutically acceptable salt thereof can be used for effectively preventing and treating cerebrovascular diseases.

Drawings

FIG. 1 is a graph of the effect of glandifolin of example 1 on survival of neuronal cells following OGD injury; in the figure: "#" indicates P <0.05 compared to the Control group, "-" indicates P <0.05 compared to the Model group;

FIG. 2 is a graphical representation of the neuronal protection effect of glandinov on OGD injury of example 1;

FIG. 3 is a statistical analysis of glandinov of example 1 for the length and number of neuronal processes injured by OGD; in the figure: A. a neuronal process length; B. the number of neuronal processes; "#" indicates that P <0.05 compared to the Control group, and "#" indicates that P <0.05 compared to the Model group.

Detailed Description

In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

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 to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The invention relates to an application of glandine or/and a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or/and treating cerebrovascular diseases.

The invention provides a new application of glatiramer and/or a pharmaceutically acceptable salt thereof, and mainly relates to the application of glatiramer and/or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating cerebrovascular diseases. The invention verifies that the glatiramer and/or the pharmaceutically acceptable salt thereof can protect brain neurons, effectively avoid the reduction of the number and/or the activity of the neurons, and protect the functional morphology of the neurons from being damaged based on the constructed cell model, which shows that the glatiramer and/or the pharmaceutically acceptable salt thereof can be used for effectively preventing and treating cerebrovascular diseases.

Preferably, the cerebrovascular disease is a cerebrovascular disease caused by brain neuron damage.

Preferably, the brain neurons are functionally morphologically impaired.

Preferably, the number of dendrites of the brain neurons is reduced.

Preferably, the dendritic length of the brain neurons is reduced.

Preferably, the brain neurons are reduced in number or/and reduced in viability.

Preferably, the damage is damage caused by cerebral hypoxia.

Preferably, the injury is an injury caused by cerebral ischemia.

Preferably, the injury is an injury caused by cerebral thrombosis.

Preferably, the brain neurons are brain cortical neurons.

Preferably, the pharmaceutically acceptable salt is a water-soluble salt of glandide.

Preferably, the glandinew water soluble salt is glandinew sulfate, glandinew stearate, glandinew monthly silicate, or glandinew hydrochloride.

Further preferably, the glandine water-soluble salt is a glandine hydrochloride.

Preferably, the medicament comprises gladiolide or/and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

It is understood that the drug may be an oral drug, an injectable drug, or a topical drug.

Preferably, the dosage form of the medicine is tablets, pills, granules, dripping pills, capsules, oral liquid, injection, freeze-dried powder injection for injection, eye drops, ointment, spray, ointment or suppository.

It is understood that the dosage forms of the medicines are different, and the preparation raw materials of the pharmaceutic adjuvant selected for preparing the dosage forms of the medicines are also different.

In the case of a pharmaceutical dosage form that is a tablet, pharmaceutically acceptable excipients include, but are not limited to, starch, acacia, sodium carboxymethylcellulose, magnesium stearate, and edible alcohols, among others. Specifically, taking the gladiodine new hydrochloride tablet as an example, the raw material formula can be selected from: 90g of gladiolide hydrochloride, 900g of starch, 4g of Arabic gum, 3g of sodium carboxymethylcellulose, 3g of magnesium stearate and 20mL of 95% edible ethanol.

Taking the pharmaceutical dosage form as an injection, the pharmaceutically acceptable excipients include but are not limited to sodium chloride, mannitol, acid-base regulation, distilled water, and the like. Specifically, taking the gladiolide hydrochloride water injection as an example, the raw material formula can be selected from: 10.0g of gladiolide hydrochloride, 20.0g of sodium chloride, 50.0g of mannitol, 1% hydrochloric acid aqueous solution and distilled water, wherein the total volume of the distilled water is adjusted to 1000 ml.

In the case of eye drops, the pharmaceutically acceptable excipients include, but are not limited to, sodium chloride, methyl paraben, propyl paraben, distilled water, and the like. Specifically, taking the gladiodine new hydrochloride eye drops as an example, the raw material formula can be selected from: 5.0g of glandine new hydrochloride, 90.0g of sodium chloride, 0.23g of methyl paraben, 0.11g of propyl paraben and distilled water are adjusted to 1000 mL.

The present invention relates to a method for preventing or/and treating cerebrovascular diseases, which comprises:

a medicament for the prophylaxis or/and treatment of cerebrovascular disease in a patient, said medicament comprising gladioxin and/or a pharmaceutically acceptable salt thereof. It is understood that the mode of administration or dosage form of the drug is not limited and may be any pharmaceutically acceptable dosage form or mode of administration.

Example 1 protective Effect of gladenafil on neurons after OGD injury

1 materials of the experiment

1.1 drugs and reagents

Dissolving gladiobin in DMSO, and storing at-80 deg.C in dark for use; fetal Bovine Serum (FBS); trypsin (Trypsin); trypsin inhibitor (Trypsin inhibitor); deoxyribonuclease (DNase); penicillin-streptomycin; cortical neuron culture medium (Neurobasal, NB); concentrated nitric acid (68-70%); ultrapure water; 75% alcohol; phosphate Buffered Saline (PBS); dissecting fluid (CMF-HBSS); 0.05% MTT; L-Polylysine (PLL); d-polylysine (poly-D-Lysine, PDL); sugar-free DMEM medium; MEM growth medium; map 2; DAPI; alexa Fluor 488/546 coat Anti-Mouse IgG secondary antibody.

1.2 instruments

A disposable culture dish; freezing and storing the cells; centrifuging the tube; glass slide; an oven; an orifice plate; a surgical instrument; a vertical superclean bench; CO 2₂A constant temperature incubator; a constant-temperature water bath kettle; an anoxic tank; a full-automatic autoclave; an LDH kit; a dissecting microscope; a fluorescence microscope; a micro-pipetting gun; a centrifuge; a vortex instrument; rotating the shaking table; an ultra-pure water system; an electronic balance.

1.3 materials

SD pregnant mouse, used for extracting primary cortical neuron cells of cerebral cortex of E18 day fetal mouse.

2 method of experiment

2.1 Primary cortical neuron extraction and culture

Primary cortical neurons were extracted from fetal mouse cerebral cortex of SD pregnant mice at day E18, and the slides, cell culture plates, and culture dishes used were treated as follows before extraction of primary cortical neuron cells:

soaking the glass slide and the cell culture plate in concentrated nitric acid in advance overnight, washing with ultrapure water for 3 times, 1 hour/time, putting the glass slide and the cell culture plate in a 200 ℃ oven for 4 hours, and then placing the glass slide and the cell culture plate in a biological safety cabinet for ultraviolet irradiation overnight; slide or PLL coated well plate or petri dish was coated with diluted PDL overnight, the coated slides, cell culture plate were washed 3 times 10 min/time with sterile water, and half volume of equilibration solution was added to equilibrate overnight for future use.

Killing the neck of the SD pregnant mouse by dislocation, sterilizing the SD pregnant mouse by using 75% alcohol, quickly dissecting the SD pregnant mouse by using a surgical instrument sterilized at high temperature, taking out the fetal mouse, cutting off the head of the fetal mouse, rinsing the fetal mouse twice by using precooled PBS, putting the fetal mouse into dissecting liquid (CMF-HBSS), removing meninges of the fetal mouse by using dissecting scissors under a dissecting microscope, separating cerebral cortex, transferring the cerebral cortex to a biological safety cabinet, cutting the cortical tissue by using a sterilized blade, transferring the cortical tissue to a 15mL centrifuge tube, adding 3mL of dissecting liquid (CMF-HBSS), washing twice, finally adding 3mL of dissecting liquid (CMF-HBSS), adding 100 XDNase and 1: adding 10 Xtrypsin (Trypsin) at a ratio of 10 (volume ratio), digesting in a constant-temperature water bath kettle preheated to 37 ℃ for 15min, shaking once every 2min to fully digest the Trypsin, adding 1% Trypsin inhibitor (Trypsin inhibitor) at a ratio of 1:20 (volume ratio) to stop digestion, mixing uniformly and centrifuging. The supernatant was aspirated off, washed once with 4mL cortical neuron culture medium (NB), centrifuged for 3min, 1000 rpm. The supernatant was discarded again, 4mL of cortical neuron culture medium was added, gently tapped 20 times, allowed to stand for 2 minutes, transferred, and allowed to stand for 2 minutes again. The supernatant was transferred to a new centrifuge tube. After mixing, 10. mu.L of cell sap was diluted 20 times with the culture medium for counting, and after counting cells, the ratio was 4X 10⁴The individual cells were inoculated into 12 wells and cultured at 8X 10⁵The individual cells were inoculated into 35mm petri dishes and cultured at 1X 10⁵The individual cells were inoculated into 96-well culture plates for culture. Half liquid change every three days of cells, culturing in vitro to 7 days(DIV 7) was used for the experiments.

2.2 construction of glucose-deficient hypoxia (OGD/R) model

Changing the culture medium of the primary cortical neurons cultured to DIV7 into an MEM growth medium, pretreating for 2h, and then changing into a sugar-free DMEM culture medium; transferring to an anoxic tank, and introducing a solution containing 95% N₂And 5% CO₂The gas is about 10min and 5L/min, an anaerobic environment is formed in the anaerobic incubator, and then the anaerobic incubator containing the cells is placed in a constant temperature incubator at 37 ℃ for 4 h; and taking out the cells, removing the sugar-free DMEM culture medium, adding the growth culture medium, continuing to culture for 24h, and then collecting the cells for subsequent experiments to construct an oxygen-deficient glucose (OGD/R) model.

The primary cortical neurons of DIV7 used in the blank control group were not subjected to the above-described hypoxic treatment, and were subjected to normal conventional culture, i.e.:

changing the culture medium of the primary cortical neurons cultured to DIV7 to an MEM growth medium, and changing to a sugar-free DMEM culture medium after 2 h; inducing in an anoxic box, and culturing in a constant temperature incubator at 37 deg.C for 4 hr; and taking out the cells, removing the sugar-free DMEM medium, adding the growth medium, continuing to culture for 24 hours, and then collecting the cells for subsequent experiments.

2.3 Experimental groups and dosing

Cultured to DIV7 primary cortical neurons at 1X 10 per well⁴Inoculating each cell in a 96-well culture plate, wherein each well contains 100 mu L of cell suspension; a blank group, a model group and 3 administration groups with different concentrations (0.2. mu.M, 0.04. mu.M and 0.008. mu.M) are set, and each group is provided with 3 parallel multiple wells. The method comprises the following specific steps:

blank group: and (3) the cells obtained in the step 2.1 are not treated, so that the cells grow normally.

Model group: treating the cells obtained in the step 2.1 with a growth medium for 2 hours, then changing the cells into a sugar-free DMEM medium, transferring the cells into an anoxic box, and introducing the cells containing 95% N₂And 5% CO₂And (3) allowing the gas to enter an anaerobic environment in an anaerobic incubator for about 10min and 5L/min, placing the anaerobic incubator containing the cells in a constant-temperature incubator at 37 ℃ for 4h, taking out the cells, removing the sugar-free DMEM medium, and adding the sugar-free DMEM medium into the cells to continue culturing for 24 h.

Administration group: by respectively containingAfter 2h of treatment with the novel growth medium of glatiramer at different final concentrations (0.2. mu.M, 0.04. mu.M and 0.008. mu.M), the medium was replaced with a novel sugar-free DMEM medium containing glatiramer at different concentrations (0.2. mu.M, 0.04. mu.M and 0.008. mu.M), transferred to an anoxic chamber, and introduced into a chamber containing 95% N₂And 5% CO₂And (3) allowing the gas to enter an anaerobic environment in an anaerobic incubator for about 10min and 5L/min, placing the anaerobic incubator containing the cells in a constant-temperature incubator at 37 ℃ for 4h, taking out the cells, removing the sugar-free DMEM medium, and adding the sugar-free DMEM medium into the cells to continue culturing for 24 h.

2.4MTT assay to test the protective effect of granisetron on cells following OGD injury

The blank, model and administration groups of the cell culture plates of step 2.3 were added to each well with 30. mu.L of MTT (5mg/mL), and after 4 hours of reaction, the supernatant was removed and 100. mu.L of DMSO was added to dissolve the reaction product, and the OD value of each well was measured at 595nm using a microplate reader.

Cell survival (%). ratio (mean OD value in experimental group/mean OD value in control group) × 100%

2.5 neuronal dendritic morphology Observation test the protective Effect of glandinew on Primary neuronal dendritic integrity after OGD

After modeling, each group of cells was removed, fixed with PFA for 20min, washed three times with PBS at room temperature. Map2 (1: 2000) and DAPI (1: 3000) were added, at 4 ℃ overnight. PBS was washed three times and coated with a fluorescent secondary antibody Alexa Fluor 488/546 coat Anti-Mouse IgG secondary antibody. And sealing the film, and taking a picture under a fluorescence microscope for observation. Indices such as the number of dendrite branches and the average neurite length were analyzed by Image J software.

2.6 statistical treatment

SPSS 13.0 statistical software is used for statistical processing, experimental data are expressed by mean +/-standard deviation, independent T test is adopted for comparison between two groups, one-factor variance analysis is adopted for comparison between multiple groups, the test level alpha is 0.05, and the difference is considered to have statistical significance when P is less than 0.05.

3 results of the experiment

3.1MTT method to test the protective Effect of glandinew on cells following OGD injury

The survival rates of neurons were measured by the MTT method, and as a result, the average survival rates of the control group, the model group, the administration group (0.2. mu.M), the administration group (0.04. mu.M), and the administration group (0.008. mu.M) were 100%, 38.5%, 82.3%, 84.5%, and 84.0%, respectively, as shown in FIG. 1. Compared with the blank group, the neuron in the model group has obviously reduced cell survival rate (p <0.01) after 4 hours of sugar deficiency and hypoxia. Whereas, the new group of glandian at each concentration significantly increased the cell viability of neurons compared to the model group (p < 0.05).

3.2 testing the protective Effect of gladioxin on Primary neuronal dendritic integrity following OGD by neuronal dendritic morphology observations

The neuron morphograms of the control group, model group and administration group are shown in fig. 2: the blank group is in a fusiform or polygonal shape, and is provided with a plurality of bulges, and the bulges are long and provided with a plurality of branches; the oxygen sugar deprivation damage of the model group neurons obviously reduces the number and the length of the neuron dendrites; the new group of glandian neurons cells have a morphology similar to that of the blank group, possessing multiple processes with long processes. It should be noted that the result labeled "glandinov" in fig. 2 is specifically the test result of the administration group at a concentration of 0.04 μ M.

The results of statistical analysis of the length and number of neurites in the control group, model group and administration group are shown in FIG. 3: the length and the number of the model group neuron cells are obviously lower than those of the blank group, which indicates that the model is successfully made; in contrast to the model group, the new group of glandian can significantly restore the integrity of the neuron dendrites. Specifically, the average number of dendrites in the control group, the model group and the administration group was 16, 5 and 9, respectively, and the average length of dendrites in the control group, the model group and the administration group was 370 μm, 80 μm and 217 μm, respectively. The result labeled "glandinov" in fig. 3 is specifically the test result of the administration group at a concentration of 0.04 μ M.

Acute hypoxic stroke has the characteristics of high mortality and disability rate, and seriously harms human health. The invention takes primary cultured cortical neurons as a model, adopts oxygen sugar deprivation to simulate hypoxia reperfusion injury, and researches the protective effect of glandinew on cortical cells through cell survival rate and observation of neuron dendritic morphology. The result shows that the glandinew can obviously improve the survival rate of the neuron cells, restore the integrity of the neuron dendrites and show obvious neuron protection effect.

EXAMPLE 2 preparation of geldanamycin hydrochloride tablets

Taking 90g of gladiolide hydrochloride, crushing into powder, adding 900g of starch, 4g of Arabic gum and 3g of sodium carboxymethylcellulose, uniformly mixing, spraying 20mL of 95% edible ethanol to prepare a soft material, placing the soft material into a granulator to prepare granules (with the size of a first sieve), drying at 60 ℃ until the moisture content is 3-5%, drying and granulating the soft material, adding a lubricant magnesium stearate, fully and uniformly mixing, pressing the mixture into 0.25 g/tablet by a tablet press, bottling, checking to be qualified, and packaging to obtain the finished product.

EXAMPLE 3 preparation of gelan New hydrochloride injection

Taking 10.0g of gladiodine hydrochloride, adding 20.0g of sodium chloride, 50.0g of mannitol and 9000mL of water for injection in a workshop with the grade below 100, fully stirring, adding 1% hydrochloric acid aqueous solution, adjusting the pH value to 3.0-5.0, stirring, adding water for injection to adjust the total volume to 10000mL, adding 0.1% activated carbon, keeping the temperature at 80 ℃ for 15min, filtering, performing ultrafiltration on filtrate by using a 0.2 mu m microporous membrane to obtain a clear solution, aseptically packaging the solution in ampoules, sealing each ampoule by 5mL, sterilizing, and packaging after the solution is qualified to obtain a finished product.

EXAMPLE 4 preparation of geldendrin hydrochloride eye drops

Taking 5.0g of gladiodine hydrochloride, adding 90.0g of sodium chloride, 0.23g of methyl paraben, propyl paraben and 100mL of distilled water in a workshop with the grade of 100, fully stirring, adding a proper amount of 1% hydrochloric acid aqueous solution, adjusting the pH value to 3.0-5.0, stirring uniformly, adding distilled water to adjust the total volume to 1000mL, adding 0.1% active carbon, keeping the temperature at 80 ℃ for 15min, filtering, ultrafiltering filtrate by a 0.2 mu m microporous membrane to obtain a clear solution, aseptically canning the solution in an eye drop bottle, sterilizing at 100 ℃ for 30min by 2mL per bottle, and packaging after the solution is qualified by inspection to obtain a finished product.

In conclusion, the invention provides a new application of glatiramer and/or a pharmaceutically acceptable salt thereof, and mainly relates to the application of glatiramer and/or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating cerebrovascular diseases. The invention verifies that the glatiramer and/or the pharmaceutically acceptable salt thereof can protect brain neurons, effectively avoid the reduction of the number and/or the activity of the neurons, and protect the functional morphology of the neurons from being damaged based on the constructed biological model, which shows that the glatiramer and/or the pharmaceutically acceptable salt thereof can be used for effectively preventing and treating cerebrovascular diseases.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.