WO2022095057A1 - 一种医药组合物及其医药用途 - Google Patents
一种医药组合物及其医药用途 Download PDFInfo
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- WO2022095057A1 WO2022095057A1 PCT/CN2020/127619 CN2020127619W WO2022095057A1 WO 2022095057 A1 WO2022095057 A1 WO 2022095057A1 CN 2020127619 W CN2020127619 W CN 2020127619W WO 2022095057 A1 WO2022095057 A1 WO 2022095057A1
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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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- 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
Definitions
- the present application relates to the technical field of medicine, in particular to a pharmaceutical composition and its medical use.
- Ischemic stroke also known as cerebral infarction
- the optimal treatment methods include alteplase (rtPA) and surgical thrombectomy.
- rtPA alteplase
- thrombectomy surgical thrombectomy
- the time window of vascular recanalization therapy is mainly set to avoid or reduce the damage of blood-brain barrier (BBB) caused by reperfusion. If the BBB can be effectively protected, the time window of revascularization therapy may be extended, which will help more people receive revascularization therapy.
- BBB blood-brain barrier
- the existing main treatment methods are intravenous alteplase rtPA thrombolysis and intra-arterial thrombectomy, and they all have strict time window restrictions, the former being 4.5 hours, the latter is 6-8 hours (a few patients can be extended to 24 hours).
- Clinical studies have shown that serious complications such as hemorrhagic transformation and cerebral edema will occur when vascular patency is performed beyond this time window. Therefore, a considerable proportion of patients with acute cerebral infarction do not seek medical treatment in time, the distance from the hospital is far away, and the traffic jams on the road are subjective and objective factors.
- BBB protection drugs there are no targeted BBB protection drugs in clinical practice.
- cerebral edema or hemorrhagic transformation if cerebral herniation has been induced, use 20% mannitol, hypertonic salt, diuretics and other dehydration treatments for mild cases, and "decompressive craniectomy" for severe cases; and if no cerebral herniation is induced , and generally give patients supportive treatment such as sedation, blood pressure reduction, correction of water, electricity and acid-base balance disorders.
- the main technical problem to be solved by the present application is to provide a pharmaceutical composition and its medical use, which can play an effective pharmaceutical role in the treatment of ischemic stroke and the blood-brain barrier damage caused by it.
- a technical solution adopted in the present application is to provide a pharmaceutical composition for the treatment of ischemic stroke, the pharmaceutical composition comprising: an effective dose of lithium for the treatment of ischemic stroke and a pharmaceutically acceptable compound.
- the accepted carrier, wherein lithium is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to protect the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- the lithium agent is lithium chloride and/or lithium carbonate.
- the pharmaceutical composition is in dosage unit form.
- the dosage of the lithium agent in the pharmaceutical composition is one of 1.5-6.0 mmol/kg, wherein mmol/kg is the amount of the lithium agent relative to the mass of the patient.
- the dosage of the lithium agent in the pharmaceutical composition is 3.0 mmol/kg.
- the pharmaceutical composition also includes an effective dose of alteplase for treating ischemic stroke, and the dose of alteplase in the pharmaceutical composition is 0.9 mg/kg, wherein mg/kg is the amount ofreteplase Quality relative to the quality of the patient.
- another technical solution adopted in the present application is to provide the use of a lithium agent in the preparation of a drug for the treatment of ischemic stroke, wherein the lithium agent is used to upregulate the Wnt/ ⁇ of cerebral vascular endothelial cells -catenin signaling pathway, and protects the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- the lithium agent is lithium chloride and/or lithium carbonate.
- another technical solution adopted in the present application is to provide a pharmaceutical composition for the treatment of blood-brain barrier damage, the pharmaceutical composition comprising: an effective dose of lithium for treating blood-brain barrier damage and a medicinally acceptable drug.
- the accepted carrier, wherein lithium is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to protect the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- another technical solution adopted in the present application is to provide a use of a lithium agent in the preparation of a medicine for treating blood-brain barrier damage, wherein the lithium agent is used to upregulate the Wnt/ ⁇ of cerebral vascular endothelial cells -catenin signaling pathway, and protects the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- another technical solution adopted in the present application is to provide a pharmaceutical composition for the treatment of blood-encephalopathy, the pharmaceutical composition comprising: an effective dose of lithium for the treatment of blood-encephalopathy and a pharmaceutically acceptable The carrier, wherein lithium is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to protect the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- another technical solution adopted in the present application is to provide the use of a lithium agent in the preparation of a medicine for the treatment of blood and brain diseases, wherein the lithium agent is used to upregulate the Wnt/ ⁇ - catenin signaling pathway, and protects the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- the lithium agent in the pharmaceutical composition of the present application can up-regulate the Wnt/ ⁇ -catenin signaling pathway in cerebral vascular endothelial cells, as well as on the tight junction protein of endothelial cells of the blood-brain barrier.
- the protection of the structure plays an important role, and then can protect the blood-brain barrier. Therefore, lithium can play an effective drug role in the treatment of ischemic stroke and its resulting blood-brain barrier damage.
- Fig. 1 is a schematic diagram of experimental comparison after staining the coronal section of mouse brain with TTC;
- Figure 2 is a schematic diagram of the relative proportion of mouse infarct volume in the cerebral hemisphere
- Figure 3 is a schematic diagram of the relative proportion of Evans blue staining
- Figure 4 is a schematic diagram of the relative percentage of Evans blue exudation to hemisphere weight
- Figure 5 is a schematic diagram of the exudation of endogenous IgG from blood vessels observed by immunofluorescence double staining
- Fig. 6 is the relative density columnar schematic diagram of the exudation of IgG from blood vessels
- Fig. 7 is a columnar schematic diagram of neurobehavioral scoring
- Figure 8 is a schematic diagram of the observation of neuronal apoptosis by immunofluorescence double staining
- Figure 9 is a histogram of the relative density of the number of apoptotic neurons in the infarcted area of mice.
- Figure 10 is a schematic diagram of the expression of active ⁇ -catenin on endothelial cells observed by immunofluorescence double staining
- Figure 11 is a histogram of the relative density of active ⁇ -catenin expression on endothelial cells
- Figure 12 is a schematic diagram of the active and total ⁇ -catenin protein levels in the brain tissue in the infarcted area of each group;
- Figure 13 is a histogram of the relative density of immunoblotting in Figure 12;
- Figure 14 is another histogram of the relative density of immunoblotting in Figure 12;
- Figure 15 is a histogram of axin2 levels in cerebral infarction tissues in each group
- Figure 16 is a histogram of apcdd1 mRNA levels in cerebral infarction tissues in each group;
- Figure 17 is a schematic diagram of the effect of different concentrations of lithium chloride on bEnd.3 Axin2 mRNA levels
- Figure 18 is a schematic diagram of the influence of different concentrations of lithium chloride on the bEnd.3 TCF/LEF TOPflash value
- Figure 19 is a schematic diagram of the effect of lithium chloride corresponding to the construction of a Wnt/ ⁇ -catenin pathway-deficient bEnd.3 cell line by knocking out Fzd4;
- Figure 20 is a schematic diagram of another effect of lithium chloride corresponding to the construction of a Wnt/ ⁇ -catenin pathway-deficient bEnd.3 cell line by knocking out Fzd4;
- Figure 21 is a histogram of axin2 mRNA levels in each group.
- the present application provides a pharmaceutical composition for treating ischemic stroke, the pharmaceutical composition comprising: an effective dose of lithium for treating ischemic stroke and a pharmaceutically acceptable carrier.
- Ischemic stroke is a general term for brain tissue necrosis caused by stenosis or occlusion of the arteries supplying blood to the brain (carotid and vertebral arteries) and insufficient blood supply to the brain.
- cerebral ischemia transient ischemic attack (TIA); reversible neurological impairment (RIND); progressive stroke (SIE); complete stroke (CS).
- TIA transient ischemic attack
- RIND reversible neurological impairment
- SIE progressive stroke
- CS complete stroke
- Cerebral ischemia can be divided into localized cerebral ischemia and diffuse cerebral ischemia from the scope of ischemia.
- the causes of localized cerebral ischemia are: middle cerebral artery embolism; extracranial internal carotid artery or vertebral artery stenosis, occlusion or thrombosis; cerebral artery spasm.
- the causes of diffuse cerebral ischemia include cardiac arrest, hypotension, anemia, and hypoglycemia.
- ischemic stroke aka cerebral infarction
- revascularization therapy including alteplase (rtPA) and surgical thrombectomy, all of which have strict Due to the time window limitation, a considerable proportion of patients cannot receive such treatment.
- the time window setting of vascular recanalization therapy is mainly to avoid or reduce the damage of the blood-brain barrier caused by reperfusion, and alteplase rtPA itself has damage to the blood-brain barrier, even if it is used within the time window, some patients will still have it.
- BBB-damaging phenotypes such as hemorrhagic transformation, cerebral edema.
- a BBB protectant and rtPA can be used in combination to reduce its damage to the BBB, it will improve the effectiveness of revascularization therapy, and the time window of revascularization therapy may be extended, which is conducive to making more Many people receive revascularization therapy.
- lithium in current clinical or basic research is to prevent and treat bipolar disorder with alternating episodes of mania and depression.
- the inventors of the present application have found in experimental studies that when lithium is used for ischemic stroke in mice, it can upregulate the Wnt/ ⁇ -catenin pathway of cerebral vascular endothelial cells, and it has a positive effect on BBB in the acute phase of cerebral infarction in mice. Destruction also has a clear protective effect, potentially increasing the indications for lithium.
- Lithium can improve the functional integrity of cerebral vascular endothelial cells by up-regulating the Wnt/ ⁇ -catenin pathway of cerebral vascular endothelial cells, and can protect the structure of tight junction proteins of endothelial cells of the blood-brain barrier, thereby realizing the protection of BBB. effect.
- the lithium agent is lithium chloride (LiCl) and/or lithium carbonate (Li2CO3).
- the lithium agent may also be any reasonable mixture of one or more of lithium compounds such as lithium hydride, lithium nitride, and lithium hydroxide, which is not limited in this application.
- the pharmaceutical composition is in dosage unit form.
- the dose of the lithium agent in the pharmaceutical composition is one of 1.5-6.0 mmol/kg, and the mmol/kg is the amount of the lithium agent relative to the mass of the patient.
- the dosage of the lithium agent in the pharmaceutical composition can also comprehensively consider changes in factors such as the toxic and side effects of the drug or blood drug concentration, and use other arbitrary A reasonable dose, which is not limited in this application.
- the dosage of the lithium agent in the pharmaceutical composition is 3.0 mmol/kg.
- the pharmaceutical composition also includes an effective dose of alteplase for treating ischemic stroke, and the dose of alteplase in the pharmaceutical composition is 0.9 mg/kg, and the mg/kg is the mass ofreteplase relative to patient quality.
- the application also provides the use of a lithium agent in the preparation of a drug for the treatment of ischemic stroke, wherein the lithium agent is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to regulate the endothelial cells of the blood-brain barrier.
- the lithium agent is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to regulate the endothelial cells of the blood-brain barrier.
- the structure of the tight junction protein is protected.
- the lithium agent is lithium chloride and/or lithium carbonate.
- the application also provides a pharmaceutical composition for treating blood-brain barrier damage, the pharmaceutical composition comprising: an effective dose of lithium for treating blood-brain barrier damage and a pharmaceutically acceptable carrier, wherein the lithium is used to upregulate brain
- a pharmaceutical composition for treating blood-brain barrier damage comprising: an effective dose of lithium for treating blood-brain barrier damage and a pharmaceutically acceptable carrier, wherein the lithium is used to upregulate brain
- the Wnt/ ⁇ -catenin signaling pathway in vascular endothelial cells protects the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- the lithium agent is lithium chloride and/or lithium carbonate.
- the pharmaceutical composition is in dosage unit form.
- the dosage of the lithium agent in the pharmaceutical composition is one of 1.5-6.0 mmol/kg, and the mmol/kg is the mass of the lithium agent relative to the patient.
- the dosage of the lithium agent in the pharmaceutical composition is 3.0 mmol/kg.
- the application also provides the use of a lithium agent in the preparation of a medicine for treating blood-brain barrier damage, wherein the lithium agent is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to regulate the endothelial cells of the blood-brain barrier.
- the lithium agent is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to regulate the endothelial cells of the blood-brain barrier.
- the structure of the tight junction protein is protected.
- the lithium agent is lithium chloride and/or lithium carbonate.
- the present application also provides a pharmaceutical composition for treating blood-brain disease, the pharmaceutical composition comprising: an effective dose of lithium for treating blood-brain disease and a pharmaceutically acceptable carrier, wherein the lithium is used to upregulate cerebral vascular endothelial cells Wnt/ ⁇ -catenin signaling pathway, and protects the structure of tight junction proteins in endothelial cells of the blood-brain barrier.
- the lithium agent is lithium chloride and/or lithium carbonate.
- the pharmaceutical composition is in dosage unit form.
- the dosage of the lithium agent in the pharmaceutical composition is one of 1.5-6.0 mmol/kg, and the mmol/kg is the mass of the lithium agent relative to the patient.
- the dosage of the lithium agent in the pharmaceutical composition is 3.0 mmol/kg.
- the present application also provides the use of a lithium agent in the preparation of a medicine for treating blood-brain diseases, wherein the lithium agent is used to upregulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and to regulate the endothelial cells of the blood-brain barrier.
- the structure of the tight junction protein is protected.
- the lithium agent is lithium chloride and/or lithium carbonate.
- the lithium agents described herein may constitute the active ingredient of a pharmaceutical composition, and may generally be administered in the form of oral tablets, intravenous injections, or capsules in admixture with an appropriately selected suitable excipient or carrier.
- Dosage compositions such as tablets, capsules, pills, suppositories, and powders depend upon the intended mode of administration, which may be by any acceptable route. These routes of administration include oral, intravenous (intravenous), intramuscular (intramuscular), subcutaneous (subcutaneous). One or more of these approaches can be used in a patient.
- the compounds of the present application are administered as intravenous injection dosage forms and may be combined with non-toxic pharmaceutically acceptable inactive carriers such as water, glycerol, ethanol, physiological saline, and the like.
- inactive carriers such as water, glycerol, ethanol, physiological saline, and the like.
- Inert excipients which are commonly used as binders, disintegrating agents and coloring agents can also be added to the oral mixture.
- the administered pharmaceutical compositions may also contain minor amounts of non-toxic substances such as pH buffering agents, emulsifiers, sodium acetate, and the like.
- the dosage regimen for use of the compound will depend on the patient's species, sex, weight, age, medical condition, route of administration, and the severity of the condition being treated. A skilled physician can easily determine and prescribe an effective dose of a drug to treat the disease.
- treatment includes one or more of curative treatment, palliative treatment, and prophylactic treatment, depending on the disease and condition of the patient.
- the precise dose of each active compound administered will vary depending on a number of factors including, but not limited to, the type of patient and disease state being treated, the age of the patient, and the route of administration.
- the dose administered will, of course, vary with the mode of administration, the treatment desired, and the disease indicated.
- the total daily dose can be administered in a single dose or in divided doses.
- Sustained release compositions are also encompassed by this application.
- the pharmaceutical composition can be in a form suitable for oral administration, such as one of tablets, capsules, pills, powders, sustained-release formulations and solutions; or, the pharmaceutical composition can also be in a form suitable for intravenous injection , such as infusion bottles or infusion bags.
- Pharmaceutical compositions can be presented in unit dosage forms suitable for single administration of precise dosages.
- Pharmaceutical compositions will include conventional pharmaceutical carriers and active compounds. In addition, it may include other pharmaceutical or pharmaceutical agents, carriers, adjuvants, and the like.
- Suitable pharmaceutical carriers include inert diluents or fillers, water. If desired, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, and the like.
- tablets containing various excipients such as citric acid can be combined with various disintegrants such as starch, alginic acid and certain complex silicates and binders such as sucrose, gelatin and gum arabic) together.
- disintegrants such as starch, alginic acid and certain complex silicates and binders such as sucrose, gelatin and gum arabic
- lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are frequently used in the preparation of tablets.
- Solid compositions of a similar type can also be used in soft and hard filled gelatin capsules. Useful components of these compositions include lactose or milk sugar and high molecular weight polyethylene glycols.
- the active compounds therein may be mixed with various sweetening or flavoring agents, coloring or dyeing agents and, if desired, emulsifying or suspending agents and diluents such as water, ethanol , propylene glycol, glycerol) or a combination thereof.
- various sweetening or flavoring agents such as water, ethanol , propylene glycol, glycerol
- emulsifying or suspending agents and diluents such as water, ethanol , propylene glycol, glycerol
- intravenous administration it can be used with distilled water or normal saline.
- doses can be adjusted based on pharmacokinetic or pharmacodynamic parameters, which can include clinical effects such as toxic effects and/or laboratory values. Accordingly, this application encompasses intra-patient dose escalation as determined by one of skill in the art. Determining appropriate dosages and regimens for administering chemotherapeutic agents is well known in the relevant art and, once provided with the teachings disclosed herein, should be understood to be encompassed by those skilled in the art.
- compositions of the present application can be prepared, packaged, or sold in bulk, in a single unit dose, or in multiple unit doses.
- a "unit dose" is an individual quantity of a pharmaceutical composition containing a predetermined quantity of an active compound.
- the amount of active compound is generally equal to the dose of active compound to be administered to a subject, or a convenient fraction of such a dose, such as, for example, one-half or one-third of such a dose.
- compositions of the present application will vary depending on the identity, size and condition of the subject being treated and further depending on the route of administration of the composition.
- the composition may contain between 0.1% and 100% (w/w) active ingredient.
- compositions of the present application may further comprise one or more additional therapeutically effective compounds as discussed above.
- lithium agent is lithium chloride as an example.
- the model used in this application is a cerebral ischemia-reperfusion model of mouse middle cerebral artery occlusion (MCAO) for 1 hour (h) and recanalization for 48 hours. Specific steps are as follows:
- mice 8 to 10 weeks old and weighing 20 to 23 g were first obtained. These mice were housed in a pathogen-free animal facility on a 12-hour light and dark cycle. Mice were randomly selected for sham surgery, ischemia models, or post-ischemia treatment studies. During surgery, anesthesia was first induced with 4% isoflurane in an induction chamber and maintained with 2% isoflurane delivered through a mask. The core temperature of each mouse was maintained at 37 ⁇ 0.5°C using a heating pad throughout the procedure, and the mice were treated with induced, transient middle cerebral artery occlusion (MCAO) using a modified intraluminal fiber model. After 60 min of MCAO, reperfusion was established by retracting the fibers.
- MCAO transient middle cerebral artery occlusion
- mice had free access to food and water throughout the reperfusion period. After 48 hours of MCAO, the mice were evaluated for neurological function by the observer, eg, on a deficit score (20), a grip test score (21), and a horizontal ladder test score (22). Mice without neurological deficits after surgery were excluded according to a pre-established exclusion plan.
- mice were injected intraperitoneally (ip) with lithium chloride (LiCl) at a concentration of 2%, starting with intraperitoneal (ip) reperfusion, and then re-injected at the same dose 24 hours later.
- LiCl lithium chloride
- mice were deeply anesthetized with isoflurane.
- the whole brain of the mouse was removed and coronal sectioning (thickness 2mm) was performed in a special groove.
- coronal sectioning Immediately immerse the sections in 1 ml of 1% 2,3,5-triphenyltetrazolium chloride (TTC) and incubate at 37°C for 10 minutes. Then, the TTC solution was replaced with 4% paraformaldehyde for 1 h at room temperature.
- Sections were photographed with a digital camera, and infarct size was measured by ImageJ software (a java-based public image processing software). To eliminate the effect of post-ischemic edema on lesion volume, infarct size was corrected as previously described (24).
- the formula for calculating the infarct area (%) is [((volume of left hemisphere ⁇ non-infarct volume of right hemisphere)/volume of left hemisphere)100%.
- the brains were then divided into the ipsilateral ischemic hemisphere and the contralateral non-ischemic hemisphere, homogenized in 1 ml of 50% trichloroacetic acid and centrifuged (10,000 rpm, 20 minutes), and the above solution was diluted four-fold with ethanol and used Evans blue concentrations were measured by a fluorescence reader (620 nm excitation; 680 nm emission) and expressed as ⁇ g/g brain tissue.
- TUNEL terminal deoxynucleotidyl transferase-mediated dUTP (deoxyuridine triphosphate)-digoxigenin terminal labeling
- DAPI 4,6-diamidino-2-phenylindole
- Slides were mounted with DAPI (4',6-diamidino-2-phenylindole) in a fade-resistant mounting medium and imaged with a microscope to obtain 10, 20 or 40 images.
- Immunofluorescence signal area or density was quantified by ImageJ (a public image processing software based on java) and normalized by vessel area (CD31 signal area) in 5 to 8 random ischemic areas per mouse.
- Proteins were extracted from the ischemic side (at approximately 3.30 mm) of 2 mm thick coronal sections into the cerebral forebrain and analyzed by Western blotting. Brain tissue was collected 48 h after occlusion. Brain tissue proteins were isolated and collected by RIPA (Soluble Protein Extracted from Animal Tissue and Animal Cells) lysis buffer supplemented with protease and phosphatase inhibitors and quantified by BCA (BCA Protein Concentration Assay) assay according to standard protocols. Equal amounts of protein lysates from each sample were separated on 10% SDS-PAGE (polyacrylamide gel electrophoresis) gels.
- RIPA Soluble Protein Extracted from Animal Tissue and Animal Cells
- BCA BCA Protein Concentration Assay
- the protein was transferred to a polyvinylidene fluoride membrane, which was then incubated with primary antibodies, including rabbit anti-claudin-5, rabbit anti-ZO-1, rabbit anti-occludin, rabbit anti-MMP-9, Rabbit anti- ⁇ -catenin, rabbit anti- ⁇ -catenin, rabbit anti-phospho-JNK Thr183/Tyr185 (rabbit anti-phospho-c-Jun N-terminal kinase-threonine 286/threonine 185), rabbit anti-JNK (c -Jun amino-terminal kinase), rabbit anti-phospho-Camk II Thr286 (calmodulin kinase II-threonine 286), rabbit anti-CamkII (calmodulin-dependent protein kinase II) at a dilution ratio of 1:1,000. ⁇ -Actin was used as a normalized loading control. Membranes were incubated with the corresponding secondary antibodies and blots were developed using the GelView 6000
- RNA was reverse transcribed using RT-qPCR (real-time quantitative PCR) using Reverse Transcription Supermix, an object-based macrolanguage.
- RT-qPCR was performed on a real-time PCR system using the Power SYBRi Script Green (powerful master mix with green excitation wavelength dye) method.
- RNA expression was calculated using the comparative Ct (electron computed tomography) method normalized to actin. Data are expressed relative to a calibrator using the 2- ⁇ Ct method.
- Mouse brain-derived endothelial cells 3 were grown in Dulbecco's (Dulbecco's phosphate buffered saline) modified Eagle's medium (DMEM, a medium containing various amino acids and glucose) containing 10% fetal bovine serum and 1% penicillin. ) were cultivated. All cultures were maintained in a CO2 incubator with 5% humidity at 37°C and routinely passaged at 80-90% confluence. After 15 hours of LiCl or vehicle treatment, cells were exposed to OGD/R (ex vivo model of cerebral ischemia from oxygen and glucose deprivation).
- DMEM Dulbecco's phosphate buffered saline modified Eagle's medium
- the culture medium was replaced with Dulbecco's modified medium with LiCl or vehicle control, and the cultured cells were placed in a modular incubator containing 0.5–1% O2 and 99% N2 (nitrogen) with O2 (Oxygen) analyzer to monitor. After 6 hours of OGD (oxygen glucose deprivation), cells were returned to normal culture conditions with LiCl to restore oxyglucose for 3 hours.
- OGD oxygen glucose deprivation
- CCK-8 Cell viability was measured with CCK-8 and cells were seeded in 96-well plates at a concentration of 5,000 cells/well. Ten mL of CCK-8 solution was added to each well containing 100 mL of medium. Cells were incubated at 37°C for 2 hours. OD values (optical density values) were measured at 450 nm with a MULTISKAN GO (multi-scanner).
- a stable bEnd.3 (mouse brain microvascular endothelial cell) cell line with Wnt/ ⁇ -catenin signaling TOP-flash firefly luciferase [with TCF/LEF (Constructs for binding sites of T-cell factor, lymphoid potentiator) and Renilla control reporters were seeded on 96-well plates. After 48 hours, cells were stimulated with 100 ng/ml Wnt3a for 24 hours. Using Dual Stop (double stop ) and Glo (globulin) systems to measure firefly and Renilla luciferase activity. Reporter activity was calculated as firefly/renilla activity in each well. In each graph, all data are normalized to The first bar represents the data point.
- TEER was measured using a Millicell-ERS-2 (Millipore, Germany). bEnd.3 cells were seeded on Transwell permeable membranes (24-well cell culture inserts) with a pore size of 0.4 ⁇ m and allowed to grow for 3 days. Baseline TEER was measured before LiCl and OGD/R treatments. All measurements were normalized by subtracting TEER values measured in blank Transwell (invasion assay) filters. After OGD/R, the effect of LiCl on endothelial monolayer permeability of fluorescein isothiocyanate-conjugated 70 kDa FITC-dextran was evaluated.
- FITC-dextran Ten microliters of FITC-dextran (5ug/ml) was added to the chamber and the mixture was incubated for 30 minutes. Permeability was assessed by measuring fluorescence at 520 nm from a 100 ⁇ l aliquot of medium taken from the chamber using a fluorescence plate reader MULTISKAN GO.
- FIG. 1 is a schematic diagram of the relative proportion of mouse infarct volume in the cerebral hemisphere
- Figure 3 is a schematic diagram of the relative proportion of Evans blue staining
- Figure 4 is a schematic diagram of the relative proportion of Evans blue staining
- Fig. 5 is a schematic diagram of the exudation of endogenous IgG from blood vessels observed by immunofluorescence double staining
- Fig. 1 is a schematic diagram of the relative proportion of mouse infarct volume in the cerebral hemisphere
- Figure 4 is a schematic diagram of the relative proportion of Evans blue staining
- Fig. 5 is a schematic diagram of the exudation of endogenous IgG from blood vessels observed by immunofluorescence double staining
- FIG. 6 is a schematic diagram of the relative density of IgG exuded from blood vessels; Fig. 7 is the histogram of the neurobehavioral score; Figure 8 is the schematic diagram of the neuron apoptosis observed by immunofluorescence double staining; Figure 9 is the histogram of the relative density of the number of apoptotic neurons in the infarcted area of mice; Figure 10 is the immunofluorescence double staining to observe the active ⁇ - Schematic diagram of the expression of catenin on endothelial cells; Figure 11 is a histogram of the relative density of active ⁇ -catenin expression on endothelial cells; Figure 12 is a schematic diagram of active and total ⁇ -catenin protein levels in brain tissue in the infarcted area of each group; Figure 13 is Figure 12 Figure 14 is another histogram of the relative density of immunoblotting in Figure 12; Figure 15 is a histogram of axin2 levels in cerebral infarction tissue in each group; Figure 16 is apcdd1
- Figure 1 shows the ischemic area after staining the coronal section of the mouse brain with TTC, and the white area is the ischemic area;
- Figure 3 shows the staining area of Evans blue (the blue area is the leakage area of Evans blue in the brain tissue);
- Figure 5 shows the exudation of endogenous IgG (green) from blood vessels (CD31, red) observed by immunofluorescence double staining, and the corresponding scale is 100um;
- Figure 8 shows the double immunofluorescence staining to observe the apoptosis of neurons (red) (TUNEL staining, green), the scale is 100um;
- Figure 10 shows the expression of active ⁇ -catenin (green) on endothelial cells (red) observed by immunofluorescence double staining, the bar is 100um;
- Figure 12 shows the active and total ⁇ -catenin protein levels in the brain tissue in the infarcted area of each group;
- lithium treatment enhanced monolayer cerebral vascular endothelial cell integrity and BBB function compared with control cells without lithium treatment.
- Lithium has dual effects of BBB and nerve cell protection.
- the BBB protection of lithium is achieved by up-regulating the Wnt/ ⁇ -catenin pathway in cerebral vascular endothelial cells and the structure of tight junction protein between endothelial cells that protects the BBB.
- experiments confirmed that the protective effect of lithium on the BBB is mainly due to the protection of tight junctions between cerebral vascular endothelial cells.
- lithium is a commonly used drug in clinic, its pharmacokinetics and side effects are clear, and its cost is low, so it is expected to be directly applied to clinical cerebral infarction patients.
- lithium not only has BBB protection effect, but also has neuroprotective effect. Compared with other drugs targeting Wnt/ ⁇ -catenin pathway, lithium has better safety.
- lithium can also be applied to other diseases that can cause BBB damage, including cerebral hemorrhage, toxic encephalopathy, metabolic encephalopathy, and cerebral hemorrhage secondary to central nervous system leukemia.
- lithium in the pharmaceutical composition of the present application can up-regulate the Wnt/ ⁇ -catenin signaling pathway of cerebral vascular endothelial cells, and play an important role in protecting the structure of tight junction proteins in endothelial cells of the blood-brain barrier, This protects the blood-brain barrier. Therefore, lithium can play an effective drug role in the treatment of ischemic stroke and its resulting blood-brain barrier damage.
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Abstract
Description
Claims (12)
- 一种治疗缺血性脑卒中的医药组合物,其特征在于,所述医药组合物包括:治疗缺血性脑卒中有效剂量的锂剂和医药上可接受的载体,其中,所述锂剂用于上调脑血管内皮细胞Wnt/β-catenin信号通路,并对血脑屏障的内皮细胞的紧密连接蛋白的结构进行保护。
- 根据权利要求1所述的医药组合物,其特征在于,所述锂剂为氯化锂和/或碳酸锂。
- 根据权利要求1或2所述的医药组合物,其特征在于,所述医药组合物呈剂量单位形式。
- 根据权利要求3所述的医药组合物,其特征在于,所述医药组合物中的所述锂剂的剂量为1.5-6.0毫摩尔/千克中的一种,其中,毫摩尔/千克为所述锂剂的物质的量相对于患者的质量。
- 根据权利要求4所述的医药组合物,其特征在于,所述医药组合物中的所述锂剂的剂量为3.0毫摩尔/千克。
- 根据权利要求1所述的医药组合物,其特征在于,所述医药组合物还包括治疗缺血性脑卒中有效剂量的阿替普酶,且所述医药组合物中的所述阿替普酶的剂量为0.9毫克/千克,其中,毫克/千克为所述阿替普酶的质量相对于患者的质量。
- 一种锂剂在治疗缺血性脑卒中药物的制备中的用途,其特征在于,所述锂剂用于上调脑血管内皮细胞Wnt/β-catenin信号通路,并对血脑屏障的内皮细胞的紧密连接蛋白的结构进行保护。
- 根据权利要求7所述的用途,其特征在于,所述锂剂为氯化锂和/或碳酸锂。
- 一种治疗血脑屏障损伤的医药组合物,其特征在于,所述医药组合物包括:治疗血脑屏障损伤的有效剂量的锂剂和医药上可接受的载体,其中,所述锂剂用于上调脑血管内皮细胞Wnt/β-catenin信号通路,并对血脑屏障的内皮细胞的紧密连接蛋白的结构进行保护。
- 一种锂剂在治疗血脑屏障损伤的药物的制备中的用途,其特征在于,所述锂剂用于上调脑血管内皮细胞Wnt/β-catenin信号通路,并对血脑屏障的内皮细胞的紧密连接蛋白的结构进行保护。
- 一种治疗血脑疾病的医药组合物,其特征在于,所述医药组合物包括:治疗血脑疾病的有效剂量的锂剂和医药上可接受的载体,其中,所述锂剂用于上调脑血管内皮细胞Wnt/β-catenin信号通路,并对血脑屏障的内皮细胞的紧密连接蛋白的结构进行保护。
- 一种锂剂在治疗血脑疾病的药物的制备中的用途,其特征在于,所述锂剂用于上调脑血管内皮细胞Wnt/β-catenin信号通路,并对血脑屏障的内皮细胞的紧密连接蛋白的结构进行保护。
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