Blood-brain barrier protector

Abstract

The present invention pertains to a vascular endothelial cell protecting agent, a blood-cerebrospinal fluid barrier protecting agent, and a central nervous system protecting agent, comprising at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, bismuth-containing compounds, and pharmaceutically acceptable salts thereof. Additionally, the present invention pertains to a pharmaceutical composition for preventing and / or treating diseases associated with blood-cerebrospinal fluid barrier impairments, such as damage to the central nervous system, infarction and hemorrhaging, inflammatory diseases of the central nervous system, degenerative diseases of the central nervous system, symptomatic nerve diseases, spinal cord impairments associated with spinal cord degeneration, drug-based impairments, infectious diseases, or anaphylaxis. The pharmaceutical composition comprises at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, bismuth-containing compounds, and pharmaceutically acceptable salts thereof.

Description

[Technical Field]

[0001] The present invention relates to a blood-brain-spinal barrier protecting agent containing a compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. [Background technology]

[0002] The blood-brain spinal cord barrier (BBSCB), which is the blood barrier of the central nervous system, plays an important role in maintaining homeostasis of the central nervous system parenchyma by restricting the exchange of substances between the blood and the central nervous system tissue fluid. The barrier function of the BBSCB is mediated by tight junctions between vascular endothelial cells, and pericytes and astrocytes surrounding the vascular endothelial cells are thought to be involved in maintaining the barrier function.

[0003] The BBSCB includes the blood-brain barrier (BBB) ​​and the blood-spinal cord barrier (BSCB). When the BBSCB is disrupted, its permeability increases, allowing cytotoxic substances and inflammatory cells in the blood to leak into the central nervous system, damaging the central nervous system and becoming a cause or exacerbating factor for various central nervous system diseases.

[0004] For example, in spinal cord injury, after mechanical damage (primary injury) caused by external force, tissue damage (secondary injury) occurs due to biological reactions such as hematoma, ischemia, edema, inflammatory cell infiltration, and cell damage due to leakage of neurotransmitters, resulting in an expansion of the lesion area. Therefore, suppression of secondary injury is expected as a therapeutic target for preventing the expansion of the lesion area and a deterioration of functional prognosis. Methylprednisolone succinate sodium ester, the only approved treatment for acute spinal cord injury patients in Japan, is said to have the effect of suppressing secondary injury, but its effectiveness has been questioned worldwide, and more effective treatments are needed.

[0005] Although drugs that protect the BBSCB could be used as therapeutic agents for spinal cord injury to prevent secondary damage, no BBSCB-protecting drugs have yet been shown to be clinically effective. Basic research has shown that drugs such as cilostazol (Non-Patent Document 1), metformin (Non-Patent Document 2, Patent Document 1), and rosiglitazone (Non-Patent Document 3) have BBSCB-protecting effects. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Takagi T., et al. J Cereb Blood Flow Metab. 2017;37(1):123-139. [Non-patent document 2] Takata F., et al. Biochem Biophys Res Commun. 2013; 433(4):586-590. [Non-patent document 3] Zhao., et al. Inflammation. 2019;42(3):841-856. [Patent documents]

[0007] [Patent Document 1] WO2012 / 081713 DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a BBSCB protecting agent that protects the BBSCB, thereby inhibiting its breakdown, and is effective in preventing or treating diseases or pathological conditions associated with BBSCB disorders. [Means for solving the problem]

[0009] The present inventors have found that mubritinib, brexpiprazole, papaverine and bismuth-containing compounds have protective effects on vascular endothelial cells and BBSCB, and have completed the following inventions.

[0010] (1) A vascular endothelial cell protecting agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. (2) A blood-brain-spinal barrier protecting agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. (3) A central neuroprotective agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. (4) A pharmaceutical composition for preventing and / or treating a disease associated with blood-brain barrier damage, comprising at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. (5) The pharmaceutical composition according to (4), wherein the disease accompanied by blood-brain-spinal barrier damage is selected from the group consisting of central nervous system damage, infarction and hemorrhage, central nervous system inflammatory disease, central nervous system degenerative disease, symptomatic neurological disease, spinal cord damage associated with spinal cord degeneration, drug-induced disorder, infectious disease, and anaphylaxis. (6) The pharmaceutical composition according to (4) or (5), wherein the disease accompanied by blood-brain-spinal barrier damage is selected from the group consisting of brain injury, spinal cord injury, cerebral infarction, spinal cord infarction, cerebral hemorrhage, spinal cord hemorrhage, multiple sclerosis, encephalomyelitis, optic neuritis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, epilepsy, compressive myelopathy, blood-brain-spinal barrier damage caused by immunosuppressants, brain infection, spinal cord infection, and anaphylaxis. (7) The pharmaceutical composition according to any one of (4) to (6), wherein the disease associated with blood-brain-spinal cord barrier damage is brain injury, spinal cord injury, or compressive myelopathy. [Effects of the Invention]

[0011] According to the present invention, by protecting the BBSCB and suppressing its breakdown, it is possible to prevent or treat central nervous system diseases and pathologies associated with BBSCB disorders. The compounds used in the present invention do not need to penetrate the BBSCB to exert their pharmacological effects, and since many of them are existing drugs, they have the advantage of being free of safety issues. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a graph showing sodium fluorescein (Na-F) permeability in a rat cerebrovascular endothelial cell monolayer culture model after glucose-free anoxia / reoxygenation in the presence of papaverine, mubritinib, brexpiprazole, or bismuth subnitrate. [Figure 2] Figure 2A shows an overview of the BBSCB model. Figure 2B shows the schedule of the glucose-free anoxia / reoxygenation test. [Figure 3] 1 is a graph showing Na—F permeability of the BBSCB model in the presence of papaverine, mubritinib, brexpiprazole, or bismuth subnitrate. [Figure 4] Representative photographs of spinal cord tissue sections immunostained with IgG antibody from mice that underwent partial spinal cord sectioning and were administered papaverine or bismuth subnitrate (center photograph; left photograph is a section from an animal that received the vehicle, saline), along with a graph showing the area of ​​the IgG-positive region (right side of the figure). [Figure 5] Representative photographs of spinal cord tissue sections immunostained with anti-IgG antibody from mice that underwent partial spinal cord resection and were administered mubritinib or brexpiprazole (center photograph in the figure; the photograph on the left is a section from an animal that received the vehicle, DMSO), and a graph showing the area of ​​the IgG-positive region (right side of the figure). [Figure 6] 1 is a graph showing the area of ​​GFAP-positive regions in spinal cord tissue sections from rats with spinal cord crush injury administered with papaverine, mubritinib, or brexpiprazole. [Figure 7]1 is a graph showing the area of ​​the injury cavity in spinal cord tissue sections from rats with spinal cord crush injury administered with papaverine, mubritinib, or brexpiprazole. [Figure 8] 1 is a graph showing the number of NeuN-positive cells in spinal cord tissue sections from rats with spinal cord crush injury administered with papaverine, mubritinib, or brexpiprazole. [Figure 9] 1 is a graph showing the stimulus response time before spinal cord injury in rats with spinal cord crush injury administered with papaverine, mubritinib, or brexpiprazole. [Figure 10] 1 is a graph showing the stimulus response time 8 weeks after spinal cord injury in rats with spinal cord crush injury that were administered papaverine, mubritinib, or brexpiprazole. [Figure 11] Representative photographs of spinal cord tissue sections immunostained with GFAP antibody from a spinal cord crush injury model that received a single dose of bismuth subnitrate (top left photograph; right photograph is a section from an individual that received the vehicle saline solution), a graph showing the area of ​​the GFAP-positive region (bottom left in the figure), and a graph showing the area of ​​the injury cavity (bottom right in the figure). [Figure 12] FIG. 1 shows representative photographs of spinal cord tissue sections immunostained with NeuN antibody from a spinal cord crush injury model that received a single dose of bismuth subnitrate (low-magnification image on the left side of the upper panel, and high-magnification image in the center; the left and center of the lower panel are sections from an individual that received the vehicle saline solution), as well as graphs showing the number of NeuN-positive cells present on a line 1.5 mm rostral from the injury center (upper right in the figure) and the number of NeuN-positive cells present on a line 1.5 mm caudal from the injury center (lower right in the figure). [Figure 13] 1 is a graph showing the stimulus reaction time before spinal cord injury, and 4 and 8 weeks after spinal cord injury in rats with spinal cord crush injury that were administered a single dose of bismuth subnitrate. [Figure 14] 1 is a graph showing the paw area of ​​each limb before spinal cord injury and 8 weeks after spinal cord injury in rats with spinal cord crush injury that had been administered a single dose of bismuth subnitrate. [Figure 15]1 is a graph showing the maximum walking speed of rats with spinal cord crush injury that received a single dose of bismuth subnitrate, where the horizontal axis represents treadmill speed and the vertical axis represents the number of rats corresponding to each maximum walking speed. [Figure 16] Representative photographs of cerebral tissue sections immunostained with anti-IgG antibody from mice with cerebral cortex damage that had been administered papaverine, mubritinib, brexpiprazole, or bismuth subnitrate (the upper left photograph in the figure is a section from an individual that had been administered bismuth subnitrate; the lower left photograph is a section from an individual that had been administered vehicle saline or DMSO), and a graph showing the area of ​​the IgG-positive region (right side of the figure). [Figure 17] 1 is a graph showing the cell viability of human cerebrovascular endothelial cells subjected to reactive oxygen stress in the presence of bismuth subcitrate, bismuth subnitrate, bismuth tartrate, or zinc sulfate. DETAILED DESCRIPTION OF THE INVENTION

[0013] Mubritinib (IUPAC name: 4-[[4-[4-(triazol-1-yl)butyl]phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole, CAS registration number 366017-09-6) is a receptor tyrosine kinase inhibitor that selectively inhibits the tyrosine kinase activity of human epidermal growth factor receptor type 2 (HER2).

[0014] Brexpiprazole (IUPAC name: 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one, CAS registration number 913611-97-9) is a drug called a serotonin dopamine activity modulator (SDAM) that acts as a partial agonist at dopamine D2 receptors and serotonin 5-HT1A receptors and as an antagonist at serotonin 5-HT2A receptors, and is used as a treatment for schizophrenia.

[0015] Papaverine (IUPAC name: 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline, CAS registration number 58-74-2) is a natural alkaloid of the isoquinoline family that has a smooth muscle relaxant effect. It is used as a medicine to dilate blood vessels and improve symptoms of visceral smooth muscle spasms, acute arterial embolism, acute pulmonary embolism, peripheral circulatory disorders, and coronary circulatory disorders.

[0016] Bismuth-containing compounds are compounds containing bismuth as a constituent atom, such as pharmaceutically acceptable bismuth complexes, that can be administered to living organisms, particularly humans, as pharmaceuticals. Bismuth is less toxic than its periodic congeners arsenic and ammotine, and various bismuth-containing compounds are used as pharmaceutical ingredients for intestinal disorders, antacids, astringents, and the like. Examples of bismuth-containing compounds that can be used in the present invention include bismuth subnitrate, bismuth subcitrate, bismuth subsalicylate, ranitidine bismuth citrate, bismuth subgallate, bismuth subcarbonate, bismuth aluminate, bismuth carbonate, bismuth citrate, bismuth nitrate, bismuth salicylate, and bismuth tartrate. Preferably, the bismuth-containing compound is one or more compounds selected from the group consisting of bismuth subnitrate, bismuth subcitrate, bismuth subsalicylate, ranitidine bismuth citrate, bismuth subgallate, and bismuth subcarbonate. More preferably, the bismuth-containing compound is bismuth subnitrate, bismuth subcitrate, or bismuth tartrate.

[0017] The pharmaceutically acceptable salts of the above four compounds can be acid addition salts or base addition salts. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate. Examples of base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt. Furthermore, examples include amino acid salts of basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid. Preferred pharmaceutically acceptable salts of the above four compounds include hydrochloride, potassium salt, and sodium salt.

[0018] The above four compounds or pharmaceutically acceptable salts thereof may exist as hydrates or solvates. In the present invention, the above four compounds may be used in free form or in the form of a pharmaceutically acceptable salt, as well as their hydrates or solvates.

[0019] As the above four compounds or pharmaceutically acceptable salts thereof, those already on the market as pharmaceuticals or those produced by known methods can also be used.

[0020] The above four compounds or pharmaceutically acceptable salts thereof can be used as the active ingredients of vascular endothelial cell protecting agents, BBSCB protecting agents, blood-organ barrier protecting agents, central nervous system protecting agents, and pharmaceutical compositions for preventing and / or treating diseases associated with BBSCB disorders, as described below.

[0021] With regard to these agents and compositions, "containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, bismuth-containing compounds, and pharmaceutically acceptable salts thereof" means containing at least one compound selected from the group consisting of mubritinib and pharmaceutically acceptable salts thereof, or one compound selected from the group consisting of brexpiprazole and pharmaceutically acceptable salts thereof, or one compound selected from the group consisting of papaverine and pharmaceutically acceptable salts thereof, or one compound selected from the group consisting of bismuth-containing compounds and pharmaceutically acceptable salts thereof, and includes containing two or more of these compounds.

[0022] Similarly, "containing at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, and pharmaceutically acceptable salts thereof" means containing at least one compound selected from the group consisting of papaverine and pharmaceutically acceptable salts thereof, or one compound selected from the group consisting of a bismuth-containing compound and pharmaceutically acceptable salts thereof, and includes containing two or more of these compounds.

[0023] Furthermore, "containing at least one compound selected from the group consisting of bismuth-containing compounds and pharmaceutically acceptable salts thereof" means containing at least one compound selected from the group consisting of bismuth-containing compounds and pharmaceutically acceptable salts thereof, and includes containing two or more of these compounds.

[0024] Vascular endothelial cell protective agent The above four compounds and pharmaceutically acceptable salts thereof have the ability to protect vascular endothelial cells and can therefore be used as vascular endothelial cell protective agents. In the present invention, a vascular endothelial cell protective agent refers to a substance that has the ability to protect vascular endothelial cells from external or internal stress and prevent damage to blood endothelial cells, such as cell death and decreased cell function. In the present invention, the vascular endothelial cell protective agent can be used on any vascular endothelial cells, such as vascular endothelial cells in peripheral blood vessels and vascular endothelial cells in blood vessels present in the central nervous system. In the present invention, the vascular endothelial cell protective agent is particularly suitable for protecting vascular endothelial cells present in the brain or spinal cord.

[0025] Thus, one embodiment of the present invention provides a vascular endothelial cell protective agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. The vascular endothelial cell protective agent preferably contains at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, and a pharmaceutically acceptable salt thereof. The vascular endothelial cell protective agent more preferably contains at least one compound selected from the group consisting of a bismuth-containing compound and a pharmaceutically acceptable salt thereof. Descriptions of each compound and pharmaceutically acceptable salt thereof, as well as examples of compounds and salts, including those that are preferably used, are as described above.

[0026] BBSCB Protectant Vascular endothelial cell protective agents protect the BBSCB through the protection of central nervous system vascular endothelial cells, thereby suppressing the occurrence and severity of BBSCB damage under stress loads such as primary injury in spinal cord injury. Therefore, vascular endothelial cell protective agents can also be used as BBSCB protective agents, and this BBSCB protective agent is also an aspect of the present invention. In the present invention, a BBSCB protective agent refers to a substance that protects the BBSCB from external or internal stresses that cause BBSCB damage and has the ability to prevent a decline in its function, particularly the barrier function that limits the exchange of substances between blood and central nervous system tissue fluid based on the selective permeability of tight junctions. In the present invention, the BBSCB protective agent is particularly suitable for protecting the blood-brain barrier (BBB) ​​or blood-spinal cord barrier (BSCB).

[0027] Thus, one embodiment of the present invention provides a BBSCB protecting agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. The BBSCB protecting agent preferably contains at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, and a pharmaceutically acceptable salt thereof. The BBSCB protecting agent more preferably contains at least one compound selected from the group consisting of a bismuth-containing compound and a pharmaceutically acceptable salt thereof. Descriptions of each compound and pharmaceutically acceptable salt thereof, as well as examples of compounds and salts, including those that are preferably used, are as described above.

[0028] In central nervous system infarction, typically cerebral infarction, the risk of cerebral hemorrhage due to BBB damage is extremely high, so the use of thrombolytic agents such as tissue-type plasminogen activator (t-PA) is limited to within 4.5 hours of onset. Because BBSCB protecting agents can reduce the risk of cerebral hemorrhage in cerebral infarction patients through their BBB-protecting effects, they are expected to enable the use of thrombolytic agents in cerebral infarction patients for whom the use of thrombolytic agents has traditionally been avoided. Thus, the present invention also encompasses the use of BBSCB protecting agents in combination with thrombolytic agents to extend the treatment period with thrombolytic agents.

[0029] In addition to the BBSCB, there are other blood-organ barriers in the body that function as barriers that limit the exchange of substances between blood and organs. Because vascular endothelial cells are responsible for the barrier function in blood-organ barriers, just like the BBSCB, vascular endothelial cell protective agents can also be used as protective agents for blood-organ barriers other than the BBSCB, and these blood-organ barrier protective agents are also an aspect of the present invention. Examples of blood-organ barriers other than the BBSCB include the blood-retina barrier, blood-bile barrier, blood-thymus barrier, blood-testis barrier, and blood-nerve barrier.

[0030] Thus, one embodiment of the present invention provides a blood-organ barrier protecting agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. The blood-organ barrier protecting agent preferably contains at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, and a pharmaceutically acceptable salt thereof. The blood-organ barrier protecting agent more preferably contains at least one compound selected from the group consisting of a bismuth-containing compound and a pharmaceutically acceptable salt thereof. Descriptions of each compound and pharmaceutically acceptable salt thereof, as well as examples of each compound and salt, including those that are preferably used, are as described above.

[0031] Central neuroprotective agents Vascular endothelial cell protective agents can protect the central nervous system by suppressing BBSCB disorder through protection of the BBSCB and thereby suppressing central nervous system damage associated with BBSCB disorder (such as secondary damage in spinal cord injury). Therefore, vascular endothelial cell protective agents can also be used as central nervous system protective agents, and this central nervous system protective agent is also an aspect of the present invention. In the present invention, a central nervous system protective agent refers to a substance that has the ability to protect central nervous cells from external or internal stress and prevent central nervous system damage associated with BBSCB disorder, such as cell death and decreased cell function. In the present invention, the central nervous system protective agent is particularly suitable for protecting the brain or spinal cord from secondary damage in brain injury, spinal cord injury, or compressive myelopathy.

[0032] Thus, one embodiment of the present invention provides a central neuroprotective agent containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, a bismuth-containing compound, and a pharmaceutically acceptable salt thereof. The central neuroprotective agent preferably contains at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, and a pharmaceutically acceptable salt thereof. The central neuroprotective agent more preferably contains at least one compound selected from the group consisting of a bismuth-containing compound and a pharmaceutically acceptable salt thereof. Descriptions of each compound and pharmaceutically acceptable salt thereof, as well as examples of compounds and salts, including those that are preferably used, are as described above.

[0033] Pharmaceutical Composition As described above, mubritinib, brexpiprazole, papaverine, bismuth-containing compounds, and pharmaceutically acceptable salts thereof have vascular endothelial cell activity, BBSCB protective activity, and central neuroprotective activity, and therefore can be used to prevent and / or treat diseases associated with BBSCB disorders. Therefore, in another aspect, the present invention provides a pharmaceutical composition containing at least one compound selected from the group consisting of mubritinib, brexpiprazole, papaverine, bismuth-containing compounds, and pharmaceutically acceptable salts thereof for preventing and / or treating diseases associated with BBSCB disorders. The pharmaceutical composition preferably contains at least one compound selected from the group consisting of bismuth-containing compounds, papaverine, and pharmaceutically acceptable salts thereof. More preferably, the pharmaceutical composition contains at least one compound selected from the group consisting of bismuth-containing compounds and pharmaceutically acceptable salts thereof. The description of each compound and pharmaceutically acceptable salt thereof, as well as examples of compounds and salts, including those that are preferably used, are as described above.

[0034] BBSCB dysfunction refers to a condition in which some abnormality in the BBSCB results in decreased or disrupted BBSCB function and increased permeability to substances. Furthermore, diseases associated with BBSCB dysfunction are diseases in which BBSCB permeability is increased, including diseases caused by or exacerbated by increased BBSCB permeability. Examples of diseases associated with BBSCB disorders include central nervous system injuries such as brain injury and spinal cord injury; central nervous system infarctions such as cerebral infarction and spinal cord infarction; central nervous system hemorrhages such as cerebral hemorrhage and spinal cord hemorrhage; central nervous system inflammatory diseases such as multiple sclerosis, encephalomyelitis, and optic neuritis; central neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; symptomatic neurological diseases such as dementia and epilepsy; spinal cord disorders associated with spinal degeneration such as compressive myelopathy; BBSCB disorders caused by drugs such as immunosuppressants (adverse symptoms such as tremors, delirium, and abnormal behavior); central nervous system infections or anaphylaxis caused by the transfer of viruses or allergens (e.g., Neuron 2008, 57(2):178-201; Nat Med. 2013, 19(12):1584-96, Physiol Rev, 2019 Jan 1;99(1):21-78. doi: 10.1152 / physrev.00050.2017.) In the present invention, the pharmaceutical composition is particularly suitable for treating brain injury, spinal cord injury or compressive myelopathy.

[0035] As used herein, the term "prevention" encompasses all types of medically acceptable preventative interventions aimed at preventing or suppressing the onset or development of a disease. Furthermore, the term "treatment" encompasses all types of medically acceptable therapeutic interventions aimed at curing or temporarily alleviating a disease. In other words, prevention and / or treatment of a disease associated with BBSCB disorder encompasses medically acceptable interventions for various purposes, including delaying or halting the progression of a disease associated with BBSCB disorder, regression or elimination of lesions, prevention of onset, or prevention of recurrence.

[0036] The pharmaceutical composition contains at least one compound (active ingredient) selected from the group consisting of mubritinib, brexpiprazole, papaverine, bismuth-containing compounds, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable ingredients. Examples of pharmaceutically acceptable ingredients include drugs other than the active ingredients (e.g., thrombolytic agents), buffers, antioxidants, preservatives, proteins, hydrophilic polymers, amino acids, chelating agents, nonionic surfactants, excipients, stabilizers, and carriers. Pharmaceutically acceptable ingredients are well known to those skilled in the art, and can be appropriately selected and used from ingredients listed in, for example, the 17th Edition of the Japanese Pharmacopoeia and other specifications, depending on the formulation, within the scope of ordinary skill in the art.

[0037] The pharmaceutical composition may be in any form, but preferred examples include oral preparations (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, etc.) and parenteral preparations (injections, drip infusions, topical preparations, etc.).

[0038] The method of administration of the pharmaceutical composition is not particularly limited, and in the case of a parenteral preparation, examples include intravascular administration (preferably intravenous administration), intraperitoneal administration, intraintestinal administration, subcutaneous administration, etc. In one preferred embodiment, the pharmaceutical composition is administered to a living body by oral administration or intravenous administration.

[0039] The pharmaceutical composition is administered in an amount effective for preventing or treating a disease accompanied by BBSCB disorder, which is determined appropriately depending on the dosage, the age of the subject, the state of the disease, and other conditions. The usual dosage per kg of body weight for an adult is, in terms of the amount of active ingredient, approximately 10 μg to 200 mg, preferably 20 μg to 100 mg, and more preferably 40 μg to 40 mg for papaverine; approximately 0.5 μg to 10 mg, preferably 1 μg to 5 mg, and more preferably 2 μg to 2 mg for mubritinib and brexpiprazole; and approximately 250 μg to 5000 mg, preferably 500 μg to 2500 mg, and more preferably 1 mg to 1000 mg for bismuth-containing compounds such as bismuth subnitrate, which can be administered once a day, in divided doses, or intermittently.

[0040] In another aspect, the present invention provides a method for preventing and / or treating a disease associated with BBSCB disorder, which comprises administering an effective amount of at least one compound selected from the group consisting of the above four compounds and pharmaceutically acceptable salts thereof to a subject in need thereof.

[0041] The present invention will be described in more detail by the following examples, but is not limited thereto. In the examples, unless otherwise specified, experimental data are expressed as mean ± standard error. Statistical analysis was performed using statistical analysis software JMP Pro 11.0 (SAS Institute). Student's t-test was used for comparison between two groups. Tukey's test was used for comparison between multiple groups. A p-value of less than 0.05 was considered significant. [Example]

[0042] Example 1 Evaluation of vascular endothelial cell protective effect (in vitro) The protective effects of papaverine, mubritinib, brexpiprazole, and bismuth subnitrate on vascular endothelial cells were evaluated in a rat brain endothelial cell (RBEC) monolayer culture model subjected to oxygen-glucose deprivation / reoxigenation (OGD / R).

[0043] Papaverine and mubritinib were purchased from Tokyo Chemical Industry Co., Ltd., brexpiprazole from Funakoshi Co., Ltd., and bismuth subnitrate from Santa Cruz Biotechnology (USA) and were used as test compounds.

[0044] Primary culture of RBECs was performed using 1cm of brain tissue from 3-week-old rats. 3The RBECs were then minced and enzymatically treated with type II collagenase (1 mg / ml, Worthington Biochemical Corp., USA) and DNase (15 μg / ml) at 37°C for 1.5 hours with shaking. The resulting capillary fragments were treated with collagenase-dispase (1 mg / ml, Roche Applied Sciences, Switzerland) and DNase (6.7 μg / ml) at 37°C for 45 minutes. The RBEC cell pellet was then dissociated with 33% Percoll (Pharmacia, Sweden), and the capillary fragment-containing layer was collected and seeded onto a 35-mm plastic dish coated with type IV collagen (0.1 mg / ml) and fibronectin (0.1 mg / ml) (Day 0). RBECs were cultured in RBEC I medium (DMEM / F12, 10% fetal bovine plasma derived from serum (PDS) (Animal Technologies, Inc., USA), basic fibroblast growth factor (bFGF, Roche Applied Sciences, 1.5 ng / ml), heparin (100 μg / ml), insulin (5 μg / ml), transferrin (5 μg / ml), sodium selenite (5 ng / ml) (insulin-transferrin-sodium selenite media supplement), gentamycin (50 μg / ml), and puromycin (4 μg / ml). From day 3 onward, the medium was changed to RBEC I medium (RBEC II medium) without puromycin. When the cultured cells reached 80% confluence, purified endothelial cells were passaged by brief treatment with trypsin (0.05% w / v)-EDTA (0.02% w / v) solution (day 4).

[0045] The RBECs prepared above were placed in a 2.0 × 10 swell on the polyester membrane on the top of a collagen- and fibronectin-coated Transwell insert for a 24-well plate. 5 cell / cm 2 The cells were seeded at 100°C and cultured for 6 hours at 37°C under normoxia (20%) in DMEM / F12 containing 4.5 g / L (concentration) glucose, or under anoxia in glucose-free DMEM / F12. The medium was replaced with RBEC medium supplemented with the test compound, and the cells were cultured for an additional 18 hours under normoxia. Wells in which the medium supplemented with the test compound was replaced with medium supplemented with the same concentration of DMSO (0.1%) were prepared as controls.

[0046] Na-F permeability, an index of paracellular transport through tight junctions (TJs), was evaluated in a RBEC monolayer culture model. The previously cultured Transwell inserts were transferred to a 24-well plate and 0.9 mL of Dulbecco's PBS (assay buffer, pH 7.4) containing 4.5 g / L glucose and 10 mM Hepes was added. Instead of medium, 0.5 mL of buffer containing 10 μg / mL Na-F (molecular weight: 376 Da) was added to the inserts. After 15 and 45 minutes of Na-F addition, the inserts were transferred to separate wells containing assay buffer, and measurements were performed at 535 nm (excitation wavelength: 485 nm) using a Wallac 1420 ARVO Multilabel Counter (Perkin Elmer, Waltham, MA, USA). Na-F permeability was expressed as the permeability coefficient Pe (cm / s) and calculated according to Fick's law.

[0047] The results are shown in Figure 1. All test compounds significantly reduced the increased Na-F permeability caused by OGD / R, demonstrating their protective effect on RBECs from stress caused by OGD / R.

[0048] Example 2 Evaluation of the protective effect of BBSCB (in vitro) The protective effects of papaverine, mubritinib, brexpiprazole, and bismuth subnitrate on BBSCB were evaluated in an in vitro BBSCB co-culture model using RBECs, rat brain-derived astrocytes, and rat brain-derived pericytes, subjected to OGD / R.

[0049] Rat brain-derived astrocytes were prepared as follows. Brain cortex pieces from newborn rats were mechanically dissociated in astrocyte culture medium (DMEM containing 10% fetal bovine serum) and seeded in culture flasks. To obtain type 1 astrocytes, confluent culture flasks were shaken overnight at 37°C, and floating cells were collected and cultured. The purity of astrocytes was confirmed by immunostaining for glial fibrillary acidic protein (GFAP) and cryopreserved in CELLBANKER (Zenoaq, Koriyama, Japan). Cells from the second passage were used.

[0050] Rat brain-derived pericytes were prepared as follows: RBECs were prepared as in Example 1 and then seeded onto uncoated plastic dishes with DMEM containing 10% FBS. The medium was changed every 3 days for 2 weeks and then cryopreserved in CELLBANKER.

[0051] Next, an in vitro BBSCB co-culture model was prepared as follows. A Transwell insert for a 24-well plate was inverted upside down, and pericytes (2.0 × 10 cells) were placed in a hemispherical shape on the collagen-coated polycarbonate membrane underneath the insert. 4 cell / cm 2 ), and cultured for 3 hours to allow pericytes to adhere. Astrocytes were seeded on the bottom of the plate (1.0 × 10 5 cell / cm 2 After overnight adhesion, RBECs prepared as in Example 1 were seeded (2.0 × 10 5 cell / cm 2) (day 4). For the BBSCB co-culture model, RBEC II medium containing 500 nM hydrocortisone was used.

[0052] The cells were then cultured at 37°C for 6 hours under normoxia (20%) in DMEM / F12 containing 4.5 g / L glucose or under anoxia in glucose-free DMEM / F12. The medium was replaced with RBEC medium supplemented with the test compound, and the cells were cultured for an additional 18 hours under normoxia (Figure 2B). Control wells were used in which the medium supplemented with the test compound was replaced with the same concentration of DMSO (0.1%).

[0053] Na-F permeability, an index of paracellular transport through tight junctions (TJs), was evaluated in the same manner as in Example 1. The results are shown in Figure 3. All test compounds significantly reduced the Na-F permeability increased by OGD / R. This indicates that these compounds have a protective effect on BBSCB tight junction function.

[0054] Example 3 Evaluation of the protective effect of BBSCB (in vivo, partial spinal cord transection model) C57BL / 6 mice (male, 8-13 weeks old, n = 5 / group) were intraperitoneally administered 200 μL of test compound or vehicle dissolved in saline or DMSO. The doses were papaverine 20 mg / kg body weight, mubritinib 1 mg / kg body weight, brexpiprazole 1 mg / kg body weight, and bismuth subnitrate 500 mg / kg body weight. The day after administration, mice were anesthetized and fixed in a stereotaxic frame. The dorsal columns of the spinal cord were partially transected with a wire knife at the level of the fourth cervical cord (C4). The same amount of test compound was then intraperitoneally administered. The day after partial spinal cord transection, the right heart of the mice was opened under anesthesia, and blood was exsanguinated. PBS solution was then irrigated into the left heart, and the mice were then transfused with 4% paraformaldehyde-supplemented PBS for transcardial fixation. After perfusion fixation, a 3 mm length of spinal cord was excised centered on the injury site.

[0055] The excised spinal cords were cut into 30 μm-thick sagittal sections using a microtome (REM-710, Yamato, Japan), and six sections were used for each staining. After blocking for 1 hour with Tris-buffered saline (TBS; pH 8.4) containing 5% normal horse serum (Thermo Fisher Scientific, Waltham, MA) and 0.25% Triton X-100 (Sigma-Aldrich, St. Louis, MO), staining was performed overnight at 4°C using an antibody (Alexa 488-conjugated donkey secondary antibody (1:1000, Jackson immunoresearch, West 14 Grove, PA)) in TBS. The sections were mounted on glass slides (Platinum Pro, Matsunami Glass Ind., Japan) and dried. Then, the sections were covered with Mowiol (Sigma-Aldrich, MO, USA) and covered with a cover glass (NEO cover glass, Matsunami Glass Ind., Japan) for observation. Histological evaluation was performed using a single sagittal section from the epicenter of the injury, and the tissue was observed under a fluorescence microscope (Keyence BX-710, Osaka, Japan) at 100x magnification. The IgG staining area was evaluated by binarizing images taken with Photoshop CS3 (Adobe, CA, USA) to black and white, and then quantified using Image J (Schneider et al., 2012). Normal tissue was defined as 5 mm rostral to the injury. All quantitative evaluations were performed blinded across slides.

[0056] The results are shown in Figures 4 and 5. In each photograph, the rupture extending from the upper center downward corresponds to the partial transection site of the spinal cord, and the area stained with anti-IgG antibodies around this site corresponds to the IgG leakage area. All four tested compounds significantly inhibited IgG leakage. This indicates that these compounds have a protective effect on BBSCB function.

[0057] Example 4 Evaluation of the protective effect of BBSCB (in vivo, spinal cord crush injury model) A crush injury was induced at the fifth cervical spinal cord (C5) of anesthetized Lewis rats (female, 8-14 weeks old, n = 14-18 / group) using an IH impactor with 200 kdyn of pressure. Starting on the day of injury, 380-420 μL of the test compound or vehicle dissolved in saline or DMSO was administered intraperitoneally for 7 consecutive days. The daily doses were 20 mg / kg body weight of papaverine, 1 mg / kg body weight of mubritinib, and 1 mg / kg body weight of brexpiprazole. After 8 weeks of injury, the rats were subjected to histological evaluation of the chronic phase of spinal cord injury and evaluation of sensory function.

[0058] Histological evaluation After perfusion fixation of rats as in Example 3, a 2 cm length of spinal cord was excised from the injury site. The excised spinal cord was immersed overnight in PBS containing 30% sucrose and then cut horizontally to prepare 30 μm-thick frozen sections. The sections were washed with TBS and then blocked in blocking buffer (TBS containing 5% normal horse serum and 0.25% Triton X-100) at room temperature for 1 hour. After washing with PBS, the sections were incubated with primary antibodies overnight at 4°C. The primary antibodies used were purified anti-glial fibrillary acidic protein (GFAP) antibody (Biolegend) at a dilution of 1:1000 and anti-NeuN antibody, clone A60 (Millipore) at a dilution of 1:500 in TBS containing 5% normal horse serum and 0.25% Triton X-100. After washing with TBS, the sections were incubated with secondary antibodies at room temperature for 3 hours. The secondary antibodies used were Alexa Fluor 594 donkey anti-mouse IgG (Jackson ImmunoResearch) and Alexa Fluor 594 donkey anti-chicken IgG (Jackson ImmunoResearch), each diluted 1:500 in TBS containing 3% normal horse serum and 0.25% Triton X-100. After washing with TBS, sections were observed with a BZ-X710 (KEYENCE) microscope to obtain fluorescent images. For sections from the central spinal cord of rats, the area of ​​the lesion cavity, the area of ​​the area immunostained with GFAP antibody, and the number of cells immunostained with NeuN antibody in a line 1.5 mm rostral and caudal to the lesion epicenter were counted. GFAP is a marker for reactive astrocytes, and NeuN is a marker for neurons.

[0059] The GFAP-positive area, i.e., the reactive astrocyte area, is shown in Figure 6. Reactive astrocytes are an indicator of glial scarring, and a smaller reactive astrocyte area indicates a smaller extent of spinal cord damage. The mean reactive astrocyte area was smaller in all test compound-treated groups than in the vehicle-treated group, and papaverine and brexpiprazole in particular significantly reduced the reactive astrocyte area.

[0060] The lesion cavity area is shown in Figure 7. The lesion cavity area is an index of the degree of spinal cord injury, with the cavity area increasing with increasing injury. The mean lesion cavity area in all groups administered with the test compound was smaller than that in the vehicle-administered group, and papaverine in particular significantly reduced the lesion cavity area.

[0061] The number of NeuN-positive cells, i.e., the number of remaining neurons, is shown in Figure 8. The mean number of remaining neurons was higher in all groups administered with the test compound than in the vehicle-administered group, and papaverine and mubritinib in particular significantly increased the number of remaining neurons.

[0062] Sensory function assessment One week before spinal cord injury, rats were placed in a dark room for 10 minutes per day for acclimation. Before spinal cord injury and 8 weeks after spinal cord injury, rats were placed in the dark room for 5 minutes, after which pain stimulation was administered to each limb using a Dynamic Plantar Aesthesiometer (Ugo Basile). Stimulation was performed using a 0.5mm diameter metal filament, with an increment of 2 g / s. The latency time for the rat to feel pain and withdraw from the filament was measured three times for each limb. Pain stimulation was administered at an interval of at least 3 minutes, and the same limb was not stimulated twice consecutively.

[0063] The reaction time to stimulation for each limb is shown in Figures 9 and 10. A shorter reaction time indicates a more sensitive reaction to stimulation. Before the lesion, there was no difference in sensory function between the vehicle-administered group and the test compound-administered group (Figure 9). Eight weeks after the lesion, the reaction time of the upper limb innervated by C5 in the vehicle-administered group was shortened, indicating a hypersensitive reaction to stimulation, whereas the reaction time of the upper limb in both test compound-administered groups was significantly longer than that in the vehicle-administered group, indicating an improvement in upper limb sensory function (Figure 10).

[0064] The above results demonstrate that all test compounds suppress the increase in reactive astrocytes, tissue loss, and loss of nerve cell bodies, which are pathological conditions in the chronic stage of spinal cord injury, and also suppress the decline in sensory function.

[0065] Example 5 Evaluation of the BBSCB Protective Effect of Bismuth-Containing Compounds (in vivo, Spinal Cord Crush Injury Model) Immediately after a crush injury was created at the fifth cervical spinal cord (C5) of anesthetized Lewis rats (female, 8-14 weeks old, n=8 / group) in the same manner as in Example 4, 500 mg / kg of bismuth subnitrate dissolved in saline or vehicle (saline) was administered intraperitoneally. The rats were then housed for 8 weeks after the injury, after which histological evaluation of the chronic phase of spinal cord injury and evaluation of sensory function were performed.

[0066] Histological evaluation As in Example 4, sections from the central spinal cord of rats were analyzed for reactive astrocyte area, lesion cavity area, and the number of surviving neurons present on a line 1.5 mm craniocaudal from the lesion epicenter. Representative photographs of GFAP immunostaining, reactive astrocyte area, and lesion cavity area are shown in Figure 11, and representative photographs of NeuN immunostaining and the number of surviving neurons are shown in Figure 12. Compared with the vehicle-treated group, the bismuth subnitrate-treated group showed a significant decrease in lesion cavity area, and the number of surviving neurons increased both rostral and caudal to the lesion site.

[0067] Sensory function assessment As in Example 4, the sensory function in response to pain stimuli was evaluated for rats before spinal cord injury, and 4 and 8 weeks after spinal cord injury. The time it took for each limb to react to the stimulus is shown in Figure 13. In the bismuth subnitrate-treated group, the reaction time of the forelimbs was significantly longer than in the vehicle-treated group, confirming that sensory dysfunction was suppressed.

[0068] Gait function analysis The paw area and maximum walking speed of rats were measured before and 8 weeks after spinal cord injury using the DigiGait small animal gait analysis system (BioResearch Center Co., Ltd.) according to the manual. The bismuth subnitrate-treated group showed a significant increase in paw area on one side compared with the vehicle-treated group (Figure 14). Furthermore, while all rats before spinal cord injury could walk at a treadmill speed of 20 cm / s, only two rats in the vehicle-treated group could walk at speeds of 15 cm / s or greater, whereas six rats in the bismuth subnitrate-treated group could walk at speeds of 15 cm / s or greater (Figure 15).

[0069] These results indicate that bismuth subnitrate suppresses the tissue loss and neuronal cell body loss that are pathological conditions in the chronic stage of spinal cord injury, and also suppresses the decline in sensory and ambulatory function.

[0070] Example 6 Evaluation of the protective effect of BBSCB (in vivo, cerebral cortex injury model) Protection of BBSCB function by papaverine, mubritinib, brexpiprazole, and bismuth subnitrate in traumatic brain injury was confirmed by observing the suppression of IgG leakage from the injury site using the following method.

[0071] C57BL / 6 mice (male, 8-13 weeks old, n = 3-4 per group) were intraperitoneally administered 200 μL of the test compound or vehicle dissolved in saline or DMSO. The doses were papaverine 20 mg / kg body weight, mubritinib 1 mg / kg body weight, brexpiprazole 1 mg / kg body weight, and bismuth subnitrate 500 mg / kg body weight. The day after administration, under anesthesia, lesions were created in the left cerebral hemisphere of the mice using the wire-knife transection method. Mice were fixed in a stereotaxic frame, and a window was created in the skull 1 mm lateral to the anterior annuli with a microdrill. The wire-knife was inserted 1.0 mm lateral to the annuli and 0.5 mm deep in the left cerebral hemisphere, and the wire was extended caudally and pulled up to create the lesion. To confirm complete transection, no brain tissue remained above the pulled wire-knife. After the cerebral cortical injury, the same amount of test compound was administered intraperitoneally again on the same day. The day after the cerebral cortical injury, the right heart of the mouse was incised under anesthesia, blood was exsanguinated, and PBS solution was infused into the left heart. After that, 4% paraformaldehyde-containing PBS was perfused into the mouse for transcardial fixation, and the cerebrum was removed.

[0072] The excised brains were cut into 30 μm-thick coronal sections using a microtome (REM-710, Yamato, Japan). Six sections were used for each staining. After blocking for 1 hour in Tris-buffered saline (TBS; pH 8.4) containing 5% normal horse serum (Thermo Fisher Scientific, Waltham, MA) and 0.25% Triton X-100 (Sigma-Aldrich, St. Louis, MO), the sections were placed overnight at 4°C in TBS containing anti-IgG antibody Alexa 488-conjugated donkey secondary antibody (1:1000, Jackson immunoresearch, West 14 Grove, PA). The sections were mounted on glass slides (Platinum Pro, Matsunami Glass Ind., Japan) and dried. Then, the sections were placed on Mowiol (Sigma-Aldrich, MO, USA) with a cover glass (NEO cover glass, Matsunami Glass Ind., Japan) and examined.

[0073] The IgG staining area was assessed by binarizing images taken with Photoshop CS3 (Adobe, CA, USA) to black and white and then quantifying using Image J (Schneider et al., 2012). Normal tissue was referenced to a location 5 mm rostral to the injury. All quantitative assessments were performed blinded across slides. The area of ​​IgG leakage was corrected for injury depth.

[0074] Representative photographs of cerebral tissue sections immunostained with anti-IgG antibodies from bismuth subnitrate-administered cerebral cortex injury model mice are shown on the left side of Figure 16, and the IgG leakage areas for bismuth subnitrate, papaverine, mubritinib, and brexpiprazole are shown on the right side of Figure 16. Bismuth subnitrate and papaverine significantly inhibited IgG leakage from the site of cerebral cortical injury, indicating that these compounds have a protective effect on BBSCB function.

[0075] Example 7 Protective effect on cerebrovascular endothelial cells

[0076] Human cerebrovascular endothelial cells (hCMEC / D3, Sigma) were cultured at 5,000 cells / cm in a 96-well plate (Falcon Cell Culture 96-well multiwell plate with flat-bottom lid) coated with 0.1 mg / ml collagen type 1 (Sigma-Aldrich). 2 Cells were seeded at 1000 x g for 24 hours in Endothelial Cell Growth Medium (PromoCell, Germany) and cultured at 37°C in 5% CO2 for 24 hours. Bismuth citrate, bismuth subnitrate, bismuth tartrate, or zinc sulfate dissolved in saline and hydrogen peroxide were added to the medium at a final concentration of 450 μM, and the cells were incubated for 6 hours. Cell viability after stress was measured using PrestoBlue® Cell Viability Reagent (Life Technologies).

[0077] Figure 17 shows the cell viability, where the cell viability of the control not stressed with hydrogen peroxide is set to 1 and the cell-free control is set to 0. Bismuth subcitrate, bismuth subnitrate, and bismuth tartrate all exhibited significantly higher cytoprotective effects on hCMEC / D3 than zinc sulfate. Furthermore, the cell viability of cells stressed with hydrogen peroxide but not treated with the test compound was approximately 0.2. These results confirmed that bismuth-containing compounds have a protective effect on cerebrovascular endothelial cells, and that this effect is stronger than that of zinc, a metal known for its cytoprotective effects.

Claims

1. A vascular endothelial cell protecting agent comprising at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, mubritinib, brexpiprazole, and pharmaceutically acceptable salts thereof.

2. The agent according to claim 1, characterized in that it contains a bismuth-containing compound or a pharmaceutically acceptable salt thereof as an active ingredient.

3. The agent described in claim 2, wherein the bismuth-containing compound or a pharmaceutically acceptable salt thereof is bismuth subnitrate, bismuth subcitrate, or bismuth tartrate.

4. A blood-brain-spinal barrier protecting agent comprising at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, mubritinib, brexpiprazole, and pharmaceutically acceptable salts thereof.

5. The agent according to claim 4, characterized in that it contains a bismuth-containing compound or a pharmaceutically acceptable salt thereof as an active ingredient.

6. The agent described in claim 5, wherein the bismuth-containing compound or a pharmaceutically acceptable salt thereof is bismuth subnitrate, bismuth subcitrate, or bismuth tartrate.

7. A central neuroprotective agent containing at least one compound selected from the group consisting of a bismuth-containing compound, mubritinib, and pharmaceutically acceptable salts thereof, wherein the central neuroprotection is the suppression of central nervous system damage associated with blood-brain-spinal cord barrier dysfunction.

8. The agent described in claim 7, characterized in that it contains a bismuth-containing compound or a pharmaceutically acceptable salt thereof as an active ingredient.

9. The agent described in claim 8, wherein the bismuth-containing compound or a pharmaceutically acceptable salt thereof is bismuth subnitrate, bismuth subcitrate, or bismuth tartrate.

10. A pharmaceutical composition for preventing and / or treating a disease associated with blood-brain-spinal cord barrier damage, comprising at least one compound selected from the group consisting of a bismuth-containing compound, papaverine, mubritinib, and pharmaceutically acceptable salts thereof, wherein the disease associated with blood-brain-spinal cord barrier damage is brain injury, spinal cord injury, or compressive myelopathy.

11. The composition according to claim 10, characterized in that it contains a bismuth-containing compound or a pharmaceutically acceptable salt thereof as an active ingredient.

12. The composition of claim 11, wherein the bismuth-containing compound or a pharmaceutically acceptable salt thereof is bismuth subnitrate, bismuth subcitrate, or bismuth tartrate.

13. A pharmaceutical composition used for the prevention or treatment of a disease selected from spinal cord injury, brain injury, or compressive myelopathy, characterized in that the pharmaceutical composition contains a bismuth-containing compound or a pharmaceutically acceptable salt thereof as an active ingredient.

14. The composition of claim 13, wherein the bismuth-containing compound or a pharmaceutically acceptable salt thereof is bismuth subnitrate, bismuth subcitrate, or bismuth tartrate.

15. A composition described in claim 13 or 14, characterized in that it suppresses secondary damage by inhibiting the breakdown of the blood-brain-spinal cord barrier during the acute phase of spinal cord injury.

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