Pharmaceutical compositions for preventing or treating degenerative brain disease and method of screening the same

Abstract

A pharmaceutical composition for preventing or treating a degenerative brain disease, and a method of screening a material for preventing or treating a degenerative brain disease. The method may effectively screen a prophylactic or therapeutic candidate material for preventing or treating a degenerative brain disease. A variety of degenerative brain diseases may be effectively prevented or treated using the pharmaceutical composition including a screened material for preventing or treating a degenerative brain disease.

1 . A method of screening candidate materials for preventing or treating a degenerative brain disease, the method comprising:
 (a) contacting a target assay sample to a reactive astrocyte; and   (b) determining if the target assay sample reduces a concentration of γ-aminobutylic acid (GABA) in the reactive astrocyte or reduce release of GABA from the reactive astrocyte,   wherein the target assay sample is determined as a candidate material for diagnosing or treating a degenerative brain disease if the target assay sample is determined to reduce the concentration of GABA in the reactive astrocyte or to reduce the release of GABA from the reactive astrocyte.   
     
     
         2 . A method of screening candidate materials for preventing or treating a degenerative brain disease, the method comprising:
 (a) contacting a target assay sample to a reactive astrocyte; and   (b) measuring an expression amount of a gene encoding a monoamine oxidase B (MAO-B) in the reactive astrocyte, or an amount or activity of an MAO-B protein,   wherein the target assay sample is determined as a candidate material for diagnosing or treating a degenerative brain disease if the expression amount of the gene encoding the MAO-B, or the amount or activity of the MAO-B protein is found to be down-regulated.   
     
     
         3 . A method of screening candidate materials for preventing or treating a degenerative brain disease, the method comprising:
 (a) contacting a target assay sample to a reactive astrocyte; and   (b) determining a subcellular localization pattern of a bestrophine 1 channel in the reactive astrocyte,   wherein the target assay sample is determined as a candidate material for diagnosing or treating a degenerative brain disease if the subcellular localization pattern of the bestrophine 1 channel is determined to be changed from a cell body and a main process Into a microdomain direction.   
     
     
         4 . A method of screening candidate materials for preventing or treating a degenerative brain disease, the method comprising:
 (a) contacting a target assay sample to a reactive astrocyte; and   (b) measuring an expression amount of a gene encoding Best1 in the reactive astrocyte or an amount or activity of Best1 protein,   wherein the target assay sample is determined as a candidate material for preventing or treating the degenerative brain disease if the expression amount of the gene encoding Best 1, or the amount or activity of the Best1 protein is found to be down-regulated.   
     
     
         5 . A method of screening candidate materials for preventing or treating a degenerative brain disease, the method comprising:
 (a) contacting a target assay sample to a reactive astrocyte; and   (b) measuring an expression amount of a gene encoding a γ-aminobutylic acid (GABA) transaminase in the reactive astrocyte, or an amount or activity of a GABA transaminase protein,   wherein the target assay sample is determined as a candidate material for preventing or treating the degenerative brain disease if the expression amount of the gene encoding the GABA transaminase, or the amount or activity of the GABA transaminase protein is found to be up-regulated.   
     
     
         6 . The method of  claim 1 , wherein the reactive astrocyte originates from a brain tissue of an animal model with brain injury, a brain tissue of a virus-infected animal, a brain tissue of a Parkinson's disease animal model, or a brain tissue of an Alzheimer's disease animal model. 
     
     
         7 . The method of  claim 6 , wherein the brain tissue is selected from the group consisting of the hippocampus, corpus striatum, substantia nigra pars compacta, and thalamic nuclei. 
     
     
         8 . The method of  claim 1 , wherein the degenerative brain disease is selected from among Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, lewy body dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS) and other viral infections, brain abscess, brain tumor, multiple sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, post-traumatic stress disorder, spinal cord injury, and myelitis. 
     
     
         9 . A pharmaceutical composition for preventing or treating a degenerative brain disease, the pharmaceutical composition comprising an effective component that is a material reducing a concentration of γ-aminobutylic acid (GABA) in a reactive astrocyte. 
     
     
         10 . A pharmaceutical composition for preventing or treating a degenerative brain disease, the pharmaceutical composition comprising an effective component that is a material suppressing an expression of a gene encoding a monoamine oxidase B (MAO-B) in a reactive astrocyte, or a material reducing an activity of an MAO-B protein. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the material reducing the activity of the MAO-B protein is a compound selected from the group consisting of a compound represented by Formula I below, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, and a combination thereof. 
       
         
           
           
               
               
           
         
         wherein, in Formula I above, R1 and R2 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a hydroxyl group, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, a substituted or unsubstituted C2-C12 alkynyl group, a substituted or unsubstituted C3-C15 cycloalkyl group, a substituted or unsubstituted C3-C40 heterocycloalkyl group, (a substituted or unsubstituted C6-C20 aryl) C1-C12 alkyl group, a substituted or unsubstituted C1-C12 alkoxy group, a substituted or unsubstituted C6-C20 arylamine group, a substituted or unsubstituted C 6 -C 30  diarylamine group, a substituted or unsubstituted C6-C20 aryloxy group, a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C5-C20 heteroaryl group; and X is —O—, —S—, or —N(H)—. 
       
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the material reducing the activity of the MAO-B protein is a compound selected from the group consisting of a compound represented by Formula I below, a pharmaceuetically acceptable salt, an isomer, a solvate, a hydrate, and a combination thereof. 
       
         
           
           
               
               
           
         
         wherein, in Formula I above, R1 and R2 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a substituted or unsubstituted C1-C12 alkyl group, or a substituted or unsubstituted C1-C12 alkoxy group; and X is —O—, or —S—. 
       
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the material reducing the activity of the MAO-B protein is
 N-cyclohexyl-2-phenyloxazolo[5,4-b]pyridine,   2-phenyl-5-(pyrrolidine-1-yl)oxazolo[5,4-b]pyridine, 2-phenyl-5-(pyrrolidine-1-yl)thiazolo[5,4-b]pyridine, 2-(2-chlorophenyl)-5-(pyrrolidine-1-yDoxazolo[5,4-b]pyridine, 2-(3-chlorophenyl)-5-(pyrrolidine-1-yl)oxazolo[5,4-b]pyridine, 2-(4-fluorophenyl)-5-(pyrrolidine-1-yl)oxazolo[5,4-b]pyridine, 2-phenyl-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 2-phenyl-5-(piperidine-1-yl)thiazolo[5,4-b]pyridine, 2-(2-chlorophenyl)-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 2-(3-fluorophenyl)-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 2-(3-chlorophenyl)-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 3-(5-(piperidine-1-yl)oxazolo[5,4-b]pyridine-2-yl)benzonitrile, 2-(4-fluorophenyl)-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 2-(4-bromophenyl)-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 2-(4-methoxyphenyl)-5-(piperidine-1-yl)oxazolo[5,4-b]pyridine, 2-(3-chlorophenyl)-N-methyloxazolo[5,4-b]pyridine-5-amine, or 2-(4-chlorophenyl)-N-methyloxazolo[5,4-b]pyridine-5-amine.   
     
     
         14 . A pharmaceutical composition for preventing or treating a degenerative brain disease, the pharmaceutical composition comprising an effective component that is a material changing a subcellular localization pattern of a bestrophine 1 channel in a reactive astrocyte from a cell body and a main process into a microdomain direction. 
     
     
         15 . A pharmaceutical composition for preventing or treating a degenerative brain disease, the pharmaceutical composition comprising an effective component that is a material inhibiting an expression of a gene encoding bestrophin1 channel in a reactive astrocyte, or a material reducing an activity of a bestrophin1 protein. 
     
     
         16 . A pharmaceutical composition for preventing or treating a degenerative brain disease, the pharmaceutical composition comprising an effective component that is a material inducing an expression of a gene encoding a γ-aminobutylic acid (GABA) transaminase in a reactive astrocyte, or a material increasing an activity of a GABA transaminase protein. 
     
     
         17 . The pharmaceutical composition of  claim 9 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         18 . The method of  claim 2 , wherein the reactive astrocyte originates from a brain tissue of an animal model with brain injury, a brain tissue of a virus-infected animal, a brain tissue of a Parkinson's disease animal model, or a brain tissue of Alzheimer's disease animal model. 
     
     
         19 . The method of  claim 3 , wherein the reactive astrocyte originates from a brain tissue of an animal model with brain injury, a brain tissue of a virus-infected animal, a brain tissue of a Parkinson's disease animal model, or a brain tissue of Alzheimer's disease animal model. 
     
     
         20 . The method of  claim 4 , wherein the reactive astrocyte originates from a brain tissue of an animal model with brain injury, a brain tissue of a virus-infected animal, a brain tissue of a Parkinson's disease animal model, or a brain tissue of Alzheimer's disease animal model. 
     
     
         21 . The method of  claim 5 , wherein the reactive astrocyte originates from a brain tissue of an animal model with brain injury, a brain tissue of a virus-infected animal, a brain tissue of a Parkinson's disease animal model, or a brain tissue of Alzheimer's disease animal model. 
     
     
         22 . The method of  claim 2 , wherein the degenerative brain disease is selected from among Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, lewy body dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS) and other viral infections, brain abscess, brain tumor, multiple sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, post-traumatic stress disorder, spinal cord injury, and myelitis. 
     
     
         23 . The method of  claim 3 , wherein the degenerative brain disease is selected from among Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, lewy body dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS) and other viral infections, brain abscess, brain tumor, multiple sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, post-traumatic stress disorder, spinal cord injury, and myelitis. 
     
     
         24 . The method of  claim 4 , wherein the degenerative brain disease is selected from among Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, lewy body dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS) and other viral infections, brain abscess, brain tumor, multiple sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, post-traumatic stress disorder, spinal cord injury, and myelitis. 
     
     
         25 . The method of  claim 5 , wherein the degenerative brain disease is selected from among Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, lewy body dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS) and other viral infections, brain abscess, brain tumor, multiple sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, post-traumatic stress disorder, spinal cord injury, and myelitis. 
     
     
         26 . The pharmaceutical composition of  claim 10 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         27 . The pharmaceutical composition of  claim 11 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         28 . The pharmaceutical composition of  claim 12 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         29 . The pharmaceutical composition of  claim 13 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         30 . The pharmaceutical composition of  claim 14 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         31 . The pharmaceutical composition of  claim 15 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis. 
     
     
         32 . The pharmaceutical composition of  claim 16 , wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, vascular dementia, frontotemporal dementia, Louis corpuscle dementia, Creutzfeld-Jakob disease, traumatic head injuries, syphilis, acquired immune deficiency syndrome (AIDS), viral infection, brain abscess, brain tumor, sclerosis, dementia in metabolic disease, hypoxia, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis (ALS), epilepsy, ischemia, stroke, attention deficit hyperactivity disorder (ADHD), schizophrenia, depression, manic-depression, stress disorder, spinal cord injury, and myelitis.