Inhibitor for TDP-43 aggregation, cell death inhibitor for TDP-43 overexpression cells, and therapeutic or prophylactic agent for diseases associated with TDP-43 aggregation

Abstract

An inhibitor of aggregation of TDP-43 comprising a combination of at least one compound selected from the group consisting of cycloserine and terizidone and their salts, and edaravone. An inhibitor of the aggregation of TDP-43, which contains at least one compound selected from the group consisting of cycloserine and terizidone, and salts thereof, in combination with edaravone. An inhibitor of aggregation of TDP-43 comprising edaravone in combination with at least one compound selected from the group consisting of cycloserine and terizidone and their salts.

Description

TECHNICAL FIELD

[0001] The present application relates to an inhibitor of aggregation of TDP-43, an inhibitor of cell death of TDP-43 overexpressing cells, and a therapeutic or prophylactic agent for a disease accompanied by aggregation of TDP-43. BACKGROUND

[0002] TDP-43 (TAR DNA-binding protein of 43 kDa) is a heterogeneous nuclear ribonucleoprotein. TDP-43 was identified as a major component protein of ubiquitin-positive inclusions that appear in degenerative nerve cells and glial cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is a nuclear localization protein, but in cells that form ubiquitin-positive inclusions, TDP-43 is transferred from the nucleus to the cytoplasm and aggregated to become insoluble, thereby accumulating in the cytoplasm.

[0003] In TDP-43 accumulated in the brain and spinal cord of ALS patients and FTLD patients, multiple serine residues at the C-terminus are abnormally phosphorylated. In ALS patients and FTLD patients, full-length molecules of TDP-43 do not need to aggregate, but a C-terminal fragment of TDP-43 aggregates. Previous studies strongly suggest that aggregation of TDP-43 causes abnormal RNA metabolism or elicits cytotoxicity, thereby causing and developing various diseases.

[0004] As an example of a disease accompanied by aggregation of TDP-43, TDP-43 proteinopathy is known. Patent Literature 1 proposes the use of N,N,N',N'-tetramethyl-10H-phenothiazine-3,7-diammonium bis(methanesulfonate) as a therapeutic or prophylactic agent for TDP-43 proteinopathy.

[0005] PRIOR ART DOCUMENTS PATENT LITERATURE Patent Literature 1: Japanese Patent No. 5898701 SUMMARY

[0006] PROBLEMS TO BE SOLVED BY THE INVENTION An object of the present application is to provide an inhibitor of aggregation of TDP-43, an inhibitor of cell death of TDP-43 overexpressing cells, and a therapeutic or prophylactic agent for a disease accompanied by aggregation of TDP-43.

[0007] TECHNICAL SOLUTION According to embodiments of the present invention, an inhibitor of TDP-43 aggregation or an inhibitor of cell death in TDP-43-overexpressing cells is provided, comprising a combination of at least one compound selected from the group consisting of cyclic serine and terizone and their salts with edaravone.

[0008] In the above-mentioned inhibitors of TDP-43 aggregation or inhibitors of cell death in TDP-43-overexpressing cells, the active ingredient may be a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0009] In this disclosure, "essentially constitutes" means that the active ingredient does not contain other ingredients, and does not exclude the presence of other ingredients such as excipients and / or lubricants.

[0010] In the above-mentioned inhibitors of TDP-43 aggregation or cell death inhibitors of TDP-43 overexpressing cells, the active ingredient may be a combination of at least one compound selected from the group consisting of cyclic serine and terizone and their salts with edaravone.

[0011] In the above-mentioned inhibitors of TDP-43 aggregation or inhibitors of cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cyclic serine and terizone and their salts may be cyclic serine or a salt of cyclic serine.

[0012] In the above-mentioned inhibitors of TDP-43 aggregation or cell death in TDP-43-overexpressing cells, cyclic serine can be D-cyclic serine. In the above-mentioned inhibitors of TDP-43 aggregation or cell death in TDP-43-overexpressing cells, cyclic serine can be L-cyclic serine.

[0013] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may contain 15 mg or more but less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0014] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may contain edaravone in amounts of 30 mg to 60 mg.

[0015] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may not contain acampolic acid.

[0016] According to embodiments of the present invention, a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone is provided for inhibiting the aggregation of TDP-43 or for inhibiting cell death in cells overexpressing TDP-43.

[0017] In the above combinations, the active ingredient may essentially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0018] In the above combinations, the active ingredient may be a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0019] In the above combinations, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0020] In the above combinations, cyclic serine can be D-cyclic serine. In the above combinations, cyclic serine can be L-cyclic serine.

[0021] The above combination may contain more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0022] The above combination may contain edaravone at a dose of 30 mg or more but less than 60 mg.

[0023] The above combination may not contain acampalic acid.

[0024] According to embodiments of the present invention, a use is provided for a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone, for the manufacture of an inhibitor of TDP-43 aggregation or an inhibitor of cell death in TDP-43-overexpressing cells.

[0025] In the above-described uses, the active ingredient of the TDP-43 aggregation inhibitor or the cell death inhibitor of TDP-43 overexpressing cells may essentially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0026] In the above-described uses, the active ingredient of the TDP-43 aggregation inhibitor or the cell death inhibitor of TDP-43 overexpressing cells may comprise a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0027] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0028] In the above uses, cyclic serine can be D-cyclic serine. In the above uses, cyclic serine can be L-cyclic serine.

[0029] In the above uses, the above combination may contain more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0030] In the above-mentioned uses, the above combination may contain edaravone at a dose of 30 mg or more and 60 mg or less.

[0031] In the above-mentioned uses, the inhibitor of TDP-43 aggregation or the inhibitor of cell death in TDP-43-overexpressing cells may not contain acampolic acid.

[0032] According to embodiments of the present invention, a method for inhibiting the aggregation of TDP-43 in a subject, or a method for inhibiting cell death in TDP-43-overexpressing cells of a subject, is provided, the method comprising administering to the subject a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0033] In the above-mentioned methods for inhibiting TDP-43 aggregation or for inhibiting cell death in TDP-43-overexpressing cells, the active ingredient for inhibiting TDP-43 aggregation may essentially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0034] In the above-mentioned method for inhibiting TDP-43 aggregation or for inhibiting cell death in TDP-43-overexpressing cells, the active ingredient for inhibiting TDP-43 aggregation may be a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0035] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0036] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, cyclic serine can be D-cyclic serine. In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, cyclic serine can be L-cyclic serine.

[0037] In the above-mentioned method for inhibiting TDP-43 aggregation or for inhibiting cell death in TDP-43-overexpressing cells, the dosage of at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 15 mg and less than 250 mg per administration.

[0038] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, the dosage of edaravone administered each time can be more than 30 mg and less than 60 mg.

[0039] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, acampolic acid may not be administered to the subject.

[0040] According to embodiments of the present invention, an inhibitor of TDP-43 aggregation or an inhibitor of cell death in TDP-43-overexpressing cells is provided, comprising at least one compound selected from the group consisting of cyclic serine and terizone and their salts, used in combination with edaravone.

[0041] Among the above-mentioned inhibitors of TDP-43 aggregation or inhibitors of cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cyclic serine and terizone and their salts may be used without being combined with any active ingredient other than edaravone.

[0042] In the above-mentioned inhibitors of TDP-43 aggregation or inhibitors of cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cyclic serine and terizone and their salts may be cyclic serine or a salt of cyclic serine.

[0043] In the above-mentioned inhibitors of TDP-43 aggregation or cell death in TDP-43-overexpressing cells, cyclic serine can be D-cyclic serine. In the above-mentioned inhibitors of TDP-43 aggregation or cell death in TDP-43-overexpressing cells, cyclic serine can be L-cyclic serine.

[0044] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may contain 15 mg or more but less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0045] Among the above-mentioned inhibitors of TDP-43 aggregation or inhibitors of cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cyclic serine and terizone and their salts may be used in combination with edaravone at a dose of 30 mg or more and 60 mg or less.

[0046] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may not contain acampolic acid.

[0047] According to embodiments of the present invention, at least one compound selected from the group consisting of cyclic serine and terizone and their salts is provided for use in conjunction with edaravone, for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43 overexpressing cells.

[0048] At least one compound selected from the group consisting of cycloserine and terizone and their salts may not be used in combination with any active ingredient other than edaravone.

[0049] At least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0050] In at least one compound selected from the group consisting of cycloserine and terizone and their salts, cycloserine may be D-cycloserine. In at least one compound selected from the group consisting of cycloserine and terizone and their salts, cycloserine may be L-cycloserine.

[0051] The mass of at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 15 mg and less than 250 mg.

[0052] The mass of edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 30 mg and less than 60 mg.

[0053] The above-mentioned edaravone can be used without acamprine.

[0054] According to an embodiment of the present invention, there is provided the use of at least one compound selected from the group consisting of cyclic serine and terizone and their salts, in combination with edaravone, for the manufacture of an inhibitor of TDP-43 aggregation or an inhibitor of cell death in TDP-43-overexpressing cells.

[0055] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with an active ingredient other than edaravone.

[0056] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0057] In the above uses, cyclic serine can be D-cyclic serine. In the above uses, cyclic serine can be L-cyclic serine.

[0058] In the above-described uses, the mass of at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 15 mg and less than 250 mg.

[0059] In the above-described uses, the mass of edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 30 mg and less than 60 mg.

[0060] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with acampalic acid.

[0061] According to embodiments of the present invention, a method for inhibiting the aggregation of TDP-43 in a subject, or a method for inhibiting cell death in TDP-43-overexpressing cells of a subject, is provided, comprising administering to the subject in combination with edaravone at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0062] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with an active ingredient other than edaravone.

[0063] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0064] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, cyclic serine can be D-cyclic serine. In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, cyclic serine can be L-cyclic serine.

[0065] In the above-mentioned method for inhibiting TDP-43 aggregation or for inhibiting cell death in TDP-43-overexpressing cells, the dosage of at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 15 mg and less than 250 mg per administration.

[0066] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used in combination with edaravone at a dose of 30 mg or more and 60 mg or less.

[0067] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, acampolic acid may not be administered to the subject.

[0068] According to embodiments of the present invention, an inhibitor of TDP-43 aggregation or an inhibitor of cell death in TDP-43-overexpressing cells is provided, comprising edaravone in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0069] In the above-mentioned inhibitors of TDP-43 aggregation or cell death of TDP-43-overexpressing cells, edaravone may be used without being combined with any active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0070] In the above-mentioned inhibitors of TDP-43 aggregation or inhibitors of cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cyclic serine and terizone and their salts may be cyclic serine or a salt of cyclic serine.

[0071] In the above-mentioned inhibitors of TDP-43 aggregation or cell death in TDP-43-overexpressing cells, cyclic serine can be D-cyclic serine. In the above-mentioned inhibitors of TDP-43 aggregation or cell death in TDP-43-overexpressing cells, cyclic serine can be L-cyclic serine.

[0072] Among the above-mentioned inhibitors of TDP-43 aggregation or cell death inhibitors of TDP-43-overexpressing cells, edaravone may be used in combination with at least one compound selected from the group consisting of cyclic serine and terizone and their salts, at a dose of 15 mg or more and less than 250 mg.

[0073] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may contain edaravone in amounts of 30 mg to 60 mg.

[0074] The above-mentioned inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells, may not contain acampolic acid.

[0075] According to embodiments of the present invention, edaravone is provided for use in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts, for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43 overexpressing cells.

[0076] The above-mentioned edaravone may not be used in combination with any active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0077] The compound used in combination with edaravone, selected from the group consisting of cyclic serine and terizone and their salts, may be cyclic serine or a salt of cyclic serine.

[0078] The cyclic serine used in combination with edaravone mentioned above can be D-cyclic serine. The cyclic serine used in combination with edaravone mentioned above can be L-cyclic serine.

[0079] The above-mentioned edaravone can be used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts, at doses of 15 mg or more and less than 250 mg.

[0080] The above-mentioned edaravone dosage can be above 30 mg and below 60 mg.

[0081] The above-mentioned compound selected from the group consisting of cycloserine and terizone and their salts and used in combination with edaravone may be used without being combined with acanonical acid.

[0082] According to embodiments of the invention, the use of edaravone in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts is provided for the production of an inhibitor of TDP-43 aggregation or an inhibitor of cell death in TDP-43-overexpressing cells.

[0083] In the above uses, edaravone may be used without being combined with any active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0084] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0085] In the above uses, cyclic serine can be D-cyclic serine. In the above uses, cyclic serine can be L-cyclic serine.

[0086] In the above-mentioned uses, the mass of at least one compound selected from the group consisting of cycloserine and terizone and their salts used in conjunction with edaravone may be more than 15 mg and less than 250 mg.

[0087] In the above-mentioned uses, the mass of edaravone can be more than 30 mg and less than 60 mg.

[0088] In the above applications, edaravone can be used without acamprine.

[0089] According to embodiments of the present invention, a method for inhibiting the aggregation of TDP-43 in a subject, or a method for inhibiting cell death in TDP-43-overexpressing cells of a subject, is provided, the method comprising administering edaravone to the subject in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0090] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, edaravone may be used without being combined with an active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0091] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0092] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, cyclic serine can be D-cyclic serine. In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, cyclic serine can be L-cyclic serine.

[0093] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, the dosage of at least one compound selected from the group consisting of cycloserine and terizine and their salts, used in combination with edaravone, may be more than 15 mg and less than 250 mg per administration.

[0094] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, the dosage of edaravone administered each time can be more than 30 mg and less than 60 mg.

[0095] In the above-mentioned methods for inhibiting TDP-43 aggregation or inhibiting cell death in TDP-43-overexpressing cells, acampolic acid may not be administered to the subject.

[0096] According to an embodiment of the present invention, a therapeutic or preventive agent for a disease accompanied by TDP-43 accumulation is provided, comprising a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0097] In the above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 aggregation, the active ingredient may substantially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0098] In the above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation, the active ingredient may be composed of at least one compound selected from the group consisting of cycloserine and terizine and their salts, combined with edaravone.

[0099] In the above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0100] In the aforementioned therapeutic or preventative agents for diseases associated with TDP-43 aggregation, cyclic serine may be D-cyclic serine. In the aforementioned therapeutic or preventative agents for diseases associated with TDP-43 aggregation, cyclic serine may be L-cyclic serine.

[0101] Among the aforementioned therapeutics or preventative agents for diseases associated with TDP-43 aggregation, the disease associated with TDP-43 aggregation can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0102] The above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation may contain more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizine and their salts.

[0103] The above-mentioned treatments or preventative agents for diseases accompanied by TDP-43 accumulation may contain edaravone at a dose of 30 mg or more but less than 60 mg.

[0104] Therapeutic or preventative agents for the aforementioned diseases associated with TDP-43 accumulation may not contain acampolic acid.

[0105] According to embodiments of the present invention, a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone is provided for the treatment or prevention of diseases associated with the accumulation of TDP-43.

[0106] In the above combinations, the active ingredient may essentially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0107] In the above combinations, the active ingredient may be a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0108] In the above combinations, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0109] In the above combinations, cyclic serine can be D-cyclic serine. In the above combinations, cyclic serine can be L-cyclic serine.

[0110] In the above combination, the disease associated with the aggregation of TDP-43 can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0111] The above combination may contain more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0112] The above combination may contain edaravone at a dose of 30 mg or more but less than 60 mg.

[0113] The above combination may not contain acampalic acid.

[0114] According to embodiments of the invention, there is use of at least one compound selected from the group consisting of cycloserine and terizone and their salts in combination with edaravone for the manufacture of a therapeutic or preventative agent for a disease associated with the aggregation of TDP-43.

[0115] In the above-described uses, the active ingredient of a therapeutic or preventative agent for a disease associated with TDP-43 aggregation may essentially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0116] In the above-described uses, the active ingredient of a therapeutic or preventative agent for a disease associated with TDP-43 aggregation may be a combination of at least one compound selected from the group consisting of cycloserine and terizine and their salts with edaravone.

[0117] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0118] In the above uses, cyclic serine can be D-cyclic serine. In the above uses, cyclic serine can be L-cyclic serine.

[0119] In the above-described uses, the disease associated with the aggregation of TDP-43 can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0120] In the above uses, the above combination may contain more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0121] In the above-mentioned uses, the above combination may contain edaravone at a dose of 30 mg or more and 60 mg or less.

[0122] In the above applications, the combination may not contain acampanol.

[0123] According to an embodiment of the present invention, a method for treating or preventing a disease associated with the accumulation of TDP-43 in a subject is provided, comprising administering to the subject a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0124] In the above-mentioned treatment or prevention methods for diseases accompanied by TDP-43 aggregation, the active ingredient for inhibiting TDP-43 aggregation may essentially consist of a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0125] In the above-mentioned treatment or prevention methods for diseases accompanied by TDP-43 aggregation, the active ingredient for inhibiting TDP-43 aggregation may be a combination of at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

[0126] In the above-mentioned treatment or prevention methods for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0127] In the above-mentioned treatments or preventions of diseases accompanied by TDP-43 accumulation, cyclic serine may be D-cyclic serine. In the above-mentioned treatments or preventions of diseases accompanied by TDP-43 accumulation, cyclic serine may be L-cyclic serine.

[0128] In the above-mentioned treatments or prevention methods for diseases accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0129] In the above-mentioned treatment or prevention of diseases accompanied by TDP-43 accumulation, the dosage of at least one compound selected from the group consisting of cycloserine and terizine and their salts may be more than 15 mg and less than 250 mg per administration.

[0130] In the treatment or prevention of the above-mentioned diseases accompanied by TDP-43 accumulation, the dosage of edaravone may be more than 30 mg and less than 60 mg per administration.

[0131] In the treatment or prevention of the above-mentioned diseases accompanied by TDP-43 accumulation, acampolic acid may not be administered to the subject.

[0132] According to embodiments of the present invention, a therapeutic or preventive agent for a disease associated with the accumulation of TDP-43 is provided, comprising at least one compound selected from the group consisting of cycloserine and terizine and their salts, used in combination with edaravone.

[0133] In the above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may not be used in combination with an active ingredient other than edaravone.

[0134] In the above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0135] In the aforementioned therapeutic or preventative agents for diseases associated with TDP-43 aggregation, cyclic serine may be D-cyclic serine. In the aforementioned therapeutic or preventative agents for diseases associated with TDP-43 aggregation, cyclic serine may be L-cyclic serine.

[0136] Among the aforementioned therapeutics or preventative agents for diseases associated with TDP-43 aggregation, the disease associated with TDP-43 aggregation can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0137] The above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation may contain more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizine and their salts.

[0138] In the treatment or preventative agents for the aforementioned diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used in combination with edaravone at a dose of 30 mg or more and 60 mg or less.

[0139] Therapeutic or preventative agents for the aforementioned diseases associated with TDP-43 accumulation may not contain acampolic acid.

[0140] According to embodiments of the present invention, at least one compound selected from the group consisting of cycloserine and terizone and their salts is provided for use in conjunction with edaravone for the treatment or prevention of diseases associated with the accumulation of TDP-43.

[0141] At least one compound selected from the group consisting of cycloserine and terizone and their salts may not be used in combination with any active ingredient other than edaravone.

[0142] At least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0143] In at least one compound selected from the group consisting of cycloserine and terizone and their salts, cycloserine may be D-cycloserine. In at least one compound selected from the group consisting of cycloserine and terizone and their salts, cycloserine may be L-cycloserine.

[0144] Among the compounds selected from the group consisting of cycloserine and terizone and their salts, diseases associated with the aggregation of TDP-43 can be TDP-43 protein disorders. TDP-43 protein disorders can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. TDP-43 protein disorders can be amyotrophic lateral sclerosis (ALS).

[0145] The mass of at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 15 mg and less than 250 mg.

[0146] The mass of edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 30 mg and less than 60 mg.

[0147] At least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with acanonical acid.

[0148] According to an embodiment of the invention, there is a use in conjunction with edaravone of at least one compound selected from the group consisting of cycloserine and terizone and their salts, for the manufacture of a therapeutic or preventative agent for a disease associated with the aggregation of TDP-43.

[0149] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with an active ingredient other than edaravone.

[0150] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0151] In the above uses, cyclic serine can be D-cyclic serine. In the above uses, cyclic serine can be L-cyclic serine.

[0152] In the above-described uses, the disease associated with the aggregation of TDP-43 can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0153] In the above-described uses, the mass of at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 15 mg and less than 250 mg.

[0154] In the above-described uses, the mass of edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts may be more than 30 mg and less than 60 mg.

[0155] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with acampalic acid.

[0156] According to an embodiment of the present invention, a method for treating or preventing a disease associated with the accumulation of TDP-43 in a subject is provided, comprising administering to the subject, in combination with edaravone, at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0157] In the treatment or prevention of the above-mentioned diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used without being combined with an active ingredient other than edaravone.

[0158] In the above-mentioned treatment or prevention methods for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0159] In the above-mentioned treatments or preventions of diseases accompanied by TDP-43 accumulation, cyclic serine may be D-cyclic serine. In the above-mentioned treatments or preventions of diseases accompanied by TDP-43 accumulation, cyclic serine may be L-cyclic serine.

[0160] In the above-mentioned treatments or prevention methods for diseases accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0161] In the above-mentioned treatment or prevention of diseases accompanied by TDP-43 accumulation, the dosage of at least one compound selected from the group consisting of cycloserine and terizine and their salts may be more than 15 mg and less than 250 mg per administration.

[0162] In the treatment or prevention of the above-mentioned diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be used in combination with edaravone at a dose of more than 30 mg and less than 60 mg.

[0163] In the treatment or prevention of the above-mentioned diseases accompanied by TDP-43 accumulation, acampolic acid may not be administered to the subject.

[0164] According to embodiments of the present invention, a therapeutic or preventative agent for a disease associated with the accumulation of TDP-43 is provided, comprising edaravone in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0165] In the treatment or preventative agents for the aforementioned diseases accompanied by TDP-43 accumulation, edaravone may be used without being combined with an active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0166] In the above-mentioned therapeutic or preventive agents for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0167] In the aforementioned therapeutic or preventative agents for diseases associated with TDP-43 aggregation, cyclic serine may be D-cyclic serine. In the aforementioned therapeutic or preventative agents for diseases associated with TDP-43 aggregation, cyclic serine may be L-cyclic serine.

[0168] Among the aforementioned therapeutics or preventative agents for diseases associated with TDP-43 aggregation, the disease associated with TDP-43 aggregation can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0169] In the treatment or preventative agents for the aforementioned diseases associated with TDP-43 accumulation, edaravone may be used in combination with at least one compound selected from the group consisting of cycloserine and terizine and their salts, at a dose of 15 mg or more but less than 250 mg.

[0170] The above-mentioned treatments or preventative agents for diseases accompanied by TDP-43 accumulation may contain edaravone at a dose of 30 mg or more but less than 60 mg.

[0171] Therapeutic or preventative agents for the aforementioned diseases associated with TDP-43 accumulation may not contain acampolic acid.

[0172] According to embodiments of the present invention, edaravone is provided for use in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts, for the treatment or prevention of diseases associated with the accumulation of TDP-43.

[0173] The above-mentioned edaravone may not be used in combination with any active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0174] The compound used in combination with edaravone, selected from the group consisting of cyclic serine and terizone and their salts, may be cyclic serine or a salt of cyclic serine.

[0175] The cyclic serine used in combination with edaravone mentioned above can be D-cyclic serine. The cyclic serine used in combination with edaravone mentioned above can be L-cyclic serine.

[0176] Among the aforementioned edaravone, diseases associated with TDP-43 aggregation can be TDP-43 protein disorders. TDP-43 protein disorders can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. TDP-43 protein disorders can be amyotrophic lateral sclerosis (ALS).

[0177] The above-mentioned edaravone can be used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts, at doses of 15 mg or more and less than 250 mg.

[0178] The above-mentioned edaravone dosage can be between 30 mg and 60 mg.

[0179] The above-mentioned edaravone can be used without acamprine.

[0180] According to embodiments of the present invention, there is a use for edaravone in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts, for the manufacture of a therapeutic or preventative agent for a disease associated with the aggregation of TDP-43.

[0181] In the above uses, edaravone may be used without being combined with any active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0182] In the above-described uses, at least one compound selected from the group consisting of cycloserine and terizone and their salts can be cycloserine or a salt of cycloserine.

[0183] In the above uses, cyclic serine can be D-cyclic serine. In the above uses, cyclic serine can be L-cyclic serine.

[0184] In the above-described uses, the disease associated with the aggregation of TDP-43 can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0185] In the above-mentioned uses, the mass of at least one compound selected from the group consisting of cycloserine and terizone and their salts used in conjunction with edaravone may be more than 15 mg and less than 250 mg.

[0186] In the above-mentioned uses, the mass of edaravone can be more than 30 mg and less than 60 mg.

[0187] In the above applications, edaravone can be used without acamprine.

[0188] According to an embodiment of the present invention, a method for treating or preventing a disease associated with the accumulation of TDP-43 in a subject is provided, comprising administering edaravone to the subject in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0189] In the treatment or prevention of diseases associated with TDP-43 accumulation, edaravone may be used without being combined with any active ingredient other than at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0190] In the above-mentioned treatment or prevention methods for diseases accompanied by TDP-43 accumulation, at least one compound selected from the group consisting of cycloserine and terizone and their salts may be cycloserine or a salt of cycloserine.

[0191] In the above-mentioned treatments or preventions of diseases accompanied by TDP-43 accumulation, cyclic serine may be D-cyclic serine. In the above-mentioned treatments or preventions of diseases accompanied by TDP-43 accumulation, cyclic serine may be L-cyclic serine.

[0192] In the above-mentioned treatments or prevention methods for diseases accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation can be a TDP-43 protein disease. A TDP-43 protein disease can be at least one disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy. A TDP-43 protein disease can be amyotrophic lateral sclerosis (ALS).

[0193] In the treatment or prevention of diseases accompanied by TDP-43 accumulation described above, the dosage of at least one compound selected from the group consisting of cycloserine and terizine and their salts, used in combination with edaravone, may be more than 15 mg and less than 250 mg per administration.

[0194] In the treatment or prevention of diseases accompanied by TDP-43 accumulation, the dosage of edaravone may be more than 30 mg and less than 60 mg per administration.

[0195] In the treatment or prevention of the above-mentioned diseases accompanied by TDP-43 accumulation, acampolic acid may not be administered to the subject.

[0196] Technical effect According to the present invention, it is possible to provide an inhibitor of TDP-43 aggregation, an inhibitor of cell death in TDP-43-overexpressing cells, and a therapeutic or preventive agent for diseases associated with TDP-43 aggregation. Attached Figure Description

[0197] Figure 1 The photograph shows the soluble fraction and the insoluble fraction of TDP-43 involved in Reference Example 1.

[0198] Figure 2 This is a graph showing the relationship between the time elapsed since the transfection of the TDP-43 gene involved in Reference Example 1 and the proportion of insoluble fractions of TDP-43 in the cells.

[0199] Figure 3 It is a photograph of the cells involved in Example 2.

[0200] Figure 4 This is a graph showing the relationship between the concentration of the compound involved in Reference Example 2 and the relative survival rate of cells.

[0201] Figure 5 The photograph shows the soluble fraction and the insoluble fraction of TDP-43 involved in Reference Example 3.

[0202] Figure 6 This is a graph showing the relationship between the proportion of the compound involved in Reference Example 3 and the insoluble fraction of TDP-43 in the cells.

[0203] Figure 7 The photograph shows the soluble fraction and the insoluble fraction of TDP-43 involved in Reference Example 4.

[0204] Figure 8 This is a graph showing the proportions of the insoluble fractions of TDP-43 involved in Reference Example 4.

[0205] Figure 9 This is a graph showing the relationship between the concentration of the compound involved in Example 1 and the relative survival rate of cells.

[0206] Figure 10 This is an EC2 assay demonstrating the cell death inhibitory effect of D-cyclic serine at various concentrations of edaravone involved in Example 1. 50 The chart.

[0207] Figure 11 This is an EC2 assay demonstrating the cell death inhibitory effect of D-cyclic serine at various concentrations of edaravone involved in Example 1. 50 A table showing the values ​​of the combined index. Detailed Implementation

[0208] The following describes embodiments of the present invention. However, these embodiments should not be construed as limiting the present invention. Various alternative embodiments, examples, and techniques will be apparent to those skilled in the art based on this disclosure. It should be understood that the present invention includes various embodiments not described herein.

[0209] The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 (TAR DNA-binding protein of 43kDa), the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments comprise a combination of at least one compound selected from the group consisting of cyclic serine and its physiologically permissible salts with edaravone.

[0210] Additionally, the therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments comprise at least one compound selected from the group consisting of cycloserine and its physiologically permissible salts, used in combination with edaravone.

[0211] Additionally, the therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments comprise edaravone in combination with at least one compound selected from the group consisting of cycloserine and its physiologically permissible salts.

[0212] Examples of diseases associated with TDP-43 accumulation include TDP-43 protein disorders, neurodegenerative diseases, and muscle diseases.

[0213] Examples of TDP-43 protein disorders include amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTLD), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA). Frontotemporal degeneration (FTLD) can be frontotemporal degeneration with TDP-43 accumulation (FTLD-TDP).

[0214] Examples of neurodegenerative diseases include Lewy body dementia (DLB), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Guamian amyotrophic lateral sclerosis-Parkinsonism dementia complex, hippocampal sclerosis, Pick's disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, argyrophilic grain disease (AGD), chronic traumatic encephalopathy (boxing dementia, CTE), multiple system atrophy (MSA), and limbic-predominant age-related TDP-43 encephalopathy.

[0215] Examples of muscle diseases include Paget's disease of bone, inclusion body myopathy with frontotemporal dementia (FTD), diffuse IBM (IBM), myofibril myopathy, oculopharyngeal muscular dystrophy, and distal myopathy with rimmed vacuolar lesions.

[0216] Cyclic serine can be either D-cyclic serine or L-cyclic serine.

[0217] The IUPAC name of D-cycloserine (CAS number: 68-41-7) is (4R)-4-Amino-1,2-oxazolidin-3-one. The chemical formula of D-cycloserine is C3H6N2O2. The chemical structural formula of D-cycloserine is as follows.

[0218] [Chemical Formula 1]

[0219] L-Cycloserine (CAS No.: 339-72-0) has the IUPAC name (4S)-4-amino-1,2-oxazolidin-3-one. The chemical formula of L-Cycloserine is C3H6N2O2. The chemical structural formula of L-Cycloserine is as follows.

[0220] [Chemical Formula 2]

[0221] The IUPAC name of edaravone (CAS No.: 89-25-8) is 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one. The chemical formula of edaravone is C2. 10 H 10 N2O. The chemical structural formula of edaravone is as follows.

[0222] [Chemical Formula 3]

[0223] The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments may contain a prodrug of at least one of the above compounds or a physiologically permissible salt thereof.

[0224] For example, terizone is known as a prodrug of D-cycloserine. Terizone (CAS No.: 25683-71-0) has the IUPAC name 4,4'-{1,4-phenylenebis[(E)methylene(E)azanylylidene]}bis(1,2-oxazolidin-3-one)). The chemical formula of terizone is C1. 14 H 14N4O4. The chemical structure of terizone is shown below. Terizone is broken down in vivo and exerts the same effect as D-cycloserine.

[0225] [Chemical Formula 4]

[0226] The therapeutic or preventative agents for diseases associated with TDP-43 aggregation, inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells involved in the embodiments can be prepared into pharmaceutically permissible dosage forms. For example, the therapeutic or preventative agents for diseases associated with TDP-43 aggregation, inhibitors of TDP-43 aggregation, or inhibitors of cell death in TDP-43-overexpressing cells can be prepared as injections, solutions, suspensions, tablets, capsules, pills, granules, syrups, suppositories, inhalers, and sprays. Injectables include, for example, solutions for injection, sterile powders for injection, and concentrated solutions for injection.

[0227] It has been reported that the maximum plasma concentration (Cmax) of D-cycloserine in humans after oral administration of 15 mg is approximately 5.6 μmol / L (van Berckel, B., Lipsch, C., Timp, S. et al. Behavioraland Neuroendocrine Effects of the Partial NMDA Agonist D-cycloserine in Healthy Subjects. Neuropsychopharmacol 16, 317-324 (1997). https: / / doi.org / 10.1016 / S0893-133X(96)00196-0, and van Berckel, B. Erratum: Behavioral and Neuroendocrine Effects of the Partial NMDA Agonist D-cycloserine in Healthy Subjects. Neuropsychopharmacol 17, 116 (1997). https: / / doi.org / 10.1016 / S0893-133X(97)00082-1).

[0228] It has been reported that D-cycloserine has a brain transport rate of 95%. Therefore, the maximum concentration of D-cycloserine in the brain is estimated to be approximately 5.3 μmol / L. This concentration of approximately 5.3 μmol / L is higher than the EC50 of D-cycloserine shown in Reference Example 2 (described later), which inhibits cell death in neurons that force TDP-43 expression.50 That is, 128 nmol / L. Furthermore, it has been reported that the half-life of D-cycloserine is approximately 10 hours. Therefore, it is speculated that the trough value of a twice-daily oral administration of 15 mg of D-cycloserine would also be higher than the EC50. 50 That is, 128 nmol / L. Therefore, the therapeutic or preventive agent for diseases accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments, by comprising more than 15 mg of at least one compound selected from the group consisting of cycloserine and terizine and their salts, can fully exert the therapeutic or preventive effect on diseases accompanied by TDP-43 aggregation, such as amyotrophic lateral sclerosis in humans.

[0229] Furthermore, it has been reported that when D-cycloserine is used to treat tuberculosis, administration of 250 mg to humans can cause serious side effects such as epileptic seizures and mental confusion. Therefore, the therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments, by comprising less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizine and their salts, is capable of suppressing the side effects caused by at least one compound selected from the group consisting of cycloserine and terizine and their salts.

[0230] It should be noted that, according to reports, administering 150 mg of D-cycloserine to humans can cause headaches. However, because diseases such as amyotrophic lateral sclerosis (ALS) associated with TDP-43 accumulation are extremely serious, even though headaches are a side effect, these diseases should be prioritized for treatment.

[0231] The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments may contain, for example, more than 17 mg, more than 20 mg, or more than 25 mg of at least one compound selected from the group consisting of cycloserine and terizine and their salts.

[0232] The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments may contain, for example, less than 249.9 mg, less than 249 mg, less than 240 mg, less than 230 mg, less than 220 mg, less than 210 mg, less than 200 mg, less than 190 mg, less than 180 mg, less than 170 mg, less than 160 mg, less than 150 mg, less than 100 mg, less than 80 mg, or less than 60 mg of at least one compound selected from the group consisting of cycloserine and terizone and their salts.

[0233] The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments are administered by comprising at least 15 mg and less than 250 mg of at least one compound selected from the group consisting of cycloserine and terizine and their salts, wherein the at least one compound selected from the group consisting of cycloserine and its salts has an agonist-like effect on NMDA receptors.

[0234] The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments comprises, for example, edaravone at a dose of 30 mg or more and 60 mg or less. By comprising edaravone at a dose of 30 mg or more and 60 mg or less, the therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments can exert the efficacy of edaravone while suppressing its side effects. Examples of side effects of edaravone include liver dysfunction and rash. The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments may comprise, for example, edaravone at a dose of 32 mg or more, 34 mg or more, or 36 mg or more. The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments may contain, for example, less than 58 mg, less than 56 mg, or less than 54 mg of edaravone.

[0235] The therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments may comprise a mixture of at least one compound selected from the group consisting of cycloserine and its physiologically permissible salts, and edaravone. At least one compound selected from the group consisting of cycloserine and its physiologically permissible salts may be prepared together with edaravone. Alternatively, in the therapeutic or preventative agent for diseases associated with TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the cell death inhibitor of TDP-43-overexpressing cells involved in the embodiments, at least one compound selected from the group consisting of cycloserine and its physiologically permissible salts and edaravone may also be prepared separately.

[0236] At least one compound selected from the group consisting of cycloserine and its physiologically permissible salts may be used in combination therapy with edaravone. At least one compound selected from the group consisting of cycloserine and its physiologically permissible salts may be administered to the subject simultaneously or at different times. The subject may be given at least one compound selected from the group consisting of cycloserine and its physiologically permissible salts first, followed by edaravone several minutes, hours, or days later. Alternatively, the subject may be given edaravone first, followed by at least one compound selected from the group consisting of cycloserine and its physiologically permissible salts several minutes, hours, or days later.

[0237] As stated above, it is strongly evident that TDP-43 accumulation leads to abnormal RNA metabolism or cytotoxicity, thereby causing and developing various diseases. The therapeutic or preventative agents for diseases associated with TDP-43 accumulation according to the embodiments can treat or prevent these diseases by inhibiting TDP-43 accumulation. Alternatively, the therapeutic or preventative agents for diseases associated with TDP-43 accumulation according to the embodiments can treat or prevent these diseases by inhibiting cell death in TDP-43-overexpressing cells.

[0238] The therapeutic or preventative agents for diseases associated with TDP-43 aggregation, inhibitors of TDP-43 aggregation, or cell death inhibitors of TDP-43-overexpressing cells involved in the embodiments may not contain acamprosate. Acamprosate is a derivative of homotaurine, also known as 3-(acetamido)propanesulfonic acid or N-acetylglucosauric acid. When acamprosate is administered to humans, as a side effect, allergic reactions such as systemic rash, eruption, urticaria, stomatitis, laryngospasm, and shortness of breath may occur. Additionally, as a side effect, when acamprosate is administered to humans, angioedema with symptoms such as tongue swelling and lymphadenopathy may occur. Since the therapeutic or preventative agents for diseases associated with TDP-43 aggregation, inhibitors of TDP-43 aggregation, or cell death inhibitors of TDP-43-overexpressing cells involved in the embodiments do not require combination with acamprosate, these side effects are avoided.

[0239] The invention has been described above by way of embodiments, but the description and drawings that form a part of this disclosure should not be construed as limiting the invention. Various alternative embodiments, examples, and techniques will be apparent to those skilled in the art based on this disclosure. It should be understood that the invention includes various embodiments not described herein.

[0240] (See Example 1 for reference) Mouse neuroblastoma (Neuro2a) cells were seeded into culture dishes. Neuro2a cells were cultured in DMEM + 10% FBS medium at 37°C in the presence of 5% CO2 to induce differentiation into neurons from day 1 after seeding. Neuronal differentiation was further induced using DMEM + 2% FBS + 20 μmol / L retinoic acid medium. On day 4 after seeding, TDP-43 mRNA was transfected into the cells via lipid transfection. Cell samples were taken at 6, 9, 12, 15, 18, and 21 hours after transfection. Cell death was observed 21 hours after transfection. For sampling, cells were lysed with RIPA lysis buffer, centrifuged at 22000×g for 30 minutes at 4°C, and the supernatant was used as the soluble fraction, while the precipitate was used as the insoluble fraction. Equal volumes of 2×SDS sample buffer were added to each fraction, and the fractions were heated at 95°C for 5 minutes to obtain electrophoresis samples. After electrophoresis of each sample using polyacrylamide gel electrophoresis, TDP-43 was transferred to a PVDF membrane. Anti-TDP-43 antibody was used as the primary antibody, and HRP-labeled anti-rabbit antibody was used as the secondary antibody. Chemiluminescence was then used to detect TDP-43. The results are shown below. Figure 1 and Figure 2It was confirmed that the intracellular insoluble fraction of TDP-43 increased from the time of TDP-43 gene transfection until cell death. The insoluble fraction of TDP-43 indicates that TDP-43 is accumulating.

[0241] (See Example 2 for reference) Neuro2a cells were seeded into culture dishes. They began differentiating into neurons from day 1 after seeding. On day 4 after seeding, the TDP-43 gene was transfected into the cells. Five hours after transfection, D-cyclic serine or L-cyclic serine at concentrations of 10 nmol / L, 50 nmol / L, 100 nmol / L, 500 nmol / L, 1000 nmol / L, 5000 nmol / L, or 10000 nmol / L were added to the culture medium. As a control group, ropinirole at concentrations of 10 nmol / L, 50 nmol / L, 100 nmol / L, 500 nmol / L, 1000 nmol / L, 5000 nmol / L, or 10000 nmol / L were added to the culture medium. ropinirole has been reported to have therapeutic effects on ALS.

[0242] The proportion of dead cells was assessed on day 7, starting from the transfection of cells with the TDP-43 gene. Figure 3 As shown in A, no cell death was observed in cells not transfected with the TDP-43 gene. Figure 3 As shown in B, cell death was observed in cells transfected with the TDP-43 gene without the addition of D-cyclic serine, L-cyclic serine, or ropinirole. Figure 3 As shown in Figure C, cell death was inhibited in cells transfected with the TDP-43 gene and supplemented with D-cyclic serine.

[0243] like Figure 4 As shown, D-cyclic serine and L-cyclic serine exhibited concentration-dependent inhibitory effects on cell death. The EC50 of D-cyclic serine... 50 The EC50 of L-cycloserine is 128 nmol / L. 50 The concentration is 237 nmol / L. The EC50 of ropinirole is... 50 The concentration was 198 nmol / L. It should be noted that relative survival rate represents the proportion of TDP-43-overexpressing cells that survive when the survival rate of cells without TDP-43 overexpression is set at 100%.

[0244] (See Example 3 for reference) Neuro2a cells were seeded into culture dishes. Differentiation into neurons began on day 1 after seeding. On day 4 after seeding, the TDP-43 gene was transfected into the cells. Six hours after transfection, the cells were supplemented with 10 μmol / L of D-cyclic serine, L-cyclic serine, ropinirole, or DMSO (dimethyl sulfoxide) and cultured for 12 hours. The soluble and insoluble fractions of TDP-43 within the cells were then analyzed, and the results are presented below. Figure 5 .like Figure 5 As shown, it was confirmed that in control cells treated with DMSO, the insoluble fraction of TDP-43 was greater than the soluble fraction. Conversely, it was confirmed that in cells treated with D-cycloserine and L-cycloserine, the soluble fraction of TDP-43 was greater than the insoluble fraction.

[0245] The proportion of the insoluble fraction was quantified relative to the total of the soluble and insoluble fractions of intracellular TDP-43, and the results are presented in... Figure 6 In cells treated with D-cycloserine and L-cycloserine, the proportion of insoluble fractions was less than half.

[0246] (See Example 4 for reference) 100 μL of EHS gel basement membrane matrix (Fujifilm and Kodenpaste) was added to 12.5 mL of DMEM (Dulbecco's Modified Eagle Medium, Fujifilm and Kodenpaste) and mixed. This mixture was then added to each well of a 24-well plate at a rate of 600 μL / well. After the plates were allowed to stand at room temperature for 2 hours, the solution was removed from the wells. Next, DMEM was added to each well at a rate of 600 μL / well, and the plates were allowed to stand at room temperature for 2 hours.

[0247] Motor neurons derived from iPS cells of healthy individuals and iPS cells of ALS patients were obtained from iXCells Biotechnologies. The motor neurons were rapidly thawed in a 37°C incubator and then suspended in motor neuron maintenance medium (iXCells Biotechnologies). The medium was centrifuged at 600×g for 5 minutes, and the motor neurons were collected. The medium was then removed, and the motor neurons were suspended in motor neuron maintenance medium.

[0248] With the density of motor neurons becoming 3×10 5After being diluted in culture medium at cell / mL, 600 μL of culture medium containing motor neurons was added to multiple wells of a matrix-coated plate, and the motor neurons were cultured at 37°C in the presence of 5% CO2. Every two to three days, 300 μL of culture medium was removed from each well, and 300 μL of fresh culture medium was added to each well.

[0249] On day 7 of incubation, remove 300 μL of culture medium from each well and add 300 μL of medium containing 0.2% DMSO, 20 μmol / L D-cyclic serine (Cayman Chemical), or 20 μmol / L ropinirole (Fujifilm and Koden Chemical) to each well. Every two to three days, remove 300 μL of culture medium from each well and add 300 μL of medium containing the same compound as the removed medium, i.e., 0.1% DMSO, 10 μmol / L D-cyclic serine, or 10 μmol / L ropinirole.

[0250] Cell extraction buffer was prepared by adding 5 μL of a mixture of protease and phosphatase inhibitors (Halt Protease and Phosphatase Inhibitor Cocktail, 100×, registered trademark, Thermo Fisher Scientific) to 500 μL of a protein extraction buffer (RIPA lysis buffer, NacalaiTesque) containing surfactant. 50 μL of the cell extraction buffer was added to motor neurons cultured for 20 days in the presence of DMSO, D-cycloserine, or ropinirole, and the cell extract was collected into a 1.5 mL tube by pipetting. The cell extract was centrifuged at 21,000×g for 30 minutes at 4°C.

[0251] After separating 45 μL of the supernatant from centrifugation, 45 μL of electrophoresis buffer (AE-1430EzApply, ATTO) was added to the supernatant, and the mixture was heated at 95°C for 5 minutes to prepare the soluble protein fraction. Separately, the centrifuged precipitate was washed twice with 50 μL of RIPA lysis buffer, and then 45 μL of RIPA lysis buffer and 45 μL of electrophoresis buffer were added to the precipitate, and the mixture was heated at 95°C for 5 minutes to prepare the insoluble protein fraction.

[0252] SDS-PAGE of soluble and insoluble protein fractions was performed to transfer the proteins onto a PVDF membrane. The PVDF membrane was then blocked by immersing it in blocking solution and shaking at room temperature for 1 hour. The PVDF membrane was then immersed in a solution containing TDP-43 polyclonal antibody (PGI Proteintech Group) and shaken overnight at 4°C. After washing the PVDF membrane three times with buffer, it was immersed in a solution containing HRP-labeled secondary antibody (Anti-Rabbit IgG, HRP-Linked F(ab')2 Fragment Donkey, Cytiva) and shaken at room temperature for 1 hour. Next, the PVDF membrane was washed three times with buffer, and the labeled secondary antibody was luminescent using 1 mL of luminescent reagent (Immunostar LD, Fujifilm, and photopurifier), and the PVDF membrane was photographed. The photographed PVDF membrane is shown below. Figure 7 .

[0253] like Figure 7 As shown, as a control, in motor neurons derived from healthy human iPS cells cultured in the presence of DMSO, the soluble fraction of TDP-43 was clearly observed as a band, while the insoluble fraction was faintly banded. In motor neurons derived from healthy human iPS cells cultured in the presence of D-cycloserine, the soluble fraction of TDP-43 was clearly observed as a band, while the insoluble fraction was faintly banded. In motor neurons derived from healthy human iPS cells cultured in the presence of ropinirole, the soluble fraction of TDP-43 was clearly observed as a band, while the insoluble fraction was faintly banded.

[0254] like Figure 7 As shown, in motor neurons derived from iPS cells of ALS patients cultured in the presence of DMSO (as a control), both soluble and insoluble fractions of TDP-43 were clearly observed. In motor neurons derived from iPS cells of ALS patients cultured in the presence of D-cycloserine, soluble fractions of TDP-43 were clearly observed, while the insoluble fractions were faint. In motor neurons derived from iPS cells of ALS patients cultured in the presence of ropinirole, soluble fractions of TDP-43 were clearly observed, while the insoluble fractions were faint.

[0255] Open the captured image of the PVDF membrane using ImageJ software and invert the black and white image using the Invert command. After removing the background using the Subtract Background command, enclose the TDP-43 bands in each lane within identically sized boxes, and quantify the band intensity using the Measure command. Calculate the proportion of the insoluble TDP-43 fraction based on the band intensity of the soluble fraction and the insoluble fraction of TDP-43 in each sample using the following formula.

[0256] R={I I / (I I +I S )}×100 In the above formula, R represents the proportion (%) of the insoluble fraction of TDP-43, and I I I represents the band intensity of the insoluble fraction of TDP-43. S This indicates the band strength of the soluble fraction of TDP-43.

[0257] Three experiments were conducted, and the average proportion of the insoluble fraction of TDP-43 was calculated. Figure 8 In the figures, dots represent the proportion of insoluble fractions of TDP-43 in each experiment, and bars represent the average value. In motor neurons derived from iPS cells of healthy individuals, the average proportion of insoluble fractions of TDP-43 was approximately 7.4%. On the other hand, in motor neurons derived from iPS cells of ALS patients, the average proportion of insoluble fractions of TDP-43 was approximately 46.1%. However, in motor neurons derived from iPS cells of ALS patients in the presence of D-cycloserine, the average proportion of insoluble fractions of TDP-43 decreased to approximately 17.4%. Furthermore, in motor neurons derived from iPS cells of ALS patients in the presence of ropinirole, the average proportion of insoluble fractions of TDP-43 decreased to approximately 19.3%.

[0258] FTLD-TDP and ALS share many similarities, including the accumulation of TDP-43. Therefore, in motor neurons derived from iPS cells of ALS patients in the presence of D-cycloserine, the average proportion of the insoluble fraction of TDP-43 was reduced, indicating that even in cells from FTLD-TDP patients, administration of D-cycloserine can inhibit TDP-43 accumulation.

[0259] (Example 1) Neuro2a cells were seeded into culture dishes. They were induced to differentiate into neurons starting on day 1. On day 4, the TDP-43 gene was transfected into the cells. Five hours after transfection, D-cyclic serine was added to the culture medium at concentrations of 10 nmol / L, 30 nmol / L, 100 nmol / L, 300 nmol / L, 1000 nmol / L, 3000 nmol / L, or 10000 nmol / L. Immediately afterwards, edaravone was added to the culture medium containing the respective concentrations of D-cyclic serine at concentrations of 10 nmol / L, 30 nmol / L, 100 nmol / L, 300 nmol / L, 1000 nmol / L, 3000 nmol / L, or 10000 nmol / L.

[0260] The proportion of dead cells was assessed on day 7 after transfection of cells with the TDP-43 gene. The relative survival rates of cells at different concentrations of D-cycloserine and edaravone are shown in the figure. Figure 9 It should be noted that relative survival rate represents the proportion of cells overexpressing TDP-43 that survive when the survival rate of cells without TDP-43 overexpression is set at 100%. Additionally, according to... Figure 9 The results showed that the EC50 of edaravone and D-cycloserine at various concentrations inhibited cell death. 50 Shown Figure 10 and Figure 11 The EC50 of D-cycloserine's inhibitory effect on cell death was observed when edaravone was administered at various concentrations. 50 The concentration of edaravone was 151.36 nmol / L when it was 0 nmol / L, 149.44 nmol / L when it was 10 nmol / L, 135.18 nmol / L when it was 30 nmol / L, 118.85 nmol / L when it was 100 nmol / L, 106.76 nmol / L when it was 300 nmol / L, and 87.62 nmol / L when it was 1000 nmol / L. The synergistic effect of the combination of D-cyclic serine and edaravone was quantified using the combination index (CI) by Chou et al. (TC Chou, P Talay., Adv Enzyme Regul. 1984; 22:27-55.). The CI was calculated using the following mathematical formula.

[0261] [Mathematical Expression 1]

[0262] In the above mathematical formula, Da represents the concentration of D-cycloserine that produces a 50% cell death inhibition effect when used in combination with D-cycloserine and edaravone, Db represents the concentration of edaravone that produces a 50% cell death inhibition effect when used in combination with D-cycloserine and edaravone, Dxa represents the concentration of D-cycloserine that produces a 50% cell death inhibition effect when used alone, and Dxb represents the concentration of edaravone that produces a 50% cell death inhibition effect when used alone.

[0263] If CI = 1, it indicates a cumulative effect; if CI > 1, it indicates an antagonistic effect; and if CI < 1, it indicates a synergistic effect. Figure 11 As shown, the CI for the combined use of D-cycloserine and edaravone was 0.99 at edaravone concentration of 10 nmol / L, 0.91 at edaravone concentration of 30 nmol / L, 0.83 at edaravone concentration of 100 nmol / L, and 0.83 at edaravone concentration of 300 nmol / L. Therefore, the combined use of D-cycloserine and edaravone showed a synergistic effect.

Claims

1. An inhibitor of TDP-43 aggregation, characterized in that, Combining at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

2. The TDP-43 aggregation inhibitor according to claim 1, characterized in that, Contains cyclic serine or salts of cyclic serine.

3. The TDP-43 aggregation inhibitor according to claim 1, characterized in that, The cyclic serine is D-cyclic serine.

4. The TDP-43 aggregation inhibitor according to claim 1, characterized in that, The cyclic serine is L-cyclic serine.

5. An inhibitor of TDP-43 aggregation, characterized in that, It includes at least one compound selected from the group consisting of cyclic serine and terizone and their salts, used in conjunction with edaravone.

6. The inhibitor of TDP-43 aggregation according to claim 5, characterized in that, Contains cyclic serine or salts of cyclic serine.

7. The TDP-43 aggregation inhibitor according to claim 5, characterized in that, The cyclic serine is D-cyclic serine.

8. The inhibitor of TDP-43 aggregation according to claim 5, characterized in that, The cyclic serine is L-cyclic serine.

9. The TDP-43 aggregation inhibitor according to claim 1, characterized in that, It contains more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of said cycloserine and said terizone and their salts.

10. The TDP-43 aggregation inhibitor according to claim 1, characterized in that, The edaravone contained in amounts of 30 mg or more but less than 60 mg.

11. The TDP-43 aggregation inhibitor according to claim 1, characterized in that, It does not contain acampalic acid.

12. An inhibitor of TDP-43 aggregation, characterized in that, Edaravone includes edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

13. The TDP-43 aggregation inhibitor according to claim 12, characterized in that, Contains cyclic serine or salts of cyclic serine.

14. The TDP-43 aggregation inhibitor according to claim 12, characterized in that, The cyclic serine is D-cyclic serine.

15. The TDP-43 aggregation inhibitor according to claim 12, characterized in that, The cyclic serine is L-cyclic serine.

16. The TDP-43 aggregation inhibitor according to claim 12, characterized in that, It may be used in combination with at least one compound selected from the group consisting of the cyclic serine and the terizone and their salts, at a dose of 15 mg or more but less than 250 mg.

17. The inhibitor of TDP-43 aggregation according to claim 12, characterized in that, The edaravone contained in amounts of 30 mg or more but less than 60 mg.

18. The TDP-43 aggregation inhibitor according to claim 12, characterized in that, It does not contain acampalic acid.

19. A cell death inhibitor for TDP-43-overexpressing cells, characterized in that, Combining at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

20. The cell death inhibitor for TDP-43 overexpressing cells according to claim 19, characterized in that, Contains cyclic serine or salts of cyclic serine.

21. The cell death inhibitor for TDP-43 overexpressing cells according to claim 19, characterized in that, The cyclic serine is D-cyclic serine.

22. The cell death inhibitor for TDP-43 overexpressing cells according to claim 19, characterized in that, The cyclic serine is L-cyclic serine.

23. The cell death inhibitor for TDP-43 overexpressing cells according to claim 19, characterized in that, It contains more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of said cycloserine and said terizone and their salts.

24. The cell death inhibitor for TDP-43 overexpressing cells according to claim 19, characterized in that, The edaravone contained in amounts of 30 mg or more but less than 60 mg.

25. The cell death inhibitor for TDP-43 overexpressing cells according to claim 19, characterized in that, It does not contain acampalic acid.

26. A cell death inhibitor for TDP-43-overexpressing cells, characterized in that, It includes at least one compound selected from the group consisting of cyclic serine and terizone and their salts, used in conjunction with edaravone.

27. The cell death inhibitor for TDP-43 overexpressing cells according to claim 26, characterized in that, Contains cyclic serine or salts of cyclic serine.

28. The cell death inhibitor for TDP-43 overexpressing cells according to claim 26, characterized in that, The cyclic serine is D-cyclic serine.

29. The cell death inhibitor for TDP-43 overexpressing cells according to claim 26, characterized in that, The cyclic serine is L-cyclic serine.

30. The cell death inhibitor for TDP-43 overexpressing cells according to claim 26, characterized in that, It contains more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of said cycloserine and said terizone and their salts.

31. The cell death inhibitor for TDP-43 overexpressing cells according to claim 26, characterized in that, Used in combination with edaravone at doses of 30 mg or more but less than 60 mg.

32. The cell death inhibitor for TDP-43 overexpressing cells according to claim 26, characterized in that, It does not contain acampalic acid.

33. A cell death inhibitor for TDP-43-overexpressing cells, characterized in that, Edaravone includes edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

34. The cell death inhibitor for TDP-43 overexpressing cells according to claim 33, characterized in that, Contains cyclic serine or salts of cyclic serine.

35. The cell death inhibitor for TDP-43 overexpressing cells according to claim 33, characterized in that, The cyclic serine is D-cyclic serine.

36. The cell death inhibitor for TDP-43 overexpressing cells according to claim 33, characterized in that, The cyclic serine is L-cyclic serine.

37. The cell death inhibitor for TDP-43 overexpressing cells according to claim 33, characterized in that, It may be used in combination with at least one compound selected from the group consisting of the cyclic serine and the terizone and their salts, at a dose of 15 mg or more but less than 250 mg.

38. The cell death inhibitor for TDP-43 overexpressing cells according to claim 33, characterized in that, The edaravone contained in amounts of 30 mg or more but less than 60 mg.

39. The cell death inhibitor for TDP-43 overexpressing cells according to claim 33, characterized in that, It does not contain acampalic acid.

40. A therapeutic or preventative agent for a disease associated with the accumulation of TDP-43, characterized in that, Combining at least one compound selected from the group consisting of cycloserine and terizone and their salts with edaravone.

41. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, Contains cyclic serine or salts of cyclic serine.

42. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, The cyclic serine is D-cyclic serine.

43. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, The cyclic serine is L-cyclic serine.

44. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, The disease associated with the aggregation of TDP-43 is a TDP-43 protein disease.

45. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 44, characterized in that, The TDP-43 protein disease is at least one disease selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy.

46. ​​The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 44, characterized in that, The TDP-43 protein disease is amyotrophic lateral sclerosis (ALS).

47. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, It contains more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of said cycloserine and said terizone and their salts.

48. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, The edaravone contained in amounts of 30 mg or more but less than 60 mg.

49. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 40, characterized in that, It does not contain acampalic acid.

50. A therapeutic or preventative agent for a disease associated with the accumulation of TDP-43, characterized in that, It includes at least one compound selected from the group consisting of cyclic serine and terizone and their salts, used in conjunction with edaravone.

51. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 50, characterized in that, Contains cyclic serine or salts of cyclic serine.

52. The therapeutic or preventative agent for diseases associated with TDP-43 aggregation according to claim 50, characterized in that, The cyclic serine is D-cyclic serine.

53. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 50, characterized in that, The cyclic serine is L-cyclic serine.

54. The therapeutic or preventative agent for diseases associated with TDP-43 aggregation according to claim 50, characterized in that, The disease associated with the aggregation of TDP-43 is a TDP-43 protein disease.

55. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 54, characterized in that, The TDP-43 protein disease is at least one disease selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy.

56. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 54, characterized in that, The TDP-43 protein disease is amyotrophic lateral sclerosis (ALS).

57. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 50, characterized in that, It contains more than 15 mg and less than 250 mg of at least one compound selected from the group consisting of said cycloserine and said terizone and their salts.

58. The therapeutic or preventative agent for diseases associated with TDP-43 aggregation according to claim 50, characterized in that, Used in combination with edaravone at doses of 30 mg or more but less than 60 mg.

59. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 50, characterized in that, It does not contain acampalic acid.

60. A therapeutic or preventative agent for a disease associated with the accumulation of TDP-43, characterized in that, Edaravone includes edaravone used in combination with at least one compound selected from the group consisting of cycloserine and terizone and their salts.

61. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 60, characterized in that, Contains cyclic serine or salts of cyclic serine.

62. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 60, characterized in that, The cyclic serine is D-cyclic serine.

63. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 60, characterized in that, The cyclic serine is L-cyclic serine.

64. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 60, characterized in that, The disease associated with the aggregation of TDP-43 is a TDP-43 protein disease.

65. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 64, characterized in that, The TDP-43 protein disease is at least one disease selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal degeneration, primary lateral sclerosis, and progressive muscular atrophy.

66. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 64, characterized in that, The TDP-43 protein disease is amyotrophic lateral sclerosis (ALS).

67. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 60, characterized in that, It may be used in combination with at least one compound selected from the group consisting of the cyclic serine and the terizone and their salts, at a dose of 15 mg or more but less than 250 mg.

68. The therapeutic or preventative agent for diseases associated with TDP-43 aggregation according to claim 60, characterized in that, The edaravone contained in amounts of 30 mg or more but less than 60 mg.

69. The therapeutic or preventative agent for diseases associated with the aggregation of TDP-43 according to claim 60, characterized in that, It does not contain acampalic acid.

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