Method for alleviating oxidative stress

Abstract

The present invention provides a method for treating or preventing oxidative stress-related disorders, the method comprises: administering, to a subject requiring said treatment or prevention, an effective dose of a very-long-chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt of the fatty acid or derivative thereof.

Description

How to alleviate oxidative stress

[0001] The present invention relates to a method for alleviating oxidative stress in a living body caused by reactive oxygen species, and also to a method for treating or preventing a disease or disorder caused by oxidative stress.

[0002] Oxygen is essential for the survival of many living organisms. However, reactive oxygen species (ROS), such as hydrogen peroxide and hydroxyl radicals, generated by oxygen taken into the body are known to cause damage to tissues and cells. The body has mechanisms to inhibit the generation of ROS and to scavenge ROS. These mechanisms protect tissues and cells from oxidative stress. However, when ROS production exceeds the processing capacity of these antioxidant mechanisms, oxidative stress occurs. Oxidative stress results from an imbalance between the ROS present in the body, particularly within cells, and the cellular ability to neutralize them. ROS are characterized by superoxide anions, which can damage cellular nucleic acids, proteins, and lipids. Damage to nucleic acids, such as deoxyribose nucleic acid (DNA), can include base damage and double-strand breaks. Damage to proteins can disrupt cell signaling and function. ROS-mediated damage to lipids can lead to membrane disruption.

[0003] Oxidative stress is associated with a variety of diseases, including eye diseases, neurological diseases, Down's syndrome, cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, ear, nose, and throat diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases.

[0004] Fish are known to be rich in n-3 polyunsaturated fatty acids. Numerous studies have demonstrated that frequent fish consumption reduces the risk of cardiovascular disease. In particular, a pioneering epidemiological study in Greenland highlighted the n-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) as a potential treatment for cardiovascular disease. This study revealed that the indigenous Greenlandic Inuit population had a low incidence of acute myocardial infarction and a low mortality rate from ischemic heart disease. Furthermore, dietary analysis revealed that a diet high in seals and fish contributed to a high intake of n-3 polyunsaturated fatty acids, such as EPA and docosahexaenoic acid (DHA), while their intake of n-6 polyunsaturated fatty acids, which are abundant in terrestrial animals and plants, was low. It has been reported that this difference in the fatty acid composition of the diet is the reason why the Inuit have a low incidence of acute myocardial infarction and a low mortality rate from ischemic heart disease (Non-Patent Documents 1 to 3). EPA is used as a prescription drug to treat arteriosclerosis obliterans and hyperlipidemia.

[0005] EPA has been reported to inhibit the oxidation of high-density lipoprotein (HDL) (Non-Patent Document 4). Other studies on the antioxidant activity of polyunsaturated fatty acids have been reported (Patent Documents 1-4, Non-Patent Document 5). In recent years, there have been reports on the availability and activity test results of very long-chain polyunsaturated fatty acids (VLC-PUFAs, e.g., n-3 VLC-PUFAs), which have carbon chains even longer than DHA and EPA, and their hydroxylated derivatives known as erovanoids (Patent Documents 5-7, Non-Patent Document 6).

[0006] Patent Publication No. 2014-527029A, Patent Publication No. 2016-138138A, Patent Publication No. 2017-214305A, Patent Publication No. 2013-509439A, Patent Publication No. 2018-506584, WO2020 / 206448A1, US2013 / 0190399A1

[0007] Dyerberg J et al. Am J Clin Nutr, 28(9):958-66, 1975Dyerberg J et al. Lancet, 2(8081):117-9, 1978Bang HO et al. Am J Clin Nutr, 33(12):2657-61, 1980.Sherratt SCR et al. Biochemical and Biophysical Research Communications 496 (2018) 335-338Kikukawa K., Lipid Nutrition, Vol. 15, No. 1 (2006), 77-83Molecular Aspects of Medicine 64 (2018) 18-33

[0008] Although various studies have been reported on methods for alleviating oxidative stress caused by reactive oxygen species, there is still a strong demand for methods that adequately address oxidative stress. In one aspect, the present invention aims to provide a method for alleviating oxidative stress.

[0009] In the course of an intensive search for substances that suppress oxidative stress caused by ROS, the present inventors discovered that the inhibitory effect of oxidative stress can be imparted or enhanced by extending the carbon chain length of PUFAs, and found that very long-chain polyunsaturated fatty acids (VLC-PUFAs) in which the chain length of PUFAs has been extended are useful as active ingredients in oxidative stress inhibitors, thereby completing the present invention.

[0010] The present specification includes the disclosure of the following inventions: [A-1] A composition comprising, as an active ingredient, a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof, for use in alleviating oxidative stress or treating or preventing an oxidative stress-related disorder.

[0011] [A-2] The composition according to [A-1], wherein the pharmaceutically functional derivative is selected from the group consisting of esters, ethers, and amides.

[0012] [A-3] The composition according to [A-1] or [A-2], wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic salts and organic salts.

[0013] [A-4] The composition according to any one of [A-1] to [A-3], wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more carbon atoms and 42 or less, 40 or less, or 38 or less carbon atoms, containing 3 or more, or 4 or more, and 6 or less double bonds, and containing 0 or more, and 1 or less, 2 or less, or 3 or less hydroxyl groups.

[0014] [A-5] The very long chain polyunsaturated fatty acid is represented by the following formula: [wherein m1, m2, m3, and m4 are independently integers selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18, or 10 to 18, and R is a hydrogen atom].

[0015] [A-6] The composition according to any one of [A-1] to [A-5], wherein the very long chain polyunsaturated fatty acid is selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

[0016] [A-7] The composition according to any one of [A-1] to [A-6], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid. [A-8] The composition according to any one of [A-1] to [A-7], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is an ethyl ester of a very long chain polyunsaturated fatty acid.

[0017] [A-9] The composition according to any one of [A-1] to [A-7], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid. [A-10] The composition according to [A-9], wherein the pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid is a lysine salt.

[0018] [A-11] The composition according to any one of [A-1] to [A-10] for use in the treatment or prevention of an oxidative stress-related disorder. [A-12] The composition according to [A-11], wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases.

[0019] [A-13] The composition according to [A-11], wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataracts, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down's syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathies.

[0020] [A-14] The composition described in [A-11], wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

[0021] [A-15] The composition according to any one of [A-1] to [A-14], wherein the oxidative stress-related disorder is a disorder caused by free radicals or reactive oxygen species in the body. [A-16] The oxidative stress-related disorder is ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO －(peroxynitrite), NO ・ , １ O ２ (singlet oxygen), O ３ (ozone), or ・ NO ２ The composition according to any one of [A-1] to [A-15], which is a disorder associated with the presence of (nitrogen dioxide).

[0022] [A-17] The composition according to any one of [A-1] to [A-10] for use in alleviating oxidative stress. [A-18] The composition according to any one of [A-1] to [A-17], wherein the oxidative stress is damage caused by free radicals or reactive oxygen species in the body.

[0023] [A-19] Oxidative stress, ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), NO ・ , １ O ２ (singlet oxygen), O ３ (ozone), or ・ NO ２ The composition according to any one of [A-1] to [A-18], which is a disorder associated with the presence of (nitrogen dioxide).

[0024] [B-1] A method for treating or preventing an oxidative stress-related disorder, comprising administering an effective amount of a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof to a subject in need of said treatment or prevention.

[0025] [B-2] The method according to [B-1], wherein the pharmaceutically functional derivative is selected from the group consisting of esters, ethers, and amides.

[0026] [B-3] The method according to [B-1] or [B-2], wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic salts and organic salts.

[0027] [B-4] The method according to any one of [B-1] to [B-3], wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more carbon atoms and 42 or less, 40 or less, or 38 or less carbon atoms, containing 3 or more, or 4 or more, and 6 or less double bonds, and containing 0 or more, 1 or less, or 2 or less, or 3 or less hydroxyl groups.

[0028] [B-5] The very long chain polyunsaturated fatty acid is represented by the following formula: [wherein m1, m2, m3, and m4 are independently integers selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18, or 10 to 18, and R is a hydrogen atom].

[0029] [B-6] The method according to any one of [B-1] to [B-5], wherein the very long chain polyunsaturated fatty acid is a very long chain polyunsaturated fatty acid selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

[0030] [B-7] The method according to any one of [B-1] to [B-6], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid. [B-8] The method according to any one of [B-1] to [B-7], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is an ethyl ester of a very long chain polyunsaturated fatty acid.

[0031] [B-9] The method according to any one of [B-1] to [B-7], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid. [B-10] The method according to [B-9], wherein the pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid is a lysine salt.

[0032] [B-11] The method according to any one of [B-1] to [B-10], wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down's syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases.

[0033] [B-12] The method according to any one of [B-1] to [B-11], wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataract, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down's syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathies.

[0034] [B-13] The method according to any one of [B-1] to [B-11], wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

[0035] [B-14] The method according to any one of [B-1] to [B-13], wherein the oxidative stress-related disorder is a disorder caused by free radicals or reactive oxygen species in the body. [B-15] The oxidative stress-related disorder is ・ O ２ － (superoxide anion), H２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), NO ・ , １ O ２ (singlet oxygen), O ３ (ozone), or ・ NO ２ The method according to any one of [B-1] to [B-14], wherein the disorder is associated with the presence of nitrogen dioxide.

[0036] [C-1] A method for alleviating oxidative stress, comprising administering an effective amount of very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof to a subject in need of said treatment or prevention.

[0037] [C-2] The method according to [C-1], wherein the pharmaceutically functional derivative is selected from the group consisting of esters, ethers, and amides.

[0038] [C-3] The method according to [C-1] or [C-2], wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic salts and organic salts.

[0039] [C-4] The method according to any one of [C-1] to [C-3], wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more carbon atoms and 42 or less, 40 or less, or 38 or less carbon atoms, containing 3 or more, or 4 or more, and 6 or less double bonds, and containing 0 or more, and 1 or less, 2 or less, or 3 or less hydroxyl groups.

[0040] [C-5] The very long chain polyunsaturated fatty acid is represented by the following formula: [wherein m1, m2, m3, and m4 independently represent integers selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18, or 10 to 18, and R represents a hydrogen atom].

[0041] [C-6] The method according to any one of [C-1] to [C-5], wherein the very long chain polyunsaturated fatty acid is a very long chain polyunsaturated fatty acid selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

[0042] [C-7] The method according to any one of [C-1] to [C-6], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid. [C-8] The method according to any one of [C-1] to [C-7], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is an ethyl ester of a very long chain polyunsaturated fatty acid.

[0043] [C-9] The method according to any one of [C-1] to [C-7], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid. [C-10] The method according to [C-9], wherein the pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid is a lysine salt.

[0044] [C-11] The method according to any one of [C-1] to [C-10], wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases. [C-12] The method according to any one of [C-1] to [C-11], wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataracts, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathies.

[0045] [C-13] The method according to any one of [C-1] to [C-12], wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

[0046] [C-14] The method according to any one of [C-1] to [C-13], wherein the oxidative stress is a disorder caused by free radicals or reactive oxygen species in the body. [C-15] The oxidative stress is ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), NO ・ , １ O ２ (singlet oxygen), O３ (ozone), or ・ NO ２ The method according to any one of [C-1] to [C-14], wherein the disorder is associated with the presence of nitrogen dioxide.

[0047] [D-1] A composition for use in alleviating oxidative stress or treating or preventing oxidative stress-related disorders, comprising a very long chain polyunsaturated fatty acid (VLC-PUFA), a salt thereof, or an ester thereof as an active ingredient, wherein the ester is C １－６ The composition is an alkyl ester or a glyceride.

[0048] [D-2] The composition according to [D-1], wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more and 40 or less or 38 or less carbon atoms and containing 3 or more, or 4 or more, and 6 or less double bonds.

[0049] [D-3] The composition described in [D-1] or [D-2], wherein the very long chain polyunsaturated fatty acid has 3 to 6 double bonds and has a 6n-3, 5n-3, 4n-6, or 3n-6 chemical structure similar to that of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (ARA), or dihomo-γ-linolenic acid (DGLA).

[0050] [D-4] The composition according to any one of [D-1] to [D-3], wherein the very long chain polyunsaturated fatty acid is selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

[0051] [D-5] The composition according to any one of [D-1] to [D-4], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid. [D-6] The composition according to any one of [D-1] to [D-5], comprising a very long chain polyunsaturated fatty acid ethyl ester.

[0052] [D-7] The composition described in any one of [D-1] to [D-6] for use in the treatment or prevention of an oxidative stress-related disorder. [D-8] The composition described in [D-7], wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases. [D-9] The composition described in [D-7], wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataracts, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathies.

[0053] [D-10] The composition described in [D-7], wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

[0054] [D-11] The composition according to any one of [D-1] to [D-10], wherein the oxidative stress-related disorder is a disorder caused by free radicals or reactive oxygen species in the body. [D-12] The oxidative stress-related disorder is ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), or NO ・The composition according to any one of [D-1] to [D-11], which is a disorder associated with the presence of

[0055] [D-13] The composition according to any one of [D-1] to [D-6] for use in alleviating oxidative stress. [D-14] The composition according to any one of [D-1] to [D-13], wherein the oxidative stress is damage caused by free radicals or reactive oxygen species in the body.

[0056] [D-15] Oxidative stress, ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), or NO ・ The composition according to any one of [D-1] to [D-14], which is a disorder associated with the presence of

[0057] [D-16] The composition according to any one of [D-1] to [D-5] and [D-7] to [D-15], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a salt thereof, or an ester thereof is a pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid. [D-17] The composition according to [D-16], wherein the pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid is a lysine salt.

[0058] [E-1] A method for treating or preventing an oxidative stress-related disorder, comprising administering an effective amount of a very long chain polyunsaturated fatty acid (VLC-PUFA), a salt thereof, or an ester thereof to a subject in need of said treatment or prevention, wherein the ester is C １－６ The method of claim 1, wherein the hydroxy group is an alkyl ester or a glyceride.

[0059] [E-2] The method according to [E-1], wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more and 40 or less, or 38 or less carbon atoms and containing 3 or more, or 4 or more, and 6 or less double bonds.

[0060] [E-3] The method according to [E-1] or [E-2], wherein the very long chain polyunsaturated fatty acid has 3 to 6 double bonds and has a 6n-3, 5n-3, 4n-6, or 3n-6 chemical structure similar to that of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (ARA), or dihomo-γ-linolenic acid (DGLA).

[0061] [E-4] The method according to any one of [E-1] to [E-3], wherein the very long chain polyunsaturated fatty acid is a very long chain polyunsaturated fatty acid selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

[0062] [E-5] The method according to any one of [E-1] to [E-4], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid. [E-6] The method according to any one of [E-1] to [E-5], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid.

[0063] [E-7] The method according to any one of [E-1] to [E-6], wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down's syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases.

[0064] [E-8] The method according to any one of [E-1] to [E-6], wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataract, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down's syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathies.

[0065] [E-9] The method according to any one of [E-1] to [E-6], wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

[0066] [E-10] The method according to any one of [E-1] to [E-9], wherein the oxidative stress-related disorder is a disorder caused by free radicals or reactive oxygen species in the body. [E-11] The oxidative stress-related disorder is ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), or NO ・ The method according to any one of [E-1] to [E-10], wherein the disorder is associated with the presence of

[0067] [E-12] The method according to any one of [E-1] to [E-5] and [E-7] to [E-11], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a salt thereof, or an ester thereof is a pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid. [E-13] The method according to [E-12], wherein the pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid is a lysine salt.

[0068] [F-1] A method for alleviating oxidative stress, comprising administering an effective amount of a very long chain polyunsaturated fatty acid (VLC-PUFA), a salt thereof, or an ester thereof to a subject in need of said treatment or prevention, wherein the ester is C １－６ The method of claim 1, wherein the hydroxy group is an alkyl ester or a glyceride.

[0069] [F-2] The method according to [F-1], wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more and 40 or less, or 38 or less carbon atoms and containing 3 or more, or 4 or more, and 6 or less double bonds.

[0070] [F-3] The method according to [F-1] or [F-2], wherein the very long chain polyunsaturated fatty acid has 3 to 6 double bonds and has a 6n-3, 5n-3, 4n-6, or 3n-6 chemical structure similar to that of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (ARA), or dihomo-γ-linolenic acid (DGLA).

[0071] [F-4] The method according to any one of [F-1] to [F-3], wherein the very long chain polyunsaturated fatty acid is a very long chain polyunsaturated fatty acid selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

[0072] [F-5] The method according to any one of [F-1] to [F-4], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid. [F-6] The method according to any one of [F-1] to [F-5], wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid.

[0073] [F-7] The method according to any one of [F-1] to [F-6], wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down's syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases. [F-8] The method according to any one of [F-1] to [F-6], wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataracts, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down's syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathies.

[0074] [F-9] The method according to any one of [F-1] to [F-6], wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

[0075] [F-10] The method according to any one of [F-1] to [F-9], wherein the oxidative stress is a disorder caused by free radicals or reactive oxygen species in the body. [F-11] The method according to any one of [F-1] to [F-9], wherein the oxidative stress is a disorder caused by free radicals or reactive oxygen species in the body. ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), or NO ・ The method according to any one of [F-1] to [F-10], wherein the disorder is associated with the presence of

[0076] [F-12] The method according to any one of [F-1] to [F-5] and [F-7] to [F-11], wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a salt thereof, or an ester thereof is a pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid. [F-13] The method according to [F-12], wherein the pharmaceutically acceptable basic amino acid salt of the very long chain polyunsaturated fatty acid is a lysine salt.

[0077] In one aspect of the present invention, there is provided a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an oxidative stress-related disorder. In one aspect of the present invention, there is provided use of a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a composition for the treatment or prevention of an oxidative stress-related disorder.

[0078] The present invention provides methods for alleviating oxidative stress, and methods for treating or preventing diseases or conditions caused by oxidative stress.

[0079] Fig. 1 is a graph showing the results of evaluation of oxidative stress by quantification of reactive oxygen species. Fig. 2 is a graph showing the results of evaluation of protective effect against oxidative stress in Example 2. Fig. 3 is a graph showing the results of evaluation of protective effect against oxidative stress in Example 3. Fig. 4 is a graph showing the results of evaluation of protective effect against oxidative stress in Example 4.

[0080] DEFINITIONS Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0081] Unless otherwise defined, technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

[0082] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a relatively non-toxic carrier or diluent, that does not destroy the biological activity or properties of the active ingredients (i.e., such a material can be administered to a subject without causing undesired biological effects or adversely reacting with any of the components of the composition in which it is contained).

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed very long chain polyunsaturated fatty acid obtained by converting the acid or base moiety present in the very long chain polyunsaturated fatty acid or its derivative into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic salts of acidic residues such as carboxylic acids; mineral or organic acid salts of basic residues such as amines; and the like. Examples of inorganic salts of acidic residues such as carboxylic acids include alkali metal salts such as potassium salts and sodium salts, and Group 2 element salts such as calcium salts and magnesium salts. Examples of organic salts of acidic residues such as carboxylic acids include amine salts such as lysine salts, arginine salts, ornithine salts, choline salts, meglumine salts, benzathine salts, and tromethamine salts.

[0084] Pharmaceutically acceptable salts of the present invention include non-toxic salts of very long-chain polyunsaturated fatty acids formed, for example, from well-known non-toxic inorganic or organic salts. The pharmaceutically acceptable salts of the present invention can be synthesized from very long-chain polyunsaturated fatty acids having a basic or acidic moiety by well-known chemical methods. Generally, such salts can be prepared by reacting the free acid or base of these very long-chain polyunsaturated fatty acids with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0085] As defined herein, "pharmaceutically functional derivatives" of very long chain polyunsaturated fatty acids include derivatives that have or provide the same biological function and / or activity as any of the very long chain polyunsaturated fatty acids of the present invention. Thus, the term includes esters, ethers, amides, and prodrugs of very long chain polyunsaturated fatty acids.

[0086] The "ethers" of very long chain polyunsaturated fatty acids include derivatives in which the hydroxyl groups present in very long chain unsaturated fatty acids are converted into ethers, and derivatives in which the carboxyl groups (-CO ２ H) to a reduced hydroxymethyl group (-CH ２ This includes derivatives in which the alkyl group (OH) is converted into an ether.

[0087] A "prodrug" of a very long chain polyunsaturated fatty acid includes a compound that, after oral or parenteral administration, is metabolized in vivo to form experimentally detectable amounts of the very long chain polyunsaturated fatty acid within a given time period (e.g., within a 6- to 24-hour dosing interval (i.e., once to four times daily)).

[0088] Prodrugs of very long chain polyunsaturated fatty acids can be prepared by modifying functional groups present in the very long chain polyunsaturated fatty acid so that the modification is cleaved in vivo when the prodrug is administered to a subject. The modification is typically achieved by protecting the functional group of the very long chain polyunsaturated fatty acid with a prodrug substituent. For example, the hydroxy, amino, sulfhydryl, carboxy, or carbonyl group of the very long chain polyunsaturated fatty acid can be protected with any group that can be cleaved in vivo to regenerate the free hydroxy, amino, sulfhydryl, carboxy, or carbonyl group, respectively.

[0089] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, ester groups of carboxy functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H., Design of Prodrugs, p. I-92, Elsevier, New York-Oxford (1985).

[0090] In this specification, very long chain polyunsaturated fatty acids, pharmaceutically functional derivatives thereof, and pharmaceutically acceptable salts thereof may be referred to collectively or as part of the "active ingredients."

[0091] When describing fatty acids, numerical notation is sometimes used to abbreviate the number of carbon atoms, the number of double bonds, and the location of the double bonds using numbers and letters, respectively. For example, a saturated fatty acid with 20 carbon atoms is represented as "C20:0," a monounsaturated fatty acid with 18 carbon atoms is represented as "C18:1," and eicosapentaenoic acid is represented as "C20:5n-3." Here, "n-3" is also represented as ω-3, which indicates that the first double bond is the third bond position when counting from the last carbon (ω) toward the carboxyl. In this notation, all double bonds are cis-type, and the double bonds of polyunsaturated fatty acids have a methylene-interrupted structure with one methylene between them and the next double bond. This notation method is well known to those skilled in the art, and fatty acids represented according to this method can be easily identified by those skilled in the art.

[0092] As used herein, the very long chain polyunsaturated fatty acid is not particularly limited as long as it has 24 or more carbon atoms and three or more double bonds. In one aspect of the present invention, the very long chain polyunsaturated fatty acid has 24 to 42, 24 to 40, 26 to 40, 28 to 40, 30 to 40, 24 to 38, 26 to 38, 28 to 38, or 30 to 38 carbon atoms. In one aspect of the present invention, the very long chain polyunsaturated fatty acid has 4 to 6 double bonds. In one aspect of the present invention, the very long chain polyunsaturated fatty acid has 3 to 6 double bonds. In one aspect of the present invention, the very long chain polyunsaturated fatty acid has 0 to 3 hydroxyl groups. In one aspect of the present invention, the very long chain polyunsaturated fatty acid has 0 to 2 hydroxyl groups.

[0093] In one embodiment of the present invention, the very long chain polyunsaturated fatty acid has 3 to 6 cis-type double bonds arranged in succession with one methylene between them. In one embodiment of the present invention, the very long chain polyunsaturated fatty acid has a chemical structure similar to that of docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, or dihomo-γ-linolenic acid and has 3 to 6 double bonds arranged in succession with one methylene between them.

[0094] In one aspect of the invention, the very long chain polyunsaturated fatty acid is an n-3 or n-6 very long chain polyunsaturated fatty acid (n-3 VLC-PUFA, n-6 VLC-PUFA) containing 24 to 42 carbons (C24-C42), examples of which include C32:6n-3 (32 carbons, 6 double bonds, ω-3), C34:6n-3, C32:5n-3, and C34:5n-3.

[0095] In one aspect of the present invention, the very long chain polyunsaturated fatty acid is a fatty acid represented by the following formula:

[0096]

[0097] [In the formula, m1, m2, m3, and m4 are independently integers selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18, or 10 to 18, and R is a hydrogen atom].

[0098] In one aspect of the present invention, the very long chain polyunsaturated fatty acid, salt thereof, or ester thereof is a fatty acid, salt thereof, or ester thereof represented by the following formula:

[0099]

[0100] [In the formula, m1, m2, and m3 are independently integers selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18, or 10 to 18; R is a hydrogen atom, a cation such as an alkali metal ion, or C １－６ alkyl, etc.].

[0101] In one aspect of the present invention, very long chain polyunsaturated fatty acids can be used as very long chain polyunsaturated fatty acids (VLC-PUFAs), pharmaceutically functional derivatives thereof, or pharmaceutically acceptable salts thereof.

[0102] In one embodiment of the present invention, a pharmaceutically functional derivative of a very long chain polyunsaturated fatty acid can be used as a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof. Pharmaceutically functional derivatives of very long chain unsaturated fatty acids include esters, ethers, amides, and prodrugs, with esters being particularly preferred. Ester derivatives are not particularly limited and include alkyl esters, glycerides, and the like. Alkyl esters include, for example, C １－６ The glyceride may be a triglyceride, a diglyceride, or a monoglyceride, and at least one of the constituent fatty acids is a very long chain polyunsaturated fatty acid. Preferably, the ester of the very long chain polyunsaturated fatty acid is an ethyl ester.

[0103] The ether derivatives of very long chain unsaturated fatty acids are not particularly limited and include alkyl ethers and alkenyl ethers. The alkyl ethers include, for example, C １－６ Alkenyl ethers are, for example, C alkyl ethers containing one double bond. ２－６ It is an alkenyl ether.

[0104] The amide derivative of the very long chain unsaturated fatty acid is not particularly limited, and may be an amide (—CONH ２ ), N-alkylamide, N,N-dialkylamide. N-Alkylamide is, for example, N-C １－６ N,N-dialkylamides are, for example, N,N-diC １－６ It is an alkylamide.

[0105] In one aspect of the present invention, pharmaceutically acceptable salts of very long chain polyunsaturated fatty acids or their derivatives can be used as very long chain polyunsaturated fatty acids (VLC-PUFAs), pharmaceutically functional derivatives thereof, or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of very long chain polyunsaturated fatty acids or their derivatives include inorganic salts and organic salts. Examples of inorganic salts include alkali metal salts such as potassium salts and sodium salts, and Group 2 element salts such as calcium salts and magnesium salts. Examples of organic salts include amine salts such as lysine salts, arginine salts, ornithine salts, choline salts, meglumine salts, benzathine salts, and tromethamine salts.

[0106] In one aspect of the present invention, a pharmaceutically acceptable salt of a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof can be used. The pharmaceutically acceptable salt of a very long chain polyunsaturated fatty acid is preferably a basic amino acid salt such as a lysine salt, an arginine salt, or an ornithine salt, and more preferably a basic amino acid salt such as a lysine salt.

[0107] In one aspect of the present invention, a very long chain polyunsaturated fatty acid, a salt thereof, or an ester thereof can be used. The ester is not particularly limited, and examples thereof include C １－６ Examples of the glycerides include alkyl esters, glycerides, etc. The glycerides may be triglycerides, diglycerides, or monoglycerides, and at least one of the constituent fatty acids is a very long chain polyunsaturated fatty acid. Preferably, the ester of the very long chain polyunsaturated fatty acid is an ethyl ester. Examples of salts of the very long chain polyunsaturated fatty acid include alkali metal salts such as potassium salts and sodium salts.

[0108] In one embodiment of the present invention, active ingredients such as very long-chain polyunsaturated fatty acids can be obtained by chemical synthesis using long-chain polyunsaturated fatty acids (e.g., docosahexaenoic acid, eicosapentaenoic acid, or arachidonic acid) as starting materials. In one embodiment of the present invention, active ingredients such as very long-chain polyunsaturated fatty acids can be obtained by recovering those biosynthesized in cells containing elongase enzymes. For example, active ingredients such as very long-chain polyunsaturated fatty acids can be obtained by concentrating and purifying them from, for example, fish oil, squid oil, algae oil, or krill oil.

[0109] Active ingredients such as very long chain polyunsaturated fatty acids can be obtained by known methods, for example, the methods described in JP-A-2018-506584, US2013 / 0190399A1, WO2017 / 002353A1, JP-A-2018-506584, etc.

[0110] In one aspect of the present invention, the composition of the present invention can be used as a therapeutic or preventive agent for oxidative stress-related disorders, particularly diseases caused by oxidative stress. As used herein, oxidative stress refers to a stressful state in which the body is unable to adequately process endogenous or exogenous reactive oxygen species (such as superoxide anion, hydroxyl radical, hydrogen peroxide, hypochlorous acid, and nitric oxide) due to excessive production of the reactive oxygen species. Here, the reactive oxygen species associated with oxidative stress-related disorders are not particularly limited, and examples thereof include O2- (superoxide anion), H ２ O ２ (hydrogen peroxide), OH (hydroxyl radical), ROOH (organic hydroperoxide), RO (alkoxyl radical), ROO (peroxyl radical), HOCl (hypochlorous acid), OONO- (peroxynitrite), NO. １ O ２ (singlet oxygen), O ３ (ozone), ・ NO ２ (nitrogen dioxide), etc.

[0111] In one aspect of the present invention, the disease caused by oxidative stress according to the present invention is not particularly limited, and examples thereof include ophthalmic diseases (retinal degeneration (age-related macular degeneration (AMD) (e.g., age-related macular degeneration due to oxidative stress), diabetic retinopathy, etc.), cataracts, dry eye, etc.), neurological diseases (Alzheimer's disease, Parkinson's disease, synucleinopathies, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, epilepsy, schizophrenia, bipolar disorder (BP), tardive dyskinesia, etc.), inflammatory responses to oxidative stress, Down's syndrome (DS), cancer, cardiovascular diseases (arteriosclerosis (atherosclerosis, etc.), ischemic heart disease (angina, myocardial infarction, etc.), heart failure, stroke, brain damage (e.g., ischemic brain damage), reperfusion injury, hypertension, hyperhomocysteinemia, etc.), These include respiratory diseases (such as emphysema and bronchial asthma), lifestyle-related diseases (such as metabolic syndrome, diabetes, and high blood pressure), skin disorders (such as dermatitis and photoaging of the skin), digestive diseases (such as gastroesophageal reflux disease, gastric ulcers, and inflammatory bowel disease), liver diseases (such as alcoholic liver disease and non-alcoholic steatohepatitis), kidney diseases (such as renal failure and glomerulonephritis), autoimmune diseases (such as collagen diseases and rheumatoid arthritis), ear, nose, and throat diseases (such as stomatitis and hay fever), sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases (such as physiological aging).

[0112] In one aspect of the present invention, the oxidative stress-related disorder is an ocular disease, for example, retinal degeneration (age-related macular degeneration (AMD) (e.g., age-related macular degeneration due to oxidative stress), diabetic retinopathy, etc.), cataract, or dry eye. Preferably, the oxidative stress-related disorder is age-related macular degeneration (AMD) (e.g., age-related macular degeneration due to oxidative stress). The role of oxidative stress in age-related macular degeneration has been reported (Beatty S et al., Survey Ophtalm. 2000; 45: 115-134; (de Jong Paulus T V M Age-related macular degeneration. The New England journal of medicine 2006; 355(14): 1474-85); Wu J, Seregard S et al., Survey Ophtalm. 2006; 51: 461-481).

[0113] Oxidative stress has been reported to play a major role in the pathogenesis of AMD (Beatty S et al., Survey Ophthalm. 2000; 45:115-134). Increased levels of PUFA peroxidation products, such as 4-hydroxynonenal (HNE) and 4-hydroxyhexanal (HHE), have been reported in the retina (Long EK et al., Free Rad. Biol. Med. 2010; 49:1-8). PUFA peroxidation products play a major role in the formation of retinal pigment epithelial (RPE) lipofuscin, which can itself generate ROS upon exposure to visible light and play a major role in the pathogenesis of AMD (Katz ML, Arch. Gerontol. Geriatr. 2002; 34:359-370). PUFA peroxidation products, including malondialdehyde (MDA), play a prominent role in lens pathologies, including cataract formation, as it has been published that PUFA peroxidation is the initiating step in the pathogenesis of human cataract pathology (Borchman D. et al., J. Lipid Res. 2010;51:2473-2488). The role of PUFA peroxidation products in the pathophysiology of human corneal diseases, including pterygium and keratoconus, is equally important (Shoham A. et al., FreeRad. Biol. Med. 2008;45:1047-1055). Diabetic retinopathy is also associated with oxidative stress and PUFA peroxidation (Baynes JW, Thorpe SR. Diabetes 1999;48:1-9).

[0114] In one aspect of the present invention, the oxidative stress-related disorder is a neurological disease, such as Alzheimer's disease, Parkinson's disease, synucleinopathies, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), schizophrenia, and bipolar disorder (BP). Major neurological diseases have been reported to be associated with oxidative stress. For example, oxidized membrane components promote β- and α-synuclein aggregation through covalent and noncovalent mechanisms, respectively, which are associated with Alzheimer's disease (AD) and Parkinson's disease (PD) as well as synucleinopathies. Reaction products of PUFA peroxidation can induce protein misfolding in sporadic amyloid diseases, the most clinically significant neurological brain disorders (Bieschke J. et al., Acc. Chem. Res. 2006;39:611-619).

[0115] Alzheimer's disease (AD) and mild cognitive impairment (MCI) have been reported in Cooper JL. Drugs & Aging 2003;20:399-418. Amyloid plaques and neurofibrillary tangles are neuropathological hallmarks of AD, but whether they are a cause or a consequence of the disease remains controversial. Oxidative stress and associated inflammation are involved in the AD process. Direct evidence supporting increased oxidative stress in AD includes (1) increased ROS-stimulating Fe, Al, and Hg in AD brains, (2) increased PUFA peroxidation and decreased PUFAs in AD brains, and increased 4-HNE in AD ventricular fluid, (3) increased protein and DNA oxidation in AD brains, (4) impaired energy metabolism and decreased cytochrome c oxidase in AD brains, (5) advanced glycation end products (AGEs), MDA, carbonyls, peroxynitrite, heme oxygenase-1, and SOD-1 in neurofibrillary tangles, and AGEs, heme oxygenase-1, and SOD-1 in senile plaques, and (6) studies demonstrating that amyloid-β peptide can generate ROS (Markesberry WR. Free Rad. Biol. Med. 1997;23:134-147).

[0116] Amyotrophic lateral sclerosis (ALS) is a slow-onset, progressive neurodegenerative disease that affects motor neurons (loss of upper and lower motor neurons), resulting in muscle wasting and death from respiratory failure (Boillee S. et al., Neuron 2006; 52:39-59). While the etiology of most ALS cases remains unknown, ALS is recognized to be strongly associated with oxidative stress. Familial ALS (fALS) is caused by the oxidation of mutant SOD (superoxide dismutase) (Kabashi E. et al., Ann. Neurol. 2007; 62:553-559). There are over 100 mutations in SOD associated with fALS (Barnham KJ et al., Nature Rev. Drug Discov. 2004;3:205-214). The first step is "monomerization" of SOD, followed by aggregation of SOD monomers and subsequent formation of abnormal disulfide bonds between them (Kabashi E. et al., Ann. Neurol. 2007;62:553-559), resulting in toxic aggregates (Barnham KJ et al., Nature Rev. Drug Discov. 2004;3:205-214). The etiology of ALS cases remains unclear, but it is recognized that ALS is associated with oxidative stress and inflammation. Protein oxidation has been reported in as many as 85% of sporadic ALS (sALS) patients in one study (Coyle JT et al., Science 1993;262:689-695). Increased lipid peroxidation and HNE formation in central nervous system (CNS) tissue, cerebrospinal fluid, and serum have also been reported in both familial and sporadic ALS cases (Simpson EP et al., Neurology 2004;62:1758-1765). The source of oxidative stress in ALS is unclear but could result from several processes, including excitotoxicity, mitochondrial dysfunction, iron accumulation, or immune activation (Simpson EP et al., Neurology 2004;62:1758-1765).There is evidence that mitochondria play an important role in fALS and sALS, both of which are triggers and targets of oxidative stress in ALS (Bacman SR et al., Molec. Neurobiol. 2006;33:113-131). Cyclooxygenase-2 (COX-2) inhibition has been reported to reduce spinal cord neurodegeneration and prolong survival of ALS transgenic mice (Minghetti L. J Neuropathol Exp Neurol 2004;63:901-910), highlighting the role of PUFA oxidation products in the pathogenesis of ALS. There is also evidence of increased HHE-protein coupling in ALS patients (Long EK, Picklo MJ. Free Rad. Biol. Med. 2010;49:1-8). Despite the association of oxidative stress with ALS, attempts at antioxidant therapy have not yet been successful (Barber SC et al., Biochim. Biophys. Acta 2006;1762:1051-1067).

[0117] Parkinson's disease (PD) is associated with oxidative stress caused by reactive oxygen species (ROS), which contribute to the cascade that leads to dopaminergic cell degeneration in PD. However, oxidative stress is closely linked to other components of the disease and degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity, and inflammation. The formation of toxic lipid peroxides within cells has been directly linked to damage in nigral neurons through the activation of toxic cellular cascades. PD-related oxidative damage begins at the PUFA level and then propagates to proteins and nuclear and mtDNA DNA (e.g., in synuclein processing / Lewy body formation). Toxic carbonyl products of oxidative damage, such as HNE and MDA, can further react with proteins and impair cell viability. Nitric oxide is known to react with superoxide to generate peroxynitrite and ultimately hydroxyl radicals. Altered proteolysis has been implicated as crucial for dopaminergic cell death in PD. Oxidative stress can directly impair these processes, and products of oxidative damage, such as HNE, can damage the 26S proteasome. HNE has been directly implicated in PD pathogenesis (Selley ML. Free Rad. Biol. Med. 1998;25:169-174; Zimniak P. Ageing Res. Rev. 2008;7:281-300). Furthermore, dysfunction of proteasome function leads to free radical generation and oxidative stress (Jenner P. Annals Neurol. 2003;53:S26-S36). A further source of ROS relevant to the pathogenesis of PD is the turnover of dopamine (DA) within dopaminergic neurons (Hastings TG, J. Bioenerg. Biomembr. 2009;41:469-72).Oxidative damage to nucleic acids mediated through PUFA peroxidation products also contributes to the pathogenesis of PD (Martin LJ, J. Neuropathol. Exp. Neurol. 2008;67:377-87; Nakabeppu Y. et al., J. Neurosci. Res. 2007;85:919-34). Whether oxidative stress is a cause or a consequence of PD, reducing oxidative stress is likely to affect disease progression.

[0118] In both schizophrenia and bipolar disorder (BP), oxidative stress and HNE levels are significantly elevated (Wang JF et al., Bipolar Disorders 2009;11:523-529). Synaptic dysfunction is known to be an early pathogenic event in neuropathologies such as AD, ALS, and PD (LoPachin RM et al., Neurotoxicol. 2008;29:871-882). Although the molecular mechanisms of this synaptic toxicity are unknown, published evidence suggests that these diseases are characterized by a common pathophysiological cascade of oxidative stress, PUFA peroxidation (Figure 1), and the subsequent release of α,β-unsaturated carbonyl derivatives such as acrolein and 4-HNE.

[0119] In one aspect of the present invention, the oxidative stress-related disorder is Down's syndrome (DS). DS (trisomy of chromosome 21) is associated with premature aging and mental retardation similar to Alzheimer's disease. There is also a high incidence of autoimmune diseases and cataracts, indicating increased oxidative stress in DS subjects (Jovanovic SV et al., Free Rad. Biol. Med. 1998;25:1044-1048). Chromosome 21 encodes Cu / ZnSOD and amyloid β-peptide; therefore, DS is characterized by an overflow of these gene products and metabolites, particularly an elevated SOD to catalase ratio accompanied by excess H2O2 (Sinet PM. Ann. NY Acad. Sci. 1982;396:83-94). Markers of protein and lipid oxidation (e.g., MDA, HNE), as well as advanced glycation end products and advanced lipoxidation end products, are significantly increased in subjects with DS (Busciglio J, Yankner BA. Nature 1995;378:776-779; Odetti P et al., Biochem. Biophys. Res. Comm. 1998;243:849-851).

[0120] In one aspect of the present invention, the composition of the present invention may be used to treat (cure or alleviate) an oxidative stress-related disorder that has already occurred, or may be used to prevent the onset of an anticipated oxidative stress-related disorder.

[0121] In one aspect of the present invention, the composition of the present invention may be used in combination with other therapeutic agents. In this case, the composition may be used to prevent or treat side effects caused by the other therapeutic agents. Specific examples of the other therapeutic agents include anticancer agents, antipyretic analgesics, etc.

[0122] Anticancer drugs include doxorubicin, cisplatin, vinblastine, mitomycin C, and camptothecin, and their side effects include fatigue, nausea, loss of appetite, depression, bone marrow suppression (leukopenia, anemia, thrombocytopenia, etc.), gastrointestinal disorders (stomatitis, diarrhea, etc.), skin disorders (hair loss, nail changes, etc.), myocardial damage, kidney damage, lung damage, and peripheral neuropathy.

[0123] Antipyretic analgesics include diclofenac sodium, loxofenac sodium, acetaminophen, and aspirin, and their side effects include liver damage, kidney damage, gastrointestinal disorders (erosive gastritis, gastric ulcers, duodenal ulcers, etc.), and Stevens-Johnson syndrome.

[0124] In one aspect of the present invention, the composition of the present invention can be used as a drug for preventing or treating side effects, with the aim of preventing side effects caused by oxidative stress due to other therapeutic agents.

[0125] In one aspect of the present invention, the composition of the present invention may contain, in addition to the active ingredient, one or more pharmaceutically acceptable additives. The additives are not particularly limited as long as they are used as pharmaceutical additives, and examples thereof include diluents (e.g., solvents and excipients), binders, lubricants, glidants, plasticizers, disintegrants, buffers, stabilizers, etc.

[0126] In one aspect, the composition of the present invention can be formulated in a dosage form that is appropriately selected depending on the route of administration. In one embodiment, the composition is a liquid or soft capsule. The administration may be oral or parenteral (e.g., intravenous, intramuscular, subcutaneous, transdermal, intrathecal, or intraocular), with oral administration being preferred. Administration is preferably daily for multiple days. For example, to better achieve antioxidant induction, the composition can be administered daily for 7 days or more, preferably 14 days or more.

[0127] In one aspect of the present invention, the composition of the present invention can be used to alleviate oxidative stress. In one embodiment of the present invention, the composition can be used as a food composition (antioxidant-inducing food composition) or a cosmetic composition (antioxidant-inducing cosmetic composition). The composition for use in alleviating oxidative stress can be used to alleviate, for example, muscle fatigue, mental fatigue, rough skin, aging, etc.

[0128] In one aspect of the present invention, a composition for use in alleviating oxidative stress may contain, in addition to the active ingredient, one or more ingredients acceptable for food use. Such ingredients include flavorings, sweeteners, coloring agents, etc., in addition to the additives described above. More specifically, the food composition may be a dietary supplement in the form of a conventional food composition, such as a beverage, confectionery, dairy product, seasoning, or supplement.

[0129] In one aspect of the present invention, when the composition is in the form of a food, the food is not particularly limited and may be beverages, confectioneries, breads, soups, etc., and examples thereof include common retort foods, frozen foods, instant foods (such as noodles), canned foods, sausages, cookies, biscuits, cereal bars, crackers, snacks (such as potato chips), pastries, cakes, pies, candy, chewing gum (including pellets and sticks), jelly, soup, ice cream, dressings, yogurt, etc., supplements in the form of tablets, capsules, emulsions, etc., soft drinks, etc. These foods are not particularly limited as long as they do not impair the effects of the present invention, and can be produced according to the production methods used by those skilled in the art for each food.

[0130] In one aspect of the present invention, a composition for use in alleviating oxidative stress may contain, in addition to an active ingredient, one or more cosmetically acceptable ingredients. Such ingredients include solvents, surfactants, lubricants, stabilizers, colorants, preservatives, etc. More specifically, the cosmetic composition may be a quasi-drug of a conventional cosmetic, such as a skin cosmetic or hair cosmetic.

[0131] In one aspect of the present invention, a composition for use in alleviating oxidative stress may be an emulsion composition in which an active ingredient is mixed as an oil phase with an aqueous phase. The emulsion composition may be an oil-in-water (O / W) emulsion composition obtained by adding the oil phase to a D phase (surfactant phase) containing a surfactant (e.g., a nonionic surfactant), water, and glycerin, and then adding an aqueous phase.

[0132] In one aspect of the present invention, the practice of the present invention includes selling a product of the present invention by displaying the effects of the composition on packaging containers (boxes, bags, cans, bottles, etc.), product instructions, and pamphlets. The practice of the present invention also includes advertising and selling a product of the present invention by displaying the effects of the present invention on television, internet websites, pamphlets, newspapers, magazines, etc.

[0133] In one aspect of the present invention, the amount of an active ingredient selected from very long chain polyunsaturated fatty acids, their pharmaceutically functional derivatives, or their pharmaceutically acceptable salts ingested by a subject is not particularly limited, and may be ingested in an amount equal to or greater than the effective amount for achieving the desired oxidative stress-alleviating effect. In one aspect of the present invention, the amount of an ingredient selected from very long chain polyunsaturated fatty acids, their salts, and their esters ingested by a subject is not particularly limited, and may be ingested in an amount equal to or greater than the effective amount for achieving the desired oxidative stress-alleviating effect. For example, in the case of an adult, depending on conditions such as the age, weight, and health condition of the subject, the amount of very long-chain polyunsaturated fatty acids may be 2 mg / kg body weight / day or more, for example, 3 mg / kg body weight / day or more, 4 mg / kg body weight / day or more, 5 mg / kg body weight / day or more, 6 mg / kg body weight / day or more, 7 mg / kg body weight / day or more, 8 mg / kg body weight / day or more, 9 mg / kg body weight / day or more, 10 mg / kg body weight / day or more, 11 mg / kg body weight / day or more, 12 mg / kg body weight / day or more, 13 mg / kg body weight / day or more, 14 mg / kg body weight / day or more, 15 mg / kg body weight / day or more, 16 mg / kg body weight / day or more, 17 mg / kg body weight / day or more, 18 mg / kg body weight / day or more, 19 mg / kg body weight / day or more, 20 mg / kg body weight / day or more, 21 mg / kg body weight / day or more, 22 mg / kg body weight / day or more, 23 mg / kg body weight / day or more, 24 mg / kg body weight / day or more, 25 mg / kg body weight / day or more, 30 mg / kg body weight / day or more, 40 mg / kg body weight / day or more, 50 mg / kg body weight / day or more, 100 mg / kg body weight / day or more, or 200 mg / kg body weight / day or more of the active ingredient can be ingested for 4 weeks or more, for example, 5 weeks or more, 6 weeks or more, 7 weeks or more, 8 weeks or more, 9 weeks or more, 10 weeks or more, 11 weeks or more, or 12 weeks or more.

[0134] Furthermore, since the active ingredient selected from very long chain polyunsaturated fatty acids, their pharmaceutically functional derivatives, or their pharmaceutically acceptable salts does not have any significant side effects, there is no limit to the daily intake amount.Similarly, since the ingredient selected from very long chain polyunsaturated fatty acids, their salts, and their esters does not have any significant side effects, there is no limit to the daily intake amount.Examples of the present invention are described below, but the present invention is not limited to these in any way.

[0135] Example 1: Evaluation of oxidative stress by quantification of reactive oxygen species. Human alveolar epithelial cells were cultured at 1.5 x 10 4 Cells were seeded at 1 / well in a 96-well microplate and cultured overnight at 37°C in 5% CO2. The medium was removed by aspiration and replaced with medium containing 40 μM DCFH-DA (Wako Pure Chemical Industries), followed by incubation for 30 minutes. The medium was then removed by aspiration, the cells were washed with PBS, and then treated with 800 μM hydrogen peroxide for 1 hour. Fluorescence intensity was measured at excitation (485 nm) and emission (538 nm) using a fluorescence plate reader. The absorbance value of the well not treated with hydrogen peroxide was set to 1, and the relative fluorescence intensity of the treated wells was calculated.

[0136] The results are shown in Figure 1. The vertical axis of the graph shows the relative production of ROS (reactive oxygen species). ROS production was significantly increased in the 800 μM hydrogen peroxide-treated group compared to the untreated group.

[0137] [Example 2] Evaluation of protective effect against oxidative stress Human alveolar epithelial cells (8x10 3 Cells were seeded at 1 / well in a 96-well microplate and cultured overnight at 37°C and 5% CO2. The medium was removed by aspiration and replaced with medium containing various concentrations of fatty acid ethyl esters (prepared according to the method described in US 2013 / 0190399 A1) and incubated at 37°C and 5% CO2 for 24 hours. After removing the medium by aspiration, the medium was replaced with medium containing 800 μM hydrogen peroxide and incubated for an additional 8 hours at 37°C and 5% CO2. CCK8 (Dojindo Laboratories) was added to each well, and the absorbance at 450 nm of the samples was measured after 1.5 hours. The absorbance value of the wells not treated with hydrogen peroxide was set to 1, and the relative survival rate of each treatment was calculated.

[0138] Test area 1: Control Test area 2: Hydrogen peroxide Test area 3: 10 μM arachidonic acid (C20:4n-6) ethyl ester + hydrogen peroxide Test area 4: 30 μM arachidonic acid (C20:4n-6) ethyl ester + hydrogen peroxide Test area 5: 10 μM C32:4n-6 ethyl ester + hydrogen peroxide Test area 6: 30 μM C32:4n-6 ethyl ester + hydrogen peroxide

[0139] The results are shown in Figure 2. Figure 2 is a graph showing the relative cell viability of human retinal pigment epithelial cells after treatment with hydrogen peroxide obtained in the above test. At the same treatment concentration, C32:4n-6 ethyl ester showed a significantly higher cell viability than arachidonic acid (C20:4n-6) ethyl ester.

[0140] Furthermore, compared with the treatment with hydrogen peroxide alone, arachidonic acid (C20:4n-6) ethyl ester showed a significantly lower cell survival rate, while C32:4n-6 ethyl ester showed a significantly higher survival rate.

[0141] [Example 3] Evaluation of protective effect against oxidative stress Human retinal pigment epithelial cells were cultured at 1x10 4 Cells were seeded at 1 / well onto a 96-well microplate and cultured overnight at 37°C and 5% CO2. The medium was removed by aspiration and replaced with medium containing various concentrations of fatty acid ethyl esters, followed by 24 hours of incubation at 37°C and 5% CO2. After removing the medium by aspiration, the medium was replaced with medium containing 300 μM hydrogen peroxide and further incubated for 24 hours at 37°C and 5% CO2. CCK8 (Dojindo Laboratories) was added to each well, and the absorbance at 450 nm of the samples was measured after 1.5 hours. The absorbance value of the wells not treated with hydrogen peroxide was set to 1, and the relative survival rate of each treatment was calculated.

[0142] Test area 1: Control Test area 2: Hydrogen peroxide Test area 3: 10 μM arachidonic acid (C20:4n-6) ethyl ester + hydrogen peroxide Test area 4: 30 μM arachidonic acid (C20:4n-6) ethyl ester + hydrogen peroxide Test area 5: 10 μM C32:4n-6 ethyl ester + hydrogen peroxide Test area 6: 30 μM C32:4n-6 ethyl ester + hydrogen peroxide

[0143] The results are shown in Figure 3. Figure 3 is a graph showing the relative cell viability of human retinal pigment epithelial cells after treatment with hydrogen peroxide obtained in the above test. At the same treatment concentration, C32:4n-6 ethyl ester showed a significantly higher cell viability than either the untreated control or arachidonic acid (C20:4n-6) ethyl ester.

[0144] [Example 4] Evaluation of protective effect against oxidative stress Human retinal pigment epithelial cells were cultured at 1x10 4 Cells were seeded at 1 / well onto a 96-well microplate and cultured overnight at 37°C and 5% CO2. The medium was removed by aspiration and replaced with medium containing various concentrations of fatty acid ethyl esters, followed by 24 hours of incubation at 37°C and 5% CO2. After removing the medium by aspiration, the medium was replaced with medium containing 300 μM hydrogen peroxide and further incubated for 24 hours at 37°C and 5% CO2. CCK8 (Dojindo Laboratories) was added to each well, and the absorbance at 450 nm of the samples was measured after 1.5 hours. The absorbance value of the wells not treated with hydrogen peroxide was set to 1, and the relative survival rate of each treatment was calculated.

[0145] Test area 1: Control Test area 2: Hydrogen peroxide Test area 3: 10 μM eicosapentaenoic acid (C20:5n-6) ethyl ester + hydrogen peroxide Test area 4: 30 μM eicosapentaenoic acid (C20:5n-6) ethyl ester + hydrogen peroxide Test area 5: 10 μM C34:5n-3 ethyl ester + hydrogen peroxide Test area 6: 30 μM C34:5n-3 ethyl ester + hydrogen peroxide

[0146] The results are shown in Figure 4. Figure 1 is a graph showing the relative cell survival rate of human retinal pigment epithelial cells after treatment with hydrogen peroxide obtained in the above test. At the same treatment concentration, C34:5n-3 ethyl ester showed a higher cell survival rate than either untreated or eicosapentaenoic acid (C20:5n-3) ethyl ester.

[0147] The present invention provides a method for alleviating oxidative stress, or a method for treating or preventing an oxidative stress-related disease.

Claims

1. A composition for treating or preventing an oxidative stress-related disorder, comprising a very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein the pharmaceutically functional derivative is selected from the group consisting of esters, ethers and amides.

3. The composition of claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic salts and organic salts.

4. 2. The composition of claim 1, wherein the very long chain polyunsaturated fatty acid is a fatty acid having 24 or more, 26 or more, 28 or more, or 30 or more carbon atoms and 42 or less, 40 or less, or 38 or less carbon atoms, 3 or more, or 4 or more, and 6 or less double bonds, and 0 or more, and 1 or less, 2 or less, or 3 or less hydroxyl groups.

5. The very long chain polyunsaturated fatty acid has the following formula: 【Chemistry 1】 wherein m1, m2, m3, and m4 are independently an integer selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18, or 10 to 18, and R is a hydrogen atom. The composition according to claim 1, wherein the fatty acid is any one of the following:

6. 2. The method of claim 1, wherein the very long chain polyunsaturated fatty acid is selected from C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3, C34:6n-3, C32:3n-6, and C34:3n-6.

7. 2. The composition according to claim 1, wherein the very long chain polyunsaturated fatty acid is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid.

8. 2. The composition of claim 1, wherein the very long chain polyunsaturated fatty acid (VLC-PUFA), a pharmaceutically functional derivative thereof, or a pharmaceutically acceptable salt thereof is an ethyl ester of a very long chain polyunsaturated fatty acid.

9. The composition according to claims 1 to 8, wherein the oxidative stress-related disorder is selected from the group consisting of eye diseases, neurological diseases, inflammatory responses to oxidative stress, Down's syndrome (DS), cancer, cardiovascular diseases, respiratory diseases, lifestyle-related diseases, skin disorders, digestive diseases, liver diseases, kidney diseases, autoimmune diseases, otorhinolaryngological diseases, sepsis, stress after organ transplantation, chronic fatigue syndrome, and age-related diseases.

10. The composition according to claims 1 to 8, wherein the oxidative stress-related disorder is selected from the group consisting of age-related macular degeneration (AMD), cataracts, diabetic retinopathy, Alzheimer's disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down's syndrome (DS), schizophrenia, bipolar disorder (BD), and synucleinopathy.

11. 9. The composition according to any one of claims 1 to 8, wherein the oxidative stress-related disorder is selected from the group consisting of inflammatory response to oxidative stress, retinal degeneration, atherosclerosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Friedreich's ataxia, tardive dyskinesia, brain injury (e.g., ischemia), photoaging of the skin, reperfusion injury, stroke, myocardial infarction, hypertension, heart failure, epilepsy, hyperhomocysteinemia, physiological aging, sepsis, and stress after organ transplantation.

12. The composition according to any one of claims 1 to 8, wherein the oxidative stress-related disorder is a disorder caused by free radicals or active oxygen in the body.

13. Oxidative stress-related disorders ・ O ２ － (superoxide anion), H ２ O ２ (hydrogen peroxide), ・ OH (hydroxyl radical), ROOH (organic hydroperoxide), RO ・ (alkoxyl radical), ROO ・ (peroxyl radical), HOCl (hypochlorous acid), OONO － (peroxynitrite), NO ・ , １ O ２ (singlet oxygen), O ３ (ozone), or ・ NO ２ The composition according to any one of claims 1 to 8, which is a disorder associated with the presence of nitrogen dioxide.

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