WO2017119481A1

WO2017119481A1 - Cyclic dipeptide-containing composition for preventing neurological diseases

Info

Publication number: WO2017119481A1
Application number: PCT/JP2017/000255
Authority: WO
Inventors: 斉志渡辺; 寿栄鈴木; 満広ゼイ田; 雅史伊藤; 泰典藤田; 恭司郎川上
Original assignee: サントリーホールディングス株式会社
Priority date: 2016-01-08
Filing date: 2017-01-06
Publication date: 2017-07-13
Also published as: JPWO2017119481A1; TW201733608A

Abstract

Provided are: a composition for preventing neurological diseases; use of a material for preventing neurological diseases; and a method for preventing neurological diseases. It has been discovered that a particular cyclic dipeptide or a salt thereof is effective in preventing neurological diseases. The present invention provides a novel means for preventing neurological diseases such as dementia, schizophrenia, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, etc.

Description

Cyclic dipeptide-containing composition for preventing neurological diseases

The present invention relates to a composition for preventing neurological diseases. More specifically, a composition for preventing a neurological disease containing a specific cyclic dipeptide or a salt thereof having an amino acid as a constituent unit as an active ingredient, use of a specific cyclic dipeptide or a salt thereof for preventing a neurological disease, and a specification The present invention relates to a method for preventing neurological diseases using the cyclic dipeptides or salts thereof.

The increase in the number of patients with neurological diseases accompanying the arrival of an aging society is a serious problem in modern society. The neurological disease is a disease that occurs due to a decrease in function or death of a specific group of nerve cells present in the brain or spinal cord. Representative neurological diseases include dementia, schizophrenia, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis and the like. It has been reported that the onset of these neurological diseases involves neuronal inflammation resulting from microglial cell activation (Non-patent Documents 1 and 2). For example, Non-Patent Documents 3 and 4 report that microglial cell activation is involved in the development of dementia and schizophrenia. Non-patent documents 5 and 6 report that neuronal inflammation caused by nitric oxide and inflammatory cytokines secreted with microglial cell activation is involved in the development of Alzheimer's disease and Parkinson's syndrome. Yes. Furthermore, it has been reported that microglia cells are involved in amyotrophic lateral sclerosis (Non-patent Document 7).

Since the above-mentioned neurological diseases have such characteristics that they have a long incubation period and are difficult to treat after onset, prevention before onset is important. On the other hand, taking an artificially synthesized compound for a long period before the onset of a neurological disease is not preferable because of the possibility of unexpected side effects. Therefore, development of an active ingredient that is safe and can be taken for a long time is desired.

Under such circumstances, “dipeptides” in which two amino acids are combined are attracting attention as functional substances. Dipeptides can be added with physical and chemical properties and new functions not found in single amino acids, and are expected to have a range of applications beyond single amino acids.

In recent years, diketopiperazine derivatives, which are cyclic dipeptides having a cyclic structure formed by dehydration condensation of an amino group and a carboxyl group present at the end of a dipeptide, have been developed. The cyclic dipeptide has been reported to have various physiological activities, and the demand is expected to expand in the medical field and the pharmacological field. For example, Patent Document 1 reports that a cyclic dipeptide having a 2,5-diketopiperazine structure has an antidepressant action, a learning motivation improving action, and the like. In Non-Patent Document 8, cyclohistidylproline [Cyclo (His-Pro)] is a central nervous system action such as a decrease in body temperature and appetite suppression, and a hormone-like action such as suppression of prolactin secretion and promotion of growth hormone secretion. In addition, cycloleucylglycine [Cyclo (Leu-Gly)] has an effect of improving memory function, and cycloaspartylproline [Cyclo (Asp-Pro)] suppresses fat preference. There are also reports that it works. Non-patent document 9 reports that cyclohistidylproline [Cyclo (His-Pro)] exhibits a cytoprotective action.

Non-Patent Document 10 discloses that cyclotryptophanylproline [Cyclo (Trp-Pro)] exhibits anticancer activity, cyclohistidylproline [Cyclo (His-Pro)] and cycloglycylproline [Cyclo (Gly -Pro)] exhibits antibacterial activity, cycloglycylproline [Cyclo (Gly-Pro)] exhibits memory function improving activity, and cyclotyrosylproline [Cyclo (Tyr-Pro)] and cyclophenylalanyl It is described that proline [Cyclo (Phe-Pro)] exhibits an action as a biological herbicide.

Special table 2012-517998 gazette

An object of the present invention is to provide a composition for preventing neurological diseases, use of a material for preventing neurological diseases, and a method for preventing neurological diseases.

As a result of intensive studies on the above problems, the present inventors have found that a specific cyclic dipeptide has a preventive effect on neurological diseases. In addition, it has been found that a specific cyclic dipeptide has an inhibitory effect on the secretion of nitric oxide from microglia cells, and as a result, it is considered that a specific cyclic dipeptide has an inhibitory effect on microglial cell activation and an inhibitory effect on neuronal inflammation. The present invention has been completed.

That is, the present invention relates to the following, but is not limited thereto.
(1) A composition for preventing neurological diseases comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosylglycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)], cyclolysylphenylalanine. One or more selected from the group consisting of [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)]. The above-mentioned composition for preventing neurological diseases.
(2) The composition for preventing neurological diseases according to (1), wherein the cyclic dipeptide or a salt thereof contains three or more selected from the group described in (1).
(3) The agent for preventing a neurological disease according to (1) or (2), which has an action of suppressing inflammation of nerve cells.
(4) The composition for preventing neurological diseases according to any one of (1) to (3), which has an action of suppressing secretion of nitric oxide from microglia cells.
(5) The composition for preventing neurological disease according to any one of (1) to (4), which has an action of suppressing activation of microglia cells.
(6) The composition for preventing neurological disease according to any one of (1) to (5), which has an effect of preventing dementia.
(7) The composition for preventing neurological disease according to any one of (1) to (5), which has a preventive effect on schizophrenia.
(8) The neurological disease preventive agent according to any one of (1) to (5), which has an effect of preventing Alzheimer's disease.
(9) The composition for preventing neurological disease according to any one of (1) to (5), which has a preventive effect on Parkinson's syndrome.
(10) The composition for preventing neurological disease according to any one of (1) to (5), which has an effect of preventing amyotrophic lateral sclerosis.
(11) The composition for preventing neurological disease according to any one of (1) to (10), which is labeled with a function regarding prevention of neurological disease,
Function indications are `` reducing the risk of developing neurological disease '', `` reducing the risk of developing dementia '', `` reducing the risk of developing Alzheimer's disease '', `` reducing the risk of developing Parkinson's syndrome '', `` schizophrenia The composition for preventing neurological disease, which is selected from the group consisting of “reducing the onset risk of” and “reducing the onset risk of amyotrophic lateral sclerosis”.
(12) Use of a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for preventing neurological diseases,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosylglycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)], cyclolysylphenylalanine. One or more selected from the group consisting of [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)]. The use as described above.
(13) A method for preventing neurological diseases, comprising using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosylglycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)], cyclolysylphenylalanine. One or more selected from the group consisting of [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)]. The method as described above.

According to the present invention, a composition having a preventive effect on neurological diseases can be provided. Since the specific cyclic dipeptide or a salt thereof contained as an active ingredient in the composition of the present invention has high safety, it can be said that the composition of the present invention has high utility value in the market. Further, by ingesting the composition of the present invention, an effect of suppressing secretion of nitric oxide from microglia cells, an effect of suppressing activation of microglia cells, an effect of suppressing inflammation of nerve cells, and the like are obtained, thereby preventing dementia. The effect of preventing schizophrenia, the effect of preventing Alzheimer's disease, the effect of preventing Parkinson's syndrome, the effect of preventing amyotrophic lateral sclerosis and the like are exhibited.

FIG. 1 shows a cyclic dipeptide (Cyclo (Lys-Lys), Cyclo (Tyr-Gly), Cyclo (Ile-Pro), Cyclo (Lys-Phe), Cyclo (Leu-Lys), Cyclo (Thr-Tyr): final concentration 50 [mu] M) and LPS (final concentration 100 ng / mL) in the simultaneous addition conditions, in the case of the production of production amount (distilled water added group of nitric oxide produced from BV2 microglial cells and 100 NO ₂ ^- production Amount). FIG. 2 shows cyclic dipeptides (Cyclo (Lys-Lys), Cyclo (Tyr-Gly), Cyclo (Ile-Pro), Cyclo (Lys-Phe), Cyclo (Leu-Lys), Cyclo (Thr-Tyr), Cyclo (His-Pro): the production amount of nitric oxide produced from BV2 microglia cells under the simultaneous addition conditions of LPS (final concentration 100 ng / mL) and LPS (final concentration 50 μM) NO ₂ in the case of ^- produced amount) shows a. FIG. 3 shows cyclic dipeptides (Cyclo (Lys-Lys), Cyclo (Tyr-Gly), Cyclo (Ile-Pro), Cyclo (Lys-Phe), Cyclo (Leu-Lys), Cyclo (Thr-Tyr): final concentration 100 [mu] M) and LPS (final concentration 100 ng / mL) in the simultaneous addition conditions, in the case of the production of production amount (distilled water added group of nitric oxide produced from BV2 microglial cells and 100 NO ₂ ^- production Amount). FIG. 4 shows cyclic dipeptides (Cyclo (Lys-Lys), Cyclo (Tyr-Gly), Cyclo (Ile-Pro), Cyclo (Lys-Phe), Cyclo (Leu-Lys), Cyclo (Thr-Tyr), Cyclo (His-Pro): the amount of nitric oxide produced from BV2 microglia cells under the simultaneous addition conditions of LPS (final concentration 100 ng / mL) and LPS (final concentration 100 μM) NO ₂ in the case of ^- produced amount) shows a. FIG. 5 shows cyclic dipeptides (Cyclo (Lys-Lys), Cyclo (Tyr-Gly), Cyclo (Ile-Pro), Cyclo (Lys-Phe), Cyclo (Leu-Lys), Cyclo (Thr-Tyr): final concentration 200 [mu] M) and LPS (final concentration 100 ng / mL) in the simultaneous addition conditions, in the case of the production of production amount (distilled water added group of nitric oxide produced from BV2 microglial cells and 100 NO ₂ ^- production Amount). FIG. 6 shows cyclic dipeptides (Cyclo (Lys-Lys), Cyclo (Tyr-Gly), Cyclo (Ile-Pro), Cyclo (Lys-Phe), Cyclo (Leu-Lys), Cyclo (Thr-Tyr), Cyclo (His-Pro): the production amount of nitric oxide produced from BV2 microglia cells under the simultaneous addition conditions of LPS (final concentration of 100 ng / mL) and LPS (final concentration of 200 μM). NO ₂ in the case of ^- produced amount) shows a.

1. Term 1-1. Neurological disease As used herein, “neurological disease” refers to a disease that occurs due to a decrease in function or death of a specific group of nerve cells present in the brain or spinal cord. Representative neurological diseases include, but are not limited to, dementia, schizophrenia, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, and the like.

1-2. Microglial cells In the present specification, it is reported that the inflammation of neuronal cells resulting from the activation of microglial cells is involved in the onset of the above-mentioned neurological diseases. In this specification, “microglial cells” refers to central nerves existing in the brain. This is one of the constituent cells of the system, and is responsible for immune defense in the brain through the function of cleaning the brain damage site and the function of presenting antigens. When microglial cells are activated by various stimuli, they release humoral factors such as inflammatory cytokines, nitric oxide and active oxygen, and cause inflammation of nerve cells existing in the brain. In addition, neuronal inflammation leads to the onset of neurological diseases such as dementia, schizophrenia, Alzheimer's disease, Parkinson's syndrome, and amyotrophic lateral sclerosis. Therefore, if the activation of microglia cells and the release of inflammatory cytokines, nitric oxide, active oxygen and other humoral factors from microglia cells can be suppressed, neuronal inflammation can be suppressed, resulting in dementia and schizophrenia. Effects of neurological diseases such as symptom, Alzheimer's disease, Parkinson's syndrome, and amyotrophic lateral sclerosis.

The activation of microglia cells and the suppression of inflammation of nerve cells can be evaluated by measuring the concentration of humoral factors such as inflammatory cytokines, nitric oxide and active oxygen released from microglia cells. The concentrations of inflammatory cytokines, nitric oxide, and active oxygen released from microglia cells can be measured according to known methods. For example, ELISA (Enzyme-Linked ImmunoSorbent Assay) method or Griess assay method can be used. it can.

2. Active ingredient 2-1. Cyclic dipeptide In this specification, “cyclic dipeptide” refers to a cyclic dipeptide having a diketopiperazine structure formed by dehydration condensation of an amino group and a carboxyl group of an amino acid. Say. In the present specification, cyclic dipeptides or salts thereof may be collectively referred to simply as cyclic dipeptides. Further, in this specification, as long as the cyclic dipeptides have the same amino acid configuration, any of their description order may be first, for example, [Cyclo (Tyr-Gly)] and [Cyclo (Gly-Tyr)] are It represents the same cyclic dipeptide.

Cyclic dipeptides have two amino acid terminal moieties attached via an amide bond, so they are more lipophilic than linear dipeptides that have a polar carboxyl group or amino group exposed at the molecular end. Is characterized by high. Therefore, cyclic dipeptides are superior in gastrointestinal permeability and membrane permeability compared to linear dipeptides.

Cyclic dipeptides or salts thereof contained as active ingredients in the present invention include cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosyl glycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile -Pro)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)] More preferably, the active ingredient is one or two or more selected from the cyclic dipeptides or salts thereof.

As used herein, the term “cyclic dipeptide salt” refers to any pharmacologically acceptable salt (including inorganic salts and organic salts) of the cyclic dipeptide, such as sodium salt and potassium salt of the cyclic dipeptide. , Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate , Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, and the like), but are not limited thereto. Cyclic dipeptide salts can be readily prepared by those skilled in the art by any method known in the art.

The cyclic dipeptide used in the present invention can be prepared according to a method known in the art. For example, it may be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or may be synthesized by dehydration and cyclization of a linear peptide. JP 2003-252896 A, Journal of Peptide や Science, 10, 737-737, 2004. For example, an animal and plant derived peptide heat-treated product rich in cyclic dipeptide can be obtained by further heat-treating an animal and plant derived peptide obtained by subjecting a raw material containing animal and plant derived protein to enzyme treatment or heat treatment.

In this specification, “high temperature heat treatment” means that the treatment is performed for a certain period of time at a temperature of 100 ° C. or higher and a pressure exceeding atmospheric pressure. As the high-temperature and high-pressure treatment device, a pressure-resistant extraction device, a pressure cooker, an autoclave, or the like can be used according to conditions.

The temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, but is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, and still more preferably 120 ° C to 140 ° C. In addition, this temperature shows the value which measured the exit temperature of an extraction column, when using a pressure-resistant extraction apparatus as a heating apparatus, and when using an autoclave as a heating apparatus, it is the temperature of the center temperature in a pressure vessel. The measured value is shown.

The pressure in the high-temperature heat treatment is not particularly limited as long as it is a pressure exceeding atmospheric pressure, but is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, and even more preferably 0.101 MPa to 0. 48 MPa.

The high-temperature heat treatment time is not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably about 60 minutes to 300 minutes. It is.

In addition, the high-temperature heat treatment conditions for the animal and plant derived peptides are not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but preferably [temperature: pressure: time] is [100 ° C. to 170 ° C .: 0.101 MPa to 0.001. 79 MPa: 15 minutes to 600 minutes], more preferably [110 ° C. to 150 ° C .: 0.101 MPa to 0.60 MPa: 30 minutes to 500 minutes], even more preferably [120 ° C. to 140 ° C .: 0.101 MPa to 0 48 MPa: 60 minutes to 300 minutes].

In addition, you may perform processes, such as filtration, centrifugation, concentration, ultrafiltration, freeze-drying, and pulverization, with respect to the heat-processed peptide derived from animals and plants as desired. In addition, if the specific cyclic dipeptide in the heat-treated product of animal and plant derived peptides does not satisfy the desired content, the specific cyclic dipeptide that is deficient may be appropriately added using other animal or plant derived peptides, commercial products, or synthetic products. it can.

3. Animal and Plant Derived Peptide The “animal and plant derived peptide” in the present specification is not particularly limited, and for example, soybean peptide, whey peptide, malt peptide, placenta peptide, collagen peptide and the like can be used. Animal and plant-derived peptides may be prepared and used from animal or plant-derived proteins or raw materials containing proteins, but commercially available products may also be used.

3-1. Soybean peptide As used herein, “soybean peptide” refers to a low molecular weight peptide obtained by subjecting soy protein to enzyme treatment or heat treatment to lower the molecular weight of the protein. Soybeans (scientific name: Glycine max) used as a raw material can be used without restriction of varieties and production areas, and can also be used in processed products such as pulverized products.

3-2. Whey peptide As used herein, “whey peptide” means whey (whey protein) is hydrolyzed by an enzyme such as protease, and the filtrate obtained by filtering this is sterilized and / or concentrated and dried. The obtained low molecular weight peptide. The whey peptide raw material is not particularly limited, and examples thereof include WPC (whey protein concentrate) and WPI (whey protein isolate) which are whey proteins. There are various degrees of decomposition, but when the degree of decomposition is low, the milky odor becomes strong and the liquidity after dissolution tends to be opaque (white turbidity). On the other hand, when the degree of decomposition is high, the liquidity at the time of dissolution becomes transparent, but it tends to increase bitterness and astringency.

3-3. Malt peptide As used herein, the term “malt peptide” refers to a malt-derived low molecular weight peptide obtained by subjecting an extract obtained from malt or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of the protein. . Although the malt peptide used as a raw material can be used without restriction of varieties and production areas, barley malt obtained by germinating barley seeds is particularly preferably used.

3-4. The placenta peptide placenta is the placenta of mammals and has been used as a health food, cosmetics, and pharmaceutical material in recent years because of its excellent functionality. In the present specification, “placenta peptide” refers to a placenta that has been solubilized and reduced in molecular weight by enzyme treatment or subcritical treatment. In addition, although different from the original meaning, extracts obtained from plant placenta are used in health foods, cosmetics, etc. as having a physiological effect equivalent to placenta derived from placenta. be called. The “placenta peptide” in the present specification includes those obtained by subjecting plant placenta to enzyme treatment or subcritical treatment, solubilization and low molecular weight.

3-5. Collagen peptide As used herein, the term “collagen peptide” refers to a low molecular peptide obtained by subjecting collagen or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of collagen. Collagen is a major protein in animal connective tissue and is the most abundant protein in mammalian bodies including humans.

4). 4. Composition for preventing neurological diseases 4-1. Cyclic dipeptide-containing composition for preventing neurological diseases One embodiment of the present invention is a composition for preventing neurological diseases comprising a specific cyclic dipeptide or a salt thereof as an active ingredient.

The composition for preventing neurological diseases of the present invention includes cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosyl glycine [Cyclo (Tyr-Gly)], cycloisoleucil proline [Cyclo (Ile-Pro)]. 1 or 2 selected from the group consisting of cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)] One or more cyclic dipeptides or salts thereof are used as active ingredients. Preferably, three or more selected from the cyclic dipeptides or salts thereof are used as active ingredients.

The content of the cyclic dipeptide or a salt thereof in the composition for preventing neurological diseases of the present invention may be an amount that can achieve the desired effect of the present invention, taking into consideration its administration form, administration method, etc. It is not limited. For example, when soybean peptide, whey peptide, malt peptide, placenta peptide, or collagen peptide is used as a raw material, the total content of the cyclic dipeptide or its salt in the present invention is 1.0 × 10 ppm or more, preferably 1.0. × 10 ² ppm or more, more preferably 1.0 × 10 ³ ppm or more, 2.0 × 10 ⁵ ppm or less, preferably 1.0 × 10 ⁵ ppm or less, more preferably 2.5 × 10 ⁴ ppm Typically, 1.0 × 10 ppm to 2.0 × 10 ⁵ ppm, preferably 1.0 × 10 ² ppm to 1.0 × 10 ⁵ ppm, more preferably 1.0 ppm × 10 ³ ~ 2.5 × 10 ⁴ ppm. Further, cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosyl glycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)] in the composition for preventing neurological diseases of the present invention. ], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloleucillysine [Cyclo (Leu-Lys)], cyclothreonyltyrosine [Cyclo (Thr-Tyr)], or a salt corresponding to each, Is 1.0 × 10 ppm or more, preferably 1.0 × 10 ² ppm or more, more preferably 1.0 × 10 ³ ppm or more, and 2.0 × 10 ⁵ ppm or less, preferably 1.0 × 10 ⁵ ppm or less, more preferably 2.5 × 10 ⁴ ppm or less, typically 1.0 × 10 ppm to 2.0 × 10 ⁵ ppm, preferably 1.0 × 10 ² ppm to 1.0 × ¹⁰ 5 ppm, more preferably 1.0 × 1 Is ^{^{3 ppm ~ 2.5 × 10 4 ppm}} .

Unless otherwise specified, “ppm” used herein means ppm by weight / volume (w / v), 1.0 ppm is converted to 1.0 × 10 ⁻³ mg / mL, It is converted to 1.0 × 10 ⁻⁴ wt%.

Further, when a synthetic product or purified product is used as the cyclic dipeptide or a salt thereof, the total amount of the cyclic dipeptide or a salt thereof in the composition for preventing neurological diseases of the present invention is not particularly limited, For example, 1.0 ppm or more, preferably 1.0 × 10 ppm or more, more preferably 1.0 × 10 ² ppm or more, 5.0 × 10 ⁵ ppm or less, preferably 5.0 × 10 ⁴ ppm or less, More preferably 5.0 × 10 ³ ppm or less, typically 1.0 ppm to 5.0 × 10 ⁵ ppm, preferably 1.0 × 10 ppm to 5.0 × 10 ⁴ ppm, more preferably 1.0 × 10 ² ppm to 5.0 × 10 ³ ppm. In addition, when a synthetic product or purified product is used as the cyclic dipeptide or a salt thereof, cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosyl glycine [Cyclo (Tyr-Gly)], cycloisoleucylproline [Cyclo (Ile-Pro)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], cyclothreonyltyrosine The content of [Cyclo (Thr-Tyr)] or a salt corresponding to each is not particularly limited, but is, for example, 1.0 ppm or more, preferably 1.0 × 10 ppm or more, more preferably 1. 0 × 10 ² ppm or more, 5.0 × 10 ⁵ ppm or less, preferably 5.0 × 10 ⁴ ppm or less, more preferably 5.0 × 10 ³ ppm or less. 0 ppm to 5.0 × 10 ⁵ pp m, preferably 1.0 × 10 ppm to 5.0 × 10 ⁴ ppm, more preferably 1.0 × 10 ² ppm to 5.0 × 10 ³ ppm.

The content of the cyclic dipeptide or a salt thereof can be measured according to a known method. For example, it can be measured by subjecting to LC-MS / MS.

4-2. Mechanism of action Microglial cells are present in the brain as one of the constituent cells of the central nervous system, and are responsible for immune defense in the brain through functions such as cleaning the brain damage site and providing antigens. When microglial cells are activated by various stimuli, they release humoral factors such as inflammatory cytokines, nitric oxide, and active oxygen, and cause inflammation of nerve cells existing in the brain. Further, neuronal inflammation promotes the onset of neurological diseases such as dementia, schizophrenia, Alzheimer's disease, Parkinson's syndrome, and amyotrophic lateral sclerosis. Therefore, if the activation of microglia cells and the release of humoral factors such as inflammatory cytokines, nitric oxide, and active oxygen from microglia cells can be suppressed, neuronal inflammation can also be suppressed. As a result, dementia, schizophrenia Effects of neurological diseases such as symptom, Alzheimer's disease, Parkinson's syndrome, and amyotrophic lateral sclerosis.

4-3. Other Components The composition for preventing neurological diseases of the present invention can contain any additive and any commonly used component in addition to the cyclic dipeptide or a salt thereof, depending on the form. Examples of these additives and / or ingredients include vitamins such as vitamin E and vitamin C, bioactive ingredients such as minerals, nutritional ingredients, and fragrances, as well as excipients and binders incorporated in the formulation. , Emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, colorants, coagulants, or coating agents, but are not limited thereto. It is not something.

4-4. Use The composition for preventing neurological diseases of the present invention contains the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient, thereby releasing humoral factors such as inflammatory cytokines, nitric oxide and active oxygen from microglia cells. In particular, the release of nitric oxide can be suppressed. Thereby, the inhibitory effect of the inflammation of the nerve cell in a brain is exhibited. Therefore, by ingesting the composition of the present invention, diseases caused by inflammatory disorders of nerve cells, such as dementia, Alzheimer's disease, Parkinson's syndrome, schizophrenia, amyotrophic lateral sclerosis, etc. Disease prevention effects can be obtained.

The composition for preventing a neurological disease of the present invention includes, for example, a raw material containing a cyclic dipeptide or a salt thereof, if necessary, a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient, a binder, a disintegrant, Or, add a lubricant, etc., and formulate it into a solid agent such as a tablet, granule, powder, powder, or capsule, or a liquid agent such as a normal solution, suspension, or emulsion according to a known method. be able to. These compositions can be taken with water or the like as it is. Moreover, after preparing the form (for example, powder form and granule form) which can be mix | blended easily, it can use, for example as a raw material of a pharmaceutical.

The present invention can be provided in the form of a composition as an example, but is not limited to this form, and may be provided in the form of an agent, for example. Moreover, the said agent can also be provided as a composition as it is, or as a composition containing the said agent. As an example, it can be provided in the form of a medicine or the like, but is not limited to this form. Examples of the composition of the present invention include, but are not limited to, a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like. Non-limiting examples of food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.

The composition for preventing neurological diseases of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it does not belong to pharmaceuticals, quasi-drugs, cosmetics, etc., or the Pharmaceutical Affairs Law, but it prevents neurological diseases, dementia, Alzheimer's disease, Parkinson's syndrome, schizophrenia Use as a composition that explicitly or implicitly promotes a prophylactic effect, a preventive effect of amyotrophic lateral sclerosis, etc.

In another aspect, the present invention relates to a composition containing the composition for preventing a neurological disease, which is labeled with a function related to the prevention of the neurological disease. Such indications or functional indications are not particularly limited. For example, “Preventing neurological diseases”, “Reducing the risk of developing neurological diseases”, “Preventing dementia”, “Preventing the risk of developing dementia” Reduce, "Prevent Alzheimer's disease," "Reduce the risk of developing Alzheimer's disease," "Prevent Parkinson's syndrome," "Reduce the risk of developing Parkinson's syndrome," "Prevent schizophrenia," "Integration “Reduce the risk of developing ataxia”, “Prevent amyotrophic lateral sclerosis”, or “Reduce the risk of developing amyotrophic lateral sclerosis”. In the present specification, such indications and indications such as function indications may be attached to the composition itself, or may be attached to the container or packaging of the composition.

The composition for preventing neurological diseases of the present invention can be taken by an appropriate method according to the form. Examples of ingestion methods include internal (oral), external, and injection methods, but the method is not particularly limited as long as the desired effect of the present invention is exhibited. In the present specification, “ingestion” is used to include all aspects of ingestion, taking, drinking, and the like.

The application amount of the composition for preventing a neurological disease of the present invention is set in a timely manner according to the form, administration method, purpose of use, and age, weight, and symptom of the subject patient or animal, and is not constant. The effective human intake of the cyclic dipeptide of the present invention or a salt thereof in the present invention is not constant, but for example, it is preferably 10 mg or more, more preferably 100 mg or more per day for a human with a body weight of 50 kg. Further, administration may be performed once or several times within one day within a desired dose range. The administration period is also arbitrary. Here, the effective human intake of the cyclic dipeptide of the present invention or a salt thereof is the total intake of the cyclic dipeptide or a salt thereof showing an effective effect in humans, and the type of the cyclic dipeptide is not particularly limited.

The subject of application of the composition for preventing neurological disease of the present invention is preferably a human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or mice, rats, guinea pigs, It may be a laboratory animal such as a monkey. When a non-human animal is administered to a subject, the amount used per day for about 20 g per mouse is the content of the active ingredient in the composition, the state of the subject, weight, sex, age, etc. Usually, the total amount of the cyclic dipeptide or its salt is preferably 10 mg / kg or more, more preferably 100 mg / kg or more.

5). Use of a cyclic dipeptide or a salt thereof for preventing a neurological disease One embodiment of the present invention is the use of a specific cyclic dipeptide or a salt thereof having an amino acid as a structural unit for the prevention of a neurological disease. Preferably, cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosyl glycine [Cyclo (Tyr-Gly)], cycloisoleucyl proline [Cyclo (Ile-Pro)], cyclolysyl phenylalanine [Cyclo (Lys-Lys- Phe)], cycloleucyl lysine [Cyclo (Leu-Lys)], and cyclothreonyl tyrosine [Cyclo (Thr-Tyr)], or one or more cyclic dipeptides or salts thereof Use for prevention of neurological diseases. More preferably, it is a use for the prevention of neurological disease of the thing containing 3 or more selected from the said cyclic dipeptide or its salt.

The use of the specific cyclic dipeptide or a salt thereof of the present invention includes, for example, use for preventing dementia, Alzheimer's disease, Parkinson's syndrome, schizophrenia, amyotrophic lateral sclerosis, etc. It is not limited to these. In addition, the use is a use in a human or non-human animal, and may be a therapeutic use or a non-therapeutic use. Here, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.

6). Method for Preventing Neurological Disease One aspect of the present invention provides a method for treating a neurological disease comprising administering to a subject in need of neurological disease prevention a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient. It provides a way to prevent. Preferably, cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosyl glycine [Cyclo (Tyr-Gly)], cycloisoleucyl proline [Cyclo (Ile-Pro)], cyclolysyl phenylalanine [Cyclo (Lys-Lys- Phe)], cycloleucyl lysine [Cyclo (Leu-Lys)], and cyclothreonyl tyrosine [Cyclo (Thr-Tyr)], or one or more cyclic dipeptides or salts thereof The present invention provides a method for preventing neurological diseases, comprising administering a therapeutically effective amount as an active ingredient. More preferably, the present invention provides a method for preventing a neurological disease, which comprises administering a therapeutically effective amount using a substance containing three or more selected from the above cyclic dipeptides or salts thereof as an active ingredient.

The subject in need of neurological disease prevention is the same as the administration subject of the composition for preventing neurological disease of the present invention.

In addition, in the present specification, the therapeutically effective amount is an amount that can prevent a neurological disease when a specific cyclic dipeptide of the present invention or a salt thereof is ingested by the subject, compared to a subject that is not ingested. That is. The specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, weight, symptom, etc. of the subject and is not constant.

In the method of the present invention, the specific cyclic dipeptide or a salt thereof may be administered as it is or as a composition containing the specific cyclic dipeptide or a salt thereof so that the therapeutically effective amount is obtained.

According to the method of the present invention, it becomes possible to prevent neurological diseases without causing side effects.

Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereby. Those skilled in the art can use the method of the present invention with various changes and modifications, and these are also included in the scope of the present invention.

Example 1: Evaluation of production amount of nitric oxide (NO) derived from microglia cells (simultaneous addition of cyclic dipeptide and LPS)
The inhibitory effect of nitric oxide produced from LPS-stimulated BV2 microglia cells was evaluated under the cyclic dipeptide addition conditions. The cyclic dipeptide used was synthesized by Kobe Natural Products Chemical Co., Ltd. A 96-well plate was seeded with 100 μL of BV2 microglia cells adjusted to a concentration of 2.0 × 10 ⁵ cells / mL with 10% FBS-added DMEM medium. 24 hours after sowing, LPS (final concentration 100 ng / mL) and cyclic dipeptide (

final concentration

50, 100, or 200 μM) were added simultaneously. After 24 hours, the culture supernatant was collected, and the amount of nitric oxide metabolite (NO ₂ ⁻ ) was measured by Griess assay (n = 2). Griess assay was performed using Griess Reagent System (same composition as Promega cat. # G2930).

The results are shown in FIGS. As a result of the experiment, as shown in FIGS. 1 to 6, by simultaneously adding a specific cyclic dipeptide and LPS, production of nitric oxide metabolites (NO ₂ ⁻ ) from BV2 microglia cells caused by LPS stimulation was It was revealed that the cyclic dipeptide was suppressed depending on the concentration. Thus, it was shown that certain cyclic dipeptides suppress nitric oxide production from BV2 microglial cells due to LPS stimulation.

The present invention provides a composition for preventing neurological diseases containing a specific cyclic dipeptide or a salt thereof as an active ingredient. Therefore, the present invention provides a new means for the prevention of neurological diseases such as dementia, schizophrenia, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, etc. High nature.

Claims

A composition for preventing neurological disease comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosylglycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)], cyclolysylphenylalanine. One or more selected from the group consisting of [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)]. The above-mentioned composition for preventing neurological diseases.
The composition for preventing a neurological disease according to claim 1, wherein the cyclic dipeptide or a salt thereof comprises three or more selected from the group according to claim 1.
The composition for preventing a neurological disease according to claim 1 or 2, which has an action of suppressing inflammation of nerve cells.
The composition for preventing neurological diseases according to any one of claims 1 to 3, which has an action of suppressing secretion of nitric oxide from microglia cells.
The composition for preventing a neurological disease according to any one of claims 1 to 4, which has an action of suppressing activation of microglia cells.
The composition for preventing a neurological disease according to any one of claims 1 to 5, which has a dementia-preventing effect.
6. The composition for preventing neurological diseases according to any one of claims 1 to 5, which has a preventive effect on schizophrenia.
The composition for preventing a neurological disease according to any one of claims 1 to 5, which has a preventive effect against Alzheimer's disease.
The composition for preventing neurological diseases according to any one of claims 1 to 5, which has a preventive effect against Parkinson's syndrome.
The composition for preventing a neurological disease according to any one of claims 1 to 5, which has a preventive effect on amyotrophic lateral sclerosis.
A composition for preventing a neurological disease according to any one of claims 1 to 10, which is labeled with a function related to the prevention of the neurological disease,
Function indications are `` reducing the risk of developing neurological disease '', `` reducing the risk of developing dementia '', `` reducing the risk of developing Alzheimer's disease '', `` reducing the risk of developing Parkinson's syndrome '', `` schizophrenia The composition for preventing neurological disease, which is selected from the group consisting of “reducing the onset risk of” and “reducing the onset risk of amyotrophic lateral sclerosis”.
Use of a cyclic dipeptide having amino acid as a structural unit or a salt thereof for preventing neurological diseases,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosylglycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)], cyclolysylphenylalanine. One or more selected from the group consisting of [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)]. The use as described above.
A method for preventing a neurological disease using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cyclotyrosylglycine [Cyclo (Tyr-Gly)], cycloisoleuyl proline [Cyclo (Ile-Pro)], cyclolysylphenylalanine. One or more selected from the group consisting of [Cyclo (Lys-Phe)], cycloleucyllysine [Cyclo (Leu-Lys)], and cyclothreonyltyrosine [Cyclo (Thr-Tyr)]. The method as described above.