JP2019064955A - AMYLOID β TOLERANCE ENHANCER - Google Patents

Abstract

To provide an amyloid β tolerance enhancer that can improve tolerance of neurons to amyloid β.SOLUTION: An amyloid β tolerance enhancer has 6-methylsulfinyl hexyl isothiocyanate or a glycoside thereof, and at least one selected from the group of unsaturated fatty acid and polyphenol.SELECTED DRAWING: Figure 1

Description

  The present invention relates to an amyloid β tolerance enhancer.

Maintenance and improvement of brain functions such as memory ability and learning ability are required for a wide generation from young people to elderly people, including students and working people studying for examinations and qualification examinations.
Diseases resulting from the decrease in brain function include not only dementia represented by Alzheimer's disease, but also mental diseases such as depression and delirium. The cause of the decline in brain function is the death of nerve cells. Killing of nerve cells is said to be caused by accumulation of amyloid β and the like. When amyloid β is fibrillated and accumulated in the brain as clumps (senile plaques), such effects cause abnormal changes in tau protein and synapse. This abnormal change impairs substance transport in neurons and communication between neurons, resulting in a decrease in brain function.

  Currently, natural materials that are effective for preventing and improving the decrease in brain function are being sought. As such a natural material, for example, rosemary, rice bran and the like (Patent Document 1), Ginkgo biloba, curcumin, astaxanthin and the like (Patent Document 2) and the like are known. Moreover, DHA etc. are known as an amyloid (beta) reduction effect (patent document 3).

  However, it is strongly desired to find a substance effective for preventing and improving the decrease in brain function and to examine the possibility of using it for medicines and the like.

Japanese Patent Application Publication No. 2013-526865 JP, 2015-107960, A JP, 2015-147775, A

  The present invention has been made in view of such circumstances, and an object thereof is to provide an amyloid β tolerance enhancer capable of enhancing the resistance of neurons to amyloid β.

The amyloid β tolerance enhancer of the present invention comprises 6-methylsulfinylhexyl isothiocyanates or a glycoside thereof;
At least one member selected from the group consisting of unsaturated fatty acids and polyphenols;
Have.

  According to the amyloid β tolerance enhancer of the present invention, the resistance of neuronal cells to amyloid β can be enhanced.

It is a figure which shows the amyloid beta neurotoxicity tolerance test result of Experimental example 1. FIG. It is a figure which shows the hydrogen peroxide toxicity tolerance test result of Experimental example 2. FIG.

  The amyloid β resistance enhancer according to the present embodiment comprises (A) 6-methylsulfinylhexyl isothiocyanate (hereinafter also referred to as “6-MSITC”) or an isothiocyanate such as a glycoside thereof; And at least one selected from the group consisting of saturated fatty acids and (C) polyphenols.

(A) Isothiocyanates In this embodiment, isothiocyanates refer to a compound having a -NCS group. The isothiocyanates may have, for example, aliphatic or aromatic groups as side chains. As isothiocyanates having an aliphatic group, for example, isopropyl isothiocyanate, isobutyl isothiocyanate, 2-butyl isothiocyanate, isoamyl isothiocyanate, amyl isothiocyanate, allyl isothiocyanate, 3-butenyl isothiocyanate, 4-pentenyl Isothiocyanate, 5-hexenyl isothiocyanate, 6-heptenyl isothiocyanate, 3-methylthiopropyl isothiocyanate, 4-methylthiobutyl isothiocyanate, 5-methylthiopentyl isothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate , 4-methylsulfinylbutyl isothiocyanate, 5-methylsulfinylpentyl isothiocyanate And 6-methylsulfinylhexyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanates (6-MSITCs), and 7-methylsulfinylheptyl isothiocyanate, and one or more selected from the group consisting of Methyl sulfinyl butyl isothiocyanate, 5-methyl sulfinyl pentyl isothiocyanate, 6-MSITCs, 7-methyl sulfinyl heptyl isothiocyanate is preferable. Examples of isothiocyanates having an aromatic group include phenethyl isothiocyanate.

In the present embodiment, isothiocyanates are a concept also including glycosides.
In this embodiment, preferred among isothiocyanates are 6-MSITCs or their glycosides.

  In this embodiment, the 6-MSITCs are meant to include 6-MSITC and 6-MSITC analogs. 6-MSITC is represented by the following chemical formula.

  In this embodiment, 6-MSITC analogs include naturally occurring analogs of 6-methylsulfinylhexyl isothiocyanate, and analogs of non-naturally occurring 6-methylsulfinylhexyl isothiocyanate obtained by synthesis. For example, 6-methylthiohexyl isothiocyanate (sulfur is not oxidized, ie a structure having a methyl sulfide group) and 6-methylsulfonylhexyl isothiocyanate (sulfur is peroxidized, ie a structure containing a methylsulfonyl group), etc. Point to

  The 6-MSITCs used in the present embodiment are, for example, contained in plants of the family Brassicaceae. Among Brassicaceae, the present wasabi and / or horseradish contains many 6-MSITCs.

  The 6-MSITCs used in the present embodiment can be obtained by a chemical synthesis method, but may be extracted and purified from plants. Examples of plants that can be used as raw materials for 6-MSITCs include, for example, Bataceae (Bataceae), Brassicaceae (Brassicaceae), Bresch Neidaceae (Bretschneideraceae), Amaryngea (Capparaaceae), Papaya (Caricaceae), and Euphorbiaceae ( Euphorbiaceae), Gyrostemonaceae (Gyrostemonaceae), Limnantes (Limnanthaceae), Horseradish (Moringaceae), Pentadiplandracea (Pentadiplandraceae), Phytolactocae (Phytolaccaceae), Tobella (Pittosporaceae), Molybdaceae (Salv doraceae), Towaria family (Tovariaceae), Nouzenharen family (Tropaeolaceae), mention may be made of the plant or the like. Specifically, for example, wasabi (Wasabi japonica) [alias: this horseradish], horseradish (Armoracia rusticana) [alias: mountain wasabi], Batis maritima (Japanese name unknown), mustard (Brassica juncea), broccoli (Brassica) oleracea var. italica, Arabidopsis thaliana, Capsella bursa-pastoris, watercress (Nasturtium officinale), Bretschneidera sinensis (Japanese name unknown), caper (Capparis spinosa), papaya (Carica papaya rica) Unknown name); Putranjiva roxburghii (Japanese name unknown), Tersonia brevipes (Japanese name unknown), Limnanthes douglasii (Japanese name unknown), Wasabi tree (Moringa oleifera), Pentadiplandra brazzeana (Japanese name unknown), Phytolacca (Phytolacca americana) Bursaris spinosa var. Examples thereof include incana (Japanese name unknown), Shinobumokuso (Reseda alba), Salvadora persica (Japanese name unknown), Tovaria pendula (Japanese name unknown), Kinrenka (Tropaeolum majus) and the like. However, 6-MSITCs that can be used in the present disclosure are not limited to those obtained from the above-mentioned plants, and all natural resources containing 6-MSITCs can be used as a raw material.

  Examples of the method for extracting and purifying the plant include a method for extracting 6-MSITCs from wasabi and horseradish which are cruciferous plants. A preferred extraction method is disclosed by patent 3919489.

  In the present embodiment, the glycoside of 6-MSITCs is a compound in which a sugar residue is bound to 6-MSITCs. The sugar residue binding to 6-MSITCs may be one or more sugars selected from the group consisting of glucose, rhamnose, fructose and galactose, with glucose being more preferred. The sugar residue may be either monosaccharide or polysaccharide, but monosaccharide is preferred. A monosaccharide refers to a sugar consisting of monosaccharide molecules. A polysaccharide refers to a sugar chain to which two or more monosaccharide molecules are linked. The polysaccharide is preferably formed by combining 2 or more and 10 or less monosaccharides, and more preferably formed by combining 2 or more and 5 or less monosaccharides.

The bonding position of the sugar residue bonded to 6-MSITCs is preferably an NCS group moiety, and is further preferably bonded to S.
The glycoside of 6-MSITCs is, for example, glucohesperin. Glucohesperin is a compound represented by the following chemical formula.

  The glycosides of 6-MSITCs can be obtained from plants containing glycosides of 6-MSITCs, such as the present wasabi. For example, after the enzyme reaction is stopped by heating (including electromagnetic waves, far infrared rays, baking, etc.), drying, freezing, enzyme treatment, chemical treatment, etc., the plant is subjected to solvent extraction with water, an organic solvent, etc. The glycosides of 6-MSITCs are extracted or separated and purified by performing means such as pressing, drying, crushing, purification, enzyme reaction, chemical reaction and the like. In addition, glycosides of 6-MSITCs can also be obtained by chemical synthesis.

(B) Unsaturated fatty acids Unsaturated fatty acids refer to fatty acids having one or more double bonds. Unsaturated fatty acids having two or more double bonds are preferred. The carbon number of the unsaturated fatty acid is not particularly limited, but is preferably 12 to 24, more preferably 15 to 24, and preferably 18 to 22.

The position of the double bond possessed by the unsaturated fatty acid may be any one or more of the ω3 position, the ω6 position, and the ω9 position. In particular, the unsaturated fatty acid is preferably an ω3 fatty acid.
Omega 3 fatty acids refer to unsaturated fatty acids having a double bond in at least the ω 3 position of fatty acids. The ω3 fatty acids, for example, docosahexaenoic acid (DHA, 22: 6 (△ 4,7,10,13,16,19)), docosapentaenoic acid (DPA, 22: 5 (△ 7,10,13,16 ^{, 19} )), eicosapentaenoic acid (EPA, 20: 5 (Δ ^{5, 8, 11, 14 , 17} )), α-linolenic acid (ALA, 18: 3 (Δ ^{9, 12, 15} )). .

  Omega 3 fatty acids may be extracted from fish and / or fish oil. DHA is, for example, contained in blue fish. EPA is contained, for example, in fish oils such as cod, herring, mackerel, salmon, sardines and krill. Among them, DHA and EPA are preferred, and DHA is more desirable.

(C) Polyphenol In this embodiment, a polyphenol is a general term for a compound having a plurality of phenolic hydroxy groups in a molecule. The polyphenol may consist of one or more selected from the group of curcuminoids and flavonoids.

  The curcuminoid may be represented by the following formula (I).

(Wherein, Ar represents an aromatic group having an OH group)
Curcuminoids include curcumin dimethoxycurcumin and bisdimethoxycurcumin, of which curcumin is preferred. Among curcumins, those shown in the following formulas (II) to (I-IV) are exemplified.

Examples of the component having curcumin include turmeric extract, turmeric pigment, and turmeric pigment.
Curcuminoids may be extracted from turmeric. The curcuminoid containing curcumin can be obtained, for example, by an extraction separation method using an organic solvent, an alcohol solvent or the like with turmeric or the like as a raw material, or a synthesis method.

  The flavonoid is preferably a flavonol represented by the following formula (II).

(Wherein, X represents -O ^- or -OH, Y represents -O ^- or -OH, Z represents -O ^- or -OH, and X, Y and Z represent two or more in total. N represents an integer of 1 to 4, and m represents an integer of 1 to 5.)
As flavonols, those shown in the following formulas (II-I) to (II-XI) can be mentioned. Among these, isorhamnetin represented by the formula (II-III) is preferable.

As a component containing isorhamnetin, for example, ginkgo biloba (ginkgo) extract can be mentioned.
Flavonoids may be extracted from Ginkgo biloba. The flavonoid can be obtained by a known method from a plant containing flavonoid or a known synthetic method. Isorhamnetin can be extracted from Ginkgo leaves by known methods.

  The amyloid β tolerance enhancer of the present embodiment may have 6-MSITCs, docosahexaenoic acid (DHA), curcumin, isorhamnetin alone or in combination of two or more.

The amyloid β tolerance enhancer of the present embodiment may have a combination of the following components.
6-MSITCs and DHA,
6-MSITCs and curcumin,
6-MSITCs and isorhamnetin.

  When the amyloid β tolerance enhancer of the present embodiment has (A) 6-MSITCs and (B) docosahexaenoic acid (DHA), the molar ratio of (B) DHA to (A) 6-MSITCs is 0. The number is preferably 2 or more and 400 or less, preferably 0.2 or more and 80 or less, and more preferably 1 or more and 80 or less.

  When the amyloid β tolerance enhancer of the present embodiment has (A) 6-MSITCs and (CI) curcumin, the molar ratio of (CI) curcumin to (A) 6-MSITCs is 0.04 or more and 25 or less It is preferable that it is 0.2 or more and 25 or less.

  When the amyloid β tolerance enhancer of the present embodiment has (A) 6-MSITCs and (CII) isorhamnetin, the molar ratio of (CII) isorhamnetin to (A) 6-MSITCs is 0.008 or more and 5 or less It is preferable that it is 0.04 or more and 0.2 or less.

In these cases, it is possible to more effectively enhance the neuronal resistance to amyloid β.
The dose of the amyloid β tolerance enhancer of the present embodiment is determined by considering the patient's age, sex, body weight, usage, dosage and the like. As the usage, oral administration, vascular injection, external use, application and the like can be mentioned. In the case of oral administration, the daily dose of 6-MSITCs in the amyloid β tolerance enhancer may be 10 μg to 100 mg / day, the dose of unsaturated fatty acid may be 100 mg / day to 10 g / day, and polyphenols The dosage may be 0.1 mg / day to 10 g / day.

  When the dosage form of the amyloid β tolerance enhancer of the present embodiment is vascular injection, the daily dose of 6-MSITCs in the amyloid β tolerance enhancer is preferably 1 μg / day to 5 mg / day, and unsaturated fatty acid The dose may be 1 mg / day to 100 mg / day, and the dose of polyphenol may be 0.1 μg / day to 1 mg / day.

  The amyloid β tolerance enhancer of the present embodiment may further contain an additive. As the additive, for example, an excipient, a disintegrant, a binder, an antioxidant, a coating, a coloring agent, a flavoring agent, a surfactant, a plasticizer and the like can be blended.

Moreover, an antiallergic agent, a cooling agent, vitamins, and another component can also be mix | blended in the range which does not impair the effect of this invention.
The amyloid β tolerance enhancer of the present embodiment may be contained in food, quasi-drugs, and pharmaceuticals.

  The form of the food containing the amyloid β tolerance enhancer of the present embodiment is optional and is not limited. Specific food forms are, for example, general foods, general beverages, supplements, health foods, functional display foods, health functional foods such as foods for specified health and food for specific applications, soft drinks, tea drinks, drink agents And alcoholic beverages such as wine, confectionery, cooked rice, breads, noodles, vegetables, seasonings and the like.

Although the usage of quasi-drugs and pharmaceuticals containing the amyloid β tolerance enhancer of the present embodiment is optional and is not limited, for example, internal and external preparations and the like can be mentioned.
Although the dosage form of cosmetics and quasi-drugs containing the amyloid beta tolerance enhancer of this embodiment is not limited, For example, a capsule, a tablet, a powder, a granule, a liquid agent etc. are mentioned.

The amyloid β tolerance enhancer of the present embodiment can enhance the resistance of nerve cells to amyloid β and can protect nerve cells.
Amyloid beta tolerance enhancers of this embodiment include dementia, type 2 diabetes, Alzheimer's disease, diabetes, Parkinson's disease, transmissible spongiform encephalopathy, so-called "mad cow disease", Huntington's disease, medullary thyroid carcinoma, arrhythmia, Arteriosclerosis, rheumatoid arthritis, aortic medial amyloid, prolactin producing tumor, familial amyloid polyneuropathy, hereditary non-neuropathic amyloidosis, dialysis amyloidosis, Finnish amyloidosis, lattice corneal dystrophy, cerebral amyloid angiopathy, systemic AL amyloidosis , Associated body myositis (Sporadic Inclusion Body Myositis), pheochromocytoma, osteomyelitis, multiple myeloma, encephalitis, meningitis, pre-Alzheimer's disease, mild cognitive impairment, early Alzheimer's disease, late Alzheimer's disease, related to aging Dementia, Parkinson's disease, Han Tonton's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), prion disease, Creutzfeldt-Jakob disease, Lewy body disease, Friedreich's ataxia, stroke, genetic encephalopathy It is effective in improving symptoms such as schizophrenia, depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger's syndrome, and Down's syndrome.

(Experimental example 1)
Resistance test of nerve cells to amyloid β (1) Preparation of various components (a) 6-MSITC (component 1)
6-MSITC (manufactured by Gold Seal Co., Ltd.) was obtained. 6-MSITC used in this example was obtained by a chemical synthesis method. The chemical synthesis method of 6-MSITC is specifically described as follows.

In principle, the method of Kjaer et al. Is followed (Kjaer et al., Acta chem .. Scand., 11, 1298, 1957). Reflux with CH ₃ -SNa using 6-chlorohexanol to give 6-methylthiohexanol. This is reacted with thionyl chloride (SOCl ₂ ) to give 6-chlorohexyl methyl sulfide. Next, using the Gabriel method, an amino group is introduced with phthalimide potassium salt to form N- (6-methylthiohexyl) -phthalimide. Hydrazine hydrate is added thereto and refluxed to obtain 6-methylthiohexylamine, which is then reacted with thiocarbonyl chloride to obtain 6-methylthiohexyl isothiocyanate.

  Furthermore, the obtained 6-methylthiohexyl isothiocyanate is oxidized in methylthio group with m-chloroperbenzoic acid to obtain 6-methylsulfinylhexyl isothiocyanate (6-MSITC) (Morimitsu et. Al., J. Biol. Chem., 277, 3456, 2002).

In addition, 6-MSITC according to the present invention is contained in cruciferous plants and the like, and can also be obtained by solvent extraction or grinding of these plants.
100 mg of 6-MSITC was dissolved in DMSO (dimethyl sulfoxide) solvent to prepare a 6-MSITC solution with 100 mM 6-MSITC.
(B) DHA (component 2)
DHA (manufactured by Nacalai Tesque, product number 14122-64) was obtained. This DHA is extracted from blue fish. 100 mg DHA was dissolved in DMSO solvent to prepare DHA solution with 100 mM DHA.
(C) Curcumin (component 3)
Curcumin (CAS No. 458-37-7, manufactured by Tokyo Chemical Industry Co., Ltd., product No. C2302) was obtained. Curcumin is represented by the following chemical formula.

This curcumin is a synthetic one. 67.56 mg of curcumin was dissolved in DMSO solvent to prepare a curcumin solution with 200 mM curcumin.
(D) isorhamnetin (component 4)
Isolamnetin (manufactured by EXTRASYNTHESE, product number 1120S) was obtained. Isorhamnetin is extracted from ginkgo leaves. An isorhamnetin solution having 10 mM isorhamnetin was prepared by dissolving in DMSO solvent using a pipette for 10 mg isorhamnetin.

(2) Preparation of medium A growth medium A and a differentiation medium B containing the following components were prepared.
(A) Component of growth medium A DMEM (Dulbecco's Modified Eagle Medium, manufactured by Nacalai Tesque, product number 08458-45)
10 wt% horse serum (Thermo Fisher Scientific, product number 16050-122)
5 wt% bovine serum (Thermo Fisher Scientific, product number 10437-028)
1 wt% penicillin streptomycin (Nacalai Tesque, product number 26253-84)
(B) Component of differentiation medium B DMEM (Dulbecco's Modified Eagle Medium, manufactured by Nacalai Tesque, product number 08458-45)
2 wt% horse serum (Thermo Fisher Scientific, product number 16050-122)
1 wt% penicillin streptomycin (Nacalai Tesque, product number 26253-84)
(3) PC12 Cell Proliferation The above growth medium A was placed in a cell culture flask (manufactured by TPP), and then PC12 cells (manufactured by RIKEN, product number RCB 0009) were placed and proliferated. PC12 cells are pheochromocytomas from rat adrenal medulla and are models of neuronal differentiation. When PC12 cells reached 80-90% of confluency, expanded PC12 cells were placed in a new flask containing growth medium A and passaged. The ratio of the culture solution in which the cells were grown to the new growth medium A was 1: 5 (volume ratio). Such passaging was repeated three times or more.

(4) Differentiation of PC12 cells 100 μl of growth medium A containing 5 × 10 ⁴ / ml of PC12 cells after passage obtained in (3) was seeded in each well of a 96-well plate. Leave at room temperature overnight to stabilize PC12 cells. The plate was spun to sediment PC12 cells in each well of the plate. The supernatant was removed. In each well in which PC12 cells were precipitated, 100 μl of differentiation medium B was added and stirred to suspend PC12 cells in differentiation medium B.
NGF (Sigma-Aldrich, product number N 2513) was added to the medium in each well. The concentration of NGF contained in the media in all the wells was 50 ng / ml. The well plate was placed in a carbon dioxide incubator (5% CO ₂ , 37 ° C.) and PC12 cells were cultured for 72 hours.

  The various components 1 to 4 prepared in (1) were added to the medium in each well so as to have various concentrations in one type or a combination of two types, and used as samples 1 to 38, respectively. Differentiation medium B was used for concentration adjustment. Table 1 shows the concentrations of components constituting each sample in the medium in each well. Furthermore, amyloid beta (Ana Spec, product number AS-24224) was added to the medium in each well. The concentration of amyloid β in the medium was 1 μmol / L. A sample in which none of the components 1 to 4 and amyloid β was added to the medium other than the above samples was used as “control”. Moreover, the sample which added amyloid (beta) to the culture medium, but was not added about components 1-4 was made into "AMB."

Thereafter, the well plate was placed in a carbon dioxide incubator (5% CO ₂ , 37 ° C.) to culture PC12 cells for 24 hours.

(5) Amyloid β neurotoxicity resistance test The resistance of PC12 cells to amyloid β is evaluated using MTT (3- (4,5-di-methylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, yellow tetrazole) reagent. It was tested.

In order to investigate the toxicity of each sample to PC12 cells, after performing the above step (4) PC12 cell differentiation, MTT reagent (manufactured by Nacalai Tesque, product number 23547-21, MTT 5 mg / ml in phosphate buffered saline) Water (10 μl / well) was added. Furthermore, PC12 cells were cultured for 4 hours in a carbon dioxide incubator (5% CO ₂ , 37 ° C.).

  The plates were spun to sediment the cells in the wells and the supernatant removed. 100 μl / well of DMSO was added to each well, shaken and agitated, and PC12 cells were suspended in DMSO to obtain a cell solution.

  The absorbance at 490 nm was measured for the cell fluid in each well. The value obtained by converting the absorbance of the control cell fluid into a fraction using the absorbance of the cell fluid of the PC12 cells cultured in a culture solution containing each sample as a numerator and a fraction was calculated as a MTT assay. The measurement results are shown in FIG.

In FIG. 1, "M", "C", "D", and "I" mean "6-MSITC", "curcumin", "DHA", and "isorhamnetin" in that order. The same applies to FIG.
As shown in FIG. 1, when PC12 cells were cultured in a medium containing only amyloid β (AMB), the MTT assay was significantly reduced as compared to the case where they were cultured in a medium not containing amyloid β (control) . The effect of 6-MSITC in enhancing amyloid β resistance of PC12 cells was higher than that of curcumin, DHA, and isorhamnetin. MTT assay was higher when 6-MSITC and curcumin, DHA or isorhamnetin were combined and added to the medium together with amyloid β compared to when cells were cultured in a medium containing only amyloid β (AMB) .

(Experimental example 2)
Resistance Test of Neuronal Cells to Hydrogen Peroxide In Example 2, the resistance of PC12 cells to hydrogen peroxide was tested. The test method is the same as that of Experimental Example 1 except that hydrogen peroxide is added to differentiation medium B instead of adding amyloid β to differentiation medium B in Experimental Example 1 above. The concentration of hydrogen peroxide in the differentiation medium B was 100 μM. The experimental results are shown in FIG.

As shown in FIG. 2, when PC12 cells are cultured in a medium containing only hydrogen peroxide (H ₂ O ₂ ), it is much more remarkable than when cultured in a medium not containing hydrogen peroxide (control). MTT assay decreased. When 6-MSITC, curcumin, DHA or isorhamnetin was added alone, or a combination of 6-MSITC and curcumin, DHA or isorhamnetin was added to the medium, the MTT assay had a value without a problem.

  From the above experiment, in the case of the combination of 6-MSITC with curcumin, DHA, or isorhamnetin, amyloid β produced in the body and in the body as compared with the case without these components and when these components are used alone It has been found that it has a function of protecting neurons against hydrogen peroxide.

  The effect of amyloid β on nerve cells is also considered to be related to reactive oxygen species, and reactive oxygen species have various forms such as singlet oxygen, hydrogen peroxide, lipid peroxide and the like because of their high reactivity. It is known that the damage to cells is increased. The combined resistance to amyloid β and hydrogen peroxide is more useful because it may be able to broadly suppress the damage caused by these various reactive oxygen species.

Claims (14)

6-methylsulfinylhexyl isothiocyanates or a glycoside thereof;
At least one selected from the group of unsaturated fatty acids and polyphenols,
Amyloid beta tolerance enhancer.   The amyloid β tolerance enhancer according to claim 1, wherein the unsaturated fatty acid is an ω3 fatty acid.   The amyloid β resistance enhancer according to claim 2, wherein the ω3 fatty acid comprises one or more selected from the group consisting of docosahexaenoic acid and eicosapentaenoic acid.   The agent for enhancing amyloid β resistance according to claim 2 or 3, wherein the ω3 fatty acid is extracted from fish and shellfish and / or fish oil.   The amyloid β tolerance enhancer according to claim 1, wherein the polyphenol comprises one or more selected from the group of curcuminoids and flavonoids.   The agent for enhancing amyloid β resistance according to claim 5, wherein the curcuminoid comprises curcumin.   The agent for enhancing amyloid β resistance according to claim 5 or 6, wherein the curcuminoid is extracted from turmeric.   The amyloid β tolerance enhancer according to claim 5, wherein the flavonoid comprises isorhamnetin.   The amyloid β tolerance enhancer according to claim 5 or 8, wherein the flavonoid is extracted from Ginkgo biloba leaves.   The agent for enhancing the amyloid β resistance according to claim 1, comprising 6-methylsulfinylhexyl isothiocyanates and docosahexaenoic acid.   The amyloid beta tolerance enhancer according to claim 1 having 6-methylsulfinyl hexyl isothiocyanates and curcumin.   The amyloid beta tolerance enhancer according to claim 1 having 6-methylsulfinyl hexyl isothiocyanates and isorhamnetin. Isothiocyanates,
At least one selected from the group consisting of unsaturated fatty acids and polyphenols;
Amyloid beta tolerance enhancer.   6. Amyloid β tolerance enhancer having 6-methylsulfinylhexyl isothiocyanates or a glycoside thereof.

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