Β-secretase inhibitor and composition for preventing or treating dementia

Abstract

To provide novel means and methods for inhibiting the activity of β-secretase.SOLUTION: The present invention pertains to a β-secretase inhibitor containing at least one of turmeronol A, turmeronol B, and bisacron as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a β-secretase inhibitor and a composition for preventing or treating dementia. [Background technology]

[0002] Amyloid beta is produced by cleaving amyloid precursor protein (APP) with the beta-secretase enzyme. It has been shown that accumulation of amyloid beta in the brain leads to deterioration of brain function. The accumulation of amyloid degeneration in cerebral blood vessels, causing abnormalities in the blood vessels, is called cerebral amyloid angiopathy. Along with hypertension, cerebral amyloid angiopathy is considered to be one of the causes of cognitive decline (vascular dementia) caused by cerebral hemorrhage.

[0003] Dementia mainly includes Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. Alzheimer's disease is a typical disease that deteriorates brain function, and amyloid beta can accumulate in the brain during onset and progression. However, accumulation of amyloid beta in the brain is not necessarily required for the onset of Alzheimer's disease. Although amyloid angiopathy is frequently associated with Alzheimer's pathology, there are also reports of cognitive decline due to amyloid angiopathy alone without Alzheimer's pathology. Dementia with Lewy bodies develops when α-synuclein, which plays an important role in nerve cells, aggregates and accumulates in the brain (Lewy bodies) (Bassil, et al., Neuron. 105(2):260-275, 2020). It has also been suggested that the accumulation of amyloid beta in the brain may be a factor in dementia with Lewy bodies (Shimada, et al., Mov Disord. 28(2):169-75, 2013). Furthermore, the accumulation of amyloid beta in the brain may cause cerebral amyloid angiopathy, which is a factor in vascular dementia.

[0004] On the other hand, it has been known that turmeric and its extracts have various physiological activities. For example, it has been reported that turmeric extracts or its components are used to improve Alzheimer's or Alzheimer's dementia (Patent Documents 1 and 2). It has also been reported that α-turmerone, β-turmerone, and ar-turmerone in turmeric extracts (hexane extraction, ethyl acetate extraction) suppress β-secretase activity in a cell-free system (Patent Document 3). It has also been reported that curcumin, a component contained in turmeric, increases APOE expression, promotes the clearance of amyloid β, inhibits APP synthesis, and suppresses brain inflammation, providing prevention and treatment of Alzheimer's (Patent Document 4). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6998212 [Patent Document 2] Patent No. 6814240 [Patent Document 3] Patent No. 6998212 [Patent Document 4] Patent No. 6814240 Summary of the Invention [Problem to be solved by the invention]

[0006] It is believed that by inhibiting the activity of β-secretase, which is involved in the production of amyloid β, the accumulation of amyloid β in the brain is inhibited, and brain function is improved or the decline of brain function can be prevented. Therefore, the present invention aims to provide a new means and method for inhibiting the activity of β-secretase, and further to provide a means and method for preventing or treating dementia by inhibiting the accumulation of amyloid β in the brain. It should be noted that there has been no report to date that turmeronol A, turmeronol B, and bisaclone, which are components contained in turmeric extract, inhibit the activity of β-secretase and reduce the accumulation of amyloid β in the brain. [Means for solving the problem]

[0007] In the course of intensive research into the effects of turmeric extract, the inventors discovered that turmeric extract and the components contained therein, turmeronol A, turmeronol B and bisaclone, each inhibit the activity of β-secretase, and gained the knowledge that turmeric extract or at least one of turmeronol A, turmeronol B and bisaclone can inhibit the accumulation of amyloid β in the brain, and ultimately prevent or treat dementia caused by the accumulation of amyloid β in the brain, thereby completing the present invention.

[0008] Thus, the present invention encompasses, for example: [1] A beta-secretase inhibitor containing at least one of turmeronol A, turmeronol B, and bisacron as an active ingredient. [2] The β-secretase inhibitor described in [1], which consists of at least one of turmeronol A, turmeronol B and bisacron as active ingredients. [3] A composition for preventing or treating dementia, comprising at least one of turmeronol A, turmeronol B, and bisacron as an active ingredient. [4] The composition described in [3], consisting of at least one of turmeronol A, turmeronol B and bisacron as an active ingredient. [5] A composition for preventing or treating dementia, comprising turmeric extract as an active ingredient. [6] The composition described in [5], consisting solely of turmeric extract as an active ingredient. [7] The composition described in [5], wherein the turmeric extract comprises a turmeric extract using at least one extraction solvent selected from the group consisting of water and hydrophilic organic solvents. [8] The composition described in [5], wherein the turmeric extract comprises a mixture of a turmeric extract obtained by extraction with water and a turmeric extract obtained by extraction with supercritical carbon dioxide. [9] The composition described in [5], wherein the turmeric extract contains at least one of turmeronol A, turmeronol B and bisacron.

[10] The composition described in [3] or [5], wherein the dementia is Lewy body dementia or vascular dementia.

[11] The composition described in [3] or [5], wherein the dementia is not Alzheimer's disease.

[0009]

[12] Use of at least one of turmeronol A, turmeronol B and bisacron for producing a β-secretase inhibitor.

[13] Use of at least one of turmeronol A, turmeronol B and bisacron for the manufacture of a composition for the prevention or treatment of dementia.

[14] Use of turmeric extract for the manufacture of a composition for preventing or treating dementia.

[0010]

[15] administering at least one of turmeronol A, turmeronol B, and bisacron to a subject in need of inhibition of beta-secretase activity; and Inhibiting beta-secretase activity in said subject. A method for inhibiting β-secretase activity in a subject, comprising:

[16] Administering at least one of turmeronol A, turmeronol B, and bisacron to a subject in need of prevention or treatment of dementia; and Preventing or treating dementia in said subject. 23. A method for preventing or treating dementia in a subject, comprising:

[17] administering a turmeric extract to a subject in need of prevention or treatment of dementia; and Preventing or treating dementia in said subject. 23. A method for preventing or treating dementia in a subject, comprising:

[0011]

[18] At least one compound selected from the group consisting of turmeronol A, turmeronol B and bisacron for use in inhibiting β-secretase activity.

[19] At least one compound of turmeronol A, turmeronol B and bisacron for use in the prevention or treatment of dementia.

[20] Turmeric extract for use in the prevention or treatment of dementia. Effect of the Invention

[0012] In accordance with one or more embodiments of the present invention, there are provided beta-secretase inhibitors. According to one or more further embodiments of the present invention, there is provided a composition for preventing or treating dementia. [Brief description of the drawings]

[0013] [Figure 1] 1 is a graph showing that turmeric extract inhibits β-secretase activity in mouse microglial cells BV-2. [Diagram 2] 1 is a graph showing that turmeronol A, turmeronol B, or bisaclone inhibits β-secretase activity of mouse microglial cells BV-2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention is based on the finding that administration or ingestion of turmeric extract or components of turmeric extract, turmeronol A, turmeronol B and / or bisacron, inhibits the activity of the enzyme β-secretase that produces amyloid β protein, which is a causative substance of dementia, and inhibits the accumulation of amyloid β in the brain. In human trials, cerebral amyloid angiopathy alone did not cause cognitive decline, but it has been reported that there was a difference in cognitive decline between those with severe and mild Aβ accumulation in the brain parenchyma (Malek-Ahmadi, et al., J Alzheimers Dis. 67(1):411-422, 2019), so it is possible to prevent or treat dementia, particularly vascular dementia, by inhibiting the accumulation of Aβ in the brain parenchyma.

[0015] Therefore, in one aspect, the present invention provides a β-secretase inhibitor containing, as an active ingredient, turmeric extract, or at least one of turmeronol A, turmeronol B, and bisacron. In another aspect, the present invention provides a composition for preventing or treating dementia, containing, as an active ingredient, turmeric extract, or at least one of turmeronol A, turmeronol B, and bisacron.

[0016] <Composition containing turmeric extract> The composition according to the present invention contains a turmeric extract. In the present invention, the turmeric extract refers to an extract (turmeric extract) of a plant material derived from a plant of the genus Curcuma of the Zingiberaceae family using an extraction solvent. The turmeric extract is not limited to a solvent extract obtained by extraction with an extraction solvent, but also includes a solvent extract that has been fractionated and purified by column chromatography or the like. The turmeric extract used in the present invention can be in the form of an extract liquid after the completion of an extraction operation (including a fractionation and purification operation when fractionation and purification is performed), a concentrate obtained by partially removing the solvent from the extract liquid, or a dried product obtained by removing the solvent from the extract liquid. The removal of the solvent from the extract can be carried out by volatilizing the solvent by heating and / or reducing pressure, etc. The method of heating and reducing pressure is not particularly limited, and for example, a conventionally known method can be used.

[0017] The plant raw material may be the rhizome of Curcuma longa, Curcuma aromatica, Curcuma zedoaria, Curcuma phaeocaulis, Curcuma kwangsiensis, Curcuma wenyujin, and / or Curcuma xanthorrhiza, which are plants of the Zingiberaceae family, and the rhizome of Curcuma longa is particularly preferred. The rhizome may be collected from the ground, and an appropriate part of the rhizome may be used as is, or cut to an appropriate size or shape, or in the form of a pulverized product. These plant raw materials may be appropriately dried.

[0018] As the extraction solvent, at least one selected from the group consisting of water and hydrophilic organic solvents can be used. As the at least one extraction solvent selected from the group consisting of water and hydrophilic organic solvents, any of water, hydrophilic organic solvents, and mixed solvents of water and hydrophilic organic solvents can be used. The hydrophilic organic solvent can be a mixed solvent of multiple hydrophilic organic solvents. "Water" also includes hot water. As the hot water, for example, hot water of 95°C or higher can be used. As the hydrophilic organic solvent, at least one alcohol (which may be a mixed solvent of multiple alcohols) can be mentioned, and the alcohol is not particularly limited, but ethanol is preferable. When a mixed solvent of alcohol and water is used as the extraction solvent, the mixing ratio is not particularly limited, but for example, a range of 10:90 to 90:10 by weight ratio is preferable, and a range of 20:80 to 50:50 is more preferable. In addition, supercritical carbon dioxide can also be used as the extraction solvent.

[0019] The method for extracting turmeric from plant raw materials is not particularly limited, and any extraction method commonly used in the art can be used.

[0020] In the present invention, the turmeric extract may contain one type of turmeric extract, or may contain two or more types of turmeric extracts with different extraction solvents and / or extraction methods. In one embodiment, the turmeric extract contains a mixture of a turmeric extract obtained using at least one selected from the group consisting of water and a hydrophilic organic solvent as an extraction solvent, and a turmeric extract obtained using supercritical carbon dioxide, for example, a mixture of a turmeric extract obtained by extraction with water and a turmeric extract obtained by extraction with supercritical carbon dioxide. The ratio of each extract in the mixture is not particularly limited, and may be, for example, a weight ratio of 1:0.01 to 1:1.

[0021] In a preferred embodiment, the turmeric extract comprises at least one of an extract with water, such as hot water, and an extract with supercritical carbon dioxide.

[0022] In one embodiment, the turmeric extract used in the present invention contains at least one of turmeronol A, turmeronol B and bisacron.

[0023] <Agent or composition containing at least one of turmeronol A, turmeronol B, and bisacron> The agent or composition of the present invention contains at least one of turmeronol A, turmeronol B and bisacron.

[0024] Turmeronol A and turmeronol B are compounds having the following planar structures:

[0025] [ka]

[0026] [ka]

[0027] In the present invention, turmeronol A and turmeronol B each have the above-mentioned planar structure, and may be any optical isomer or a mixture of multiple optical isomers.

[0028] It is known that the configuration of the 6-carbon atom in the partial structure of 2-methyl-2-hepten-4-one in natural products isolated from turmeric extract is S-configuration for turmeronol A and turmeronol B. However, in the present invention, turmeronol A and turmeronol B may have the above-mentioned planar structure, and the configuration may be S-configuration, R-configuration, or a mixture of S-configuration and R-configuration.

[0029] In the present invention, bisaclone is a compound having the following planar structure: Bisaclone has an asymmetric carbon at the position indicated by the * mark in the planar structural formula and may contain multiple optical isomers, but in the present invention, bisaclone may be any optical isomer or a mixture of two or more optical isomers.

[0030] [ka]

[0031] At least one of turmeronol A, turmeronol B and bisacron (hereinafter sometimes referred to as "active compound") used in the present invention may be derived from a plant or may be artificially synthesized. For example, optically active (+)-turmeronol A can be synthesized by the method described in Biosci Biotechnol Biochem. 1993; 57(7):1137-40.

[0032] The active compound used in the present invention is more preferably derived from a plant material, more preferably derived from a plant of the genus Curcuma of the Zingiberaceae family. Specific examples of plants of the genus Curcuma of the Zingiberaceae family and their parts are as described above. The active compound can be obtained from parts such as rhizomes of plants of the genus Curcuma of the Zingiberaceae family.

[0033] The active compound can be extracted from the plant material containing it. The extraction method is as described above. The active compound may be in the form of a plant extract, in particular a turmeric extract with at least one extraction solvent selected from the group consisting of water and hydrophilic organic solvents.

[0034] In addition, a fraction of the plant extract containing the active compound, in which the active compound has been highly purified, may be used in the present invention, or may be incorporated in the composition of the present invention. For example, the plant extract containing the active compound may be subjected to liquid-liquid partitioning of ethyl acetate / water, and the active compound may be highly purified in the ethyl acetate fraction. In addition, the plant extract containing the active compound or a fraction thereof may be subjected to purification treatment by chromatography to obtain a highly purified active compound. As the chromatography, reverse phase column chromatography, normal phase thin layer chromatography, etc. may be used.

[0035] The plant extract or a fraction thereof containing the active compound may be processed by a conventional method, such as drying, powdering, granulation, or solution.

[0036] <β-Secretase Inhibitor of the Present Invention> In one aspect, the present invention relates to a β-secretase inhibitor containing at least one of turmeronol A, turmeronol B, and bisacron as an active ingredient. In another aspect, the present invention relates to a β-secretase inhibitor containing turmeric extract as an active ingredient. By administering the agent of the present invention according to this aspect to a subject such as a human, the activity or action of β-secretase in the subject can be suppressed or inhibited. Here, each of the active ingredients is administered in an effective amount for suppressing or inhibiting β-secretase activity. As the administration route, oral administration, nasal administration, intracerebral administration, or intrathecal administration is preferable, oral or nasal administration is more preferable, and oral administration is particularly preferable. The agent of the present invention can suppress the production of amyloid precursor protein (APP) by suppressing the activity of β-secretase in the brain, and as a result, can suppress the accumulation of amyloid β in the brain.

[0037] β-secretase activity can be measured by a method known in the art, and a kit that can be used for measuring activity is also commercially available. Inhibition of β-secretase activity refers to the activity being suppressed to a significant degree compared to the activity in the absence of the inhibitor of the present invention, for example, the activity being suppressed to 95% or less, preferably 90% or less, more preferably 80% or less compared to the activity in the absence of the inhibitor of the present invention.

[0038] <Composition of the Present Invention> In one aspect, the present invention relates to a composition for preventing or treating dementia, which contains at least one of turmeronol A, turmeronol B, and bisacron as an active ingredient. In another aspect, the present invention relates to a composition for preventing or treating dementia, which contains turmeric extract as an active ingredient. By administering the composition of the present invention according to these aspects to a subject such as a human, dementia can be prevented or treated in the subject. Here, each of the active ingredients is administered in an effective amount for preventing or treating dementia. As the administration route, oral administration, nasal administration, intracerebral administration, or intrathecal administration is preferred, oral or nasal administration is more preferred, and oral administration is particularly preferred. The composition of the present invention can prevent or treat dementia by suppressing the production of amyloid precursor protein (APP) by suppressing the activity of β-secretase in the brain, thereby suppressing the accumulation of amyloid β in the brain.

[0039] Dementia is known as a disorder in which cognitive functions such as memory and thinking are impaired due to various causes, causing problems in daily life and social life. In the present invention, it refers to dementia that can be prevented or treated by suppressing the accumulation of amyloid beta in the brain. Such dementia includes Alzheimer's dementia, Lewy body dementia, vascular dementia, etc. In one embodiment, the target dementia is Lewy body dementia or vascular dementia. In another embodiment, the target dementia is not Alzheimer's dementia.

[0040] Prevention or treatment of dementia includes preventing dementia or delaying its onset, treating dementia or delaying its progression, improving at least one symptom of dementia (e.g., memory impairment, aphasia, disorientation, impaired comprehension / judgment, etc.), etc. Diagnosis of dementia and its degree is known in the art and can be performed by neuropsychological tests, brain imaging tests (CT, MRI, etc.), etc.

[0041] The agent or composition of the present invention may be in the form of a pharmaceutical, food or drink, feed, food additive, feed additive, etc., and is more preferably a pharmaceutical or food or drink. Food or drink includes functional food, food for specified health use, nutritional supplement, etc. The agent or composition of the present invention is in the form of a composition that is ingested or administered orally, nasally, intracerebrally, or intrathecally, preferably in the form of a composition that is ingested or administered orally or nasally, and more preferably in the form of a composition that is ingested or administered orally.

[0042] In the agent or composition of the present invention according to the embodiment, which contains at least one of turmeronol A, turmeronol B and bisacron as active ingredients, the content of at least one of turmeronol A, turmeronol B and bisacron per daily intake or administration amount of the agent or composition of the present invention, preferably per daily intake or administration amount for one human, particularly per daily intake or administration amount for one adult, is preferably 17 μg or more, preferably 28 μg or more, more preferably 43 μg or more, even more preferably 57 μg or more, and most preferably 77 μg or more of turmeronol A, and / or 5 μg or more, preferably 8 μg or more, more preferably 12 μg or more, even more preferably 16 μg or more, and most preferably 22 μg or more of turmeronol B, and / or 80 μg or more, preferably 133 μg or more, more preferably 200 μg or more, even more preferably 267 μg or more, and most preferably 360 μg or more of bisacron, in order to effectively obtain the effect of inhibiting β-secretase activity and the effect of preventing or treating dementia. Here, the "daily intake or administration amount" is typically 0.1 g to 500 g as the amount of the agent or composition of the present invention when taken or administered orally, nasally, intracerebrally or intrathecally, preferably orally or nasally, more preferably orally. The agent or composition of the present invention may be taken or administered continuously, or may be taken or administered when needed.

[0043] The content of the turmeric extract in the composition of the present invention according to the embodiment containing the turmeric extract as an active ingredient is such that the total amount of turmeronol A and turmeronol B is 100 μg or more per daily intake or administration of the composition of the present invention, and / or the amount of turmeronol A is 17 μg or more, preferably 28 μg or more, more preferably 43 μg or more, even more preferably 57 μg or more, and most preferably 80 μg or more. It is preferable to contain 5 μg or more of turmeronol B, preferably 8 μg or more, more preferably 12 μg or more, even more preferably 16 μg or more, and most preferably 20 μg or more, and / or 80 μg or more of bisaclone, preferably 133 μg or more, more preferably 200 μg or more, even more preferably 267 μg or more, and most preferably 360 μg or more, in order to effectively obtain the action of inhibiting β-secretase and the action of preventing or treating dementia. Here, the "daily intake or administration amount" is typically 0.1 g to 500 g as the amount of the composition of the present invention when taken or administered orally, nasally, intracerebrally, or intrathecally, preferably orally or nasally, more preferably orally. The composition of the present invention may be taken or administered continuously, or may be taken or administered when necessary.

[0044] The agent or composition of the present invention according to the embodiment containing at least one of turmeronol A, turmeronol B and bisacron as an active ingredient may be at least one compound of turmeronol A, turmeronol B and bisacron itself, or may contain the compound and at least one other ingredient. When the agent or composition of the present invention contains the compound and at least one other ingredient, it may be an agent or composition in which the compound and at least one other ingredient are mixed, or the compound and at least one other ingredient are formulated by a suitable means, or the compound and at least one other ingredient are further mixed with another ingredient. In one embodiment, the agent or composition of the present invention is an agent or composition consisting of at least one of turmeronol A, turmeronol B and bisacron as an active ingredient. "Consisting of at least one of turmeronol A, turmeronol B and bisacron as active ingredients" means that the active ingredients exhibiting the desired activity (beta-secretase inhibitory effect, or dementia prevention or treatment effect) are at least one of turmeronol A, turmeronol B and bisacron, and do not contain any other active ingredients. However, components other than the active ingredients, such as carriers and excipients, may be contained in the agent or composition of the present invention.

[0045] The composition of the present invention according to the embodiment containing the turmeric extract as an active ingredient may be the turmeric extract itself, or may be a composition containing the turmeric extract and at least one other ingredient. When the composition of the present invention contains the turmeric extract and at least one other ingredient, it may be a composition in which the turmeric extract and at least one other ingredient are mixed, or a composition in which the turmeric extract and at least one other ingredient are formulated by an appropriate means, or a composition in which the turmeric extract and at least one other ingredient are further mixed with other ingredients. In one embodiment, the composition of the present invention is a composition consisting of only turmeric extract as an active ingredient. "Consisting only of turmeric extract as an active ingredient" means that the active ingredient exhibiting the desired activity (beta-secretase inhibitory activity or dementia prevention or treatment activity) is only turmeric extract, and does not contain any other active ingredient. However, components other than the active ingredient, such as carriers and excipients, may be contained in the composition of the present invention.

[0046] The form of the agent or composition of the present invention is not particularly limited, and may be, for example, any form such as liquid, fluid, gel, semi-solid, or solid.

[0047] The at least one other component that may be contained in the agent or composition of the present invention is not particularly limited, but preferably includes a component that is acceptable in the final form of a pharmaceutical product, food or drink, nutritional supplement, supplement, feed, food additive, feed additive, etc., and that can be orally ingested.

[0048] Examples of such other components include sweeteners, acidulants, vitamins, minerals, thickeners, emulsifiers, antioxidants, water, etc. Furthermore, colorants, flavors, preservatives, antiseptics, fungicides, and further physiologically active substances may be added as necessary.

[0049] Examples of sweeteners include monosaccharides and disaccharides such as glucose, fructose, sucrose, lactose, maltose, palatinose, trehalose, and xylose, isomerized sugars (glucose-fructose liquid sugar, fructose-glucose liquid sugar, mixed isomerized sugar, etc.), sugar alcohols (erythritol, xylitol, lactitol, palatinite, sorbitol, reduced starch syrup, etc.), honey, and high-intensity sweeteners (sucralose, acesulfame potassium, thaumatin, stevia, aspartame, etc.).

[0050] The acidulant may be citric acid, malic acid, gluconic acid, tartaric acid, lactic acid, phosphoric acid, or a salt thereof, and one or more of these may be used.

[0051] Examples of vitamins include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin E, niacin, and inositol.

[0052] Examples of minerals include calcium, magnesium, zinc, and iron.

[0053] Examples of thickening agents include carrageenan, gellan gum, xanthan gum, gum arabic, tamarind gum, guar gum, locust bean gum, karaya gum, agar, gelatin, pectin, soybean polysaccharides, and carboxymethylcellulose (CMC).

[0054] Examples of the emulsifier include glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, lecithin, plant sterols, and saponin.

[0055] Antioxidants include vitamin C, tocopherol (vitamin E), enzyme-treated rutin, and the like. The other ingredients can be appropriately blended in amounts within the ranges that are normally used by those skilled in the art in compositions such as foods, beverages, and pharmaceuticals.

[0056] The agent or composition of the present invention formulated by an appropriate means with at least one other component may be in the form of a solid composition such as powder, granules, capsules, tablets (including coated tablets such as sugar-coated tablets or multi-layer tablets, orally disintegrating tablets, chewable tablets, etc.), or in the form of a liquid composition such as a solution.

[0057] In addition, the agent or composition of the present invention is relatively safe and can be easily taken continuously for a long period of time. Therefore, the agent or composition of the present invention can be preferably used in foods and beverages, nutritional supplements, supplements, and feeds. The agent or composition of the present invention has the above-mentioned functions or activities, and contains at least one of the turmeric extracts that have been conventionally taken and / or the components contained therein, turmeronol A, turmeronol B, and bisacron, and is relatively safe. Furthermore, it can be added to various foods and beverages and taken continuously, and is expected to exert the intended function or action.

[0058] The agent or composition of the present invention is preferably an agent or composition that is taken continuously, specifically, an agent or composition that is taken continuously once or twice a day, preferably for 4 weeks or more, more preferably for 8 weeks or more, and most preferably for 12 weeks or more.

[0059] <Method for inhibiting β-secretase activity> A further aspect of the present invention comprises administering the turmeric extract or at least one of turmeronol A, turmeronol B and bisacron to a subject in need of inhibition of β-secretase activity; and Inhibiting beta-secretase activity in said subject. The present invention relates to a method for inhibiting β-secretase activity, comprising:

[0060] The turmeric extract, or at least one of turmeronol A, turmeronol B and bisacron used in the method according to this embodiment may be in the above-mentioned form of the agent of the present invention.

[0061] The subject in the method according to this embodiment is typically a human, but may be a mammal other than a human.

[0062] In the method according to this embodiment, the administration route is preferably oral administration, nasal administration, intracerebral administration or intrathecal administration, more preferably oral or nasal administration, and particularly preferably oral administration.

[0063] In the method of this embodiment, the amount of the turmeric extract, or at least one of turmeronol A, turmeronol B and bisacron administered to a subject is not particularly limited as long as it is an effective amount for inhibiting β-secretase activity. For example, when the subject is an adult, it is preferable to administer the turmeric extract, or at least one of turmeronol A, turmeronol B and bisaclone to an adult per day so that the total amount of turmeronol A and turmeronol B is 100 μg or more, and / or turmeronol A is 17 μg or more, preferably 28 μg or more, more preferably 43 μg or more, even more preferably 57 μg or more, and most preferably 80 μg or more, and / or turmeronol B is 5 μg or more, preferably 8 μg or more, more preferably 12 μg or more, even more preferably 16 μg or more, and most preferably 20 μg or more, and / or bisaclone is 80 μg or more, preferably 133 μg or more, more preferably 200 μg or more, even more preferably 267 μg or more, and most preferably 360 μg or more.

[0064] The dosage or intake of the agent of the present invention varies depending on the age and weight of the subject, the route of administration and intake, the number of times of administration and intake, the purpose of administration (such as inhibition of β-secretase activity), etc., and can be changed widely at the discretion of a person skilled in the art so as to achieve the desired effect. The ratio of at least one of turmeric extract, turmeronol A, turmeronol B, and bisacron in the agent is not particularly limited, and may be appropriately adjusted according to the ease of production, the preferred daily dose, etc. Since the turmeric extract and the compounds contained therein are relatively safe, the intake amount can be further increased. The daily intake amount may be taken once or in several divided doses. The frequency of administration or intake is also not particularly limited, and can be appropriately selected according to various conditions such as the route of administration and intake, the age and weight of the subject, and the desired effect.

[0065] <Methods for preventing or treating dementia> A further aspect of the present invention is to administer the turmeric extract or at least one of turmeronol A, turmeronol B and bisacron to a subject in need of prevention or treatment of dementia; and Preventing or treating dementia in said subject. The present invention relates to a method for preventing or treating dementia, comprising:

[0066] The turmeric extract or at least one of turmeronol A, turmeronol B and bisacron used in the method according to this embodiment may be in the above-mentioned form of the composition of the present invention.

[0067] The subject in the method according to this embodiment is typically a human, but may be a mammal other than a human.

[0068] In the method according to this embodiment, the administration route is preferably oral administration, nasal administration, intracerebral administration or intrathecal administration, more preferably oral or nasal administration, and particularly preferably oral administration.

[0069] In the method of this embodiment, the dosage of the turmeric extract, or at least one of turmeronol A, turmeronol B and bisacron administered to a subject is not particularly limited as long as it is an effective amount for preventing or treating dementia. For example, when the subject is an adult, it is preferable to administer the turmeric extract, or at least one of turmeronol A, turmeronol B and bisaclone to an adult per day so that the total amount of turmeronol A and turmeronol B is 100 μg or more, and / or turmeronol A is 17 μg or more, preferably 28 μg or more, more preferably 43 μg or more, even more preferably 57 μg or more, and most preferably 80 μg or more, and / or turmeronol B is 5 μg or more, preferably 8 μg or more, more preferably 12 μg or more, even more preferably 16 μg or more, and most preferably 20 μg or more, and / or bisaclone is 80 μg or more, preferably 133 μg or more, more preferably 200 μg or more, even more preferably 267 μg or more, and most preferably 360 μg or more.

[0070] The amount of administration or intake of the composition of the present invention varies depending on the age and weight of the subject, the route of administration or intake, the number of times of administration or intake, the purpose of administration (prevention or treatment of dementia, etc.), etc., and can be changed widely at the discretion of a person skilled in the art so as to achieve the desired effect. The ratio of at least one of the turmeric extract, turmeronol A, turmeronol B, and bisacron in the composition is not particularly limited, and may be appropriately adjusted according to the ease of production, the preferred daily dose, etc. Since the turmeric extract and the compounds contained therein are relatively safe, the intake amount can be further increased. The daily intake amount may be taken in one dose, or may be taken in several doses. The frequency of administration or intake is also not particularly limited, and can be appropriately selected according to various conditions such as the route of administration or intake, the age and weight of the subject, and the desired effect. EXAMPLES

[0071] [Reference example] (1) Method for producing turmeric extract Turmeric extracts were prepared by water extraction and supercritical gas extraction. In the water extraction method, the turmeric rhizome parts were extracted with water (including hot water) and the resulting extract was dried under reduced pressure to remove moisture. In the supercritical gas extraction method, the turmeric rhizome parts were contacted with supercritical carbon dioxide and the extracted components were mixed with vegetable oil. In the following examples, the turmeric extracts prepared by each extraction method were mixed at a weight ratio of 8:1 and used.

[0072] (2) Amount of Turmeronol A, Turmeronol B and Bisacron in Turmeric Extract The amounts of turmeronol A, turmeronol B and bisacron in the turmeric extract were measured by HPLC as follows: The amount of turmeronol A per gram of turmeric extract was confirmed to be 724 μg, the amount of turmeronol B per gram of turmeric extract was 578 μg, and the amount of bisacron per gram of turmeric extract was 2182 μg.

[0073] Turmeronol A Analysis Turmeric extract was weighed, water and ethyl acetate were added, and the mixture was centrifuged to obtain a supernatant. The ethyl acetate was removed by vacuum distillation, and the mixture was dissolved in acetonitrile. The obtained liquid was used as a measurement sample and subjected to HPLC. HPLC was performed under the following conditions. Column: L-column ODS 5μm (4.6 mm φ×250 mm) Mobile phase: 48% acetonitrile (20 min) ⇒ 100% acetonitrile (5 min) ⇒ 48% acetonitrile (10 min) Flow rate: 1.0mL / min Column temperature: 40℃ Detection wavelength: 238 nm

[0074] Analysis of Turmeronol B Turmeric extract was weighed, water and ethyl acetate were added, and the mixture was centrifuged to obtain a supernatant. The ethyl acetate was removed by vacuum distillation, and the mixture was dissolved in acetonitrile. The obtained liquid was used as a measurement sample and subjected to HPLC. HPLC was performed under the following conditions. Column: COSMOSIL 5PYE Packed Column (4.6 mm φ × 150 mm) Mobile phase: 57% methanol (30 min) ⇒ 100% methanol (5 min) ⇒ 57% methanol (15 min) Flow rate: 1.0mL / min Column temperature: 40℃ Detection wavelength: 238 nm

[0075] Analysis of Bisacron Turmeric extract was weighed, water and ethyl acetate were added, and the mixture was centrifuged to obtain a supernatant. The ethyl acetate was removed by vacuum distillation, and the mixture was dissolved in acetonitrile. The obtained liquid was used as a measurement sample and subjected to HPLC. HPLC was performed under the following conditions. Column: Wakopak Navi C18-5 (4.6 mm φ × 250 mm) Mobile phase: 30% acetonitrile (20 min) ⇒ 20% acetonitrile (5 min) ⇒ 80% acetonitrile (10 min) Flow rate: 0.7mL / min Column temperature: 50℃ Detection wavelength: 240nm

[0076] (3) Obtaining Turmeronol A, Turmeronol B, and Bisacron Turmeronol A, Turmeronol B and Bisacron were purchased as commercial products from Nagara Science Co., Ltd. and dissolved in dimethyl sulfoxide before use in the tests.

[0077] [Example 1] Evaluation of the effect of suppressing β-secretase activity in microglial cells 1 Mouse microglial cells BV-2 were suspended in DMEM medium (containing 10% FBS) and plated in a 100 mm cell culture dish at a cell count of 4.0 × 10 6The cells were seeded at 100 μg / mL, and cultured at 37°C in the presence of 5% CO2. After 48 hours, the turmeric extract prepared in the Reference Example was added to the dishes at concentrations of 100 μg / mL, 200 μg / mL, and 400 μg / mL, and cultured for 24 hours. After the culture was completed, the β-secretase activity of the cells was measured according to the protocol attached to the Beta-Scretase Activity Assay Kit (Fluorometric) (Abcam: ab65357).

[0078] The results are shown in Figure 1. Figure 1 shows that 200 and 400 μg / mL of turmeric extract inhibited β-secretase activity in mouse microglial cells BV-2.

[0079] [Example 2] Evaluation of the effect of suppressing β-secretase activity in microglial cells 2 Mouse microglial cells BV-2 were cultured in the same manner as in Example 1. After 48 hours, turmeronol A, turmeronol B, and bisacron were added to the dish at concentrations of 6.25 μM, 12.5 μM, and 25 μM, respectively, and cultured for 24 hours. After the culture was completed, the β-secretase activity of the cells was measured according to the protocol attached to the Beta-Scretase Activity Assay Kit (Fluorometric) (Abcam: ab65357).

[0080] The results are shown in Figure 2. Figure 2 shows that β-secretase activity in mouse microglial cells BV-2 was inhibited by 6.25 to 25 μM turmeronol A and turmeronol B, and by 12.5 and 25 μM bisaclone.

Claims

1. A beta-secretase inhibitor containing at least one of turmeronol A, turmeronol B, and bisacron as an active ingredient.

2. The β-secretase inhibitor according to claim 1, which consists of at least one of turmeronol A, turmeronol B and bisacron as active ingredients.

3. A composition for preventing or treating dementia, comprising at least one of turmeronol A, turmeronol B and bisacron as an active ingredient.

4. The composition according to claim 3, which consists of at least one of turmeronol A, turmeronol B and bisacron as active ingredients.

5. A composition for preventing or treating dementia, comprising turmeric extract as an active ingredient.

6. 6. The composition according to claim 5, which consists solely of turmeric extract as an active ingredient.

7. 6. The composition of claim 5, wherein the turmeric extract comprises an extract of turmeric with at least one extraction solvent selected from the group consisting of water and hydrophilic organic solvents.

8. The composition according to claim 5 , wherein the turmeric extract comprises a mixture of a turmeric extract obtained by extraction with water and a turmeric extract obtained by extraction with supercritical carbon dioxide.

9. The composition of claim 5, wherein the turmeric extract contains at least one of turmeronol A, turmeronol B and bisacron.

10. The composition of claim 3 or 5, wherein the dementia is Lewy body dementia or vascular dementia.

11. The composition according to claim 3 or 5, wherein the dementia is not Alzheimer's dementia.

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