JP7602312B2 - Antidementia agents and agents for improving/suppressing short-term memory impairment - Google Patents

Description

The present invention relates to an anti-dementia agent and an agent for improving/suppressing short-term memory impairment.

Dementia is a condition in which brain cells die or function poorly due to a variety of causes, causing various disorders and interfering with daily life. As the brain shrinks as dementia develops, physical functions may also be lost.

In recent years, therefore, active research has been conducted into ingredients that have the effect of suppressing dementia. For example, Patent Document 1 discloses that royal jelly exhibits anti-dementia activity.

International Publication No. 2017/078175

Japanese Pharmacology Journal, 130(2), pp.112-116, 2007

The present invention aims to provide a novel anti-dementia agent and an agent for improving/suppressing short-term memory impairment.

The inventors have found through in vivo testing that a decomposed extract of bagasse has the effect of improving short-term memory impairment caused by the accumulation of amyloid β protein.

That is, in a first aspect, the present invention provides an anti-dementia agent that contains a decomposed extract of bagasse as an active ingredient.

The decomposition extract of bagasse may be a decomposition treatment liquid obtained by at least one decomposition treatment selected from the group consisting of hydrothermal treatment, acid treatment, alkali treatment, subcritical water treatment, pulverization treatment, and explosion treatment.

The decomposition extract of bagasse may be a fraction obtained by passing the decomposition treatment liquid through a column packed with a fixed carrier. The fixed carrier is preferably a synthetic adsorbent or an ion exchange resin.

When the fixed carrier is a synthetic adsorbent, the decomposed extract of bagasse may be a fraction obtained by eluting the components adsorbed on the synthetic adsorbent with at least one solvent selected from the group consisting of water, methanol, ethanol, and mixtures thereof.

The synthetic adsorbent is preferably an aromatic resin, an acrylic acid-based methacrylic resin, or an acrylonitrile-aliphatic resin.

The decomposition extract of bagasse may be a fraction obtained by passing the decomposition treatment liquid through a column packed with a synthetic adsorbent as a fixed carrier and eluting the components adsorbed by the synthetic adsorbent with a mixed solvent of ethanol and water. In this case, the synthetic adsorbent is an unsubstituted aromatic resin, the temperature of the column is 20 to 60°C, and the volume ratio of ethanol and water in the mixed solvent (ethanol/water) may be 50/50 to 60/40.

In a second aspect, the present invention provides an agent for improving/suppressing short-term memory impairment, which contains a decomposed extract of bagasse as an active ingredient.

The present invention provides a novel anti-dementia agent and an agent for improving/suppressing short-term memory impairment.

1 is a graph showing the evaluation results in a Y-maze test.

The following describes an embodiment of the present invention. However, the present invention is not limited to the following embodiment.

The anti-dementia agent of the present invention has an anti-dementia effect. In the present invention, the term "anti-dementia effect" refers to a concept including an effect of preventing the onset of dementia, an effect of delaying the onset of dementia, and an effect of recovering from the state at the time of onset of dementia once it has developed. The dementia targeted by the anti-dementia agent of the present invention may be Alzheimer's dementia. There are two types of Alzheimer's dementia: a pathology caused by the loss of acetylcholine-stimulating neurons in the Meynert nucleus of the basal forebrain (cholinergic hypothesis) and a pathology caused by the accumulation of amyloid β protein (amyloid hypothesis). Both of these are different pathologies, and are not the same pathology viewed from different angles. The dementia targeted by the anti-dementia agent of the present invention may be Alzheimer's dementia based on any theory, and is preferably Alzheimer's dementia based on the amyloid hypothesis. That is, the dementia targeted by the anti-dementia agent of the present invention may be Alzheimer's dementia caused by the accumulation of amyloid β protein. In other words, the present invention can provide an anti-dementia agent for Alzheimer's dementia, an anti-dementia agent for Alzheimer's dementia based on the amyloid hypothesis, or an anti-dementia agent for Alzheimer's dementia caused by the accumulation of amyloid β protein.

In Alzheimer's dementia based on the amyloid hypothesis, it is believed that cognitive function is impaired because the accumulation of tau protein in addition to amyloid β protein in the brain causes the death of brain nerve cells. In the early stages, amyloid β protein begins to accumulate, and after about 10 years, tau protein begins to accumulate. Thereafter, it is believed that the continued accumulation of amyloid β protein and tau protein causes the death of brain nerve cells, leading to the onset of dementia about 25 years after the early stages. In another aspect, the anti-dementia agent of the present invention can be said to have an effect of suppressing the accumulation of amyloid β protein in the brain and an effect of reducing amyloid β protein accumulated in the brain, and can also be said to have an effect of suppressing the accumulation of tau protein in the brain and an effect of reducing tau protein accumulated in the brain.

The present invention can also be said to provide a memory impairment improving/suppressing agent. The memory impairment improving/suppressing agent of the present invention has the effect of improving/suppressing memory impairment. In the present invention, "improving/suppressing memory impairment" is a concept that includes the effect of preventing the onset of memory impairment, the effect of delaying the onset of memory impairment, and the effect of recovering memory impairment from the state at the time of onset once it has occurred. The memory impairment targeted by the memory impairment improving/suppressing agent of the present invention may be either long-term memory impairment or short-term memory impairment, but is preferably short-term memory impairment. In other words, the present invention can be said to provide a short-term memory impairment improving/suppressing agent, and further, can be said to provide an improving/suppressing agent for short-term memory impairment caused by the accumulation of amyloid β protein.

An anti-dementia agent according to one embodiment contains a decomposition extract of bagasse as an active ingredient. The decomposition extract of bagasse preferably contains at least one selected from the group consisting of phenylpropanoids such as p-coumaric acid, ferulic acid, caffeic acid and vanillin, as well as lignin and its decomposition products.

"Bagasse" typically refers to bagasse discharged during the sugar manufacturing process in the raw sugar manufacturing process. The bagasse discharged during the sugar manufacturing process in a raw sugar factory includes not only the final bagasse that leaves the final press, but also shredded sugarcane that is eaten into the subsequent presses, including the first press. A suitable bagasse is bagasse discharged after the sugar juice is compressed in the compression process in a raw sugar factory. The moisture, sugar content, and composition ratio of the bagasse vary depending on the type of sugarcane, harvest time, etc., but in the present invention, any of these bagasses can be used. Furthermore, in this embodiment, as in the raw sugar factory, bagasse remaining after sugarcane compression discharged from, for example, a brown sugar manufacturing factory, or bagasse after sugar juice is compressed from sugarcane in a small-scale laboratory-level implementation can also be used as the raw bagasse.

In one embodiment, the decomposition extract of bagasse may be a decomposition treatment liquid of bagasse (and/or a processed product thereof). The decomposition treatment liquid can be obtained by at least one decomposition treatment selected from the group consisting of an alkali treatment, a hydrothermal treatment, an acid treatment, a subcritical water treatment, a fine pulverization treatment, and an explosion treatment. From the viewpoint of facilitating the production of a decomposition extract of bagasse, the decomposition treatment is preferably an alkali treatment or a hydrothermal treatment.

The alkaline treatment may be a treatment in which the bagasse is brought into contact with an alkaline solution. Examples of methods for bringing the bagasse into contact with the alkaline solution include a method in which the bagasse is sprinkled with the alkaline solution, and a method in which the bagasse is immersed in the alkaline solution. In the method in which the bagasse is immersed in the alkaline solution, the bagasse may be immersed in a mixture of the bagasse and the alkaline solution while being stirred.

Examples of alkaline solutions include aqueous sodium hydroxide solutions, aqueous potassium hydroxide solutions, and aqueous ammonia solutions. The alkaline solution may be one of these solutions alone or a mixture of two or more of them. From the viewpoints of being inexpensive and easily usable in food manufacturing processes, the alkaline solution is preferably an aqueous sodium hydroxide solution.

The temperature of the alkaline solution (liquid temperature) is preferably 40°C or higher, more preferably 100°C or higher, and even more preferably 130°C or higher, from the viewpoint of shortening the processing time of the decomposition process. The temperature of the alkaline solution is preferably 250°C or lower, more preferably 200°C or lower, and even more preferably 150°C or lower, from the viewpoint of not leaving polysaccharides in the decomposition process liquid.

The alkali treatment may be carried out under normal pressure or under pressure. When pressure is applied, the pressure may be 0.1 MPa or more, or 0.2 MPa or more, and may be 4.0 MPa or less, 1.6 MPa or less, or 0.5 MPa or less.

Hydrothermal treatment may be a process in which bagasse is brought into contact with high-temperature water or steam under high pressure. More specifically, hydrothermal treatment may be a process in which water is added so that the solids concentration of the bagasse is 0.1 to 50%, and decomposition treatment is carried out under high-temperature and high-pressure conditions. The temperature of the water or steam is preferably 130 to 250°C, and the applied pressure is preferably 0.1 to 0.5 MPa higher than the saturated steam pressure of water at each temperature.

The acid treatment may be a treatment in which the bagasse is brought into contact with an acidic solution. Examples of the acidic solution include dilute sulfuric acid. The method of bringing the bagasse into contact with the acidic solution, the temperature of the acidic solution in the acid treatment, and the pressure conditions in the acid treatment may be the same as the method or conditions in the alkali treatment described above.

The subcritical water treatment may be a treatment in which subcritical water is brought into contact with bagasse. The method for bringing subcritical water into contact with bagasse may be the same as the method for the alkaline treatment described above. There are no particular limitations on the conditions for the subcritical water treatment, but it is preferable that the temperature of the subcritical water is 160 to 240°C and the treatment time is 1 to 90 minutes.

The fine pulverization process may be a process in which bagasse is pulverized to a size of several μm to several hundred μm by compression, impact, shear, friction, etc. The explosion process may be a process in which the insoluble xylan contained in the bagasse is decomposed to a certain extent by hydrothermal treatment, and then the bagasse is pulverized by instantly releasing it to atmospheric pressure by suddenly opening a valve installed in a pressure-resistant reaction vessel, for example.

After the above-mentioned decomposition process, the decomposition liquid may be subjected to a process for separating the solid and liquid components. In this case, the liquid obtained after the separation may be used as the decomposition liquid. The method for separating the solid and liquid components may be separation using a strainer, filtration, centrifugation, decantation, etc.

In the decomposition treatment liquid, polymeric components such as polysaccharides may be removed by membrane separation. In this case, the liquid after membrane separation can be used as the decomposition treatment liquid. There are no particular limitations on the separation membrane as long as it is an ultrafiltration membrane (UF membrane). The molecular weight cutoff of the ultrafiltration membrane is preferably 2,500 to 50,000, and more preferably 2,500 to 5,000.

Materials that can be used for the ultrafiltration membrane include polyimide, polyethersulfone (PES), polysulfone (PS), polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), regenerated cellulose, cellulose, cellulose ester, sulfonated polysulfone, sulfonated polyethersulfone, polyolefin, polyvinyl alcohol, polymethyl methacrylate, and polytetrafluoroethylene.

The filtration method of the ultrafiltration membrane may be dead-end filtration or cross-flow filtration, but cross-flow filtration is preferred from the viewpoint of suppressing membrane fouling.

The ultrafiltration membrane may be of any suitable type, such as flat membrane, spiral, tubular, hollow fiber, etc. More specifically, examples include the GE series, GH series, and GK series from GE Power &Water; the G-5 type, G-10 type, G-20 type, G-50 type, PW type, and HWSUF type from DESAL; the HFM-180, HFM-183, HFM-251, HFM-300, HFK-131, HFK-328, MPT-U20, MPS-U20P, and MPS-U20S from KOCH; the SPE1, SPE3, SPE5, SPE10, SPE30, SPV5, SPV50, and SOW30 from Synder; the Microza (registered trademark) UF series from Asahi Kasei Corporation, which has a molecular weight cutoff of 3,000 to 10,000; and the NTR7410 and NTR7450 from Nitto Denko Corporation.

In another embodiment, the decomposition extract of bagasse may be a fraction obtained by passing the above-mentioned decomposition treatment liquid through a column packed with a fixed carrier. By passing the decomposition treatment liquid through the column, the components (active ingredients) having anti-dementia effects in the decomposition treatment liquid are adsorbed onto the fixed carrier, and most of the sugars and inorganic salts flow out as they are.

The above-mentioned decomposition treatment liquid can be passed through the column directly or after being adjusted to any concentration with water. The pH of the decomposition treatment liquid may be adjusted before passing through the column. From the viewpoint of improving the adsorption rate, it is preferable that the decomposition treatment liquid is adjusted to a pH of 6 or less. The pH of the decomposition treatment liquid may be more than 4.5 and 6 or less.

The fixed carrier is preferably either a synthetic adsorbent or an ion exchange resin.

The synthetic adsorbent is preferably a synthetic porous adsorbent. As the synthetic adsorbent (synthetic porous adsorbent), an organic resin is preferably used. The organic resin is preferably an aromatic resin, an acrylic acid-based methacrylic resin, or an acrylonitrile aliphatic resin.

Examples of aromatic resins include styrene-divinylbenzene resins. Examples of aromatic resins include porous resins such as aromatic resins with hydrophobic substituents, unsubstituted aromatic resins, and aromatic resins that have been specially treated to be unsubstituted. Of these, unsubstituted aromatic resins and aromatic resins that have been specially treated to be unsubstituted are preferred.

Synthetic adsorbents that are commercially available include Diaion (trademark) HP-10, HP-20, HP-21, HP-30, HP-40, HP-50 (all unsubstituted aromatic resins, all trade names, manufactured by Mitsubishi Chemical Corporation); SP-825, SP-800, SP-850, SP-875, SP-70, SP-700 (all unsubstituted aromatic resins that have been specially treated, all trade names, manufactured by Mitsubishi Chemical Corporation); SP-900 (aromatic resin, trade name, manufactured by Mitsubishi Chemical Corporation); Amberlite (trademark) XAD-2, XAD-4, XAD-16, XAD-2000 (aromatic resins, all trade names, manufactured by Organo Corporation); Diaion Examples of such resins include POLY(TM) SP-205, SP-206, and SP-207 (aromatic resins having hydrophobic substituents, all trade names, manufactured by Mitsubishi Chemical Corporation); HP-2MG and EX-0021 (aromatic resins having hydrophobic substituents, all trade names, manufactured by Mitsubishi Chemical Corporation); Amberlite(TM) XAD-7 and XAD-8 (acrylic ester resins, all trade names, manufactured by Organo Corporation); Diaion(TM) HP1MG and HP2MG (acrylic acid methacrylic resins, all trade names, manufactured by Mitsubishi Chemical Corporation); Sephadex(TM) LH20 and LH60 (crosslinked dextran derivatives, all trade names, manufactured by Pharmacia Biotech Co., Ltd.). Among these, aromatic resins without substituents (e.g., HP-20) or aromatic resins that have been specially treated with an unsubstituted type (e.g., SP-850) are preferred.

The amount of synthetic adsorbent to be packed into the column can be determined appropriately depending on the size of the column, the type of synthetic adsorbent, etc.

When a synthetic adsorbent is used as the fixed carrier, the flow rate of the decomposition treatment liquid can be appropriately changed depending on the size of the column, the type of elution solvent, the type of synthetic adsorbent, etc., but is preferably SV = 1 to 30 h ^{- 1.} Note that SV (Space Velocity) is a unit that indicates how many times the resin volume the liquid is passed per hour.

The adsorbed components (active ingredients) adsorbed to the synthetic adsorbent can be eluted with a solvent (elution solvent). From the viewpoint of recovering the adsorbed components more efficiently, it is preferable to wash away the sugars and inorganic salts remaining in the column with water before eluting the adsorbed components. In this case, the eluted components can be used as a decomposition extract of bagasse.

When a synthetic adsorbent is used as the fixed carrier, the elution solvent may be at least one selected from the group consisting of water, methanol, ethanol, and mixtures thereof. The elution solvent is preferably a mixed solvent of alcohol and water, more preferably a mixed solvent of ethanol and water, and even more preferably a mixed solvent of ethanol and water with a volume ratio of 50/50 to 60/40 (ethanol/water) from the viewpoint of enabling the adsorbed components to be eluted more efficiently at room temperature.

When a synthetic adsorbent is used as the fixed carrier, the temperature of the column during elution (column temperature) may be room temperature, but by increasing the column temperature above room temperature, the mixing ratio of ethanol in the mixed solvent of ethanol and water can be reduced, and the adsorbed components can be eluted more efficiently. The temperature is preferably 20 to 60°C, and more preferably 40 to 60°C. The inside of the column may be under normal pressure or under pressurized conditions.

When a synthetic adsorbent is used as the fixed carrier, the elution rate can be appropriately set depending on the size of the column, the type of elution solvent, the type of synthetic adsorbent, etc., but is preferably SV=0.1 to 10 hr ^-1 .

Ion exchange resins are classified into gel-type resins and porous resins such as porous, microporous, or highly porous resins based on the form of the resin, but there are no particular limitations. The ion exchange resin is preferably an anion exchange resin. As the anion exchange resin, a strong basic anion exchange resin or a weak basic anion exchange resin may be used. When an alkaline processing liquid is used as the raw material, a strong basic anion exchange resin is preferably used, but there are no particular limitations when a decomposition processing liquid from other processes is used as the raw material.

Commercially available strong basic anion exchange resins include Diaion (trademark) PA306, PA308, PA312, PA316, PA318L, HPA25, SA10A, SA12A, SA11A, SA20A, and UBA120 (all manufactured by Mitsubishi Chemical Corporation), Amberlite (trademark) IRA400J, IRA402B1, IRA404J, IRA900J, IRA904, IRA458RF, IRA958, IRA410J, IRA411, and IRA910CT (all manufactured by Organo Corporation), and Dowex (trademark) Marathon A, Marathon MSA, MONOSPHERE550A, and Marathon A2 (all manufactured by Dow Chemical Japan).

Commercially available weakly basic anion exchange resins include Diaion (trademark) WA10, WA20, WA21J, and WA30 (all manufactured by Mitsubishi Chemical Corporation), Amberlite (trademark) IRA478RF, IRA67, IRA96SB, IRA98, and XE583 (all manufactured by Organo Corporation), and Dowex (trademark) Marathon WBA, 66, MONOSPHERE 66, and MONOSPHERE 77 (all manufactured by Dow Chemical Japan Ltd.).

The amount of ion exchange resin to be packed in the column can be determined appropriately depending on the size of the column, the type of ion exchange resin, etc., but a wet volume of 2 to 10,000 times the solid content of the decomposition treatment liquid is preferable, and a wet volume of 5 to 500 times is more preferable.

The liquid passing conditions can be appropriately set depending on the type of pretreatment liquid, the type of ion exchange resin, etc. Preferably, the flow rate is SV=0.3 to 30 h ^-1 , the amount of liquid passing is 100 to 300% of the ion exchange resin, and the column temperature is 40 to 90° C. The inside of the column may be at normal pressure or under pressure.

When an ion exchange resin is used as the fixed carrier, the decomposed extract of bagasse may be a fraction obtained by passing the extract through a column packed with an ion exchange resin and eluting it with an eluent such as a salt, an acid, an alcohol, or a mixed aqueous solution of these. The eluent may be degassed.

In one embodiment, the decomposition extract of bagasse may be a concentrate obtained by concentrating the above-mentioned decomposition treatment liquid or fraction. The concentration method may be a known method, such as distillation of the solvent under reduced pressure or freeze-drying. When concentration is performed, the decomposition treatment liquid or fraction may be concentrated 15 to 30 times, and the concentrated components may be used as the decomposition extract of bagasse.

A decomposition extract of bagasse can be obtained, for example, as follows. A 1% by mass aqueous solution of sodium hydroxide is added to the bagasse so that the solid concentration is 0.1 to 50%, and the bagasse is boiled at 100°C to obtain a decomposition treatment liquid (alkaline treatment liquid). The decomposition treatment liquid is ultrafiltered using a UF membrane with a molecular weight cutoff of 2500 to 5000, and the obtained filtrate is adjusted to be acidic and then passed through a column packed with an unsubstituted aromatic resin at a column temperature of 20 to 60°C. The components adsorbed in the column are then eluted with a mixed solvent of ethanol and water (elution solvent) with a volume ratio of 50/50 to 60/40 (ethanol/water) at a column temperature of 20 to 60°C, and the fraction in which the amount of elution liquid collected from the start of elution with the mixed solvent of ethanol and water is within 45 times the wet volume of the aromatic resin is collected. The recovered fractions (fractions containing components with anti-dementia effects) can be collected and concentrated by conventional means (solvent distillation under reduced pressure, freeze-drying, etc.) to obtain a decomposition extract of bagasse. The decomposition extract of bagasse thus obtained can be stored as a liquid or powder extract concentrated to a solid content of 30% by mass or more. When the extract is in liquid form, it is preferable to store it in a refrigerator.

As another example, the decomposition extract of bagasse can be obtained, for example, as follows. That is, water is added to bagasse so that the solid concentration is 0.1 to 50%, and the bagasse is subjected to hydrothermal treatment with water at 130 to 250°C under a pressure of 0.2 to 4.0 MPa, and a decomposition treatment liquid (hydrothermally treated liquid) is obtained by solid-liquid separation by filtration. The obtained hydrothermally treated liquid is passed through a column packed with aromatic resin that has been specially treated to be unsubstituted at a temperature of 20 to 60°C, and the components adsorbed in the column are eluted with a mixed solvent of ethanol and water (elution solvent) with a volume ratio of 50/50 to 60/40 (ethanol/water) at a column temperature of 20 to 60°C, and the fraction eluted in an amount of elution liquid collected from the start of elution with the mixed solvent of ethanol and water within 5 times the wet volume of the aromatic resin is recovered. The recovered fractions (fractions containing components with anti-dementia effects) can be collected and concentrated by conventional means (solvent distillation under reduced pressure, freeze-drying, etc.) to obtain a decomposition extract of bagasse. The decomposition extract of bagasse thus obtained can be stored as a liquid or powder extract concentrated to a solid content of 30% by mass or more. When the extract is in liquid form, it is preferable to store it in a refrigerator.

The bagasse decomposition extract in each of the above-mentioned embodiments may be in liquid or powder form. A powdered bagasse decomposition extract can be produced, for example, by using a liquid bagasse decomposition extract by a spray drying method, a freeze-drying method, a fluidized bed granulation method, or a powdering method using an excipient.

The anti-dementia agent may consist only of the active ingredient, a decomposed extract of bagasse, or may further contain ingredients that can be used in foods, quasi-drugs, or medicines. There are no particular limitations on the ingredients that can be used in foods, quasi-drugs, or medicines, but examples of these include amino acids, proteins, carbohydrates, oils and fats, sweeteners, minerals, vitamins, flavorings, excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizers, suspending agents, etc.

Examples of proteins include milk casein, whey, soy protein, wheat protein, and egg white. Examples of carbohydrates include corn starch, cellulose, pregelatinized starch, wheat starch, rice starch, and potato starch. Examples of fats and oils include salad oil, corn oil, soy oil, safflower oil, olive oil, and palm oil. Examples of sweeteners include sugars such as glucose, sucrose, fructose, glucose-fructose liquid sugar, and fructose-glucose liquid sugar; sugar alcohols such as xylitol, erythritol, and maltitol; artificial sweeteners such as sucralose, aspartame, saccharin, and acesulfame K; and stevia sweeteners. Examples of minerals include calcium, potassium, phosphorus, sodium, manganese, iron, zinc, magnesium, and salts thereof. Examples of vitamins include vitamin E, vitamin C, vitamin A, vitamin D, vitamin B, biotin, niacin, etc. Examples of excipients include dextrin, starch, lactose, crystalline cellulose, etc. Examples of binders include polyvinyl alcohol, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, etc. Examples of lubricants include magnesium stearate, calcium stearate, talc, etc. Examples of disintegrants include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, dextrin, etc. Examples of emulsifiers or surfactants include sucrose fatty acid esters, citric acid, lactic acid, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, lecithin, etc. Examples of bases include cetostearyl alcohol, lanolin, polyethylene glycol, etc. Examples of solubilizing agents include polyethylene glycol, propylene glycol, sodium carbonate, sodium citrate, etc. Examples of suspending agents include glycerin monostearate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, sodium alginate, etc. These may be used alone or in combination of two or more.

When the anti-dementia agent contains other materials, the content of the active ingredient, the decomposed extract of bagasse, may be appropriately set depending on the form and intended use of the anti-dementia agent described below, but from the viewpoint of exerting the anti-dementia effect more effectively, the content is preferably 1% by mass or more, more preferably 3% by mass or more, even more preferably 5% by mass or more, and also preferably 50% by mass or less, more preferably 40% by mass or less, and even more preferably 30% by mass or less, in terms of solid content excluding monosaccharides and oligosaccharides.

The anti-dementia agent can be used as a food, a quasi-drug, or a medicine. The food may be provided in the form of, for example, a health food, a food for specified health uses, a functional food, a food with nutrient function claims, a supplement, etc.

Anti-dementia agents can also be used as feed or feed additives. Examples of feed include companion animal feed such as dog food and cat food, livestock feed, poultry feed, and farmed fish and shellfish feed. "Feed" includes anything that animals take orally for nutritional purposes. More specifically, when classified in terms of nutrient content, it includes all roughage, concentrated feed, inorganic feed, and special feed, and when classified in terms of official standards, it includes all compound feed, mixed feed, and single feed. When classified in terms of feeding method, it includes all feed that is fed directly, fed mixed with other feed, or added to drinking water to supplement nutrients.

The anti-dementia agent may be in any form, such as a solid (powder, granules, etc.), liquid (solution, suspension, etc.), or paste, and may be in any dosage form, such as a powder, pill, granule, tablet, capsule, lozenge, liquid, or suspension.

The anti-dementia agent may be administered parenterally, such as intravenously, or orally. It is preferable that the anti-dementia agent be administered orally.

When the anti-dementia agent is administered parenterally, the dosage is, for example, preferably 100 μg/kg (body weight) or more of the decomposition extract of bagasse per administration, more preferably 150 μg/kg (body weight) or more, and even more preferably 200 μg/kg (body weight) or more. Also, it is preferable that the decomposition extract of bagasse is administered at a dose of 200 μg/kg (body weight) or more per day, more preferably 300 μg/kg (body weight) or more, and even more preferably 400 μg/kg (body weight) or more. Also, it is preferable that the decomposition extract of bagasse is administered at a dose of 2000 mg/kg (body weight) or less per administration, more preferably 1500 mg/kg (body weight) or less, and even more preferably 1000 mg/kg (body weight) or less. In addition, the decomposition extract of bagasse is preferably administered at a daily dose of 4000 mg/kg (body weight) or less, more preferably at a daily dose of 3000 mg/kg (body weight) or less, and even more preferably at a daily dose of 2000 mg/kg (body weight) or less. Within this range, a sufficient blood concentration can be achieved, and the anti-dementia effect can be better expressed.

When the anti-dementia agent is orally administered, if the above product containing the anti-dementia agent is ingested intensively, the intake amount of the above product (intake amount or dosage per day) is preferably 50 to 3,000 mg/kg (body weight), more preferably 100 to 2,000 mg/kg (body weight), based on the total amount (solid content) of the decomposed extract of bagasse excluding monosaccharides and oligosaccharides. If ingested on a daily basis for a long period of time, the intake amount of the above product (intake amount per day) is preferably 1 to 1,000 mg/kg (body weight), based on the total amount (solid content) of the decomposed extract of bagasse excluding monosaccharides and oligosaccharides.

The anti-dementia agent of this embodiment can be used for humans or animals with accumulation of amyloid β protein. The anti-dementia agent of this embodiment can also be used for humans or animals suffering from dementia (or Alzheimer's dementia) or memory disorder (or short-term memory disorder), and the dementia and memory disorder may be caused by accumulation of amyloid β protein.

Specific aspects of the short-term memory impairment improving/suppressing agent according to one embodiment may be similar to those of the anti-dementia agent described above. That is, the short-term memory impairment improving/suppressing agent according to one embodiment may be obtained by replacing "antidementia agent" with "short-term memory impairment improving/suppressing agent" in the description of the anti-dementia agent described above.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

Hereinafter, the bagasse decomposition extract may simply be referred to as the "extract." In descriptions of the dosage of the bagasse decomposition extract, for example, "500 mg/kg" means that 500 mg was administered per kg of body weight. "Amyloid β protein" may simply be referred to as "amyloid β."

<Production of bagasse decomposition extract>
[Production Example 1]
15 kg of bagasse (water content 50% by mass), which is sugarcane pomace, and 100 L of 0.5% (w/w) aqueous sodium hydroxide solution were mixed and subjected to an alkali treatment under the condition of 150 ° C. The mixture after the alkali treatment was separated into a solid portion and a liquid portion, and about 100 L of the liquid portion was obtained. Ultrafiltration was performed using a UF membrane (GE Water & Process Technology, GH8040F30) with a molecular weight cutoff of 2500, and 80 L of filtrate was obtained. 1 liter of synthetic adsorbent (manufactured by Mitsubishi Chemical Corporation, HP-20) was filled in a resin tower (inner diameter 80 mm, height 400 mm), and the above filtrate was passed through it at a flow rate of 10 liters / hour (SV = 10.0 (hour ^-1 )) after adjusting the pH to 6.

Subsequently, 5 liters of purified water was passed through the resin tower at a flow rate of 10 liters/hour (SV=10.0 (hour ^-1 )) to wash the resin tower. Next, 2 liters of 60% aqueous ethanol solution (ethanol/water=60/40 (volume/volume)) was passed through the resin tower at a flow rate of 2 liters/hour (SV=2.0 (hour ^-1 )) as an elution solvent. Subsequently, 2 liters of purified water was passed through the resin tower at a flow rate of 2 liters/hour (SV=2.0 (hour ^-1 )) to elute the components adsorbed to the synthetic adsorbent. The fraction eluted from the resin tower was concentrated under reduced pressure to about 10 times the concentration using a rotary evaporator, and then freeze-dried overnight to obtain 20 g of a brownish powder as a decomposition extract of bagasse. This was designated as Extract A.

[Production Example 2]
30 kg of bagasse (water content 50% by mass), which is sugarcane pomace, was hydrothermally treated with 100 L of hot water at 200 ° C. The pretreated mixed liquid was separated into a solid and a liquid, and about 88 L of the liquid was obtained. Ultrafiltration was performed using a UF membrane (GE Water & Process Technology, GH8040F30) with a molecular weight cutoff of 2500, and 70 L of filtrate was obtained. 1 L of synthetic adsorbent (Mitsubishi Chemical Corporation, SP-850) was packed in a resin tower (inner diameter 80 mm, height 400 mm), and 25 L of the above filtrate was passed through it at a flow rate of 20 L/hour (SV = 20.0 (hour ^-1 )).

Subsequently, 3.3 liters of purified water was passed through the resin tower at a flow rate of 20 liters/hour (SV=20.0 (hour ^-1 )) to wash the resin tower. Next, 2 liters of 60% aqueous ethanol solution (ethanol/water=60/40 (volume/volume)) was passed through the resin tower at a flow rate of 2 liters/hour (SV=2.0 (hour ^-1 )) as an elution solvent. Subsequently, 2 liters of purified water was passed through the resin tower at a flow rate of 2 liters/hour (SV=2.0 (hour ^-1 )) to elute the components adsorbed to the synthetic adsorbent. The fraction eluted from the resin tower was concentrated under reduced pressure to about 10 times the concentration using a rotary evaporator, and then freeze-dried overnight to obtain 40 g of a brownish powder as a decomposition extract of bagasse. This was designated as Extract W.

<Preparation of test solutions>
The above Extract A and Extract W were stored in a powder state at room temperature (control temperature: 18.0 to 28.0°C) until they were used for testing. Water for injection (Otsuka Distilled Water, Otsuka Pharmaceutical Factory, Inc.) was prepared as a medium for dissolving the extract. The required amount of the extract was weighed and dissolved in the water for injection, and then diluted to a predetermined concentration to prepare a test solution.

<Preparation of amyloid β solution>
Amyloid β (Amyloid-β Protein (25-35), manufactured by Polypeptide Laboratories) used for the amyloid β solution was stored frozen (control temperature: −30° C. to −20° C. (actual value: −27.1° C. to −24.0° C.) until it was used for the test. Amyloid β was dissolved in water for injection to a concentration of 2 mM to prepare an amyloid β solution.

<Test animals>
Male Slc:ddY mice (SPF, manufactured by Japan SLC Co., Ltd.) were used as test animals. Five-week-old mice were obtained. The mice are an animal species commonly used in behavioral pharmacological tests, and their lineage maintenance is clear. The weight range of the mice one day after acquisition was 23.8 to 30.0 g. The obtained mice were given a preliminary breeding period of five days.

(Breeding conditions)
The mice were housed in an animal breeding room maintained at a controlled temperature of 20.0-26.0°C, humidity of 40.0-70.0%, light and dark periods of 12 hours each (lighting: 6:00 a.m. to 6:00 p.m.), and ventilation rate of 12 times/hour (filtered fresh air).
From the preliminary rearing period until the day of grouping, the mice were reared in plastic cages (W: 310 × D: 360 × H: 175 mm) with up to 10 mice per cage, and after grouping, the mice were reared in groups with up to 5 mice per cage. They were allowed to freely consume solid feed (MF, Oriental Yeast Co., Ltd.) and tap water as drinking water.

(Grouping method and individual identification method)
The mice were randomly divided into groups on the day of the start of administration of the test solution so that the average body weight of each group was almost uniform. The four groups were a sham operation group, a vehicle control group, and an extract A and extract W administration group. The volume of the solution administered to the extract A administration group was calculated at 10 mL/kg based on the body weight on the administration day so that the dose of extract A was 500 mg/kg per mouse. Similarly, the volume of the solution administered to the extract W administration group was calculated at 10 mL/kg based on the body weight on the administration day so that the dose of extract W was 500 mg/kg per mouse. The sham operation group and vehicle control group were administered 10 mL/kg of 0.5% (w/v) methylcellulose solution.

(Experiment Schedule)
The day when the test solution was administered was set as day 1, and the test solution was administered once a day. On day 8, the amyloid β solution was injected into the mice. Then, on day 14, the Y-maze test was performed. Each procedure will be described later.

(Route and method of administration of test solution)
The administration route was oral administration. The administration method was according to the usual method used in the test facility, and the test solution was orally administered using a polypropylene disposable syringe (manufactured by Terumo Corporation) equipped with a disposable oral probe for mice (manufactured by Fuchigami Kikai Co., Ltd.). During administration, the test solution was mixed by inversion for each administration, and then aspirated into the syringe. On the day of amyloid β solution injection, the test solution was administered after the injection of amyloid β solution, and on the day of the Y-maze test, the test solution was administered 30 minutes before the measurement.

(Method of injecting amyloid beta)
Mice were anesthetized by intraperitoneally administering 40 mg/kg of sodium pentobarbital (Tokyo Chemical Industry Co., Ltd.) (amount of solution administered: 10 mL/kg). After anesthesia, levobupivacaine hydrochloride (Bobskine (registered trademark) 0.25% injection, Maruishi Pharmaceutical Co., Ltd.) was administered subcutaneously (0.1 mL) to the scalp. The scalp was incised to expose the skull, and a hole for inserting a stainless steel pipe was made in the skull 1 mm lateral (right side) and 0.2 mm posterior to the bregma using a dental drill. A stainless steel pipe connected to a silicon tube with an outer diameter of 0.5 mm and a microsyringe was inserted vertically to a depth of 2.5 mm from the bone surface. In the SCE1 administration group and the vehicle control group, 3 μL of amyloid β solution (6 nmol/3 μL) was injected into the ventricle over 3 minutes using a microsyringe pump. Meanwhile, 3 μL of water for injection was injected into the sham operation group in the same manner. After the injection, the stainless steel pipe was left inserted for 3 minutes and then slowly removed.Then, the skull hole was sealed with a non-absorbable bone marrow hemostatic agent (Nestop (registered trademark), manufactured by Alfresser Pharma Co., Ltd.), and the scalp was sutured.

(Evaluation by Y-maze test)
A Y-maze test (e.g., Non-Patent Document 1), which is a method for evaluating learning and memory behavior, particularly short-term memory, was performed. For the test, a plastic Y-maze (manufactured by Unicom Co., Ltd.) was used, which had an arm length of 39.5 cm, a floor width of 4.5 cm, a wall height of 12 cm, and three arms each branching at 120 degrees.
Before the evaluation, the illuminance of the floor of the apparatus was adjusted to 10-40 lux. The evaluation was performed 30 minutes after administration of the test solution. The mouse was placed in one of the arms of the Y-shaped maze and allowed to freely explore the maze for 8 minutes. The order of the arms that the mouse moved to within the measurement time was recorded, and the number of times the mouse moved to the arm was counted, which was taken as the total number of entries. Next, the combinations in which three different arms were consecutively selected were examined, and this number was taken as the number of spontaneous alternation behaviors. The spontaneous alternation behavior rate was then calculated using the following formula.
Spontaneous alternation rate (%) = [number of spontaneous alternations/(total number of entries-2)] x 100

A Y-maze test was performed on each group of mice, and the mean and standard error of the total number of entries, the number of spontaneous alternations, and the rate of spontaneous alternation were calculated. The significance test was performed between the sham-operated group and the vehicle control group, and between the vehicle control group and the extract-administered group. The comparison test between the two groups was performed by F-test to test for equal variances, and Student's t-test was performed in the case of equal variances, and Aspin-Welch test was performed in the case of unequal variances. The significance level was set at 1%. A commercially available statistical program (SAS system, SAS Institute Japan Co., Ltd.) was used for the significance test. The results are shown in Table 1 and Figure 1. As shown in Table 1 and Figure 1, the spontaneous alternation rate of the vehicle control group was lower than that of the sham-operated group, and a significant difference was observed (p<0.01). The spontaneous alternation rate of the extract A-administered group was higher than that of the vehicle control group, and a significant difference was observed (p<0.01). Additionally, the spontaneous alternation behavior rate was higher in the Extract W-administered group than in the vehicle control group, and a significant difference was observed (p<0.05).

Claims (2)

An agent for preventing or delaying the onset of Alzheimer's disease caused by accumulation of amyloid β protein, comprising a decomposed extract of bagasse as an active ingredient,
The bagasse decomposition extract is a fraction obtained by passing a decomposition solution obtained by decomposing bagasse through a column packed with a synthetic adsorbent as a fixed carrier, and eluting the components adsorbed by the synthetic adsorbent with a mixed solvent of ethanol and water.
The bagasse decomposition treatment is an alkali treatment or a hydrothermal treatment,
The synthetic adsorbent is a non-substituted aromatic resin,
The volume ratio of ethanol and water in the mixed solvent (ethanol/water) is 60/40. An agent for preventing or delaying the onset of short-term memory impairment caused by accumulation of amyloid β protein, comprising a decomposed extract of bagasse as an active ingredient,
The bagasse decomposition extract is a fraction obtained by passing a decomposition solution obtained by decomposing bagasse through a column packed with a synthetic adsorbent as a fixed carrier, and eluting the components adsorbed by the synthetic adsorbent with a mixed solvent of ethanol and water.
The bagasse decomposition treatment is an alkali treatment or a hydrothermal treatment,
The synthetic adsorbent is a non-substituted aromatic resin,
The volume ratio of ethanol and water in the mixed solvent (ethanol/water) is 60/40.

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