JP2020089318A - Cognitive function improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cognitive function improving agent and a food for improving cognitive function, which are effective for improving brain functions such as memory and learning ability.
SOLUTION: A cognitive improvement agent containing catechins and ornithine as active ingredients. A food for improving cognitive function, which comprises catechins and ornithine as active ingredients. A cognitive function improving agent and a food for improving cognitive function, wherein the mass ratio of catechins and ornithine is 1:0.1-10.
[Selection diagram] None

Description

The present invention relates to a cognitive function improving agent.

In recent years, the ratio of elderly people to the total population has risen, and memory and learning abilities have deteriorated with age, and dementia as a disease has increased. Examples of dementia-causing diseases include neurodegenerative diseases represented by Alzheimer's disease, cerebrovascular accidents such as cerebral infarction and cerebral hemorrhage, brain tumors, head trauma, infectious diseases, metabolic diseases and the like. Particularly, it is Alzheimer's disease that the number of patients is remarkably increasing with the progress of aging. Alzheimer's disease has become a social problem from the aspect of nursing care because it causes rapid short-term memory, memory loss, personality disorder, and the like.

Alzheimer's disease is the most prevalent type of dementia and is characterized by cognitive decline and devastating neurodegeneration. Various factors may be involved in the prevention and/or treatment of Alzheimer's disease. The currently widely recognized hypothesis that extracellular accumulation of β-amyloid peptide (Aβ) and intracellular accumulation of tau are the etiological factors of Alzheimer's disease is strong, but drug therapy targeting Aβ or tau is successful. Not, and the only clinically effective drug therapy for Alzheimer's disease is drugs that target the cholinergic pathway.

Ammonia in the body is converted into nontoxic urea by the urea cycle of the liver and excreted in urine. Arginine, ornithine and citrulline are involved in the hepatic urea cycle which converts ammonia into non-toxic urea. It has been reported that ornithine, citrulline, or arginine, which are amino acids involved in the urea cycle, suppress the elevation of blood ammonia (Patent Documents 1 and 2 and Non-Patent Document 1).
Ammonia is a normal end-product of metabolism in human tissues with demonstrated toxicity to brain function, and for example, increased blood ammonia due to reduced liver function reduces brain function, known as hepatic encephalopathy. There is. Further, conventionally, various associations between blood ammonia levels and Alzheimer's disease have been proposed and suggested (Non-patent Documents 2-6), and recently, depending on the duration and size of ammonia exposure, Elevated brain ammonia causes typical neurological symptoms common to Alzheimer's disease including memory dysfunction, cognitive and spatial learning, pathophysiologically, mitochondrial dysfunction, disruption of cellular glucose metabolism, neurotransmission It has been reported that a decrease in E. coli and an inflammatory response occur, and that the conventional estimation that a chronically elevated ammonia level is associated with the onset of Alzheimer's disease is valid (Non-Patent Document 7).

In Non-Patent Document 7, the relationship between the brain of Alzheimer's disease and ammonia is considered as follows. In the brain, either in the normal or hyperammonia state, the pathway for ATP-dependent formation of glutamine by glutamine synthetase (1-glutamic acid:ammonia ligase (ADP formation; EC 6.3.1.2)) (GS) is , Mainly used for ammonia removal. In Alzheimer's brain, the extracellular deposition density of Aβ and senile plaque (SP) in the cortex not only enhances the neurotoxicity of Aβ, but also induces oxidative structural changes in GS by interacting with it. It causes a loss of astrocyte GS activity, triggering the brain's ammonia clearance mechanism (glutamate-glutamine cycle) and astrocyte damage.
That is, in Non-Patent Document 7, extracellular deposition of Aβ and senile plaque (SP) in the brain of Alzheimer's disease not only causes neuropathy by itself but also reduces ammonia clearance ability of the brain, resulting in cognitive decline. It has been shown that the cause of Ammonia reduction and the importance of ammonia reduction in Alzheimer's disease have been proposed.

Furthermore, Non-Patent Document 7 describes that a diet containing a large amount of lactic acid bacteria is effective for treating Alzheimer's disease, and the mechanism is that lactic acid bacteria suppress ammonia production or absorption from the digestive tract and cause It is considered that this is because the ammonia concentration was lowered.
Therefore, it is considered that acting on the periphery to lower the blood ammonia concentration is effective in treating Alzheimer's disease.

On the other hand, catechins contained in green tea and the like have been reported to have various pharmacological actions and have an effect of improving cognitive function (Patent Document 3). However, the effect of combination with ornithine has not been reported.

JP, 2011-132174, A International Publication No. 2009/048148 Japanese Patent Publication No. 2009-533991

Takeda et al., J. Nutr. Sci. Vitaminol., 2011, 57:246-250 Fisman M. et.al., J. Am. Geriatr. Soc., 1989, 37, 1102-1102 Fisman M. et.al., AM. J. PSYCHIATRY, 1985, 142, 71-73 Hoyer S., ADV. EXP. MED. BIOL., 1994, 368, 197-205 Seiler N., Neurochem. Int., 2002, 41, 189-207 Seiler N., Neurochem Res., 1993, 18, 235-245 Jin Y.Y. et.al., Nutrients, 2018, 10, 564

The present invention relates to providing a cognitive function improving agent effective for improving brain functions such as memory and learning ability.

The present inventors have found that the combined use of catechins and ornithine significantly improves ammonia metabolism in hepatocytes as compared with the case of catechins alone or ornithine alone, which is useful for improving cognitive function. I found that.

That is, the present invention provides the following.
1) A cognitive-improving agent containing catechins and ornithine as active ingredients.
2) A food for improving cognitive function containing catechins and ornithine as active ingredients.
3) A preventive or ameliorating agent for Alzheimer's disease containing catechins and ornithine as active ingredients.
4) A food for preventing or improving Alzheimer's disease, which contains catechins and ornithine as active ingredients.

The cognitive function improving agent of the present invention can promote ammonia metabolism in the body, and effectively prevent or improve disorders associated with a decrease in cognitive functions such as brain memory and learning ability, for example, Alzheimer's disease.

Effects of catechins and ornithine on hepatocyte ammonia metabolism. The horizontal axis represents the hepatocyte culture medium, and the vertical axis represents the ammonia concentration in the medium. Data are mean±SE (n=3), *p<0.05 (Dunnett test, vs. control group). Effects of catechins and ornithine on blood ammonia levels. A: Blood ammonia concentration for the first time (without intake of the test material), B: Blood ammonia concentration for the second time (after intake of the test material). Data are mean±SE (n=15 for each group).

In the present specification, “non-therapeutic” does not include a medical act, that is, does not include a method of operating, treating, or diagnosing a human, more specifically, a doctor, or a medical worker or an instruction of a doctor. It is a concept that does not include a method in which a recipient performs surgery, treatment, or diagnosis on a human.

As used herein, “prevention” refers to preventing, suppressing or delaying the onset of a disease or condition in an individual, or reducing the risk of developing an individual's disease or condition. Further, in the present specification, “improvement” means prevention, suppression or delay of improvement of disease or condition, deterioration of disease or condition, or reversal, prevention, suppression or delay of progression of disease or condition.

In the present specification, "catechins" means catechin (C), gallocatechin (GC), catechin gallate (Cg), gallocatechin gallate (GCg), epicatechin (EC), epigallocatechin (EGC), epicatechin. It means at least one selected from the group consisting of gallate (ECg) and epigallocatechin gallate (EGCg).

Catechins are those belonging to the genus Camellia, such as C.I. sinensis var. sinensis, C.I. sinensis var. Tea leaves produced from leaves obtained from Assamica, Yabukita seeds or hybrids thereof can be extracted with water or hot water, optionally with an extraction aid added thereto. The tea leaves include (1) green tea such as sencha, bancha, gyokuro, tencha, and tea in a kettle; (2) semi-fermented tea such as iron kannon, color varieties, golden katsura, and Wuyiwaiwa tea, which are collectively called oolong tea. (3) It includes fermented tea leaves such as Darjeeling, Uva, and Kiemann called black tea. The catechins can be extracted from the tea leaves by a usual method such as stirring extraction. An organic acid or organic acid salt such as sodium ascorbate may be added in advance to the extraction water or hot water. If necessary, extraction may be carried out in combination with a method of extracting in a so-called non-oxidizing atmosphere while boiling degassing or aeration of an inert gas such as nitrogen gas to remove dissolved oxygen.

Alternatively, instead of extracting the catechins directly from the tea leaves, a concentrate or purified product of the tea extract may be used. The tea extract concentrate is, for example, a concentrate of an extract extracted from tea leaves with hot water or a water-soluble organic solvent, and the purified tea extract is, for example, a solvent or a column of the extract. It was purified using. Examples of concentrates or purified products of the tea extract are detailed in JP-A-59-219384, JP-A-4-20589, JP-A-5-260907, JP-A-5-306279 and the like. One prepared by the method described above. A commercially available product may be used as the tea extract and its concentrate or purified product, and examples thereof include “Polyphenon” of Mitsui Norin Co., Ltd., “Theafran” of ITO EN Co., Ltd. and “Sunphenon” of Taiyo Kagaku Co., Ltd. , Suntory Co., Ltd., “Sun-oolong” and the like. Examples of the form of the concentrate or purified product of the tea extract include solids, liquids, slurries, and those obtained by dissolving or diluting them in water, carbonated water, a tea extract extracted by a usual procedure, or the like. It is not particularly limited.

Furthermore, the catechins in the present invention may be derived from other raw materials than tea leaves, such as grapes and processed products thereof (wine, juices, etc.) or cacao beans and processed products thereof, or chemically synthesized products. Good.

The catechins of the present invention are preferably used in the form of a concentrate or purified product of tea extract, more preferably in the form of a concentrate or purified product of green tea extract.

In the present invention, ornithine can be used in the form of a free form or a salt thereof. The ornithine may be any of L-form, D-form, DL-form, and a mixture thereof, but is preferably L-form.

Examples of ornithine salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, and acetate, maleate, fumarate, citrate, malate, lactate, α-ketoglutar. Organic acid salts such as acid salts, gluconates, caprylates and the like can be mentioned. Examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like. Examples of the ammonium salt include salts such as ammonium and tetramethylammonium. Examples of the organic amine addition salt include salts such as morpholine and piperidine. Examples of the amino acid addition salt include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like. Among these, sodium salts or hydrochlorides are preferred.

The free form of ornithine or a salt thereof can be obtained by a method of isolating and purifying from animals and plants containing them, chemical synthesis, fermentation production and the like. Alternatively, a commercially available product may be purchased.

As shown in Examples described later, by using catechins and ornithine in combination, a significantly higher ammonia metabolism promoting action is achieved as compared with the case of using catechins or ornithine alone. As described above, a high concentration of ammonia accumulates in blood, and a part of it accumulates in the brain, which causes various neurological symptoms. For example, depending on the duration and magnitude of ammonia exposure, elevated brain ammonia causes typical neurological symptoms common to Alzheimer's disease, including memory impairment, cognitive and spatial learning, blood ammonia It has been reported that lowering the concentration is effective in treating Alzheimer's disease (Non-Patent Document 7).

Therefore, a combination of catechins and ornithine having an excellent effect of promoting ammonia metabolism is a cognitive function improving agent (preferably, an agent for improving cognitive function deterioration accompanied by excessive accumulation of ammonia, an agent for improving cognitive function deterioration due to Alzheimer-type dementia). Further, it can be a preventive or ameliorating agent for Alzheimer's disease (hereinafter, also referred to as “cognitive function improving agent etc.”), and can be used for producing the cognitive function improving agent and the like.

In addition, a combination of catechins and ornithine is for improving cognitive function (preferably, improving cognitive decline accompanied by excessive accumulation of ammonia, improving cognitive decline due to Alzheimer-type dementia), and preventing or improving Alzheimer's disease. Can be used. Here, the use may be administration to a human or non-human animal, or use in a specimen derived therefrom, and may be therapeutic use or non-therapeutic use. Here, the non-human animals include non-human mammals, amphibians, and cartilaginous fish, and examples of the non-human mammals include apes, other primates, mice, rats, horses, cows, pigs, sheep, dogs. , Cats, hamsters, and companion animals.
Targets to which the combination of the catechins and ornithine of the present invention are applied preferably include humans having a decreased ammonia metabolism, humans having a decreased cognitive function, and humans who desire prevention or amelioration of Alzheimer's disease.

In the present invention, as for the combination of catechins and ornithine, both components may be administered simultaneously, or each component may be administered separately, as long as they can cooperate in vivo.

In the present invention, the “cognitive function” includes memory, learning, thinking, attention or perception, language, spatiotemporal recognition, orientation, cognitive or comprehensive judgment ability of other abstract events, and execution ability, and the like. Include memory or learning ability, comprehensive judgment ability, and execution ability.
“Improvement of cognitive function” means maintenance/improvement of cognitive function and alleviation/healing of various symptoms (cognitive dysfunction) associated with deterioration of cognitive function.
Therefore, the cognitive function improving agent of the present invention is useful for preventing or ameliorating a disease or condition exhibiting cognitive dysfunction. Such diseases or conditions exhibiting cognitive impairment include, for example, dementia (eg, senile dementia, Alzheimer's disease, cerebrovascular dementia, post-traumatic dementia, brain tumor, chronic subdural hematoma, normal Dementia caused by various diseases such as pressure edema, meningitis, Parkinson's disease, non-dementia cognitive impairment (eg, mild cognitive impairment (MCI)), memory or learning impairment (eg, brain developmental disorder) And the like), but Alzheimer's disease or Alzheimer's dementia is preferable.

The cognitive function-improving agent and the like of the present invention include improvement of cognitive function (preferably, improvement of cognitive decline caused by excessive accumulation of ammonia, improvement of cognitive decline due to Alzheimer-type dementia), or prevention or improvement effect of Alzheimer's disease. It can be a human or veterinary drug, a quasi drug, or a food that exerts the above-mentioned effect, or a material or a formulation used by being mixed with the drug, a quasi drug, or a food.
In addition, in the food, improvement of cognitive function (preferably, improvement of cognitive decline with excessive accumulation of ammonia, improvement of cognitive decline due to Alzheimer's dementia), or the concept of preventing or improving Alzheimer's disease , Foods labeled as such, foods with functional claims, foods for specified health use, foods for patients, supplements are included.
The pharmaceutical product, quasi drug, and food may be provided as one composition containing catechins and ornithine, or may be provided as a combination of compositions containing catechins and ornithine, respectively.

When the cognitive function-improving agent or the like of the present invention is used as a drug (including a quasi drug), the drug can be administered in any dosage form. Examples of the dosage form include oral administration by tablets, capsules, granules, powders, syrups and the like or parenteral administration by injections, suppositories, inhalants, transdermal agents, etc. Administration.
Such various dosage forms of pharmaceutical preparations include catechins and ornithine of the present invention and other pharmaceutically acceptable excipients, binders, fillers, disintegrants, surfactants, lubricants, dispersions. It can be prepared by appropriately combining agents, buffers, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents and the like.

When using the cognitive function improving agent of the present invention as a food, the form of the food, bread, cakes, noodles, confectionery, jellies, frozen foods, ice cream, dairy products, various food compositions such as beverages In addition to the products, forms similar to the above-mentioned oral administration preparations (tablets, capsules, syrups, etc.) can be mentioned.
Foods in various forms include catechins and ornithine of the present invention and other food materials, solvents, softeners, oils, emulsifiers, preservatives, perfumes, stabilizers, colorants, antioxidants, moisturizers, and enhancers. It can be prepared by appropriately combining a sticky agent and the like.

The content of catechins in the drug (including quasi drugs) is not particularly limited, but is preferably 0.1% by mass or more, more preferably 1% by mass or more, and further preferably 3% by mass or more. And preferably 20% by mass or less, more preferably 10% by mass or less, and further preferably 5% by mass or less. Furthermore, as an example of the said content, 0.1-20 mass%, 0.1-10 mass%, 0.1-5 mass%, 1-20 mass%, 1-10 mass%, 1-5 mass% 3 to 20% by mass, 3 to 10% by mass, and 3 to 5% by mass.

The content of ornithine in the drug (including quasi drugs) is not particularly limited, but is preferably 0.3 mass% or more, more preferably 3 mass% or more, still more preferably 5 mass% in terms of ornithine free form. It is at least mass%, more preferably at least 9 mass%, and preferably at most 60 mass%, more preferably at most 30 mass%, even more preferably at most 20 mass%, further preferably at most 15 mass%. Furthermore, as an example of the said content, 0.3-60 mass%, 0.3-30 mass%, 0.3-20 mass%, 0.3-15 mass%, 3-60 mass%, 3-30 % By mass, 3-20% by mass, 3-15% by mass, 5-60% by mass, 5-30% by mass, 5-20% by mass, 5-15% by mass, 9-60% by mass, 9-30% by mass , 9 to 20% by mass, and 9 to 15% by mass.

In the drug (including quasi drugs), the concentration of the catechins listed above (0.1 to 20% by mass, 0.1 to 10% by mass, 0.1 to 5% by mass, 1 to 20% by mass) %, 1 to 10% by mass, 1 to 5% by mass, 3 to 20% by mass, 3 to 10% by mass, and 3 to 5% by mass) and the ornithine concentrations listed above (0.3 to 60% by mass). %, 0.3 to 30% by mass, 0.3 to 20% by mass, 0.3 to 15% by mass, 3 to 60% by mass, 3 to 30% by mass, 3 to 20% by mass, 3 to 15% by mass, 5 to 60% by mass, 5 to 30% by mass, 5 to 20% by mass, 5 to 15% by mass, 9 to 60% by mass, 9 to 30% by mass, 9 to 20% by mass, and 9 to 15% by mass). Any of them can be combined arbitrarily.

The content of catechins in the food is not particularly limited, but is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, further preferably 1% by mass or more, and preferably 10% by mass. % Or less, more preferably 5% by mass or less, still more preferably 1% by mass or less. Furthermore, as an example of the said content, 0.05-10 mass %, 0.05-5 mass %, 0.05-1 mass %, 0.1-10 mass %, 0.1-5 mass %, 0 0.1 to 1% by mass, 1 to 10% by mass, and 1 to 5% by mass.

The content of ornithine in the food is not particularly limited, but is preferably 0.15 mass% or more, more preferably 0.3 mass% or more, still more preferably 3 mass% or more, still more preferably, in terms of ornithine free form. Is 5% by mass or more, and preferably 30% by mass or less, more preferably 20% by mass or less, further preferably 15% by mass or less, further preferably 5% by mass or less, further preferably 3% by mass or less. Furthermore, as an example of the content, 0.15 to 30 mass%, 0.15 to 20 mass%, 0.15 to 15 mass%, 0.15 to 5 mass%, 0.15 to 3 mass%, 0 0.3 to 30% by mass, 0.3 to 20% by mass, 0.3 to 15% by mass, 0.3 to 5% by mass, 0.3 to 3% by mass, 3 to 30% by mass, 3 to 20% by mass 3 to 15% by mass, 3 to 5% by mass, 5 to 30% by mass, 5 to 20% by mass, and 5 to 15% by mass.

In the food, the concentrations of the catechins listed above (0.05 to 10% by mass, 0.05 to 5% by mass, 0.05 to 1% by mass, 0.1 to 10% by mass, 0.1 to 0.1% by mass) 5% by mass, 0.1 to 1% by mass, 1 to 10% by mass, and 1 to 5% by mass), and the ornithine concentrations listed above (0.15 to 30% by mass, 0.15 to 20% by mass). %, 0.15 to 15% by mass, 0.15 to 5% by mass, 0.15 to 3% by mass, 0.3 to 20% by mass, 0.3 to 30% by mass, 0.3 to 15% by mass, 0.3-5% by mass, 0.3-3% by mass, 3-30% by mass, 3-20% by mass, 3-15% by mass, 3-5% by mass, 5-30% by mass, 5-20% by mass %, and 5 to 15% by mass) can be arbitrarily combined.

The mass ratio of the catechins used in the present invention to ornithine (as free form) is preferably 1:0.1-10, more preferably 1:0.5-10, and further preferably It is 1:1 to 8, more preferably 1:1 to 5, and still more preferably 1:2 to 4.

In the present invention, other materials having an action of promoting ammonia metabolism can be used in combination with catechins and ornithine. Examples of such other materials include arginine, citrulline and combinations thereof.

In the present invention, the dose and administration schedule of catechins and ornithine may be appropriately determined by those skilled in the art according to the species, weight, sex, age, condition, or other factors of the subject. Non-limiting examples of daily doses of catechins and ornithines according to the present invention per adult for oral administration are as follows:
[Catechins] preferably 100 to 3000 mg/60 kg body weight, more preferably 250 to 2000 mg/60 kg body weight, further preferably 250 to 1000 mg/60 kg body weight, further preferably 250 to 600 mg/60 kg body weight;
[Ornithine (as free form)] 100 to 5000 mg/60 kg body weight, more preferably 250 to 3000 mg/60 kg body weight, further preferably 400 to 2000 mg/60 kg body weight, further preferably 500 to 2000 mg/60 kg body weight, further preferably 800-1600 mg/60 kg body weight, in another example, preferably 250-800 mg/60 kg body weight, more preferably 500-800 mg/60 kg body weight,
It is preferable to administer the above dose, for example, once a day, or divided into two or three or more times a day.

As a preferred embodiment when the cognitive function-improving agent of the present invention is used as a food, the catechins and ornithine include catechins in an amount of 1 to 10% by mass and ornithine in an amount of 5 to 20% by mass (equivalent free form). Examples thereof include a composition containing and having a mass ratio of catechins and ornithine (as free form) of 1:0.5 to 10.

In a preferred embodiment when the cognitive function-improving agent of the present invention is used as a beverage, the catechins and ornithine are catechins of 0.057 to 0.567 mass% and ornithine of 0.283 to 1. A composition containing 132% by mass (equivalent to the free form) and having a mass ratio of catechins and ornithine (equivalent to the free form) of 1:0.5 to 10 can be mentioned.

As a preferred embodiment when the cognitive function-improving agent or the like of the present invention is used as a medicine, the catechins and ornithines are 1 to 10% by mass of catechins and 5 to 20% by mass of ornithine (as free form). Examples thereof include a composition containing and having a mass ratio of catechins and ornithine (as free form) of 1:0.5 to 10.

Preferred examples of the dose of the cognitive function-improving agent of the present invention are catechins 250 to 1,000 mg/60 kg body weight and ornithine 400 to 2000 mg (equivalent to free form)/60 kg as an oral dose per adult per day. It's weight. It is preferable to administer the above dose, for example, once a day, or divided into two or three or more times a day.

Regarding the above-described embodiment, the following aspects are further disclosed in the present invention.
<1> A cognitive improvement agent containing catechins and ornithine as active ingredients.
<2> A food for improving cognitive function, which comprises catechins and ornithine as active ingredients.
<3> The agent according to <1> or the food according to <2>, wherein the improvement in cognitive function is improvement in cognitive decline accompanied by excessive accumulation of ammonia.
<4> The agent according to <1> or <3>, or the food according to <2> or <3>, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's dementia.
<5> An agent for preventing or improving Alzheimer's disease, which comprises catechins and ornithine as active ingredients.
<6> A food for preventing or improving Alzheimer's disease, which contains catechins and ornithine as active ingredients.

<7> Use of catechins and ornithine for producing a cognitive improvement agent.
<8> Use of catechins and ornithine for producing food for improving cognitive ability <9> Improvement of cognitive function is improvement of cognitive decline accompanied by excessive accumulation of ammonia, <7> or <8> use.
<10> Use of any one of <7> to <9>, in which the improvement in cognitive function is an improvement in cognitive decline associated with Alzheimer's dementia.
<11> Use of catechins and ornithine for producing a preventive or ameliorating agent for Alzheimer's disease.
<12> Use of catechins and ornithine for producing a food for preventing or improving Alzheimer's disease.

<13> A combination of catechins and ornithine for use in improving cognitive ability.
<14> The combination of <13>, wherein the improvement in cognitive function is an improvement in cognitive decline accompanied by excessive accumulation of ammonia.
<15> The combination of <13> or <14>, in which the improvement in cognitive function is an improvement in cognitive decline associated with Alzheimer's dementia.
<16> A combination of catechins and ornithine for use in the prevention or amelioration of Alzheimer's disease.

<17> Non-therapeutic use of catechins and ornithine for improving cognitive ability.
<18> Use of <17>, in which improvement in cognitive function is improvement in cognitive decline accompanied by excessive accumulation of ammonia.
Use of <17> or <18>, wherein the improvement of <19> cognitive function is improvement of cognitive decline associated with Alzheimer's dementia.
<20> Non-therapeutic use of catechins and ornithine for preventing or ameliorating Alzheimer's disease.

<21> A method for improving cognitive ability, which comprises administering an effective amount of catechins and ornithine to a subject in need thereof.
<22> The method according to <21>, wherein the improvement in cognitive function is improvement in cognitive decline accompanied by excessive accumulation of ammonia.
<23> The method according to <21> or <22>, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's dementia.
<24> A method for preventing or improving Alzheimer's disease, which comprises administering an effective amount of catechins and ornithine to a subject in need thereof.

In <25><1> to <24>, the mass ratio of catechins and ornithine is preferably 1:0.1-10, more preferably 1:0.5-10, and further preferably 1:1-8. , More preferably 1:1 to 5, still more preferably 1:2 to 4.
In <26><1> to <24>, the catechins are selected from the group consisting of catechin, gallocatechin, catechin gallate, gallocatechin gallate, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate. It is at least one kind.
In <27><2>, <3>, <4>, and <6>, the content of catechins in the food is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, further It is preferably 1% by mass or more, and preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 1% by mass or less, or 0.05 to 10% by mass, 0.05 to 5%. %, 0.05 to 1% by mass, 0.1 to 10% by mass, 0.1 to 5% by mass, 0.1 to 1% by mass, 1 to 10% by mass, and 1 to 5% by mass.
In <28><2>, <3>, <4>, and <6>, the content of ornithine in the food is preferably 0.15% by mass or more, more preferably 0.3% in terms of ornithine free form. Mass% or more, more preferably 3 mass% or more, further preferably 5 mass% or more, and preferably 30 mass% or less, more preferably 20 mass% or less, further preferably 15 mass% or less, and further preferably 5 mass% or less. % Or less, more preferably 3% by weight or less, or 0.15 to 30% by weight, 0.15 to 20% by weight, 0.15 to 15% by weight, 0.15 to 5% by weight, 0. 15-3% by mass, 0.3-30% by mass, 0.3-20% by mass, 0.3-15% by mass, 0.3-5% by mass, 0.3-3% by mass, 3-30 %, 3 to 20% by mass, 3 to 15% by mass, 3 to 5% by mass, 5 to 30% by mass, 5 to 20% by mass, and 5 to 15% by mass.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

Reference Example 1 Preparation of Green Tea Extract Containing Catechins 1,000 g of a commercially available green tea extract (“Polyphenon HG” of Mitsui Norin Co., Ltd.) was stirred at 25° C. and 200 rpm to obtain a 95% by mass aqueous ethanol solution of 9,000 g. Suspended therein. To this, 200 g of activated carbon (Kuraray Chemical Co., Ltd., “Kuraray Coal GLC”) and 500 g of acid clay (Mizusawa Chemical Co., Ltd., “Mizuka Ace #600”) were added, and stirring was continued for about 10 minutes. The stirring treatment was continued at 25° C. for 30 minutes. Next, the suspension was filtered through No. 2 filter paper to remove activated carbon, acid clay, and precipitate, and then the filtrate was refiltered with a 0.2 μm membrane filter. Deionized water (200 g) was added to the filtrate, ethanol was distilled off at 40° C. and 3.3 kPa, and the mixture was concentrated under reduced pressure. 750 g of the concentrate was put into a stainless steel container, and the total amount was adjusted to 10,000 g with ion-exchanged water, and 30 g of a 5 mass% sodium bicarbonate aqueous solution was added to adjust the pH to 5.5. An enzyme solution prepared by dissolving 2.7 g of Kikkoman Tannase KTFH (Industrial Grade, 500 U/g or more) in 10.7 g of ion-exchanged water was added to a solution containing the obtained concentrate under stirring conditions of 22° C. and 150 rpm. Was added. After 30 minutes, when the pH of the reaction solution had dropped to 4.24, the stainless steel container was immersed in a 95°C warm bath and kept at 90°C for 10 minutes to completely deactivate the enzyme activity. Next, the reaction solution was cooled to 25° C. and then concentrated to obtain a purified green tea extract. The purified green tea extract thus obtained had a content of catechins (A) of 14.9% by mass, and the proportion of catechin gallates in the catechins was 45.3% by mass.

Example 1 Effect of catechins and ornithine on ammonia metabolism of hepatocytes For hepatocytes, hepatocyte culture kit P-2 (HPC03P-BAL, male Balb/c mouse-derived, 24 well, 1×10 ⁵ cells/well, Cosmo Bio Co., Ltd.) was used. As the catechins, the green tea extract (containing 14.9% by mass of catechins) prepared in Reference Example 1 was used. Hepatocytes were treated with control medium, ornithine-containing medium (1 mM ornithine hydrochloride (0.0132% as ornithine equivalent) containing control medium), catechins-containing medium (0.001 mass% green tea extract (catechins 0.000149 mass). %) containing control medium) or a medium containing ornithine and catechins (control medium containing 1 mM ornithine hydrochloride and 0.001% by mass green tea extract) at 37° C. for 20 hours. As a control medium, DMEM medium containing 5 mM ammonium chloride (high glucose, GlutaMAX added, penicillin/streptomycin added, pyruvate-free, phenol red-free, glutamine-free, FBS-free) was used. The culture medium supernatant after culturing was collected, and the ammonia contained therein was quantified using the Ammonia Assay Kit (abcam). The quantitative value was tested for significant difference from the control group (Dunnett test, vs. control group, n=3).

The quantitative results of ammonia are shown in FIG. Compared with the control group, in the group containing ornithine hydrochloride and catechins, it was shown that the ammonia concentration in the medium was statistically significantly reduced and the ammonia metabolism was promoted.

Example 2 Effect of catechins and ornithine on human blood ammonia concentration Method (subject)
Fifteen healthy adult men (21 to 39 years old) were used as test subjects.
(Experimental plan)
In the test, as the main measurement 1, all the subjects were given 1 control drink (placebo hercia water grapefruit taste 500 mL: catechins-free) and 12 placebo supplements (placebo plus (placebo pharmaceutical Co., Ltd.)), and 50 minutes later. The blood ammonia concentration was measured.
After main measurement 1, 15 people were set as main measurement 2 in 3 groups of 5 people (catechins alone group, ornithine alone group, catechins and ornithine group so that there is no difference in the average value of blood ammonia concentration in main measurement 1). Combination group), and after 1 to 2 weeks from the main measurement,
In the catechins alone group, one catechin drink (500 ml of hercia water grapefruit taste: Kao Corporation, containing 540 mg of catechins) and 12 placebo supplements (placebo plus (placebo pharmaceutical company)),
In the ornithine alone group, one control beverage (placebo hercia water grapefruit flavor 500 mL: catechins-free) and ornithine supplement (ornithine (Kyowa Hakko Bio Co., Ltd.), 12 ornithine 1600 mg in 12 tablets,
In the combined use group of catechins and ornithine, 1 catechin drink (500 ml of hercia water grapefruit taste: Kao Corporation, containing 540 mg of catechins) and ornithine supplement (Ornithine (Kyowa Hakko Bio Co., Ltd.), 12 tablets containing 1600 mg of ornithine) 12 grain,
Was ingested, and 50 minutes after that, the blood ammonia concentration was measured.

(Test material)
Details of the test materials are as follows:
Catechins Beverage: Helcia Water Grapefruit Flavor 500 mL (Kao Corporation) Containing 540 mg of catechins per bottle;
Placebo supplement: Placebo (Placebo Pharmaceutical Co., Ltd.), amino acid-free;
Ornithine supplement: Ornithine (Kyowa Hakko Bio Co., Ltd.), containing 1600 mg of ornithine in 12 tablets;
The test materials were provided by a single blind method.

(Blood ammonia concentration measurement)
In main measurements 1 and 2, 50 minutes after ingestion of the test material, blood was collected from the fingertips of each subject. The blood ammonia concentration of the collected blood (whole blood) was measured using a blood ammonia measuring device (Pocketchem BA PA-4140, Arkray Co., Ltd.).
The data of all subjects obtained in the two tests were subjected to a significant difference test between the measurements (t-test).

2. Results (blood ammonia concentration)
The results are shown in Figure 2. The value at the time of main measurement 1 of each group is shown by A, and the value at the time of main measurement 2 is shown by B. As shown in FIG. 2, in the catechins alone group (Cat) and the ornithine alone group (Orn), the blood ammonia concentration did not decrease in the main measurement 2 as compared with the control intake (main measurement 1). In contrast, the catechins and ornithine combination group (Cat+Orn) decreased by 20% or more (p<0.1). From this, it was shown that the combined intake of catechins and ornithine lowered the blood ammonia concentration.

Claims (8)

A cognitive-improving agent containing catechins and ornithine as active ingredients. A food for improving cognitive function, which comprises catechins and ornithine as active ingredients. The agent according to claim 1 or the food according to claim 2, wherein the improvement in cognitive function is improvement in cognitive decline accompanied by excessive accumulation of ammonia. The agent according to claim 1 or 3, or the food according to claim 2 or 3, wherein the improvement in cognitive function is an improvement in cognitive decline associated with Alzheimer's dementia. A preventive or ameliorating agent for Alzheimer's disease containing catechins and ornithine as active ingredients. A food for preventing or improving Alzheimer's disease, which comprises catechins and ornithine as active ingredients. The agent or food according to any one of claims 1 to 6, wherein the mass ratio of catechins and ornithine is 1:0.1-10. The catechins are at least one selected from the group consisting of catechin, gallocatechin, catechin gallate, gallocatechin gallate, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate. The agent or food according to any one of 1.