JP7197340B2 - Cognitive function improver - Google Patents

Description

TECHNICAL FIELD The present invention relates to a cognitive function improving agent.

In recent years, the ratio of elderly people to the total population has been increasing, and deterioration of memory and learning ability due to aging and an increase in dementia as a disease have become problems. Diseases that cause dementia include neurodegenerative diseases such as Alzheimer's disease, cerebrovascular disorders due to cerebral infarction, cerebral hemorrhage, brain tumors, head injuries, infectious diseases, metabolic diseases, and the like. In particular, the number of patients with Alzheimer's disease is increasing remarkably as the population ages. Alzheimer's disease has become a social problem in terms of nursing care because it causes rapid short-term memory loss, memory loss, personality disorder, and the like.

Alzheimer's disease is the most common 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. Although the currently widely recognized hypothesis that extracellular accumulation of β-amyloid peptide (Aβ) and intracellular accumulation of tau is the etiology of Alzheimer's disease, drug therapy targeting Aβ or tau has been successful. However, the only clinically effective drug therapies for Alzheimer's disease are drugs that target the cholinergic pathway.

Ammonia in the body is converted to non-toxic urea by the liver's urea cycle and excreted in the urine. Arginine, ornithine and citrulline are involved in the hepatic urea cycle that converts ammonia to non-toxic urea. It has been reported that ornithine, citrulline, or arginine, which are amino acids involved in the urea cycle, suppress the increase in blood ammonia (Patent Documents 1, 2, and Non-Patent Document 1).
Ammonia is a normal end product of metabolism in human tissues that has demonstrated toxicity to brain function, e.g., elevated blood ammonia due to decreased liver function reduces brain function, known as hepatic encephalopathy. there is In addition, various relationships between blood ammonia levels and Alzheimer's disease have been conventionally proposed and suggested (Non-Patent Documents 2-6), and recently, depending on the duration and magnitude of ammonia exposure, Elevated brain ammonia causes typical neurological symptoms common to Alzheimer's disease, including memory dysfunction, cognition and spatial learning; It has been reported that a decrease in and an inflammatory response occur, and the conventional assumption that chronically elevated ammonia levels are associated with the development of Alzheimer's disease has been reported to be valid (Non-Patent Document 7).

Non-Patent Document 7 considers the relationship between the brain of Alzheimer's disease and ammonia as follows. In the brain, the pathway for ATP-dependent formation of glutamine by glutamine synthetase (1-glutamate:ammonia ligase (ADP formation; EC 6.3.1.2)) (GS) in either normal or hyperammonic conditions is , mainly used for ammonia removal. In Alzheimer's disease brains, the extracellular deposition density of Aβ and neuritic plaques (SPs) in the cortex not only enhances the neurotoxicity of Aβ, but also induces oxidative structural changes in GS by interacting with it. This causes loss of astrocytic GS activity, triggering impairment of the brain's ammonia clearance mechanism (glutamate-glutamine cycle) and astrocytes.
That is, in Non-Patent Document 7, extracellular deposition of Aβ and senile plaques (SP) in the brain of Alzheimer's disease not only causes neurological disorders per se, but also reduces the ammonia clearance capacity of the brain, leading to cognitive decline. , and the importance of ammonia reduction in Alzheimer's disease has been proposed.

Furthermore, in Non-Patent Document 7, it is described that a diet containing a large amount of lactic acid bacteria is effective in treating Alzheimer's disease. It is considered that this is due to the decrease in ammonia concentration.
Therefore, it is thought that reducing the blood ammonia level by acting on the periphery 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 are also reported to have an effect of improving cognitive function (Patent Document 3). However, no effects have been reported when combined with ornithine.

JP 2011-132174 A WO2009/048148 Japanese translation of PCT publication No. 2009-539991

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

TECHNICAL FIELD The present invention relates to providing a cognitive function improving agent effective in 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 compared to 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 improvement agent containing catechins and ornithine as active ingredients.
2) A food for improving cognitive function containing catechins and ornithine as active ingredients.
3) A prophylactic or ameliorating agent for Alzheimer's disease containing catechins and ornithine as active ingredients.
4) A food for preventing or improving Alzheimer's disease containing 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 deterioration of cognitive functions such as brain memory and learning ability, such as 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 concentration of ammonia in the medium. Data are means±SE (n=3), *p<0.05 (Dunnett test, vs. control group). Effects of catechins and ornithine on blood ammonia concentration. A: blood ammonia concentration at the first time (without ingestion of test material), B: blood ammonia concentration at second time (after ingestion of test material). Data are mean±SE (n=15 for each group).

As used herein, "non-therapeutic" does not include medical procedures, i.e., methods of surgery, treatment or diagnosis of humans, more specifically physicians, or instructions of medical personnel or physicians. It is a concept that does not include the method by which a recipient performs surgery, therapy or diagnosis on humans.

As used herein, "prevention" refers to preventing, suppressing or delaying the onset of a disease or condition in an individual, or reducing an individual's risk of developing a disease or condition. As used herein, "amelioration" refers to amelioration of a disease or condition, prevention, suppression or delay of worsening of a disease or condition, or reversal, prevention, suppression or delay of progression of a disease or condition.

As used herein, the term "catechins" refers to 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 of the genus Camellia, such as C. sinensis var. sinensis, C. sinensis var. can be extracted with water or hot water, optionally with the addition of an extraction aid, from tea leaves produced from leaves obtained from assamica, Yabukita species, or hybrids thereof. The tea leaves include (1) green teas such as sencha, bancha, gyokuro, tencha, and kamairicha; (2) semi-fermented teas such as Tieguanyin, Irotane, Ogonkatsura, and Wuyi rockcha, which are collectively called oolong tea. (3) tea leaves of fermented teas called black tea such as Darjeeling, Uva, Keemun; Extraction of catechins from the tea leaves can be performed by a usual method such as stirring extraction. An organic acid such as sodium ascorbate or an organic acid salt may be added in advance to the water or hot water for extraction. If necessary, the extraction may be performed in combination with a method of extracting in a so-called non-oxidizing atmosphere while removing dissolved oxygen by degassing by boiling or passing an inert gas such as nitrogen gas.

Alternatively, instead of extracting catechins directly from tea leaves, a concentrate or purified tea extract may be used. A concentrate of a tea extract is, for example, a product obtained by concentrating an extract extracted from tea leaves with hot water or a water-soluble organic solvent, and a purified product of a tea extract is, for example, a solvent, a column, etc. It is purified using Examples of the concentrate or purified product of the tea extract are exemplified in detail in JP-A-59-219384, JP-A-4-20589, JP-A-5-260907, JP-A-5-306279, etc. prepared by the method Commercially available products may be used as the tea extract and its concentrate or purified product. ”, and Suntory Co., Ltd. “Sun Oolong”. Forms of concentrates or purified tea extracts include solids, liquids, slurries, and those obtained by dissolving or diluting them in water, carbonated water, tea extracts extracted by ordinary procedures, etc. , is not particularly limited.

Furthermore, the catechins in the present invention are derived from raw materials other than tea leaves, such as grapes and their processed products (wine, juices, etc.), cocoa beans and their processed products, or chemically synthesized products. good.

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

In the present invention, ornithine can be used in free form or in the form of salts thereof. Ornithine may be L-form, D-form, DL-form, or a mixture thereof, preferably L-form.

Salts of ornithine include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, and acetate, maleate, fumarate, citrate, malate, lactate and α-ketoglutarate. Examples include organic acid salts such as acid salts, gluconates, and caprylate. Examples of the metal salt include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like. Examples of the ammonium salt include salts such as ammonium and tetramethylammonium. Examples of the organic amine addition salts include salts of morpholine, piperidine and the like. The amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like. Among them, preferred examples include sodium salts and hydrochlorides.

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, or the like. Or you may purchase a commercial item.

As shown in the examples described later, the combined use of catechins and ornithine achieves a significantly higher ammonia metabolism promoting effect than the use of catechins or ornithine alone. As described above, high-concentration ammonia accumulates in the blood and part of it migrates into the brain, causing 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 dysfunction, cognitive and spatial learning, blood ammonia It has been reported that reducing the concentration is effective in treating Alzheimer's disease (Non-Patent Document 7).

Therefore, the combination of catechins and ornithine having an excellent ammonia metabolism promoting action is a cognitive function improving agent (preferably, an improving agent for cognitive function decline accompanied by excessive accumulation of ammonia, an improving agent for cognitive decline due to Alzheimer's dementia ), furthermore, it can be a prophylactic or improving agent for Alzheimer's disease (hereinafter also referred to as "cognitive function improving agent etc."), and can be used for manufacturing the cognitive function improving agent etc.

In addition, a combination of catechins and ornithine is used to improve cognitive function (preferably, improve cognitive function decline associated with excessive ammonia accumulation, improve cognitive decline due to Alzheimer's dementia), prevent or improve 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 or non-therapeutic. Here, non-human animals include non-human mammals, amphibians, and cartilaginous fish, and non-human mammals include, for example, apes, other primates, mice, rats, horses, cows, pigs, sheep, and dogs. , cats, hamsters, and companion animals.
Subjects to which the combination of catechins and ornithine of the present invention is applied preferably include humans with decreased ammonia metabolism, humans with decreased cognitive function, and humans who wish to prevent or improve Alzheimer's disease.

In the present invention, the combination of catechins and ornithine may be administered at the same time or separately as long as they can work together in vivo.

In the present invention, "cognitive function" includes memory, learning, thinking, attention or perception, language, spatiotemporal recognition, orientation, recognition of other abstract events or comprehensive judgment ability, and execution ability, etc., preferably includes memory or learning ability, ability to make decisions, and ability to execute.
"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 agent for improving cognitive function of the present invention is useful for preventing or improving diseases or conditions exhibiting cognitive impairment. Diseases or conditions exhibiting such cognitive impairment include, for example, dementia (e.g., senile dementia, Alzheimer's disease, cerebrovascular dementia, post-traumatic dementia, brain tumor, chronic subdural hematoma, normal Dementia caused by various diseases such as hydrocephalus, meningitis, and Parkinson's disease), non-dementia cognitive impairment (e.g., mild cognitive impairment (MCI)), memory or learning impairment (e.g., brain developmental disorders) Accompanying memory and learning disorders), etc., preferably Alzheimer's disease or Alzheimer's dementia.

The cognitive function-improving agent, etc. of the present invention is effective in improving cognitive function (preferably, improving cognitive function decline associated with excessive accumulation of ammonia, improving cognitive decline due to Alzheimer's disease), or preventing or improving Alzheimer's disease. It can be a drug, quasi-drug, or food for humans or animals that exhibits
In addition, the food has the concept of improving cognitive function (preferably, improving cognitive function decline associated with excessive accumulation of ammonia, improving cognitive decline due to Alzheimer's disease), or preventing or improving Alzheimer's disease. , foods labeled as such, foods with function claims, foods for specified health uses, foods for the sick, and supplements.
The pharmaceuticals, quasi-drugs, and foods may be provided as one composition containing catechins and ornithine, or as a combination of compositions containing catechins or ornithine, respectively.

When the agent for improving cognitive function and the like of the present invention is used as a pharmaceutical (including quasi-drugs), the pharmaceutical can be administered in any dosage form. Examples of dosage forms include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration using injections, suppositories, inhalants, percutaneous absorption agents, etc., and the preferred form is oral administration. administration.
Pharmaceutical formulations of such various dosage forms may contain the catechins and ornithine of the present invention together with other pharmaceutically acceptable excipients, binders, fillers, disintegrants, surfactants, lubricants and dispersants. It can be prepared by appropriately combining agents, buffering agents, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents and the like.

When the agent for improving cognitive function of the present invention, etc. is used as food, the form of the food is bread, cakes, noodles, confectionery, jellies, frozen foods, ice creams, dairy products, various food compositions such as beverages. In addition to products, the same forms as the oral administration formulations described above (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, fragrances, stabilizers, coloring agents, antioxidants, moisturizing agents, thickening agents. It can be prepared by appropriately combining viscous agents 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 still more preferably 3% by mass or more. , and preferably 20% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less. Furthermore, examples of the content include 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 , 3-20% by weight, 3-10% by weight, and 3-5% by weight.

The content of ornithine in the drug (including quasi-drugs) is not particularly limited, but is preferably 0.3% by mass or more, more preferably 3% by mass or more, more preferably 5% by mass or more in terms of ornithine free form. % by mass or more, more preferably 9% by mass or more, and preferably 60% by mass or less, more preferably 30% by mass or less, even more preferably 20% by mass or less, and even more preferably 15% by mass or less. Furthermore, examples of the content include 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 % 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 , 9-20% by weight, and 9-15% by weight.

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 concentration 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) Either 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, still more preferably 1% by mass or more, and preferably 10% by mass. % or less, more preferably 5% by mass or less, and even more preferably 1% by mass or less. Furthermore, examples of the content include 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 5% by mass, 0 .1-1% by weight, 1-10% by weight, and 1-5% by weight.

The content of ornithine in the food is not particularly limited, but is preferably 0.15% by mass or more, more preferably 0.3% by mass or more, still more preferably 3% by mass or more, and 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, even more preferably 15% by mass or less, even more preferably 5% by mass or less, and even more preferably 3% by mass or less. Furthermore, examples of the content include 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 .3-30% by mass, 0.3-20% by mass, 0.3-15% by mass, 0.3-5% by mass, 0.3-3% by mass, 3-30% by mass, 3-20% by mass , 3-15% by weight, 3-5% by weight, 5-30% by weight, 5-20% by weight, and 5-15% by weight.

In the food, the concentration 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 5% by mass, 0.1-1% by mass, 1-10% by mass, and 1-5% by mass) and the ornithine concentration listed above (0.15-30% by mass, 0.15-20% 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 combined arbitrarily.

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

In the present invention, other materials having ammonia metabolism promoting action 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 regimen of catechins and ornithine may be appropriately determined by those skilled in the art according to the subject species, body weight, sex, age, condition, or other factors. Non-limiting examples of daily doses per adult for catechins and ornithine according to the present invention when administered orally are as follows:
[Catechins] preferably 100 to 3000 mg/60 kg body weight, more preferably 250 to 2000 mg/60 kg body weight, still more preferably 250 to 1000 mg/60 kg body weight, still more preferably 250 to 600 mg/60 kg body weight;
[Ornithine (as free form)] Preferably 100 to 5000 mg/60 kg body weight, more preferably 250 to 3000 mg/60 kg body weight, still more preferably 400 to 2000 mg/60 kg body weight, still more preferably 500 to 2000 mg/60 kg body weight, still more 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 doses, for example, once a day, or in divided doses of two or more times a day.

In a preferred embodiment when the agent for improving cognitive function of the present invention, etc. is used as a food, the catechins and ornithine are 1 to 10% by mass of catechins and 5 to 20% by mass of ornithine (converted to free form). and a composition containing catechins and ornithine (as free form) in a mass ratio of 1:0.5-10.

In a preferred embodiment when the cognitive function improving agent of the present invention is used as a beverage, the catechins and ornithine are 0.057 to 0.567% by mass and 0.283 to 1.0% ornithine. 132% by mass (as free form) and having a mass ratio of catechins and ornithine (as free form) of 1:0.5-10.

In a preferred embodiment when the agent for improving cognitive function of the present invention, etc. is used as a pharmaceutical, the catechins and ornithine are 1 to 10% by mass of catechins and 5 to 20% by mass of ornithine (converted to free form). and a composition containing catechins and ornithine (as free form) in a mass ratio of 1:0.5-10.

A preferred example of the dosage of the cognitive function improving agent of the present invention is the daily oral dosage of catechins 250 to 1,000 mg/60 kg body weight and ornithine 400 to 2000 mg (free form conversion)/60 kg per adult. Weight. It is preferable to administer the above doses, for example, once a day, or in divided doses of two or three or more times a day.

The following aspects are further disclosed in this invention regarding embodiment mentioned above.
<1> Cognitive ability improving agent containing catechins and ornithine as active ingredients.
<2> A food for improving cognitive function containing catechins and ornithine as active ingredients.
<3> The agent of <1> or the food of <2>, wherein the improvement in cognitive function is improvement in cognitive decline associated with excessive accumulation of ammonia.
<4> The agent of <1> or <3> or the food of <2> or <3>, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's disease.
<5> A prophylactic or ameliorating agent for Alzheimer's disease containing catechins and ornithine as active ingredients.
<6> A food for preventing or improving Alzheimer's disease containing catechins and ornithine as active ingredients.

<7> Use of catechins and ornithine for producing a cognition improving agent.
<8> Use of catechins and ornithine to produce 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> The use of any one of <7> to <9>, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's dementia.
<11> Use of catechins and ornithine for producing an agent for preventing or improving 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 cognition.
<14> The combination of <13>, wherein the improvement in cognitive function is improvement in cognitive decline associated with excess accumulation of ammonia.
<15> The combination of <13> or <14>, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's dementia.
<16> A combination of catechins and ornithine for use in preventing or improving Alzheimer's disease.

<17> Non-therapeutic use of catechins and ornithine to improve cognition.
<18> The use of <17>, wherein the improvement in cognitive function is improvement in cognitive decline associated with excessive accumulation of ammonia.
<19> The use of <17> or <18>, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's dementia.
<20> Non-therapeutic use of catechins and ornithine for preventing or improving Alzheimer's disease.

<21> A method for improving cognitive ability, comprising administering effective amounts of catechins and ornithine to a subject in need thereof.
<22> The method of <21>, wherein the improvement in cognitive function is improvement in cognitive decline associated with excessive accumulation of ammonia.
<23> The method of <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, comprising administering effective amounts of catechins and ornithine to a subject in need thereof.

<25> In <1> to <24>, the mass ratio of catechins and ornithine is preferably 1:0.1 to 10, more preferably 1:0.5 to 10, still more preferably 1:1 to 8 , more preferably 1:1-5, still more preferably 1:2-4.
<26> In <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. is at least one
<27> In <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, and 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, or 0.05 to 10% by mass, 0.05 to 5% by mass % by weight, 0.05-1% by weight, 0.1-10% by weight, 0.1-5% by weight, 0.1-1% by weight, 1-10% by weight, and 1-5% by weight.
<28> In <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 educt % by mass or more, more preferably 3% by mass or more, more preferably 5% by mass or more, and preferably 30% by mass or less, more preferably 20% by mass or less, even more preferably 15% by mass or less, further preferably 5% by mass or less. % by mass or less, more preferably 3% by mass or less, or 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 .15-3% 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% by mass 3-20% by weight, 3-15% by weight, 3-5% by weight, 5-30% by weight, 5-20% by weight, and 5-15% by weight.

EXAMPLES The present invention will be described in more detail below using examples. However, the technical scope of the present invention is not limited to these examples.

Reference Example 1 Preparation of catechin-containing green tea extract 1,000 g of a commercially available green tea extract (Mitsui Norin Co., Ltd. "Polyphenon HG") was stirred at 25°C and 200 rpm, and 9,000 g of a 95% by mass ethanol aqueous solution was added. suspended in. 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 thereto, and stirring was continued for about 10 minutes. Stirring was continued for an additional 30 minutes at 25°C. Next, the suspension was filtered through No. 2 filter paper to remove activated carbon, acid clay, and precipitates, and then the filtrate was refiltered through a 0.2 μm membrane filter. 200 g of ion-exchanged water was added to the filtrate, ethanol was distilled off at 40° C. and 3.3 kPa, and the residue was concentrated under reduced pressure. 750 g of the concentrate was put into a stainless steel container, the total amount was adjusted to 10,000 g with deionized water, and 30 g of a 5% by 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 the solution containing the obtained concentrate under stirring conditions of 22° C. and 150 rpm. added. After 30 minutes, when the pH of the reaction solution decreased to 4.24, the stainless container was immersed in a hot bath at 95°C and held at 90°C for 10 minutes to completely inactivate the enzyme activity. Then, the reaction solution was cooled to 25° C. and concentrated to obtain a purified green tea extract. The purified green tea extract obtained had a content of (A) catechins of 14.9% by mass and a ratio of catechin gallates in the catechins of 45.3% by mass.

Example 1 Effect of catechins and ornithine ^on hepatocyte ammonia metabolism Cosmo Bio Co., Ltd.) was used. As catechins, the green tea extract (containing 14.9% by mass of catechins) prepared in Reference Example 1 was used. Hepatocytes, control medium, ornithine-containing medium (control medium containing 1 mM ornithine hydrochloride (0.0132% in terms of ornithine)), catechins-containing medium (0.001 mass% green tea extract (0.000149 mass as catechins %) control medium) or ornithine and catechins-containing medium (control medium containing 1 mM ornithine hydrochloride and 0.001% by mass of green tea extract) at 37° C. for 20 hours. DMEM medium containing 5 mM ammonium chloride (high glucose, GlutaMAX added, penicillin/streptomycin added, pyruvic acid-free, phenol red-free, glutamine-free, FBS-free) was used as a control medium. After the culture, the medium supernatant was recovered, and the ammonia contained therein was quantified using the Ammonia Assay Kit (abcam). A significant difference test between the quantified values and the control group was performed (Dunnett test, vs. the control group, n=3).

Fig. 1 shows the quantitative results of ammonia. Compared to the control group, in the ornithine hydrochloride and catechins-containing group, the ammonia concentration in the medium was statistically significantly reduced, indicating that ammonia metabolism was promoted.

Example 2 Effect of catechins and ornithine on human blood ammonia concentration 1 . Method (Subjects)
Fifteen healthy adult males (ages 21-39) were used as subjects.
(Experimental plan)
In the test, as the main measurement 1, all subjects were given 1 control drink (Placebo Healthya Water Grapefruit Flavor 500 mL: catechin-free) and 12 placebo supplements (Placebo Pharmaceutical Co., Ltd.), and 50 minutes after that. , the blood ammonia concentration was measured.
After main measurement 1, 15 people were selected as main measurement 2, and three groups of 5 people each so that there was no difference in the average blood ammonia concentration in main measurement 1 (catechins alone group, ornithine alone group, catechins and ornithine) Combined group), after 1 to 2 weeks or more of this measurement, respectively,
In the catechins alone group, 1 catechin drink (Healthia Water Grapefruit Flavor 500 mL: Kao Corporation, containing 540 mg of catechins) and a placebo supplement (Place Plus (Placebo Pharmaceutical Co., Ltd.)) 12 grains,
In the ornithine alone group, 1 control drink (500 mL of placebo healthy water grapefruit flavor: catechin-free) and ornithine supplement (ornithine (Kyowa Hakko Bio Co., Ltd.), containing 1600 mg of ornithine in 12 tablets) 12 tablets,
In the catechins and ornithine combination group, one catechin drink (Healthia Water Grapefruit Flavor 500 mL: Kao Corporation, containing 540 mg of catechins) and ornithine supplement (ornithine (Kyowa Hakko Bio Co., Ltd.), 12 capsules containing 1600 mg of ornithine) 12 grain,
, and 50 minutes later, the blood ammonia concentration was measured.

(test material)
Details of the test material are as follows:
Catechin drink: Healthya Water Grapefruit Flavor 500 mL (Kao Corporation), containing 540 mg of catechins per bottle;
Placebo supplement: Placebo Plus (Placebo Pharmaceutical Co., Ltd.), no amino acids;
Ornithine supplement: Ornithine (Kyowa Hakko Bio Co., Ltd.), containing 1600 mg of ornithine in 12 tablets;
The provision of study material was performed in a single-blind fashion.

(blood ammonia concentration measurement)
In this measurement 1 and 2, blood was collected from each subject's fingertip 50 minutes after ingestion of the test material. The blood ammonia concentration of the collected blood (whole blood) was measured using a blood ammonia measuring device (Pocketchem BA PA-4140, ARKRAY, Inc.).
Data of all subjects obtained in two tests were tested for significance between measurements (t-test).

2. Results (blood ammonia concentration)
The results are shown in FIG. The value of each group in the main measurement 1 is indicated by A, and the value in the main measurement 2 is indicated 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 during this measurement 2 compared to the time of control intake (this measurement 1). In contrast, the catechins and ornithine combination group (Cat+Orn) decreased by more than 20% (p<0.1). From this, it was shown that the combined intake of catechins and ornithine lowered the blood ammonia level.

Claims (7)

A cognitive ability improving agent comprising catechins and ornithine as active ingredients, wherein the mass ratio of catechins and ornithine is 1:0.1-10 . A food for improving cognitive function, comprising catechins and ornithine as active ingredients, wherein the mass ratio of catechins and ornithine is 1:0.1-10 . 3. The agent according to claim 1 or the food according to claim 2, wherein the improvement in cognitive function is improvement in cognitive decline associated with excessive accumulation of ammonia. 4. The agent according to claim 1 or 3, or the food according to claim 2 or 3, wherein the improvement in cognitive function is improvement in cognitive decline associated with Alzheimer's dementia. A prophylactic or ameliorating agent for Alzheimer's disease, comprising catechins and ornithine as active ingredients, wherein the mass ratio of catechins and ornithine is 1:0.1-10 . A food for preventing or improving Alzheimer's disease, comprising catechins and ornithine as active ingredients, wherein the mass ratio of catechins and ornithine is 1:0.1-10 . Claims 1 to 6 , wherein 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 the above.

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