WO2018207791A1

WO2018207791A1 - Arc expression promoter

Info

Publication number: WO2018207791A1
Application number: PCT/JP2018/017830
Authority: WO
Inventors: 恵子石田; 瞳西村; 征輝山本; 幸一三澤
Original assignee: 花王株式会社
Priority date: 2017-05-12
Filing date: 2018-05-08
Publication date: 2018-11-15
Also published as: JP6499787B1; JP2019178131A

Abstract

Provided is an Arc expression promoter that has a high safety and can be continuously taken. The Arc expression promoter comprises chlorogenic acid or a salt thereof as an active ingredient.

Description

Arc expression promoter

The present invention relates to an Arc expression promoter that promotes the expression of Arc.

Arc (activity-regulated <RTIgt; cytoskeleton-associated </ RTI> protein, also known as: Arg 3.1) is one of the immediate early genes that are rapidly and transiently induced by brain neural activity. Since the expression of Arc mRNA and protein correlates with the neural activity of individual nerve cells (Non-patent Document 1), it is used as a marker of neural activity and has the promoter activity of the Arc / Arg3.1 gene. DNA is used as a technique for identifying a cranial nerve active site (Patent Document 1).

Nerve cells transmit information between nerve cells at a nerve connection site called a synapse. Synaptic transmission efficiency is not constant. For example, high-frequency stimulation causes long-term potentiation that increases synaptic transmission efficiency for a long time. On the other hand, constant stimulation with low frequency causes long-term suppression that lowers synaptic transmission efficiency for a long time. Such a mechanism in which synaptic transmission efficiency is changed by neural activity and is maintained for a long time is called synaptic plasticity. Synaptic plasticity is thought to be important for the establishment of memory / learning because of its property of changing and fixing the information transmission pathway of nerves.

Arc proteins are involved in maintaining such synaptic plasticity and are reported to be important for the formation of long-term memory (Non-patent Document 2). In addition, Arc-deficient mice have decreased results of various types of tests that evaluate long-term memory such as the Morris water maze and novel object recognition test (Non-patent Document 3). In the brain of Alzheimer-type cognitive impairment mice, It has been reported that Arc gene expression decreases with aging (Non-patent Document 4). It has also been reported that the expression of Arc is increased by administration of a substance that up-regulates learning and memory (Patent Document 2).
For this reason, it is suggested that the increase in the expression of Arc may improve the normal memory / learning function and improve cognitive functions such as aging and Alzheimer's disease.

In addition, it has been reported that mice lacking Arc have different stimuli responsiveness in the primary visual cortex of the cerebral cortex (Non-patent Document 5), and Arc plays an important role in the processing of visual information. It is thought to suggest.

Neural networks (networks) created by the arrangement and wiring of various neurons are important for the expression of brain functions. In the immaturity period, which is the embryonic period, the formation of a network by nerve cells moves toward the target site after immature cells are produced from neural stem cells. Stem cells that have reached a predetermined position, such as the cerebral cortex and hippocampus, extend neurites after differentiation. This neurite binds to a specific target, a synapse is formed, a network between cells is created, and an immature neural circuit that functions as a brain is created. Thereafter, synaptic pruning that leaves the neural circuit necessary for postnatal development and removes the excess neural circuit occurs, and the circuit that can express the brain function in the mature period is reorganized. Non-Patent Document 6 reports that induction of Arc gene expression promotes synaptic pruning. Therefore, induction of Arc expression is important for the formation of a functional neural circuit, and a decrease in Arc expression is thought to cause abnormal development of the neural circuit. Since it has been suggested that developmental abnormalities in neural circuits are deeply related to the onset of neurodevelopmental disorders, Arc is considered to be useful for the prevention and treatment of developmental disorders.
Diseases in which the expression of Arc actually has an effect include tuberous sclerosis in which symptoms such as epileptic seizures, developmental disorders, and autism appear, and the expression of Arc in the brain of tuberous sclerosis model mice A decrease has been reported (Non-Patent Document 7).

On the other hand, chlorogenic acids have been found in coffee beans and potatoes in plants, and so far, antioxidant effects, blood pressure lowering effects, etc. have been reported (Patent Document 3). In addition, it has been reported that di-O-caffeoylquinic acid in which two caffeic acids are ester-bonded has a protective effect on nerve cells (Patent Document 4).

However, it is not known that chlorogenic acids promote the expression of Arc, and are useful for the prevention or treatment of neural circuit formation and neurodevelopmental disorders.

(Patent Document 1) International Publication No. 2014/045674 (Patent Document 2) Japanese Patent Publication No. 2016-532683 (Patent Document 3) Japanese Patent Application Laid-Open No. 2002-53464 (Patent Document 4) International Publication No. 2007/091613 Patent Document 1) Guzowsuki JF et al. Nat Neurosci, 2: 1120-1124, 1999
(Non-Patent Document 2) Okuno H et al. Cell, 149: 886-898, 2012
(Non-Patent Document 3) Plath N et al. Neuron, 52: 437-444, 2006
(Non-Patent Document 4) Dickey CA et al. J Neurosci, 88: 434-442, 2004
(Non-Patent Document 5) Wang KH et al. Cell, 126: 389-402, 2006
(Non-patent document 6) Mikuni T et al. Neuron, 78: 1024-1035, 2013
(Non-patent document 7) Auerbach BD et al. Nature, 480: 63-68, 2012

The present invention relates to the following 1) to 28).
1) An Arc expression promoter containing chlorogenic acids or salts thereof as an active ingredient.
2) A neuronal circuit formation promoter comprising chlorogenic acids or salts thereof as an active ingredient.
3) A preventive, therapeutic or ameliorating agent for neurodevelopmental disorders or tuberous sclerosis comprising chlorogenic acids or salts thereof as an active ingredient.
4) A preventive, therapeutic or ameliorating agent for visual cognitive function deterioration containing chlorogenic acids or salts thereof as an active ingredient.
5) A food for promoting Arc expression comprising chlorogenic acids or salts thereof as an active ingredient.
6) A food for promoting neural circuit formation containing chlorogenic acids or salts thereof as an active ingredient.
7) A food for preventing or improving neurodevelopmental disorders or tuberous sclerosis comprising chlorogenic acids or salts thereof as an active ingredient.
8) A food for preventing or improving visual cognitive function deterioration containing chlorogenic acids or salts thereof as an active ingredient.
9) Use of chlorogenic acids or salts thereof for producing an Arc expression promoter.
10) Use of a chlorogenic acid or a salt thereof for producing a neural circuit formation promoter.
11) Use of chlorogenic acids or salts thereof for producing a preventive, therapeutic or ameliorating agent for neurodevelopmental disorder or tuberous sclerosis.
12) Use of chlorogenic acids or salts thereof for producing a preventive, therapeutic or ameliorating agent for visual cognitive decline.
13) Use of chlorogenic acids or salts thereof for producing a food for promoting Arc expression.
14) Use of chlorogenic acids or salts thereof for producing a food for promoting neural circuit formation.
15) Use of chlorogenic acids or salts thereof for producing a food for preventing or improving neurodevelopmental disorder or tuberous sclerosis.
16) Use of a chlorogenic acid or a salt thereof for producing a food for preventing or improving deterioration of visual cognitive function.
17) Chlorogenic acids or salts thereof for use in promoting Arc expression.
18) Chlorogenic acids or salts thereof for use in promoting neural circuit formation.
19) Chlorogenic acids or salts thereof for use in the prevention, treatment or amelioration of neurodevelopmental disorders or tuberous sclerosis.
20) Chlorogenic acids or salts thereof for use in the prevention, treatment or improvement of visual cognitive decline.
21) Non-therapeutic use of chlorogenic acids or salts thereof to promote Arc expression.
22) Non-therapeutic use of chlorogenic acids or salts thereof to promote neural circuit formation.
23) Non-therapeutic use of chlorogenic acids or salts thereof for preventing or ameliorating neurodevelopmental disorder or tuberous sclerosis.
24) Non-therapeutic use of chlorogenic acids or salts thereof to prevent or ameliorate visual cognitive decline.
25) A method for promoting Arc expression, comprising administering or ingesting chlorogenic acids or salts thereof in an effective amount to a subject in need thereof.
26) A method for promoting the formation of neural circuits, comprising administering or ingesting chlorogenic acids or salts thereof in an effective amount to a subject in need thereof.
27) A method for preventing, treating, or improving neurodevelopmental disorders or tuberous sclerosis, wherein chlorogenic acids or salts thereof are administered or taken in an effective amount to a subject in need thereof.
28) A method for preventing, treating or improving visual cognitive decline, comprising administering or ingesting chlorogenic acids or salts thereof in an effective amount to a subject in need thereof.

The figure which shows the Arc gene expression improvement in a mouse | mouth hippocampus by chlorogenic acid intake. Error bars: ± standard error (n = 9-10), ** p <0.01, *** p <0.001 (One way ANOVA Bonferroni test).

Detailed Description of the Invention

The present invention relates to providing an Arc expression promoter that is highly safe and can be ingested continuously.

As a result of various investigations on highly safe ingredients that can be taken or ingested over the long term, the present inventors have found that chlorogenic acids have an excellent Arc expression promoting action, promoting the formation of neural circuits and neurodevelopmental disorders Or it discovered that it was useful for the prevention or improvement of tuberous sclerosis.

According to the present invention, the expression of Arc is promoted, and diseases and symptoms caused by neural network breakdown or underdevelopment, such as pervasive developmental disorders (such as autism and Asperger's syndrome), attention deficit / hyperactivity disorder Drugs and foods useful for prevention, treatment or improvement of neurodevelopmental disorders such as (ADHD) and tuberous sclerosis are provided.

The “chlorogenic acids” in the present invention are monocaffeoylquina of 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA) and 5-caffeoylquinic acid (5-CQA). 3-feruloylquinic acid (3-FQA), 4-feruloylquinic acid (4-FQA) and 5-feruloylquinic acid (5-FQA) monoferloylquinic acid, and 3,4- Dicafe oil of dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA) and 4,5-dicaffeoylquinic acid (4,5-diCQA) It is a general term for quinic acid. The content of chlorogenic acids is defined based on the total amount of the above nine types.
The “chlorogenic acids” of the present invention may contain at least one of the above nine chlorogenic acids, but preferably contains monocaffeoylquinic acid from the viewpoint of promoting amyloid β degradation / extraction. -More preferably caffeoylquinic acid. The content of 5-caffeoylquinic acid is preferably 15% by mass or more in chlorogenic acids, more preferably 25% by mass or more, and further preferably 35% by mass or more.

The chlorogenic acids may be in the form of a salt, such as a pharmaceutically acceptable salt, for example, an alkali metal salt such as sodium or potassium, an alkaline earth metal salt such as magnesium or calcium, monoethanolamine, diethanolamine, or triethanol. Examples include organic amine salts such as amines, and basic amino acid salts such as arginine, lysine, histidine, ornithine and the like.

As the chlorogenic acids or salts thereof of the present invention, plant extracts containing them, concentrates thereof, or purified products thereof can be used. Examples of such plant extracts include sunflower seeds, apple immature fruits, coffee beans, Simon leaves, pine cones, pine seed shells, potatoes, sweet potatoes, sugar cane, wheat, southern leaves, Examples include those extracted from burdock, carrot, cabbage, lettuce, arch chalk, tomato, morroheiya, eggplant skin, pear, plum, peach, apricot, cherry, ume fruit, dandelion, grape plant and the like. Among them, coffee bean extract is preferable from the viewpoint of chlorogenic acid content and the like, and deep roasted coffee beans (L value: 16.8 or less) may be used, but medium roasted coffee beans (L value: more than 16.8). 24.2 or less), shallow roasted coffee beans (L value: more than 24.2 and less than 30.2), finely roasted coffee beans (L value: more than 30.2) or fresh coffee beans are more preferred. Coffee beans are more preferred. Here, the “L value” is a value obtained by measuring the brightness of roasted coffee beans with a color difference meter, with black as L value 0 and white as L value 100. The type of coffee tree may be any of Arabica, Robusta, Revelica and Arabsta.

The coffee bean extract is preferably obtained by removing caffeine, and the mass ratio of caffeine to chlorogenic acids (caffeine / chlorogenic acids) is preferably 0.05 or less, more preferably 0.03 or less from the viewpoint of flavor. Preferably, 0.02 or less is more preferable, 0.005 or less is more preferable, 0.003 or less is more preferable, and 0.001 or less is more preferable. The lower limit of the ratio of caffeine / chlorogenic acids is not particularly limited, and may be 0. The coffee bean extract has a mass ratio of the sum of potassium (K) and sodium (Na) to chlorogenic acids [(K + Na) / chlorogenic acids] of 0.18 or less, more preferably 0.14 or less. Further, 0.1 or less, particularly 0.06 or less is preferable. The lower limit of the mass ratio [(K + Na) / chlorogenic acids] is not particularly limited and may be 0, but from the viewpoint of production efficiency, 0.0001 and 0.001 are preferable.

As a preferable example of the coffee bean extract used in the present invention, the mass ratio of caffeine to chlorogenic acids (caffeine / chlorogenic acids) is 0.02 or less, and 5-caffeoylquinic acid in the total amount of chlorogenic acids. A green coffee bean extract having a content (5-CQA / total chlorogenic acids) of 35% by mass or more. More preferred examples include fresh coffee bean extracts having (caffeine / chlorogenic acids) of 0.001 or less and (5-CQA / total chlorogenic acids) of 35% by mass or more.

Methods and conditions for extraction, concentration and purification of the chlorogenic acids or salts thereof of the present invention are not particularly limited, and known methods and conditions can be employed. Of these, extraction with an ascorbic acid aqueous solution, a citric acid aqueous solution or hot water is preferred.
Commercially available chlorogenic acid-containing preparations may be used as raw materials for chlorogenic acids or salts thereof, such as flavor holder RC (Hasegawa Fragrance Co., Ltd.), fresh coffee bean extract P (manufactured by Oriza Oil Chemical Co., Ltd.), Svetol. (Manufactured by Nulex Inc.) and OXCH100 (manufactured by Toyo Fermentation Co., Ltd.).

As shown in Examples below, chlorogenic acids have an action of promoting the expression of the Arc gene in the hippocampus. Arc is one of the immediate early genes that are promptly and transiently induced by neural activity in the brain, and the expression of Arc mRNA and protein correlates with the neural activity of individual neurons (non-patented). Reference 1), the induction of Arc gene expression promotes synaptic pruning during postnatal development, so the promotion of Arc expression is important for the formation of functional neural circuits, and is caused by the breakdown and underdevelopment of neural networks It is considered useful for the prevention, treatment or improvement of diseases and symptoms such as neurodevelopmental disorders and tuberous sclerosis (Non-Patent Documents 6 and 7). In addition, since Arc is involved in the processing of visual information (Non-patent Document 5), the promotion of the expression of Arc is the function of recognizing and analyzing information entering the eye in the brain, that is, preventing the deterioration of visual cognitive function, It is considered useful for treatment or improvement.
Therefore, chlorogenic acids or salts thereof are Arc expression promoters, neural circuit formation promoters, neurodevelopmental disorders or tuberous sclerosis preventive, therapeutic or ameliorating agents, as well as visual cognitive function preventive, therapeutic or ameliorating agents. (Hereinafter also referred to as “Arc expression promoter of the present invention”), to promote the expression of Arc, to promote the formation of neural circuits, to prevent, treat or improve neurodevelopmental disorder or tuberous sclerosis In addition, it can be used to prevent, treat or ameliorate visual cognitive decline, and can also prevent, treat or treat Arc expression promoters, neural circuit formation promoters, neurodevelopmental disorders or tuberous sclerosis It can be used to produce an improving agent, and further a preventive, therapeutic or improving agent for visual cognitive decline.
Here, “use” may be administration or ingestion to a human or non-human animal, and may be therapeutic use or non-therapeutic use. Note that “non-therapeutic” means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing a person, more specifically, a doctor or a person who has received instructions from a doctor It is a concept that does not include a method of performing surgery, treatment or diagnosis.

In the present invention, promoting the expression of Arc includes promoting the expression at the gene level and promoting the expression at the protein level. The promotion of expression at the gene level includes the promotion of mRNA expression, preferably the promotion of transcription into mRNA, and the promotion of expression at the protein level includes the promotion of translation, but preferably the expression of mRNA. Here, “Arc (activity-regulated cytoskeleton-associated protein, aka: Arg3.1)” is the NCBI database (Gene) [http://www.ncbi.nlm.nih.gov/gene/] It means a protein registered as “ARC”.

Further, in the present invention, “promotion of neural circuit formation” means that the synaptic connection between a nerve axon and a target cell is promoted and the neural network is reconstructed or activated.
Therefore, the neural circuit formation promoter of the present invention is useful for the prevention, treatment or improvement of diseases and symptoms caused by the breakdown or underdevelopment of the neural network, for example, neurodevelopmental disorder or tuberous sclerosis.
In the present invention, “neurodevelopmental disorder” means a developmental delay that occurs in early childhood due to congenital brain dysfunction, and specifically pervasive developmental disorders (such as autism, Asperger's syndrome, Tourette syndrome) , Attention deficit / hyperactivity disorder (ADHD), learning disorder (LD), and the like. In addition, “tuberous sclerosis” refers to congenital diseases that show hamartoma of various parts of the body such as the brain, skin, kidneys, lungs, bones, epileptic seizures, developmental disorders, and autism. means.

In the present invention, “visual cognitive function” means a function of recognizing / analyzing information received from the eye in the brain and understanding it, and understanding of the creation of figures and kanji, and recognition of images such as left and right recognition. This includes power, operating skills such as working with hands or moving the body with the eyes of sports, space recognition ability such as memory of seen objects and understanding distance.

As used herein, “prevention” refers to preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of developing an individual's disease or symptom.
“Improvement” refers to improvement of a disease, symptom or condition, prevention or delay of deterioration of a disease, symptom or condition, or reversal, prevention or delay of progression of a disease or symptom.
“Treatment” also includes amelioration of symptoms in addition to complete cure of the disease.

In order to prevent, treat or improve neurodevelopmental disorder or tuberous sclerosis, the Arc expression promoter of the present invention of the present invention itself promotes the expression of Arc, promotes the formation of neural circuits, Furthermore, it may be a pharmaceutical, a quasi-drug, a supplement or a food for preventing, treating, or improving visual cognitive function deterioration, or a material used in combination with the pharmaceutical, quasi-drug, or food. Or a formulation may be sufficient.
The food has the concept of promoting the expression of Arc, promoting the formation of neural circuits, preventing or improving neurodevelopmental disorders or tuberous sclerosis, and further preventing or improving the deterioration of visual cognitive function. The indicated foods, functional foods, foods for the sick, foods for specified health use, and supplements are included. Since these foods are foods whose function is permitted, they can be distinguished from general foods.

Examples of the administration form of the above-mentioned pharmaceuticals (including quasi drugs) include oral administration by tablets, capsules, granules, powders, syrups, etc., or parenteral administration by injections, suppositories, inhalants and the like. It is done. In addition, the preparations of such various dosage forms include the chlorogenic acids or salts thereof of the present invention alone or other pharmaceutically acceptable excipients, binders, extenders, disintegrants, surfactants. , Lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents, medicinal components other than the chlorogenic acids of the present invention or salts thereof, and the like, can be prepared as appropriate. . Of these dosage forms, the preferred form is oral administration.

As the form of the food, in addition to various foods such as soft drinks, tea beverages, coffee beverages, fruit juice beverages, carbonated beverages, jelly, wafers, biscuits, bread, noodles, sausages and nutritional foods, Includes a nutritional supplement composition in the same form (tablet, capsule, syrup, etc.) as the above-mentioned oral preparation.

Various forms of foods are the chlorogenic acids or salts thereof of the present invention alone, or other food materials, solvents, softeners, oils, emulsifiers, preservatives, acidulants, sweeteners, bitterings, aromatics, It can be prepared by appropriately combining stabilizers, colorants, antioxidants, humectants, thickeners, active ingredients other than chlorogenic acids or salts thereof, and the like.

The content of the chlorogenic acids or salts thereof of the present invention in the above-mentioned pharmaceuticals (including quasi-drugs) and foods varies depending on the form of use, but is usually preferably 0.001% by mass or more in the total amount as chlorogenic acids More preferably, it is 0.01 mass% or more, More preferably, it is 0.1 mass% or more, Preferably it is 90 mass% or less, More preferably, it is 60 mass% or less, More preferably, it is 30 mass% or less. Further, it is preferably 0.001 to 90% by mass, more preferably 0.01 to 60% by mass, and still more preferably 0.1 to 30% by mass.

The dose or intake of the above-mentioned pharmaceuticals (including quasi-drugs) and foods can be determined as appropriate, but is usually preferably 100 mg or more, more preferably as chlorogenic acids per day for adults (60 kg). Is 300 mg or more, preferably 3000 mg or less, more preferably 1000 mg or less. In the present invention, such an amount is preferably administered or ingested once.

The above-mentioned preparation is administered or ingested according to an arbitrary plan, and the administration or ingestion period is not particularly limited, but it is preferable to administer or ingest repeatedly, and more preferably to administer or ingest continuously for 7 days or more. More preferably, it is administered or ingested continuously for 28 days or more.

Examples of subjects to be administered or ingested include humans with delayed language development, humans with interpersonal relationships / social disorders, humans with patterned behavior, and interests / interests Humans who are not good at responding to changes, humans with attention deficit / hyperactivity disorder, humans with learning disabilities, etc.

With respect to the above-described embodiment, the following aspects are disclosed in the present invention.
<1> An Arc expression promoter comprising a chlorogenic acid or a salt thereof, or a plant extract containing the active ingredient as an active ingredient.
<2> A neuronal circuit formation promoter comprising a chlorogenic acid or a salt thereof, or a plant extract containing the active ingredient as an active ingredient.
<3> A preventive, therapeutic or ameliorating agent for neurodevelopmental disorder or tuberous sclerosis comprising chlorogenic acids or salts thereof, or a plant extract containing the active ingredient as an active ingredient.
<4> A preventive, therapeutic or ameliorating agent for deterioration of visual cognitive function, comprising chlorogenic acids or salts thereof, or a plant extract containing the active ingredient as an active ingredient.
<5> A food for promoting Arc expression comprising a chlorogenic acid or a salt thereof, or a plant extract containing the active ingredient as an active ingredient.
<6> A food for promoting the formation of neural circuits, comprising a chlorogenic acid or a salt thereof, or a plant extract containing the active ingredient as an active ingredient.
<7> A food for preventing or improving neurodevelopmental disorders or tuberous sclerosis, comprising chlorogenic acids or salts thereof, or a plant extract containing the active ingredient as an active ingredient.
<8> A food for preventing or improving visual cognitive function deterioration comprising a chlorogenic acid or a salt thereof, or a plant extract containing the active ingredient as an active ingredient.

<9> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing an Arc expression promoter.
<10> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing a neural circuit formation promoter.
<11> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing an agent for preventing, treating or improving neurodevelopmental disorder or tuberous sclerosis.
<12> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing an agent for preventing, treating or improving visual cognitive function deterioration.
<13> Use of chlorogenic acids or a salt thereof, or a plant extract containing the same for producing a food for promoting Arc expression.
<14> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing a food for promoting the formation of neural circuits.
<15> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing a food for preventing or improving neurodevelopmental disorder or tuberous sclerosis.
<16> Use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for producing a food for preventing or improving visual cognitive function deterioration.
<17> The use according to any one of <9> to <12>, wherein the agent is a preparation for oral administration.

<18> A chlorogenic acid or a salt thereof, or a plant extract containing the same for use in promoting the expression of Arc.
<19> A chlorogenic acid or a salt thereof, or a plant extract containing the same for use in promoting the formation of a neural circuit.
<20> A chlorogenic acid or a salt thereof, or a plant extract containing the same for use in prevention, treatment or improvement of neurodevelopmental disorder or tuberous sclerosis.
<21> A chlorogenic acid or a salt thereof, or a plant extract containing the same for use in prevention, treatment or improvement of visual cognitive function deterioration.
<22> A chlorogenic acid according to any one of <18> to <21> or a salt thereof, or a plant extract containing the same, which is orally administered.

<23> Non-therapeutic use of chlorogenic acids or salts thereof, or plant extracts containing the same to promote Arc expression.
<24> Non-therapeutic use of chlorogenic acids or salts thereof, or plant extracts containing the same to promote neural circuit formation.
<25> Non-therapeutic use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for preventing or improving neurodevelopmental disorder or tuberous sclerosis.
<26> Non-therapeutic use of a chlorogenic acid or a salt thereof, or a plant extract containing the same for preventing or improving a decrease in visual cognitive function.
<27> The non-therapeutic use according to any one of <23> to <26>, wherein the chlorogenic acid or a salt thereof, or a plant extract containing the same is orally administered.

<28> A method for promoting Arc expression, comprising administering or ingesting an effective amount of a chlorogenic acid or a salt thereof, or a plant extract containing the chlorogenic acid to a subject in need thereof.
<29> A method for promoting the formation of a neural circuit, comprising administering or ingesting an effective amount of a chlorogenic acid or a salt thereof, or a plant extract containing the chlorogenic acid to a subject in need thereof.
<30> A method for preventing, treating, or improving neurodevelopmental disorders or tuberous sclerosis, comprising administering or ingesting an effective amount of a chlorogenic acid or a salt thereof, or a plant extract containing the chlorogenic acid to a subject in need thereof.
<31> A method for preventing, treating, or improving a decrease in visual cognitive function, wherein a chlorogenic acid or a salt thereof, or a plant extract containing the same is administered or ingested to a subject in need thereof in an effective amount.
<32> The method according to any one of <28> to <31>, wherein the administration is oral administration.

<33> In <1> to <32>, the chlorogenic acids are 3-CQA, 4-CQA, 5-CQA, 3-FQA, 4-FQA, 5-FQA, 3,4-diCQA, 4,5- One or more selected from at least one of diCQA and 3,5-diCQA.

<34> In <1> to <33>, the plant extract containing chlorogenic acids or salts thereof is a coffee bean extract, preferably a green coffee bean extract.
<35> In <34>, the green coffee bean extract preferably has a mass ratio of caffeine to chlorogenic acids (caffeine / chlorogenic acids) of 0.02 or less and 5-cafe in the total amount of chlorogenic acids. Oil quinic acid content (5-CQA / total chlorogenic acids) is 35% by mass or more, more preferably (caffeine / chlorogenic acids) is 0.001 or less and (5-CQA / total chlorogenic acids) is 35% by mass or more.

In <36> <3>, <7>, <11>, <15>, <20>, <25>, <30>, the neurodevelopmental disorder is pervasive developmental disorder or attention deficit / hyperactivity disorder is there.

<37> <1> and <9> Arc expression promoter, <2> and <10> neural circuit formation promoter, <3> and <11> neurodevelopmental disorder or tuberous sclerosis prevention and treatment Or <4> and <12> prevention, treatment or improvement agent, <5> and <13> Arc expression promoting food, <6> and <14> neural circuit formation promotion <7> and <15> food for prevention or improvement of neurodevelopmental disorder or tuberous sclerosis, <8> and <16> food for prevention or improvement of visual cognitive function deterioration, The content is preferably 0.001% by mass or more, more preferably 0.01% by mass or more, still more preferably 0.1% by mass or more, and preferably 90% by mass or less, in the total amount as chlorogenic acids. Preferably it is 60% by mass or less, and more preferable Is 30% by mass or less. Further, it is preferably 0.001 to 90% by mass, more preferably 0.01 to 60% by mass, and still more preferably 0.1 to 30% by mass.

<38> In <18> to <32>, the daily dose per adult is preferably 100 mg or more, more preferably 300 mg or more, and preferably 3000 mg or less, more preferably as chlorogenic acids. 1000 mg or less.

Production Example 1 Preparation of chlorogenic acid-containing composition 1) Raw Robusta coffee beans were extracted with hot water, and the resulting extract was dried by spray drying to obtain a crude chlorogenic acid-containing composition. The composition of the crude chlorogenic acid or its salt-containing composition is as follows: chlorogenic acids 40.8% by mass, caffeine 9.8% by mass, mass ratio (caffeine / chlorogens) 0.241, mass ratio ((K + Na) / Chlorogenic acids) was 0.19.
2) 189 g of the crude chlorogenic acid-containing composition, 756 g of an ethanol aqueous solution having an ethanol concentration of 52.4% by mass, 94.5 g of acid clay (Mizuka Ace # 600, manufactured by Mizusawa Chemical Co., Ltd.), filter aid (Solka Flock, Nippon Mining Procurement) 1051 g of a chlorogenic acid-containing slurry was obtained by mixing with 10.7 g. The pH of the chlorogenic acid-containing slurry was 5.7.
3) 1051 g of the chlorogenic acid-containing slurry and then 189 g of an ethanol aqueous solution having an ethanol concentration of 52.4% by mass were filtered through No. 2 filter paper on which diatomaceous earth was deposited as a precoat agent, and 1054 g of the filtrate was recovered.

4) Next, a column packed with 132 mL of activated carbon (Shirakaba WH2C, manufactured by Nippon Enviro Chemicals) and a column packed with 105 mL of H-type cation exchange resin (SK1BH, manufactured by Mitsubishi Chemical) were connected to the filtrate. 1019 g was passed through, followed by 231 g of an aqueous ethanol solution having an ethanol concentration of 52.4% by mass, and 1072 g of the eluted column processing solution was recovered. The amount of activated carbon used relative to the chlorogenic acid content in the filtrate was 0.81 times by mass (g / g). The amount of ion exchange resin used was 0.74 (mL / g) based on the solid content in the crude chlorogenic acid-containing composition.
5) 1038 g of the column treatment solution was filtered through a 0.2 μm membrane filter, and then ethanol was distilled off by a rotary evaporator to obtain 225 g of a chlorogenic acid-containing solution. The composition of the chlorogenic acid-containing liquid is as follows: chlorogenic acids or salts thereof 22.6% by mass, caffeine 0.29% by mass, mass ratio (caffeine / chlorogenic acids or salts thereof) is 0.013, ethanol concentration 0% by mass And the pH was 3.1.
6) The chlorogenic acid-containing liquid was diluted with distilled water to adjust the concentration of chlorogenic acids to 3% by mass. 10 g of the obtained diluted solution was sampled in a centrifuge tube, centrifuged at 3000 rpm, 15 ° C., 60 minutes, and the supernatant was freeze-dried to obtain a chlorogenic acid-containing purified coffee polyphenol (CPP). . In the CPP, the content of 5-CQA in the total amount of chlorogenic acids is 36.9%, and monocaffeoylquinic acid and monoferuloylquinic acid (3-CQA, 4-CQA, 5-CQA, 3-FQA The content of 5-CQA in the total amount of 4-FQA and 5-FQA) was 45.6%. The composition ratio of chlorogenic acids in CPP is shown in Table 1.

Example 1 Arc Gene Expression Promoting Action by Chlorogenic Acids (1) Breeding of mice C57BL / 6J mice (male, 8 weeks old) (Claire Japan) were used. Mice were reared at room temperature 22 ± 2 ° C., humidity 55 ± 10%, and 12-hour lighting cycle (7:00 am to 7:00 pm), and food and water were freely consumed during the breeding period. The animals were divided into three groups: a control group, a chlorogenic acid 0.5 mass% intake group, and a chlorogenic acid 1.0 mass% intake group. The chlorogenic acid intake group ingested a standard diet containing 0.5% by mass and 1% by mass of purified chlorogenic acid-containing purified coffee polyphenol (CPP) prepared in Production Example 1 as a CPP amount for 4 weeks. In the control group, feed containing no chlorogenic acids (corn oil 10%, casein 20%, cellulose 4%, minerals 3.5%, vitamins 1%, potato starch 61.5%), chlorogenic acids In the 0.5% by mass intake group, feed containing 0.5% by mass of chlorogenic acids (chlorogenic acids 0.5% by mass, corn oil 10% by mass, casein 20% by mass, cellulose 4% by mass, mineral 3.5 1% by mass of vitamin, 1% by mass of vitamins, 61% by mass of potato starch), 1.0% by mass of chlorogenic acids added to 1.0% by mass of chlorogenic acids (1.0% by mass of chlorogenic acids, corn oil) 10% by mass, 20% by mass casein, 4% by mass cellulose, 3.5% by mass mineral, 1% by mass vitamin, and 59.5% by mass potato starch).

(2) On the 4th week of ingestion of test meal, thoracotomy was performed under deep anesthesia with isoflurane (Abbott), a perfusion needle connected to a peristaltic pump was placed in the left ventricle, and the right atrial appendage was cut with scissors. A total of 20 mL of PBS containing heparin (5 U / mL) (Mochida Pharmaceutical) under ice cooling was perfused at a rate of about 3 mL / min, and then the brain was removed. The hippocampus was isolated from the removed brain and immediately frozen using liquid nitrogen. The frozen tissue was thawed at room temperature and then crushed with a bead homogenizer, and total RNA was extracted using RNeasy universal kit (QIAGEN). From the extracted total RNA, cDNA was synthesized using the High Capacity RNA-to-cDNA kit (Applied Biosystems). Using the obtained cDNA as a template, quantitative PCR was performed using Taqman Fast Universal PCR Master Mix (Applied Biosystems) and ABI Prism 7700 (Applied Biosystems). Primers and probes used for this PCR were purchased in advance using Taqman Gene Expression Assays (Applied Biosystems). The expression level of the Arc gene (Mm01204954_g1) was corrected by the expression level of the GAPDH gene (Mm99999999_g1). The Arc gene expression level in the control group was taken as 1, and the relative expression level of each gene in the chlorogenic acid intake group was determined.

(3) The results are shown in FIG. In the chlorogenic acid intake group, the expression of the hippocampal Arc gene increased in a dose-dependent manner. Therefore, chlorogenic acids were suggested to promote hippocampal neural circuit formation.

Claims

Arc expression promoter containing chlorogenic acids or salts thereof as active ingredients.
Neural circuit formation promoter containing chlorogenic acids or salts thereof as active ingredients.
An agent for preventing, treating or improving neurodevelopmental disorders or tuberous sclerosis comprising chlorogenic acids or salts thereof as an active ingredient.
An agent for preventing, treating, or improving visual cognitive function deterioration containing chlorogenic acids or salts thereof as an active ingredient.
Food for promoting Arc expression comprising chlorogenic acids or salts thereof as active ingredients.
Food for promoting neural circuit formation containing chlorogenic acids or salts thereof as active ingredients.
Food for prevention or improvement of neurodevelopmental disorder or tuberous sclerosis comprising chlorogenic acids or salts thereof as active ingredients.
Food for preventing or improving visual cognitive function deterioration containing chlorogenic acids or salts thereof as an active ingredient.
The chlorogenic acids are at least one of 3-CQA, 4-CQA, 5-CQA, 3-FQA, 4-FQA, 5-FQA, 3,4-diCQA, 4,5-diCQA, and 3,5-diCQA. The Arc expression promoter according to claim 1, the neural circuit formation promoter according to claim 2, the neurodevelopmental disorder or tuberous sclerosis according to claim 3, which is one or more selected from the following: An agent for preventing, treating or improving visual cognitive function deterioration according to claim 4, a food for promoting Arc expression according to claim 5, a food for promoting neural circuit formation according to claim 6, and a neurodevelopmental disorder according to claim 7. Or the food for prevention or improvement of tuberous sclerosis or the food for prevention or improvement of visual cognitive function deterioration according to claim 8.
The neurodevelopmental disorder or the tuberculous sclerosis prevention, treatment or ameliorating agent according to claim 3, or the neurodevelopmental disorder according to claim 7, wherein the neurodevelopmental disorder is pervasive developmental disorder or attention deficit / hyperactivity disorder Or food for preventing or improving tuberous sclerosis.
Use of chlorogenic acids or salts thereof for producing an Arc expression promoter.
Use of chlorogenic acids or salts thereof for producing a neural circuit formation promoter.
Use of chlorogenic acids or salts thereof for producing an agent for preventing, treating or improving neurodevelopmental disorder or tuberous sclerosis.
使用 Use of chlorogenic acids or salts thereof for the manufacture of a preventive, therapeutic or ameliorating agent for visual cognitive decline.
Use of chlorogenic acids or salts thereof for producing foods for promoting Arc expression.
Use of chlorogenic acids or salts thereof to produce food for promoting neural circuit formation.
Use of chlorogenic acids or salts thereof for producing foods for preventing or improving neurodevelopmental disorders or tuberous sclerosis.
使用 Use of chlorogenic acids or their salts to produce foods for prevention or improvement of visual cognitive decline.
The use according to any one of claims 11 to 14, wherein the agent is a preparation for oral administration.
Chlorogenic acids or salts thereof for use in promoting Arc expression.
Chlorogenic acids or salts thereof for use in promoting neural circuit formation.
Chlorogenic acids or salts thereof for use in the prevention, treatment or improvement of neurodevelopmental disorders or tuberous sclerosis.
クロロ Chlorogenic acids or their salts for use in the prevention, treatment or improvement of visual cognitive decline.
The chlorogenic acids or salts thereof according to any one of claims 20 to 23, which are orally administered.
Non-therapeutic use of chlorogenic acids or salts thereof to promote Arc expression.
Non-therapeutic use of chlorogenic acids or their salts to promote neural circuit formation.
Non-therapeutic use of chlorogenic acids or their salts to prevent or ameliorate neurodevelopmental disorders or tuberous sclerosis.
Non-therapeutic use of chlorogenic acids or their salts to prevent or ameliorate visual cognitive decline.
The non-therapeutic use according to any one of claims 25 to 28, wherein the chlorogenic acid or a salt thereof is administered orally.
A method for promoting Arc expression, comprising administering or ingesting chlorogenic acids or salts thereof in an effective amount to a subject in need thereof.
A method for promoting the formation of neural circuits, comprising administering or ingesting chlorogenic acids or salts thereof in an effective amount to a subject in need thereof.
A method for the prevention, treatment or improvement of neurodevelopmental disorder or tuberous sclerosis, in which chlorogenic acids or salts thereof are administered or taken in an effective amount to a subject in need thereof.
A method for preventing, treating, or improving a decrease in visual cognitive function, wherein chlorogenic acids or salts thereof are administered or taken in an effective amount to a subject in need thereof.
The method according to any one of claims 30 to 33, wherein the administration is oral administration.