JP2018145100A - Brain-derived neurotrophic factor production improver and food and drink - Google Patents

Abstract

An object of the present invention is to provide a brain-derived neurotrophic factor production enhancer capable of improving the production of BDNF in the body. It is also an object to provide food and drink.
A brain-derived neurotrophic factor production improver comprising caffeic acid esters as active ingredients.
[Selection figure] None

Description

  The present invention relates to an agent for improving brain-derived neurotrophic factor production and food and drink.

Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors, and plays an important role in the formation or development of the brain neural network and the maintenance of its survival. Particularly in recent years, BDNF is decreased in brain degenerative diseases, and it has been found that increasing the BDNF content in the ventricle improves the symptoms of brain degenerative diseases.
As a preparation focusing on the physiological function of BDNF as described above, Patent Document 1 describes “BDNF (brain-derived neurotrophic factor) stabilized preparation characterized by containing a surfactant”.

JP-A-10-212241

If a formulation containing BDNF is to be administered directly into the ventricle, extensive surgery is required. On the other hand, when a preparation containing BDNF is orally ingested, there is a problem that it is difficult to supply a necessary amount into the ventricle because it undergoes absorption from the digestive tract and a metabolic process.
In view of the above circumstances, it is preferable to promote the production of BDNF in the body by administering a drug rather than taking BDNF directly into the body.

  Then, this invention makes it a subject to provide the brain origin neurotrophic factor production improvement agent which can improve the production of BDNF in the body. Moreover, this invention also makes it a subject to provide food-drinks.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that caffeic acid esters have an action of promoting the production of BDNF (hereinafter also referred to as “BDNF production improving effect”), and the present invention. Has been reached.
That is, it has been found that the above-described problem can be achieved by the following configuration.

[1] A brain-derived neurotrophic factor production improver comprising caffeic acid esters as active ingredients.
[2] The brain-derived neurotrophic factor production enhancer according to [1], which promotes the production of brain-derived neurotrophic factor in intestinal epithelial cells.
[3] The [1] or [2], wherein the caffeic acid esters are at least one selected from the group consisting of monocaffeoylquinic acid, dicaffeoylquinic acid, and tricaffeoylquinic acid. Brain-derived neurotrophic factor production improver.
[4] The brain-derived neurotrophic factor production enhancer according to any one of [1] to [3], wherein the caffeic acid esters contain 3,4,5-tricaffeoylquinic acid.
[5] The brain-derived neurotrophic factor production enhancer according to any one of [1] to [4], which is for oral intake.
[6] A food and drink product that contains the brain-derived neurotrophic factor production enhancer according to any one of [1] to [5] and promotes the production of brain-derived neurotrophic factor in intestinal epithelial cells.

  ADVANTAGE OF THE INVENTION According to this invention, the brain origin neurotrophic factor production improvement agent which can improve the production of BDNF in the body can be provided. Moreover, this invention can also provide food-drinks.

Hereinafter, the present invention will be described in detail.
The description of the constituent elements described below may be made based on typical embodiments of the present invention, but the present invention is not limited to such embodiments.
In the present specification, a numerical range expressed using “to” means a range including numerical values described before and after “to” as a lower limit value and an upper limit value.

  The present inventors have discovered for the first time that caffeic acid esters improve the production of BDNF in cells, and have completed the present invention. According to the brain-derived neurotrophic factor production enhancer (hereinafter also referred to as “BDNF production enhancer”) according to an embodiment of the present invention, the production of BDNF can be improved in cells, and the produced BDNF is produced in the brain. It is expected to act on the brain through the blood flow barrier.

  The BDNF production improver according to the embodiment of the present invention contains caffeic acid esters as active ingredients. The BDNF production enhancer according to the embodiment of the present invention can promote the production of BDNF in cells. Unlike other neurotrophic factors (eg, NGF), BDNF can cross the cerebral blood flow barrier. Therefore, it is presumed that BDNF produced in the cells efficiently reaches the ventricle and can improve symptoms of brain degenerative diseases.

Caffeic acid esters that are active ingredients of the BDNF production improver according to the embodiment of the present invention are not particularly limited, but quina such as monocaffeoylquinic acid, dicaffeoylquinic acid, and tricaffeoylquinic acid. Esters of acids and caffeic acids (hereinafter also referred to as “caffeoylquinic acids”), esters of hexoses such as glucose, fructose, mannose, and galactose with caffeic acid, xylose, arabinose, ribose, etc. And esters of caffeic acid and saccharides (oligosaccharides or polysaccharides) in which a plurality of pentose and hexose sugars are combined. Of these, caffeoylquinic acids are preferred as caffeic acid esters in that they have a better BDNF production improving effect.
Caffeic acid esters may be used alone or in combination of two or more.

  Caffeoylquinic acid (hereinafter also referred to as “CQA”) includes 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), and 5-caffeoylquinic acid. Monocaffeoylquinic acid such as (5-CQA); 3,4-dicaffeoylquinic acid (3,4-DCQA), 3,5-dicaffeoylquinic acid (3,5-DCQA), and 4 Dicaffeoylquinic acid such as, 5-dicaffeoylquinic acid (4,5-DCQA); 3,4,5-tricaffeoylquinic acid (3,4,5-TCQA); Tricaffeoylquinic acid such as 5-tricaffeoylquinic acid (1,3,5-TCQA); 1,3,4,5-tetracaffeoylquinic acid (1,3,4,5-tetraCQA) Tetracaffeoylquinic acid, among others, In terms of having an excellent BDNF production improving effect, at least one selected from the group consisting of monocaffeoylquinic acid, dicaffeoylquinic acid, and tricaffeoylquinic acid is preferred, and dicaffeoylquinic acid, or , Tricaffeoylquinic acid is more preferable, tricaffeoylquinic acid is more preferable, and 3,4,5-tricaffeoylquinic acid is particularly preferable.

  The caffeic acid esters may contain a carboxyl group or a salt thereof. The basic substance for forming the salt is not particularly limited, but alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; magnesium hydroxide, calcium hydroxide, etc. Alkaline earth metal hydroxides; inorganic bases such as ammonium hydroxide; basic amino acids such as arginine, lysine, histidine, and ornithine; organic bases such as monoethanolamine, diethanolamine, and triethanolamine Of these, alkali metal or alkaline earth metal hydroxides are particularly preferred.

Caffeic acid esters can be extracted from plants. Examples of plants containing caffeic acid esters include convolvulaceae plants and asteraceae plants.
Examples of the convolvulaceae plant include sweet potato, convolvulus, morning glory, yorgao, wild rhinoceros, chrysanthemum, prunus, evolvulus, and ensai.
As for Asteraceae, Asteraceae, Achillea, Burdock, Artemisia, Aster, Buccaris, Daisies, Calendula, Ezogiku, Safflower, Cornflower, Nemophila, Shungiku, Margaret, Sea Anemone, Chicory, Mulchicore, Datura, Pythria , Murasaki Barengiku, Himejoon, Fujibakama, Tsuwabuki, Gerbera, Hachakogusa, Miyakowasle, Sunflower, Yomena, Lettuce, Senbon Yari, Chamomile, Cinellaria, Fuki, Yakon, Ginseng, Nogeshi, Ulsinia, Hyacinthiacho
As caffeic acid esters that can be used in the BDNF production improver of the present invention, those extracted from plants other than the above-mentioned plants can also be used. In addition, it does not restrict | limit especially as a method of extracting caffeic acid ester from a plant body, A well-known method can be used.

  Moreover, as said plant body, what increased content of caffeic acid ester (especially CQA) in a plant body can also be used. Examples of the method for increasing the content of caffeic acid esters in the plant include the methods described in paragraphs 0018 to 0037 of JP-A-2006-106621, and the above contents are incorporated herein. .

  Caffeic acid esters may be produced by synthesis. In this specification, the term “synthesis” means chemical synthesis and biosynthesis. A known method can be used for the synthesis of caffeic acid esters. For example, the method described in paragraphs 0009 to 0075 of JP-A-2006-74606, the method described in paragraphs 0009 to 0078 of JP-A-2015-199674, and the like can be used. Incorporated in the description.

The BDNF production enhancer according to the embodiment of the present invention is preferably used for promoting the production of BDNF in intestinal epithelial cells. Since BDNF can pass through the cerebral blood flow barrier, it is presumed that when BDNF production is promoted in intestinal epithelial cells, the produced BDNF acts on the brain more efficiently.
In addition, in order to administer the BDNF production enhancer directly into the ventricle, a large-scale operation or the like is required, whereas the BDNF production enhancer according to the embodiment of the present invention may be administered orally. Since intestinal epithelial cells promote BDNF production, the blood content of BDNF tends to increase as a result. Therefore, the BDNF production improver according to the embodiment of the present invention used for promoting the production of BDNF in intestinal epithelial cells has a more excellent effect.

  The dose and frequency of administration of the BDNF production improver according to the embodiment of the present invention vary depending on symptoms, age, body weight, dosage form, and the like. 0.1 to 500 mg / day per kg body weight is preferable, and 0.01 to 50 mg / day per kg body weight is preferable for humans. The above amount may be a single dose per day, or may be several times (for example, a total of 2 or 3 times per day).

The BDNF production improver according to the embodiment of the present invention contains caffeic acid esters as active ingredients.
The content of caffeic acid esters in the BDNF production improver is not particularly limited, but is usually preferably 15% by mass or more, more preferably 30% by mass or more, and more preferably 45% by mass or more based on the total mass of the BDNF production improver. Is more preferable. The upper limit is not particularly limited, but may be 100% by mass, often 80% by mass or less.
Moreover, as long as the BDNF production improver contains caffeic acid esters, it may contain other components as necessary. Examples of other components include excipients.

  Excipients include, for example, lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, and sodium chloride as solids, Examples thereof include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and water.

  The BDNF production improver according to the embodiment of the present invention includes a base, a surfactant, a preservative, an emulsifier, a colorant, a flavoring agent, a fragrance, a stabilizer, an antiseptic, as necessary, in addition to the excipient. Agents, antioxidants, lubricants, antibacterial agents, solubilizing agents, suspending agents, binders, disintegrating agents and the like may be contained.

  The dosage form of the BDNF production improver according to the embodiment of the present invention is not particularly limited, and examples thereof include tablets, powders, granules, capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, Examples include injections, creams, gels, lotions, and patches.

The ingestion (or administration) method of the BDNF production improver according to the embodiment of the present invention is not particularly limited, and examples thereof include inhalation, enema, eye drops, ear drops, nasal, dermal application, and oral. .
Especially, it is preferable that the BDNF production improvement agent which concerns on embodiment of this invention is an object for oral intake by the point which has the more excellent BDNF production improvement effect.
When the brain-derived neurotrophic factor production enhancer according to the embodiment of the present invention is for oral intake, the production of BDNF is easily promoted particularly in intestinal epithelial cells. Therefore, the BDNF production enhancer is more excellent in the present invention. Has an effect.

The food / beverage products which concern on 2nd embodiment of this invention are the food / beverage products for containing the said BDNF production improvement agent and promoting the production of BDNF in an intestinal epithelial cell.
In the present specification, food and drink means foods that humans ingest daily as foods, health foods that are used as foods that contribute to the maintenance and promotion of health, and animal feed. Examples of the food and drink include various foods and drinks such as beverages, confectionery, breads, and soups and their additive components; pet food such as dog food and cat food or their additive components; and the like. The method for producing these foods and drinks is not particularly limited, and known methods can be used.
Ingestion of the food or drink promotes the production of BDNF in the intestinal epithelial cells.

  The content of the BDNF production improver contained in the food and drink according to the above embodiment is not particularly limited as long as the production of BDNF is promoted in the intestinal epithelial cells, and is a guideline for food and drink per day. Although it varies depending on the amount of intake and the number of times of intake, the amount of 0.01 to 500 mg / day of body weight per kg as caffeic acid esters is preferable. The above may be the target intake amount per day, or may be several times (for example, a total of 2 or 3 times per day).

Although caffeic acid esters are contained in the plants already described, the content thereof is very small. For example, the average amount of caffeic acid esters contained in the leaf portion of sweet potato, which is said to have a high content of caffeic acid esters, is 5-CQA, 4,5-CQA, 3,5-CQA, 3, In the order of 4-CQA and 3,4,5-CQA, it is 0.45 g, 0.80 g, 1.68 g, 0.35 g, and 0.09 g per 100 g of the freeze-dried sample, respectively (Kyushu) Okinawa Agricultural Research Center Research Results Information 2001 “Total Polyphenol Content and Polyphenol Composition in Sweet Potato” http://www.naro.affrc.go.jp/org/karc/seika/kyushhu_seika/2001/001085.html) .
Here, assuming that the moisture content of the sweet potato leaves is 85 to 95%, for example, if a human with a body weight of 60 kg tries to ingest caffeic acid esters of the same level as the food and drink according to this embodiment, at least 600 g / It will be necessary to ingest potato leaves for more than a day.
On the other hand, the average daily vegetable intake by Japanese is 283.1 g according to the National Health and Nutrition Survey (2013). In view of the above, it is difficult to obtain the same effect as the food and drink according to the embodiment of the present invention with the existing food and drink. In other words, the intestinal epithelial cell is the first time with the food and drink according to the embodiment of the present invention. Thus, the effect of improving the production of BDNF is obtained.

  Hereinafter, the present invention will be described in more detail based on examples. The materials, amounts used, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the following examples.

[Test Example 1]
As intestinal epithelial cells, human colon cancer-derived intestinal epithelial cells (Caco-2 cells) were cultured in a monolayer. Also, 10 mg / mL DMSO (dimethyl sulfoxide) of 3,4,5-tricaffeoylquinic acid (TCQA), 3,5-dicaffeoylquinic acid (DCQA), and 5-caffeoylquinic acid (MCQA) ) Each solution was prepared and diluted with a medium (Dulbecco's modified Eagle medium, 10% FBS (Fetal bovine serum), 1% non-essential amino acid) so that the caffeoylquinic acid concentration was 100 μM. The resulting solution was added to each Caco-2 cell cultured in a monolayer. In addition, a solution obtained by diluting only the same amount of DMSO as the caffeoylquinic acid DMSO solution in a medium was added to Caco-2 cells as a control. Each of the Caco-2 cells thus prepared was cultured at 37 ° C. for 3 days, and the amount of BDNF produced was evaluated by ELISA (Enzyme-Linked Immuno Sorbent Assay) method. The results were evaluated according to the following criteria and are shown in Table 1.
A: The increase in BDNF production was more than 6 times the control.
B: The increase in BDNF production was more than 3 times and less than 6 times the control.
C: The increase in BDNF production was less than 3 times the control.

    In Table 1, “-” indicates that it is not subject to evaluation.

[Test Example 2]
According to the following method, 3,4,5-tricaffeoylquinic acid (TCQA) or 3,5-dicaffeoylquinic acid (DCQA) is administered to an aging promotion model mouse (SAMP8), and Morris water maze The memory learning of spatial recognition was evaluated by the test.

  Mice (both aging-promoting model mouse SAMP-8 and healthy mouse SAMR-1 were male) were obtained from Japan SLC Co., Ltd. and acclimated until the start of administration. During this period, those in which no abnormality was found were considered healthy and were used for the test. For SAMP-8, the body weight before the start of administration was used as an index, and 10 groups were grouped into 3 groups by stratified continuous randomization.

-TCQA administration group Solution 1 was prepared by preparing a 0.5% aqueous solution of sodium carboxymethyl cellulose (hereinafter CMC) so that the content of TCQA was 1 mg / mL. Next, solution 1 was orally administered to one group of SAMP-8 (10 mice) with a sonde so that the daily dose of solution 1 was 6.67 mg TCQA per kg body weight of the mouse. Administration was once a day and continued for 12 weeks (84 days).

-DCQA administration group Instead of TCQA, BDNF production improver 2 produced using DCQA was administered to one group (10 mice) of SAMP-8 under the same conditions as in the TCQA administration group.

・ Non-administration group (SAMP-8)
It replaced with BDNF production improvement agent 1, and it administered to 1 group (10 animals) of the said SAMP-8 on the same conditions as the TCQA administration group except having used CMC0.5% aqueous solution.

Non-administration group (SAMR-1)
A CMC 0.5% aqueous solution was added to SAMR-1 (10 mice) under the same conditions as in the non-administration group (SAMP-8) except that healthy mice (SAMR-1) were used instead of aging promoting model mice (SAMP-8). Administered.

All mice were subjected to the Morris water maze test at 81-84 days after administration. The water maze was 90 cm in diameter and 60 cm in height manufactured by Bio Research, and water was clouded with a harmless paint. The water maze was divided into four virtual quadrants (east, west, south, and north), and a circular platform was submerged to a depth of about 1.0 cm from the water surface and installed in the center of the north quadrant. As a clue outside the maze, a black mark was placed on the wall of the water maze.
The time to reach the platform installed in the water maze was measured continuously for 4 days (once / day). Each measurement was started from any quadrant except the north quadrant with the mouse face facing the outer edge of the water maze. When the mouse reached the platform and rested for 10 seconds, it was judged as “escape” and the measurement was terminated. In addition, when the mouse could not find the platform within 120 seconds, the mouse was guided to the platform and held there for 10 seconds, and then finished (the time required for “escape” in this case was evaluated as 120 seconds) ).
The results were evaluated according to the following criteria and are shown in Table 2.

A: Time required for “escape” in the test on the 84th day of administration is equivalent to that of healthy mice B: Time required for “escape” in the test on the 84th day of administration is inferior to that of healthy mice, but the non-administered group (SAMP -8) Improvement is observed C: Time required for “escape” in the 84th day of administration is equivalent to that in the non-administration group (SAMP-8)

  After all the tests were completed, blood of an aging accelerated model mouse (SAMP-8) was collected, and the blood BDNF content was measured by ELISA. The results were evaluated according to the following criteria and are shown in Table 2.

A: Compared with the non-administered group (SAMP-8), the rate of increase in the blood BDNF content was 10% or more.
B: Compared with the non-administration group (SAMP-8), the increase rate of the blood BDNF content was 5% or more and less than 10%.
C: The rate of increase in blood BDNF content is less than 5% compared to the non-administered group (SAMP-8)

  In Table 2, “-” indicates that it is not subject to evaluation.

Claims (6)

  A brain-derived neurotrophic factor production improver comprising caffeic acid esters as active ingredients.   The brain-derived neurotrophic factor production enhancer according to claim 1, for promoting production of brain-derived neurotrophic factor in intestinal epithelial cells.   The brain-derived nerve according to claim 1 or 2, wherein the caffeic acid ester is at least one selected from the group consisting of monocaffeoylquinic acid, dicaffeoylquinic acid, and tricaffeoylquinic acid. Nutritional factor production improver.   The brain-derived neurotrophic factor production enhancer according to any one of claims 1 to 3, wherein the caffeic acid esters contain 3,4,5-tricaffeoylquinic acid.   The brain-derived neurotrophic factor production enhancer according to any one of claims 1 to 4, which is for oral intake.   A food or drink comprising the brain-derived neurotrophic factor production enhancer according to any one of claims 1 to 5 and promoting production of brain-derived neurotrophic factor in intestinal epithelial cells.