JPH07143862A - Functional food having cerebral function-improving effect - Google Patents

Abstract

PURPOSE:To provide a functional food having cerebral function-improving effects such as a learning ability-strengthening effect, a mneme-strengthening effect and a dementia-preventing effect, excellent in safety, and useful for the therapy of Alzheimer's disease, etc., by adding a cerebral function-improving composition containing docosahexaenoic acid to a food. CONSTITUTION:This functional food is produced by adding a cerebral function- improving composition containing one or more kinds of the ester, amide, triglyceride and phospholipid of docosahexaenoic acid or its derivative as an active ingredient to a food. The docosahexaenoic acid derivative is preferably the triglyceride or phospholipid extracted from natural oils and fats.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a substance having an effect of improving brain function, that is, a brain function improving composition, and learning ability enhancement, memory enhancement and dementia embodied using the brain function improving composition. The present invention relates to a functional food having an effect of improving brain function such as prevention.

[0002]

2. Description of the Related Art In recent years, many studies and studies have been conducted in various fields on substances and methods that act on brain function improvement such as learning ability, memory ability, dementia, etc., and the results have been announced little by little. According to it, the methods that have been studied to improve the brain function are the brain energy metabolism improvement method that makes the brain cells absorb nutrients efficiently and activates the function of the cells, and the blood circulation of the brain is improved. It is broadly divided into cerebral circulation improvement methods that try to supply necessary nutrients and oxygen to brain cells sufficiently, and research is being conducted on drugs and therapeutic methods having their respective pathological actions, and brain disorders ( Dementia) is recognized as being divided into two types: Alzheimer's dementia caused by nervous system disorders and cerebrovascular dementia caused by cerebrovascular disorders, and drugs and treatment methods corresponding to each type. Research seems to be underway.

However, it is difficult to say that the researches in this field have been fully studied and elucidated both theoretically and practically, and in general, remarkable therapeutic effects have been confirmed and they have been put to practical use. There are few substances and medicines.

As a memory enhancer and a therapeutic agent for senile dementia which have been recently announced, for example, a memory enhancer containing 2- (7-indenyloxymethyl) morpholine or an acid addition salt thereof as an active ingredient (JP-A-56) No. 123,915), a therapeutic agent for Alzheimer's disease comprising a salt of deferoxamine to which a pharmaceutically acceptable acid is added (JP-A-58-12123), H-X-Y-OH (wherein X and Y is different and means Tyr or Arg.) A memory-improving agent containing a dipeptide compound represented by Tyr or Arg (JP-A-58-170719).
No.), 3.7-dihydro-3-methyl-1- (5-oxohexyl) -7-propyl-1H-purine-2.6-dione as an active ingredient, a therapeutic agent for memory disorders (JP-A-61-61 No. 229823) and the like, and PCT international application (patent application publication number 61-501564) as a treatment method for memory diseases of the elderly.
Furthermore, a pharmaceutical composition for treating senile or senile dementia contains a lithium compound and / or an essential fatty acid or a salt thereof (JP-A-62-62).
-185018).

[0005]

With the recent aging of society, there is a strong demand for development of such substances and drugs not only medically but also socially. In response to such a demand, conventionally, various memory enhancing agents and senile dementia therapeutic agents as described above, and pharmaceutical compositions have been developed, but the cause of Alzheimer's disease and the mechanism of the brain have not been clarified. , Because there is no substance that has a marked therapeutic effect,
In practice, it was not always satisfactory.

In particular, JP-A-62-185018 (Holobin Patent) discloses a lithium compound, an essential fatty acid and a salt thereof as a pharmaceutical composition for treating senile or senile dementia. The type of lithium salt is described as a group, as long as the lithium compound is a lithium salt. The types of essential fatty acids or salts thereof are also specifically described as a group. However, the technical idea in the invention is that "dementia such as Alzheimer's disease is related to the imbalance of conversion of essential fatty acids (EFAs) into prostaglandins (PGs), and to PGs of EFAs. Of the lithium compounds and their salts can act to correct the imbalance of conversion of EFAs to PGs. Regarding the essential fatty acid group and its salt, "in addition to acting as a precursor of PG biosynthesis, E
FAs are biologically important in their own right, and EFA deficiency is responsible for certain effects of dementia such as Alzheimer's disease. Is a vague view. That is, the present invention relates to the imbalance of conversion of EFAs into PGs as a common property of these substances, not to the specific pharmacological actions of individual substances of the lithium compound group and essential fatty acid group. On the basis of the vague speculative view that substances belonging to the group may have some effect on dementia such as Alzheimer's disease (there is no description demonstrating a medicinal or pharmacological action effect),
It is composed. However, from other researchers, among the essential fatty acids, ω-6 series fatty acids (dihomogamma linolenic acid, arachidonic acid, gamma linolene) and ω-3 series fatty acids (eicosapentaenoic acid, docosahexaenoic acid, alpha linolenic acid) were identified. Is a completely different physiological effect,
Since it has been reported that it has a pharmacological action, and that excessive intake of ω-6 series fatty acids causes adverse effects, the disclosure content of the horobin patent that does not take these into consideration and its usefulness I have doubts about sex.
Further, docosahexaenoic acid is also described in one of the essential fatty acid groups, but in that case also, it is expected that a vague effect caused by the common general characteristics of docosahexaenoic acid as an essential fatty acid group is caused. , There is no description demonstrating a medically or pharmacologically recognizable effect. Furthermore, no mention is made of the effect of docosahexaenoic acid on improving brain function, which is unique as a substance, and the physiological and pharmacological effects on dementia.

The present inventors have reported that with aging, the function of the cerebrum is decreased while the fatty acid composition of the brain is also changed, and the fatty acid composition of the brain is affected by the ingested lipid. However, docosahexaenoic acid is
Since it is actively retained in the brain, and especially docosahexaenoic acid is selectively concentrated in the phospholipids of the brain membrane, it was considered that it plays a major role in the function of the central nervous system. And, from these, paying attention to this docosahexaenoic acid, while studying its physiological activity and drug activity, as a result of docosahexaenoic acid or its derivatives in animal tests, surprisingly powerful learning ability improvement, memory improvement, We found the fact that it has a dementia preventive and therapeutic effect. The pathological effects of docosahexaenoic acid, such as learning ability improvement, memory improvement, dementia prevention and treatment effect, are novel findings that have not yet been reported to academic societies. Moreover, it differs from the extremely vague speculative view that "the essential fatty acid group is responsible for certain effects of dementia such as Alzheimer's disease" disclosed in the above-mentioned Holobin Patent (JP-A-62-185018). However, the fact that the physiological action and pharmacological action of a specific substance called docosahexaenoic acid have been clarified by behavioral pharmacological verification by a maze test is a finding that has great scientific and academic significance. Therefore, both findings are scientifically
From a technical point of view, there are marked differences in their ideas, levels, and contents, and they are essentially different.

[0008] The present inventor has obtained new scientific knowledge on the brain function improving effect of docosahexaenoic acid obtained by such behavioral pharmacological verification, and docosahexaenoic acid is found in many oils obtained from herrings and sardines. Focusing on the fact that it is contained as a part of the composition components of natural foods, including that it is contained, and the fact that safety has been confirmed empirically, this is due to the fact that drugs that have the effect of improving brain function I got the idea that it is extremely useful as a food. Then, the inventor, based on the idea, a brain function improving composition containing docosahexaenoic acid according to the present invention as an active ingredient, and a functional food having a brain function improving effect such as learning ability enhancement, memory enhancement, and dementia prevention. It is an embodiment.

[0009]

In the present invention, docosahexaenoic acid (hereinafter referred to as DHA) found and useful as an active ingredient having an effect of improving brain function is C22H.
32O2, molecular weight 328.49, 4,7,10,13,
It is a linear hexaenoic acid having 22 carbon atoms and having a cis double bond at the 16th and 19th positions, and has a melting point of -44.5 to -44.
It is 1 ° C. This is abundantly contained in fish oils such as herrings and sardines, and is also detected as phospholipids in mammals from various organs such as the liver, but it is characteristically contained in large amounts particularly in the cerebrum. In recent years, it has been found that the DHA, together with eicosapentaenoic acid (EPA), has a physiological action such as preventing hypercholesterolemia by lowering plasma cholesterol and suppressing platelet aggregation ability. , EPA, and their esters and triglycerides are attracting attention as being effective in the prevention and treatment of thrombotic diseases such as myocardial infarction and cerebral infarction. However, it has not been reported yet about the pharmacological action that this DHA has the effects of improving learning ability, improving memory ability, and preventing and treating dementia. The present inventor has found from the experimental results that the DHA is effective for improving the learning ability, improving the memory ability, and preventing and treating senile dementia. It does not embody products such as food. Hereinafter, the above-mentioned pharmacological effects will be described in detail based on experiments. Specifically, an experiment for improving the learning ability and the memory improving effect is performed by using rats fed with a feed containing at least one or more of docosahexaenoic acid derivatives as an active ingredient and a control group with the Y maze to improve learning ability and memory ability. It is a thing.

That is, in order to examine whether DHA has an effect of improving learning ability, Wistar rats, a diet containing DHA ethyl ester as an active ingredient, and a Y maze were prepared, and the rats were placed in the Y maze. After putting it in, the following experiment was conducted. First, the Wistar rat
A total of 80 male Wistar 4-week-old rats were prepared,
This is divided into 4 groups of 20 animals each, and is divided into a test group 3 and a control group 1 according to the kind of feed to be fed for a predetermined period.

Next, the test feed divided into the test group 3 and the control group 1 in the above experiment is a feed compounded as follows. In other words, the compounded feed used in the experiment is composed of the raw materials having the compounding ratios shown in Table 1, and the fatty acid composition of the fat, which is the constituent component, has three different tests as shown in Table 2. Try to use feed.

[0012]

[Table 1]

[0013]

[Table 2]

<Experimental Example 1. > Experiments to improve learning ability and memory of "DHA ester group". 20 male 4-week-old Wistar rats are preliminarily bred for 1 week and then bred with a test feed (E test feed group in Table 2) mixed with DHA-containing ethyl ester for 11 weeks. After that, the rats are put into an individual cage so that the body weight of the rats becomes 85% and Shaping is performed for 2 weeks before the main test. Hereinafter, the group of rats thus fed with the E test feed will be referred to as "DHA ester group".

The experiments were carried out 5 times a day for 20 animals per animal in the DHA ester group (18 experiments in total per day).
It was carried out for a day and measured. In the experimental method, the animal is first placed at the starting point. Then, the animal starts exploratory behavior and reaches the selection point after a while, and it chooses whether there is a lighted side with food or a side without light or food. The animals that could reach the side with food within 30 seconds from the starting point were defined as correct answers, and those that took longer and those that entered the side without food were incorrect. For the first time, the animal can see only the light at the selected point in the Y maze and learns that it can take food to the lighted side, and the memory ability is examined by repeating this every day. As a control group, rats fed with a control feed (control feed group in Table 2) in which safflower oil and olive oil were mixed instead of DHA were used.

The results are shown in FIGS. 1 to 3. First
As shown in the figure, the positive reaction rate of the DHA ester group reached 75% on the 18th day from the start of the experiment, which was extremely higher than that of the control group (correct reaction rate).

Further, FIG. 2 shows the changes in the reaction in the DHA ester group and in FIG. 3 in the control group. Initially, both groups prefer nocturnal nature, so that R- (number of incorrect responses) is better. R +
(Number of correct responses), but 5 for DHA ester group
While R- decreased significantly around the day, R + increased significantly, whereas R- hardly decreased in the control group, and thus the correct answer rate did not increase so much. In other words, the DHA ester group learns to get food if it goes to the side of the light earlier than the control group, and remembers it for many days. From the above,
It was found that the "DHA ester group" strongly enhances the learning effect and the memory ability in the light-dark discrimination feeding behavior performed using the Y maze.

<Experimental example 2. > Experiments to improve learning ability and memory ability of "DHA triglyceride group". Diet containing Wistar rats and DHA-containing triglyceride as an active ingredient (T test diet group in Table 2)
And a Y maze were prepared, the rat was placed in the Y maze, and the following experiment was performed. That is, 20 4-week-old male Wistar strain rats are preliminarily bred for 1 week and then bred with a test feed containing DHA-containing triglyceride as an active ingredient for 11 weeks. After that, the rat weighs 85 for two weeks.
% -Shap-pi in individual cages
ng was performed before the main test. Below, like this,
The group of rats fed with the test feed (T test feed group in Table 2) is referred to as "DHA triglyceride group".

The experiment was carried out once for each of the DHA triglyceride groups, 5 times a day for 20 animals (total of 100 times a day).
This was measured for 8 days. The method of the experiment is the same as in Experimental Example 1. An experiment was conducted in the same manner as in. The results are shown in FIGS. 4 to 6. As shown in FIG. 4, the positive reaction rate of the DHA triglyceride group reached 74% on the 18th day from the start of the experiment, and the control group (positive reaction rate).
The reaction rate was extremely higher than that of the above.

Further, as shown in FIGS. 5 and 6,
Initially, R- (number of incorrect responses) is R + in both groups
It is higher than the number of correct responses, but in the control group, R- decreases from around 10 days, whereas in the "DHA triglyceride group", R- decreases from around 6 days and R +
Will increase significantly. In other words, the DHA group learns that if they go to the side of the light earlier, they will get food, and they will remember it for days. That is,
Even when DHA-containing triglyceride is used as an active ingredient, D
Similar to the case where HA-containing ethyl ester was used as the active ingredient, the learning effect was strongly enhanced and the memory effect was enhanced in the light-dark discrimination feeding behavior performed using the Y maze.

<Experimental example 3. > Experiments to improve learning ability and memory of "DHA phospholipids". 20 male 4-week-old Wistar rats were preliminarily bred for 1 week and then bred with a test feed containing DHA-containing phospholipid as an active ingredient for 11 weeks, and then the rat was weighed 85% for 2 weeks. Shap by putting it in an individual cage
Ping before performing the main test. Hereinafter, the group of rats thus fed with the test feed is referred to as "DHA phospholipid group". In the experiment, 20 animals were not tested for 18 days (total of 100 experiments per day) at a rate of 5 times a day for each animal in the DHA phospholipid group, and this was measured. The method of the experiment is the same as that of the first experimental example.

The results are as shown in FIGS. 7 to 9. Also in this case, the positive reaction rate of the DHA phospholipid group reached 73% on the 18th day from the start of the experiment, which is extremely higher than that of the control group (positive reaction rate). In addition, as shown in FIGS. 8 and 9, initially, R- (number of incorrect responses) was higher than R + (number of correct responses) in both groups, but the control group started from around 10th day. R-
On the other hand, in the DHA phospholipid group, R- decreases and R + increases significantly from around the 4th day.
In other words, the DHA phospholipid group learns that if they go to the side of the light earlier, they will get food, and they will remember it for days. In other words, in the case of DHA-containing phospholipids, as in the case of using DHA-containing triglyceride or DHA-containing ethyl ester as the active ingredient,
The learning effect in the light-dark discrimination feeding behavior performed using the Y maze was strongly enhanced, and the effect of enhancing the memory was obtained.

<Experimental Example 4. > Measurement of platelet aggregation ability. Blood was collected from 10 rats in each of the DHA ester group and the control group that had been subjected to the learning ability improving effect test for 18 days using the Y maze, and the blood was measured as follows. 9 volumes of blood collected from rat heart and 1 volume of 3.8% sodium citrate were mixed and spun at 1000 rpm for 5 minutes in a centrifuge.
In addition, the supernatant was washed with platelet rich plasma (Platelet Ri).
ch Pla-sma; R. P. Called. ), And this P. R. P. Platelet count of about 20-4
It was adjusted to 0 × 10 4 pieces / ml. In addition, Platelet Poor Plasma
a; hereinafter P. P. P. Called. ) Is the same centrifuge 3000
Spinning was carried out for 15 minutes, and the supernatant was used as a blank. For the measurement, an automatic platelet aggregometer AA-100 (sysmex) manufactured by Toa Medical Electronics Co., Ltd. was used.
Adenosine diphosphate (ADP) at a concentration of 1 μM was used as an inducer. The results are shown in Table 3 and FIG. 10 below.

[0024]

[Table 3]

That is, it is easily conceivable that the DHA ester group in the test section can prevent the formation of thrombus by suppressing the platelet aggregation, as compared with the target group in both the primary aggregation and the secondary aggregation. As described above, dementia is classified into two categories, that is, Hartzheimer's dementia and cerebrovascular dementia caused by cerebrovascular disorder, according to the causal classification.
Since HA prevents thrombus formation, it has been clarified that it has an effect on the prevention and treatment of cerebrovascular dementia.

It should be noted that, when DHA-containing triglyceride is used as an active ingredient and when DHA-containing phospholipid is used as an active ingredient, the results of separate experiments show that the blood has a similar preventive and therapeutic effect to the above measurement results. There was found. As described above, the present invention is a composition containing at least one or more of docosahexaenoic acid or a derivative thereof as an active ingredient, and has the effect of improving brain function even as a drug or a functional food. It was found that not only the learning ability-enhancing effect and the memory-enhancing effect, but also the effect of preventing and treating dementia and improving brain function.

Therefore, the scope of the invention that the inventor desires to obtain a patent for the present invention is as follows.

The first invention to be granted a patent is a brain function improving effect characterized by mixing a brain function improving composition containing docosahexaenoic acid or a derivative thereof as an active ingredient in a food. It is a functional food having.

A second invention for which a patent is sought is a brain function improving composition in which the docosahexaenoic acid derivative described in the first to sixth inventions is a phospholipid or triglyceride extracted from natural fat or oil, and learning ability. It is a potentiator, a memory enhancer, a dementia preventive agent, a dementia therapeutic agent, or a functional food having a brain function improving effect.

A third invention for obtaining a patent is a brain function improving composition, wherein the docosahexaenoic acid derivative described in the first to sixth inventions is an amide or an ester obtained by alcoholysis. It is a capacity enhancer, a memory enhancer, a dementia preventive agent, a dementia therapeutic agent, or a functional food having a brain function improving effect.

The above-mentioned docosahexaenoic acid used in the present invention can be used not only as the acid itself but also as an ester, amide, phospholipid, triglyceride derivative or the like.

Further, preferred esters include esters with polyhydric alcohols such as aliphatic triglycerides and esters with lower alkyl alcohols such as methanol and ethanol.

The docosahexaenoic acid and its derivatives according to the present invention can enhance learning ability, memory ability, and dementia prevention as they are, but an oil and fat containing docosahexaenoic acid in a high concentration is sufficient and functional. To make a food, it may be added in consideration of the balance of the content of docosahexaenoic acid and the flavor. Since docosahexaenoic acid and its derivatives can be treated in the same manner as food fats and oils, various foods containing fats and oils, for example, margarine, mayonnaise, dressings, butter, seasoning oil, processed marine products, meat products, etc. It's easy to eat.

[0034]

EXAMPLES Next, examples of the functional food of the present invention will be shown.
Functional food containing docosahexaenoic acid according to the present invention may be fat or oil containing docosahexaenoic acid in an amount of 10% or more, but for the enhancement of docosahexaenoic acid,
Oil containing 18% or more is desirable.

(Margarine containing docosahexaenoic acid) * [Combined example] Liquid oil 32.3% 25% DHA acid oil 10.0% Hardened oil 42.3% Monoglyceride 0.25% Lecithin 0.1% Flavor 0.044% Added water 12.566% Skim milk powder 1.0% Dietary salt 1.4% Vitamin E 0.04% Total 100.00%

(Mayonnaise containing docosahexaenoic acid) * [Composition example] Egg yolk 8.0% Salad oil 70.0% 25% DHA oil 10.0% Vinegar 11.0% Salt 0.8% Seasoning 0.2% Total 100.00% In addition, functional foods The form is not limited to these foods.

"Effect of the present invention" The present invention, as described above, is an ester of docosahexaenoic acid or a derivative thereof,
When ingested into the human body by eating a food containing a brain function improving composition containing at least one or more of amides, triglycerides, and phospholipids as an active ingredient, the active ingredient causes physiological action and enhances learning ability. As a result, memory capacity is enhanced, and dementia caused by brain damage is prevented. That is, the functional food obtained by mixing the docosahexaenoic acid or the derivative thereof according to the present invention and increasing the content thereof from the ordinary content has the functionality to be smarter than the food produced by the conventional method. It will be a high value-added product as food.

[Brief description of drawings]

FIG. 1 is an experimental example 1 according to the present invention. FIG. 7 is a graph showing the learning process (correct reaction rate%) of the Y maze light / dark discrimination food feeding behavior experiment.

FIG. 2 Experimental Example 1. Is a graph showing the number of correct reactions and the number of incorrect reactions of the DHA ester group in

FIG. 3 Experimental Example 1. It is a graph showing the number of correct responses and incorrect responses of the control group in,

FIG. 4 Experimental Example 2. In the graph showing the learning progress (positive reaction rate%) of the Y maze light and dark discrimination feeding experiment

FIG. 5: Experimental example 2. Is a graph showing the number of correct responses and the number of incorrect responses of the DHA triglyceride group in

FIG. 6 is an experimental example 2. It is a graph showing the number of correct responses and incorrect responses of the control group in,

FIG. 7: Experimental example 3. In the graph showing the learning progress (positive reaction rate%) of the Y maze light and dark discrimination feeding experiment

FIG. 8: Experimental example 3. Is a graph showing the number of correct responses and the number of incorrect responses of the DHA-containing phospholipid group in

FIG. 9: Experimental example 3. It is a graph showing the number of correct responses and incorrect responses of the control group in,

FIG. 10: Experimental Example 4. 3 is a graph showing the results of measuring the platelet aggregation ability using the automatic platelet aggregation measuring device in FIG.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Reference number within the agency FI Technical indication location A61K 31/23 9454-4C 31/66 9454-4C 38/00 C11B 7/00 2115-4H 11/00 2115- 4H C11C 3/00 2115-4H // C07C 57/03 (72) Inventor Kazuki Maruyama 3-2-9 Tsukishima, Chuo-ku, Tokyo Taiyo Fisheries Co., Ltd., Ocean Research Institute (72) Inventor Michio Nonaka Central Tokyo 3-2-9 Tsukishima, Ward Taiyo Fisheries Co., Ltd.

Claims (1)

[Claims] 1. A learning ability enhancing method, characterized in that a brain function improving composition containing at least one or more of an ester, an amide, a triglyceride and a phospholipid of docosahexaenoic acid or a derivative thereof as an active ingredient is mixed in food. A functional food having a brain function improving effect such as memory enhancement and dementia prevention. 1. A functional food having a cerebral function improving effect such as learning ability enhancement, memory enhancement, dementia prevention, etc., wherein the docosahexaenoic acid derivative according to claim 1 is a triglyceride or phospholipid extracted from natural fats and oils. 1. A derivative of docosahexaenoic acid according to claim 1, which is an amide or an ester obtained by alcoholysis, to enhance learning ability, enhance memory, prevent dementia,
Functional foods that have the effect of improving brain function such as.