JPH01279827A - Cerebral function improver, learning ability enhancer, mneme enhancer, preventive agent or remedy for dementia or functional food having cerebral functional improving effect - Google Patents

Abstract

PURPOSE:To obtain a cerebral function improving composition, containing docosahexaenoic acid or a derivative thereof as an active ingredient, having cerebral function improving effects and useful for enhancing learning ability, mneme and preventing and treating senile dementia. CONSTITUTION:A composition containing at least one or more of docosahexaenoic acid abundantly contained in fish oils obtained from herrings, sardines, etc., and derivatives thereof as an active ingredient. The docosahexaenoic acid is a straight-chain hexaenoic acid, having properties of C22H32O2, 328.49 molecular weight and -44.5--44.1 deg.C melting point and detected from phospholipids of the above-mentioned fishes or mammals, bovine liver, etc., with physiological action of dissolving cholesterol together with eicosapentaenoic acid and discharging the cholesterol to the outside of bodies. The docosahexaenoic acid has also pharmacological action of improving mneme, learning ability, etc., and useful.

Description

Detailed Description of the Invention "Prior art in the field of industrial application" The present invention is embodied using a substance that has the effect of improving brain function, that is, a brain function improving composition, and the brain function improving composition. The present invention relates to learning ability enhancers, memory enhancers, dementia preventive agents, dementia therapeutic agents, and functional foods having brain function improving effects.

``Conventional Technology J'' In recent years, many studies and studies have been conducted in various fields regarding substances and methods that improve brain functions such as learning ability, memory, and dementia, and the results are being announced little by little. According to the research, the method to improve brain function that has been studied so far is to make brain cells absorb nutrients more efficiently.
It is broadly divided into methods for improving brain energy metabolism, which activates cell function, and methods for improving cerebral circulation, which improves blood circulation in the brain to supply sufficient nutrients and oxygen to brain cells. Research is progressing on drugs and treatments that have positive effects, and regarding brain disorders (dementia), there are two types of dementia: Alzheimer's dementia caused by nervous system disorders,
It is recognized that it is divided into two types: cerebrovascular dementia caused by cerebrovascular disorders, and research on drugs and treatments for each type is currently underway.

However, research in this field is still far from being fully researched and elucidated, both theoretically and in terms of practical application. There are few drugs.

Examples of memory enhancers and senile dementia therapeutics that have been announced in recent years include: ■Memory enhancers containing 2-(7-inzonyloxymethyl)morpholine or its acid addition salt as an active ingredient (Japanese Patent Application Laid-Open No. 1983-1999); No. 123915), ■ A therapeutic agent for Alzheimer's disease characterized by comprising a salt of deferoxamine to which pharmaceutically acceptable licoric acid has been added (Japanese Patent Application Laid-Open No. 58-1
2123), ■Memory improving agent containing a dipeptide compound represented by H-X-Y-OH (in the formula, x and Y are different and mean Tyr or Arg) (Japanese Patent Application Laid-Open No. 58-17
0719), ■3,7-sihydro-3-methyl-1-
There is a treatment for memory disorders containing (5-oxohexyl)-7-broby-IH-purine-2,6-sion as an active ingredient (Japanese Patent Application Laid-open No. 61-229823), and other treatments include: ■ Treatment of memory disorders in the elderly. To some extent, the law has been published by the PCT International (Patent Application Publication No. 501564/1983).

With the aging of society in recent years, the development of such substances and drugs is desired not only medically but also socially.

"Problems to be Solved by the Invention" The present invention addresses the above-mentioned needs by improving brain function,
Through this, we aim to realize a functional food that enhances learning ability, enhances memory, prevents and treats senile dementia, and has the effect of improving brain function.

While researching the physiological and drug activities of docosahexaenoic acid, which is abundantly contained in oils obtained from herrings and sardines, the present inventors found that this substance or its derivatives were unexpectedly found in animal tests. It also has strong learning ability improvement, memory improvement, dementia prevention and treatment effects, and these things exist as part of the composition of food in the natural world, and their safety has been empirically confirmed. , etc., and found that it is extremely useful as a drug or food that has an effect of improving brain function, and completed the present invention.

``Means for Solving Problems j'' In the present invention, docosahexaenoic acid (hereinafter referred to as DH
It is called A. ) is C*tHsxO□, molecular weight 328.4
9 is a linear hexaenoic acid having 22 carbon atoms and having cis-double bonds at positions 4, 7, 10, 13° and 16.19, and its melting point is -44°5 to -44.1°C. This is contained in large amounts in fish oils such as herring and sardines, and
It has been detected in phospholipids of mammals, bovine liver, etc.
In recent years, it has been discovered that DHA, along with eicosapentaenoic acid (EPA), has the physiological effect of dissolving cholesterol and removing it from the body. It is attracting attention as being effective in the prevention and treatment of thrombotic diseases.

However, the pathological effects of DHA, such as improving learning ability, improving memory, and preventing and treating dementia, have not yet been reported.

The present inventor has found through experimental results that the DHA is effective in improving learning ability, improving memory, and preventing and treating senile dementia. It is intended to embody products such as food and food products. Hereinafter, the above pharmacological effects will be explained in detail based on experiments. Specifically, rats raised on a diet containing at least one type of docosahexaenoic acid derivative as an active ingredient are used together with control rats to conduct an experiment to determine the effects of improving learning ability and memory using a Y-maze. It is something.

That is, in order to examine whether DHA has an effect on improving learning ability, we prepared Wistar rats, feed containing DHA ethyl ester as an active ingredient, and a Y-maze.
The rats were placed in a Y-maze, and the following experiment was conducted.

First, the Wistar rat is a male Wistar rat 4
A total of 80 adult rats were prepared and divided into 4 groups of 20 rats each, with test group 3 and control group 1 depending on the type of feed to be fed for a predetermined period.

Next, in the above experiment, the test feed that was divided into test group 3 and control group 1 was a feed containing the following ingredients. In other words, the compound feed used in the experiment is composed of raw materials with the mixing ratio shown in Table 1, and the fatty acid composition of the fat that is its constituent component is different between the three types of tests as shown in Table 2. Try to use feed.

Table 1: Mixing ratio of each component in feed <Experimental Example 1> Experiment on the learning ability improvement and memory ability improvement effect of the "DHA ester group".

Twenty 4-week-old male Twinster rats were preliminarily fed for one week and then fed with a test feed mixed with DHA-containing ethyl ester (test feed group E in Table 2) for 11 weeks. Thereafter, the rats were placed in individual cages for 2 weeks so that their body weight was 85%, and Shapping was performed before the main test. Hereinafter, the group of rats fed with the E test diet will be referred to as the "DHA ester group".

The experiment was conducted on 20 animals in the DHA ester group, 5 times a day for 18 days (a total of 100 experiments on -day).
This was measured.

In this experimental method, the animal is first placed at a starting point.

Then, the animal begins to explore, and after a while it reaches a selected point, where it chooses either the side with lights and food, or the side with no lights and food, and within 30 seconds from the starting point it chooses the side with food. The animal that was able to reach the target was considered correct, and the animal that took longer than that or went to the side that was not relevant was considered incorrect. Animals see only the light for the first time at the selected point in the Y-maze, and learn that they can take food from the side with the light, and repeat this every day to test their memory. In addition, the control group used rats that were fed and raised with a control feed containing a mixture of safflower oil and olive oil instead of DHA (control feed group in Table 2).

The results are shown in FIGS. 1 to 3.

As shown in Figure 1, the correct reaction rate of the DHA ester group reached 75% on the 18th day after the start of the experiment, showing an extremely high correct reaction rate compared to the control group (correct reaction rate). Ta.

In addition, as shown in Figures 2 and 3, R- (number of incorrect responses) was initially higher than R'' (number of correct responses) in both groups, but the control group From TarikaraR
- decreases, whereas in the DHA ester group, R- decreases and Ro increases significantly from around the 5th cycle. In other words, compared to the control group, the animals in the DHA ester group learned that if they went to the light earlier, they would receive food, and they remembered this for many days.

From the above, it was found that the "D HA ester group" strongly enhanced the learning effect and enhanced memory in the light/dark discrimination feeding behavior performed using the Y maze.

<Experimental example 2. 〉Experiment on the learning ability improvement and memory improvement effect of “DHA triglyceride group”.

Wistar rats and feed mixed with DHA-containing triglyceride as an active ingredient (T test feed group in Table 2)
A Y-maze and a Y-maze were prepared, and the rat was placed in the Y-maze, and the following experiment was conducted.

That is, 20 4-week-old male twin-star rats were preliminarily fed for one week, and then fed for 11 weeks with a test feed containing DHA-containing triglyceride as an active ingredient. Thereafter, the rats were placed in individual cages for 2 weeks so that their body weight was 85%, and then subjected to Shapping, and then the main test was conducted. Hereinafter, the group of rats fed with the test feed (T test feed group in Table 2) will be referred to as the "DHA triglyceride group."

The experiment was conducted on 20 animals in the DHA triglyceride group five times a day for 18 days (a total of 100 experiments on -day), and the results were measured.

The method of the experiment is as described in Experiment Example 1 above. The experiment was conducted in a similar manner.

The results are shown in FIGS. 4 to 6.

As shown in Figure 4, on the 18th day after the start of the experiment, the correct reaction rate of the DHAt-liglyalide group reached 7.4%, which was significantly higher than that of the control group (correct reaction rate). The correct reaction rate was shown.

In addition, as shown in Figures 5 and 6, initially R- (number of incorrect responses) was higher than R゛ (number of correct responses) in both groups, but the control group In contrast, in the "DHAJ liglyceride group," R- decreases from around 6 cycles, and R''' increases significantly.In other words, the DHA group moves toward the light faster. If you go there, you will learn that you will receive food, and you will remember this for many days.In other words, even if DHA-containing triglyceride is used as an active ingredient, DHA-containing ethyl ester is used as an active ingredient. Almost in the same way as if
In the light/dark discrimination feeding behavior performed using the Y-maze, the learning effect was strongly enhanced and the effect of enhancing memory was obtained.

<Experimental example 3. 〉Experiment on the effect of “DHA phospholipid group” on improving learning ability and memory ability.

Twenty 4-week-old male Twinster rats were preliminarily bred for one week, then fed with a test diet containing DHA-containing phospholipid as an active ingredient for 11 weeks, and then for 2 weeks until the rats' body weight was 85%. Place in individual cage for 5 haps
The main test was conducted after p i ng.Hereinafter, a group of rats fed with the test diet was subjected to "DH" test.
A phospholipid group.

The experiment was conducted for 20 animals in the DHA phospholipid group, 5 times a day for 18 days (total of 100 experiments on -day), and the results were measured.

The experiment was conducted in the same manner as in Experimental Example 1 above.

The results are shown in Figures 7 to 9. In this case as well, on the 188th day after the start of the experiment, the correct reaction rate of the DHA phospholipid group reached 73%, and the control group (positive reaction rate) reached 73%. The positive reaction rate is extremely high compared to the reaction rate (reaction rate). Also,
As shown in Figures 8 and 9, initially both groups were R-
(Number of incorrect responses) is higher than R” (Number of correct responses)
However, in the control group, R- decreased from around day 100, whereas in the DHA phospholipid group, R- decreased from around day 4.
- decreases, and Ro increases significantly. In other words, the DHA phospholipid group learns that the sooner they go to the light, the more food they will receive, and they remember this for days on end. In other words, in the case of DHA-containing phospholipids, the learning effect in light-dark discrimination feeding behavior performed using a Y-maze is as strong as in the case of using DHA-containing triglycerides or DHA-containing ethyl esters as active ingredients. The effect of strengthening and enhancing memory power was obtained.

Experimental example 4. 〉Measurement of platelet aggregation ability.

Blood was collected from each of 10 rats in the DMA ester group and the control group that underwent an 18-day learning ability improvement effect test using a Y maze, and the blood was measured as follows.

Nine volumes of blood collected from a rat heart and one volume of 3.8% sodium citrate were mixed, centrifuged at 1000 rpm for 5 minutes in a centrifuge, and the clear mixture was mixed with platelet-rich plasma (Platelet-rich plasma).
t Rich Pla-suma; hereinafter referred to as P,
The platelet count of P, R, P was adjusted to about 20 to 40×10'/m I2. In addition, platelet-poor plasma (Platelet P
oorPlasuma (hereinafter referred to as P, P, P) was centrifuged at 3000 rpm for 15 minutes in the same centrifuge, and the supernatant was used as a blank. For measurement, Toa Medical Electronics Co., Ltd.'s automatic platelet aggregation measuring device AA-100 (sysmex
) and adenosine diphosphate (ADP) at a concentration of 9.14 M was used as the eliciting substance.

The results are shown in Table 3 and Figure 10 below.Table 3: Measurement results of platelet aggregation ability using an automatic platelet aggregation measuring device.

That is, it can be easily considered that the DMA ester group in the test group inhibits platelet aggregation and thereby prevents the formation of thrombus, compared to the control group in terms of both secondary aggregation and secondary aggregation. As mentioned above, dementia is classified into two types, Hartzheimer dementia and cerebrovascular dementia, which are caused by cerebrovascular disorders. It has been revealed that it is effective in the prevention and treatment of cerebrovascular dementia.

Separate experiments revealed that when using DHA-containing triglyceride as the active ingredient and when DHA-containing phospholipid was used as the active ingredient, they had almost the same preventive and therapeutic effects from the blood side as the above measurement results. .

As mentioned above, the present invention provides that a composition containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient has the effect of improving brain function whether it is used as a drug or as a functional food. It has been found that it not only has the effect of enhancing learning ability and memory, but also has the effect of improving brain function, such as preventing and treating dementia.

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

The first invention to be patented is a brain function improving composition containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient. This is the basic invention, and the following will be applied inventions.

The second invention for which a patent is sought is a learning ability enhancer containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient.

The third invention for which a patent is sought is a memory enhancer containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient.

The fourth invention for which a patent is sought is a dementia preventive agent containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient.

The fifth invention for which a patent is sought is a dementia therapeutic agent containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient.

The sixth invention for which a patent is sought is a function having a brain function improving effect, characterized in that a brain function improving composition containing at least one or more of docosahexaenoic acid or its derivatives as an active ingredient is mixed into a food. It is a sexual food.

The seventh invention for which a patent is sought is the first invention to the sixth invention.
A composition for improving brain function, a learning ability enhancer, a memory enhancer, in which the docosahexaenoic acid derivative described in the invention is a fatty acid, a phospholipid, or a triglyceride extracted from natural oils and fats,
It is a dementia preventive agent, a dementia treatment agent, or a functional food that has the effect of improving brain function.

The eighth invention for which a patent is sought is the first invention to the sixth invention.
A composition for improving brain function, a learning ability enhancer, a memory enhancer, a dementia preventive agent, a dementia therapeutic agent, or a brain function improving agent, wherein the derivative of docosahexaenoic acid described in the invention is a salt, an amide, or an ester obtained by alcoholysis. It is a functional food that has ameliorating effects.

"Effects of the present invention" As mentioned above, the present invention provides docosahexaenoic acid (DHA)
) or its derivatives as an active ingredient to enhance brain function or recover from brain damage, and its pharmacological effects can be used to create drugs and functional foods. or mix it with appropriate pharmacologically acceptable carriers, excipients, and diluents to create solutions, powders, granules, tablets, injections, capsules, suppositories, etc. Of course, it may be processed into a desired form and commercialized, and the solution may be administered orally or parenterally in the form described above. It goes without saying that when administering medication, the dosage may be adjusted depending on age, body weight, symptoms, etc.

Thus, according to the present invention, in the form of a drug or a food product,
When at least one of docosahexaenoic acid or its derivatives, which is a substance that has the effect of improving brain function, is ingested into the human body, its active ingredients will enhance learning ability and memory. . Further, by ingesting the brain function improving composition as a medicine or food as in the present invention, it is effective in preventing dementia caused by brain damage or in treating various types of dementia.

[Brief explanation of the drawing]

FIG. 1 shows experimental example 1 according to the present invention. This is a graph showing the acquisition progress (correct response rate %) of the Y maze light/dark discrimination floor plan behavioral experiment.
Figure 2 shows the same experimental example 1. FIG. 3 is a graph showing the number of correct reactions and the number of incorrect reactions of the DHA ester group in Experimental Example 1. FIG. 4 is a graph showing the number of correct responses and the number of incorrect responses of the control group in Experimental Example 2. FIG. 5 is a graph showing the acquisition progress (correct response rate %) of the Y-maze light-dark discrimination behavior experiment in Experiment 2. FIG. 6 is a graph showing the number of correct and incorrect reactions of the DHA I-liguxeride group in Experimental Example 2. FIG. 7 is a graph showing the number of correct responses and the number of incorrect responses of the control group in Experimental Example 3. Figure 8 is a graph showing the acquisition progress (correct response rate %) of the Y-maze light/dark discrimination floor plan behavior experiment of Example 3 of the same experiment. Figure 9 is a graph showing the number of correct reactions and the number of incorrect reactions for the DHA-containing phospholipid group in Experiment Example 3.
．． FIG. 10 is a graph showing the number of correct responses and the number of incorrect responses of the control group in Experimental Example 4. It is a graph showing the results of measuring platelet aggregation ability using an automatic platelet aggregation measuring device. Patent applicant: Taiyo Fishery Co., Ltd., -1 Representative: Patent attorney Hiroo Otsu -,'! WVa needle? t+-1 emotion-concern Q艷?

Claims (8)

[Claims] (1) A brain function improving composition containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient. (2) A learning ability enhancer containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient. (3) A memory enhancer containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient. (4) A dementia preventive agent containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient. (5) A dementia therapeutic agent containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient. (6) A functional food having a brain function improving effect, which is characterized in that a brain function improving composition containing at least one kind of docosahexaenoic acid or its derivatives as an active ingredient is mixed into the food. (7) A brain function improving composition, a learning ability enhancer, wherein the docosahexaenoic acid derivative according to claim 1, 2, 3, 4, 5, or 6 is a fatty acid, phospholipid, or triglyceride extracted from natural oils and fats; A functional food that is a memory enhancer, a dementia preventive agent, a dementia treatment agent, or has a brain function improving effect. (8) A brain function improving composition, a learning ability enhancer, wherein the docosahexaenoic acid derivative according to claim 1, 2, 3, 4, 5, or 6 is a salt, an amide, or an ester obtained by alcoholysis. , a memory enhancer, a dementia preventive agent, a dementia treatment agent, or a functional food that has a brain function improving effect.