JP2003252756A - Dopamine isolation inhibiting composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide foods or beverages and medicines capable of safely improving excess and abnormality of isolation of an intracerebral dopamine without fear of adverse effect. <P>SOLUTION: It was found to directly improve intracerebral GABA concentration by orally ingesting GABA composition when stress is loaded, though GABA does not pass through a blood-brain barrier. It was further found that GABA composition controls isolation of dopamine increased by stress to a normal level. The present invention provides an antipsychotic dopamine isolation- inhibiting composition enabling long-term ingestion without fear of adverse effect and provides foods or beverages and medicines containing the composition. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a brain dopamine release inhibiting composition containing GABA produced from fermentation of lactic acid bacteria. Furthermore, the present invention relates to foods and pharmaceuticals containing the dopamine release inhibiting composition.

[0002]

Dopamine is a neurotransmitter of the central nervous system that is widely distributed in the brain, and is called catecholamine together with epinephrine (adrenaline) and norepinephrine (noradrenaline). It is a substance that is released. Therefore, in the central nervous system, dopamine is said to be involved in fighting instinct such as aggression, and acts as a defense instinct that protects itself from foreign enemies, while it is also called a pleasure hormone, and dopamine is secreted in large amounts in the brain. It is said that the whole body will be filled with joy and happiness when it is done, and the head will clear up.

It is known that substances that are involved in excitement as described above and conversely neurotransmitters that suppress the excitement are widely localized in the brain, and are distributed in the highest concentration. The substance is gamma aminobutyric acid (GABA).

As described above, the central nervous system constantly regulates the excited state and the suppressed state in a well-balanced manner, but it is well known that the above-mentioned catecholamines react sensitively even when stressed. Therefore, in a modern stressed society, dopamine is often secreted in the brain, and in an environment where excessive stress lasts for a long time, the balance between excitatory substances and inhibitory substances in the central nervous system collapses, Results Excessive release of dopamine causes a variety of diseases.

On the other hand, schizophrenia (former schizophrenia) is a kind of brain disease, and it is known that it is caused by abnormality of nerve cells in the brain. Schizophrenia is said to be a modern-day disease that affects about 1% of the population, and is becoming a huge social problem. It is known that when this disease develops, disorder in life occurs, and positive symptoms cause symptoms such as hallucinations, delusions, and poor cohesion of thoughts, and negative reactions slow the reaction of emotions. Symptoms such as lack of motivation, indifference to anything, shutting up in one's own world.
Although there are various theories regarding the onset, it is said that this symptom occurs especially when the function of dopamine in the central nervous system is abnormal.

From the reports so far, the most standard method for treating this symptom is the use of anti- (psychotropic) drugs.
Antipsychotics can alleviate symptoms such as hallucinations and delusions by suppressing the action of dopamine in the central nervous system. However, it is known that side effects of antipsychotics are very common, especially hand and body tremors, fatigue, constipation, drowsiness, lightheadedness, dry mouth, drooling, excessive appetite, rash, fever, It has been reported that irregular menstruation and the like cannot be used regularly for a long time, and the drug cannot be used especially when side effect symptoms are strong.

It is known that if the intake of the drug is interrupted due to the relief of schizophrenia, the function of dopamine becomes excessive and the disease is likely to recur. Further, in the state of continuous stress, dopamine is generally apt to become excessive as in the above-mentioned operation, and the risk of recurrence becomes very high. Continuing with antipsychotics can suppress the excessive action of dopamine and prevent recurrence considerably, but the current situation is that side effects are likely to occur.

Under the present circumstances, there is a demand for urgent development of a substance capable of safely controlling dopamine release without causing side effects even if taken for a long period of time.

As described above, GABA, which is an inhibitory neurotransmitter, is widely distributed in the brain to regulate excitatory neurotransmitters originating from dopamine. But GA
It is known that BA does not cross the blood-brain barrier, so generally GABA does not migrate into the brain when ingested.

[0010]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a substance which regulates a hypersecretion state of dopamine which is a stress state. In particular, it is an object of the present invention to provide a substance that suppresses excessive secretion of dopamine in the event of abnormal release of dopamine in schizophrenia, and can be continued to be taken safely without worrying about side effects. Furthermore, since the risk of recurrence becomes higher in a person who has been treated for this disease state under continuous stress, it is an object of the present invention to provide a substance that suppresses excessive dopamine action.

[0011]

Means for Solving the Problems As a result of intensive investigations by the present inventors, GABA normally does not pass through the blood-brain barrier, so that GABA concentration in the brain does not change even when taken orally. However, surprisingly, GABA in the brain decreased due to stress
It was found that the concentration was improved to the normal level by ingesting the GABA composition. As a result, GAB
It was found that by ingesting the composition A orally, the release of dopamine increased by stress can be adjusted to a normal level.
The present invention has been completed based on these findings.

That is, the dopamine release inhibiting composition of the present invention is characterized by containing GABA as an active ingredient.

The dopamine release inhibiting composition of the present invention preferably contains GABA in an amount of 5 to 70% by mass.

According to the present invention, it is possible to provide an antipsychotic-like dopamine release inhibiting composition which can be taken for a long time without fear of side effects.

The food or drink of the present invention is characterized by containing the above dopamine release inhibiting composition.

Further, the pharmaceutical of the present invention is characterized by containing the above dopamine release inhibiting composition.

According to the present invention, there can be provided foods and pharmaceuticals that are free from side effects and that effectively suppress the release of dopamine by oral ingestion.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION GABA, which is the active ingredient of the dopamine release inhibiting composition of the present invention, is tea as a food ingredient,
Γ, a type of amino acid contained in trace amounts in vegetables and cereals
-It means aminobutyric acid.

In the present invention, a preferred method for producing GABA is a fermentation method using lactic acid bacteria, which is capable of obtaining GABA in large quantities and at low cost. For example, sodium glutamate,
Add lactic acid bacteria (Lactobacillus) to a culture solution containing glucose, baker's yeast extract, sodium acetate, magnesium sulfate, etc.
Brevis (IFO12005 strain), Lactobacillus hirugardi K-3 strain (FERM P-18422), etc.)
The culture broth is added and the mixture is cultivated at 20 to 30 ° C. for 1 to 3 days. The culture is sterilized by heating and then filtered to obtain a filtrate.
As lactic acid bacteria, Lactobacillus hirugardi K
When strain -3 (FERM P-18422) is used, the GABA content in the culture broth is about 5% by mass, and GABA accounts for about 70% in terms of solid content.

The filtrate may be appropriately concentrated and used as it is, or may be further dried and used as a powder to be used as the dopamine release inhibiting composition of the present invention. GABA can be further purified by subjecting the filtrate to a treatment such as column chromatography. For example, a composition having a higher GABA content (80% by mass or more) can be obtained by performing column chromatography using an ion exchange resin DSR-01 (trade name, manufactured by Mitsubishi Chemical Corporation).

The lactic acid bacterium fermentation solution described above may be dried by freeze-drying or spray-drying to be powdered. Although not particularly limited, the content of GABA is 5% to 30% in the liquid state and 10% to 90% in the powder state.
%.

The content of GABA in the dopamine release inhibiting composition of the present invention is not particularly limited, but is preferably 5 to 70% by mass, more preferably 20 to 70% by mass.

GAB in dopamine release inhibiting composition
When the content of A is less than 5% by mass, it becomes difficult to add an amount that can be expected to have a dopamine release suppressing effect when it is added to foods and drinks. It is costly and not preferable.

The effective intake of the dopamine release inhibiting composition of the present invention varies depending on the specific symptoms, age, etc., but is usually 10 to 3000 mg / person in terms of GABA.
Day is preferable, and 100 to 500 mg / day is more preferable.

When the dopamine release inhibiting composition of the present invention is added to foods and drinks and pharmaceuticals, the addition amount can be set as appropriate, but normally it is preferably 0.05 to 20 mass% in terms of GABA, 10 mass% is more preferable. If the amount of the dopamine release inhibiting composition added is out of the above range, a sufficient dopamine release inhibiting effect cannot be imparted or the flavor of food or drink is affected.

The food and drink are not particularly limited,
Examples thereof include bread, cakes, confectionery (cookies, snacks, gums, chocolates, etc.), beverages (soft drinks, mineral water, favorite beverages, alcoholic beverages, etc.), and supplements (tablets, soft capsules, etc.).

[0027]

The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1 Preparation of Lactobacillus fermented GABA Fermentation raw materials (pH 5.
0) 50 L was sterilized by heating at 90 ° C. for 10 minutes, and then kimchi-derived lactic acid bacteria (Lactobacillus hirgardii K-
50 mL of a culture solution of 3 strains (FERM P-18422) was inoculated and cultured at 30 ° C. for 3 days. The GABA content of the fermented liquid after the fermentation was 51 g / L. This fermentation broth was sterilized by heating at 90 ° C for 10 minutes, then a filter aid was added and filtered, and the obtained filtrate was concentrated with a vacuum concentrator, dried with a freeze dryer, pulverized into powder. Lactic acid bacteria fermentation G
An ABA composition (GABA content: 65% by mass) was obtained.

[0029]

[Table 1]

As the GABA fermentation raw material, glutamic acid, wheat gluten, shochu lees protein, etc. may be used as the glutamic acid source in addition to sodium glutamate.

Test Example 1 Measurement of GABA Concentration GABA concentration was measured by the following method. After appropriately diluting each sample with a 0.2N sodium citrate buffer (pH 2.2), centrifugation or filtration was performed to remove the solid matter, and this was used as a measurement sample. The GABA content was analyzed by a high performance liquid chromatograph under the following conditions according to a conventional method for measuring the amino acid content.

Equipment used: High Performance Liquid Chromatograph LC-9A manufactured by Shimadzu Corporation Analytical column: Strongly acidic cation exchange resin column Shin
-Pack Isc-07 Na type moving layer buffer: amino acid moving layer kit manufactured by Shimadzu Corporation Na type moving layer flow rate: 0.3 ml / min Reaction layer 1: 0.04% sodium hypochlorite solution (pH
10 ml of boric acid-carbonate buffer solution (500 ml) and hypochlorous acid (0.2 ml) Reaction layer 2: Amino acid analysis kit O manufactured by Shimadzu Corporation
Flow rate of PA reagent reaction layer: 0.2 ml / min Detection: Fluorescence detection Ex348 nm, Em450 nm

Example 2 Absorption test of GABA Clean animal rat Wistar system, 4 weeks old (body weight about 1
A GABA administration and absorption test was performed using males (00 g). As a GABA sample, lactic acid bacteria fermented GABA
(Pharma Gabber 60; Pharma Foods Co., Ltd.)
Powder was used. GABA powder is dissolved in physiological saline,
An administration test using an oral probe was conducted in the following 4 groups (5 animals per group) so that the dose of GABA was 100 mg / animal.

Group 1 without GABA administration (control) 30 minutes after administration of Lactobacillus fermentative GABA 60 minutes after administration of 3 groups lactic acid bacteria fermented GABA 120 minutes after administration of 4th group lactic acid fermentation GABA

The mice were sacrificed at the above administration time, and the GABA concentration in each blood and brain (cerebral cortex) was measured.

The results of GABA concentration in blood are shown in FIG. 1, and the results of GABA concentration in cerebral cortex are shown in FIG.

From these results, as shown in FIG. 1, lactic acid bacteria fermented GAB
The GABA concentration in the blood was increased by administration of the composition A, but no change was observed in the GABA concentration in the brain as shown in FIG.

Example 3 Stress Dopamine Release Inhibition Test Clean animal rat, Wistar system 4 weeks old (body weight: about 10)
0 g) male, water, lactic acid bacterium fermentation GABA of the present invention (GBA (G
ABA (100 mg / kg body weight) was orally ingested for 15 days. Then, the test was divided into the following three groups and a stress load test was conducted. The stress inundation stress method was used for the stress load, and the stress load was applied for 1 hour.

1 group 15 days water administration (control) 2 groups 15 days water administration + stress load 3 groups 15 days lactic acid bacteria fermentation GABA administration + stress load

Immediately after the end of the stress load, the animals were sacrificed and the GABA and dopamine concentrations in the brain (cerebral cortex) were measured.

Dopamine was measured by the HPLC method (analytical column; ODS (Eicompack MA-5 ODS, detector); electrification detector (VMD-101A, Yanagim.
oto), working electrode; Ag / AgCl (WE-3G, E
icom)) was used for the measurement.

The results of changes in the GABA concentration in the brain in this test are shown in FIG. 3, and the changes in the dopamine concentration in the brain are shown in FIG.

From these results, it was found that the GABA amount in the brain of the stress-loaded rat tended to decrease, and that the decrease was improved to the normal level by ingesting GABA fermented with lactic acid bacteria. On the other hand, conversely, the amount of dopamine in the brain increases remarkably when stress is applied,
It was shown that ingestion of GABA fermented with lactic acid bacteria can reduce the amount of released dopamine.

The present results show that excessive release of dopamine caused by stress can be adjusted to a normal level by ingesting lactic acid bacterium fermentation GABA.

Example 4 Hereinafter, although not particularly limited, prescription examples of foods and pharmaceuticals containing the dopamine release inhibiting substance of the present invention will be given.

(1) Formulation example of granular foods Reduced maltose 71 mg Crystalline cellulose 70 mg Sucrose ester 9 mg The composition of the present invention 170 mg (10 as GABA)
0 mg)

(2) Formulation example of pharmaceutical film-coated tablet Composition of the present invention 200 mg (12 as GABA
0 mg)

[0048]

As described above, according to the present invention, the GA
It has been discovered that BA compositions surprisingly directly influence the GABA content in the brain under stress and also regulate the release level of dopamine. According to the present discovery, it is possible to provide foods and pharmaceuticals that improve the excessive release state of dopamine, which is caused by stress, and the abnormal release state of dopamine in schizophrenia, without fear of side effects.

[Brief description of drawings]

FIG. 1 is a diagram showing a time-dependent change in blood GABA concentration in Example 2.

FIG. 2 is a diagram showing changes in GABA concentration in the brain over time in Example 2.

FIG. 3 is a diagram showing changes in cerebral cortex GABA concentration due to stress load in Example 3.

FIG. 4 is a diagram showing changes in cerebral cortex dopamine concentration due to stress load in Example 3.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kim Takehisa             24 Koshinishi-cho, Kichijoin Ishihara-do, Minami-ku, Kyoto-shi, Kyoto Prefecture             No. 5 within Pharma Foods Laboratories, Inc. F-term (reference) 4B017 LC03 LK14 LL09                 4B018 LB08 LE01 LE05 MD19 ME14                 4C206 AA01 AA02 FA45 MA01 MA04                       MA63 MA72 ZC02

Claims (4)

[Claims] 1. A composition for suppressing dopamine release, which contains GABA as an active ingredient. 2. The dopamine release inhibiting composition according to claim 1, which contains GABA in an amount of 5 to 70% by mass. 3. A food or drink comprising the composition for suppressing dopamine release according to claim 1 or 2. 4. A pharmaceutical product comprising the dopamine release inhibiting composition according to claim 1 or 2.