Lactic acid phenylalanine-containing composition

Abstract

Provided is, as a novel application of lactic acid phenylalanine, a composition for stress relief or increase in motivation, which is characterized by containing lactic acid phenylalanine as an active ingredient.

Description

Composition containing lactic acid phenylalanine

[0001] The present invention relates to a composition for stress relief or motivation enhancement, and food and drink products and pharmaceuticals containing this composition.

[0002] Lactic acid phenylalanine (hereinafter may be referred to as "Lac-Phe") is a substance in which lactic acid and phenylalanine are amide-bonded, and is known to be contained in fermented foods such as pickles and cheese. Recently, it has been reported that this substance increases in the blood after exercise, and that administering this substance to obese mice suppresses appetite and leads to weight loss (Non-Patent Document 1).

[0003] Li V. L.et al., Nature, 606, 785-790 (2022).

[0004] Since exercise has a preventive effect against diseases such as obesity and diabetes, Lac-Phe, which increases after exercise, is expected to have beneficial effects on the body in addition to appetite suppression. The present invention has been made under such a background, and an object thereof is to provide a new use of Lac-Phe.

[0005] As a result of intensive studies to solve the above problems, the present inventors have found that Lac-Phe exhibits a stress relief effect and a motivation enhancement effect via the dopamine pathway. Since the dopamine pathway is deeply related to the reward system in the brain, it is expected to be more related to substances that increase appetite than to substances that suppress appetite. Therefore, it was completely unexpected that Lac-Phe, which has an appetite suppressing effect, exhibits an action effect via the dopamine pathway. The present invention has been completed based on the above findings. The present invention provides the following (1) to (9).

[0006] (1) A composition for stress relief or motivation enhancement, characterized by containing lactic acid phenylalanine as an active ingredient.

[0007] (2) The composition for stress relief or motivation enhancement according to (1), which is used for mental stress relief.

[0008] (3) The stress-relieving or motivation-enhancing composition according to (1), characterized in that it is used to improve spatial cognitive function.

[0009] (4) The stress-relieving or motivation-enhancing composition according to (1), characterized in that it is used to improve depressive states.

[0010] (5) The stress-relieving or motivation-enhancing composition according to (1), characterized in that it is used to improve coordinated motor function.

[0011] (6) The stress-relieving or motivation-enhancing composition according to (1), characterized in that it is used to improve the amount of physical activity.

[0012] (7) A food or beverage for stress relief or motivation enhancement, characterized by comprising a stress relief or motivation enhancement composition as described in any of (1) to (6).

[0013] (8) A stress-relieving or motivation-enhancing pharmaceutical characterized by comprising a stress-relieving or motivation-enhancing composition as described in any of (1) to (6).

[0014] (9) The stress-relieving or motivation-enhancing drug according to (8), characterized in that it is administered orally.

[0015] This invention provides a novel composition used for stress relief or motivation enhancement. This composition is expected to have effects such as reducing mental stress, improving spatial cognitive function, alleviating depressive states, improving coordinated motor function, and increasing physical activity.

[0016] A schematic diagram of the elevated cruciate maze test. A diagram showing the results of the elevated cruciate maze test (intracerebroventricular administration) (N=6). A diagram showing the results of the elevated cruciate maze test (intraperitoneal administration) (N=7). A diagram showing the results of the elevated cruciate maze test (oral administration) (N=6). A schematic diagram of the novel environment feeding suppression test. A diagram showing the results of the novel environment feeding suppression test (intracerebroventricular administration) (N=7). A diagram showing the results of the novel environment feeding suppression test (intraperitoneal administration) (N=4). A diagram showing the results of the novel environment feeding suppression test (oral administration) (N=4). A diagram showing the results of the elevated cruciate maze test (dopamine D1-R inhibitor administration, Lac-Phe administration) (N=5). A diagram showing the results of the elevated cruciate maze test (Lac alone, Phe alone, Lac-Phe etc. administered intracerebroventricularly) (N=4). Figures showing the results of the elevated cross maze test (oral administration of Lac alone, Phe alone, Lac-Phe, etc.) (N=4). Figures showing the results of the Y-maze test. Figures showing the results of the tail suspension test. Figures showing the results of the tail suspension test (LPS administration). Figures showing the results of the rotorod test. Figures showing the results of the rotorod test (1st and 5th tests). Figures showing the results of the rotating cage test.

[0017] The present invention will now be described in detail. The stress-relieving or motivation-enhancing composition of the present invention is characterized by containing Lac-Phe as an active ingredient. The stress-relieving and motivation-enhancing effects of Lac-Phe are thought to be brought about by the activation of the dopamine pathway, as shown in the examples described later.

[0018] Since the Lac-Phe used in the composition of the present invention is a known substance, commercially available products can be used.

[0019] Specific examples of stress reduction or motivation enhancement include reduction of mental stress, improvement of spatial cognitive function, improvement of depressive symptoms, improvement of coordinated motor function, and increase in physical activity.

[0020] The composition of the present invention can be used as is as a food or beverage or pharmaceutical for stress relief or motivation enhancement, or it can be added to food or beverages or pharmaceuticals and used as a food or beverage or pharmaceutical for stress relief or motivation enhancement.

[0021] The intake amount of the composition of the present invention is not particularly limited, but in one embodiment, the intake amount of the active ingredient may be 0.01 g / day or more, 0.05 g / day or more, 0.1 g / day or more, 0.2 g / day or more, 0.3 g / day or more, 0.4 g / day or more, 0.5 g / day or more, 0.6 g / day or more, 0.7 g / day or more, or 0.8 g / day or more. The upper limit may be, in any case of the lower limit, for example, 2 g / day or less, or 1 g / day or less.

[0022] The content of the active ingredient in the composition of the present invention is not particularly limited, but in one embodiment, the content of the active ingredient per 100 g of the composition may be, for example, 0.01 g or more, 0.05 g or more, 0.1 g or more, 0.2 g or more, 0.3 g or more, 0.4 g or more, 0.5 g or more, 0.6 g or more, 0.7 g or more, or 0.8 g or more. The upper limit may be, for example, 2 g or less, or 1 g or less, regardless of the lower limit.

[0023] The food and beverages of the present invention are not limited to human use, but include feed for mammals such as dogs and cats kept as pets or livestock. In addition to ordinary beverages and foods, the food and beverages of the present invention also include supplements, health foods, enteral nutrition foods, special-purpose foods, nutritional functional foods, and foods for specified health uses. The food and beverages may be in any form suitable for consumption, such as solid, liquid, granular, granular, powder, capsule, cream, or paste. Depending on the type, the food and beverages of the present invention may contain additives that are commonly used. Any additive that is acceptable from a food hygiene perspective can be used.

[0024] The pharmaceutical product of the present invention can be administered orally or parenterally for stress relief or motivation enhancement. The formulation can be in a form suitable for oral administration, such as powder, granules, tablets, or capsules, or in a form suitable for parenteral administration, such as injection, patch, lotion, or cream. The above-mentioned formulations can be prepared by known methods using Lac-Phe with pharmaceutically acceptable and appropriately selected base materials and carriers, as well as additives (e.g., excipients, diluents, binders, lubricants, disintegrants or disintegration aids, solubilizers, stabilizers, preservatives, antiseptics, bulking agents, dispersants, lubricants, wetting agents, buffers, fragrances, etc.).

[0025] The pharmaceutical product of the present invention is not limited to human use, but can also be administered to mammals such as dogs and cats kept as pets or livestock.

[0026] The administration routes for the pharmaceutical product of the present invention include, for example, oral administration, intraventricular administration, intraperitoneal administration, and transdermal administration. The preferred administration route for the pharmaceutical product of the present invention is oral administration.

[0027] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0028] (1) Materials and Methods The mice used were 8-12 week old male C57BL / 6N mice. The mice were reared under a 12-hour light-dark cycle (light period: 7am to 7pm).

[0029] In the evaluation tests, the elevated cruciate maze test and the novel environment feeding suppression test, mice were fasted for 4 hours before the start of the test, administered Lac-Phe 2 hours before, and the test started at 2 PM. In the Y-maze test, mice were fasted for 4 hours before the start of the test and administered Lac-Phe 2 hours before. In the tail suspension test, LPS 0.8 mg / kg was administered intraperitoneally, and the test was conducted the following day or the day after. In this test as well, mice were fasted for 2 hours before the start of the test and administered Lac-Phe 1 hour before. The test duration for each mouse was 6 minutes for the elevated cruciate maze test and the Y-maze test, and 10 minutes for the novel environment feeding suppression test. Mouse behavior was automatically analyzed using EthoVision XT.

[0030] Lac-Phe administration: Lac-Phe was administered as shown in the table below.

[0031] The reagents used are as follows: SIGMA Lac-Phe (N-Lactoylphenylalanine): SMB01375-10MG, Lac (L-(+)-Lactic acid): L1750-10G, Phe (L-Phenylalanine): P2126-100G, LPS (Lipopolysaccharides from Escherichia coil O111:B4): L4391-1MG, TOCRIS dopamine D1-R inhibitor SCH (SCH 23390 hydrochloride)

[0032] (2) Results Elevated Cross Maze Test The stress reduction effect of Lac-Phe was evaluated using the elevated cross maze test. The elevated cross maze test is a test that measures anxiety-like behavior in mice (Figure 1). Because the maze is at a high elevation, mice tend to stay in the closed arm out of fear of falling. Anxiety indicators can be examined from the number of times mice enter the open arm and the time they stay there (increased number of times and time spent in the open arm ⇒ lower anxiety level).

[0033] Figures 2, 3, and 4 show the results of intracerebroventricular, intraperitoneal, and oral administration of Lac-Phe, respectively. While no statistically significant difference was observed when Lac-Phe was administered intracerebroventricularly, a tendency toward stress reduction was seen in the Lac-Phe group (Figure 2). Stress reduction effects were confirmed when Lac-Phe was administered intraperitoneally (Figure 3). Stress reduction effects were also confirmed when Lac-Phe was administered orally (Figure 4).

[0034] The stress-reducing effect of Lac-Phe was evaluated using a novel environment feeding inhibition test. This test measures the behavior of fasted mice approaching food placed in the center of an open field (Figure 5). Since high anxiety levels prevent mice from eating the food in the center even when hungry, the number of times they enter the center zone and the duration of their stay can be used to examine anxiety levels (increased number of center zone entries and duration of stay ⇒ lower anxiety level).

[0035] Figures 6, 7, and 8 show the results of intracerebroventricular, intraperitoneal, and oral administration of Lac-Phe, respectively. Intracerebroventricular administration of Lac-Phe confirmed a stress-reducing effect (Figure 6). Intraperitoneal administration also confirmed a stress-reducing effect (Figure 7). However, while no significant difference was observed with oral administration, a tendency toward stress reduction was seen with Lac-Phe administration (Figure 8).

[0036] Mechanism of action confirmed by dopamine D1-R inhibitor administration: We investigated whether the stress-reducing effect of Lac-Phe is suppressed by administering a dopamine D1-R inhibitor. Dopamine D1-R inhibitors were administered intracerebroventricularly, followed by intraperitoneal administration of Lac-Phe 30 minutes later, and an elevated cruciate maze test was performed 2 hours later. 1 μL of dopamine D1-R inhibitor was administered per mouse. For Lac-Phe, 200 μL of saline containing 100 μg of Lac-Phe was administered per mouse. For comparison, an equal amount of saline was administered instead of dopamine D1-R inhibitor and Lac-Phe to serve as a control group.

[0037] In the dopamine D1-R inhibitor (An) + Lac-Phe group, the anxiolytic effect observed in the Lac-Phe monotherapy group was suppressed (Figure 9). This result suggests that Lac-Phe exerts its anxiolytic effect via the dopamine pathway.

[0038] Comparison with Lac or Phe monotherapy groups: In addition to the control and Lac-Phe groups, three additional groups were added: L-lactic acid (Lac), L-phenylalanine (Phe), and a mixed group of lactate and phenylalanine (Lac+Phe). An elevated cruciform maze test was performed.

[0039] The administration of the drugs in each group was carried out as shown in the table below.

[0040] The molar concentrations of L-lactic acid (Lac), L-phenylalanine (Phe), and a mixture of lactic acid and phenylalanine (Lac+Phe) were standardized based on the molar concentration of Lac-Phe, and the tests were conducted accordingly.

[0041] The results of intracerebroventricular administration and oral administration are shown in FIGS. 10 and 11, respectively. When administered intracerebroventricularly, a stress-reducing effect was confirmed only in the Lac-Phe administration group (FIG. 10). When administered orally, a higher stress-reducing effect was confirmed in the Lac-Phe administration group compared to the Phe and Lac administration groups (FIG. 11).

[0042] Y-maze test The recovery effect of Lac-Phe on spatial cognitive function was evaluated by the Y-maze test. For mice whose spatial cognitive function had been reduced by pre-administering LPS, Lac-Phe was administered intraperitoneally, and the spontaneous alternation behavior rate (spatial cognitive function) in the Y-maze test was examined.

[0043] Compared with the LPS group, the spontaneous alternation behavior rate was improved in the LPS + Lac-Phe group (FIG. 12). From this result, it is suggested that Lac-Phe has an effect of restoring the spatial cognitive function reduced by LPS.

[0044] Tail suspension test The motivation-enhancing effect of Lac-Phe was evaluated by the tail suspension test. The results when LPS was not administered and the results when LPS was administered are shown in FIGS. 13 and 14, respectively. The immobile time was shortened by the administration of Lac-Phe (FIGS. 13 and 14). From this result, it is suggested that Lac-Phe has a motivation-enhancing effect.

[0045] Rotarod test The effect of improving the coordinated motor function of Lac-Phe was evaluated by the rotarod test. The relationship between the number of test runs and the running duration is shown in FIG. 15. Also, the running durations in the first and fifth tests are shown in FIG. 16. The running duration became longer by the administration of Lac-Phe (FIGS. 15 and 16). From this result, it is suggested that Lac-Phe has an effect of improving the coordinated motor function.

[0046] Rotating cage test The effect of improving the amount of exercise of Lac-Phe was evaluated by the rotating cage test. The total running distance became longer by the administration of Lac-Phe (FIG. 17). From this result, it is suggested that Lac-Phe has an effect of improving the amount of exercise.

[0047] The present invention can be used in industrial fields related to pharmaceuticals and foods.

Claims

1. A composition for stress relief or motivation enhancement, characterized by containing phenylalanine lactate as an active ingredient.

2. The stress-relieving or motivation-enhancing composition according to claim 1, characterized in that it is used to alleviate mental stress.

3. The stress-relieving or motivation-enhancing composition according to claim 1, characterized in that it is used to improve spatial cognitive function.

4. The stress-relieving or motivation-enhancing composition according to claim 1, characterized in that it is used to improve depressive states.

5. The stress-relieving or motivation-enhancing composition according to claim 1, characterized in that it is used to improve coordinated motor function.

6. The stress-relieving or motivation-enhancing composition according to claim 1, characterized in that it is used to improve the amount of physical activity.

7. A food or beverage for stress relief or motivation enhancement, characterized by comprising the stress relief or motivation enhancement composition described in any one of claims 1 to 6.

8. A stress-relieving or motivation-enhancing pharmaceutical product characterized by comprising the stress-relieving or motivation-enhancing composition described in any one of claims 1 to 6.

9. The stress-relieving or motivation-enhancing drug according to claim 8, characterized by being administered orally.

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