Blood flow increasing agent for dorsal-lateral prefrontal cortex, activating agent for dorsal-lateral prefrontal cortex, food for increasing blood flow of dorsal-lateral prefrontal cortex, and food for activating dorsal-lateral prefrontal cortex

Abstract

The present disclosure relates to a blood flow increasing agent for the dorsal-lateral prefrontal cortex, which contains 6-methylsulfinylhexyl isothiocyanate.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This international application claims the benefit of Japanese Patent Application No. 2022-057070 filed in the Japan Patent Office on March 30, 2022, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] The present disclosure relates to an agent for increasing blood flow to the dorsolateral prefrontal cortex, an agent for activating the dorsolateral prefrontal cortex, a food for increasing blood flow to the dorsolateral prefrontal cortex, and a food for activating the dorsolateral prefrontal cortex. Background Art

[0004] Improving, maintaining, or improving cognitive function is pursued in a wide range of age groups from the elderly to the young. It is known that the improvement of cognitive function is related to an increase in the amount of activity of various parts of the brain (for example, an increase in cerebral blood flow).

[0005] Here, the dorsolateral prefrontal cortex refers to a region located above the prefrontal cortex of the brain. The dorsolateral prefrontal cortex is known to be related to working memory, which is one type of cognitive function (Non-Patent Document 1).

[0006] In recent years, compositions for the purpose of increasing brain activity have been developed. For example, Patent Document 1 discloses that a composition containing specific flavanols as a main component activates brain regions such as the right side of the dorsolateral prefrontal cortex in a subject used to evaluate cognitive function.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent Application No. 2009-539991

[0010] Non-patent literature

[0011] Non-patent literature 1: Olesen, P., Westerberg, H. & Klingberg, T. Increased prefrontaland parietal activity after training of working memory. Nat Neurosci 7, 75-79 (2004). Summary of the invention

[0012] Technical problem to be solved by the invention

[0013] The inventors have devoted themselves to developing a new substance that can increase blood flow to the dorsolateral prefrontal cortex.

[0014] One aspect of the present disclosure preferably provides a novel agent for increasing blood flow to the dorsolateral prefrontal cortex.

[0015] Technical solutions to the problem

[0016] One embodiment of the present disclosure is a blood flow increasing agent for increasing blood flow to the dorsolateral prefrontal cortex, which contains 6-methylsulfinylhexyl isothiocyanate.

[0017] In one embodiment of the present disclosure, the agent for increasing blood flow to the dorsolateral prefrontal cortex can improve and / or enhance cognitive function by increasing blood flow to the dorsolateral prefrontal cortex.

[0018] In one embodiment of the present disclosure, the cognitive function may be episodic memory.

[0019] In one embodiment of the present disclosure, the cognitive function may be working memory.

[0020] In one embodiment of the present disclosure, the agent for increasing blood flow to the dorsolateral prefrontal cortex may be administered as a single dose.

[0021] In one embodiment of the present disclosure, the agent for increasing blood flow to the dorsolateral prefrontal cortex may be orally administered.

[0022] In one embodiment of the present disclosure, 6-methylsulfinylhexyl isothiocyanate can be extracted from Beauvillaea truncatula or synthesized.

[0023] One embodiment of the present disclosure is a dorsolateral prefrontal cortex blood flow enhancer comprising an extract of galangal.

[0024] One embodiment of the present disclosure is a food for increasing blood flow to the dorsolateral prefrontal cortex, which contains a blood flow increasing agent to the dorsolateral prefrontal cortex.

[0025] One embodiment of the present disclosure is an activator for activating the dorsolateral prefrontal cortex, which contains 6-methylsulfinylhexyl isothiocyanate.

[0026] One aspect of the present disclosure is a food for activating the dorsolateral prefrontal cortex, which contains an activator of the dorsolateral prefrontal cortex.

[0027] Effects of the Invention

[0028] According to the above configuration, a blood flow increasing agent for the dorsolateral prefrontal cortex can be provided. In addition, the blood flow increasing agent improves and / or enhances cognitive function (eg, episodic memory or working memory) by increasing blood flow in the dorsolateral prefrontal cortex. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1It is a figure showing the score evaluation results of logical memory (real time), logical memory (delayed), face and name associative memory. In each figure, the vertical axis in the figure represents the change in score before and after life intervention. The change is represented by mean ± standard error. In each figure, the bar graph on the left represents the test preparation group, and the bar graph on the right represents the control preparation group.

[0030] Figure 2 It is a graph showing the score evaluation results of the digit span test (backwards). The vertical axis in the figure represents the change in the score before and after the life intervention. The change is represented by the mean ± standard error. The bar graph on the left represents the test preparation group, and the bar graph on the right represents the control preparation group.

[0031] Figure 3 This is a schematic diagram that explains the method of the N-back task.

[0032] Figure 4 This is a graph showing the calculation results of the correct score rate for the 2-back task before, 30 minutes after, and 60 minutes after the preparation is taken. The vertical axis in the figure represents the correct score rate. The score is represented by the average value. The bar graph on the left represents the test preparation group at each time, and the bar graph on the right represents the control preparation group at each time.

[0033] Figure 5 It is a graph showing the results of brain activity measurement of the left dorsolateral prefrontal cortex during the 2-back task before, 30 minutes after, and 60 minutes after the ingestion of the preparation. The vertical axis in the figure represents the measured value of brain activity. The measured value is represented by the average value. The bar graph on the left represents the test preparation group at each time, and the bar graph on the right represents the control preparation group at each time. DETAILED DESCRIPTION

[0034] The blood flow increasing agent disclosed herein contains isothiocyanates. In the present disclosure, isothiocyanates refer to compounds having -NCS groups. Isothiocyanates are compounds having, for example, aromatic or aliphatic groups as side chains. Examples of isothiocyanates having aromatic groups include, for example, phenethyl isothiocyanate. Examples of the isothiocyanates having an aliphatic group include at least one selected from the group consisting of isopropyl isothiocyanate, isobutyl isothiocyanate, 2-butyl isothiocyanate, isopentyl isothiocyanate, pentyl isothiocyanate, allyl isothiocyanate, 3-butenyl isothiocyanate, 4-pentenyl isothiocyanate, 5-hexenyl isothiocyanate, 6-heptenyl isothiocyanate, 3-methylthiopropyl isothiocyanate, 4-methylthiobutyl isothiocyanate, 5-methylthiopentyl isothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, 4-methylsulfinylbutyl isothiocyanate, 5-methylsulfinylpentyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanate, and 7-methylsulfinylheptyl isothiocyanate. The blood flow increasing agent of the present disclosure preferably contains 4-methylsulfinylbutyl isothiocyanate, 5-methylsulfinylpentyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanate, or 7-methylsulfinylheptyl isothiocyanate. The blood flow increasing agent of the present disclosure most preferably contains 6-methylsulfinylhexyl isothiocyanate. The blood flow increasing agent of the present disclosure containing 6-methylsulfinylhexyl isothiocyanate will be described in detail hereinafter.

[0035] The blood flow increasing agent disclosed in the present invention contains 6-Methylsulfinyhexyl isothiocyanate (abbreviated as: 6-MSITC).

[0036] The blood flow increaser of the present disclosure increases the blood flow of the dorsol lateral prefrontal cortex (DLPFC). In the present disclosure, "increased blood flow" refers to an increase in the amount of blood flowing into a unit volume of tissue per unit time. That is, the increase in blood flow of the DLPFC is an increase in the amount of blood flowing into a unit volume of the DLPFC per unit time. The increase in blood flow of the DLPFC can be associated with an increase in the amount of activity of the DLPFC.

[0037] The blood flow increasing agent disclosed in the present invention improves and / or enhances cognitive function by increasing the blood flow of DLPFC. In the present disclosure, "improvement" refers to the improvement of function or ability, and the inhibition or delay of the decline of function or ability. In the present disclosure, "improvement" refers to the enhancement or progress of function or ability. In the present disclosure, "cognitive function" refers to the following high-level function of the brain, which is used to correctly grasp the surrounding things and the state of oneself based on the information obtained from the outside through vision or hearing, and take appropriate actions. The cognitive function disclosed in the present disclosure can be any cognitive function in which DLPFC participates, and examples include episodic memory, working memory, executive function, attention, visual spatial ability, processing ability, etc. Here, "episodic memory" refers to the memory of events experienced by an individual and is accompanied by memory of incidental information such as time, place, and emotions, and the ability to remember events experienced by an individual accompanied by the incidental information. In addition, "working memory" refers to the ability to perform a series of operations while temporarily retaining information. In addition, "executive function" refers to the ability to maintain appropriate actions and thinking in order to achieve future goals. In addition, "attention" refers to the ability to turn attention to specific matters, or the ability to maintain attention. In addition, "visual-spatial ability" refers to the ability to process information obtained through vision and recognize the entire space. In addition, "processing ability" refers to the ability to process new information.

[0038] The blood flow increasing agent of the present disclosure can preferably be used to improve and / or enhance episodic memory and / or working memory by increasing blood flow to the DLPFC.

[0039] Here, various reports have been made on the relationship between episodic memory and working memory and the parts of the brain related to the memory, and the parts of the brain that are activated have been determined for each memory. For example, it is known that working memory is responsible for DLPFC (Olesen, P et.al., Nat Neurosci., 7, 75-79, 2004). In addition, it is known that episodic memory is responsible for the prefrontal lobe (e.g., DLPFC and orbitofrontal cortex) and hippocampus (M. Natasha Rajah et.al., Brain., Volume 128, Issue 9, Pages 1964-1983, September 2005, and Georg Gron et.al., Neurobiology ofAging, Volume 24, Issue 3, Pages 453-462, 2003, etc.). Therefore, by increasing the blood flow of DLPFC (increasing the activity of DLPFC), episodic memory and / or working memory can be improved and / or enhanced.

[0040] 6-MSITC used in the blood flow increasing agent of the present disclosure can be extracted and purified from plants. Examples of plants include plants of the families Bataceae, Brassicaceae, Bretschneideraceae, Capparaceae, Caricaceae, Euphorbiaceae, Gyrostemonaceae, Limnanthaceae, Moringaceae, Pentadiplandraceae, Phytolaccaceae, Pittosporaceae, Resedaceae, Salvadoraceae, Tovariaceae, and Tropaeolaceae. Specific examples include Wasabia japonica [other name: wasabi], Armoracia rusticana [other name: wasabi], Batismaritima, Brassica juncea, Brassica oleracea var. italica, Arabidopsis thaliana, Capsella bursa-pastoris, Nasturtium officinale, Bretschneidera sinensis, Capparis spinosa, Carica papaya, Drypetes roxburghii (Chinese name unknown), Putranjiva roxburghii, Tersonia brevipes (Chinese name unknown), Limnanthes douglasii, Moringa oleifera, Pentadiplandra brazzeana (Chinese name unknown), Phytolaccaamericana, Bursaris spinose var. incana, Reseda alba, Salvadorapersica, Tovaria pendula, Tropaeolum majus, etc.However, the 6-MSITC that can be used in the present disclosure is not limited to those obtained from the above-mentioned plants, and all natural resources containing 6-MSITC can also be used as raw materials.

[0041] 6-MSITC is preferably extracted from Beauvillaea oxyphylla.

[0042] In addition, 6-MSITC used in the blood flow increasing agent of the present disclosure can be obtained by chemical synthesis. The following is a detailed description of the chemical synthesis method of 6-MSITC.

[0043] In principle, it is in accordance with the Kjaer et al. method (Kjaer et al., Actachem., Scand., 11, 1298, 1957), which is a common method for synthesizing isothiocyanates. 6-Chlorohexanol is used and refluxed with CH3-SNa to obtain 6-methylthiohexanol. Sulfonyl chloride (SOCl2) is reacted with 6-methylthiohexanol to obtain 6-chlorohexyl methyl sulfide. Then, the well-known Gabriel method is used as a method for synthesizing primary amines, and an amine group is introduced through potassium phthalimide to generate N-(6-methylthiohexyl)-phthalimide. Hydrazine hydrate is added thereto and refluxed to obtain 6-methylthiohexylamine, which is then reacted with thiocarbonyl chloride to obtain 6-methylthiohexyl isothiocyanate.

[0044] Furthermore, the methylthio group in the obtained 6-methylthiohexyl isothiocyanate is oxidized with m-chloroperbenzoic acid to obtain 6-methylsulfinylhexyl isothiocyanate (6-MSITC) (Morimitsu et al., J. Biol. Chem., 277, 3456, 2002).

[0045] The blood flow increasing agent disclosed in the present invention may contain an extract of Lepidium sativum L. The extract of Lepidium sativum L. preferably contains 6-MSITC.

[0046] The blood flow increasing agent of the present disclosure may be contained in food, cosmetics, pharmaceuticals, or quasi-drugs.

[0047] The form of the food containing the blood flow increasing agent of the present disclosure is arbitrary and not limited. Specific forms of food include, for example, general food, general beverage, nutritional supplement, health food, functional label food, health functional food such as food for specific health use, and food for specific use, soft drinks, tea beverages, health beverages, alcoholic beverages such as wine, cakes, rice, bread, noodles, cooked food, seasonings, etc.

[0048] The form of the cosmetics, pharmaceuticals and quasi-drugs containing the blood flow increasing agent of the present disclosure is arbitrary and not limited. Specific cosmetics, pharmaceuticals and quasi-drugs include, for example, internal and external preparations, lotions, emulsions, creams, ointments, facial masks, skin cleansers, shampoos, conditioners, bath preparations, etc.

[0049] In addition, previous studies have shown that 6-MSITC increases VEGF (Vascular Endothelial Growth Factor) in cultured cells, which promotes angiogenesis (Food Science and Technology Research, 24 (3), 567-572, 2018). It is believed that there is the following possibility: 6-MSITC, for example, by applying it to the scalp, promotes peripheral angiogenesis and increases blood flow in the brain (such as DLPFC).

[0050] In addition, the dosage form of the cosmetics, pharmaceuticals and quasi-drugs containing the blood flow increasing agent disclosed herein is not limited. Specific dosage forms of cosmetics, pharmaceuticals and quasi-drugs include, for example, capsules, tablets, powders, granules, liquids, emulsions, creams, gels, ointments, films, mousses, etc.

[0051] The blood flow increasing agent of the present disclosure may contain, in addition to 6-MSITC as a main component, various optional components generally used in foods, cosmetics, pharmaceuticals, and quasi-drugs as auxiliary components as needed, within the range not impairing the efficacy of the present disclosure.

[0052] The blood flow increasing agent of the present disclosure can be administered via various administration routes, and is preferably administered orally.

[0053] The dosage of the blood flow increasing agent disclosed in the present invention is determined by considering the age, sex, weight, usage, dosage, etc. of the subject. In the case of oral administration, the daily dosage of 6-MSITC in the blood flow increasing agent is preferably 0.01 mg / day to 10 mg / day, more preferably 0.05 mg / day to 5.0 mg / day, and the ideal value is 0.1 mg / day to 1 mg / day. By making the dosage of the blood flow increasing agent within the above numerical range, the blood flow of the DLPFC of the subject can be increased.

[0054] When using the extract of Sanguisorba officinalis as a blood flow increasing agent, it is preferred to ingest the extract of Sanguisorba officinalis so that the daily dosage of 6-MSTIC in the extract of Sanguisorba officinalis is 0.01 mg / day to 10 mg / day. In addition, it is preferred to ingest the extract of Sanguisorba officinalis so that the daily dosage of 6-MSTIC in the extract of Sanguisorba officinalis is 0.01 mg / day to 10 mg / day, and it is ideal to ingest the extract of Sanguisorba officinalis so that the daily dosage of 6-MSTIC in the extract of Sanguisorba officinalis is 0.1 mg / day to 1 mg / day.

[0055] The blood flow increasing agent of the present disclosure can be administered once. The blood flow increasing agent of the present disclosure can increase the blood flow of the DLPFC of a subject by administering the agent to the subject only once.

[0056] In addition, the blood flow increasing agent disclosed herein can also be repeatedly administered over a long or short period of time. The number of administrations is not limited, and can be three times a day, twice a day, once a day, once every two days, once every three days, once a week, once every two weeks, once a month, etc. In addition, the administration period is not limited, and can be one day, two days, three days, one week, two weeks, one month, half a year, one year, or more than one year.

[0057] The blood flow increasing agent disclosed in the present invention can be administered to subjects of various ages, including the elderly (eg, over 60 years old) or young adults (eg, 10 to 30 years old).

[0058] In addition, one embodiment of the present disclosure is an activator of DLPFC containing 6-MSTIC for activating DLPFC. In addition to increasing the blood flow of DLPFC as described above, the activation of DLPFC may also include various reactions related to the increase in the activity of DLPFC. Various reactions related to the increase in the activity of DLPFC may include, for example, changes in electrical activity (i.e., brain waves) caused by the neural activity of the brain, changes in magnetic fields, and changes in neurotransmitters.

[0059] In addition, one embodiment of the present disclosure is a method for increasing blood flow in DLPFC, which comprises administering a blood flow increasing agent to a subject. In addition, the method for increasing blood flow can improve and / or enhance cognitive function by increasing blood flow in the dorsolateral prefrontal cortex.

[0060] The above text describes in detail the blood flow increaser of the present invention and / or the activator of DLPFC for activating DLPFC containing 6-MSITC, however, isothiocyanates other than these can also be used in the blood flow increaser of the present invention and / or the activator of DLPFC. As an example, the blood flow increaser of the present invention may contain 4-methylsulfinylbutyl isothiocyanate. In addition, the activator of DLPFC for activating DLPFC of the present invention may contain 4-methylsulfinylbutyl isothiocyanate. Moreover, the blood flow increaser of the present invention and / or the activator of DLPFC for activating DLPFC containing 4-methylsulfinylbutyl isothiocyanate can show the same degree of effect as the blood flow increaser of the present invention and / or the activator of DLPFC for activating DLPFC containing 6-MSITC.

[0061] Example

[0062] Example 1: Preparation of the formulation

[0063] In order to investigate the effects of administration on cognitive function in humans, the preparations shown in Table 1 below were prepared as nutritional supplements for the subjects. The difference between the test preparation and the control preparation was whether or not WASABI SULFINYL (registered trademark), an ingredient extracted from yam serrata, was contained.

[0064] [Table 1]

[0065] Table 1 Test preparations and control preparations prepared

[0066]

[0067] [Table 2]

[0068] Table 2 Nutrients of the test preparation and control preparation

[0069] Nutrients (per 100g) Test preparation Control preparation Moisture 7.1g 8.2g protein 20.0g 17.1g Lipids 6.1g 5.3g Ash 2.7g 2.4g carbohydrate 64.1g 67.0g Heat 391kcal 384kcal sodium 44.1mg 34.5mg Salt Equivalent 0.112g 0.08765g

[0070] Example 2: Evaluation of cognitive function in the elderly

[0071] A long-term intervention study on elderly people was conducted using the test preparation and control preparation prepared in Example 1. The details are as follows.

[0072] (1) Test process

[0073] Taking into account the gender of the subjects, stratified randomization was used to assign the subjects to the test preparation group and the control preparation group. In the experiment of Example 2, the prior explanation (explanation of cognitive function test and questionnaire test), the prior test (cognitive function test and questionnaire test), the life intervention, and the post-test (cognitive function test and questionnaire test) were implemented in sequence. Among them, the cognitive function test refers to a test for measuring cognitive function; the questionnaire test refers to a test using a questionnaire to confirm living habits, personality, behavioral habits, and mental state (that is, stress). In the prior explanation, each subject was informed that he would take either a yamabushige nutritional supplement or a placebo. The prior explanation, the prior test, and the post-test were implemented for one day at the Institute of Aging Medicine, Tohoku University, Japan. Life intervention was implemented for twelve weeks.

[0074] During the lifestyle intervention, the test preparation group was asked to take the test preparation, and the control preparation group was asked to take the control preparation. For the subjects, although there was a difference in taking the test preparation or the control preparation, the lifestyle intervention period and the frequency of intake (i.e., daily) were the same. The content of the test was the same for all subjects, but the order of the tests was changed according to the subjects to reduce the influence caused by the order of test implementation and the influence caused by fatigue from the test implementation.

[0075] (2) Selection of subjects

[0076] 72 healthy elderly men and women (53 males: 19 females) were selected as subjects (average age 65.43 years (SD = 3.78)). The 72 subjects were native Japanese speakers and right-handed. It is known that handedness affects brain activity. In brain imaging studies, only right-handed subjects are usually used as subjects. Therefore, in this Example 2, only right-handed subjects are used as subjects. In addition, those who do not meet the following exclusion criteria are selected as subjects. Regarding this exclusion criterion, reference is made to the selection criteria of studies on lifestyle interventions for the elderly (Nouchi et al., 2016: Nouchi et al., 2012).

[0077] Exclusion criteria

[0078] ·People with a history of mental illness, diabetes, brain nerve disease, or heart disease (heart disease)

[0079] Those who are currently taking drugs that affect cognitive function (such as benzodiazepines, antidepressants, and central nervous system drugs)

[0080] · Those with a score of 26 or less on the Mini Mental State Examination (MMSE) for cognitive impairment screening

[0081] · Those who score 5 or above on the depression test (Geriatric Depression Scale)

[0082] Those with a score of 12 or less on the Frontal Assessment Battery at Bedside (FAB) test

[0083] People who may have allergic symptoms due to food intake (especially those who are allergic to bezoars, milk, eggs, wheat, buckwheat, peanuts, shrimp or crab)

[0084] ・People who have a drinking habit of drinking more than 60g of pure alcohol (equivalent to 3 bottles of medium beer or 3 cups of sake (540ml)) per day on average during a one-week observation

[0085] Currently participating in other researchers other than this Example 2, or has participated in other researchers within two months before the start of the trial

[0086] ・Those who are unable to fill out a life diary regarding whether they have taken the test product or the control product and the lifestyle intervention

[0087] Before the start of the trial, a number was assigned to each subject, and a number list was generated that stratified by gender and randomly divided the subject numbers into two groups. The subjects were assigned to each group based on this number list.

[0088] According to the explanatory documents approved by the Ethics Committee of Tohoku University, the purpose and safety of the trial were explained to the subjects in written and oral forms, and then the subjects were allowed to participate in the trial after obtaining their written consent.

[0089] (3) Lifestyle intervention

[0090] In the test of Example 2, each group took one capsule once a day for a total of twelve weeks. The subject took one test preparation or control preparation with water or warm water before going to bed during the intake period. Whether the subject has taken the preparation is confirmed by a life log. The life log is a log for recording whether the preparation is taken and the time of intake, or for keeping records of matters different from daily life (for example, excessive exercise, travel, or taking drugs other than the test preparation and the control preparation). In addition, until the end of the trial, the subject himself and the researcher are not aware of which group the subject is assigned to. No special restrictions are set on the diet during the life intervention period, and the same life as before the intervention period is maintained.

[0091] The test preparation and the control preparation are provided to the researcher team by the applicant of this application, that is, Kinyin Co., Ltd. The packaging of the preparation is printed with text to identify each preparation. In addition, the preparations are prepared and sent by employees who are not involved in the test in Kinyin Co., Ltd. The researcher is only informed of the identification method of the two preparations (identified by the printed text on the bottom). Therefore, the researcher is in a state where he does not know which one is the test preparation and which one is the control preparation, although he can distinguish the two preparations. Each preparation of the capsule type is a color of the same color system that cannot be distinguished by appearance, and is provided to the subject by the researcher. The test adopts a double-blind test, and the team of the researcher who implements the test (that is, the research leader, the co-researcher, and the person in charge of distribution) and the subject do not know which preparation group it is until the test and analysis are all completed. The distribution information of the subject is opened after all the analyses are completed.

[0092] (4) Cognitive function test

[0093] A cognitive function test was implemented in order to measure cognitive function. The cognitive function test described later is a standardized cognitive function test, and is a cognitive function test for testing memory, etc. All cognitive function tests are implemented by trained psychological testers. Use a pen and a test paper for filling in the answers in the test, and implement the cognitive function test in the form of filling in the answers. In the test using a pen and a test paper, the above-mentioned standardized tests of "logical memory", "associative memory of face and name" and "digit span test" for testing working memory were used. Each test is implemented in a face-to-face form. In addition, in each test, the time for the subject to answer is about 5 minutes.

[0094] (5) Test Overview

[0095] "Logical memory": A test in which the participants listen to and remember a story, and then recall the contents of the story. Both the test was repeated immediately after listening to the story (real time) and the test was repeated about 30 minutes later (delayed).

[0096] "Associative memory of faces and names": memorize faces and names, and then answer a test of the name that matches the face shown.

[0097] "Digit span test": When a number column is displayed, the student must answer the number column in reverse order (recite the number column backwards).

[0098] (6) Statistical analysis

[0099] The change in the scores of each test measured before and after the life intervention was calculated (after intervention - before intervention), and a permutation ANCOVA (analysis of covariance) was used to statistically test whether there was a difference in effect through life intervention. The scores before intervention, age, gender, and MMSE scores were used as covariates. In addition, all analyses were performed using the statistical software R.

[0100] (7) Results and research

[0101] The evaluation results of logical memory (real-time), logical memory (delayed), associative memory of faces and names are as follows: Figure 1 The score evaluation results of the digit span test (reverse) are shown as follows Figure 2 shown.

[0102] As a result of the analysis, the test preparation group was compared with the control preparation group, and the test preparation group showed improvements in the real-time reproduction, delayed reproduction, face and name memory of logical memory as indicators of episodic memory, and reverse recitation as an indicator of working memory.

[0103] This shows that by administering the test preparation, episodic memory and working memory can be improved. In addition, it is known that for the elderly, when implementing a topic related to episodic memory, the activity of DLPFC is related to the performance of the topic (M. Natasha Rajah et.al., Brain., Volume 128, Issue 9, Pages 1964-1983, September 2005). Therefore, it is shown that for the elderly, the blood flow of DLPFC is increased by taking 6-MSITC, thereby improving episodic memory.

[0104] Example 3: Assessment of working memory in young adults

[0105] A single-dose test in young adults was conducted using the test preparation and control preparation prepared in Example 1. The details are as follows.

[0106] (1) Test process

[0107] In the experiment of Example 3, a pre-test, a pre-ingestion test, drug administration, and a post-ingestion test (immediately after ingestion, 30 minutes after ingestion, and 60 minutes after ingestion) were implemented. Those who obtained informed consent on the pre-visit day and were clearly able to participate in the experiment were registered as subjects of the experiment of Example 3. Then a pre-test was implemented. A cognitive function test was implemented in the pre-test. The subjects were asked to ingest the preparation on the test day in the future, and a pre-ingestion test and a post-ingestion test were implemented before and after. The preparations ingested by the subjects were divided into two preparations, the test preparation and the control preparation, and the subjects were asked to ingest one of the preparations once. In the pre-ingestion test and the post-ingestion test, brain activity was measured using questionnaires and NIRS (Near-infrared spectroscopy).

[0108] (2) Selection of subjects

[0109] 40 healthy men and women (age: 20 years old or older and 30 years old or younger) were selected as subjects. The 40 subjects were native Japanese speakers and right-handed. In Example 3, only right-handed subjects were selected for the same reasons as in Example 2. Among them, subjects who did not meet the following exclusion criteria were selected. The exclusion criteria refer to the above benchmarks, etc. (Saito et al., 2018).

[0110] Exclusion criteria

[0111] ·People with a history of mental illness, diabetes, brain nerve disease, or heart disease (heart disease)

[0112] Those who are currently taking drugs that affect cognitive function (such as benzodiazepines, antidepressants, and central nervous system drugs)

[0113] · Those who have difficulty distinguishing between red, blue, green, and yellow

[0114] People who may have allergic symptoms due to food intake (especially those who are allergic to bezoars, milk, soy, eggs, wheat, buckwheat, peanuts, shrimp or crab)

[0115] Currently participating in other studies other than this Example 3, have participated in other studies within one month before the start of the study, or are scheduled to participate in other studies during the study period

[0116] ・Those who are judged by the research leader (physician) or co-researchers as unsuitable as research subjects based on their self-reported medical history or nutritional supplement intake.

[0117] Before the test day, a number was assigned to each subject, and a number list was prepared in which the subject numbers were randomly divided into two groups by gender. The subjects were assigned to each group based on this number list.

[0118] According to the explanatory documents approved by the Ethics Committee of Tohoku University, the purpose and safety of the trial were explained to the subjects in written and oral forms, and then the subjects were allowed to participate in the trial after obtaining their written consent.

[0119] (3) Administration

[0120] The subjects were asked to take one tablet of the test preparation or the control preparation together with water or warm water.

[0121] The test preparation and the control preparation are provided to the researcher team by the applicant of the present application, that is, Kinyin Co., Ltd. The packaging of the preparation is printed with texts to identify each preparation. Moreover, the preparations are prepared and sent by employees who are not involved in the test in Kinyin Co., Ltd. The researcher is only informed of the identification method of the two preparations (identified by the printed text on the bottom). Therefore, the researcher is in a state where he does not know which one is the test preparation and which one is the control preparation, although he can distinguish the two preparations. Each preparation of the capsule type is a color of the same color system that cannot be distinguished by appearance, and is provided to the subject by the researcher. The test adopts a double-blind test, and the team of researchers who implement the test (that is, the research leader, the co-researcher, and the person in charge of distribution) and the subject do not know which preparation group it is until the test and analysis are all completed. The distribution information of the subject is opened after all the analyses are completed.

[0122] (4) Evaluation items and methods

[0123] Cognitive function tests were conducted to measure cognitive function. The cognitive function tests used the "Raven's Reasoning Test" and the "Japanese Reading Ability Test" to measure all cognitive functions. The Raven's Reasoning Test is a test in which a figure that matches the missing part of a certain figure is selected from multiple choice figures. The Japanese Reading Ability Test is a test in which questions are asked about the reading of Chinese characters. Each subject was tested only once for all cognitive functions.

[0124] As a working memory task, an N-back task is used. The N-back task is a task using words. In the N-back task, two tasks, 2-back and 0-back, are performed (see Figure 3 ).

[0125] In the 2-back task, for the text displayed at 2-second intervals, determine whether it is the same as the previous text. For example, when the text is displayed in the order of 4→2→4→2→8, the third displayed number "4" is the same as the first displayed number "4", so the button is pressed when the third "4" is displayed. In addition, the fourth displayed number "2" is the same as the second displayed number "2", so the button is pressed when the fourth "2" is displayed. In addition, when the fifth number "8" is displayed, since the third displayed number is "4", the numbers are different, so the button is not pressed.

[0126] In the 0-back task, the subject is asked to judge whether the designated character is displayed for the characters displayed at 2-second intervals. For example, if "4" is designated in advance, the subject presses the button when "4" is displayed.

[0127] In addition, NIRS (HOT1000, manufactured by NeU) was used to measure the brain activity of the left dorsolateral prefrontal cortex (DLPFC) of the subject in the process of implementing the N-back topic. NIRS uses a faint near-infrared light to measure the blood flow of the cerebral cortex part to measure brain activity, thereby, it is possible to measure the brain activity of DLPFC. In the measurement of brain activity, the 2-back topic and the 0-back topic were alternately repeated twice in a cycle of implementing each topic for 30 seconds and resting for 30 seconds before and after the topic. The two topics were implemented in the above manner before the preparation was taken, after 30 minutes of taking, and after 60 minutes of taking.

[0128] (5) Statistical analysis

[0129] The Rate Correct Score (RCS) was calculated using the accuracy and reaction time (i.e., the time to give an answer) of each N-back topic measured before, 30 minutes after, and 60 minutes after the ingestion of the preparation. RCS is an index that integrates the accuracy and reaction time of the N-back topic. In addition, a generalized linear mixed model (GLMM) was used to statistically test whether there was a difference in the effect on RCS or brain activity by ingesting the test preparation. The preparation (test preparation or control preparation) and the time of the test (before, 30 minutes after, and 60 minutes after the ingestion of the preparation) were used as fixed effects of the GLMM, the subject was used as a variable effect, and age and gender were used as covariates.

[0130] (6) Results and research

[0131] The calculation results of RSC for the 2-back task are as follows Figure 4 As shown in Figure 2, the brain activity measurements of the left DLPFC are as follows: Figure 5shown.

[0132] Comparing the test group with the control group in young adults, the test group performed better in the N-back task 60 minutes after taking the drug. In addition, the brain activity of the left DLPFC in the 2-back task was significantly improved in the test group.

[0133] According to the above research results, it can be considered that the improvement of cognitive functions such as memory is achieved by the antioxidant effect caused by the inhibition of reactive oxygen species, the inhibitory effect on cell damage caused by reactive oxygen species, etc. (i.e., long-term cell protection effect), etc. In this Example 3, by a single administration of 6-MSITC contained in the extract of the yam tree to young adults, a real-time effect on working memory was obtained for the first time 60 minutes after administration. In addition, this real-time effect was shown to be associated with an increase in blood flow to the DLPFC.

Claims

1. A blood flow increasing agent for increasing blood flow to the dorsolateral prefrontal cortex, It is characterized in that Contains 6-methylsulfinylhexyl isothiocyanate.

2. The blood flow increasing agent according to claim 1, It is characterized in that Cognitive function is improved and / or enhanced by increasing blood flow to the dorsolateral prefrontal cortex.

3. The blood flow increasing agent according to claim 2, It is characterized in that The cognitive function is episodic memory.

4. The blood flow increasing agent according to claim 2, It is characterized in that The cognitive function is working memory.

5. The blood flow increasing agent according to claim 4, It is characterized in that The blood flow increasing agent is administered as a single dose.

6. The blood flow increasing agent according to any one of claims 1 to 5, It is characterized in that The blood flow increasing agent is administered orally.

7. The blood flow increasing agent according to any one of claims 1 to 6, It is characterized in that The 6-methylsulfinylhexyl isothiocyanate is extracted from Behenium officinale or synthesized.

8. A blood flow enhancer for the dorsolateral prefrontal cortex, It is characterized in that Contains chayote extract.

9. A food product for increasing blood flow to the dorsolateral prefrontal cortex, It is characterized in that A method comprising the blood flow increasing agent according to any one of claims 1 to 8.

10. An activator of the dorsolateral prefrontal cortex for activating the dorsolateral prefrontal cortex, It is characterized in that Contains 6-methylsulfinylhexyl isothiocyanate.

11. A food for activating the dorsolateral prefrontal cortex, It is characterized in that Contains the activator according to claim 10.

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