JP6242746B2 - Medicines, foods, and compositions that improve memory learning function - Google Patents

Description

  The present invention relates to a composition having an action of maintaining, improving and improving brain functions such as improvement of learning ability and enhancement of memory ability, and a medicine and functional food and drink containing the composition as an active ingredient.

  In recent years, as brain functions have been elucidated, attempts have been actively made to search for substances that can improve brain functions such as learning ability and memory ability.

  For students such as junior high school students and high school students, it is desired to support improvement of memory and learning ability from the aspect of brain function when studying for exams and taking exams. In addition, there is an increasing need for learning and memory enhancement in a wide range of generations, such as young people who are in the brain development period, and working adults who live in a modern society that they often learn.

  From these viewpoints, natural products as foods that can be easily taken on a daily basis are actively searched for substances that can maintain, improve, and improve learning ability and memory ability. So far, it has been disclosed that docosahexaenoic acid contained in a large amount in herring and sardine fish oil and components contained in lactic acid bacteria fermented milk have an effect of improving brain development and brain function (Patent Documents 1 and 2). .

  The present inventor has found that a hop extract, which is a raw material for bittering beer and adding aroma, contains components that enhance brain functions such as learning ability and memory ability. Hops (scientific name: Humulus luplus) is a perennial herbaceous perennial plant in the family of cassaceae, and has long been used as a herb in Europe and the United States. Has been used as a folk medicine.

  For example, it has been reported that xanthohumol contained in a hop extract promotes the production of nerve growth factor (NGF) in the brain, even if the effect is limited to the cranial nervous system. (Patent Document 3). In addition, isohumulones are known to have various effects such as activation of the transcription factor Nrf2 and regulation of autonomic nerves (Patent Documents 4 and 5).

  However, so far, isohumulones contained in the hop extract have not been known to have any effect on the memory learning function and on the production of dopamine in the hippocampus. The present inventors have found that humulones contained in hop extracts and isohumulones isomerized from these humulones have the effect of maintaining, improving and improving brain function, particularly memory learning function, through dopamine production, and completed the present invention. did.

Japanese Patent Laid-Open No. 7-17855 Japanese Patent Laid-Open No. 9-23848 International Publication No. 2003/006037 International Publication No. 2006/043671 JP 2013-124237 A JP 2010-018631 A

Bethus, I., et al., J. Neurosci., 2010, Vol. 30 (5), pp. 1610-1618. Borta, A., & Hoglinger, G. U., J. Neurochem., 2007, Vol.100, pp.587-595. Money, K.M., & Stanwood, G.D., Front.Cell.Neurosci., 2013, Vol.7, Article 260 Bustos G., et al., Brain Res. Brain Res. Rev. Vol. 47, pp.126-144. Savitz J, et al., Genes Brain Behav., 2006, Vol.5, pp.311-328. Guillin, O. et al., Int. Rev. Neurobiol., 2004, Vol. 59, pp.425-444 Toshio Mikami, Journal of Nihon Medical University, 2012, Vol.8, pp.168-173. Yajima, H., et al., J. Biol. Chem., 2004, Vol.279, pp.33456-33462 Taniguchi, Y. et al., J. Agric. Food Chem., 2013, Vol.61, pp.3121-3130

  This invention makes it a subject to provide the composition which improves a memory learning function, the pharmaceutical containing this, and food-drinks. In particular, as a food that can be ingested on a daily basis, it is an object of the present invention to provide a drug with low risk of side effects and a food and beverage that can be easily ingested by using an ingredient contained in a natural product as an active ingredient.

The present invention is a composition for maintaining, improving and improving a memory learning function, wherein the active ingredient is represented by the formula (I):

[In the above formula, R ¹ and R ² represent a C _1-6 alkyl group or a C _2-6 alkenyl group, and R ³ and R ⁴ represent a hydroxyl group, a C _1-6 alkyl group, or a C _2-6 alkenyl group. R ³ and R ⁴ do not represent a hydroxyl group at the same time. ],

Formula (II):
[Wherein R ⁵ , R ⁶ and R ⁷ represent a hydrogen atom, a C _1-6 alkyl group or a C _2-6 alkenyl group, R ⁸ and R ⁹ represent a hydrogen atom, a hydroxyl group, C _1-6 Represents an alkyl group, a C _2-6 alkenyl group, —C (═O) R ¹⁰ , or —CH (—OH) R ¹⁰ , wherein R ¹⁰ represents a C _1-6 alkyl group or a C _2-6 alkenyl group. , R ⁸ and R ⁹ do not represent a hydroxyl group at the same time. ],

Formula (III):
[In the above formula, R ¹¹ and R ¹² represent a hydrogen atom, a C _1-6 alkyl group, or a C _2-6 alkenyl group, and R ¹³ and R ¹⁴ represent a hydroxyl group, a C _1-6 alkyl group, C _2-6. Represents an alkenyl group, —C (═O) R ¹⁵ , or —CH (—OH) R ¹⁵ , wherein R ¹⁵ represents a C _1-6 alkyl group or a C _2-6 alkenyl group, and R ¹³ and R ¹⁴ represent At the same time, it does not represent a hydroxyl group. ],

Formula (IV):
[In the above formula, R ¹⁶ , R ¹⁷ and R ¹⁸ represent a hydrogen atom, a C _1-6 alkyl group, or a C _2-6 alkenyl group. ], Or

Formula (V):

[In the above formula, R ¹⁹ represents a C _1-6 alkyl group or a C _2-6 alkenyl group. ]
Or a pharmaceutically acceptable salt or solvate thereof.

  In the present invention, maintaining the memory learning function means, for example, in senior citizens and the like, preventing a decrease in memory ability due to aging and maintaining memory ability and learning ability. Further, the improvement of the memory learning function means that the growth of the brain and the proliferation of nerve cells are promoted especially in the younger generation, and as a result, the memory learning ability is improved from the current level. Furthermore, the improvement of the memory learning function refers to recovery of a function that has once decreased or has a sign of decrease by promoting the proliferation of nerve cells or the improvement of information transmission between synapses.

  As a result of experiments using mice, the present inventors increase the production of dopamine, BDNF (Brain-derived neurotrophic factor) and IGF-1 (insulin-like growth factor) in the hippocampus by ingesting the above compounds. I found. It is known that dopamine production in the hippocampus enhances memory learning function (Non-patent Document 1). Furthermore, the result of the enhancement of the memory learning function was obtained from the experimental results using the Y-maze in mice.

  In addition, dopamine, BDNF, and IGF-1 have been shown to promote proliferation of nerve cells, contribute to brain development and development, and enhance memory learning function (Non-Patent Documents 2 to 7).

  The compound represented by the above chemical formula is a compound contained in a hop extract or an isomerized hop extract, and a derivative thereof (Patent Document 6). Therefore, a composition for improving the memory learning function can be obtained by extracting or synthesizing these compounds.

  The composition for maintaining, improving, and improving the memory learning function of the present invention is characterized in that the active ingredient is contained in a hop extract or an isomerized hop extract.

  As described above, the present inventors have found that hop extract or isomerized hop extract contains a component that improves and enhances the memory learning function. The composition of the present invention is a component in a hop extract or an isomerized hop extract, and is originally contained in beer and the like, so that it can be taken without worrying about side effects.

  Further, in the composition for maintaining, improving and improving the memory learning function of the present invention, the active ingredient is at least one of humulones, isohumulones, or a pharmacologically acceptable salt or solvate thereof. One or more.

  Among the above compounds, the active ingredients contained in the isomerized hop extract are collectively referred to as isohumulones. The humulonic acid contained in hop spikelets is converted into isohumulone, which is a bitter component of beer, in the brewing process of beer.

  Isohumulones have been reported to have various physiological functions so far, such as improvement of lipid metabolism and enhancement of microglia phagocytic activity. However, there has been no report regarding maintenance, improvement, and improvement of the memory learning function.

  The composition for maintaining, improving and improving the memory learning function of the present invention is characterized in that the improvement of the memory learning function is due to an increase in dopamine production.

  The present inventor has found that isohumulones maintain, improve and improve the memory learning function by increasing dopamine production. It has been reported that increased dopamine production in the hippocampus enhances memory, but isohumulones increase dopamine production in the hippocampus. Therefore, it is recognized that it is particularly effective in maintaining, improving, and improving the memory learning function by increasing dopamine production.

  The composition for maintaining, improving, and improving the memory learning function of the present invention is further characterized by containing docosahexaenoic acid (DHA).

  It is because it became clear that the effect of an isomerized hop extract is enhanced by using the active ingredient of the present invention together with DHA.

In the medicament or food for maintaining, improving and improving the memory learning function of the present invention, the active ingredient is represented by the formula (I):
[In the above formula, R ¹ and R ² represent a C _1-6 alkyl group or a C _2-6 alkenyl group, and R ³ and R ⁴ represent a hydroxyl group, a C _1-6 alkyl group, or a C _2-6 alkenyl group. R ³ and R ⁴ do not represent a hydroxyl group at the same time. ],

Formula (II):
[Wherein R ⁵ , R ⁶ and R ⁷ represent a hydrogen atom, a C _1-6 alkyl group or a C _2-6 alkenyl group, R ⁸ and R ⁹ represent a hydrogen atom, a hydroxyl group, C _1-6 Represents an alkyl group, a C _2-6 alkenyl group, —C (═O) R ¹⁰ , or CH (—OH) R ¹⁰ , wherein R ¹⁰ represents a C _1-6 alkyl group or a C _2-6 alkenyl group, R ⁸ and R ⁹ do not represent a hydroxyl group at the same time. ],

Formula (III):
[In the above formula, R ¹¹ and R ¹² represent a hydrogen atom, a C _1-6 alkyl group, or a C _2-6 alkenyl group, and R ¹³ and R ¹⁴ represent a hydroxyl group, a C _1-6 alkyl group, C _2-6. Represents an alkenyl group, —C (═O) R ¹⁵ , or CH (—OH) R ¹⁵ , wherein R ¹⁵ represents a C _1-6 alkyl group or a C _2-6 alkenyl group, and R ¹³ and R ¹⁴ are simultaneously It does not represent a hydroxyl group. ],

Formula (IV):
[In the above formula, R ¹⁶ , R ¹⁷ and R ¹⁸ represent a hydrogen atom, a C _1-6 alkyl group, or a C _2-6 alkenyl group. ], Or

Formula (V):
[In the above formula, R ¹⁹ represents a C _1-6 alkyl group or a C _2-6 alkenyl group. ]
Or a pharmaceutically acceptable salt or solvate thereof.

  By providing it as a medicine or food, it can be a product that maintains, improves, and improves the memory learning function according to the needs of various generations. In particular, by providing it as a food, it can be ingested on a daily basis, and brain growth and memory learning functions are improved in the younger generation, and memory learning functions are maintained and improved in the senior, and a wide range of memory and concentration It responds to the need to improve the brain function.

  The medicament or food for maintaining, improving, and improving the memory learning function of the present invention is characterized in that the active ingredient is contained in a hop extract or an isomerized hop extract.

  In order to maintain, improve, and improve the memory learning function, the active ingredient is a hop extract or an isomerized hop extract, that is, an ingredient contained in food such as beer. Or it shows that food can be provided.

  In the medicament or food for maintaining, improving and improving the memory learning function of the present invention, the active ingredient is at least one of humulones, isohumulones, or a pharmacologically acceptable salt or solvate thereof. One or more.

  Among the compounds represented by the above chemical formula, isohumulones known as beer's bitter ingredients have been found to have a high effect of improving and enhancing memory learning function, so foods with added isohumulones are so-called It shows that it can be provided as a functional food or drink.

  The medicinal product or food for maintaining, improving and improving the memory learning function of the present invention is characterized in that the improvement of the memory learning function is due to an increase in dopamine production.

  The inventors have confirmed that the above compounds increase dopamine production in the hippocampus. Therefore, it is considered that the increase in memory learning function that is maintained, improved, and improved by the increase in dopamine production is particularly effective.

  The medicament or food for maintaining, improving, and improving the memory learning function of the present invention further includes docosahexaenoic acid (DHA).

  Although it is known that DHA alone enhances the memory learning function, it has been revealed that it has a combined effect when taken together with the composition of the present invention. Even at a dose that cannot be expected with DHA alone, the effect of DHA can be enhanced and exhibited by using it together with the composition of the present invention.

The figure which shows the effect of the isomerization hop extract by a Y-shaped maze test. The figure which shows the effect of the isomerization hop extract by a novel object recognition test. The figure which shows the effect of isohumulone by a Y-shaped maze test. The figure which shows the effect of isohumulon by a novel object recognition test. The figure which shows the effect of humulon by a Y-shaped maze test. The figure which shows the additive action of the isomerization hop extract and docosahexaenoic acid by a Y-shaped maze test. The figure which shows the additive action of the isomerization hop extract and docosahexaenoic acid by a novel object recognition test. The figure which shows the effect of the isomerization hop extract in the alcohol induction amnesia model by a Y-shaped maze test. The figure which shows the neurotransmitter production induction by an isomerization hop extract. The figure which shows the influence on neurotransmitter production and metabolism by an isomerization hop extract. The figure which shows BDNF and IGF-1 production induction by an isomerization hop extract.

  The present inventor has found that isohumulones, which are bitterness components derived from hops, have an action of increasing production of dopamine, BDNF, and IGF-1. Isohumulones have been shown to be useful for the treatment of renal disorders associated with hypertension and for the treatment of diseases that can be treated by the activation of the transcription factor Nrf2, improvement of symptoms, lipid metabolism, and autonomic regulation. (Patent Documents 4 to 6). However, the present inventors have discovered for the first time about increasing the production of dopamine, BDNF, and IGF-1, and thereby can provide a composition, pharmaceutical, and food that improve and improve the memory learning function.

  In the present invention, the “composition” includes at least one of the compounds represented by formulas (I) to (V) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. . This composition has the effect | action which maintains, improves, and improves a memory learning function by increasing dopamine production.

  In the present invention, among the above formulas (I) to (V), there may exist stereoisomers such as geometric isomers and optical isomers, tautomers and the like. Including all possible isomers and mixtures thereof.

  In the present invention, the pharmaceutically acceptable salts of the compounds represented by the formulas (I) to (V) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts. And amino acid addition salts.

  Examples of the pharmaceutically acceptable acid addition salts of the compounds represented by the formulas (I) to (V) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, and fumarate. Organic acid salts such as acid salts, citrate salts, methanesulfonate salts, etc., and pharmaceutically acceptable metal salts include alkali metal salts such as sodium salts and potassium salts, alkali salts such as magnesium salts and calcium salts, for example. Examples include earth metal salts, aluminum salts, zinc salts, and the like, and pharmaceutically acceptable ammonium salts such as ammonium and tetramethylammonium salts, and pharmaceutically acceptable organic amine addition salts. Examples thereof include addition salts such as morpholine and piperidine, and examples of pharmaceutically acceptable amino acid addition salts include addition salts such as lysine, glycine and phenylalanine. It is.

  In the present invention, the “medicament” includes at least one of the compounds represented by formulas (I) to (V) as an active ingredient, and is mixed with a carrier, an excipient, a binder, a diluent, and the like. Can be manufactured. It can be administered orally or parenterally, and when administered orally, it may be in any form such as granules, powders, tablets, pills, capsules, syrups and the like. Examples of parenteral dosage forms include, but are not limited to, external preparations such as injections, drops, and nasal preparations.

  Moreover, in formulating, in addition to the active ingredient according to the present invention, one or more active ingredients may be further added. In particular, since DHA showed an enhancing effect on both short-term memory and long-term memory when administered together with isomerized hop extract, the component of isomerized hop extract is considered to have a different mechanism of action from DHA. It was. Therefore, when the active ingredient of the present invention and DHA are formulated or ingested so that they can be used in combination, the effect can be expected to be enhanced as compared with the case where each is ingested alone.

 In addition, when the compound of the present invention is administered as a pharmaceutical, in consideration of the following examples, the compounds represented by formulas (I) to (V), or a pharmaceutically acceptable salt thereof, or a solvate thereof The dosage and frequency of administration vary depending on the dosage form, patient age, body weight, nature or severity of symptoms to be treated, etc., but usually oral, 0.01 mg to 1 g per adult, preferably 0 Administer 0.05 to 100 mg once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.

  In the present invention, the “food” is anything other than pharmaceuticals, as long as it is ingestible, there is no particular limitation on the form thereof, and it may be liquid, semi-liquid, or solid, Also includes beverage-like forms.

  In addition, “food” includes health foods, functional foods, foods for specified insurance, dietary supplements, foods with a disease risk reduction label, foods for the sick, and so-called supplements. .

  In the present invention, isohumulones contained as a main component in the isomerized hop extract include isohumulone, isoadhumulone, isocohumulone, isoposthumulone, isoprehumulone, tetrahydroisohumulone, alloisohumulone, paraisohumulone, humunilic acid, hexahydroisohumulone. , Anti-isohumulone, and fupon, etc. are included, but any known one can be used without particular limitation.

The present invention will be described in detail by the following examples, but the present invention is not limited thereto.
[Example 1]
≪Enhancement of short-term memory by administration of isomerized hop extract≫
Isomerized hop extract (IHE, manufactured by Hopsteiner) prepared as 6-week-old male CD-1 mice at a dose of 0, 0.02, 0.2, 2.0 mg / kg isohumulone into the stomach After gavage, 40 minutes later, 0.75 mg / kg scopolamine hydrochloride (SCP) was administered intraperitoneally to induce amnesia. A Y-maze test was performed to evaluate spontaneous alternation behavior 20 minutes after administration of scopolamine (FIG. 1C).

  The mouse originally has a property of selecting a route different from the route selected immediately before. Therefore, when a mouse is put into a Y-shaped maze having three arms having the same width, length, etc., it normally enters an arm different from the arm that has just entered. The Y-shaped maze test is a test that uses the properties of mice to evaluate short-term memory.

  In the Y-maze test, the Y-maze, in which three arms, each having a length of 25 cm, a wall height of 20 cm, and a floor width of 5 cm, are connected at an angle of 120 degrees, is used as an experimental device. used.

The order of the arms that moved when the mouse was allowed to enter the tip of any arm of the Y-shaped maze and allowed to explore freely for 8 minutes was recorded. When different arms are selected three times in succession and entered, this is called spontaneous alternation. The total number of intrusions into the arm and the number of spontaneous alternation actions in time were counted, and the voluntary alternation behavior fluctuation rate (%) was calculated by the following formula (1).
Voluntary alternation behavior fluctuation rate (%) = number of voluntary alternation behavior / (total entry count−2) × 100
・ ・ ・ ・ ・ Formula (1)
The higher the voluntary alternation behavior fluctuation rate, the shorter the short-term memory is retained.

  The results are shown in FIG. The test was carried out with 10 animals per group, and the measured values are shown as mean value ± standard error. FIG. 1 (A) shows the spontaneous alternation behavior change rate (spontaneous alteration), and (B) shows the total number of entries (number of entries). In the case of scopolamine (SCP) administration, there is no significant variation in the total number of intrusions, indicating that there is no significant change in the amount of behavior even by administration of isomerized hop extract.

  On the other hand, as shown in FIG. 1 (A), in the group (SCP +) administered with scopolamine, the voluntary alternation behavior fluctuation rate is decreased as compared with the control group (SCP−). However, even in the scopolamine-administered group, by administering the isomerized hop extract, the voluntary alternation behavior change rate has been recovered in a dose-dependent manner, and the isomerized hop extract has the effect of improving short-term memory. It was seen. The isomerized hop extract was significantly improved by administration of 0.02 mg / kg of isohumulone, and it was clarified that even a very small amount of isomerized hop extract acts on the improvement of short-term memory. .

[Example 2]
≪Enhancement of long-term memory by administration of isomerized hop extract≫
Next, a novel object recognition test was performed to analyze the effect of isomerized hop extract on long-term memory.

  When a mouse originally recognizes it as a novel object, it approaches and performs a search action such as confirming its shape and smelling it. At this time, a search action is not performed on the stored object, or the search is performed for a shorter time than the novel object. The novel object recognition test uses this property.

  An outline of the experiment is shown in FIG. Two blocks X and Y having the same size as a golf ball are installed in a place 4 cm away from the adjacent corner of the container (floor is 38.5 cm × 38.5 cm, height is 40 cm). Six-week-old male CD-1 mice were treated with isomerized hop extract (IHE, manufactured by Hopsteiner) prepared as isohumulone doses of 0.0, 0.02, 0.2 and 2.0 mg / kg. Oral gavage. Sixty minutes after the administration, the mice were placed in this container, subjected to free search for 10 minutes, and returned to the cage after completion. This is an acquisition attempt.

  After 24 hours, each individual was orally administered the same dose of isomerized hop extract, placed again in the container in which the building blocks Y presented 24 hours ago were replaced with golf balls Z, and allowed to conduct a free search for 5 minutes. Each contact time with the object was measured. This is a test trial. The retention of memory is evaluated from the difference in the time length of the search action for both the objects X and Z.

  When the interval between the acquisition trial and the test trial is short, the mouse exhibits a long time searching action with a novel object (golf ball Z in this test), and its preference is increased with the interval between the acquisition trial and the test trial. Attenuate. Therefore, it is generally considered that the behavioral change with respect to novelty reflects “memory of object shape at the time of acquisition”.

  Using 10 mice in each group, the substance search time at the acquisition trial and the novel substance search time at the test trial were measured, and the Discrimination index was calculated by the formula (2). The results are shown in FIG.

Discrimination index = (search time for novel substance (seconds) −search time for substance at test trial (seconds)) / total search time (seconds) (2)
The higher the Discrimination index, the more memorized the shape of the object at the time of acquisition attempt is.

  As shown in FIG. 2 (A), the Discrimination index increased in a dose-dependent manner by administering the isomerized hop extract. It was shown that administration of isomerized hop extract preserved the memory of the shape of the object at the time of acquisition, ie enhanced long-term memory.

  The search time for a novel object (novel) and a non-new object (familiar) at the time of a test trial was measured, and the search time ratio (exploration time (%)) was calculated by the following formulas (3) and (4), and was plotted This is shown in FIG.

Search time ratio (familiar) = object X search time / total search time × 100
... Formula (3)
Search time ratio (novel) = object Z search time / total search time × 100
... Formula (4)
It is clear that administration of isomerized hop extract increases the search time ratio for novel objects depending on the dose.

Example 3
≪Effect of isohumulone on short-term memory≫
The isomerized hop extract contains various substances such as α acids (humulones) and β acids (luprons). Therefore, in order to analyze which component in the isomerized hop extract is derived from the effect on memory, the effect of cis-isoN humulone (cIH) and trans-isoN humulone (tIH) on short-term memory was examined. Cis-isoN humulone and trans-isoN humulone were used after purification by the method of Non-Patent Document 8.

  Isomerized hop extract (IHE) adjusted to 0.2 mg / kg as a dose of isohumulone to 6-week-old male CD-1 mice, or 0.2 mg / kg cis-isoN humulone (cIH); A Y-maze test was performed in the same manner as in Example 1 except that 2 mg / kg trans-isoN humulone (tIH) was forcibly orally administered into the stomach. The results are shown in FIG.

  As with the isomerized hop extract, cis-isoN humulone and trans-isoN humulone showed an effect of restoring amnesia induced by scopolamine. It was also shown that the effect is equivalent to isomerized hop extract. Therefore, it was considered that isohumulone in the isomerized hop extract has an effect of improving memory learning function.

Example 4
≪The effect of isohumulone on long-term memory≫
Next, the effect of isohumulone on long-term memory was examined. Isomerized hop extract (IHE) adjusted to 0.2 mg / kg as isohumulone to 6-week-old male CD-1 mice, or 0.2 mg / kg cis-isoN humulone, 0.2 mg / kg trans- A novel object recognition test was conducted in the same manner as in Example 2 except that an acquisition trial was performed by oral administration of iso-N humulone into the stomach. The results are shown in FIG.

  As with isomerized hop extract (IHE), cis-isoN humulone (cIH) and trans-isoN humulone (tIH) were effective in enhancing long-term memory. In view of these results, the component that maintains, improves, and improves the memory learning function found in isomerized hop extract is isohumulone, and the cis and trans isomers are considered to have almost the same effect.

Example 5
≪Effect of humron≫
We analyzed whether humulone before isomerizing hop extract had the same effect on the memory learning function. Humuron was used after being purified by the method of Non-Patent Document 9.

  6-week-old male CD-1 mice were treated with isomerized hop extract (IHE) prepared to 0.5 mg / kg as isohumulone, or 0.5 mg / kg and 5.0 mg / kg humulone (Humulone). A Y-maze test was conducted in the same manner as in Example 1 except that oral gavage was performed. The results are shown in FIG.

  Although humulone was less effective than isomerized hop extract, an effect of improving memory learning function was observed by administration of 5.0 mg / kg.

Example 6
≪Enhancement of short-term memory by administration of isomerized hop extract and docosahexaenoic acid≫
It is disclosed that docosahexaenoic acid (DHA) has the effect of improving brain function and enhancing learning ability and memory ability (Patent Document 1). Therefore, the effect on short-term memory when DHA and isomerized hop extract were used in combination was analyzed.

  In addition to administering DHA 5.0 mg / kg suspended in 0.5 w / v% methylcellulose (MC) solution and isomerized hop extract prepared to 0.5 mg / kg as isohumulone, either alone or in combination. Conducted a Y-shaped maze test in the same manner as in Example 1. In addition, what administered only the methylcellulose solution which is a solvent was set as control. The results are shown in FIG.

  Although both DHA and isomerized hop extract were effective in improving short-term memory alone, it was confirmed that the effect was enhanced by combined administration. Therefore, it was suggested that the action mechanism of DHA and isomerized hop extract is different. In addition, the amount of DHA administered in this experiment is the amount that is considered to have an effect on normal memory, but the isomerized hop extract shows a marked improvement in the voluntary alternation behavior fluctuation rate. It was. It was shown that isomerized hop extract has an excellent effect on short-term memory.

Example 7
≪Enhancement of long-term memory by administration of isomerized hop extract and docosahexaenoic acid≫
Next, the effect on enhancing long-term memory when DHA and isomerized hop extract were administered in combination was examined. The same procedure as in Example 2 was conducted except that isomerized hop extract prepared to 5.0 mg / kg DHA suspended in a methylcellulose (MC) solution and 0.5 mg / kg as isohumulone was administered alone or in combination. And a novel object recognition test. In addition, what administered only the methylcellulose solution which is a solvent was set as control. The results are shown in FIG.

  Both DHA and isomerized hop extract alone were effective in enhancing long-term memory, but the effect was enhanced by combined administration. Therefore, it was suggested that the mechanism of action of DHA and isomerized hop extract is also different for the effect on long-term memory. In addition, the isomerized hop extract showed a more remarkable effect compared to DHA.

Example 8
≪Experiment using alcohol bottle model≫
The effect of isomerized hop extract was examined using an ethanol-induced amnesia model known as an amnesia model with a mechanism of action different from that of SCP. It is known that ethanol itself acts as an agonist at the GABA _A receptor and induces an amnestic state.

  To induce amnesia in 6-week-old male CD-1 mice, 0.75 g / kg of ethanol was orally administered, and 40 minutes after that, it was prepared as 0,0.25,0.5 mg / kg as isohumulone The isomerized hop extract was forcibly administered orally into the stomach, and a Y-shaped maze test was conducted in the same manner as in Example 1 to evaluate short-term memory. The results are shown in FIG.

  As shown in FIG. 8, improvement of amnesia induced by ethanol in a dose-dependent manner was observed with the isomerized hop extract. The effect of improving short-term memory was observed in a model different from the amnesia model by SCP administration, suggesting that isomerized hop extract can be applied to various needs for improving memory learning effect.

Example 9
≪Induction of neurotransmitter production by isomerized hop extract≫
In order to analyze the mechanism of action of isomerized hop extract on memory learning function, we analyzed the production of neurotransmitters in the hippocampus.

  A microdialysis probe (AI-8-03, Aicom) was inserted into the hippocampus 3 days before the test using 8-week-old male SD rats treated with somnopentyl anesthesia. The position of the probe was set to -5.8 mm in the rear position from the hippocampus bregma, -4.8 mm in the lateral position, and 4 mm in the abdominal position. Two stainless steel screws were embedded as anchors in the skull and fixed together with the probe with dental cement to the skull.

  After a 3-day rest period, Ringer's solution was perfused at a flow rate of 2 μl / min for 3 hours under free action in a dedicated cage, and then the reflux solution was collected every 20 minutes. Then, isomerized hop extract prepared as isohumulone at 0, 0.5 and 1.5 mg / kg was orally administered, and the perfusate was collected for 50 minutes before administration and 100 minutes after administration. The collected brain perfusate was measured for dopamine and acetylcholine using an HPLC-ECD system (700 series, Aicom). The results are shown in FIG.

  The experiment was performed using 4 rats per group. When the total number of samples collected every 20 minutes when the solvent alone (0 mg / kg) is administered is 100, the relative value when 1.5 mg / kg isohumulone is administered is 189.84 ± 50. Therefore, it was shown that administration of isohumulone was effective in the production of dopamine in the hippocampus. On the other hand, no effect was observed against acetylcholine.

  Since enhancement of dopamine production in the hippocampus has been shown to have an effect on memory learning function (Non-patent Document 1), the effect of enhancing memory learning function observed in isomerized hop extract is due to increased dopamine production It was suggested that

  Therefore, isomerized hop extract was administered continuously for 10 days or once, and the influence of dopamine and dopamine on metabolite production was analyzed.

  Isomerized hop extract prepared as isohumulone at 0, 0.2, 0.6, and 1.8 mg / kg, once a day for 10 days to 6-week-old CD-1 mice in 7 mice per group Administration or single administration of 0, 0.2, 0.6 mg / kg was performed, and the hippocampus was extracted 1 hour after the final administration. The extracted hippocampus was subjected to deproteinization treatment, pretreated, and then subjected to HPLC-ECD system (700 series, Aicom) with dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3 -MT) and homovalinic acid (HVA) were quantified. The results are shown in FIG.

  Dopamine (DA) in the hippocampus and its metabolites dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovalinic acid (HVA) are all administered continuously or in a single dose. The dose increased in a dose-dependent manner.

  The increase in not only dopamine but also its metabolites showed that the metabolism was enhanced along with the production of dopamine, and it was revealed that the produced dopamine is functionally functioning.

  In recent years, it has been suggested that dopamine is involved not only as a neurotransmitter but also in the proliferation of neurons and brain development in adults (Non-Patent Documents 2 and 3). The above experimental results showed that the production of dopamine in the hippocampus was enhanced, and thus the present composition was considered effective for maintaining, improving and improving brain function through induction of dopamine production.

  Therefore, maintenance, improvement, and improvement of memory learning ability can be expected by ingesting medicines and foods containing humulones and isohumulones as components. Since dopamine and its metabolites were increased both by continuous administration and by single administration, the effect is expected both when taken daily and when taken once.

Example 10
≪Effect of isomerized hop extract on BDNF and IGF-1 production≫
Dopamine further promotes the survival, growth, and neogenesis of nerve cells by promoting the production of humoral factors such as BDNF (Brain-derived neurotrophic factor) and IGF-1 (insulin-like growth factor) that promote brain development. It is said that there is (Non-Patent Documents 4 to 7).

  Therefore, the effect of isomerized hop extract on the production of these growth factors was analyzed.

  Seven groups of 6-week-old male CD-1 mice were orally administered once daily with isomerized hop extract prepared to 0.6 mg / kg as isohumulone. Three hours after the final administration, the hippocampus was excised, and BDNF (Promega) and IGF-1 (R & D Systems) contained in the hippocampus were quantified using an ELISA kit. The results are shown in FIG.

  It was shown that the production of BDNF and IGF-1 was increased compared to the control. It was considered that isohumulone contained in the isomerized hop extract induces dopamine production and further induces production of BDNF and IGF-1.

  From the above results, maintenance, improvement and improvement of the memory learning function are expected by the production of dopamine by isohumulone and the production of BDNF and IGF-1 induced by dopamine.

Therefore, daily intake of this composition is expected to satisfy the needs for maintaining, improving and improving memory learning functions from young to senior.

Claims (12)

Maintaining the memory and learning function, a counter top to order of the composition,
A composition, wherein the active ingredient is at least one of humulones or isohumulones or a pharmaceutically acceptable salt or solvate thereof. Maintaining the memory and learning, as in claim 1, in countercurrent over to because of the composition,
A composition wherein the active ingredient is contained in an isomerized hop extract. In the composition for maintaining and improving the memory learning function according to claim 1 or 2,
The active ingredient is isohumulones,
  A composition comprising 0.081 to 13.00 mg / day of isohumulones as a human equivalent dose. Maintaining the memory and learning, as in claim 1 or 2, in countercurrent over to because of the composition,
A composition, wherein the active ingredient is at least one of cis-isoN humulone, trans-isoN humulone, humulone, or a pharmacologically acceptable salt or solvate thereof. Claims 1-4 maintain the memory and learning function according to any one, in countercurrent over to because of the composition,
Maintenance of the memory and learning functions, improvement above, composition characterized in that due to an increase in dopamine production. Claim 1-5 maintain the memory and learning function according to any one, in countercurrent over to because of the composition,
Furthermore, docosahexaenoic acid (DHA) or composition characterized and Turkey be administered in combination with these pharmaceutically acceptable salts. Maintain the memory and learning function, a counter-top to order food in,
Active ingredient humulones or isohumulones or food characterized in that at least any one or more of these pharmaceutically acceptable salt or solvate. Maintaining the memory and learning function according to claim 7, wherein, in the direction on to order the food,
The active ingredient, food you characterized in that included in the isomerized hop extract. In the food for maintaining and improving the memory learning function according to claim 7 or 8,
The active ingredient is isohumulones,
A food containing 0.081 to 13.00 mg / day of isohumulones as a human equivalent dose. Maintaining the memory and learning function according to claim 7 or 8, wherein in improvement on to order the food,
The active ingredient is cis - iso N humulone, trans - iso N humulone or humulone or food you characterized in that at least any one or more of a pharmaceutically acceptable salt or solvate thereof. Maintaining the memory and learning function according to claim 7 to 10 any one of claims, in countercurrent above to order the food,
Maintenance of the memory and learning functions, improvement above, food you wherein a due to an increase in dopamine production. Claims 7 to 11 maintain storage learning function according to any one, in countercurrent above to order the food,
Furthermore, docosahexaenoic acid (DHA) or food characterized and Turkey be administered in combination with these pharmaceutically acceptable salts.