Cognitive function improving agent

Abstract

To provide a novel agent effective for improving a cognitive function.SOLUTION: Disclosed is a cognitive function improver that contains propolis, curcumin and ginkgo leaf extract as active ingredients.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a composition, an antioxidant, an anti-glycation agent, a neurite outgrowth promoter, and a cognitive function improver.

Background Art

[0002] In recent years, the number of dementia patients has been increasing, becoming a social problem. Moreover, even among non-dementia patients, many people are troubled by forgetfulness or decline in cognitive function. Dementia includes disease types such as Alzheimer's dementia, vascular dementia, Lewy body dementia, frontotemporal lobar degeneration (FTLD), etc. The majority of dementia patients are those with Alzheimer's dementia. The accumulation of amyloid-β protein in the brain is involved in dementia. For example, Patent Document 1 discloses an oral composition containing a specific peptide as an active ingredient for improving brain dysfunction caused by amyloid-β.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] Although many treatment methods for dementia have been studied so far, they are only therapeutic agents that temporarily slow down the progression, and those with a fundamental therapeutic effect have not been established. In particular, as a method for removing amyloid-β, a fundamental treatment method has not been established. Prevention at the stage when the symptoms of cognitive function decline are mild and in a reversible phase is important.

[0005] An object of the present invention is to provide a novel agent effective for improving cognitive function.

Means for Solving the Problems

[0006] One aspect of the present invention relates to an antioxidant or anti-glycation agent containing propolis and ginkgo leaf extract as active ingredients.

[0007] The present invention also relates to a neurite outgrowth promoter containing propolis and ginkgo leaf extract as active ingredients.

[0008] The present invention also relates to a cognitive function improving agent containing propolis and ginkgo leaf extract as active ingredients.

[0009] Preferably, the above agent does not contain at least one of DHA and EPA.

[0010] Another aspect of the present invention relates to an antioxidant containing propolis and at least one selected from the group consisting of phosphatidylserine, coffee fruit extract, and gotu kola extract.

[0011] The present invention also relates to an anti-glycation agent containing propolis and at least one selected from the group consisting of phosphatidylserine, coffee fruit extract, and curcumin.

[0012] The present invention also relates to a cognitive function improving agent containing propolis and at least one selected from the group consisting of phosphatidylserine, coffee fruit extract, gotu kola extract, and curcumin.

[0013] The present invention also relates to an anti-inflammatory agent containing propolis and curcumin.

[0014] Yet another aspect of the present invention relates to a composition containing propolis and at least one of phosphatidylserine and coffee fruit extract.

[0015] The present invention also relates to a food or pharmaceutical product containing propolis and gotu kola extract.

[0016] Another aspect of the present invention relates to a composition comprising propolis, ginkgo leaf extract, coffee fruit extract, gotu kola extract, curcumin, and phosphatidylserine.

Advantages of the Invention

[0017] The present invention provides a novel agent effective for improving cognitive function.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0019] Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[0020] One aspect of the present embodiment relates to a composition comprising propolis and at least one selected from the group consisting of ginkgo leaf extract, phosphatidylserine, coffee fruit extract, gotu kola extract, and curcumin. The composition may be a food, quasi-drug, or pharmaceutical.

[0021] A composition comprising propolis and at least one selected from the group consisting of ginkgo leaf extract, phosphatidylserine, coffee fruit extract, gotu kola extract, and curcumin can be used as an antioxidant, an antiglycation agent, a neurite outgrowth promoter, and a cognitive function improver. Ginkgo leaf extract, phosphatidylserine, coffee fruit extract, gotu kola extract, and curcumin, when ingested in combination with propolis, exhibit a higher effect in at least one action selected from the group consisting of antioxidant, antiglycation, and neurite outgrowth promoting effects than when each component is used alone, and have a high cognitive function improving effect based on these actions.

[0022] By ingesting a combination of propolis and curcumin, a synergistic effect is exerted in the Nrf2 pathway activation action compared to using each component alone. It is known that activation of the Nrf2 pathway brings about anti-inflammatory, antioxidant, and cognitive function improving effects. Therefore, a composition containing propolis and curcumin can be used not only as an antioxidant or a cognitive function improver but also as an anti-inflammatory agent. Furthermore, a composition containing propolis and curcumin has liver function improving, sleep quality improving, and cognitive function improving effects based on its anti-inflammatory action. Therefore, a composition containing propolis and curcumin can also be used as a liver function improver or a sleep quality improver.

[0023] Another aspect of the present embodiment is a composition containing propolis, ginkgo leaf extract, phosphatidylserine, coffee fruit extract, gotu kola extract, and curcumin. By containing all of these components, the composition has high antioxidant, antiglycation, anti-inflammatory, and neurite outgrowth promoting effects, and based on these effects, has high sleep quality improving, liver function improving, and cognitive function improving effects. Each component will be described below.

[0024] (Propolis) Propolis can be obtained as a beekeeping product, for example, according to conventional methods. Propolis itself has effects such as antioxidation, anti-inflammation, and suppression of cognitive function decline. Propolis can be derived from any plant, such as from alecrin, eucalyptus, poplar, or plants of the genus Curcuma. From the perspective of high physiological activity, propolis derived from alecrin is preferred. Alecrin is Baccharis dracunculifolia of the genus Baccharis in the Asteraceae family.

[0025] Propolis can be, for example, of Japanese origin, Brazilian origin, Chinese origin, from European countries, from Oceania, from the United States, etc. Brazilian propolis is mainly derived from alecrin. Brazilian propolis is characterized by a high content of cinnamic acid derivatives. The antioxidant, anti-glycation agent, neurite outgrowth promoter, cognitive function improver, anti-inflammatory agent, liver function improver, and sleep quality improver according to this embodiment (hereinafter, also collectively referred to as "the agent according to this embodiment") preferably contain Brazilian propolis as an active ingredient.

[0026] Propolis can be of any rank, such as brown, red, yellow, green, super green, ultra green, etc. Among these, green, super green, or ultra green rank propolis is preferred. These ranks are determined by the content of artepillin C in propolis. Those with an artepillin C content of 3% by mass or more are called green propolis. The artepillin C content in propolis is preferably 5% by mass or more, and more preferably 8% by mass or more.

[0027] Propolis is preferably derived from bees belonging to the genus Apis of the family Apidae, and more preferably from the Western honey bee (Apis mellifera) among the genus Apis. The Western honey bee is said to have 24 to 28 subspecies, and propolis derived from any of these subspecies may be used. In particular, it is preferable to use propolis derived from Africanized honey bees, which are hybrids between the African honey bee (A. mellifera scutellata), one of the subspecies of the Western honey bee, and European subspecies of other Western honey bees.

[0028] Propolis may be, for example, a propolis mass, or a processed propolis product obtained by subjecting the propolis mass to some treatment. The processed propolis product may be, for example, a product obtained by subjecting the propolis mass to treatments such as grinding, extraction, concentration or powdering of the extract, granulation of the powder, etc., or may be the extraction residue remaining after extraction. That is, the processed propolis product may be, for example, a ground product of propolis, an extract, a concentrated extract, an extract powder, an extract granule, an extraction residue, etc. The extraction may be, for example, water extraction, hydrophilic organic solvent extraction, supercritical extraction, etc. Examples of the hydrophilic organic solvent include ethanol, glycerin, 1,3-butylene glycol, etc. The propolis extract may be obtained by extracting from the propolis mass, or may be obtained by further extracting from the residue after extraction. The treatment method may be one, or two or more methods may be combined. Among the processed propolis products, the propolis hydrophilic organic solvent extract is preferable because the active ingredients of propolis are efficiently and well-balancedly extracted in a short time. The processed propolis product is preferably a propolis ethanol extract.

[0029] As propolis, commercially available products may be used. Commercially available products containing propolis include, for example, Propolis 300, Propolis Liquid 30 (produced in Brazil), Propolis Granules, Propolis Granule APC, Propolis Mild, Propolis Drink from Yamada Bee Farm Co., Ltd., Neo Propolis Granules, Propolis Granules, Propolis Liquid, Propolis Mild Liquid, Eucalyptus Propolis from Morikawa Koutankyou Co., Ltd., La Beaute Propolis (liquid type), La Beaute Propolis (capsule type), La Beaute Propolis Honey from La Beaute Co., Ltd., and the like.

[0030] The above agent or composition can be used at a dose of, for example, 1 mg to 1000 mg per day for an adult weighing 60 kg as the solid content of propolis, preferably at a dose of 10 to 500 mg, and more preferably at a dose of 20 to 200 mg.

[0031] Also, the content of propolis in the above agent or composition, as the solid content, may be, for example, 1% by mass or more, 3% by mass or more, 4% by mass or more, or 5% by mass or more, and may be 30% by mass or less, 20% by mass or less, 10% by mass or less, or 8% by mass or less, based on the total amount of the agent or composition.

[0032] (Ginkgo biloba leaf extract) The Ginkgo biloba leaf extract is an extract obtained from the leaves of Ginkgo biloba L. The Ginkgo biloba leaf extract itself has effects such as improving cerebral blood flow and anti - inflammation. The extraction solvent may be, for example, alcohol such as ethanol, organic solvents such as acetone, water, or a mixture thereof. It is preferably water. The Ginkgo biloba leaves as the extraction raw material may be fresh, dried, or in powder form. The Ginkgo biloba leaf extract may be obtained by further processing such as purification, concentration, and drying of the extract obtained from Ginkgo biloba leaves. The Ginkgo biloba leaf extract may be one from which ginkgolic acid has been removed by resin column purification or the like.

[0033] In the agent or composition according to this embodiment, the blending ratio of propolis and ginkgo leaf extract may be, for example, 1:0.2 to 5, 1:0.3 to 2, 1:0.5 to 2, 1:1 to 2, or 1:1.3 to 1.9 as solid content.

[0034] The above agent or composition can be used at a dose of 1 mg to 1000 mg per day for an adult weighing 60 kg, preferably at a dose of 10 to 500 mg, and more preferably at a dose of 20 to 200 mg, as the solid content of the ginkgo leaf extract.

[0035] In addition, the content of the ginkgo leaf extract in the above agent or composition may be, for example, 1% by mass or more, 3% by mass or more, 5% by mass or more, or 7% by mass or more, and may be 30% by mass or less, 20% by mass or less, 15% by mass or less, or 12% by mass or less, as the solid content, based on the total amount of the agent or composition.

[0036] (Phosphatidylserine) Phosphatidylserine may be a synthetic product or may be derived from plants or animals. Phosphatidylserine can be obtained, for example, by an enzymatic reaction using plant-derived lecithin such as soybean lecithin as a raw material. Phosphatidylserine itself has effects such as improving memory and cognitive function.

[0037] In the agent or composition according to this embodiment, the ratio of propolis to phosphatidylserine may be, for example, 1:1 to 5, preferably 1:1 to 3, and more preferably 1:1.5 to 2.5.

[0038] The above agent or composition can be used at a dose of 1 mg to 1000 mg per day for an adult weighing 60 kg, preferably at a dose of 10 to 500 mg, and more preferably at a dose of 50 to 300 mg, as the solid content of phosphatidylserine.

[0039] The content of phosphatidylserine in the above agent, as a solid component, may be, for example, 1% by mass or more, 5% by mass or more, 7% by mass or more, or 10% by mass or more with respect to the total amount of the agent or composition, and may be 30% by mass or less, 20% by mass or less, 17% by mass or less, or 15% by mass or less.

[0040] (Coffee fruit extract) The coffee fruit extract is obtained by extracting from coffee fruits. Coffee fruits are the fruits of coffee trees and may include the outer skin, pulp, mucilage, husk, stem, and seeds. It is preferable to use Arabica coffee beans. The extraction solvent may be, for example, alcohols such as ethanol and methanol, organic solvents such as acetone, water, or a mixture thereof. The coffee fruit extract may be obtained by further purifying, concentrating, drying, etc. the extract obtained from coffee fruits.

[0041] The coffee fruit extract itself has effects such as neuroprotection. By ingesting the coffee fruit extract, the blood concentration of a protein called BDNF increases. BDNF is a component necessary for promoting the generation, growth, and regeneration of nerve cells and is also called the nutrition of the brain.

[0042] In the agent or composition according to this embodiment, the ratio of propolis to the coffee fruit extract may be, for example, 1:0.5 to 3, preferably 1:0.8 to 2, and more preferably 1:1 to 1.7.

[0043] The above agent or composition can be used in a dose of 1 mg to 1000 mg per day for an adult weighing 60 kg, preferably in a dose of 10 to 500 mg, and more preferably in a dose of 20 to 200 mg, as the solid component of the coffee fruit extract.

[0044] The content of the coffee fruit extract in the above agent or composition may be, for example, 1% by mass or more, 3% by mass or more, 5% by mass or more, or 7% by mass or more, and may be 30% by mass or less, 20% by mass or less, 15% by mass or less, 12% by mass or less, or 10% by mass or less, based on the total amount of the agent as the solid content.

[0045] (Curcumin) Curcumin is a pigment component contained in plants such as turmeric (Curcuma longa). Curcumin itself has effects such as antioxidant, anti-inflammatory, amyloid-β suppression, and intestinal barrier. Curcumin can be extracted, for example, from turmeric rhizomes by a known method. The turmeric extract may be, for example, one obtained by extracting from turmeric rhizomes using water, hot water, an organic solvent such as ethanol, or a mixed solution thereof as an extraction solvent. The agent or composition according to this embodiment may contain, for example, the root of turmeric or its extract as a curcumin source. The above agent or composition may contain turmeric-derived components other than curcumin. Curcumin may be one with enhanced absorbability by a known method such as micronization.

[0046] In the agent or composition according to this embodiment, the ratio of propolis to curcumin may be, for example, 1:2 to 5, preferably 1:2.5 to 4, and more preferably 1:2.7 to 3.7.

[0047] The above agent or composition can be used at a dose of 1 mg to 1000 mg per day for an adult weighing 60 kg, preferably at a dose of 10 to 500 mg, and more preferably at a dose of 100 to 350 mg, as the solid content of curcumin.

[0048] The content of curcumin in the above agent or composition may be, for example, 5% by mass or more, 10% by mass or more, 15% by mass or more, or 17% by mass or more, and may be 40% by mass or less, 30% by mass or less, 25% by mass or less, or 23% by mass or less, based on the total amount of the agent or composition as the solid content.

[0049] (Gotsu cola extract) The centella asiatica extract can be obtained by extracting from centella asiatica (Centella asiatica Umbelliferae). The centella asiatica extract itself has effects such as improving cognitive function and improving neuropathy. Centella asiatica is also called gotu kola. The extraction site of centella asiatica may be flowers, flower spikes, pericarp, fruits, stems, leaves, branches, branch leaves, trunks, barks, rhizomes, root barks, roots, seeds or whole herbs. The extraction site of centella asiatica is preferably leaves, stems or whole herbs. The extraction solvent may be, for example, water or an alcohol such as ethanol. The centella asiatica extract may be obtained by further purifying, drying, etc. the extract obtained from the plant body.

[0050] In the agent or composition according to this embodiment, the ratio of propolis to the centella asiatica extract may be, for example, 1:1 to 6, preferably 1:2 to 5, and more preferably 1:2.5 to 4.

[0051] The above agent or composition can be used at a dose of, for example, 1 mg to 1000 mg per day for an adult weighing 60 kg as the solid content of the centella asiatica extract, preferably at a dose of 10 to 500 mg, and more preferably at a dose of 100 to 350 mg.

[0052] The content of the centella asiatica extract in the above agent or composition, as the solid content, may be, for example, 1% by mass or more, 5% by mass or more, 10% by mass or more, 15% by mass or more, or 18% by mass or more, and may be 40% by mass or less, 30% by mass or less, 25% by mass or less, or 23% by mass or less with respect to the total amount of the agent or composition.

[0053] The above agent or composition preferably contains at least a combination of propolis and ginkgo leaf extract.

[0054] The above agent or composition may not contain at least one of DHA and EPA, and may not contain both DHA and EPA. In particular, when the above agent contains propolis and ginkgo leaf extract, since these components are included as active ingredients, a sufficiently high effect can be obtained even without containing DHA and EPA. The above agent or composition may also contain GABA, or may not contain it.

[0055] The above agent or composition can be used as a pharmaceutical, quasi-drug or food itself, and can also be used as a component in a pharmaceutical, quasi-drug or food.

[0056] The cause of Alzheimer's dementia has been thought to be the accumulation of amyloid-β. However, in recent years, it has become clear that amyloid-β is produced as a defense reaction against multiple threats in the brain, such as inflammation, nutritional deficiency, and the presence of toxins. Therefore, it is considered that in order to improve cognitive function, it is more effective to eliminate the cause of its production rather than trying to remove amyloid-β itself.

[0057] Inflammation in the brain is said to be caused by, for example, excessive intake of trans fatty acids, gluten or casein, and excessive intake of carbohydrates, etc., and obesity, deterioration of the oral environment, or invasion of pathogens are also considered to be the causes. Brain nutritional deficiency is considered to be caused by deficiency of nutrients such as hormones, vitamins, and minerals necessary for brain nerve cells, and lack of exercise. It is said that the brain will atrophy when the nutrition of the brain nerves is insufficient. Toxins are caused by toxic metals, toxins derived from molds, etc. Furthermore, dementia such as Alzheimer's is also caused by glycotoxicity due to hyperglycemia as a mixed type of inflammatory and atrophic. In addition, damage caused by intracerebral hemorrhage caused by arteriosclerosis or the like may also be the cause of dementia. That is, there are five types of dementia such as Alzheimer's: inflammatory, glycotoxic, atrophic, toxic, and vascular.

[0058] The agent or composition according to this embodiment not only contains, as components, those that individually exhibit various effects such as anti-inflammatory, antioxidant, anti-glycation, blood glucose level improvement, insulin resistance improvement, brain nerve protection, promotion of brain nerve regeneration, liver protection, protection of brain cells from endotoxin, and improvement of cerebral blood flow, but also, by containing components in combination with propolis, at least effects such as antioxidant, anti-glycation, anti-inflammatory, and promotion of neurite outgrowth are exerted higher than the sum of the effects of each component alone (additive effect). Therefore, the agent or composition according to this embodiment exhibits a high effect in improving cognitive function as a whole. Further, the agent or composition according to this embodiment also has the effects of improving liver function and improving the quality of sleep based on its anti-inflammatory action. Also, as described above, since the agent or composition according to this embodiment leads to prevention of the production and accumulation of amyloid-β, it can be used as a preventive agent for cognitive function decline.

[0059] From the viewpoint of bringing about high effects against all of the above five types of inflammatory, glycotoxic, atrophic, toxic, and vascular types, it is particularly preferable that the agent according to this embodiment contains all of propolis, ginkgo leaf extract, phosphatidylserine, coffee fruit extract, gotu kola extract, and curcumin. Since all of the above components contained in the agent or composition according to this embodiment can be used as foods, they also have the advantage of being easily ingested daily.

[0060] The agent according to this embodiment can also be used as an agent for improving or preventing dementia such as Alzheimer's disease, or an agent for improving or preventing mild cognitive impairment.

[0061] The administration subjects of the antioxidant, anti-glycation agent, neurite outgrowth promoter, and cognitive function improver according to this embodiment may be healthy individuals, dementia patients such as Alzheimer's disease patients, individuals with mild cognitive impairment which is the stage before dementia, individuals at risk of cognitive function decline, individuals who are aware of forgetfulness, individuals who have been pointed out by others for forgetfulness, individuals with sleep disorders, or individuals who need to improve liver function. The subject may be, for example, 45 years old or older, or may be an elderly person of, for example, 60 years old or older, 65 years old or older, 70 years old or older, or 75 years old or older.

[0062] The antioxidant, anti-glycation agent, neurite outgrowth promoter, and cognitive function improver according to this embodiment are considered to be particularly effective in those with low plasma BDNF (brain-derived neurotrophic factor) concentration and / or low brain BDNF concentration. The plasma BDNF concentration and the brain BDNF concentration are said to be correlated. The administration subjects of the antioxidant, anti-glycation agent, neurite outgrowth promoter, and cognitive function improver according to this embodiment may be those with a plasma BDNF concentration of, for example, 120 ng / ml or less, 110 ng / ml or less, 100 ng / ml or less, 90 ng / ml or less, 85 ng / ml or less, 79 ng / ml or less, or 78 ng / ml or less. The plasma BDNF concentration of the administration subject may be 10 ng / ml or more, 30 ng / ml or more, or 50 ng / ml or more. Also, the administration subject may be one with a plasma BDNF concentration that is less than or equal to the median value, less than or equal to the average value, or less than the first quartile among the plasma BDNF concentrations of a plurality of subjects.

[0063] The agent or composition according to this embodiment may further contain other components. Examples of other components include pharmaceutically acceptable components (e.g., excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizing agents, suspending agents), and food-acceptable components (e.g., minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, coloring agents, fragrances, stabilizers, preservatives, sustained-release regulators, surfactants, solvents, wetting agents).

[0064] The agent or composition according to this embodiment may be in any form such as solid, liquid, paste, etc., and includes tablets (including plain tablets, sugar-coated tablets, effervescent tablets, film-coated tablets, chewable tablets, troches, etc.), capsules, pills, powders (powders), fine granules, granules, liquids, suspensions, emulsions, syrups, pastes, injections (including the case of being formulated as a liquid by mixing with an infusion such as distilled water, amino acid infusion, or electrolyte infusion during use), and other dosage forms. These various preparations can be prepared, for example, by mixing the agent or composition obtained by the above-described method with other components as necessary and shaping them into the above dosage forms.

[0065] When used as a food composition or as a component of a food composition, it is preferable that the food composition emphasizes the tertiary function of food, that is, the body-condition regulating function. Examples of products that emphasize the tertiary function of food include health foods, foods with function claims, foods with nutritional functions, dietary supplements, supplements, and foods for specified health uses.

[0066] The agent or composition according to this embodiment is preferably ingested into the body. The administration mode may be oral administration or parenteral administration. The agent or composition according to this embodiment may be administered once a day or may be administered in multiple divided doses such as twice a day or three times a day.

Example

[0067] Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to the following examples.

[0068] [Test Example 1: Evaluation of Neurite Outgrowth Activity] Preventing cell death by targeting the transport of nerve growth factor (NGF) to cholinergic neurons, and promoting cognitive improvement by NGF stimulating cholinergic receptors at synapses have been reported. Immature cells often take a spherical shape and tend to have characteristic structures during the process of differentiation and acquisition of functionality. In the case of nerve cells, numerous protrusions are formed during terminal differentiation to become neurons. In this study, PC12 was primed in the direction of nerve differentiation by pre-treating with NGF at a low concentration (10 ng / ml), and then the sample was added to analyze the effect on the nerve differentiation-inducing ability of the sample.

[0069] The following were used as samples to be evaluated. Propolis (Propolis ethanol extract, API Propolis, EEP - B55A): Dissolved in ethanol for molecular biology at a concentration of 10 mg / mL, passed through a 0.2 μm filter, and stored at -80°C was used. Ginkgo leaf extract (aqueous extract, Tokiwa Phytochemicals): Dissolved in dimethyl sulfoxide (DMSO) at 100 mg / mL, passed through a 0.2 μm filter, and stored at -80°C was used. Nerve growth factor-β (rat-derived)

[0070] The following cells and media were used. Cells: PC12 (JCRB0733, 06082017) Medium: CCM (Completely Culture Medium) RPMI 1640 10% horse serum 5% fetal bovine serum 1% penicillin - streptomycin (Nacalai Tesque) DM (Differentiation Medium): RPMI 1640 2% horse serum 1% fetal bovine serum 1% penicillin - streptomycin 10 ng / mL NGF-β Culture conditions: 37°C, 5% CO2

[0071] CCM was used as the medium for subculturing PC12 cells. Subculturing was performed when the cell confluence reached 70%. Before use in the experiment, cell subculturing was performed more than 3 times to provide a period for cell stabilization. When inducing neural differentiation, 0.8×10 4 cells per well were seeded in 2 mL of CCM diluted in a 6-well plate and cultured overnight. The medium was replaced with DM, and then cultured for 48 hours. 48 hours after replacing with DM, the medium was replaced with DM medium with different additional conditions for each well, and time-lapse observation was performed using a fluorescence microscope (Keyence, BZ-X800). As the additional conditions, propolis alone (25 μg / mL), ginkgo leaf extract alone (10 μg / mL), and co-addition of propolis (25 μg / mL) and ginkgo leaf extract (10 μg / mL) were performed respectively.

[0072] During the 17-hour culture, for each well, three photos were taken every 15 minutes. The total number of cells in the field of view and the number of cells with neurites longer than the cell body were counted. Without considering the number of protrusions per cell, a cell with at least one protrusion longer than the cell body was defined as a cell with extended protrusions. After adding up the number of cells in each well, numerical comparison and analysis of each condition were performed. The number of cells with extended protrusions relative to the total number of cells observed after 17 hours was evaluated as the neurite formation rate (%). The results are shown in Figure 1 and Figure 2.

[0073] Figure 1 is a phase-contrast microscope photograph of PC12 cells after 17-hour culture, showing cells of control (DMSO), propolis alone addition, ginkgo leaf extract alone addition, and co-addition of propolis and ginkgo leaf extract in order from the left. Figure 2 is a graph showing the neurite formation rate under each condition. Error bars indicate the mean ± SD (n = 3). It was shown that the elongation of neuronal neurites was promoted in the combined treatment of propolis and ginkgo leaf extract compared with the control, propolis alone addition, and ginkgo leaf extract alone addition.

[0074] [Test Example 2: Antioxidant Evaluation] An antioxidant evaluation test was conducted using menadione as an oxidative stress inducer. It has been reported that the treatment of cultured cells with menadione generates reactive oxygen species (ROS) intracellularly and induces cell death due to oxidative stress. Therefore, menadione is used to evaluate materials with a protective effect against oxidative stress on cells.

[0075] Normal human keratinocytes were seeded at 3×10 4 cells / cm 2 onto a 24-well plate previously supplemented with 500 μl of keratinocyte growth medium. After culturing for 24 hours, the medium was replaced with a medium supplemented with menadione, an oxidative stress inducer, at 0 or 100 μM. In addition, to the medium supplemented with 100 μM menadione, propolis was added at 10 or 50 μg / ml, ginkgo leaf extract was added at 17 or 86 μg / ml, or a combination of ginkgo leaf extract and propolis was added at a concentration ratio of 1:1.7, at 10 or 50 μg / ml and 17 or 86 μg / ml, respectively.

[0076] One hour after administration of the test substance, the oxidative stress level of the cells was evaluated using CellROX green, an oxidative stress detection reagent. The cell count was also evaluated by the number of nuclei by Hoechst 33342 staining. The oxidative stress level was calculated as the fluorescence intensity per cell, obtained by dividing the fluorescence intensity of CellROX green by the number of nuclei, with the oxidative stress level of menadione alone set as 100%. The results are shown in Figure 3.

[0077] Figure 3 is a graph showing the oxidative stress levels at each concentration in the cases of adding propolis alone, adding ginkgo leaf extract alone, and co - adding ginkgo leaf extract and propolis. Error bars indicate the mean value ± SD. When adding propolis alone and adding ginkgo leaf extract alone, the oxidative stress levels were decreased in a concentration - dependent manner, respectively. When co - adding propolis and ginkgo leaf extract, it showed higher antioxidant activity than alone. From the above results, it was shown that the combination of propolis and ginkgo leaf extract increases the oxidative stress protection effect.

[0078] [Test Example 3: ORAC Test] The antioxidant ability of the combination of propolis and each sample was verified by an ORAC (Oxygen Radical Absorbance Capacity) test. The following were used as samples. Propolis: Ethanol extract powder (Brazilian green propolis, containing arginine as an excipient.) Phosphatidylserine: Synthetic product Coffee fruit extract: Water / ethanol extract powder Gotu kola extract: Water extract powder (containing less than 10% maltodextrin as an excipient.)

[0079] Each sample was dissolved in a 50% ethanol aqueous solution. As follows, samples that did not dissolve in the ethanol aqueous solution were suspended, and after performing shaking extraction at 100 rpm for 10 minutes and ultrasonic extraction for 10 minutes, or only ultrasonic extraction for 10 minutes, centrifugation was performed at 3000 rpm for 10 minutes to obtain the supernatant. Phosphatidylserine: After shaking extraction and ultrasonic extraction, centrifugation Propolis + Phosphatidylserine: Only ultrasonic extraction (without centrifugation) Gotu kola extract, Propolis + Gotu kola extract: After ultrasonic extraction, centrifugation Samples other than the above: Only dissolution (without extraction process and centrifugation)

[0080] The obtained test solution was diluted with 75 mM phosphate buffer and placed in a 96-well plate, and a fluorescein solution was added. While the 96-well plate was heated at 37 °C, AAPH (2,2’-azobis(2-methylpropionamidine) dihydrochloride) was added, and the decay time of the fluorescence intensity was measured every 5 minutes for 1.5 hours using a microplate reader. A standard curve was created using Trolox as a standard reagent, and the antioxidant capacity of each sample was calculated as Trolox equivalent (μmolTE / g). The results are shown in Table 1.

[0081]

Table 1

[0082] In Table 1, the expected value is the sum of the ORAC values of each component alone in each combination. The increase rate is the value obtained by multiplying the measured value divided by the expected value by 100. It was shown that phosphatidylserine, coffee fruit extract, and Gotu kola extract synergistically increase the antioxidant capacity when combined with propolis.

[0083] [Test Example 4: Measurement of AGEs] The antiglycation ability of the combination of propolis and each sample was verified by an AGEs (advanced glycation end products) measurement test. As samples, propolis, phosphatidylserine, coffee fruit extract, curcumin, and ginkgo leaf extract were used. For propolis, phosphatidylserine, and coffee fruit extract, the same ones as in Test Example 3 were used. As the ginkgo leaf extract, ginkgo leaf ethanol·water extract powder was used. As the curcumin source, turmeric extract (ethyl acetate extract powder, curcumin content 95% by mass) was used.

[0084] Each sample was dissolved in 100% dimethyl sulfoxide. 12 μL of the resulting solution or ultrapure water, 40 μL of 20 mg / mL human serum albumin solution, and 50 μL of 0.4 mol / L glucose solution or ultrapure water were combined and placed in a 1.5 mL tube. After thoroughly mixing the liquid in the tube using a vortex, it was incubated at 60 °C for 40 hours. The solution after the reaction was dispensed into a 384-well plate, irradiated with excitation light at 370 nm, and the fluorescence at 440 nm was measured to calculate the amount of AGEs produced. The AGEs production inhibition rate was calculated by the following formula. The results are shown in Table 2. AGEs production inhibition rate (%) = {1 - (A - B) / (C - D)} × 100 A: Amount of production in the mixed solution of sample solution, albumin solution, and glucose solution B: Amount of production in the mixed solution of sample solution and albumin solution C: Amount of production in the mixed solution of albumin solution and glucose solution D: Amount of production in albumin solution

[0085]

Table 2

[0086] In Table 2, the expected value of the AGEs production inhibition rate for each combination is the sum of the production inhibition rates shown for each component used alone in the combination. The increase amount is the value obtained by subtracting the expected value from the measured value. When propolis was combined with phosphatidylserine, coffee fruit extract, curcumin, or ginkgo leaf extract, the AGEs production inhibition rate was significantly higher than that in the case of each alone. It was confirmed that by combining propolis with phosphatidylserine, coffee fruit extract, curcumin, or ginkgo leaf extract, a higher anti-glycation effect can be obtained than with the components alone.

[0087] [Test Example 5: Evaluation of Nrf2 Pathway Activation] Nrf2 is a transcription factor activated by oxidative stress, and genes related to antioxidant and detoxification metabolism exist downstream of it. It has been reported at the animal level that the Nrf2 pathway affects dementia, and improvement of cognitive function by activation of Nrf2 is expected. In this study, PC12 / ARE reporter cells, in which the antioxidant response element (ARE), a transcriptional response sequence downstream of Nrf2, was incorporated into a reporter vector, were used for the test to examine the synergistic effect of Nrf2 pathway activation.

[0088] <Cell culture> PC12 / ARE reporter cells (hereinafter referred to as PC12 / ARE) provided by Kobe Pharmaceutical University were used. These cells were prepared by stably integrating into PC12 cells a promoter region containing the ARE sequence of the rat-derived NADPH:quinone oxidoreductase 1 (NQO1) gene, which is a downstream gene of Nrf2, upstream of the luciferase gene.

[0089] Basic medium: Each factor was added to RPMI-1640 medium (Nacali, Code: 30264-85) to a final concentration of 10% fetal bovine serum (FBS, BioWest), 5% horse serum (HS, Gibco), 1× penicillin / streptomycin (Nacali, Code: 09367-34), and 200 μM L-glutamine (Nacali, Code: 16948-04) for preparation. Maintenance medium: Hygromycin B (Wako, Cat: 085-06153) was added to the above basic medium to a concentration of 300 μg / mL for preparation for selection of the reporter cell line. PC12 / ARE was maintained and passaged according to the PC12 / ARE culture protocol. The medium was changed once every 2 to 3 days.

[0090] <Reporter assay> PC12 / ARE was seeded at a density of 1×10 4They were seeded in a 384-well plate (white plate) so that the cell density was 20 cells / 20 μL / well. The basal medium was used for the culture. After overnight culture, 5 μL of the sample was added. Further, 25 μL of ONE-Glo® Luciferase Assay Reagent (Promega, Cat: E6120) was added 24 hours later. After incubation for 3 minutes, the reporter activity was measured using Envision (PerkinElmer).

[0091] <Sample Preparation> Propolis, curcumin, and ginkgo leaf extract were each suspended in DMSO at a concentration of 50 mg / ml and stirred for 1 hour. After centrifugation, the supernatant was obtained. The propolis, curcumin, and ginkgo leaf extract used were the same as those used in Test Example 3 or 4. The supernatant was filtered through a 0.22-μm filter, dispensed, and stored at -30°C. Each sample was dissolved at the time of the test and diluted with DMSO and the basal medium.

[0092] <ARE Reporter Activity> PC12 / ARE cells were added with propolis at a concentration of 4.5 μg / ml, curcumin at a concentration of 13.8 μg / ml, and ginkgo leaf extract at a concentration of 6.6 μg / ml, either alone or in the combinations shown in Table 3. The reporter activity after 24 hours was measured. As a result, a synergistic effect was observed in the combination of propolis and curcumin, and the combination of propolis, curcumin, and ginkgo leaf extract, compared to the case where each component was added alone.

[0093] [Table 3]

[0094] [Test Example 6: Human Biological Test] A composite supplement containing propolis extract, ginkgo leaf extract, phosphatidylserine, curcumin, coffee fruit extract, and gotu kola extract was administered to humans to verify its effect.

[0095] <Subjects> Ninety subjects who met all of the following selection criteria and did not meet any of the following exclusion criteria were enrolled in the study. 1) Selection criteria · Men and women aged 40 or older and younger than 80 at the time of obtaining consent · Those with a Mini-Mental State Examination (MMSE) score of 24 or more and 29 or less · Those who are aware of having memory loss or those who have been pointed out by others as having memory loss 2) Exclusion criteria · Those who have been diagnosed by a doctor as having dementia or those who have a disease that may affect cognitive function · Those who are taking or have taken dementia medications · Those who regularly take medications that may affect cognition (first-generation antihistamines, benzodiazepines, sedatives, opioids, stabilizers, antidepressants, cholinergic agents, anticholinergic agents, prescription anti-inflammatory drugs) · Those with a current or past history of mental disorders (including depressive symptoms) or cerebrovascular diseases · Those who regularly use supplements or health foods (including foods with functional claims) that may affect cognitive function · Those whose lifestyle habits such as diet and sleep were extremely irregular as a result of the subject background questionnaire · Those with a score of 6 or more on the Geriatric Depression Scale-Short Version-Japanese (GDS-S-J) · Those with a past or current history of alcohol dependence · Those who consume a large amount of alcohol daily (those who drink more than 14 bottles of 350 mL beer or less than 180 mL wine per week) · Those with a current or past history of serious diseases such as diabetes, liver disease, kidney disease, and heart disease · Those with a past or current history of drug dependence or food allergy · Those with color vision impairment or those who have difficulty hearing people's voices even at close range · Those with problems in the function of both hands due to injury, surgery, etc.

[0096] <Test Food> The dosage of the composite supplement was set at 3 capsules (hard capsules) per day. The composite supplement contains, in 3 capsules, propolis (4.25 mg as artepillin C), curcumin 175 mg, soy-derived phosphatidylserine 100 mg, ginkgo leaf extract (28.8 mg as flavonoid glycosides derived from ginkgo leaves and 7.2 mg as terpene lactones derived from ginkgo leaves), gotu kola extract (225 mg), and coffee fruit extract (100 mg). Each component is the same as that used in Test Example 3 or 4. The composite supplement further contains fine silica dioxide and the like as additives. The placebo was made by replacing the above components with starch, and the composite supplement and the placebo were made to have similar appearances to each other so that they could not be distinguished among foods. The component compositions (daily intake, per 3 capsules) of the composite supplement and the placebo are as shown in Table 4.

[0097]

Table 4

[0098] <Test Method and Schedule> This test obtained the deliberation and approval of the Test Review Committee of Nihonbashi Cardiovascular Clinic, and complied with the Helsinki Declaration (amended at the 2013 VMA Fortaleza General Assembly) and the Ethical Guidelines for Medical Research Involving Human Subjects. The test protocol was registered in the Clinical Trial System of the University Hospital Medical Network.

[0099] The test design was a placebo-controlled randomized parallel-group double-blind comparative human clinical trial. After fully explaining the purpose and method of this test to the subjects, written consent was obtained voluntarily. The subjects were assigned to two groups so that age, gender, Body-Mass Index (BMI), and MMSE would be equal.

[0100] Pre-intake examinations (height, weight, blood pressure, pulse, MMSE, GDS-S-J, Mild Cognitive Impairment (MCI) screen, Cognitrax, blood tests, various Visual Analog Scales (VAS), MOS 36-Item Short-Form Health Survey (SF-36)) were conducted from October to November 2019. From mid-November 2019 to late February 2020, placebo or compound supplements were taken three capsules a day with normal-temperature water for 12 weeks. Also, 12 weeks after the intake, height, weight, blood pressure, pulse, MCI screen, Cognitrax, blood tests, various VAS, and SF-36 were conducted. During the test period, the subjects were asked to record in a diary every day whether they had taken the test food, whether there were changes in physical condition, whether there were changes in living conditions, exercise status, intake status of pharmaceuticals and health foods, interpersonal communication status, and sleep status.

[0101] <Test items> (MCI screen) The term Mild Cognitive Impairment (MCI) is used to mean the prodromal state of dementia. With the development of new treatment methods, early diagnosis of dementia has become important, so the diagnosis of MCI has attracted attention. The MCI screen is a cognitive function test developed by Shankle et al. to comprehensively evaluate memory and attention. Among the MCI screens, the MPI score and the immediate memory task score were measured. The MPI score mainly comprehensively evaluates the scores of the immediate memory task and the delayed memory task.

[0102] (Cognitrax) Cognitrax is a general cognitive test based on CNS Vital Sign. In this test, Verbal Memory Test (VBM), Visual Memory Test (VIM), Finger Tapping Test (FTT), SDC Test (SDC), Stroop Test (ST), Attention Shift Test (SAT), Continuous Performance Test (CPT), and Four-Part Continuous Performance Test (FPCPT) were conducted and evaluated with standardized scores (average 100), which are conversion values based on comparison with people of the same age. Based on these tests, ST false responses were evaluated.

[0103] (Blood test) Blood was collected from the subjects, and the amounts of tumor necrosis factor (TNF-α, serum), BDNF (plasma), and AST as a liver function index were measured. TNF-α is known as a cytokine deeply involved in the body's defense mechanism through inflammation. AST is released into the blood when hepatocytes are damaged, and inflammation is considered one of the causes. TNF-α and AST were evaluated by LSI Medience Corporation, and BDNF was evaluated by Nippon Research Zyle Co., Ltd., Japan Institute of Aging Control.

[0104] (Subjective symptoms (VAS)) VAS is a test for detecting subjective symptoms. Regarding the quality of sleep, it was evaluated by the question "How is the quality of your sleep?". A straight line was shown on the screen, with the left end (0) of the straight line being "very bad" and the right end (100) being "very good", and the subject's state at that time was marked on the straight line.

[0105] (SF-36) Among the SF-36, an evaluation scale for QOL (quality of life), social life function (the degree to which social interaction was hindered for physical or psychological reasons in the past month) was evaluated. The scores were scored based on the national standard values (norm-based scoring: NBS) and calculated as standard scores (average 50).

[0106] (Statistical analysis) The measured values were shown as mean ± standard deviation. The within-group comparison 12 weeks after drinking compared to before intake was performed by paired t-test, and the between-group comparison between the composite supplement group and the placebo group was performed by Student's t-test. Also, the between-group comparison was similarly performed for the change amount (Δ) 12 weeks after intake based on before intake. All the tests were two-sided tests. The statistical analysis software used was SPSS Ver. 25 (IBM Japan, Ltd.).

[0107] (Subjects for analysis) A total of 90 subjects (45 in each group) participated in the trial. Among them, for 7 subjects, including 2 subjects (1 in the placebo group and 1 in the compound supplement group) whose AST, ALT, and γ-GTP, which are liver function indicators reported to be related to cognitive function, decreased from abnormal values (before intake) to less than half (after 12 weeks of intake), 1 subject (in the compound supplement group) whose blood pressure fluctuation before and after intake, which is reported to be related to cognitive function, was an outlier (< mean - 3SD), 1 subject (in the placebo group) who stopped taking the blood pressure treatment drug during the trial period, 2 subjects (1 in the placebo group and 1 in the compound supplement group) whose hsCRP, which is one of the inflammatory markers reported to be related to cognitive function, had an outlier fluctuation (> mean + 3SD) before and after intake, and 1 subject whose weight fluctuation before and after intake was an outlier (< mean - 3SD), it was highly likely that their lifestyle could not be kept constant, and it was judged that there might be an adverse effect on the accuracy of verifying the impact on cognitive function, so they were excluded from the analysis.

[0108] For 1 subject whose inspection time of the MCI screen after intake was extremely short compared to before intake and was an outlier (< mean - 3SD), it was highly likely that the cognitive function test after 12 weeks of intake could not be properly evaluated, so this subject was excluded from the analysis. Therefore, the number of cases for analysis was 82. Also, for 1 subject (in the compound supplement group) who abandoned the 4-part continuous processing test of Cognitrax during the inspection after intake, the items involving the results of the 4-part continuous processing test after intake were treated as missing values. The background of the subjects for analysis is shown in Table 5. There were no significant differences between the groups in terms of age, gender, BMI, and MMSE.

[0109]

Table 5

[0110] <Results> (Cognitive function test) The results of the MCI screen are shown in Table 6. In terms of the change amount (Δ) of the MPI score and the immediate memory task score after 12 weeks of intake based on before intake, significant improvements were observed in the compound supplement group compared to the placebo group (P = 0.047 and P = 0.010 respectively).

[0111]

Table 6

[0112] The results of Cognitracks are shown in Table 7. In terms of the change amount (Δ) of ST false responses, which are components of comprehensive attention and cognitive flexibility, a significant improvement was observed in the compound supplement group compared to the placebo group (P = 0.023).

[0113]

Table 7

[0114] The results of the blood test are shown in Table 8. In terms of the change amount (Δ) of AST and TNF-α 12 weeks after ingestion compared to before ingestion, a significant improvement was observed in the compound supplement group compared to the placebo group (P = 0.014 and P = 0.026, respectively).

[0115]

Table 8

[0116] The results of the subjective symptoms (VAS) are shown in Table 9. In terms of the change amount (Δ) of the subjective symptoms of the quality of sleep 12 weeks after ingestion compared to before ingestion, a significant improvement was observed in the compound supplement group compared to the placebo group (P = 0.016).

[0117]

Table 9

[0118] The results of SF-36 are shown in Table 10. In terms of the change amount (Δ) of social life function (the degree to which interpersonal contact was hindered for physical or psychological reasons in the past month) 12 weeks after ingestion compared to before ingestion, a significant improvement was observed in the compound supplement group compared to the placebo group (P = 0.030).

[0119]

Table 10

[0120] As a result of verifying the effect of the intake of the composite supplement on cognitive function in this test, the composite supplement group showed significant improvement in ST false responses (CogniTrax), MPI score (MCI screen), immediate memory task score (MCI screen), TNF-α, AST, subjective symptoms of sleep quality, and social life function (SF-36) compared with the placebo group.

[0121] The ST test is a test in which the subject answers according to the screen about the correspondence between the meaning of characters and colors. While two different types of information, language information and color vision information, interfere with each other, it is known as a test that can evaluate the attention and concentration to direct consciousness to the target information and the judgment ability to process information and make accurate judgments. In addition, since ST false responses (errors in answering the ST test) are components of overall attention and cognitive flexibility (the ability to process in response to changes in instructions = judgment ability), improvement in ST false responses is considered to mean improvement in concentration (the ability to maintain concentration), attention (the ability to maintain attention and respond accurately), and judgment ability (the ability to process information and make accurate judgments). In addition, since the MCI screen is a cognitive function test that requires language memory and attention developed by Shankle et al., improvement in the MPI score, which is its overall score, is considered to mean improvement in language memory and attention, and regarding the improvement in attention, it is consistent with the results of CogniTrax. Specific examples in daily life for the improvement of attention include "driving a car safely for a long time" and "not missing a red light".

[0122] <Subgroup analysis> It is known that BDNF in the brain decreases in dementia patients compared with healthy people, and that the BDNF concentrations in blood and the brain are correlated. Therefore, the group with a BDNF concentration below the first quartile was classified as a group with a high risk of cognitive function decline, and a subgroup analysis was performed on the CogniTrax test results. There were no significant differences between the groups in terms of background age, gender, BMI, and MMSE (Table 11).

[0123] The analysis results are shown in Table 12. Compared with the placebo group, in the amount of change (Δ) 12 weeks after ingestion based on the pre-ingestion level, significant improvements were observed in the neurocognitive index (P = 0.001), cognitive flexibility (P = 0.022), executive function (P = 0.026), and SAT correct response (P = 0.012), which is a component of cognitive flexibility, in the composite supplement group.

[0124]

Table 11

[0125]

Table 12

[0126] As a result of performing subgroup analysis regarding CogTrack in the population where the BDNF concentration is less than the first quartile, significant improvements were observed in the neurocognitive index, cognitive flexibility, executive function (the ability to understand rules and concepts and make decisions), and SAT correct response, which is a component of cognitive flexibility. Cognitive flexibility is calculated as "SAT correct response - SAT incorrect response - ST incorrect response", executive function is calculated as "SAT correct response - SAT incorrect response", the SAT test is a test to answer according to the screen regarding the correspondence between the shape and color of the figures, and since it is very similar to the ST test, it is considered that the improvement of both cognitive flexibility and executive function means the improvement of attention, concentration, and judgment.

[0127] In this study, in addition to the improvement in cognitive function, an improvement in TNF-α was also observed. Since it has been reported that the rate of decline in cognitive function in those with acute or chronic systemic inflammation is 2 to 4 times that in those without systemic inflammation, the compound supplement may contribute to the improvement of sleep quality through its anti-inflammatory effect. Also, it has been reported that sleep quality and inflammation are related, and there are reports that anti-TNF-α therapy contributes to the improvement of sleep quality. Therefore, it is considered that the compound supplement contributes to the improvement of sleep quality through its anti-inflammatory effect. In addition, since it has been reported by meta-analysis that the risk of developing dementia is 1.51 times higher in insomnia, it is considered that the improvement of the subjective symptoms of sleep quality also contributes to the improvement of cognitive function.

[0128] In addition, AST, which was improved in this study, is released into the blood when hepatocytes are damaged, and inflammation is considered to be one of the causes. From this, it is possible that one of the mechanisms for the improvement of liver function markers is an anti-inflammatory effect. Also, social life function, which is one of the components of SF-36 improved in this study, is an index representing the degree to which interpersonal communication is hindered for physical or psychological reasons. Cognitive function decline is considered to affect social life such as interpersonal communication, as shown by phenomena such as "not being able to express what you want to say immediately", "not remembering what you said", "not being able to recall what happened just now", and "repeatedly buying foods that are already in the refrigerator in large quantities". Therefore, it is considered that the effectiveness on cognitive function observed this time leads to the improvement of social life function.

[0129] As described above, it was confirmed that the combination of propolis and curcumin synergistically increases Nrf2 activity. Also, as shown in Test Example 1, it was confirmed that the combination of propolis and ginkgo leaves synergistically promotes neurite outgrowth. Nrf2 is a transcription factor that is activated in response to oxidative stress, and it has been reported that Nrf2 activation improves cognitive function. Neurite outgrowth is thought to contribute to brain development. Therefore, it is considered that each component containing propolis exerts an antioxidant, anti-inflammatory, and neurite outgrowth-promoting effect synergistically, thereby exerting an effect on maintaining and improving cognitive function. It was confirmed that the composite supplement improves not only cognitive functions such as language memory, attention, concentration, and judgment but also the quality of sleep and the state of liver function through antioxidant, anti-glycation, anti-inflammatory effects, etc.

Claims

[Claim 1] A cognitive function improver containing propolis, curcumin and ginkgo leaf extract as active ingredients (excluding those containing guarana water extract).

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