Composition for treating cognitive dysfunction

Abstract

The present invention relates to: a pharmaceutical composition for treating or preventing cognitive dysfunction, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and a food composition for preventing or alleviating cognitive dysfunction. The compound has an effect of treating or alleviating cognitive dysfunction, and thus can be used as an active ingredient of a pharmaceutical composition and a food composition for treating cognitive dysfunction.

Description

Composition for the treatment of cognitive dysfunction

[0001] The present invention relates to a composition for treating cognitive dysfunction.

[0002]

[0003] Amnesia, commonly referred to as forgetfulness, refers to a condition in which memory for facts, information, or experiences is lost. Amnesia can be categorized into anterograde amnesia, in which the patient can recall events that occurred before brain damage but has difficulty recalling information afterward, and retrograde amnesia, in which the patient cannot recall past events or previously familiar information after brain damage. Causes of amnesia include stroke, inflammatory responses due to viral infections in the brain, lack of oxygen in the brain, excessive alcohol consumption (Korsakoff's syndrome), brain cancer, administration of sedatives such as benzodiazepines, and epilepsy.

[0004] Meanwhile, scopolamine is a nonspecific muscarinic anticholinergic drug that is known to decrease learning and cognitive abilities by interacting with cholinergic receptors and is known to cause amnesia by interfering with long-term potentiation in the hippocampus and other areas.

[0005]

[0006] In the present invention, we aimed to evaluate whether cognitive dysfunction such as amnesia is improved by administering a sobrerol compound to a scopolamine-induced amnesia mouse model.

[0007]

[0008] In the present invention, in a scopolamine-induced amnesia mouse model, administration of NRM-331 (sobrerol) was observed to increase avoidance time in the passive avoidance test, decrease movement time and movement distance in the Morris water maze test, and increase the number of stays (crossing number), and decrease amyloid-β 1-40 and 1-42 in the blood, increase acetylcholine and decrease acetylcholine hydrolase in the brain, increase neurons in the hippocampus region of the brain, and decrease p-Tau, confirming the memory-improving effect. In particular, when 100 mg / kg / day of the test substance NRM-331 (sobrerol) and 2 mg / kg / day of the positive control substance Aricept were comprehensively evaluated, it was confirmed that they had similar memory-improving effects, and thus the present invention was completed.

[0009] The purpose of the present invention is to provide a pharmaceutical composition for treating or preventing cognitive dysfunction, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] In addition, another object of the present invention is to provide a food composition for improving or preventing cognitive dysfunction, comprising a compound represented by chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.

[0011] In addition, another object of the present invention is to provide a method for preventing or treating cognitive dysfunction, comprising a step of administering to a subject a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0012] In addition, another object of the present invention is to provide a use of the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for preventing or treating cognitive dysfunction.

[0013] In addition, another object of the present invention is to provide a use of the compound represented by chemical formula 1 or a food-wise acceptable salt thereof for the manufacture of a food for improving or preventing cognitive dysfunction.

[0014]

[0015] The compound represented by chemical formula 1 of the present invention has an effect of treating or improving cognitive dysfunction, and therefore can be applied as a pharmaceutical composition and food composition for treating cognitive dysfunction.

[0016]

[0017] Figure 1 shows the results of measuring the body weight of experimental animals.

[0018] +: significantly different between G1 and G2, P<0.05

[0019] Underline: Not equal variance (Welch's t-test)

[0020] Figure 2 shows the change behavior using the Y-maze test.

[0021] +: significantly different between G1 and G2, P<0.05

[0022] Underline: Not equal variance (Welch's t-test)

[0023] Figure 3 shows the results of avoidance time measurement using a passive avoidance test device.

[0024] ++: significantly different between G1 and G2, P<0.01

[0025] **: significantly different from G2, P<0.01

[0026] Figure 4 shows the movement time required to find the platform using the Morris water maze test.

[0027] ++: significantly different between G1 and G2, P<0.01

[0028] **: significantly different from G2, P<0.01

[0029] Underline: Not equal variance (G2, G7: Welch's t-test, G3-G6: Dunnett post-hoc test)

[0030] Figure 5 shows the distance traveled to find the platform using the Morris water maze test.

[0031] ++: significantly different between G1 and G2, P<0.01

[0032] *: significantly different from G2, P<0.05

[0033] **: significantly different from G2, P<0.01

[0034] Underline: Not equal variance (G2, G7: Welch's t-test, G3-G6: Dunnett post-hoc test)

[0035] Figure 6 shows the number of stays (cross number) using the Morris water maze test.

[0036] ++: significantly different between G1 and G2, P<0.01

[0037] **: significantly different from G2, P<0.01

[0038] Underline: Not equal variance (Dunnett post-hoc test)

[0039] Figure 7 shows the levels of Amyloid-β (1-40) and Amyloid-β (1-42) in serum.

[0040] +: significantly different between G1 and G2, P<0.05

[0041] ++: significantly different between G1 and G2, P<0.01

[0042] *: significantly different from G2, P<0.05

[0043] Underline: Not equal variance (G2, G7: Welch's t-test, G3-G6: Dunnett post-hoc test)

[0044] Figure 8 shows the levels of acetylcholine and acetylcholinesterase in brain tissue.

[0045] ++: significantly different between G1 and G2, P<0.01

[0046] **: significantly different from G2, P<0.01

[0047] Underline: Not equal variance (G2, G7: Welch's t-test, G3-G6: Dunnett post-hoc test)

[0048] Figure 9 shows the number of neuronal cell bodies in the cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and dentate gyrus (DG) regions of the hippocampus using Nissl stain.

[0049] Figure 10 shows the results of quantitative analysis of p-Tau in the CA1, CA3, and DG regions of the hippocampus using immunohistochemical staining, in relative proportions, based on the negative control group (G2).

[0050] ++: significantly different between G1 and G2, P<0.01

[0051] *: significantly different from G2, P<0.05

[0052] **: significantly different from G2, P<0.01

[0053] In the above Figures 1 to 10, G1: normal control group (Saline, n=10), G2: negative control group (Saline, n=10), G3: test substance administration group (NRM-331, 20 mg / kg / day, n=10), G4: test substance administration group (NRM-331, 40 mg / kg / day, n=10), G5: test substance administration group (NRM-331, 80 mg / kg / day, n=10), G6: test substance administration group (NRM-331, 100 mg / kg / day, n=10), G7: positive control group (Aricept, 2 mg / kg / day, n=10).

[0054]

[0055] The following describes this specification in more detail.

[0056] This is specifically explained as follows. Meanwhile, each description and embodiment disclosed in the present invention can also be applied to other descriptions and embodiments thereof. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0057] Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0058] The terms or words used in the description and claims of the present invention should not be interpreted as limited to their usual or dictionary meanings, but should be interpreted as meanings and concepts that conform to the technical idea of ​​the present invention, based on the principle that the inventor can appropriately define the concept of the term to explain his or her own invention in the best way.

[0059]

[0060] In order to achieve the above-described purpose of the present invention, in one embodiment, the present invention provides a pharmaceutical composition for treating or preventing cognitive dysfunction, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0061] In the present invention, the compound represented by the chemical formula 1 is Sobrerol (5-(2-hydroxypropan-2-yl)-2-methylcyclohex-2-en-1-ol), C 10 H 18 It is one of the terpene alcohols with the chemical formula 1 of O2.

[0062] [Chemical Formula 1]

[0063]

[0064] In the present invention, in a scopolamine-induced amnesia mouse model, an increase in avoidance time in a passive avoidance test, a decrease in movement time and movement distance in a Morris water maze test, and an increase in cross number were observed by administering 80 and 100 mg / kg / day of a compound represented by chemical formula 1. In addition, a decrease in blood amyloid-β 1-40 and 1-42, an increase in acetylcholine and a decrease in acetylcholine hydrolase in the brain, an increase in neurons in the hippocampus region of the brain, and a decrease in p-Tau were observed, confirming an effect of improving memory.

[0065] Therefore, the pharmaceutical composition for treating or preventing cognitive dysfunction, including the compound represented by chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof, has an effect of improving cognitive functions such as memory by increasing avoidance time in a passive avoidance test, decreasing movement time and movement distance in a Morris water maze test, increasing the number of stays (cross numbers), decreasing amyloid-β 1-40 and 1-42 in the blood, increasing acetylcholine and decreasing acetylcholine hydrolase in the brain, increasing neurons in the hippocampus region of the brain, and decreasing p-Tau, and thus can be used as a therapeutic agent for cognitive dysfunction.

[0066] The term "cognitive function" of the present invention refers to various intellectual abilities such as attention, perception, memory, language ability, and executive ability. In the present invention, cognitive function may be used interchangeably with "cognitive ability" or "cognitive ability."

[0067] In the present invention, the term "cognitive dysfunction" is a concept that can include a state caused by a decline in cognitive function as described above, a disease resulting therefrom, and all diseases that have the condition as a symptom, and can mean a disorder caused by damage to brain nerve cells.

[0068] The term "memory" or "memory ability" used in the present invention refers to the ability to acquire new information, learned experiences, or knowledge obtained from the surrounding environment, encode and store it in a specific part of the brain, and recall it.

[0069] The term "memory disorder" as used herein refers to a condition in which the ability to retain and recognize information, experiences, and stimuli is lost or impaired, including amnesia or amnesia. Memory disorders can develop when any one of the three processes of memory—recording, retention, and retrieval—is impaired.

[0070] In addition, the composition of the present invention may have a therapeutic or preventive effect on cognitive dysfunction due to cognitive decline induced by scopolamine.

[0071] In addition, the cognitive dysfunction of the present invention can be caused by cholinergic neuronal decline, and the composition of the present invention can improve cholinergic neuronal decline, and has the effect of improving cognitive functions such as memory caused by cholinergic neuronal decline by increasing acetylcholine in brain tissue, decreasing acetylcholine hydrolase, increasing neurons in the hippocampal region of the brain, and decreasing p-Tau.

[0072] The "scopolamine" of the present invention is a competitive antagonist that blocks muscarinic receptors (mAChR), one of the subtypes of cholinergic neurons, and prevents acetylcholine from binding to the receptor in the synaptic gap without changing the amount of acetylcholine, which causes memory impairment similar to the phenomenon caused by damage to cholinergic neurons in the central nervous system.

[0073] In addition, the composition of the present invention can protect nerve cells by reducing the expression of amyloid protein (Amyloid β, Aβ) and tau protein, thereby treating or preventing cognitive dysfunction.

[0074] The term "amyloid protein" in the present invention refers to a 36-43 amino acid peptide that is the main component of amyloid plaques found in the brains of Alzheimer's patients and is critically involved in the development of Alzheimer's disease. It is known that neuronal cell death is caused by extracellular beta-amyloid deposition and intracellular hyperphosphorylated tau protein throughout the brain.

[0075] In the present invention, the disease related to cognitive dysfunction or memory impairment may be selected from the group consisting of dementia, learning disorder, agnosia, amnesia, aphasia, apraxia, delirium, mild cognitive impairment, depression, Alzheimer's disease, vascular dementia, and Binswanger's disease.

[0076] In the present invention, the pharmaceutical composition contains a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, may additionally contain a pharmaceutically acceptable carrier, and may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, and sterile injection solutions according to conventional methods.

[0077] In the present invention, “active ingredient” means an ingredient that exhibits the desired activity alone or can exhibit the activity together with a carrier that is inactive in itself.

[0078] The term "prevention" of the present invention means any act of inhibiting or delaying cognitive dysfunction by administering a composition containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0079] The term "treatment" of the present invention means any action that improves or beneficially changes symptoms of cognitive dysfunction by administering a composition containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0080] The term "pharmaceutically acceptable salt" as used herein refers to any salt that retains the desired biological and / or physiological activity of the compound while minimizing undesirable toxicological effects. It refers to a salt prepared according to methods conventional in the art, such preparation methods being well known to those skilled in the art.

[0081] In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, and for example, an inorganic ion salt manufactured with calcium, potassium, sodium and magnesium, etc.; an inorganic acid salt manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, etc.; an organic acid salt manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; a sulfonic acid salt manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, etc.; glycine, It may be any one selected from the group consisting of amino acid salts manufactured from arginine, lysine, etc., and amine salts manufactured from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but is not limited thereto.

[0082] In the present invention, the pharmaceutical composition may include a pharmaceutically acceptable carrier or additive. The term "pharmaceutically acceptable" in the present invention means that the composition does not inhibit the activity of the active ingredient and does not exhibit toxicity beyond what the subject of application (prescription) can tolerate. The "carrier" is defined as a compound that facilitates the addition of the compound into cells or tissues.

[0083] The pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0084] In addition, the pharmaceutical composition of the present invention may include diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives.

[0085] The pharmaceutical composition of the present invention can be prepared in the form of a liquid, suspension, powder, granule, tablet, capsule, pill or extract.

[0086] The composition of the present invention can be administered orally or parenterally (e.g., by topical application or intravenous, subcutaneous, or intraperitoneal injection).

[0087] In the present invention, the term “oral administration” refers to a method of injecting a drug into the mouth to improve pathological symptoms (periodontal disease), and in the present invention, the term “parenteral administration” refers to a method of administering subcutaneously, intramuscularly, intravenously, or intraperitoneally using a tube, excluding oral administration.

[0088] Solid dosage forms for oral administration include powders, granules, tablets, capsules, soft capsules, and pills. Liquid dosage forms for oral administration include suspensions, liquids, emulsions, syrups, and aerosols. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients may be included, such as wetting agents, sweeteners, flavoring agents, and preservatives.

[0089] Preparations for parenteral administration may be formulated and used in the form of external preparations such as sterilized aqueous solutions, liquids, non-aqueous solvents, suspensions, emulsions, eye drops, eye ointments, syrups, suppositories, aerosols, etc., and sterilized injection preparations according to conventional methods, and preferably, pharmaceutical compositions such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, eye ointments, eye drops, patches, or cataplasmas may be prepared and used, but are not limited thereto. Compositions for topical administration may be anhydrous or aqueous depending on clinical prescriptions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases that can be used include witepsol, macrogol, tween 61, cocoa butter, laurin butter, and glycerogelatin.

[0090] Diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives according to the present invention may be included in an amount of 0.1 to 99.9 wt% of the composition, specifically, 0.1 to 50 wt%, but is not limited thereto.

[0091] A pharmaceutical composition for treating or preventing cognitive dysfunction comprising a compound represented by Chemical Formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be administered in a conventional manner via oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular or intradermal routes, and specifically can be administered orally.

[0092] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on factors including the type and severity of the disease, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrent medications, and other factors well known in the medical field.

[0093] In the present invention, the compound represented by the above chemical formula 1 may be administered orally at a total daily dose of 20 to 100 mg / kg / day on an animal basis. Specifically, when administered to mice, the total daily dose may be orally administered at a total daily dose of 60 to 100 mg / kg / day, and more specifically, the total daily dose may be orally administered at a total daily dose of 80 to 100 mg / kg / day.

[0094] In an embodiment of the present invention, it was confirmed that the cognitive dysfunction improvement effect was excellent when administered at a dose of 60 to 100 mg / kg / day. In addition, in the present invention, it was confirmed that when the compound represented by the above chemical formula 1 was administered to mice at a dose of 60 to 100 mg / kg / day, cognitive dysfunction was improved to a level equivalent to or greater than that of the positive control group, Aricept.

[0095] Based on the animal experiment results above, the human equivalent dose (HED) can be applied to estimate the expected human dose, as shown in the following equation. This method takes into account the differences in metabolic rate and body surface area between experimental animals and humans.

[0096] HED (mg / kg) = Animal Dose (mg / kg) × (Animal Km / Human Km) × Human Body Weight (kg)

[0097] In the above formula, "Km" refers to the body surface area-based coefficient. This represents the metabolic rate relative to body surface area between animals and humans, and is used to convert drug dosages from animals to humans. The Km is based on the proportional relationship between body surface area and body weight, reflecting physiological differences between animals and humans.

[0098] Km = body weight (kg) / body surface area (m²)

[0099] Converting the dose based on mice to human dose based on a 60 kg adult is as follows:

[0100] - 20 mg / kg / day: approximately 97.3 mg / day

[0101] - 40 mg / kg / day: approximately 194.6 mg / day

[0102] - 80 mg / kg / day: approximately 389.2 mg / day

[0103] - 100 mg / kg / day: approximately 486.5 mg / day

[0104] Based on the above-mentioned animal-human dose conversion (Human Equivalent Dose, HED), the compound represented by the above chemical formula 1 can be administered at 10 to 1500 mg / day for an adult weighing 60 kg, and when the total daily dose is orally administered to a mouse at 80 to 100 mg / kg / day, the compound can be orally administered at 300 to 900 mg / day for an adult.

[0105] The above administration may be administered once a day or divided into several times.

[0106] In addition, the pharmaceutical composition of the present invention may contain 0.001 to 50 wt% of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof based on the total weight.

[0107] The pharmaceutical composition of the present invention may further include one or more active ingredients having the same or similar efficacy in addition to the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and may be administered in combination with a conventional treatment agent for cognitive dysfunction.

[0108]

[0109] In another aspect, the present invention provides a food composition for improving or preventing cognitive dysfunction, comprising a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.

[0110] In the present invention, the terms “compound represented by chemical formula 1”, “cognitive function”, and “cognitive dysfunction” are as described above.

[0111] In the present invention, the cognitive dysfunction may be selected from the group consisting of dementia, learning disorder, agnosia, amnesia, aphasia, apraxia, delirium, mild cognitive impairment, depression, Alzheimer's disease, vascular dementia, and Binswanger's disease.

[0112] The food composition of the present invention may include acceptable food additives and may further include suitable carriers, excipients and diluents commonly used in the manufacture of foods.

[0113] The food composition of the present invention may be in the form of a pill, powder, granule, infusion, tablet, capsule, or liquid, and there is no particular limitation on the type of food to which the compound represented by the chemical formula 1 of the present invention or a food-wise acceptable salt thereof can be added. Examples of foods to which the substance can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.

[0114] The above food composition may contain other ingredients in addition to the compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof, and the types thereof are not particularly limited. For example, as with conventional foods, various herbal extracts, food-wise acceptable food additives, or natural carbohydrates may be contained as additional ingredients, but are not limited thereto.

[0115] In the present invention, the term "food supplement additive" means a component that can be added to food as an auxiliary, and can be appropriately selected and used by those skilled in the art as added in the production of food of each formulation. Examples of food supplement additives include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc., but the types of food supplement additives of the present invention are not limited by the above examples.

[0116] Examples of the above natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. In addition to the above, natural flavoring agents (thaumatin, etc.), stevia extracts (rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used as flavoring agents.

[0117] The food composition of the present invention may include a health functional food. In the present invention, the term "health functional food" refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients having functional properties useful to the human body. Here, "functionality" means obtaining a beneficial effect for health purposes, such as regulating nutrients for the structure and function of the human body or physiological functions. The health functional food of the present invention can be manufactured by a method commonly used in the art, and during the manufacturing process, raw materials and ingredients commonly added in the art can be added. In addition, unlike general drugs, it has the advantage of not having side effects that may occur with long-term use, and can be highly portable.

[0118] The food composition of the present invention can be applied as a health functional food.

[0119] In the present invention, the compound represented by the above chemical formula 1 may be included in the food composition so that the total daily dosage is 20 to 100 mg / kg / day based on the animal. Specifically, when administered to a mouse, the compound may be included in the food composition so that the total daily dosage is 60 to 100 mg / kg / day, and more specifically, the compound may be included in the food composition so that the total daily dosage is 80 to 100 mg / kg / day, and may be included in a health functional food, which is an example of the food composition.

[0120] In the present invention, it was confirmed that when the compound represented by the above chemical formula 1 was administered to mice at a dose of 60 to 100 mg / kg / day, cognitive dysfunction was improved to a level equivalent to or greater than that of the positive control group, Aricept.

[0121] Based on the animal experiment results above, the human equivalent dose (HED) can be applied to estimate the expected human dose, as shown in the following equation. This method takes into account the differences in metabolic rate and body surface area between experimental animals and humans.

[0122] HED (mg / kg) = Animal Dose (mg / kg) × (Animal Km / Human Km) × Human Body Weight (kg)

[0123] In the above formula, "Km" refers to the body surface area-based coefficient. This represents the metabolic rate relative to body surface area between animals and humans, and is used to convert drug dosages from animals to humans. The Km is based on the proportional relationship between body surface area and body weight, reflecting physiological differences between animals and humans.

[0124] Km = body weight (kg) / body surface area (m²)

[0125] Converting the dose based on mice to human dose based on a 60 kg adult is as follows:

[0126] - 20 mg / kg / day: approximately 97.3 mg / day

[0127] - 40 mg / kg / day: approximately 194.6 mg / day

[0128] - 80 mg / kg / day: approximately 389.2 mg / day

[0129] - 100 mg / kg / day: approximately 486.5 mg / day

[0130] Based on the above-mentioned animal-human dose conversion (Human Equivalent Dose, HED), the compound represented by the above chemical formula 1 can be administered at 10 to 1500 mg / day for an adult weighing 60 kg, and when the total daily dose is orally administered to a mouse at 80 to 100 mg / kg / day, the compound can be orally administered at 300 to 900 mg / day for an adult.

[0131] If the above food composition is a health functional food, the administration may be administered once a day or divided into several times.

[0132] The amount of active ingredients included in the above food composition can be appropriately determined depending on the intended use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food, the active ingredient of the present invention can be added in an amount of 0.01 to 50 wt%, preferably 0.1 to 10 wt%, of the raw material composition, but is not limited thereto. However, in the case of long-term intake for the purpose of health and hygiene or health regulation, the amount may be used below the above range.

[0133]

[0134] In another aspect, the present invention provides a method for preventing or treating cognitive dysfunction, comprising administering to a subject a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0135] In another aspect, the present invention provides a use of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for preventing or treating cognitive dysfunction.

[0136] In another aspect, the present invention provides a use of the compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof for the manufacture of a food for improving or preventing cognitive dysfunction.

[0137] In the present invention, the terms “compound represented by chemical formula 1”, “pharmaceutically acceptable salt”, “food-based acceptable salt”, “cognitive dysfunction”, “prevention”, and “treatment” are as described above.

[0138] The term "subject" as used in the present invention refers to any animal, including humans, that has developed or is likely to develop cognitive dysfunction. The animal may be a mammal such as a cow, horse, sheep, pig, goat, camel, antelope, dog, or cat that requires treatment for symptoms similar to humans, but includes, without limitation, any subject whose cognitive dysfunction is prevented or treated by the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0139]

[0140] Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention may be implemented in various different forms and is not limited to the examples described below.

[0141]

[0142] Test method

[0143] 1. Breeding of laboratory animals

[0144] (SPF) C57BL / 6N male mice (C57BL / 6NCrljOri) were used and were raised in a breeding environment maintained at a temperature of 22 ± 3 ℃, a relative humidity of 55 ± 15%, a ventilation rate of 10-20 times / hr, a lighting time of 12 h (lights on at 8:00 AM - lights off at 8:00 PM), and an illuminance of 150-300 Lux.

[0145]

[0146] 2. Test group composition, group separation, and administration

[0147] 1) Composition of test group

[0148] Number of animals by group and sex Dosage (mg / kg / day) Dosage (mL / kg / day) Dosage substance G1M10-10saline G2M10-10saline G3M102010NRM-331 (Sobrerol) G4M104010G5M108010G6M1010010G7M10210Aricept

[0149] G1: Normal control G2: Negative control / Amnesia induction

[0150] G3-G6: Test substance administration group / Amnesia induction

[0151] G7: Positive control / Amnesia induction

[0152]

[0153] To evaluate the memory improvement effect of 4-week oral administration of NRM-331 (sobrerol) in a scopolamine-induced amnesia mouse model, the experimental groups were set as normal control group (G1), negative control group (G2), 20 mg / kg / day administration group of test substance NRM-331 (G3), 40 mg / kg / day administration group (G4), 80 mg / kg / day administration group (G5), 100 mg / kg / day administration group (G6), and positive control substance Aricept 2 mg / kg / day administration group (hereinafter referred to as positive control group, G7). Ten animals were used in each group.

[0154]

[0155] 2) Military separation

[0156] Experimental animals were judged healthy during the acclimatization period and subjected to a cued test to initially exclude any abnormal animals. The animals were then weighed and ranked, and randomly distributed to the test groups to ensure an even distribution of average body weights within each group.

[0157] * Cued test: After filling the pool with water and exposing the platform above the water surface, the experimental animal was brought into the pool. If it found the platform and climbed up within 60 seconds, it was considered normal. The test was repeated twice, and animals that failed to find the platform both times were excluded from the experiment.

[0158]

[0159] 3) Administration

[0160] Route of administration and reason for selection: Oral administration, clinically planned route of application. Frequency and period of administration: 7 times / week, 4 weeks (total 29 times). Calculation of dosage: 10 mL / kg / day (based on the most recent body weight measurement). Method of administration: Correct the cervicoarsal and thoracoabdominal regions of the animal and administer directly into the stomach using a 1 mL syringe equipped with a zonde.

[0161]

[0162] 3. Inducing amnesia (memory loss)

[0163] Scopolamine (Sigma-aldrich, Cat no. S1875) was prepared in a saline solution at a concentration of 1 mg / 10 mL. Scopolamine was administered intraperitoneally at a dose of 1 mg / kg once daily on the 7th day (Y-maze test)4), 14-15th days (passive avoidance test), 24-28th days (Morris water maze test), and 29th day (day of autopsy). Scopolamine was administered 30 minutes after test substance administration.

[0164]

[0165] 4. Statistical Analysis

[0166] Statistical analysis was performed using SPSS statistics 12.0K for medical science. Parametric multiple comparison procedures were used to compare the normal control group (G1) and the negative control group (G2) to determine the presence or absence of disease induction. The negative control group (G2) and the positive control group (G7) were compared. Student's t-test was used for analysis, and Welch's t-test was used when variances were not equal. One-way ANOVA was used to compare the negative control group (G2) and the test substance administration groups (G3-G6). Post hoc tests were Duncan's test for equal variances and Dunnett's test for unequal variances. All statistical analyses were considered statistically significant when P < 0.05.

[0167]

[0168] Experimental example

[0169] Experimental Example 1. Dead animals and general symptoms

[0170] During the administration and observation period, death, type of general symptoms, date of onset, and severity of symptoms were observed once a day and recorded for each individual. The start date of test substance administration was set as DAY 1, and observation was conducted until DAY 29.

[0171] During the observation period, no deaths or abnormal symptoms were observed in any of the administration groups (G1-G7).

[0172]

[0173] Experimental Example 2. Weight Measurement

[0174] 1) Test method

[0175] Measurements were taken at the time of acquisition, at the time of group separation, at the start of administration, once per week thereafter, and at the end of the observation period.

[0176] 2) Test results

[0177] Figure 1 shows the results of measuring the body weight of experimental animals.

[0178] The negative control group (G2) showed a statistically significant weight loss on Day 29 (P<0.05) compared to the normal control group (G1). No statistically significant weight changes were observed during the other observation periods. The test substance administration groups (G3-G6) and the positive control group (G7) showed no statistically significant weight changes compared to the negative control group (G2) throughout the entire observation period.

[0179]

[0180] Experimental Example 3. Y-maze test

[0181] 1) Test method

[0182] The Y-maze was administered 30 minutes after scopolamine administration on the 7th day of test substance administration. The experimental apparatus consisted of a Y-shaped enclosed maze made of transparent acrylic plates (W 10 cm x L 41 cm x H 25 cm). Each maze was positioned at a constant angle of 120°. Each maze was designated as zones A, B, and C. The experimental animal was carefully placed in one zone and allowed to move freely for 8 minutes. The zone into which the experimental animal entered was observed and recorded using a ceiling-mounted camera. The animal was judged to have completely entered the zone when its tail reached the zone. The number and order of entries into each maze were measured to assess spontaneous alteration (%). Sequential entry into three different zones was recognized as 1 point (actual alteration, i.e., in the order of ABC, BCA, CAB, etc.). Non-consecutive entries were not recognized as points.

[0183] % spontaneous alteration was calculated using the following formula:

[0184] % spontaneous alteration = total number of alterations / (total number of entries - 2) x 100

[0185]

[0186] 2) Test results

[0187] Figure 2 shows the change behavior using the Y-maze test.

[0188] As a result, the negative control group (G2) showed a statistically significant decrease in alterative behavior on DAY 7 compared to the normal control group (G1) (P<0.05). The test substance administration groups (G3-G6) and the positive control group (G7) did not show a statistically significant change on DAY 7 compared to the negative control group (G2), but a statistically insignificant increase of 31.77% in alterative behavior was observed in the positive control group (G7).

[0189]

[0190] Experimental Example 4. Passive Avoidance Test

[0191] 1) Test method

[0192] Passive avoidance experiments were conducted using a passive avoidance test device (Med. Associates Inc.). The device consists of a partition with a guillotine door, divided into two compartments. One compartment is illuminated, while the other is darkened. The floor is gridded for electric shock delivery.

[0193] The experiment was conducted at the same time for three consecutive days at 24-hour intervals. On the 13th day after test substance administration, the animals were allowed to remain in the shaded area for two minutes before being returned to the lighted area. Upon returning to the shaded area, they were immediately removed for acclimation training.

[0194] On the 14th day, 24 hours after test substance administration, two training sessions were conducted at 2-minute intervals (acquisition trial). Scopolamine was administered 30 minutes after test substance administration, and the first training session was conducted 30 minutes after scopolamine administration. The first training session involved placing the animals in the passive avoidance test chamber for 60 seconds to acclimate them to the measuring device.

[0195] At this time, the light was turned off and the guillotine door was opened to allow the animal to come and go freely. After 60 seconds of adaptation, the light was turned back on and the animal was allowed to come and go freely for 120 seconds. After moving to a darkened area, the guillotine door was closed and the animal was given a 0.20 mA scrambled shock for 2 seconds.

[0196] On the 15th day after the test substance administration, which is 24 hours later, the test substance was administered first, and then scopolamine was administered 30 minutes later. 30 minutes after the scopolamine administration, the animals were placed in a lighted area and the guillotine door was opened, and the time taken to move to the shaded area was measured (retention trial).

[0197]

[0198] 2) Test results

[0199] Figure 3 shows the results of avoidance time measurement using a passive avoidance test device.

[0200] As a result, in the acquisition trial, the avoidance time was measured, and the negative control group (G2) showed a 57.41% increase in avoidance time on DAY 14 compared to the normal control group (G1), although this was not statistically significant. The test substance administration groups (G3-G6) and the positive control group (G7) did not show any statistically significant changes on DAY 14 compared to the negative control group (G2).

[0201] In the retention trial, the avoidance time was measured, and a statistically significant decrease in avoidance time was observed in the negative control group (G2) on DAY 15 compared to the normal control group (G1) (P<0.01). No statistically significant difference in avoidance time was observed in the 20, 40, and 80 mg / kg / day NRM-331 administration groups (G3-G5) compared to the negative control group (G2), but a 26.97% increase in avoidance time was observed in the 80 mg / kg / day NRM-331 administration group (G5), although this difference was not statistically significant. The 100 mg / kg / day NRM-331 administration group (G6) and the positive control group (G7) showed a statistically significant increase in avoidance time compared to the negative control group (G2) (P<0.01).

[0202]

[0203] Experimental Example 5. Morris water maze test

[0204] 1) Test method

[0205] The Morris water maze test was conducted on days 22-28 after test substance administration. A platform was placed in a pool at one of four designated release points in a 1-m diameter aquarium, and the animals were allowed to find it within 60 seconds. After finding the platform, they were allowed to rest on it for approximately 30 seconds. If they were unable to find the platform within 60 seconds, the animals were placed on the platform and allowed to rest for approximately 30 seconds. Five animals completed one trial before the next, and two trials were conducted per day. However, the release points were randomly selected to avoid duplication. This procedure was repeated for 7 days, and the time it took to find the platform was measured (training: 2 days, behavioral experiment: 4 days, probe trial: 1 day). On the final day, the platform was removed, and a 60-second probe trial was conducted to measure the number of crosses at the location where the platform was located.

[0206]

[0207] 2) Travel time test results

[0208] Figure 4 shows the movement time required to find the platform using the Morris water maze test.

[0209] As a result of measuring the movement time to find the platform, the negative control group (G2) showed a statistically significant increase in movement time on DAY 24, 25, 26, and 27 compared to the normal control group (G1) (P<0.01). The 20 mg / kg / day NRM-331 administration group (G3) showed a decrease in movement time of 14.59%, 19.90%, 16.36%, and 22.50% on DAY 24, 25, 26, and 27, respectively, although the difference was not statistically significant compared to the negative control group (G2). In the 40, 80, 100 mg / kg / day NRM-331 administration groups (G4-G6) and the positive control group (G7), a statistically significant decrease in movement time was observed on DAY 24, 25, 26, and 27 compared to the negative control group (G2) (P<0.01), and in the 100 mg / kg / day NRM-331 administration group (G6), a 13.84% decrease in movement time was observed on DAY 24 compared to the positive control group (G7), although this was not statistically significant.

[0210]

[0211] 3) Movement distance test results

[0212] Figure 5 shows the distance traveled to find the platform using the Morris water maze test.

[0213] As a result of measuring the distance traveled to find the platform, the negative control group (G2) showed a statistically significant increase in the distance traveled on DAY 24, 25, 26, and 27 compared to the normal control group (G1) (P<0.01). The 20 mg / kg / day NRM-331 administration group (G3) showed a statistically significant decrease in the distance traveled on DAY 25 and 27 compared to the negative control group (G2) (P<0.05 or P<0.01), and a 17.47% decrease in the distance traveled on DAY 26, although not statistically significant. The 40, 80, and 100 mg / kg / day NRM-331 administration groups (G4-G6) and the positive control group (G7) showed a statistically significant decrease in moving distance compared to the negative control group (G2) (P<0.01), and the 100 mg / kg / day NRM-331 administration group (G6) showed a 15.07% decrease in moving distance on DAY 24 compared to the positive control group (G7), although this was not statistically significant.

[0214]

[0215] 4) Test results for number of stays

[0216] Figure 6 shows the number of times of staying (cross number) using the Morris water maze test.

[0217] After platform removal, the number of times the platform stayed at the location (cross number) was measured, and a statistically significant decrease in cross number was observed in the negative control group (G2) on DAY 28 compared to the normal control group (G1) (P<0.01). In the 20 mg / kg / day NRM-331 administration group (G3), no statistically significant change in cross number was observed compared to the negative control group (G2), and in the 40, 80, and 100 mg / kg / day NRM-331 administration groups (G4-G6) and the positive control group (G7), a statistically significant increase in cross number was observed compared to the negative control group (G2) (P<0.01).

[0218]

[0219] Experimental Example 6. Measurement of Amyloid-β (1-40) and Amyloid-β (1-42)

[0220] 1) Test method

[0221] On the day of autopsy, scopolamine was administered 30 minutes after the test substance was administered, and 30 minutes after scopolamine administration, inhalation anesthesia with isoflurane was administered. Once anesthesia was confirmed, the laparotomy was performed and the maximum amount of blood was collected using a 1 mL syringe from the posterior vena cava. After blood collection, the brains were removed, and the brains of the front five animals (1-5) of each group were rapidly frozen and stored in a deep freezer, and the brains of the back five animals (6-10) of each group were fixed in 10% neutral buffered formalin and used for histopathological examination.

[0222] Blood collected at autopsy was injected into a 5 mL vacutainer tube containing clot activator and left at room temperature for 15–20 minutes to coagulate. The serum was centrifuged for 10 minutes and stored in a deep freezer. The stored serum was used for measurement using the amyloid-β 1-40 (IBL, cat no. 27720) ELISA kit and the amyloid-β 1-42 (IBL, cat no. 27721) ELISA kit.

[0223]

[0224] 2) Test results

[0225] Figure 7 shows the levels of Amyloid-β (1-40) and Amyloid-β (1-42) in serum.

[0226] In the negative control group (G2), a statistically significant increase in amyloid-β 1-40 and 1-42 was observed compared to the normal control group (G1) (P<0.01 or P<0.05). Compared to the negative control group (G2), the test substance administration group (G3-G6) did not show statistically significant changes in amyloid-β 1-40 and 1-42, but the 20 mg / kg / day NRM-331 administration group (G3) showed decreases of 55.59% and 41.21%, respectively, the 40 mg / kg / day NRM-331 administration group (G4) showed decreases of 51.06% and 40.90%, respectively, the 80 mg / kg / day NRM-331 administration group (G5) showed decreases of 43.90% and 39.19%, respectively, and the 100 mg / kg / day NRM-331 administration group (G6) showed decreases of 46.49% and 28.93%, respectively, in amyloid-β 1-40 and 1-42. In the positive control group (G7), a statistically significant decrease in amyloid-β 1-42 was observed compared to the negative control group (G2) (P<0.05), and a 44.21% decrease in amyloid-β 1-40 was observed, although not statistically significant.

[0227]

[0228] Experimental Example 7. Measurement of Acetylcholine and Acetylcholinesterase

[0229] 1) Test method

[0230] Brain tissues stored in a deep freezer after autopsy were used for measurement using acetylcholine (ACh, mybiosource, cat no. MBS733116) ELISA kit and acetylcholinesterase (AChE, mybiosource, cat no. MBS721845) ELISA kit.

[0231]

[0232] 2) Test results

[0233] Figure 8 shows the levels of acetylcholine and acetylcholinesterase in brain tissue.

[0234] As a result, the negative control group (G2) showed a statistically significant decrease in brain acetylcholine compared to the normal control group (G1) (P<0.01). The 20 mg / kg / day NRM-331 administration group (G3) showed a 28.93% increase in acetylcholine compared to the negative control group (G2), although this was not statistically significant. The 40, 80, and 100 mg / kg / day NRM-331 administration groups (G4-G6) and the positive control group (G7) showed a statistically significant increase in acetylcholine compared to the negative control group (G2) (P<0.01).

[0235] The negative control group (G2) showed a statistically significant increase in acetylcholinesterase compared to the normal control group (G1) (P<0.01). The test substance administration groups (G3-G6) and the positive control group (G7) showed a statistically significant decrease in acetylcholinesterase compared to the negative control group (G2) (P<0.01).

[0236]

[0237] Experimental Example 8. Histopathological Examination

[0238] 1) Test method

[0239] Tissues fixed in 10% neutral buffered formalin were transferred to an external institution and histopathologically evaluated to determine the degree of memory improvement after Nissl staining and IHC (p-Tau). Nissl staining and IHC (p-Tau) were performed on the cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and dentate gyrus (DG) regions of the hippocampus.

[0240] Brain tissue fixed in 10% neutral buffered formalin was trimmed to include the hippocampus, processed, and embedded in paraffin to create paraffin blocks. Coronal sections were prepared for each individual, and Nissl-stained slides were prepared. These were observed and photographed using an optical microscope (BX61, Olympus, Japan) (DP80, Olympus, Japan).

[0241] Using Nissl-stained slides, the number of Nissl-stained cells in the CA1, CA3, and DG regions of the hippocampus was counted and quantitatively analyzed under high power field (hpf, x400 magnification) with reference to the method of the reference paper (Nutrients 2019, 11, 1205). Image-Pro software (Media cybernetics, USA) was used as the quantitative analysis tool.

[0242] To perform immunohistochemical staining (IHC) for p-Tau, sections were cut into 4 μm thick and mounted on superfrost glass slides (Thermo, USA). Paraffin was removed with xylene, and the sections were hydrated with ethanol. After antigen retrieval, the sections were immersed in 0.01 M citric acid buffer and pressure cooker at full pressure for 10 min at high temperature and high pressure. Afterwards, 3% H2O2 was treated for 15 min to eliminate endogenous peroxidase activity. To remove nonspecific reactions, the sections were treated with blocking reagent (Vector Laboratories, USA), and anti-phospho-Tau (Ser202, Thr205) antibody (ThermoFisher, USA) was diluted 1:500 in phosphate-buffered saline (PBS) and incubated for 16 h. The sections were then washed three times with PBS. Detection was performed using the Vectastain Elite ABC kit (Vector Laboratories, USA) and 3,3'-Diaminobenzidine (DAB), followed by counterstaining with hematoxylin, observation using an optical microscope (BX61, Olympus, Japan), and photography (DP80, Olympus, Japan).

[0243] For quantitative analysis of the immunohistochemical staining results, the captured images were measured for positive stained signal intensity using Image-Pro software (Media cybernetics, USA), and then quantitatively analyzed as a relative ratio based on the values ​​of the negative control group (G2).

[0244]

[0245] 2) Test results

[0246] Figure 9 shows the number of neuronal cell bodies in the cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and dentate gyrus (DG) regions of the hippocampus using Nissl stain.

[0247] As a result of quantitative analysis of the number of neuronal cell bodies in the cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and dentate gyrus (DG) regions of the hippocampus using Nissl stain, no statistically significant change in the number of neuronal cell bodies was observed in the negative control group (G2) compared to the normal control group (G1), but a decrease of 16.69%, 15.34%, and 12.60% in the CA1, CA3, and DG regions, respectively. The test substance administration group (G3-G6) and the positive control group (G7) did not observe a statistically significant change in the number of neuronal cell bodies compared to the negative control group (G2), but the 80 and 100 mg / kg / day NRM-331 administration groups (G5, G6) showed an increase of 11.95% and 10.44% in the CA1 region, respectively. In the 40, 80, and 100 mg / kg / day administration groups of NRM-331 (G4-G6), an increase of 12.75%, 11.20%, and 11.42% in the DG region was observed, respectively, compared to the positive control group (G7).

[0248] Figure 10 shows the results of quantitative analysis of p-Tau in the CA1, CA3, and DG regions of the hippocampus using immunohistochemical staining, in relative proportions, based on the negative control group (G2).

[0249] As a result of quantitative analysis of p-Tau in the CA1, CA3, and DG regions of the hippocampus by immunohistochemical staining in relative ratios based on the negative control group (G2), the negative control group (G2) showed a statistically significant increase in p-Tau in the CA1 and DG regions compared to the normal control group (G1) (P<0.01), and a 12.29% increase in the CA3 region, although not statistically significant. In the 20, 40, and 80 mg / kg / day administration groups (G3-G5) of NRM-331, a statistically significant decrease in p-Tau in the CA3 region was observed compared to the negative control group (G2) (P<0.05 or P<0.01). In the 100 mg / kg / day NRM-331 administration group (G6), a statistically significant decrease in p-Tau was observed in the CA3 and DG regions (P<0.01), and a statistically insignificant 11.16% decrease in p-Tau was observed in the CA1 region. In the positive control group (G7), a statistically significant decrease in p-Tau was observed in the CA1, CA3, and DG regions (P<0.05 or P<0.01).

[0250]

[0251] As a result, in the scopolamine-induced amnesia mouse model, administration of 80 and 100 mg / kg / day of NRM-331 was observed to increase avoidance time in the passive avoidance test, decrease movement time and distance in the Morris water maze test, and increase cross number. It was also observed to decrease amyloid-β 1-40 and 1-42 in the blood, increase acetylcholine and decrease acetylcholine hydrolase in the brain, increase neurons in the hippocampus region of the brain, and decrease p-Tau, suggesting that it has a memory-improving effect.

[0252] In particular, it is thought that administration of 100 mg / kg / day of test substance NRM-331 and administration of 2 mg / kg / day of positive control substance Aricept have similar memory improvement effects when comprehensively evaluated.

[0253]

[0254] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

Claims

1. A pharmaceutical composition for treating or preventing cognitive dysfunction, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof. [Chemical Formula 1] 2. A pharmaceutical composition for treating or preventing cognitive dysfunction, wherein the cognitive dysfunction in claim 1 is selected from the group consisting of dementia, learning disorder, agnosia, amnesia, aphasia, apraxia, delirium, mild cognitive impairment, depression, Alzheimer's disease, vascular dementia, and Binswanger's disease.

3. A pharmaceutical composition for treating or preventing cognitive dysfunction, wherein the compound in paragraph 1 has a total daily dosage of 60 to 100 mg / kg / day on an animal basis.

4. A pharmaceutical composition for treating or preventing cognitive dysfunction, wherein the compound in paragraph 1 is orally administered at 10 to 1,500 mg / day based on an adult weighing 60 kg.

5. A food composition for improving or preventing cognitive dysfunction, comprising a compound represented by chemical formula 1 or a food-chemically acceptable salt thereof. [Chemical Formula 1] 6. A food composition for improving or preventing cognitive dysfunction, wherein the cognitive dysfunction in paragraph 1 is selected from the group consisting of dementia, learning disorder, agnosia, amnesia, aphasia, apraxia, delirium, mild cognitive impairment, depression, Alzheimer's disease, vascular dementia, and Binswanger's disease.

7. A food composition for improving or preventing cognitive dysfunction, wherein the food composition in paragraph 5 is a health functional food.

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