WO2018155956A1 - Pharmaceutical composition, containing lily bulb extract, for preventing or treating cognitive disorder - Google Patents
Pharmaceutical composition, containing lily bulb extract, for preventing or treating cognitive disorder Download PDFInfo
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- WO2018155956A1 WO2018155956A1 PCT/KR2018/002261 KR2018002261W WO2018155956A1 WO 2018155956 A1 WO2018155956 A1 WO 2018155956A1 KR 2018002261 W KR2018002261 W KR 2018002261W WO 2018155956 A1 WO2018155956 A1 WO 2018155956A1
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- extract
- lily
- disease
- dementia
- composition
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating cognitive disorders.
- a pharmaceutical composition for preventing or treating cognitive disorders comprising lily scale extract or a fraction thereof as an active ingredient
- a method for preventing or treating cognitive disorders comprising administering the composition to a subject, lily scale extract Or functional health food composition for preventing or improving cognitive impairment, including fractions thereof as an active ingredient, lily scale extract or a functional food composition for improving memory or concentration comprising fractions thereof as an active ingredient, and lily scale extract or lily thereof
- It relates to a composition for inducing neural stem cell proliferation comprising a fraction.
- Lily means monocotyledonous lily and Lilium plant. It grows mostly in the shade of forests and trees or directly to the north where it is not exposed to direct sunlight. The leaves are rotated with their leaf sides displaced. The flowers are large, each tissue is divided into six branches, and there are wheat bulbs inside. There are 6 stamens and anther runs in T-shape. Capsules are flat seeds, and the lifespan of seeds is usually 3 years.
- the lily is a root plant corresponding to the bulb, in particular, the lily is a root plant having a scaly structure among the roots.
- the general root plant can be divided into scales, egg stems, tubers, root stems, tubers, the case of the lily is a plant corresponding to the double scales.
- Lily scales which are the roots of the lilies, grow in the ground while the bases of the leaves are enlarged and have a layered scale structure.
- the dementia patients also become a serious social problem, and the prevalence of dementia in Korea varies depending on the type and region of dementia.
- the dementia is a symptom group, and as the disease progresses, cognitive impairment and dysfunction become more severe, and early diagnosis and early treatment are important.
- Vascular dementia can prevent further progression if diagnosed and treated early, and Alzheimer's disease, which is a degenerative disease, Early detection and medication can delay the disease, so early detection and prevention are very important.
- Patent Document 1 Korean Patent Application Publication No. 2016-0088165 relating to a composition for improving cognitive function or memory ability containing onion extract or a fraction thereof as an active ingredient.
- Patent Document 2 Korean Patent Application Publication No. 2013-0107531 of the pharmaceutical composition for preventing and treating chronic obstructive pulmonary disease containing a lily extract as an active ingredient.
- Patent Document 2 Korean Patent Application Publication No. 2013-0107531 of the pharmaceutical composition for preventing and treating chronic obstructive pulmonary disease containing a lily extract as an active ingredient.
- the present inventors have made diligent research efforts to find a composition that improves cognitive function and learning ability.
- the present invention has found that the lily scale extract has an effect of improving memory or concentration while preventing or treating cognitive impairment.
- the lily scale extract has an effect of improving memory or concentration while preventing or treating cognitive impairment.
- Still another object of the present invention is to provide a dietary supplement for preventing or improving cognitive impairment, comprising a lily scaly extract or a fraction thereof as an active ingredient.
- Still another object of the present invention is to provide a health functional food composition for improving memory or concentration comprising lily scales extract or a fraction thereof as an active ingredient.
- Still another object of the present invention is to provide an in vitro neural stem cell proliferation inducing composition comprising a lily scaly extract or a fraction thereof.
- the pharmaceutical composition according to the present invention has a lily scale extract or a fraction thereof has the effect of preventing or treating cognitive impairment.
- the lily scaly extract and its fractions have the effect of improving memory or concentration even when administered against a steady state without impaired brain cognitive function.
- the lily scale extract or fractions thereof according to the present invention can be used in a method for preventing or treating cognitive impairment or in a dietary supplement for preventing or improving cognitive impairment.
- it can be provided as a dietary supplement for improving memory or concentration.
- FIG. 1 is a diagram showing a process of conducting an underwater maze experiment and a manual avoidance test for a test animal administered with a lily scale stem extract according to an embodiment of the present invention.
- Figures 2a to 2d is a result of performing a labyrinth experiment on the experimental animals administered with the lily scale stem extract according to an embodiment of the present invention
- Figures 2a and 2c is a hidden destination in the labyrinth experiment
- 2b and 2d are graphs measuring the latency time taken by an experimental animal to find a destination by the underwater maze experiment (* is p ⁇ 0.05 compared to the normal group or the experimental group 1).
- FIG. 2B is a graph measuring the latency time to reach platform in seconds.
- each experimental group means:
- Experimental group 2 the administration of scopolamine after the administration of donepezil (2mg / kg) to the normal group
- Experimental group 4 The group administered the lily scale extract to the normal group by concentration (50, or 100 mg / kg) (no scoflavin administration).
- Figure 3 is a manual evasion experiment on the experimental animals administered with lily scales extract according to an embodiment of the present invention (step-through latency time) in seconds (sec) It is a graph which shows the result of a measurement (* is p ⁇ 0.05 compared with normal group or the experimental group 1).
- Figure 4 shows the result of confirming the number of BrdU target cells in the dentate gyrus of the hippocampus of the experimental animal brain after administration of the lily scale extract according to an embodiment of the present invention
- (a) is BrdU target It is a photograph showing the staining result of the cells
- (b) is a graph showing the result of quantitatively confirmed by confirming the number of BrdU target cells for each section (*) (* is p ⁇ 0.05 compared to normal group or experimental group 1).
- Figure 5 is a photograph and graph showing the results of confirming the cell proliferation efficacy after 24 hours after treatment with lily scale extract according to an embodiment of the present invention NE-4C neural stem cell line, (a) is It is a photograph showing the results observed with an optical microscope, (b) is a graph showing the cell growth rate (* is p ⁇ 0.05 compared to 0 ⁇ g / ml).
- Figure 6 shows the cell proliferation of the neuronal cell line due to the treatment of lily scale stem extract in NE-4C neural stem cell line according to an embodiment of the present invention through BrdU
- (a) is a photograph showing the BrdU immunostaining results
- (B) is a graph of BrdU incorporation assay (* is p ⁇ 0.05 vs. 0 ⁇ g / ml).
- the inventors of the present invention in the course of making an effort to discover a substance that prevents or treats cognitive disorders such as forgetfulness, Alzheimer's disease, dementia, Parkinson's disease, Peak disease or Huntington's disease, It has also been found to improve memory or concentration.
- the present invention provides a pharmaceutical composition for the prevention or treatment of cognitive disorders comprising lily scale extract or a fraction thereof as an active ingredient.
- the present invention provides a use for the prevention or treatment of cognitive impairment of a composition comprising a lily scale extract or a fraction thereof as an active ingredient.
- the term “lilies scaly” of the present invention refers to a lily root of a lily, also called a diameter, and refers to a subterranean stem of a lily that is large in size and has dense leaves because it stores many nutrients around a short stem.
- the lily scale is a concept that is distinguished from the ground including the flowers of the lily.
- Cognitive function is the ability to use relevant information to adapt to the surrounding environment, such as perception, memory, learning, attention, vigilance, understanding, and interpretation. Means.
- the composition of the present invention can exhibit an excellent effect on cognitive function, specifically learning and memory.
- cognitive impairment is a concept that includes a condition resulting from a decrease in cognitive function, a disease according to it, and all diseases in which the symptom is a symptom, and may preferably mean a disorder caused by damage to brain neurons.
- the cognitive dysfunction may mean any one or more degenerative brain diseases selected from the group consisting of forgetfulness, Alzheimer's disease, dementia, Parkinson's disease, peak disease, Creutzfeldt-Jakob disease, Huntington's disease, ischemic stroke, and hemorrhagic stroke. Can be.
- Dementia is a syndrome in which the cognitive function of various areas such as memory, language, and judgment are reduced, and thus cannot perform daily life properly.Dementia is a brain function that is damaged by various causes. As a result, the overall decline may result in significant disruption in daily life.
- the dementia can be divided into dozens of causative diseases, but among them, Alzheimer's disease is the most common cause and exceeds 50%.
- the dementia may be selected from the group consisting of vascular dementia, Alzheimer's dementia, Louis dementia, dementia caused by head trauma, dementia caused by brain tumor, and dementia caused by metabolic disease.
- the route to the destination is also simplified, and the time is significantly reduced (FIGS. 2A and 2B).
- the route to the destination is also simplified, and the time is significantly reduced (FIGS. 2A and 2B).
- the oral administration of lily scale extract to the animal model induced brain cognitive impairment in the same way manual evasion experiments showed that the latency time was restored to normal compared to the animal model with brain impaired cognitive impairment. (FIG. 3A).
- the BrdU staining administration of the lily scale extract it was confirmed that the number of BrdU target cells significantly increased compared to the other case (Fig. 4).
- extract of the present invention means an extract obtained by extracting the lily scales or their pulverized products, a dilution or concentrate of the extract, a dried product obtained by drying the extract, a crude product or a purified product of the extract, or these And extracts of all formulations that can be formed using the extract itself and the extract, such as mixtures thereof.
- the method of extracting the lily scales is not particularly limited as long as an extract showing an effect of preventing or treating cognitive impairment can be obtained, and may be extracted according to a method commonly used in the art.
- the type of extraction solvent used to extract the lily scales in the present invention is not particularly limited as long as an extract showing an effect of preventing or treating cognitive impairment can be obtained, and any solvent known in the art may be used. Can be used.
- the extraction solvent may be used alone or in combination of one or more kinds of water, alcohol, etc.
- the extraction solvent may be alone or one or more kinds of water or alcohol having 1 to 6 carbon atoms. Mixing may be used, and as another example, the extraction solvent may be water.
- fraction of the present invention means the result obtained by performing the fractionation to separate a specific component or a specific component group from a mixture comprising various various components.
- the fraction may be the result of fractionation of the lily scale extract by various methods such as solvent fractionation, ultrafiltration fractionation, chromatography fractionation.
- the method for obtaining the fraction is also not particularly limited as long as it can obtain a fraction exhibiting the effect of preventing or treating cognitive impairment, and may be performed according to a method commonly used in the art. As an example, a method of obtaining a fraction from a lily scaly hydrothermal extract using solvent fractionation may be used.
- the kind of the fractionation solvent used to obtain the fraction in the present invention is also not particularly limited as long as it can obtain a fraction showing the effect of preventing or treating cognitive impairment, and is carried out according to a method commonly used in the art.
- the fractionating solvent may be a polar solvent such as water or alcohol;
- Non-polar solvents such as hexane, ethyl acetate, chloroform and dichloromethane may be used alone or in combination of one or more thereof.
- prevention means any action that inhibits or delays cognitive impairment by administering the composition of the invention to a subject.
- treatment refers to any action by which the composition of the present invention is administered to a subject to improve or benefit from cognitive impairment.
- composition of the present invention may be prepared in the form of a pharmaceutical composition for preventing or treating cognitive disorders further comprising a suitable carrier, excipient or diluent commonly used in the manufacture of pharmaceutical compositions.
- the carrier may be an unnatural carrier.
- the pharmaceutical composition may be formulated in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods. Can be.
- carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, It may be prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate and talc may also be used.
- Liquid preparations for oral use may include various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are simple diluents commonly used in suspensions, solutions, emulsions, and syrups. have.
- Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories.
- non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
- the content of the lily scale extract or its fraction contained in the pharmaceutical composition of the present invention is not particularly limited, but is based on the total weight of the final composition of 0.0001 to 50% by weight, more preferably 0.01 to 20% by weight May be included.
- the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount
- Sufficient amount means an effective dose level means the severity of the disease, the activity of the drug, the age, weight, health, sex, sensitivity of the patient to the drug, the time of administration of the composition of the invention used, the route of administration and the rate of excretion treatment Period of time, factors including drugs used in combination or coincidental with the compositions of the invention used, and other factors well known in the medical arts.
- the pharmaceutical composition of the present invention may be administered alone or in combination with known cognitive disorder therapeutics. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects.
- the dosage of the pharmaceutical composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the age, weight, sex, history, or type of substance used as an active ingredient of the patient.
- the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 100 mg / kg, preferably 1 ng to about 10 mg / kg, per adult, and the frequency of administration of the composition of the present invention is specifically Although not limited, it can be administered once a day or several times in divided doses.
- the dosage does not limit the scope of the invention in any aspect.
- the concentration of the lily scale extract or fractions thereof in the composition may be 5 to 200 ⁇ g / ml, more specifically 50 to 200 ⁇ g / ml.
- a method of preventing or treating a cognitive impairment comprising administering a pharmaceutical composition to a subject having or likely to develop a cognitive impairment.
- the term "individual” of the present invention may include without limitation mammals, farmed fish, etc., which may cause cognitive impairment or cause blood glucose abnormalities such as mice, livestock, and the like.
- the term "administration" means introducing the pharmaceutical composition of the present invention to a subject having suspicion of rhinitis by any suitable method, and the route of administration of the pharmaceutical composition for preventing or treating cognitive disorders of the present invention may be administered through any general route. May be administered.
- the pharmaceutical composition of the present invention is not particularly limited to this, but as desired, routes of intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, pulmonary administration, rectal administration, etc. It can be administered through.
- the oral composition when orally administered, the lily scaly extract or a fraction thereof may be denatured by gastric acid, so the oral composition should be formulated to coat the active agent or to protect it from degradation in the stomach.
- the composition may be administered by any device in which the active substance may migrate to the target cell.
- the present invention provides a dietary supplement for preventing or improving cognitive impairment, comprising a lily scale extract or a fraction thereof as an active ingredient.
- the lily scale Since the lily scale has been used for a long time as a natural substance has proven its stability, it can be prepared and consumed in the form of a food that can prevent or improve cognitive impairment.
- the term "improvement” means any action that at least reduces the parameters associated with the condition, e.g., the degree of symptoms, treated with the administration of a composition comprising a lily scaly extract of the present invention or a fraction thereof.
- the health functional food includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof, Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. Others may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
- the health functional food is any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcoholic beverage and vitamin complex Can be.
- the health functional food may further include food additives, and the suitability as a "food additive" is related to the relevant items according to the General Regulations and General Test Act of the Food Additives Code approved by the Food and Drug Administration unless otherwise specified. Judging by the standards and standards.
- Items listed in the "Food Additives Code” include, for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, cinnamon acid, natural additives such as dark blue, licorice extract, crystalline cellulose, high-lower pigment, guar gum, L Mixed preparations, such as sodium glutamate preparation, a cotton addition alkali preparation, a preservative preparation, and a tar pigment preparation, are mentioned.
- chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, cinnamon acid, natural additives such as dark blue, licorice extract, crystalline cellulose, high-lower pigment, guar gum, L Mixed preparations, such as sodium glutamate preparation, a cotton addition alkali preparation, a preservative preparation, and a tar pigment preparation, are mentioned.
- composition to be added to food including beverages in the process of manufacturing a health functional food may be appropriately added or subtracted as needed, specifically, may be added to include 1 to 15% by weight in 100% by weight of food. .
- a health functional food composition for improving memory or concentration comprising lily scale extract or a fraction thereof as an active ingredient.
- the "health functional food” or “improvement” is as described above.
- the term “memory” means the ability to store or preserve memory transmitted to the brain before external or internal damage occurs to the brain.
- concentration means a memory or learning ability that rises to a short term maximum.
- the time for finding the destination is shorter than the normal group ( 2c and 2d).
- the passive avoidance experiment conducted by administering only the lily scale extract in the normal state it was confirmed that the latency time was significantly increased than that of the normal group (FIG. 3B), and the lily scale extract improved memory and maintained memory. It can be confirmed that it is effective in.
- composition for inducing in-vitro neural stem cell proliferation comprising a lily scale extract or a fraction thereof.
- the lily scale extract induces the proliferation of the NE-4C neural stem cell line (FIG. 5), and NE-4C through BrdU immunostaining. Neuronal cell line proliferation effect can be confirmed (FIG. 6).
- the anticholinergic substance scopolamine was intraperitoneally injected at a concentration of 1 mg / kg for 2 weeks to prepare a memory-inhibited animal model.
- the extract prepared in Example 1 was orally administered for 2 weeks at a concentration of 50, 100 mg / kg daily for 2 hours before scopolamine administration.
- Donepezil hydrochloride a treatment for cholinesterase inhibitors of Alzheimer's disease, was orally administered at a concentration of 2 mg / kg.
- Experimental group 2 the administration of scopolamine after the administration of donepezil (2mg / kg) to the normal group
- Experimental group 4 The group administered the lily scale extract to the normal group by concentration (50, or 100 mg / kg) (no scoflavin administration).
- mice were sacrificed by perfusion fixation through the heart for histological examination after 2 weeks of administration, and brains were harvested. In addition, some mice underwent underwater maze experiments and passive avoidance tests for behavioral examination two weeks after the last dose. The process is shown in FIG.
- the Morris water maze test is a method of testing spatial learning and memory to measure the time it takes to find a hidden platform after a mouse is dropped into a tank filled with water. Experimental animals with better learning and memory have shorter time to find hidden platforms.
- the experimental animals of each experimental group were randomly placed in four directions in a pool having a circular hidden platform, and the experiment was performed to find the hidden platform. Experimental animals were to stay on the platform for about 5 seconds when escaping the hidden platform within 60 seconds. If the test animal could not find the platform within 60 seconds, the experimenter guided it and left it on the platform for 10 seconds to finish the test.
- the motivation for visiting the platform was to escape from the water and collected the experimental results through the image tracking system. The experiment was conducted continuously for 6 days in total, three times a day.
- Figures 2a and 2c is a schematic diagram showing the path to the experimental animal to find the hidden destination (platform) through the underwater maze experiment
- Figures 2b and 2d is a graph measuring the time taken to find the destination (platform).
- experimental group 1 induced brain cognitive impairment by scopolamine it was confirmed that the path to the hidden destination is confused, it takes a long time to find the destination.
- experimental group 3 which was administered with the lily scale extract, was able to confirm that the route to the destination was simplified, and the time was significantly shortened.
- Figure 3 shows the time (latency time) measured according to the above experiment, specifically (a) of Figure 3 (a) passive avoidance test results of experimental animals administered with Donepezil or lily scale extract to the memory model of inhibition (B) shows the results of passive avoidance of experimental animals administered with lily scale extract to normal group.
- the dentate gyrus of the hippocampus is known as a site for hippocampal neurogenesis, in which new neurons are generated throughout life as well as learning and memory.
- euthanasia was performed to confirm the survival (cell survival study) of newly formed cells in the hippocampus of the brain at 2 weeks after intraperitoneal injection of BrdU for 6 days at 100 mg / kg. I was.
- BrdU is a marker that can replace thymidine in the S phase where DNA replication takes place and can target newly proliferating cells.
- the number of BrdU target cells (the number of newly formed cells) in the dentate gyrus of the brain was confirmed.
- the brain extracted in Experimental Example 1 was sliced into 1-in-6 series in cryostat.
- DNA was denatured by treatment with 0.6% hydrogen peroxide and exposing the brain tissue sections in the order of heating, acid, and base. After washing, the cells were blocked and then reacted with an anti-rat BrdU antibody at 4 ° C. overnight, followed by 3 hours of reaction with a biotinylated anti-rat secondary antibody at room temperature. After washing, the solution was reacted with ABC solution for 1 hour at room temperature, and then stained with DAB kit and observed under an optical microscope. The 6th-10th sections of the rostro-caudal sections of the whole hippocampus were examined. After measuring the total number of BrdU target cells in the dentate gyrus of each hippocampus, samples were calculated by fractions to quantify the number of newly formed cells in the hippocampus. The researcher has improved the accuracy of the experiment.
- BrdU staining results according to the experiment (a) and the statistical results (b) are shown in Figure 4.
- experimental group 1 administered scopolamine the number of BrdU target cells decreased compared to the normal group, indicating that survival of newly formed cells in the hippocampus of the hippocampus was reduced.
- experimental group 3 to which the lily scale extract was administered before the scopolamine administration the number of BrdU target cells was significantly increased compared to the experimental group 1.
- experimental group 4 was found to increase the number of BrdU target cells, especially in the 50mg / kg, 100mg / kg increased the survival of the newly formed cells in the dentate gyrus of the hippocampus compared to the normal group, which is also the lily scales for the normal group This means that the extract has an effect of increasing the hippocampal nerve stem cells and hippocampal nerve regeneration.
- NE-4C neural stem cell line derived from cranial neural germ layers (NE-4C neural stem cell line) was treated with the concentration of the lily scale extract prepared in Example 1, 0.25 mg / ml to the cells 24 hours after treatment A concentration of MTT solution was added and incubated for another 2 hours. Then, the formazan precipitate was dissolved in dimethyl sulfoxide (DMSO), and then the absorbance was measured at 560 nm with a microplate reader (SpectraMax i3, Molecular devices, CA, USA).
- DMSO dimethyl sulfoxide
- the extract of the scales of the lily of the stem was confirmed the cell proliferation-inducing effect, especially at a concentration of 50 to 200 ⁇ g / ml cell growth rate of about 1.5 compared to the control (0 ⁇ g / ml) It was confirmed that the fold improved.
Abstract
The present invention relates to: a composition, containing a lily bulb extract or a fraction thereof as an active ingredient, for preventing or treating a cognitive disorder; a health functional food composition, containing a lily bulb extract or a fraction thereof as an active ingredient, for improving memory or concentration; and a composition, containing a lily bulb extract or a fraction thereof, for inducing the proliferation of neural stem cells in vitro.
Description
본 발명은 인지장애의 예방 또는 치료용 약학 조성물에 관한 것이다. 구체적으로는 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애의 예방 또는 치료용 약학 조성물, 상기 조성물을 개체에 투여하는 단계를 포함하는 인지장애를 예방 또는 치료하는 방법, 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애 예방 또는 개선용 건강기능식품 조성물, 백합 비늘줄기 추출물 또는 이의 분획물을 유효성분으로 포함하는 기억력 또는 집중력 개선용 건강기능식품 조성물, 및 백합 비늘줄기 추출물 또는 이의 분획물을 포함하는 인비트로 신경줄기세포 증식 유도용 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cognitive disorders. Specifically, a pharmaceutical composition for preventing or treating cognitive disorders comprising lily scale extract or a fraction thereof as an active ingredient, a method for preventing or treating cognitive disorders comprising administering the composition to a subject, lily scale extract Or functional health food composition for preventing or improving cognitive impairment, including fractions thereof as an active ingredient, lily scale extract or a functional food composition for improving memory or concentration comprising fractions thereof as an active ingredient, and lily scale extract or lily thereof It relates to a composition for inducing neural stem cell proliferation comprising a fraction.
백합(Lily)은 외떡잎식물 백합목 백합과 백합속(Lilium) 식물을 의미한다. 주로 햇볕이 직접 쬐지 않는 숲이나 수목의 그늘 또는 북향의 서늘한 곳에서 자란다. 잎은 잎면이 서로 어긋나면서 돌려서 나게 된다. 꽃은 크고, 각 조직은 6갈래로 갈라져 나며, 내면에 밀구가 있다. 수술은 6개이고, 꽃밥은 T자형으로 달린다. 삭과는 납작한 종자이며, 종자의 수명은 보통 3년이다. Lily means monocotyledonous lily and Lilium plant. It grows mostly in the shade of forests and trees or directly to the north where it is not exposed to direct sunlight. The leaves are rotated with their leaf sides displaced. The flowers are large, each tissue is divided into six branches, and there are wheat bulbs inside. There are 6 stamens and anther runs in T-shape. Capsules are flat seeds, and the lifespan of seeds is usually 3 years.
상기 백합은 구근에 해당하는 알뿌리 식물인데, 특히 상기 백합은 알뿌리 중에서 비늘줄기의 구조를 가진 알뿌리 식물이다. 즉, 일반적인 알뿌리 식물은 비늘줄기, 알줄기, 덩이줄기, 뿌리줄기, 덩이뿌리로 나눌 수 있는데, 상기 백합의 경우는 이중 비늘줄기에 해당하는 식물인 것이다. 상기 백합의 알뿌리인 백합 비늘줄기는 잎의 기부가 비대하고, 층상구조의 비늘조직을 가지면서 땅속에서 생장하게 된다. The lily is a root plant corresponding to the bulb, in particular, the lily is a root plant having a scaly structure among the roots. In other words, the general root plant can be divided into scales, egg stems, tubers, root stems, tubers, the case of the lily is a plant corresponding to the double scales. Lily scales, which are the roots of the lilies, grow in the ground while the bases of the leaves are enlarged and have a layered scale structure.
한편, 의료기술 발달로 사람의 평균 수명이 증가되고 전 세계적으로 노인 인구가 증가함에 따라 치매 환자도 증가하여 치매노인 관리가 심각한 사회문제로 대두되고 있으며 우리나라의 치매 유병률은 치매 유형 및 지역에 따라 다르지만 1997년에 65세 이상 노인의 8.3%였으며 2010년에는 8.6%, 2020년에는 9%로 증가 될 것으로 추정되고 있다. 상기 치매는 증상군으로 질환이 진행되면서 인지 장애와 기능장애가 더욱 심해져, 조기 진단과 조기 치료가 중요하며 혈관성 치매는 초기에 진단하여 치료하면 더 이상의 진행을 막을 수 있고, 퇴행성 질환인 알쯔하이머형 치매도 조기 발견하여 약물치료하면 병을 지연시킬 수 있어 조기 발견 및 예방이 매우 중요하다.On the other hand, as the life expectancy of people increases due to the development of medical technology and the elderly population worldwide increases, the dementia patients also become a serious social problem, and the prevalence of dementia in Korea varies depending on the type and region of dementia. In 1997, it was estimated that 8.3% of the elderly aged 65 or older would increase to 8.6% in 2010 and 9% in 2020. The dementia is a symptom group, and as the disease progresses, cognitive impairment and dysfunction become more severe, and early diagnosis and early treatment are important. Vascular dementia can prevent further progression if diagnosed and treated early, and Alzheimer's disease, which is a degenerative disease, Early detection and medication can delay the disease, so early detection and prevention are very important.
이에 따라, 최근 치매 등으로 인해 저하된 인지기능 및 학습기능을 개선시키고 향상시키는 다양한 치료전략을 수립하고 효과적인 약물을 개발하고자 하는 노력이 시도되고 있다. 현재까지 개발된 기억력 개선 약물들에는 아세틸콜린성전구체(acetylcholine precursor), 수용체 활성제(Receptor agonist), 아세틸콜린분해 억제제(Acetylcholine esterase inhibitor, AchEI) 등이 있으나, 효과가 일시적이고 미약하며 심각한 부작용 및 독성때문에 아직 사용에 논란의 여지가 많은 상태이다. 그러므로, 부작용이 적으며, 효능이 좋고, 원인적 치료(뇌병변의 개선)까지 가능한 새로운 기억력 개선 효과를 갖는 조성물 찾아내고 효과를 입증하여 개발하려는 노력이 요구되고 있다.Accordingly, efforts have recently been made to establish various treatment strategies for improving and improving cognitive and learning functions deteriorated due to dementia and to develop effective drugs. Memory-improving drugs developed to date include acetylcholine precursors, receptor agonists, and acetylcholine esterase inhibitors (AchEIs), but their effects are temporary, mild, and due to severe side effects and toxicity. There is still a lot of controversy over its use. Therefore, there is a need for an effort to find a composition having a new memory-improving effect capable of fewer side effects, good efficacy, and even causative treatment (improvement of brain lesions), and to develop and prove the effect.
본 발명과 관련된 선행문헌으로 양파 추출물 또는 이의 분획물을 유효성분으로 함유하는 인지기능 또는 기억능력 개선용 조성물에 관한 대한민국 공개특허 제2016-0088165호(특허문헌 1)가 있다. 또한 백합 추출물을 유효성분으로 함유하는 만성폐쇄성 폐질환 예방 및 치료용 약학 조성물에 관한 대한민국 공개특허 제2013-0107531호(특허문헌 2)가 있다. 하지만, 상기 선행문헌에서는 백합 비늘줄기 추출물을 이용하여 인지기능 및 학습능력을 개선하는 효과에 대하여는 전혀 개시된 바가 없다.As a prior art document related to the present invention, there is Korean Patent Application Publication No. 2016-0088165 (Patent Document 1) relating to a composition for improving cognitive function or memory ability containing onion extract or a fraction thereof as an active ingredient. In addition, there is a Republic of Korea Patent Publication No. 2013-0107531 (Patent Document 2) of the pharmaceutical composition for preventing and treating chronic obstructive pulmonary disease containing a lily extract as an active ingredient. However, in the prior document, there is no disclosure about the effect of improving the cognitive function and the learning ability by using a lily scale extract.
이러한 배경 하에, 본 발명자들은 인지기능 및 학습능력을 개선하는 조성물을 발견하기 위하여 예의 연구 노력한 결과, 백합 비늘줄기 추출물이 인지장애를 예방 또는 치료하면서 기억력 또는 집중력의 개선 효과가 있음을 발견하고 본 발명을 완성하였다.Under this background, the present inventors have made diligent research efforts to find a composition that improves cognitive function and learning ability. As a result, the present invention has found that the lily scale extract has an effect of improving memory or concentration while preventing or treating cognitive impairment. Was completed.
본 발명의 주된 목적은 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애의 예방 또는 치료용 약학 조성물을 제공하는 것이다.It is a main object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cognitive disorders comprising lily scale extract or a fraction thereof as an active ingredient.
본 발명의 다른 목적은 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 조성물의 인지장애의 예방 또는 치료 용도를 제공한다.It is another object of the present invention to provide a preventive or therapeutic use of cognitive impairment of a composition comprising a lily scaly extract or a fraction thereof as an active ingredient.
본 발명의 또 다른 목적은 상기 약학 조성물을 인지장애가 발병되거나 또는 발병될 가능성이 있는 개체에 투여하는 단계를 포함하는 인지장애를 예방 또는 치료하는 방법을 제공하는 것이다. It is another object of the present invention to provide a method for preventing or treating a cognitive impairment comprising administering the pharmaceutical composition to a subject having or likely to develop a cognitive impairment.
본 발명의 또 다른 목적은 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다. Still another object of the present invention is to provide a dietary supplement for preventing or improving cognitive impairment, comprising a lily scaly extract or a fraction thereof as an active ingredient.
본 발명의 또 다른 목적은 백합 비늘줄기 추출물 또는 이의 분획물을 유효성분으로 포함하는 기억력 또는 집중력 개선용 건강기능식품 조성물을 제공하는 것이다. Still another object of the present invention is to provide a health functional food composition for improving memory or concentration comprising lily scales extract or a fraction thereof as an active ingredient.
본 발명의 또 다른 목적은 백합 비늘줄기 추출물 또는 이의 분획물을 포함하는 인비트로 신경줄기세포 증식 유도용 조성물을 제공하는 것이다.Still another object of the present invention is to provide an in vitro neural stem cell proliferation inducing composition comprising a lily scaly extract or a fraction thereof.
본 발명에 따른 약학 조성물은 백합 비늘줄기 추출물 또는 그의 분획물은 인지장애를 예방 또는 치료하는 효과가 있다. 또한 상기 백합 비늘줄기 추출물 또한 그의 분획물은 뇌 인지기능에 손상 없는 정상 상태에 대하여 투여한 경우에도 기억력 또는 집중력을 개선하는 효과가 있다. 또한 본 발명에 따른 백합 비늘줄기 추출물 또는 그의 분획물은 인지장애를 예방 또는 치료하는 방법이나 인지장애 예방 또는 개선용 건강기능식품 조성물에 사용될 수 있다. 또한 기억력 또는 집중력 개선용 건강기능식품으로 제공이 가능하다.The pharmaceutical composition according to the present invention has a lily scale extract or a fraction thereof has the effect of preventing or treating cognitive impairment. In addition, the lily scaly extract and its fractions have the effect of improving memory or concentration even when administered against a steady state without impaired brain cognitive function. In addition, the lily scale extract or fractions thereof according to the present invention can be used in a method for preventing or treating cognitive impairment or in a dietary supplement for preventing or improving cognitive impairment. In addition, it can be provided as a dietary supplement for improving memory or concentration.
도 1은 본 발명의 일 실시예에 따른 백합 비늘줄기 추출물을 투여한 실험동물을 대상으로 수중미로실험과 수동회피실험을 진행하는 과정을 나타낸 그림이다. 1 is a diagram showing a process of conducting an underwater maze experiment and a manual avoidance test for a test animal administered with a lily scale stem extract according to an embodiment of the present invention.
도 2a 내지 도 2d는 본 발명의 일 실시예에 따른 백합 비늘줄기 추출물을 투여한 실험동물을 대상으로 수중미로실험을 수행한 결과로서, 도 2a 및 도 2c는 수중미로실험으로 실험동물이 숨겨진 목적지를 찾아가는 경로를 나타내는 모식도이며, 도 2b 및 도 2d는 수중미로실험으로 실험동물이 목적지를 찾아가는데 걸리는 시간(latency time)을 측정한 그래프이다(*는 정상군 또는 실험군 1 대비 p<0.05). 구체적으로 도 2b는 숨겨진 플랫폼에 도달하는데 걸리는 시간(Latency time to reach platform)을 초(sec)로 측정한 그래프이다. 여기서 각 실험군의 의미는 다음과 같다:Figures 2a to 2d is a result of performing a labyrinth experiment on the experimental animals administered with the lily scale stem extract according to an embodiment of the present invention, Figures 2a and 2c is a hidden destination in the labyrinth experiment 2b and 2d are graphs measuring the latency time taken by an experimental animal to find a destination by the underwater maze experiment (* is p <0.05 compared to the normal group or the experimental group 1). In detail, FIG. 2B is a graph measuring the latency time to reach platform in seconds. Here, each experimental group means:
- 정상군: 스코폴라민, 도네페질, 또는 추출물을 투여하지 않은 군, Normal group: no scopolamine, donepezil, or extracts,
- 실험군 1: 정상군에 스코폴라민만을 투여한 군, Experimental group 1: Scopolamine administered to the normal group,
- 실험군 2: 정상군에 도네페질(2mg/kg)을 투여한 후 스코폴라민 투여한 군, Experimental group 2: the administration of scopolamine after the administration of donepezil (2mg / kg) to the normal group,
- 실험군 3: 정상군에 백합 비늘줄기 추출물을 농도별(50, 또는 100 mg/kg)로 투여한 후 스코폴라민 투여한 군,-Experimental group 3: The group administered with scopolamine after administration of lily scale extract to the normal group by concentration (50, or 100 mg / kg),
- 실험군 4: 정상군에 백합 비늘줄기 추출물을 농도별(50, 또는 100 mg/kg)로 투여한 군 (스코플라민 투여 없음).Experimental group 4: The group administered the lily scale extract to the normal group by concentration (50, or 100 mg / kg) (no scoflavin administration).
도 3은 본 발명의 일 실시예에 따른 백합 비늘줄기 추출물을 투여한 실험동물을 대상으로 수동회피실험을 수행하여 실험동물이 밝은 방에서 머무른 시간(Step-through latency time)을 초(sec)로 측정한 결과를 나타내는 그래프이다 (*는 정상군 또는 실험군 1 대비 p<0.05). Figure 3 is a manual evasion experiment on the experimental animals administered with lily scales extract according to an embodiment of the present invention (step-through latency time) in seconds (sec) It is a graph which shows the result of a measurement (* is p <0.05 compared with normal group or the experimental group 1).
도 4는 본 발명의 일 실시예에 따른 백합 비늘줄기 추출물을 실험동물에 투여한 후, 실험동물 뇌의 해마의 치아이랑에서 BrdU 표적세포의 수를 확인한 결과를 나타내는 것으로서, (a)는 BrdU 표적세포의 염색 결과를 나타내는 사진이며, (b)는 BrdU 표적세포의 수를 섹션(section) 별로 확인하여 정량적으로 확인한 결과를 나타내는 그래프이다(*는 정상군 또는 실험군 1 대비 p<0.05).Figure 4 shows the result of confirming the number of BrdU target cells in the dentate gyrus of the hippocampus of the experimental animal brain after administration of the lily scale extract according to an embodiment of the present invention, (a) is BrdU target It is a photograph showing the staining result of the cells, (b) is a graph showing the result of quantitatively confirmed by confirming the number of BrdU target cells for each section (*) (* is p <0.05 compared to normal group or experimental group 1).
도 5는 본 발명의 일 실시예에 따른 백합 비늘줄기 추출물을 NE-4C 신경줄기세포주에 농도별로 처리하고 24시간이 경과한 후 세포증식 효능을 확인한 결과를 나타내는 사진 및 그래프로서, (a)는 광학현미경으로 관찰한 결과를 나타내는 사진이며, (b)는 세포증식율을 나타낸 그래프이다(*는 0 μg/ml 대비 p<0.05). Figure 5 is a photograph and graph showing the results of confirming the cell proliferation efficacy after 24 hours after treatment with lily scale extract according to an embodiment of the present invention NE-4C neural stem cell line, (a) is It is a photograph showing the results observed with an optical microscope, (b) is a graph showing the cell growth rate (* is p <0.05 compared to 0 μg / ml).
도 6은 본 발명의 일 실시예에 따른 NE-4C 신경줄기세포주에서 백합 비늘줄기 추출물의 처리로 인한 신경세포주의 세포증식 정도를 BrdU를 통해 확인한 것으로서, (a)는 BrdU 면역염색 결과를 나타내는 사진이며, (b)는 BrdU incorporation assay를 측정한 그래프이다(*는 0 μg/ml 대비 p<0.05).Figure 6 shows the cell proliferation of the neuronal cell line due to the treatment of lily scale stem extract in NE-4C neural stem cell line according to an embodiment of the present invention through BrdU, (a) is a photograph showing the BrdU immunostaining results (B) is a graph of BrdU incorporation assay (* is p <0.05 vs. 0 μg / ml).
본 발명자들은 건망증, 알츠하이머병, 치매, 파킨슨 병, 피크병 또는 헌팅톤병 등 인지장애를 예방하거나 치료하는 물질을 발견하기 위하여 예의 연구 노력하는 과정에서, 백합 비늘줄기 추출물이 인지장애를 예방 또는 치료하면서 기억력 또는 집중력 향상 효과도 있음을 발견하였다.The inventors of the present invention, in the course of making an effort to discover a substance that prevents or treats cognitive disorders such as forgetfulness, Alzheimer's disease, dementia, Parkinson's disease, Peak disease or Huntington's disease, It has also been found to improve memory or concentration.
상기의 목적을 달성하기 위한 하나의 양태로서, 본 발명은 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애의 예방 또는 치료용 약학 조성물을 제공한다.As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of cognitive disorders comprising lily scale extract or a fraction thereof as an active ingredient.
또한, 본 발명은 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 조성물의 인지장애의 예방 또는 치료용도를 제공한다.In addition, the present invention provides a use for the prevention or treatment of cognitive impairment of a composition comprising a lily scale extract or a fraction thereof as an active ingredient.
본 발명의 용어 "백합 비늘줄기"는 백합의 알뿌리를 지칭하는 것으로서, 인경이라고도 하며, 짧은 줄기 둘레에 많은 양분을 저장하고 있어 비대하고, 잎이 빽빽하게 자라서 된 백합의 땅속 줄기를 의미한다. 구체적으로, 참나리(Lilium lancifolium Thunberg), Lilium brownii var. viridulun Baker, 큰솔나리(Lilium pumilum DC.)의 비늘줄기를 의미할 수 있다. 상기 백합 비늘줄기는 백합의 꽃을 포함한 지상부와 구별되는 개념이다.The term “lilies scaly” of the present invention refers to a lily root of a lily, also called a diameter, and refers to a subterranean stem of a lily that is large in size and has dense leaves because it stores many nutrients around a short stem. Specifically, Lilium lancifolium Thunberg, Lilium brownii var. viridulun Baker, Lilium pumilum DC. The lily scale is a concept that is distinguished from the ground including the flowers of the lily.
인지기능이란 지각(perception), 기억(memory), 학습(learning), 주의(attention), 경계(vigilance), 이해(understanding), 해석(interpretation) 등 주위의 환경에 적응하기 위해서 관련 정보를 이용하는 능력을 의미한다. 본 발명의 조성물은 인지기능, 구체적으로 학습과 기억 개선에 우수한 효과를 나타낼 수 있다. Cognitive function is the ability to use relevant information to adapt to the surrounding environment, such as perception, memory, learning, attention, vigilance, understanding, and interpretation. Means. The composition of the present invention can exhibit an excellent effect on cognitive function, specifically learning and memory.
본 발명에서, "인지장애"는 인지기능이 저하되어 생기는 상태, 그에 따른 질환, 그를 증상으로 하는 모든 질환을 포함하는 개념으로써, 바람직하게는 뇌 신경세포의 손상으로 발생하는 장애를 의미할 수 있다. 예를 들어, 상기 인지기능 장애는 건망증, 알츠하이머병, 치매, 파킨슨 병, 피크병, 크로이츠펠트 야콥병, 헌팅톤병, 허혈성 뇌졸중, 및 출혈성 뇌졸중으로 이루어지는 군으로부터 선택되는 어느 하나 이상의 퇴행성 뇌질환을 의미할 수 있다. In the present invention, "cognitive impairment" is a concept that includes a condition resulting from a decrease in cognitive function, a disease according to it, and all diseases in which the symptom is a symptom, and may preferably mean a disorder caused by damage to brain neurons. . For example, the cognitive dysfunction may mean any one or more degenerative brain diseases selected from the group consisting of forgetfulness, Alzheimer's disease, dementia, Parkinson's disease, peak disease, Creutzfeldt-Jakob disease, Huntington's disease, ischemic stroke, and hemorrhagic stroke. Can be.
치매(dementia)는 후천적으로 기억, 언어, 판단력 등의 여러 영역의 인지 기능이 감소하여 일상생활을 제대로 수행하지 못하는 증후군을 의미하며, 다양한 원인에 의하여 뇌기능이 손상되면서 이전에 비해 인지 기능이 지속적으로 전반적으로 저하되어 일상생활에 상당한 지장이 나타날 수 있다. 상기 치매는 원인 질환으로 세분화할 경우 수십 가지에 이르나, 이 중에서도 알츠하이머병에 의한 원인이 가장 많으며 50%를 넘는다. 상기 치매는 혈관성 치매, 알츠하이머성 치매, 루이성 치매, 두부 외상에 의한 치매, 뇌종양에 의한 치매, 대사성 질환에 의한 치매로 이루어지는 군에서 선택되는 것일 수 있다. Dementia is a syndrome in which the cognitive function of various areas such as memory, language, and judgment are reduced, and thus cannot perform daily life properly.Dementia is a brain function that is damaged by various causes. As a result, the overall decline may result in significant disruption in daily life. The dementia can be divided into dozens of causative diseases, but among them, Alzheimer's disease is the most common cause and exceeds 50%. The dementia may be selected from the group consisting of vascular dementia, Alzheimer's dementia, Louis dementia, dementia caused by head trauma, dementia caused by brain tumor, and dementia caused by metabolic disease.
본 발명의 일 실시예에서는 스코폴라민에 의해 뇌 인지기능 손상이 유도된 동물모델에 백합 비늘줄기 추출물을 경구 투여한 후, 수중미로실험을 수행하면 뇌 인지기능 손상 후 백합 비늘줄기 추출물을 투여하지 않은 그룹에 비해 목적지를 찾아가는 경로도 단순해지면서, 그 시간도 현저히 단축됨을 확인하였다(도 2a 및 도 2b). 또한 동일한 방법으로 뇌 인지기능 손상이 유도된 동물모델에 백합 비늘줄기 추출물을 경구 투여한 후, 수동회피실험을 수행하면 뇌 인지기능이 손상된 동물모델에 비해 latency time이 정상 상태로 회복됨을 확인할 수 있었다(도 3의 (a)). 또한 BrdU 염색 결과 백합 비늘줄기 추출물을 투여하면, 그렇지 않은 경우에 비해 BrdU 표적세포의 수가 유의하게 증가함을 확인할 수 있었다(도 4). In one embodiment of the present invention, after administering orally administering the lily scale extract to an animal model induced brain cognitive impairment by scopolamine, and performing the underwater maze experiment, do not administer the lily scale extract after brain cognitive impairment Compared to the non-group, the route to the destination is also simplified, and the time is significantly reduced (FIGS. 2A and 2B). In addition, after the oral administration of lily scale extract to the animal model induced brain cognitive impairment in the same way, manual evasion experiments showed that the latency time was restored to normal compared to the animal model with brain impaired cognitive impairment. (FIG. 3A). In addition, when the BrdU staining administration of the lily scale extract, it was confirmed that the number of BrdU target cells significantly increased compared to the other case (Fig. 4).
본 발명의 용어 "추출물"이란, 상기 백합 비늘줄기 또는 그들의 분쇄물을 추출 처리하여 얻어지는 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함한다. The term "extract" of the present invention means an extract obtained by extracting the lily scales or their pulverized products, a dilution or concentrate of the extract, a dried product obtained by drying the extract, a crude product or a purified product of the extract, or these And extracts of all formulations that can be formed using the extract itself and the extract, such as mixtures thereof.
상기 백합 비늘줄기를 추출하는 방법은 인지장애를 예방 또는 치료하는 효과를 나타내는 추출물을 수득할 수 있는 한 특별히 이에 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 추출할 수 있다. 상기 추출 방법의 비제한적인 예로는, 열수 추출법, 초음파 추출법, 여과법, 환류 추출법 등을 들 수 있으며, 이들은 단독으로 수행되거나 2종 이상의 방법을 병용하여 수행될 수 있다.The method of extracting the lily scales is not particularly limited as long as an extract showing an effect of preventing or treating cognitive impairment can be obtained, and may be extracted according to a method commonly used in the art. Non-limiting examples of the extraction method, hot water extraction method, ultrasonic extraction method, filtration method, reflux extraction method, and the like, these may be performed alone or in combination of two or more methods.
본 발명에서 상기 백합 비늘줄기를 추출하는데 사용되는 추출 용매의 종류는 인지장애를 예방 또는 치료하는 효과를 나타내는 추출물을 수득할 수 있는 한 특별히 이에 제한되지 않고, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 일 예로서, 상기 추출 용매로는 물, 알코올 등을 단독으로 또는 1종 이상 혼합하여 사용할 수 있고, 다른 예로서, 상기 추출 용매로는 물 또는 탄소수 1 내지 6의 알코올을 단독으로 또는 1종 이상 혼합하여 사용할 수 있으며, 또 다른 예로서, 상기 추출 용매는 물을 사용할 수 있다.The type of extraction solvent used to extract the lily scales in the present invention is not particularly limited as long as an extract showing an effect of preventing or treating cognitive impairment can be obtained, and any solvent known in the art may be used. Can be used. As an example, the extraction solvent may be used alone or in combination of one or more kinds of water, alcohol, etc. As another example, the extraction solvent may be alone or one or more kinds of water or alcohol having 1 to 6 carbon atoms. Mixing may be used, and as another example, the extraction solvent may be water.
본 발명의 용어 "분획물"이란, 여러 다양한 구성 성분들을 포함하는 혼합물로부터 특정 성분 또는 특정 성분 그룹을 분리하기 위하여 분획을 수행하여 얻어진 결과물을 의미한다.The term "fraction" of the present invention means the result obtained by performing the fractionation to separate a specific component or a specific component group from a mixture comprising various various components.
본 발명에서 상기 분획물은 상기 백합 비늘줄기 추출물을 용매 분획법, 한외여과 분획법, 크로마토그래피 분획법 등의 다양한 방법으로 분획한 결과물이 될 수 있다.In the present invention, the fraction may be the result of fractionation of the lily scale extract by various methods such as solvent fractionation, ultrafiltration fractionation, chromatography fractionation.
상기 분획물을 수득하는 방법 역시 인지장애를 예방 또는 치료하는 효과를 나타내는 분획물을 수득할 수 있는 한 특별히 이에 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 수행될 수 있다. 일 예로서, 용매 분획법을 이용하여 백합 비늘줄기 열수 추출물로부터 분획물을 수득하는 방법을 사용할 수 있다.The method for obtaining the fraction is also not particularly limited as long as it can obtain a fraction exhibiting the effect of preventing or treating cognitive impairment, and may be performed according to a method commonly used in the art. As an example, a method of obtaining a fraction from a lily scaly hydrothermal extract using solvent fractionation may be used.
본 발명에서 상기 분획물을 얻는 데 사용되는 분획 용매의 종류 역시 인지장애를 예방 또는 치료하는 효과를 나타내는 분획물을 수득할 수 있는 한 특별히 이에 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 수행될 수 있다. 일 예로서, 상기 분획 용매로는 물, 알코올 등의 극성 용매; 헥산(Hexan), 에틸 아세테이트(Ethyl acetate), 클로로포름(Chloroform), 디클로로메탄(Dichloromethane) 등의 비극성 용매 등을 단독으로 또는 1종 이상 혼합한 것을 사용할 수 있다.The kind of the fractionation solvent used to obtain the fraction in the present invention is also not particularly limited as long as it can obtain a fraction showing the effect of preventing or treating cognitive impairment, and is carried out according to a method commonly used in the art. Can be. As an example, the fractionating solvent may be a polar solvent such as water or alcohol; Non-polar solvents such as hexane, ethyl acetate, chloroform and dichloromethane may be used alone or in combination of one or more thereof.
본 발명에서 사용되는 용어, "예방"은 본 발명의 상기 조성물을 개체에 투여하여 인지장애를 억제하거나 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits or delays cognitive impairment by administering the composition of the invention to a subject.
본 발명에서 사용되는 용어, "치료"는 본 발명의 상기 조성물을 개체에 투여하여 인지장애 증세가 호전되도록 하거나 이롭게 되도록 하는 모든 행위를 의미한다.As used herein, the term "treatment" refers to any action by which the composition of the present invention is administered to a subject to improve or benefit from cognitive impairment.
상기 본 발명의 조성물은, 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함하는 인지장애 예방 또는 치료용 약학 조성물의 형태로 제조될 수 있다. 이때, 상기 담체는 비자연적인 담체가 될 수 있다. 구체적으로, 상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명에서, 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화 할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물과 이의 분획물들에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함될 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The composition of the present invention may be prepared in the form of a pharmaceutical composition for preventing or treating cognitive disorders further comprising a suitable carrier, excipient or diluent commonly used in the manufacture of pharmaceutical compositions. In this case, the carrier may be an unnatural carrier. Specifically, the pharmaceutical composition may be formulated in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods. Can be. In the present invention, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it may be prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, It may be prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate and talc may also be used. Liquid preparations for oral use may include various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are simple diluents commonly used in suspensions, solutions, emulsions, and syrups. have. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 약학 조성물에 포함된 상기 백합 비늘줄기 추출물 또는 그의 분획물의 함량은 특별히 이에 제한되지 않으나, 최종 조성물 총 중량을 기준으로 0.0001 내지 50 중량%, 보다 바람직하게는 0.01 내지 20 중량%의 함량으로 포함될 수 있다.The content of the lily scale extract or its fraction contained in the pharmaceutical composition of the present invention is not particularly limited, but is based on the total weight of the final composition of 0.0001 to 50% by weight, more preferably 0.01 to 20% by weight May be included.
상기 본 발명의 약학 조성물은 약제학적으로 유효한 양으로 투여될 수 있는데, 본 발명의 용어 "약제학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학 조성물은 단독으로 투여하거나 또는 공지된 인지장애 치료제와 병용하여 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, the term "pharmaceutically effective amount" of the present invention to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention Sufficient amount means an effective dose level means the severity of the disease, the activity of the drug, the age, weight, health, sex, sensitivity of the patient to the drug, the time of administration of the composition of the invention used, the route of administration and the rate of excretion treatment Period of time, factors including drugs used in combination or coincidental with the compositions of the invention used, and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered alone or in combination with known cognitive disorder therapeutics. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects.
본 발명의 약학 조성물의 투여량은 사용목적, 질환의 중독도, 환자의 연령, 체중, 성별, 기왕력, 또는 유효성분으로서 사용되는 물질의 종류 등을 고려하여 당업자가 결정할 수 있다. 예를 들어, 본 발명의 약학 조성물은 성인 1인당 약 0.1 ng 내지 약 100 mg/kg, 바람직하게는 1 ng 내지 약 10 mg/kg로 투여할 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the age, weight, sex, history, or type of substance used as an active ingredient of the patient. For example, the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 100 mg / kg, preferably 1 ng to about 10 mg / kg, per adult, and the frequency of administration of the composition of the present invention is specifically Although not limited, it can be administered once a day or several times in divided doses. The dosage does not limit the scope of the invention in any aspect.
또한 상기 조성물내 백합 비늘줄기 추출물 또는 그의 분획물의 농도는 5 내지 200 ㎍/㎖일 수 있으며, 보다 구체적으로는 50 내지 200 ㎍/㎖일 수 있다. In addition, the concentration of the lily scale extract or fractions thereof in the composition may be 5 to 200 ㎍ / ㎖, more specifically 50 to 200 ㎍ / ㎖.
다른 양태로서, 약학 조성물을 인지장애가 발병되거나 또는 발병될 가능성이 있는 개체에 투여하는 단계를 포함하는 인지장애를 예방 또는 치료하는 방법을 제공한다. In another aspect, there is provided a method of preventing or treating a cognitive impairment comprising administering a pharmaceutical composition to a subject having or likely to develop a cognitive impairment.
본 발명의 용어 "개체"란 인지장애가 발병될 가능성이 있거나 또는 발병된 쥐, 가축 등의 혈당 이상이 유발될 수 있는 포유동물, 양식어류 등을 제한 없이 포함할 수 있다.The term "individual" of the present invention may include without limitation mammals, farmed fish, etc., which may cause cognitive impairment or cause blood glucose abnormalities such as mice, livestock, and the like.
본 발명에서 용어, "투여"는 어떠한 적절한 방법으로 비염 의심 개체에게 본 발명의 약학 조성물을 도입하는 것을 의미하며, 본 발명의 인지장애 예방 또는 치료용 약학 조성물의 투여 경로는 어떠한 일반적인 경로를 통하여도 투여될 수 있다. 본 발명의 약학 조성물은 특별히 이에 제한되지 않으나, 목적하는 바에 따라 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 비내 투여, 폐내 투여, 직장내 투여 등의 경로를 통해 투여 될 수 있다. 다만, 경구 투여 시에는 위산에 의하여 상기 백합 비늘줄기 추출물 또는 그의 분획물이 변성될 수 있기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화 되어야 한다. 또한, 상기 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention to a subject having suspicion of rhinitis by any suitable method, and the route of administration of the pharmaceutical composition for preventing or treating cognitive disorders of the present invention may be administered through any general route. May be administered. The pharmaceutical composition of the present invention is not particularly limited to this, but as desired, routes of intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, pulmonary administration, rectal administration, etc. It can be administered through. However, when orally administered, the lily scaly extract or a fraction thereof may be denatured by gastric acid, so the oral composition should be formulated to coat the active agent or to protect it from degradation in the stomach. In addition, the composition may be administered by any device in which the active substance may migrate to the target cell.
다른 양태로서, 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애 예방 또는 개선용 건강기능식품 조성물을 제공한다. In another aspect, the present invention provides a dietary supplement for preventing or improving cognitive impairment, comprising a lily scale extract or a fraction thereof as an active ingredient.
상기 백합 비늘줄기는 천연 물질로서 오랫동안 사용되어 안정성이 입증되었으므로, 상식할 수 있으면서도 인지장애의 예방 또는 개선을 도모할 수 있는 식품의 형태로 제조되어 섭취할 수 있다.Since the lily scale has been used for a long time as a natural substance has proven its stability, it can be prepared and consumed in the form of a food that can prevent or improve cognitive impairment.
본 발명의 용어, "개선"이란, 본 발명의 백합 비늘줄기 추출물 또는 이의 분획물을 포함하는 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term "improvement" means any action that at least reduces the parameters associated with the condition, e.g., the degree of symptoms, treated with the administration of a composition comprising a lily scaly extract of the present invention or a fraction thereof.
상기 건강기능식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품은 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알콜 음료 및 비타민 복합제 중 어느 하나의 형태일 수 있다.The health functional food includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof, Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. Others may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination. In addition, the health functional food is any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcoholic beverage and vitamin complex Can be.
또한 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합여부는 다른 규정이 없는 한 식품의약품안정청에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. In addition, the health functional food may further include food additives, and the suitability as a "food additive" is related to the relevant items according to the General Regulations and General Test Act of the Food Additives Code approved by the Food and Drug Administration unless otherwise specified. Judging by the standards and standards.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합 제제류들을 들 수 있다.Items listed in the "Food Additives Code" include, for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, cinnamon acid, natural additives such as dark blue, licorice extract, crystalline cellulose, high-lower pigment, guar gum, L Mixed preparations, such as sodium glutamate preparation, a cotton addition alkali preparation, a preservative preparation, and a tar pigment preparation, are mentioned.
이때, 건강기능식품을 제조하는 과정에서 음료를 포함한 식품에 첨가되는 조성물은 필요에 따라 그 함량을 적절히 가감할 수 있으며, 구체적으로는 식품 100 중량%에 1 내지 15 중량% 포함되도록 첨가할 수 있다.At this time, the composition to be added to food, including beverages in the process of manufacturing a health functional food may be appropriately added or subtracted as needed, specifically, may be added to include 1 to 15% by weight in 100% by weight of food. .
다른 양태로서, 백합 비늘줄기 추출물 또는 이의 분획물을 유효성분으로 포함하는 기억력 또는 집중력 개선용 건강기능식품 조성물을 제공한다. In another aspect, it provides a health functional food composition for improving memory or concentration comprising lily scale extract or a fraction thereof as an active ingredient.
상기 "건강기능식품" 또는 "개선"은 상술한 바와 같다.The "health functional food" or "improvement" is as described above.
본 발명의 용어 "기억력"은 뇌에 외부적 또는 내부적 손상이 발생하기 이전에 뇌로 전달된 기억을 저장하거나 보존하는 능력을 의미한다. 본 발명의 용어 "집중력"은 단기간 최대치로 상승하는 기억 능력 또는 학습 능력을 의미한다. As used herein, the term “memory” means the ability to store or preserve memory transmitted to the brain before external or internal damage occurs to the brain. As used herein, the term "concentration" means a memory or learning ability that rises to a short term maximum.
본 발명의 일 실시예에 의하면 뇌 인지기능에 손상이 없는 정상 상태에 백합 비늘줄기 추출물만을 투여하여 진행한 수중미로실험의 결과 시간이 지날수록 정상군보다 목적지를 찾아가는 시간이 단축됨을 확인할 수 있다(도 2c 및 도 2d). 또한 정상 상태에 백합 비늘줄기 추출물만을 투여하여 진행한 수동회피실험에서는 정상군보다도 latency time이 유의하게 증가하는 것을 확인하였는바(도 3의 (b)), 백합 비늘줄기 추출물이 기억력 개선 및 기억력 유지에 효과가 있음을 확인할 수 있다. 또한 정상 상태에 백합 비늘줄기 추출물은 투여한 경우에 정상군에 비하여 BrdU 표적 세포 수가 증가하여 해마의 치아이랑에 새로 생겨나는 세포의 생존이 증가한 것을 확인할 수 있고, 이는 정상군에 대해서도 백합 비늘줄기 추출물이 기억력 또는 집중력 개선 효과가 있음을 의미하는 것이다.According to one embodiment of the present invention, as a result of the underwater maze experiment conducted by administering only the lily scale extract in the normal state without damage to the brain cognitive function, it can be confirmed that the time for finding the destination is shorter than the normal group ( 2c and 2d). In addition, in the passive avoidance experiment conducted by administering only the lily scale extract in the normal state, it was confirmed that the latency time was significantly increased than that of the normal group (FIG. 3B), and the lily scale extract improved memory and maintained memory. It can be confirmed that it is effective in. In addition, when the lily scale extract was administered in the normal state, the number of BrdU target cells increased compared to the normal group, indicating that the survival of newly formed cells in the dentate gyrus of the hippocampus was increased. This means that there is an improvement in memory or concentration.
다른 양태로서, 백합 비늘줄기 추출물 또는 이의 분획물을 포함하는 인비트로(in-vitro) 신경줄기세포 증식 유도용 조성물을 제공한다. In another aspect, there is provided a composition for inducing in-vitro neural stem cell proliferation comprising a lily scale extract or a fraction thereof.
본 발명의 일 실시예에 의하면 백합 비늘줄기 추출물이 NE-4C 신경줄기세포주(NE-4C neural stem cell line)의 증식을 유도하는 것을 확인할 수 있으며(도 5), BrdU 면역염색을 통해서도 NE-4C 신경세포주의 세포증식 효과를 확인할 수 있다(도 6).According to one embodiment of the present invention, it can be seen that the lily scale extract induces the proliferation of the NE-4C neural stem cell line (FIG. 5), and NE-4C through BrdU immunostaining. Neuronal cell line proliferation effect can be confirmed (FIG. 6).
이하 본 발명을 하기 예에 의해 상세히 설명한다. 다만, 하기 예는 본 발명을 예시하기 위한 것일 뿐, 하기 예에 의해 본 발명의 범위가 제한되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the following examples.
실시예 1: 백합 비늘줄기 추출물 제조Example 1: Lily scale extract
현대약업사 (Hyundai Herbal Market, Yeongcheon, Korea)에서 입수한 백합 비늘줄기를 분쇄하여 얻은 분쇄물 50 g을 물 1 L에 넣고 1시간 동안 침적한 후, 대웅약탕기 (Daewoong EXtractor DWP-5000M, Incheon, Korea)를 이용하여 115 ℃에서 3시간 동안 열수 추출하였다. 열수 추출한 후, 감압농축하고 동결 건조하여 백합 비늘줄기 추출물 13.43 g을 수득하였다. 50 g of crushed lily scales obtained from Hyundai Herbal Market, Yeongcheon, Korea were immersed in 1 L of water and immersed for 1 hour, then Daewoong EXtractor DWP-5000M, Incheon, Korea Hydrothermal extraction for 3 hours at 115 ℃. After hot water extraction, the mixture was concentrated under reduced pressure and freeze-dried to obtain 13.43 g of a lily scale extract.
실험예 1: 기억력 저해 동물모델 제조 Experimental Example 1: Preparation of Memory Inhibited Animal Model
생후 35일된 C57BL/6 마우스를 구입 후 1주일 동안 안정화 시킨 이후에 항콜린성 물질인 스코폴라민을 1 mg/kg의 농도로 2주간 매일 복강주사하여 기억력 저해 동물모델을 제조하였다. 이때, 스코폴라민 투여 2시간 전에 매일 50, 100 mg/kg의 농도로 상기 실시예 1에서 제조한 추출물을 2주간 경구투여하였다. 양성 대조군으로는 콜린에스테라제 억제제 계열의 알츠하이머병 치료제인 도네페질 염산염을 2 mg/kg의 농도로 동일하게 경구투여하였다. After stabilizing 35 days old C57BL / 6 mice for 1 week after purchase, the anticholinergic substance scopolamine was intraperitoneally injected at a concentration of 1 mg / kg for 2 weeks to prepare a memory-inhibited animal model. At this time, the extract prepared in Example 1 was orally administered for 2 weeks at a concentration of 50, 100 mg / kg daily for 2 hours before scopolamine administration. As a positive control, Donepezil hydrochloride, a treatment for cholinesterase inhibitors of Alzheimer's disease, was orally administered at a concentration of 2 mg / kg.
구체적으로 실험군을 다음과 같이 나누어 이후의 실험을 진행하였다:Specifically, the experimental group was divided into the following experiments:
- 정상군: 스코폴라민, 도네페질, 또는 추출물을 투여하지 않은 군, Normal group: no scopolamine, donepezil, or extracts,
- 실험군 1: 정상군에 스코폴라민만을 투여한 군, Experimental group 1: Scopolamine administered to the normal group,
- 실험군 2: 정상군에 도네페질(2mg/kg)을 투여한 후 스코폴라민 투여한 군, Experimental group 2: the administration of scopolamine after the administration of donepezil (2mg / kg) to the normal group,
- 실험군 3: 정상군에 백합 비늘줄기 추출물을 농도별(50, 또는 100 mg/kg)로 투여한 후 스코폴라민 투여한 군,-Experimental group 3: The group administered with scopolamine after administration of lily scale extract to the normal group by concentration (50, or 100 mg / kg),
- 실험군 4: 정상군에 백합 비늘줄기 추출물을 농도별(50, 또는 100 mg/kg)로 투여한 군 (스코플라민 투여 없음).Experimental group 4: The group administered the lily scale extract to the normal group by concentration (50, or 100 mg / kg) (no scoflavin administration).
일부 마우스에 대해서는 2주간의 투여 후 조직학적 검사를 위해 심장을 통해 관류 고정시켜 희생시키고, 뇌를 적출하였다. 또한, 일부 마우스에 대해서는 마지막 투여 2주 후 행동학적 검사를 위해 수중미로실험과 수동회피실험을 진행하였다. 상기 과정을 도 1에 나타내었다.Some mice were sacrificed by perfusion fixation through the heart for histological examination after 2 weeks of administration, and brains were harvested. In addition, some mice underwent underwater maze experiments and passive avoidance tests for behavioral examination two weeks after the last dose. The process is shown in FIG.
실험예 2: 행동학적 검사Experimental Example 2: Behavioral Test
실시예 1의 백합 비늘줄기 추출물이 뇌인지기능에 미치는 영향과 손상된 상태에서의 뇌인지기능에 미치는 영향을 확인하는 실험을 하기와 같이 진행하였다. 모든 행동학적 검사를 수행하기 30분 전에 스코폴라민을 1 mg/kg 농도로 복강주사하였다. Experiment to determine the effect of the lily scale extract of Example 1 on the brain cognitive function and the brain cognitive function in a damaged state was carried out as follows. Scopolamine was intraperitoneally injected at a concentration of 1 mg / kg 30 minutes before all behavioral tests were performed.
2-1: 수중미로실험2-1: Underwater Maze Experiment
수중미로실험(Morris water maze test)은 공간학습능력 및 기억력 검사방법으로 물을 채운 수조에 쥐를 빠뜨린 후 숨겨진 플랫폼을 찾아가는데 걸리는 시간을 측정하는 방법이다. 학습 및 기억능력이 좋은 실험동물일수록 숨겨진 플랫폼을 찾아가는 시간이 짧다. 각 실험군의 실험동물을 원형의 숨겨진 플랫폼을 가지는 pool에 4방위에 랜덤하게 놓은 후 숨겨진 플랫폼을 찾아가는 실험을 수행하였다. 실험동물은 60초 이내에 숨겨진 플랫폼을 찾아 탈출하는 경우, 약 5초간 플랫폼에 머무르도록 하였다. 만일, 실험동물이 60초 이내에 플랫폼을 찾지 못하면 실험자가 가이드 해주어 플랫폼에 10초간 두었다가 시험을 끝내었다. 플랫폼을 찾아가는 동기는 물에서의 탈출이고 image tracking system을 통하여 실험결과를 수집하였다. 상기 실험은 1일 3회씩 총 6일간 연속적으로 실시하였다. The Morris water maze test is a method of testing spatial learning and memory to measure the time it takes to find a hidden platform after a mouse is dropped into a tank filled with water. Experimental animals with better learning and memory have shorter time to find hidden platforms. The experimental animals of each experimental group were randomly placed in four directions in a pool having a circular hidden platform, and the experiment was performed to find the hidden platform. Experimental animals were to stay on the platform for about 5 seconds when escaping the hidden platform within 60 seconds. If the test animal could not find the platform within 60 seconds, the experimenter guided it and left it on the platform for 10 seconds to finish the test. The motivation for visiting the platform was to escape from the water and collected the experimental results through the image tracking system. The experiment was conducted continuously for 6 days in total, three times a day.
도 2a 및 도 2c는 수중미로실험을 통해 실험동물이 숨겨진 목적지(플랫폼)를 찾아가는 경로를 나타내는 모식도이고, 도 2b 및 도 2d는 목적지(플랫폼)를 찾아가는데 걸리는 시간을 측정한 그래프이다. Figures 2a and 2c is a schematic diagram showing the path to the experimental animal to find the hidden destination (platform) through the underwater maze experiment, Figures 2b and 2d is a graph measuring the time taken to find the destination (platform).
도 2a 및 도 2b를 살펴보면, 스코폴라민에 의해 뇌인지기능 손상이 유도된 실험군 1의 경우에는 숨겨진 목적지를 찾아가는 경로가 혼란스러우면서, 목적지를 찾는데 걸리는 시간도 오래 걸리는 것을 확인할 수 있었다. 하지만, 이에 백합 비늘줄기 추출물을 투여한 실험군 3은 목적지를 찾아가는 경로도 단순해지면서, 그 시간도 현저히 단축되는 것을 확인할 수 있었다. Referring to Figure 2a and 2b, in the case of experimental group 1 induced brain cognitive impairment by scopolamine it was confirmed that the path to the hidden destination is confused, it takes a long time to find the destination. However, experimental group 3, which was administered with the lily scale extract, was able to confirm that the route to the destination was simplified, and the time was significantly shortened.
도 2c 및 도 2d를 살펴보면 정상군에 백합 비늘줄기 추출물을 투여한 실험군 4의 경우에는 시간이 지날수록 정상군보다도 목적지를 찾아가는 시간이 단축됨을 확인할 수 있었다. Referring to Figure 2c and Figure 2d it was confirmed that the experimental group 4 administered the lily scale extract to the normal group, the time to find the destination is shorter than the normal group as time passes.
이러한 결과를 통해 백합 비늘줄기 추출물이 손상된 뇌인지기능을 회복시킴은 물론, 정상상태에서도 학습 및 기억력 향상 효과가 우수한 것임을 확인하였다. These results confirmed that the extract of the scales of the lily of the brain restores damaged brain cognitive function, as well as the effect of improving learning and memory in the normal state.
2-2: 수동회피실험2-2: Manual Evasion Experiment
수동회피실험(Passive avoidance test)은 밝은 방에 놓여진 실험동물이 어두운 방에 들어가면 발판 grid에서 발에 전기 충격을 받게 되는데(Training day), 발에 전기 충격을 받은 다음날과 일주일 후에 각각 동일한 실험을 진행하여 밝은 방에 머무르는 시간을 측정하는 방식으로 진행되었다. 학습 및 기억능력이 좋은 실험동물일수록 발 전기 충격을 기억하여 밝은 방에 오래 머물러 어두운 방으로 넘어가는 시간이 길게 걸린다. 반면 기억력이 감퇴한 실험동물은 어두운 방에 전기 충격 장치가 있다는 것을 잊고 어두운 방으로 들어가게 된다. 실험동물은 1일 1회, 180초간 테스트하였다. In the passive avoidance test, when an animal placed in a bright room enters a dark room, it is subjected to an electric shock on the foot on the scaffold grid (Training day). It was carried out by measuring the time to stay in a bright room. Experimental animals with good learning and memory skills take longer to remember the shock of a foot and stay in a bright room for longer. On the other hand, the animals with reduced memory enter the dark room, forgetting that there is an electric shock device in the dark room. Experimental animals were tested once a day for 180 seconds.
도 3은 상기 실험에 따라 측정한 시간(latency time)을 나타낸 것이며, 구체적으로는 도 3의 (a)는 기억력 저해 동물모델에 도네페질 또는 백합 비늘줄기 추출물을 투여한 실험동물의 수동회피실험 결과이며, (b)는 정상군에 백합 비늘줄기 추출물을 투여한 실험동물의 수동회피실험 결과이다. Figure 3 shows the time (latency time) measured according to the above experiment, specifically (a) of Figure 3 (a) passive avoidance test results of experimental animals administered with Donepezil or lily scale extract to the memory model of inhibition (B) shows the results of passive avoidance of experimental animals administered with lily scale extract to normal group.
도 3의 (a)와 같이, 스코폴라민 투여로 기억력이 저해된 실험군 1의 latency time은 43.3초로 정상군 163.4초 대비 유의하게 감소되어, 학습 및 기억력이 저하된 것을 확인하였다. 반면, 백합 비늘줄기 추출물을 투여한 실험군 3의 경우, 감소된 latency time이 정상군에 이를 정도로 회복되는 것으로 나타났다. 또한, training day 7일 후에도 이와 같은 유의한 결과를 보인 것으로 보아 백합 비늘줄기 추출물이 기억 유지(memory retention)에 효과가 있음을 나타낸다. As shown in (a) of FIG. 3, the latency time of the experimental group 1 whose memory was inhibited by the administration of scopolamine was significantly reduced to 43.3 seconds compared to that of the normal group 163.4 seconds, thereby confirming that the learning and the memory were reduced. On the other hand, in the experimental group 3 administered the lily scale extract, the reduced latency time was found to recover to the normal group. In addition, even after 7 days of training day, such a significant result shows that the extract of the scales of the lily is effective for memory retention (memory retention).
한편, 도 3의 (b)와 같이, 정상군에 백합 비늘줄기 추출물을 투여한 실험군 4의 경우에는 특히 50mg/kg에서 정상군보다 latency time이 유의하게 증가하였는바, 이는 백합 비늘줄기 추출물이 정상군에서도 기억력 개선뿐만 아니라 기억 유지에 효과가 있음을 나타내는 것이다. On the other hand, as shown in Figure 3 (b), in the case of the experimental group 4 administered the lily scale extract to the normal group, in particular 50mg / kg latency time significantly increased than the normal group bar lily extract is normal In addition to improving memory, the group also indicates that it is effective in maintaining memory.
실험예 3: 면역염색 및 BrdU 표적세포 분석Experimental Example 3: Immunostaining and BrdU Target Cell Analysis
학습 및 기억력은 뇌의 측두엽 부위와 밀접한 관련이 있으며, 특히 해마(hippocampus)에서 학습 및 기억력에 관여하게 된다. 특히 해마의 치아이랑(dentate gyrus)는 학습 및 기억력뿐만 아니라 평생에 걸쳐 새로운 신경세포가 생성되는 해마신경재생성(hippocampal neurogenesis)이 일어나는 부위로 알려져 있다. 이에 본 실험예 3에서는 100 mg/kg의 농도로 BrdU를 6 pulse로 3일간 복강 주사한 다음 2주째 뇌의 해마에서 새로 생겨나는 세포의 생존(세포생존성 연구)을 확인하기 위해 실험동물을 안락사 시켰다. BrdU는 DNA 복제가 일어나는 S기에 티미딘(Thymidine)을 대체할 수 있어 새롭게 증식하는 세포를 표적할 수 있는 마커이다. 상기 실험예 1에서 적출된 뇌의 치아이랑에서 BrdU 표적세포의 수(새로 생겨나는 세포의 수)를 확인하였다. Learning and memory are closely related to the temporal lobe of the brain, especially in the hippocampus. In particular, the dentate gyrus of the hippocampus is known as a site for hippocampal neurogenesis, in which new neurons are generated throughout life as well as learning and memory. In Experimental Example 3, euthanasia was performed to confirm the survival (cell survival study) of newly formed cells in the hippocampus of the brain at 2 weeks after intraperitoneal injection of BrdU for 6 days at 100 mg / kg. I was. BrdU is a marker that can replace thymidine in the S phase where DNA replication takes place and can target newly proliferating cells. In Experimental Example 1, the number of BrdU target cells (the number of newly formed cells) in the dentate gyrus of the brain was confirmed.
구체적으로, 실험예 1에서 적출된 뇌를 cryostat에서 1-in-6 series로 절편하였다. 세포 내 퍼옥시다제를 비활성화시키기 위해 0.6% 과산화수소를 처리하고 가열, 산, 염기 순으로 뇌조직절편을 노출함으로써 DNA를 변성시켰다. 세척한 후 블로킹한 다음 항-래트 BrdU 항체로 4 ℃에서 밤새 반응시킨 후 비오티닐화된 항-래트 2차 항체로 실온에서 3시간 반응시켰다. 세척 후 ABC 용액과 실온에서 한 시간 반응한 후 DAB kit로 염색하여 광학현미경으로 관찰하였다. 전체 해마의 rostro-caudal 절편의 6-10 번째 부분을 검사하였다. 각 해마의 치아이랑에 존재하는 총 BrdU 표적 세포의 수를 측정한 후, 샘플을 분획별로 계산하여 해마 내 새로 형성된 세포의 수를 정량화하였으며, 정량분석 실험은 그룹을 블라인드한 샘플을 사용하여 2인 이상의 연구자에 의해 실험의 정확성을 높였다. Specifically, the brain extracted in Experimental Example 1 was sliced into 1-in-6 series in cryostat. To deactivate intracellular peroxidase, DNA was denatured by treatment with 0.6% hydrogen peroxide and exposing the brain tissue sections in the order of heating, acid, and base. After washing, the cells were blocked and then reacted with an anti-rat BrdU antibody at 4 ° C. overnight, followed by 3 hours of reaction with a biotinylated anti-rat secondary antibody at room temperature. After washing, the solution was reacted with ABC solution for 1 hour at room temperature, and then stained with DAB kit and observed under an optical microscope. The 6th-10th sections of the rostro-caudal sections of the whole hippocampus were examined. After measuring the total number of BrdU target cells in the dentate gyrus of each hippocampus, samples were calculated by fractions to quantify the number of newly formed cells in the hippocampus. The researcher has improved the accuracy of the experiment.
상기 실험에 따른 BrdU 염색결과(a)와 이를 통계처리한 결과(b)를 도 4에 나타내었다. 스코폴라민을 투여한 실험군 1에서는 정상군에 비해서 BrdU 표적 세포의 수가 감소하는 것으로 보아 해마의 치아이랑에 새로 생겨나는 세포의 생존이 감소한 것을 알 수 있었다. 스코폴라민 투여 전 백합 비늘줄기 추출물을 투여한 실험군 3의 경우, 실험군 1에 비하여 BrdU 표적 세포의 수가 유의하게 증가하였다.BrdU staining results according to the experiment (a) and the statistical results (b) are shown in Figure 4. In experimental group 1 administered scopolamine, the number of BrdU target cells decreased compared to the normal group, indicating that survival of newly formed cells in the hippocampus of the hippocampus was reduced. In the experimental group 3 to which the lily scale extract was administered before the scopolamine administration, the number of BrdU target cells was significantly increased compared to the experimental group 1.
한편, 실험군 4는 특히 50mg/kg, 100mg/kg 에서 정상군에 비하여 BrdU 표적 세포 수가 증가하여 해마의 치아이랑에 새로 생겨나는 세포의 생존이 증가한 것으로 나타났는바, 이는 정상군에 대해서도 백합 비늘줄기 추출물이 해마신경줄기세포 및 해마신경재생성을 증가시키는 효과가 있음을 의미한다.On the other hand, experimental group 4 was found to increase the number of BrdU target cells, especially in the 50mg / kg, 100mg / kg increased the survival of the newly formed cells in the dentate gyrus of the hippocampus compared to the normal group, which is also the lily scales for the normal group This means that the extract has an effect of increasing the hippocampal nerve stem cells and hippocampal nerve regeneration.
실험예 4: 신경줄기세포 증식 유도능 측정 Experimental Example 4: Measurement of neural stem cell proliferation induction capacity
백합 비늘줄기 추출물이 신경줄기세포를 증식을 유도하는지 확인하기 위한 실험을 하기와 같이 진행하였다.Experiments were carried out as follows to determine whether the lily scaly extract induces proliferation of neural stem cells.
먼저, 뇌신경외배엽에서 유래한 NE-4C 신경줄기세포주(NE-4C neural stem cell line)에 실시예 1에서 제조한 백합 비늘줄기 추출물을 농도별로 처리하고, 처리 24시간 후 상기 세포에 0.25 mg/ml 농도의 MTT 용액을 가하여 2시간 더 배양하였다. 그 다음, 포르마잔(formazan) 침전물을 디메틸 설폭사이드(DMSO)로 녹인 후, 흡광도를 microplate reader (SpectraMax i3, Molecular devices, CA, USA)로 560 nm에서 측정하였다. First, the NE-4C neural stem cell line derived from cranial neural germ layers (NE-4C neural stem cell line) was treated with the concentration of the lily scale extract prepared in Example 1, 0.25 mg / ml to the cells 24 hours after treatment A concentration of MTT solution was added and incubated for another 2 hours. Then, the formazan precipitate was dissolved in dimethyl sulfoxide (DMSO), and then the absorbance was measured at 560 nm with a microplate reader (SpectraMax i3, Molecular devices, CA, USA).
그 결과, 도 5에 나타난 것과 같이 백합 비늘줄기 추출물이 신경줄기세포주의 세포증식 유도 효과가 확인되었으며, 특히 50 내지 200 ㎍/㎖의 농도에서 세포증식률이 대조군(0㎍/㎖)과 비교하여 약 1.5배 정도 향상되는 것으로 확인되었다. As a result, as shown in Figure 5, the extract of the scales of the lily of the stem was confirmed the cell proliferation-inducing effect, especially at a concentration of 50 to 200 ㎍ / ㎖ cell growth rate of about 1.5 compared to the control (0 ㎍ / ㎖) It was confirmed that the fold improved.
다음으로는, BrdU 면역염색을 통해 백합 비늘줄기 추출물의 처리에 따른 NE-4C 신경세포주의 세포증식의 증가효과를 관찰하였다. 면역염색법은 상기 실험예 3과 유사하며 형광 염색의 경우 secondary antibody로 Alexa Fluor 488-conjugated secondary antibody를 사용하였다. 또한, BrdU incorporation assay를 통해 세포증식능을 확인하였다. NE-4C 신경줄기세포주에 백합 비늘줄기 추출물을 농도 별로 24시간 동안 처리한 후 BrdU(20 μM)가 포함된 배지를 2시간 동안 처리한 후, 세포를 고정시키고 DNA 변성을 일으켰다. Anti-BrdU-POD를 처리하고 TMB solution/stop solution 반응으로 생성된 BrdU의 양을 확인하였다. 흡광도를 microplate reader (SpectraMax i3, Molecular devices, CA, USA)로 450 nm에서 측정하였다. Next, the effect of increasing the cell proliferation of NE-4C neuronal cell line according to the treatment of lily scale extract through BrdU immunostaining. Immunostaining was similar to Experimental Example 3, and used a Alexa Fluor 488-conjugated secondary antibody as a secondary antibody in the case of fluorescent staining. In addition, cell proliferation was confirmed by BrdU incorporation assay. After treatment with lily scale extract for 24 hours for each concentration in the NE-4C neural stem cell line after treatment with BrdU (20 μM) containing medium for 2 hours, the cells were fixed and DNA denaturation occurred. Anti-BrdU-POD was treated and the amount of BrdU produced by TMB solution / stop solution reaction was confirmed. Absorbance was measured at 450 nm with a microplate reader (SpectraMax i3, Molecular devices, CA, USA).
그 결과, 도 6에 나타난 것과 같이 백합 비늘줄기 추출물의 처리로 인해, 새롭게 증식하여 BrdU로 염색된 세포수가 증가하였으며, 특히 50 내지 200 ㎍/㎖의 농도에서 신경줄기세포 증식 유도 효과가 유의하게 증가하는 것을 확인할 수 있었다. As a result, as shown in Figure 6, due to the treatment of the lily scale extract, the number of cells newly bred and stained with BrdU increased, especially in the effect of significantly inducing the effect of neural stem cell proliferation at a concentration of 50 to 200 ㎍ / ㎖ I could confirm that.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.
Claims (11)
- 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for preventing or treating cognitive disorders comprising lily scale extract or a fraction thereof as an active ingredient.
- 제1항에 있어서,The method of claim 1,상기 인지장애는 건망증, 알츠하이머병, 치매, 파킨슨 병, 피크병, 크로이츠펠트 야콥병, 헌팅톤병, 허혈성 뇌졸중, 및 출혈성 뇌졸중으로 이루어지는 군으로부터 선택되는 것인, 약학 조성물.The cognitive disorder is selected from the group consisting of forgetfulness, Alzheimer's disease, dementia, Parkinson's disease, Peak disease, Creutzfeldt-Jakob disease, Huntington's disease, ischemic stroke, and hemorrhagic stroke.
- 제2항에 있어서,The method of claim 2,상기 치매는 혈관성 치매, 알츠하이머성 치매, 루이성 치매, 두부 외상에 의한 치매, 뇌종양에 의한 치매, 대사성 질환에 의한 치매로 이루어지는 군에서 선택되는 것인, 약학 조성물.The dementia is selected from the group consisting of vascular dementia, Alzheimer's dementia, Lewy dementia, dementia caused by head trauma, dementia caused by brain tumor, and dementia caused by metabolic disease.
- 제1항에 있어서,The method of claim 1,상기 추출물은 상기 백합 비늘줄기 또는 그의 분쇄물을 물, 탄소수 1 내지 6의 알코올 또는 이들의 혼합 용매로 추출하여 수득하는 것인, 약학 조성물.The extract is a pharmaceutical composition that is obtained by extracting the lily scale or its pulverized with water, alcohol having 1 to 6 carbon atoms or a mixed solvent thereof.
- 제1항에 있어서,The method of claim 1,상기 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것인, 약학 조성물.Wherein said composition further comprises a pharmaceutically acceptable carrier, excipient or diluent.
- 제1항에 있어서,The method of claim 1,상기 조성물 내의 백합 비늘줄기 추출물 또는 그의 분획물의 농도는 50 내지 200 ㎍/㎖인 것인, 약학 조성물.The concentration of the lily scale extract or fractions thereof in the composition is 50 to 200 ㎍ / ㎖, pharmaceutical composition.
- 제1항 내지 제6항 중 어느 한 항의 약학 조성물을 인지장애가 발병되거나 또는 발병될 가능성이 있는 개체에 투여하는 단계를 포함하는 인지장애를 예방 또는 치료하는 방법.A method of preventing or treating a cognitive disorder comprising administering the pharmaceutical composition of any one of claims 1 to 6 to a subject having or likely to develop a cognitive disorder.
- 백합 비늘줄기 추출물 또는 그의 분획물을 유효성분으로 포함하는 인지장애 예방 또는 개선용 건강기능식품 조성물.Health functional food composition for preventing or improving cognitive impairment comprising lily scales extract or fractions thereof as an active ingredient.
- 제8항에 있어서,The method of claim 8,상기 인지장애는 건망증, 알츠하이머병, 치매, 파킨슨 병, 피크병, 크로이츠펠트, 헌팅톤병, 허혈성 뇌졸중, 및 출혈성 뇌졸중으로 이루어지는 군으로부터 선택되는 것인, 건강기능식품 조성물.The cognitive disorder is selected from the group consisting of forgetfulness, Alzheimer's disease, dementia, Parkinson's disease, Peak disease, Creutzfeldt, Huntington's disease, ischemic stroke, and hemorrhagic stroke.
- 백합 비늘줄기 추출물 또는 이의 분획물을 유효성분으로 포함하는 기억력 또는 집중력 개선용 건강기능식품 조성물.Health functional food composition for improving memory or concentration comprising lily scales extract or fractions thereof as an active ingredient.
- 백합 비늘줄기 추출물 또는 이의 분획물을 포함하는, 인비트로 신경줄기세포 증식 유도용 조성물. A composition for inducing nerve stem cell proliferation in vitro, comprising a lily scale extract or a fraction thereof.
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|---|---|---|---|---|
| KR101087608B1 (en) * | 2009-04-15 | 2011-11-29 | (주)내츄럴엔도텍 | Phytoestrogen Composition for Preventing or Alleviating Climacteric or Menopausal Syndrome |
| KR101457315B1 (en) * | 2010-08-30 | 2014-11-20 | 허베이 이링 메디슨 리서치 인스티튜트 코오포레이션 리미티드 | Pharmaceutical composition for treating insomnia and preparation method thereof |
| KR20160088165A (en) * | 2015-01-15 | 2016-07-25 | 경상대학교산학협력단 | Composition for improvement of learning and memory function comprising onion extract or its fraction as effective component |
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| KR101344013B1 (en) | 2012-03-22 | 2013-12-23 | 경희대학교 산학협력단 | Pharmaceutical composition for prevention and treatment of chronic obstructive pulmonary disease comprising extract of Lilium lancifolium Thunberg as an active ingredient |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101087608B1 (en) * | 2009-04-15 | 2011-11-29 | (주)내츄럴엔도텍 | Phytoestrogen Composition for Preventing or Alleviating Climacteric or Menopausal Syndrome |
| KR101457315B1 (en) * | 2010-08-30 | 2014-11-20 | 허베이 이링 메디슨 리서치 인스티튜트 코오포레이션 리미티드 | Pharmaceutical composition for treating insomnia and preparation method thereof |
| KR20160088165A (en) * | 2015-01-15 | 2016-07-25 | 경상대학교산학협력단 | Composition for improvement of learning and memory function comprising onion extract or its fraction as effective component |
Non-Patent Citations (2)
| Title |
|---|
| CHANGWON NATIONAL UNIVERSITY: "Screening of Preventive Effects of Natural Products Isolated from Liliaceae against Amyloid beta-induced Toxic and Their Application as a Potential Treatment for Alzheimer disease", 2006, pages 1 - 185 * |
| HWANG, K. H. ET AL.: "Monoamine oxidase inhibitory activities of Korean medicinal plants classified to cold drugs by the theory of KIMI", FOOD SCIENCE AND BIOTECHNOLOGY, vol. 12, no. 3, 30 June 2003 (2003-06-30), pages 238 - 241, XP055537187 * |
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