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WO2016006947A1 - Composition permettant de prévenir ou de traiter des maladies neurodégénératives, contenant un extrait d'humulus japonicus en tant que principe actif - Google Patents

Composition permettant de prévenir ou de traiter des maladies neurodégénératives, contenant un extrait d'humulus japonicus en tant que principe actif Download PDF

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Publication number
WO2016006947A1
WO2016006947A1 PCT/KR2015/007127 KR2015007127W WO2016006947A1 WO 2016006947 A1 WO2016006947 A1 WO 2016006947A1 KR 2015007127 W KR2015007127 W KR 2015007127W WO 2016006947 A1 WO2016006947 A1 WO 2016006947A1
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Prior art keywords
disease
extract
alzheimer
composition
degenerative brain
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PCT/KR2015/007127
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English (en)
Korean (ko)
Inventor
이철호
김경심
오원근
김용훈
황정환
김진웅
김대덕
강영
박태신
박혜연
유영경
이인복
최동희
Original Assignee
한국생명공학연구원
서울대학교 산학협력단
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Application filed by 한국생명공학연구원, 서울대학교 산학협력단 filed Critical 한국생명공학연구원
Priority to JP2017501270A priority Critical patent/JP6329689B2/ja
Priority to CN201580037624.3A priority patent/CN106659749B/zh
Publication of WO2016006947A1 publication Critical patent/WO2016006947A1/fr

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    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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

Definitions

  • the present invention is Humulus
  • the present invention relates to a pharmaceutical composition for preventing or treating degenerative brain diseases, including japonicus ) extract or a fraction thereof as an active ingredient. More specifically, the present invention relates to an inhibitory effect of dopaminergic neuron death and protection of neurons against oxidative stress.
  • a pharmaceutical composition for the prevention or treatment of degenerative brain disease comprising as an active ingredient a hwansam vine extract or a fraction thereof having an effect of improving cognitive ability and memory, and administering the pharmaceutical composition.
  • Health care function for the prevention or improvement of degenerative brain disease including the use of hwansam vine extract or fractions thereof for the treatment, the preparation of the pharmaceutical composition for the prevention or treatment of degenerative brain diseases, and hwansam vine extract or fractions thereof as an active ingredient It is about food.
  • Degenerative brain diseases are known to cause memory loss, and oxidative stress has been found to be an important factor in degenerative brain diseases of the central nervous system such as Alzheimer's syndrome, Parkinson's syndrome and Huntington's syndrome.
  • acetylcholine degrading inhibitors only improve the decreased cognitive ability and are unable to cure the underlying cause of Alzheimer's disease.
  • the long-term administration of the drug is required, in the case of the medicines have problems such as accompanied by various side effects, including liver toxicity, vomiting, loss of appetite. Therefore, the development of new therapeutics that can prevent the progression of degenerative brain disease is an urgent task.
  • the inventors of the present invention can effectively suppress the development and exacerbation of degenerative brain diseases such as Parkinson's disease and Alzheimer's disease, which are increasing in recent years in modern people, and have no side effects for treating them.
  • Efforts have been made to develop new drugs for the prevention or treatment of degenerative brain diseases using substances that do not appear.
  • Hwansam vine extract inhibits dopaminergic neuronal death, has a protective effect of neurons against oxidative stress, Parkinson's disease and
  • the present invention was completed by confirming that an animal model having degenerative brain diseases such as Alzheimer's disease has an effect of improving cognitive ability and memory, thereby confirming that it can be used for the prevention or treatment of degenerative brain diseases.
  • One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of degenerative brain diseases, including Humulus japonicus extract or fractions thereof as an active ingredient.
  • Another object of the present invention to provide a method of treating degenerative brain disease, comprising administering the pharmaceutical composition.
  • Another object of the present invention to provide a health functional food for the prevention or improvement of degenerative brain disease comprising the extract or fraction as an active ingredient.
  • Still another object of the present invention is to provide a use of hwansam vine extract or a fraction thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of degenerative brain diseases.
  • Humulus japonicus according to the present invention (Humulus The composition containing japonicus ) extract or a fraction thereof as an active ingredient inhibits dopaminergic neuronal death and has a protective effect of neurons against oxidative stress, as well as in animal models with degenerative brain diseases such as Parkinson's disease and Alzheimer's disease. Since it shows an effect of improving cognition and memory, it can be usefully used as a food or medicine for the prevention or treatment of degenerative brain diseases including Alzheimer's, Parkinson's disease, Lou Gehrig's disease, mild cognitive impairment, stroke, and Huntington's disease.
  • Figure 1a is a fluorescence micrograph showing the effect of hwansam vine extract on the production of reactive oxygen species.
  • Figure 1b is a graph showing the result of quantitative analysis using a luminometer the level of fluorescence taken with the fluorescence microscope.
  • Figure 2a is a graph showing the results of comparing the changes in intracellular TNF- ⁇ mRNA level according to the treatment concentration of hwansamvine extract in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 2b is a graph showing the results of comparing the changes in intracellular IL-1 ⁇ mRNA level according to the treatment concentration of the extract of the ginseng in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 2c is a graph showing the results of comparing the changes in intracellular IL-6 mRNA level according to the treatment concentration of hwansamvine extract in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 2d is a graph showing the result of comparing the change in intracellular iNOS mRNA level according to the treatment concentration of hwansamvine extract in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 2e is a graph showing the result of comparing the level of extracellular secreted TNF- ⁇ protein according to the treatment concentration of hwansam vine extract in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 2f is a graph showing the results of comparing the extracellular secreted IL-6 protein level according to the treatment concentration of hwansamvine extract in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 2g is a graph showing the results of comparing the extracellular secreted NO protein level according to the treatment concentration of hwansam vine extract in microglia cell line induced inflammatory response by LPS treatment.
  • Figure 3 is a graph showing the results of apomorphine-induced rotational movement in the Parkinson's disease mouse animal model induced brain dopaminergic neuron-specific cell death with 6-OHDA, according to the treatment of hwangi vine extract.
  • Figure 4 is a graph showing the results of measuring the expression level of tyrosin hydroxylase (TH), a dopaminergic neuron specific protein according to the treatment of hwansam vine extract.
  • TH tyrosin hydroxylase
  • Figure 5 is a graph showing the results of comparing the effect of the treatment concentration of hwansam vine extract in the death of dopaminergic neurons induced by 6-OHDA treatment.
  • Figure 6a is involved in apoptosis (apoptosis) according to the concentration of 6-OHDA and the various concentrations (0, 50, 100, 200 ⁇ g / ml) of hwansamvine in SH-SY5Y neurons treated It is a photograph showing the result of Western blot analysis showing the change of the expression level of the marker protein.
  • Figure 6b is a graph showing the change in the expression level of cleaved caspase 9 according to the treatment concentration of round ginseng vine obtained from the Western blot analysis of Figure 6a.
  • Figure 6c is a graph showing the change in the expression level of cleaved caspase 3 according to the treatment concentration of round ginseng vine obtained from the Western blot analysis of Figure 6a.
  • Figure 6d is a graph showing the change in the expression level of cleaved PARP according to the treatment concentration of round ginseng vine obtained from the Western blot analysis of Figure 6a.
  • FIG. 7 is a graph showing the effect of improving cognitive function and memory in a novel object recognition test (NORT) according to the treatment of gingko vine extract in a mouse animal model of Alzheimer's disease.
  • NERT novel object recognition test
  • FIG. 8 is a graph showing the effect of improving spatial perception and short-term memory in the Y-maze test of Alzheimer's disease mouse model.
  • Figure 9a is a photograph showing the results of the immunostaining for beta amyloid in the brain of the Alzheimer's disease-inducing mouse animal model that was not administered with the hwangi vine extract.
  • Figure 9b is a photograph showing the results of immunostaining for beta amyloid in the brain of Alzheimer's disease-induced mouse animal model to which the ginseng vine extract is administered.
  • Figure 9c is a graph showing the results of comparing the changes in immunostaining levels for beta amyloid according to the administration of hwansamvine extract in the brain of the mouse animal model of Alzheimer's disease.
  • Figure 10a is a photograph showing the results of immunostaining for the phosphorylated tau protein in the brain of Alzheimer's disease-induced mouse animal model not administered with the ginseng extract.
  • Figure 10b is a photograph showing the results of immunostaining for the phosphorylated tau protein in the brain of Alzheimer's disease-induced mouse animal model to which the ginseng vine extract is administered.
  • Figure 10c is a graph showing the results of comparing the changes in the immunostaining level for phosphorylated tau protein according to the administration of hwansamvine extract in the brain of the animal model of Alzheimer's disease.
  • Figure 11a is a photograph showing the results of immunostaining for the activated microglia cells in the brain of the Alzheimer's disease-induced mouse animal model not administered with the ginseng vine extract.
  • Figure 11b is a photograph showing the results of immunostaining for activated microglia cells in the brain of the Alzheimer's disease-induced mouse animal model to which the ginseng vine extract is administered.
  • Figure 11c is a graph showing the results of comparing the changes in immunostaining levels for activated microglia cells in the brain of Alzheimer's disease-induced mouse animal model.
  • Figure 12a is a photograph showing the results of immunostaining for activated astrocytic cells in the brain of the Alzheimer's disease-induced mouse animal model that is not administered with the ginseng vine extract.
  • Figure 12b is a photograph showing the results of immunostaining for activated astrocytic cells in the brain of the Alzheimer's disease-induced mouse animal model to which the ginseng vine extract is administered.
  • Figure 12c is a graph showing the results of comparing the changes in immunostaining levels for activated astroglia cells in the brain of Alzheimer's disease-induced mouse animal model.
  • Figure 13a is a graph showing the result of comparing the mRNA level of TNF- ⁇ expressed in the brain, according to the administration of hwansamvine extract.
  • Figure 13b is a graph showing the result of comparing the mRNA level of IL-6 expressed in the brain, according to the administration of hwansamvine extract.
  • Figure 13c is a graph showing the result of comparing the mRNA level of IL-1 ⁇ expressed in the brain, according to the administration of hwansamvine extract.
  • Figure 14 is a graph showing the results of conducting a behavioral analysis according to the administration of Hwansam vine extract in mouse hunting-induced.
  • the present inventors focused on extracts of Humulus japonicus, while conducting various studies on natural products with high safety for humans, in order to develop substances that can effectively suppress the onset and exacerbation of degenerative brain diseases. .
  • the Ginseng vine extract was found to inhibit dopaminergic neuron death and have a protective effect of neurons against oxidative stress.
  • animal models with degenerative brain diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease showed improvement in cognitive ability and memory.
  • the extract of Humulus japonicus can be used as an active ingredient for the prevention or treatment of degenerative brain diseases such as Alzheimer's, Parkinson's disease, Lou Gehrig's disease, mild cognitive impairment, stroke, Huntington's disease, etc. there was.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of degenerative brain disease, comprising as an embodiment an extract of Humulus japonicus or a fraction thereof as an active ingredient.
  • Human japonicus of the present invention is a vine perennial plant belonging to the family Cannabaceae and mainly distributed throughout Korea and the East Asian region, the bark of the stem is used as a fiber, and the fruit is a high-fidelity agent It is known that fruited starch is used as a diuretic.
  • diseases such as degenerative brain disease, and degenerative brain including Alzheimer's, Parkinson's disease, Lou Gehrig's disease, mild cognitive impairment, stroke, Huntington's disease, etc. It has been found that there are uses for the treatment or prevention of disease related diseases.
  • the hwansam vine in the present invention can be purchased commercially, or can be used collected or cultivated in nature.
  • extract refers to a liquid component obtained by immersing a desired substance in various solvents, followed by extraction for a predetermined time at room temperature or warmed state, solids obtained by removing the solvent from the liquid component, etc. Means the result of In addition, in addition to the result, it can be comprehensively interpreted to include all of the dilution of the resultant, their concentrates, their modifiers, purified products and the like.
  • the extract may be interpreted as an extract of hwansam vine.
  • the ginseng vine extract can be extracted from various organs of natural, hybrid, and mutant plants, for example, from roots, ground, stems, leaves, flowers, trunks of fruits, bark of fruit, as well as plant tissue cultures.
  • the hwansam vine extract may be obtained by extracting with water or various organic solvents.
  • the organic solvent to be used is not particularly limited as long as it can obtain an extract having a prophylactic or therapeutic effect of degenerative brain disease, but may preferably be water, a polar solvent or a non-polar solvent, more preferably Water, lower alcohols having 1 to 4 carbon atoms (methanol, ethanol, propanol or butanol, etc.), mixed solvents thereof, and the like, and most preferably methanol or a mixed solvent thereof can be used.
  • the method for obtaining the extract is not particularly limited as long as it can obtain an extract having a prophylactic or therapeutic effect of degenerative brain disease, but preferably, the root, stem, leaf, fruit, flower of the ginseng vine.
  • fraction of the present invention means the result obtained by the fractionation method of separating a specific component or a specific group from a mixture containing various components.
  • the fraction may be interpreted to be a fraction obtained by applying the hwansam vine extract to various fractionation methods.
  • the fraction may be obtained by applying the extract to a variety of fractionation method, the fractionation method is not particularly limited to this, but the solvent fractionation method performed by treating a variety of solvents, through an ultrafiltration membrane having a constant molecular weight cut-off value Ultrafiltration fractionation, and chromatographic fractionation (manufactured for separation according to size, charge, hydrophobicity, or affinity).
  • the solvent used in the solvent fractionation method is not particularly limited, but a polar solvent or a nonpolar solvent can be used, and preferably a nonpolar solvent can be used.
  • the solvent fractionation method may be performed by sequentially fractionating the extract using a low solvent from a solvent having a high nonpolar level.
  • a method of sequentially fractionating the extract using nucleic acid or ethyl acetate may be used. Can be.
  • degenerative brain disease refers to a disease that occurs in the brain among degenerative diseases that occur with age.
  • the degenerative brain disease is known to be caused by the aggregation of proteins due to neurodegeneration and genetic and environmental factors caused by aging, neuronal cell death, but the exact cause is not yet known.
  • the degenerative brain disease is not particularly limited thereto, and for example, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, mild cognitive impairment, stroke, Huntington's disease, and the like.
  • prevention refers to any action that inhibits or delays the onset of degenerative brain disease by administration of the pharmaceutical composition according to the present invention, and “treatment” means degenerative by administration of the pharmaceutical composition.
  • Suspicion and onset of symptoms of the brain disease means any action that improves or beneficially changes.
  • the prevention or treatment of the degenerative brain disease may be achieved by inhibiting dopaminergic neuronal death by the extract, and having a protective effect of neurons against oxidative stress, and behaviorally, Parkinson's disease and Alzheimer's disease. It may be achieved by exhibiting cognitive and memory improving effects in animal models with degenerative brain diseases such as disease.
  • dopamine is a neurotransmitter that transmits signals in the brain and is known to be related to movement and movement.
  • dopaminergic neuron death refers to the loss or denaturation of dopaminergic neurons concentrated in the substantia nigra pars compacta of the midbrain region. It is known that it can be prepared by injecting 6-OHDA (6-hydroxyldopamine).
  • oxidative stress is an important factor that causes degenerative brain disease.
  • oxidative stress is induced, and brain cell loss and Parkinson's disease, It is known that degenerative brain diseases such as Alzheimer's disease can be caused.
  • the extracts or fractions thereof of the gingival vines provided by the present invention inhibit dopaminergic neuronal death and have a protective effect of neurons against oxidative stress, as well as Parkinson's and Alzheimer's disease Animal models with the same degenerative brain disease can improve cognitive and memory.
  • methanol extract is obtained from hwansam vine, and the efficacy of the obtained hwansam vine extract is examined, and the production of reactive oxygen species is suppressed to show a protective effect against oxidative stress of neurons ( Figures 1a and 1b), shows the effect of inhibiting the inflammatory response (Figs. 2a to 2g), shows the prophylactic and therapeutic effect of Parkinson's disease (Fig. 3, 4, 5, 6a to 6d), preventive and therapeutic effect of Alzheimer's disease 7, 8, 9a to 9c, 10a to 10c, 11a to 11c, 12a to 12c, and 13a to 13c, showing the prophylactic and therapeutic effects of Huntington's disease (FIG. 14).
  • the rim extract or fraction thereof has an effect of preventing or treating various degenerative brain diseases such as Alzheimer's, Parkinson's disease, Lou Gehrig's disease, mild cognitive impairment, stroke, and Huntington's disease.
  • the pharmaceutical composition for preventing or treating degenerative brain disease of the present invention may further include a suitable carrier, excipient or diluent commonly used in the preparation of the pharmaceutical composition.
  • 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 is prepared by mixing sucrose or lactose, gelatin and the like.
  • lubricants such as magnesium styrate and talc are also 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 include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, 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 extract or fractions thereof of the Korean Peninsula vine in the pharmaceutical composition of the present invention is not particularly limited thereto, but is 0.0001 to 50% by weight, more preferably 0.01 to 20% by weight, based on the total weight of the final composition. It may be included as.
  • 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
  • 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
  • the duration of treatment, factors including drugs used in combination or coincidental with the composition of the invention used, and other factors well known in the medical art can be determined.
  • the pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. 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 may be administered, for example, 0.1 to 500 mg / kg body weight per day to a mammal, including a human, of the pharmaceutical composition of the present invention.
  • the frequency of administration of the composition of the present invention is not particularly limited, but may be administered once a day or divided doses several times. The dosage does not limit the scope of the invention in any aspect.
  • the present invention provides a method for treating degenerative brain disease, comprising administering the pharmaceutical composition to a subject suffering from degenerative brain disease in a pharmaceutically effective amount.
  • the composition may be used to treat degenerative brain disease.
  • the term "individual" of the present invention includes, without limitation, mammals including rats, livestock, humans, etc., which may or may not develop degenerative brain diseases.
  • the route of administration of the pharmaceutical composition may be administered through any general route as long as it can reach the target tissue.
  • the pharmaceutical composition of the present invention is not particularly limited, 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 should be formulated to coat the active agent or to protect it from degradation in the stomach because oral administration may denature the extract or fractions thereof by gastric acid.
  • 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 degenerative brain disease, including an extract or a fraction thereof.
  • the extract or fractions of hwansam vine which is an active ingredient of the pharmaceutical composition for preventing or treating degenerative brain disease, has been derived from hwansam vine which has been used as a traditional medicinal herb and proved its safety, the extract of hwansam vine or its fraction is common sense. It can be prepared and consumed in the form of foods that can be used to prevent or improve degenerative brain diseases.
  • the content of the extract or fractions thereof of the ginseng vines included in the food is not particularly limited thereto, but may be included in an amount of 0.001 to 50% by weight, and more preferably 0.1 to 10% by weight, based on the total weight of the food composition.
  • the food When the food is a beverage, it may be included in a ratio of 1 to 10 g, preferably 2 to 7 g based on 100 ml.
  • the composition may include additional ingredients that are commonly used in food compositions to improve the smell, taste, time and the like. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like.
  • minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu). It may also contain amino acids such as lysine, tryptophan, cysteine, valine and the like.
  • preservatives potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.
  • fungicides bleaching powder and highly bleaching powder, sodium hypochlorite, etc.
  • antioxidants butylhydroxyanisol (BHA), butylhydroxytoluene ( BHT), etc.
  • colorants such as tar pigments
  • colorants such as sodium nitrite, sodium nitrite
  • bleach sodium sulfite
  • seasonings such as MSG glutamate
  • sweeteners ducin, cyclate, saccharin, sodium, etc.
  • Food additives such as flavors (vanillin, lactones, etc.), swelling agents (alum, potassium D-tartrate, etc.), reinforcing agents, emulsifiers, thickeners (pigments), coatings, gum herbicides, foam inhibitors, solvents, improvers, etc.
  • the additive is selected according to the type of food and used in an appropriate amount
  • a food composition for preventing or improving degenerative brain disease including the extract or fractions of the hwansam vine can be prepared for the functional food for preventing or improving degenerative brain disease.
  • the food composition may be used to produce a processed food that can prevent or improve degenerative brain disease, for example, confectionery, beverages, alcoholic beverages, fermented foods, canned food, milk processed foods, meat processed foods or noodles It may be prepared as a health functional food in the form of processed foods.
  • the confectionery includes biscuits, pies, cakes, breads, candy, jelly, gum, cereals (including meal substitutes such as grain flour).
  • Beverages include drinking water, carbonated drinks, functional hot drinks, juices (eg, apples, pears, grapes, aloes, citrus fruits, peaches, carrots, tomato juices, and the like), sikhye, and the like.
  • Alcoholic beverages include sake, whiskey, shochu, beer, liquor, fruit wine, and the like.
  • Fermented foods include soy sauce, miso, and red pepper paste.
  • Canned food includes canned seafood (eg, canned tuna, mackerel, saury, canned seashells, etc.), canned livestock (eg beef, pork, chicken, turkey canned, etc.), canned produce (corn, peaches, canned apples, etc.).
  • Milk processed foods include cheese, butter, yogurt, and the like.
  • Processed meat products include pork cutlet, beef cutlet, chicken cutlet and sausage. Includes sweet and sour pork, nuggets, breadfruits and more. Noodles, such as sealed packaging fresh noodles, are included.
  • the composition may be used in retort food, soups and the like.
  • the term "functional food” of the present invention is the same term as a food for special health use (FOSHU), the medicine, medical effect processed to appear efficiently in addition to nutritional control function It means a high food, the food may be prepared in various forms such as tablets, capsules, powders, granules, liquid, pill to obtain a useful effect in the prevention or improvement of degenerative brain diseases.
  • FOSHU special health use
  • the present invention provides a use of an extract or fractions of gingival vines for use in the preparation of the pharmaceutical composition for preventing or treating degenerative brain disease.
  • the hwansam vine extract is mixed with methanol in a crushed or cut hwansam vine dry sample, sonicated for 15 minutes, and then left to stand for 2 hours at room temperature for 10 days. Afterwards, a sample frozen in a deep freezer was obtained by drying in a freeze dryer. Ring ginseng vine extract obtained as described above was used by dissolving in 0.5% CMC (carboxy methylcellulose) solution and DMSO (dimethyl sulfoxide) for animal experiments and neuronal cell experiments.
  • CMC carboxy methylcellulose
  • DMSO dimethyl sulfoxide
  • Example 1 In order to confirm the effect of the hwansam vine extract prepared in Example 1 on the neurons, the effects on the generation of reactive oxygen species known as the pathogenesis of various diseases and the induction of the inflammatory response was evaluated.
  • Neuro 2a cells which are neuronal cell lines, were treated with 400 g / ml at the concentration of 400 g / ml and cultured for 1 hour, and then treated with 300 ⁇ M of t-BHP (tert-butylhydroperoxide) for 2 hours to oxidize the neuron cell lines. Caused enemy stress. Subsequently, the neuronal cell medium was replaced with a medium containing 10 ⁇ M of DCF-DA (2 ′, 7′-Dichlorofluorescein diacetate) and further incubated for 1 hour, followed by fluorescence microscopy and luminometer. The level of reactive oxygen species (ROS) generated in the neuronal cell line was measured (FIGS. 1A and 14B).
  • ROS reactive oxygen species
  • Figure 1a is a fluorescence microscope picture showing the effect of the ring ginseng extract on the production of reactive oxygen species
  • Figure 1b is a graph showing the result of quantitative analysis using a luminometer the level of fluorescence taken by the fluorescence microscope.
  • the level of reactive oxygen species increased significantly by t-BHP in the Neuro 2a neuronal cell line, but the level of reactive oxygen species increased by t-BHP was significantly reduced by treatment In the case of treatment alone, the ginseng extract did not have any effect on the level of reactive oxygen species.
  • the hwansam vine extract has a protective effect against oxidative stress of neurons by inhibiting the generation of reactive oxygen species.
  • Example 2- 2 inflammatory response Effect
  • Inflammatory reaction was induced by treating 1 ⁇ g / ml lipopolysaccaride (LPS) on BV-2 microglia cells, a type of microglia cell, treated with 100 or 500 ⁇ g / ml round ginseng extract, followed by inflammatory cytokines.
  • Intracellular mRNA levels of Caine (TNF- ⁇ , IL-1 ⁇ and IL-6) and Inflammatory Mediated Proteins (iNOS) and protein levels of the inflammatory cytokines secreted into the media were measured and compared, respectively (FIG. 2A). To 2 g).
  • Figure 2a is a graph showing the results of comparing the changes in intracellular TNF- ⁇ mRNA level according to the treatment concentration of hwansamvine extract in microglia cell line induced inflammatory response by LPS treatment
  • Figure 2b is an inflammatory response by LPS treatment Fig.
  • FIG. 2c is a graph showing the results of intracellular IL-1 ⁇ mRNA level change according to the treatment concentration of hwansamvine extract in the induced glial cell line
  • Figure 2c is a glial vine in the glial cell line induced inflammatory response by LPS treatment It is a graph showing the result of comparing the change of intracellular IL-6 mRNA level according to the treatment concentration of the extract
  • Figure 2d is the intracellular iNOS according to the treatment concentration of hwansamvine extract in microglia cell line induced inflammatory response by LPS treatment It is a graph showing the result of comparing the mRNA level change
  • Figure 2e is a ginseng tuberculosis in microglia cell line induced inflammatory response by LPS treatment
  • Figure 2f is a cell according to the treatment concentration of the extract of the ginseng extract in the microglia cell line induced inflammatory response
  • intracellular intracellular inflammatory cytokines TNF- ⁇ , IL-1 ⁇ and IL-6
  • proinflammatory mediator proteins iNOS
  • the hwansam vine extract has an effect of suppressing the inflammatory response induced in the microglia cell line.
  • the hwansam vine extract has been confirmed to exhibit the effect of inhibiting the generation of reactive oxygen species and induction of inflammatory reactions that cause abnormalities in neurons, the hwansam vine extract is used to treat various diseases derived from the abnormalities of neurons It was analyzed to be effective.
  • Example 2 From the results of Example 2, it was analyzed that the hwansam vine extract may have an effect of treating various diseases derived from neuronal abnormalities, the degenerative brain known as hwansam vine extract is a disease derived from neuronal abnormalities. In order to confirm whether the disease has a therapeutic effect, we tried to verify the therapeutic effect of gingival vine extract on animals induced with Parkinson's disease, a type of degenerative brain disease.
  • Example 3- 1 6 - OHDA (6- hydroxyldopamine Parkinson's disease-induced experimental group by administration
  • mice 9-week-old male C57BL / 6J mice were used. The mice were allowed to freely consume sterilized feed and water in a breeding facility in a specific pathogen free (SPF) environment where the temperature was maintained at 22-24 ° C., and were maintained while maintaining a 12-hour day and night cycle.
  • SPF pathogen free
  • the experimental animal group was divided into a control group administered with 0.5% CMC (carboxy methylcellulose) and an experimental group administered with 500 mg / kg hwan extract.
  • the number of the control group and the experimental group was performed using 5 and 8 mice, respectively, 0.5% CMC and 500 mg / kg hwansamvine extract administered 6-OHDA that can specifically kill dopaminergic neurons Orally administered three days before the following.
  • mice were injected with 1 mg / kg of apomorphine intraperitoneally and observed asymmetric rotational behavior. .
  • the rotational behavior was evaluated by measuring the number of times the mouse was rotated clockwise for 1 hour in a cylinder having a diameter of 20 cm (Fig. 3).
  • Figure 3 is a graph showing the results of apomorphine-induced rotational movement in the Parkinson's disease mouse animal model induced brain dopaminergic neuron-specific cell death with 6-OHDA, according to the treatment of hwangi vine extract. As shown in Figure 3, compared with the control group ingested 0.5% CMC, it was confirmed that the rotational behavior of the experimental animals was significantly reduced in the experimental group intake of 500 mg / kg hwan extract extract.
  • Example 3-3 Tyrosine Hydroxylase in Parkinson's Disease Induced Animal Model tyrosin Determination of the amount of hydroxylase (TH) expression
  • mice In order to confirm whether dopaminergic neuronal cell death by 6-OHDA is inhibited in mice by administering Hwansam vine extract, 10% after 6-OHDA administration, 0.5% CMC control control group and 500 mg / kg Hwansam vine extract administration group mice In the striatum of the brain, the difference in the expression level of TH, a dopaminergic neuron specific protein, was analyzed by Western blot (FIG. 4).
  • Figure 4 is a graph showing the results of measuring the expression level of tyrosin hydroxylase (TH), a dopaminergic neuron specific protein according to the treatment of hwansam vine extract. As shown in Figure 4, compared with the control group, it was confirmed that the TH protein expression level of the experimental group fed the hwansamvine extract extract is a high level.
  • TH tyrosin hydroxylase
  • dopaminergic neuronal cell death is significantly suppressed due to the administration of hwansamvine extract.
  • Example 3-4 6- Parkinson's disease-inducing drug OHDA Dopaminergic by treatment Neuronal cell death Measure
  • DMEM / F containing 10% Fetal Bovine Serum and 1% penicillin / streptomycin to determine whether 6-OHDA neuronal cell death was inhibited in the dopaminergic neuronal cell line SH-SY5Y neuronal cell line
  • SH-SY5Y neuronal cell line Each well of a 96-well plate dispensed with -12 medium was inoculated with a SH-SY5Y neuronal cell line to a number of 1 X 10 ⁇ 5 cells, and 6-OHDA 50 ⁇ M and various concentrations (0, 50, 100, 200 ⁇ g / ml). After the treatment of hwansamvine extract of, cultured for 24 hours, the level of neuronal death was confirmed by MTT assay (Fig. 5).
  • the MTT assay used 3- (4,5-Dimethylthiazol-2-yl) -2,5 diphenyltetrazolium bromide (MTT) solution at a concentration of 0.5 mg / ml, reacted for 4 hours at 37 ° C, discarded the MTT solution, and DMSO The formazan crystal was dissolved and then absorbance was measured by measuring with a plate reader of 570 nm. At this time, the cells cultured without any treatment was used as a control.
  • MTT 4,5-Dimethylthiazol-2-yl
  • MTT diphenyltetrazolium bromide
  • Figure 5 is a graph showing the results of comparing the effect of the treatment concentration of hwansam vine extract in the death of dopaminergic neurons induced by 6-OHDA treatment. As shown in FIG. 5, the neuronal cell death of the 6-OHDA 50 ⁇ M-treated group was significantly induced compared to the control group, but the dopaminergic neuronal cell death was observed in all experimental groups (50, 100 or 200 ⁇ g / ml treated group) treated with the gingiva vine extract. It was confirmed that is suppressed.
  • Example 3-5 6- Parkinson's disease-inducing drug OHDA Dopaminergic by treatment Neuronal cell death Related protein change measurement
  • Figure 6a is involved in apoptosis (apoptosis) according to the concentration of 6-OHDA and the various concentrations (0, 50, 100, 200 ⁇ g / ml) of hwansamvine in SH-SY5Y neurons treated
  • Figure 6b is a photograph showing the results of Western blot analysis showing the change in the expression level of the marker protein
  • Figure 6b is a graph showing the change in the expression level of cleaved caspase 9 according to the treatment concentration of hwansam vine obtained from the Western blot analysis of Figure 6a
  • Figure 6c is a graph showing the change in the expression level of cleaved caspase 3 according to the treatment concentration of hwansam vine obtained from the western blot analysis of Figure 6a
  • Figure 6d is a treatment concentration of hwansam vine obtained from the western blot analysis of Figure 6a This is a graph showing the change in the expression level of cleaved PARP.
  • the purpose of this study was to verify the efficacy of the extract of the Korean Peninsula ginseng extract on the induction of Alzheimer's disease, a type of degenerative brain disease.
  • APPSwe and PSEN1 genes which are genes related to Alzheimer's disease, are overexpressed in the brain of mouse, and the therapeutic effect of ring vine extract is applied to mouse animal model (B6C3-Tg (APPswe / PSEN1dE9) 85DboJ, JAX, 004462) with Alzheimer's disease.
  • B6C3-Tg APPswe / PSEN1dE9 85DboJ, JAX, 004462
  • beta-amyloid deposition is prominently observed in the brain from 6 months of age, and is characterized by Alzheimer's specific cognitive dysfunction, and is maintained at 22 to 24 ° C. in a specific pathogen free (SPF) environment. Sterilized feed and water intake freely in the breeding facility, and was maintained while maintaining a 12-hour day and night cycle.
  • the test was divided into a control group administered with% CMC and an experimental group administered with 500 mg / kg hwan extract.
  • the control and experimental populations of the Alzheimer's diseased mouse group overexpressing APP / PSEN1 were performed using 10 and 12 mice, respectively. At this time, the mouse group was used for 5 months of age mice, and 0.5% CMC and 500 mg / kg of the ginseng vine extract was orally administered daily for 10 weeks.
  • NERT novel object recognition test
  • 5% CMC and 500 mg / kg hwan extract as shown in Example 2-4, was administered to each test group for 8 weeks, followed by NORT.
  • the mice were placed in 41.5 cm x 20 cm x 21.5 cm white boxes and allowed to move freely for 10 minutes. After 10 minutes of adaptation as described above, they were returned to the original cage.
  • two identical cylindrical wooden blocks were placed on both sides of the box and exposed for 10 minutes to allow the mouse to explore them.
  • the box was placed with a new cylindrical block (new object) together with the cylindrical block (used object) that was originally seen, and then the movement of the mouse was observed.
  • the time of touching the block, snoring, or moving toward the block was measured.
  • the time of interest in the cylindrical block (used object) and the search time of interest in the square pillar block (new object) were measured from the total number of times measured for the two blocks (FIG. 7).
  • the search time is (time to show interest in familiar objects) / (time to show interest in familiar objects + time to show interest in new objects) ⁇ 100 and (time to show interest in new objects) / (for used objects). Time of interest + time of interest to a new object) ⁇ 100.
  • FIG. 7 is a graph showing the effect of improving cognitive function and memory in a novel object recognition test (NORT) according to the treatment of gingko vine extract in a mouse animal model of Alzheimer's disease.
  • NERT novel object recognition test
  • hwansamvine extract is effective in the treatment of Alzheimer's disease, and hwansamvine extract administration group of the non-Tg mouse group not overexpressing APP / PSEN1 is new compared to the untreated control group.
  • the object recognition time is increased, it can be seen that the hwansam vine extract also exhibits an improvement in cognitive function and memory.
  • Example 4-3 Y maze test
  • a Y-maze test was performed to confirm the spatial perception and memory enhancement effects of the Korean Peninsula vine extract on the loss of spatial perception and memory caused by Alzheimer's disease.
  • the Y-maze test is an experiment to determine whether it helps the spatial perception and short-term memory recovery of experimental animals.
  • the Y-maze test apparatus is a transparent acrylic plate (width 10). cm, 40 cm in height, 25 cm in height) is composed of a closed maze of Y-shaped, each maze is arranged at a constant angle of 120 ° to each other. The test was conducted for 10 minutes, and each labyrinth was designated as A, B, and C regions, and experimental experiments were started in one region to freely explore the maze. At this time, the number and order of entering each maze was measured to evaluate the change behavior (spontaneous alteration,%) (Fig. 8).
  • FIG. 8 is a graph showing the effect of improving spatial perception and short-term memory in the Y-maze test of Alzheimer's disease mouse model.
  • the Alzheimer's overexpressed mouse in the Alzheimer's diseased mice compared to the control group untreated with the hwansamvine extract It was confirmed that the behavioral power increased statistically.
  • Example 4-4 Amyloid in the Brain Calmness Verification
  • the aim of this study was to determine whether the symptoms of beta amyloid deposition in the brain, which is characteristic of Alzheimer's disease, were altered by the administration of the gingival vine extract.
  • the experimental group and the control group which were administered to the Alzheimer's disease-induced mice with Alzheimer's disease at a concentration of 500 mg / kg / day for 2.5 months, were prepared, respectively, and brains were extracted from these and experimental mice. After fixation to paraformform aldehyde, a brain slice having a thickness of 40 ⁇ m was prepared. The prepared brain sections were immunostained using a Bam-10 antibody capable of detecting beta amyloid deposition, and analyzed for the ratio of Bam-10 immunostained regions in the cerebral cortex of control mice and experimental mice (FIG. 9a to 9c).
  • Figure 9a is a photograph showing the results of immunostaining for beta amyloid in the brain of the Alzheimer's disease-induced mouse animal model that is not administered with the exchange ginseng extract
  • Figure 9b is a mouse model of Alzheimer's disease-induced mouse administered with the extract
  • Figure 9c is a photograph showing the results of immunostaining for beta amyloid in the brain
  • Figure 9c is a comparison of the changes in the immunostaining level for beta amyloid according to the administration of hwansamvine extract in the brain of a mouse model of Alzheimer's disease It is a graph. As shown in Figures 9a to 9c, it was confirmed that the area of the beta amyloid-deposited area in the cerebral cortex was significantly reduced by the administration of the hwangi extract.
  • Example 4-5 in the brain Tau protein Hyperphosphorylation Verification
  • Alzheimer's Disease Onset in Mouse Animal Models The purpose of this study was to determine whether hyperphosphorylation of tau protein, a hallmark of Alzheimer's disease, was altered by the administration of P. vulgaris extract. Approximately, the brain slices prepared in Example 4-4 were immunofluorescent stained using an AT8 antibody capable of detecting phosphorylated tau protein, photographed by fluorescence microscopy in the cerebral cortex of control mice and experimental mice. The values were quantified (FIGS. 10A-10C).
  • Figure 10a is a photograph showing the results of the immunostaining for phosphorylated tau protein in the brain of the Alzheimer's disease-induced mouse animal model not administered with the rim extract
  • Figure 10b is a Alzheimer's disease-induced mouse animal administered with the rim extract
  • Immunostaining for the phosphorylated tau protein in the brain of the model is a photograph showing the results
  • Figure 10c is the immunostaining level of the phosphorylated tau protein according to the administration of Panaxia vinegar extract in the brain of Alzheimer's disease mouse animal model It is a graph showing the result of comparing a change. As shown in Figure 10a to 10c, it was confirmed that the hyperphosphorylation of tau protein in the cerebral cortex is significantly reduced by the administration of hwansamgwan extract.
  • Example 4-6 Analysis of specific inflammatory responses in the brain
  • the purpose of this study was to determine the effect of extract from the ginseng on the inflammatory response in the cerebral cortex of a mouse model of Alzheimer's disease.
  • Example 4-6-1 Effect on the level of activated microglia
  • Example 4-4 immunostaining was performed using an ionized calcium-binding adapter molecule (Iba-1) antibody that can specifically bind to activated microglia, and controls After measuring the level of activated microglia in the cerebral cortex of mice and experimental mice, it was compared (Figs. 11A to 11C).
  • Iba-1 ionized calcium-binding adapter molecule
  • Figure 11a is a photograph showing the results of the immunostaining for activated microglia cells in the brain of the Alzheimer's disease-induced mouse animal model not administered with the exchange ginseng extract
  • Figure 11b is an Alzheimer's-onset mouse administered with the exchange ginseng extract
  • Immunostaining of activated microglial cells in the brain of the animal model is a photograph showing the results
  • Figure 11c is immune to the activated microglial cells according to the administration of the exchange ginseng extract in the brain of the mouse animal model of Alzheimer's disease It is a graph which shows the result of comparing the change of staining level. As shown in Figures 11a to 11c, it was confirmed that the level of activated microglia cells in the cerebral cortex is significantly reduced by the administration of hwansamgwan extract.
  • Example 4-6-2 Effect on the level of activated astrocytes
  • Figure 12a is a photograph showing the results of immunostaining for activated astroglia cells in the brain of the Alzheimer's disease-inducing mouse animal model not administered with the exchange ginseng extract
  • Figure 12b is an Alzheimer's-onset mouse administered with the exchange ginseng extract
  • Immunostaining for activated astrocytic cells in the brain of an animal model is a photograph showing the results
  • Figure 12c is the immune to activated astrocyte glial cells in accordance with the administration of the rim extract extract in the brain of a mouse animal model of Alzheimer's disease It is a graph which shows the result of comparing the change of staining level. As shown in Figure 12a to 12c, it was confirmed that the level of activated glial cells in the cerebral cortex is significantly reduced by the administration of hwansamgwan extract.
  • Example 4-6-3 Effects on levels of inflammatory cytokines
  • the level of inflammatory cytokines (TNF- ⁇ , IL-6 and IL-1 ⁇ ) known to be secreted by activated microglia and astroglia are real- Measured by time PCR method and compared (FIGS. 13A-13C).
  • the control group (Non-Tg) used a brain extracted from a normal mouse that did not receive anything, and the control group used a brain extracted from an animal model of Alzheimer's disease-inducing mouse that received nothing. We used the brains extracted from Alzheimer's disease-induced mouse animal models to which the gingiva vine extract was administered.
  • Figure 13a is a graph showing the results of comparing the mRNA levels of TNF- ⁇ expressed in the brain, according to the administration of the hwansamvine extract
  • Figure 13b is a mRNA of IL-6 expressed in the brain
  • 13C is a graph showing the results of comparing the mRNA levels of IL-1 ⁇ expressed in the brain, according to administration of hwansamvine extract.
  • Figure 13a to 13c the expression level of various inflammatory cytokines in the brain of the Alzheimer's disease-inducing mouse animal model compared to the brain of the normal mouse, but the level of the inflammatory cytokine is increased when administration It was confirmed that the decrease.
  • the extract of Panax ginseng may inhibit the inflammatory response induced at the onset of Alzheimer's disease.
  • Examples 4-1 to 4-6 showed that the extract of Panax ginseng inhibits beta amyloid deposition and tau protein hyperphosphorylation in cerebral cortex during the onset of Alzheimer's disease, and inhibits inflammatory responses in the brain. As a result, it was confirmed that an improvement effect on spatial perception ability and short-term memory loss was observed, and therefore, the extract of Ginseng vine showed a therapeutic effect on Alzheimer's disease.
  • 3-nitropropionic acid (3) known as a toxic substance that damages brain cells, can be used to conduct a behavioral analysis to improve the dyskinesia caused by degenerative brain diseases such as Huntington's disease.
  • -nitropropionic acid (3-NP) was administered to experimental animals to induce Huntington's disease, and anomalous behavior was analyzed in terms of behavior.
  • a 9-week-old male C57BL / 6J mouse was used as a test animal, and the test animal group was fed a control group containing 0.5% CMC (carboxy methylcellulose) and a test group fed 500 mg / kg persimmon vine extract per day. Tested by dividing. At this time, the number of control group and the experiment group was carried out using each 6 dogs, 0.5% CMC and 500 mg / kg of the ginseng vine extract starting to feed five days before the administration of 3-NP causing Huntington's disease, the point of drug administration Continue to supply until.
  • CMC carboxy methylcellulose
  • mice After 2-hour administration of 3-NP at a concentration of 60 mg / kg to the experimental animals of the two groups, and intraperitoneally at a concentration of 80 mg / kg after 12 hours, dysregulation of the mice was evaluated through behavioral analysis (FIG. 14). At this time, the behavioral evaluation is to observe the behaviors such as back squeezing, scoliosis, hind limb tension, shaking the body on both sides, twisting the upper body in one direction. Was evaluated by summing.
  • Figure 14 is a graph showing the results of conducting a behavioral analysis according to the administration of Hwansam vine extract in mouse hunting-induced. As shown in FIG. 14, it was confirmed that the mice administered with the Korean Peninsula vine extract were statistically significantly reduced in behavioral evaluation scores.
  • the ginseng vine extract exhibits an improvement effect on behavioral abnormalities occurring at the onset of Huntington's disease, and thus, the ginseng vine extract has a therapeutic effect on Huntington's disease.

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Abstract

La présente invention concerne : une composition pharmaceutique permettant de prévenir ou de traiter des maladies neurodégénératives, contenant un extrait d'Humulus japonicus, qui a un effet inhibiteur sur la mort des neurones dopaminergiques, un effet de protection des neurones contre le stress oxydatif et un effet d'amélioration des capacités cognitives et de la mémoire, ou une fraction associée en tant que principe actif ; une méthode permettant de traiter des maladies neurodégénératives, comprenant une étape consistant à administrer la composition pharmaceutique ; une utilisation d'un extrait d'Humulus japonicus ou d'une fraction associée pour préparer la composition pharmaceutique afin de prévenir ou de traiter des maladies neurodégénératives ; et un complément alimentaire permettant de prévenir ou d'atténuer des maladies neurodégénératives, contenant un extrait d'Humulus japonicus ou une fraction associée en tant que principe actif.
PCT/KR2015/007127 2014-07-11 2015-07-09 Composition permettant de prévenir ou de traiter des maladies neurodégénératives, contenant un extrait d'humulus japonicus en tant que principe actif WO2016006947A1 (fr)

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KR102136662B1 (ko) * 2019-02-14 2020-07-22 중앙대학교 산학협력단 율초 추출물을 함유하는 장폐색증 예방 또는 치료용 조성물
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