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WO2016032249A1 - Composition pharmaceutique contenant un extrait de vaccinium bracteatum thunb. ou une fraction de celui-ci comme principe actif pour prévenir ou traiter une inflammation des nerfs ou des maladies neurodégénératives - Google Patents

Composition pharmaceutique contenant un extrait de vaccinium bracteatum thunb. ou une fraction de celui-ci comme principe actif pour prévenir ou traiter une inflammation des nerfs ou des maladies neurodégénératives Download PDF

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WO2016032249A1
WO2016032249A1 PCT/KR2015/008976 KR2015008976W WO2016032249A1 WO 2016032249 A1 WO2016032249 A1 WO 2016032249A1 KR 2015008976 W KR2015008976 W KR 2015008976W WO 2016032249 A1 WO2016032249 A1 WO 2016032249A1
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extract
disease
composition
fraction
group
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Korean (ko)
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장춘곤
권승환
최상호
이중구
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Sungkyunkwan University
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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)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH

Definitions

  • the present invention is Vaccinium Bracteatum Thunb.
  • the present invention relates to a pharmaceutical composition and a food composition for preventing, treating or improving neuroinflammatory or degenerative neurological disease, including extracts or fractions thereof as an active ingredient.
  • Inflammatory reactions are associated with various mediators and immune cells of local blood vessels and body fluids when infected with tissues (cells) or external infectious agents (bacteria, fungi, viruses, and various types of allergens). It has a series of complex physiological reactions, including substance secretion, fluid infiltration, cell migration, and tissue destruction, as well as external symptoms such as erythema, edema, fever, and pain. In normal cases, the inflammatory response removes external infectious agents and regenerates damaged tissues to restore life function.However, if the inflammatory response is excessive or persistent due to the absence of antigens or internal substances, the mucosal damage is promoted. Some lead to diseases such as cancer.
  • small neuroglial cells which are immune cells present in the central nervous system, can be activated by various exogenous and endogenous substances, and activated small neuroglial cells are inflammatory cytokines TNF- ⁇ and IL-1 ⁇ , nitric oxide, prostaglandin, and superoxide.
  • activated small neuroglial cells are inflammatory cytokines TNF- ⁇ and IL-1 ⁇ , nitric oxide, prostaglandin, and superoxide.
  • Produce and release substances (Gao et al., J Neurochem, 81, 1285-97, 2002; Nelson, PT. Et al., Ann Med, 34, 491-500, 2002; Griffin, WS et al., J Neuroinflammation, 3, 5, 2006).
  • Vaccinium bracteatum Thunb. is a subtropical evergreen broad-leaved tree that grows in the mountains of the seashore.
  • the fruit of the small leaves were used for medicinal purposes, such as the south fruit, the root of the fruit, and the leaf of the fruit. It has been disclosed about skin whitening application with respect to the extract of the young tree (Korea Patent No. 10-1230644), but it is not known yet for the prevention or treatment of neuro-inflammatory or degenerative neurological diseases.
  • the present inventors have made diligent research and efforts to develop a method for preventing and treating dementia, and as a result, it was confirmed that the extract of the young tree or its fractions not only suppresses the neuroinflammatory response, but also improves the learning or memory and improves the results.
  • the invention was completed.
  • An object of the present invention is Vaccinium Bracteatum Thunb. It is to provide a pharmaceutical composition for the prevention or treatment of neuroinflammatory or degenerative neurological disease comprising the extract or a fraction thereof as an active ingredient.
  • Still another object of the present invention is to provide a composition for enhancing or improving learning ability or memory, which includes the extract of Hedgehog or fractions thereof as an active ingredient.
  • the extract of the present invention or fractions thereof is derived from natural products that have been used as natural medicines and not only inhibit the expression of NO, PGE 2 , iNOS and / or COX-2 genes or proteins, which are inflammation-related factors, In addition, it can be usefully used in the prevention or treatment of neuro-inflammatory or degenerative neurological diseases because of its excellent learning or memory enhancement and improvement effects.
  • 1 is a diagram showing the neuroprotective effect of the neurons by the Methanol methanol extract treatment in SH-SY5Y neuronal cell line.
  • Figure 2 is a diagram showing the NO production inhibitory effect by the Methanol methanol extract treatment in BV-2 microglia.
  • Figure 3 is a diagram showing the effect of inhibiting PGE 2 production by the Methanol methanol extract treatment in BV-2 microglia.
  • Figures 4a and 4b is a diagram showing the inhibitory effect of iNOS protein and mRNA expression by Methanol methanol extract treatment in BV-2 microglia.
  • Figures 5a and 5b is a diagram showing the effect of inhibiting COX-2 protein and mRNA expression by Methanol methanol extract treatment in BV-2 microglia.
  • FIG. 6 is a diagram showing the inhibitory effect of ⁇ -CTF expression by the Methanol methanol extract treatment in SH-SY5Y neuronal cell line.
  • Figures 7a and 7b is a diagram showing the inhibitory effect of BACE1 expression by Methanol methanol extract treatment in SH-SY5Y neuronal cell line.
  • Figures 8a and 8b is a diagram showing the effect of improving the working memory of the extract of the bark or fractions thereof through the Y-maze experiment.
  • Figures 9a and 9b is a diagram showing the effect of improving the working memory of the extract of the young tree or its fraction through the Y-maze experiment in the scopolamine induced forgetfulness model.
  • Figures 10a and 10b is a diagram showing the learning and memory enhancement effect of the extract of the young tree or fractions thereof through passive avoidance experiment.
  • Figure 11a is a diagram showing the learning and memory improvement effect of the extract of the young tree or fractions thereof through passive avoidance experiments in the scopolamine-induced forgetfulness model.
  • FIG. 12 is a diagram showing the effect of improving the working memory of the bark extract through the Y-maze experiment in the A ⁇ 25 -35 induced dementia model.
  • FIG. 13 is a diagram showing the learning and memory improvement effects of H. bark extract through passive avoidance experiment in A ⁇ 25 -35 induced dementia model.
  • the present invention is Vaccinium Bracteatum Thunb. It provides a pharmaceutical composition for the prevention or treatment of neuro-inflammatory or degenerative neurological disease comprising the extract or fractions thereof as an active ingredient.
  • the pharmaceutical composition for the prevention or treatment of neuroinflammatory or degenerative neurological diseases of the present invention may include the extract of Hedgehog and / or fractions thereof.
  • Baccinium Vaccinium bracteatum Thunb.
  • Vaccinium bracteatum Thunb. is a subtropical evergreen broad-leaved tree that grows in the mountains of the seashore. It is a plant species that can be edible during the winter season as its fruit matures in November-December. It is distributed in Korea, Japan, China, etc. In Korea, it grows in Jeju island, Jeonnam and Jeonbuk regions, Wolchulsan, etc. Flowers bloom in June in reddish purple and black fruits in June. Also, the fruit of the hawks is called nectar, the root is nectar, and the leaves are medicinal.
  • the "barberry extract” is an extract obtained by extracting the bark.
  • the mosae wood extract is from about 2 to 20 times that of the mosae wood pulverized by dry weight, preferably from about 3 carbon number of 1 such as to 5 times the volume of water up to, methanol, ethanol and butanol (C 1) to 4 (C 4 ) using a polar solvent of the lower alcohol or a mixed solvent having a mixing ratio of about 1: 0.1 to 1:10 as the elution solvent
  • the extraction temperature is 20 to 100 °C, preferably at room temperature
  • the extraction period is about 12 hours to 4 days, preferably 3 days can be extracted using an extraction method such as hot water extraction, cold needle extraction, reflux cooling extraction or ultrasonic extraction, but the substance having a prophylactic or therapeutic activity of neuro-inflammatory or degenerative brain nerve disease If the extraction method can be used without limitation.
  • the mixture is extracted once or five times by cold extraction and filtered under reduced pressure, and the filtrate is concentrated under reduced pressure at 20 to 100 ° C., preferably at room temperature using a vacuum rotary condenser, and soluble in water, lower alcohols, or a mixed solvent thereof.
  • It may be a result of obtaining a crude crude extract, but is not limited thereto, as long as it can exhibit the prophylactic or therapeutic activity of the neuroinflammatory or degenerative neurological disease of the present invention, extracts, dilutions or concentrates of extracts, extracts It can contain the dried thing obtained by drying, or all these adjustment agents or refined products.
  • the shrub extract may be extracted from various organs of natural, hybrid, and mutant plants, and may be extracted from, for example, roots, ground, stems, branches, leaves, fruits or plant tissue cultures.
  • a "fraction” in the present invention is the result obtained by the fractionation method of separating a specific component or a specific group from a mixture comprising various components.
  • the fraction of the present invention may be obtained by suspending the extract of the camphor tree and then fractionating the mixture using a polar solvent such as water, methanol, ethanol, or a nonpolar solvent such as hexane and ethyl acetate, respectively. have.
  • the crude crude extract is suspended in distilled water or the like, and then water of about 1 to 100 times the volume of the suspension, preferably about 1 to 5 times the volume, alcohol having 1 (C 1 ) to 4 (C 4 ), chloroform And polar or nonpolar solvents such as ethyl acetate, hexane, butanol or a mixed solvent thereof may be added to extract and separate a polar or nonpolar solvent soluble layer from 1 to 10 times, preferably 2 to 5 times. have.
  • water of about 1 to 100 times the volume of the suspension preferably about 1 to 5 times the volume
  • chloroform And polar or nonpolar solvents such as ethyl acetate, hexane, butanol or a mixed solvent thereof may be added to extract and separate a polar or nonpolar solvent soluble layer from 1 to 10 times, preferably 2 to 5 times. have.
  • the fraction of the present invention may be obtained by further performing a conventional fractionation process (Harborne J. B. Plant Pathology, 1998, 3rd Ed. P6-7).
  • a conventional fractionation process For example, fractions obtained by passing an extract of the youngberry according to the present invention through an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity), and the like.
  • the active fractions obtained through various purification methods additionally carried out as well are included in the Hedgehog fraction of the present invention.
  • the active fraction is separated from the fraction having a higher physiological activity and the like, also referred to as active fraction or effective fraction. It is possible to prepare specific active fractions having stronger activity by separating them according to the nature of the active ingredient through concentration gradient column chromatography among fractions in which various components obtained through conventional fractionation processes such as systematic fractionation are mixed. .
  • the column chromatography is subjected to column chromatography using a filler selected from the group consisting of silica gel, Sephadex, LH-20, ODS gel, RP-18, polyamide, Toyopearl and XAD resin to separate the active fractions And may be purified, and column chromatography may be performed several times by selecting an appropriate filler as necessary, but is not limited thereto.
  • the elution solvent, the elution rate and the elution time may be applied to a solvent, rate or time generally used in the art.
  • the suspension of methanol obtained by adding distilled water was suspended, and then the same amount of ethyl acetate was added and separated into an ethyl acetate layer and a water layer, which was filtered and concentrated under reduced pressure to obtain an ethyl acetate fraction. Then, the ethyl acetate fraction was removed and the same amount of butanol was added to the remaining water layer to obtain a butanol fraction in the same manner as above, and the remaining water layer was concentrated to obtain a water fraction (Examples 1 and 2).
  • the moss extract or fractions thereof according to the present invention may develop neuritis by or inhibiting the expression of nitrogen monoxide (NO), prostaglandin (PGE 2 ), iNOS and / or COX-2 genes or proteins known as inflammation-related factors. It can be used for the prevention or treatment of neurodegenerative neurodegenerative diseases.
  • NO nitrogen monoxide
  • PGE 2 prostaglandin
  • iNOS iNOS
  • COX-2 proteins known as inflammation-related factors
  • neuroritis refers to an inflammatory response occurring in the nervous system, that is, nerve cells, nervous tissues, and the like.
  • Small neuroglial cells immune cells present in the central nervous system, are activated by various exogenous and endogenous substances, producing and releasing substances such as inflammatory cytokines TNF- ⁇ and IL-1 ⁇ , nitric oxide, prostaglandin, and superoxide. It may include.
  • the production of these substances is known to cause an immune response in the short term, but its excessive production or continuous production induces the death of neighboring neurons and eventually neurodegeneration.
  • the extract or fractions thereof from the hedgehog suppressed the expression level of proteins, mRNAs of NO, PGE 2 , iNOS and COX-2, which are known as inflammation-related factors, without having neurotoxicity.
  • mRNAs of NO, PGE 2 , iNOS and COX-2 which are known as inflammation-related factors, without having neurotoxicity.
  • the extract of the young tree according to the present invention or fractions thereof can be used for the prevention or treatment of degenerative brain neuron disease by inhibiting the expression of ⁇ -CTF and beta-secretase (BACE1) known as Alzheimer's enzyme.
  • BACE1 beta-secretase
  • degenerative brain nerve disease refers to a disease that causes various symptoms with degenerative changes in the nerve cells of the central nervous system, and specifically, cognitive function, learning or memory impairment, or neuroinflammation accompanied by a neuroinflammatory response. Disease may be included.
  • Representative degenerative neurological diseases according to the present invention include dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakt disease (Creutzfeld) Jakob disease (CJD), stroke, multiple sclerosis, cognitive impairment, learning disability, memory impairment.
  • AD Alzheimer's disease
  • a ⁇ amyloid beta
  • APP amyloid precursor protein
  • BACE1 beta-secretase 1
  • gamma-secretase gamma-secretase
  • the expression level of a protein or mRNA of ⁇ -secretase-cleaved carboxyl-terminal fragment (B-CTF) and BACE1 (beta-secretase 1, beta-site APP-cleaving enzyme 1) known as Alzheimer's gene was confirmed the prevention or treatment effect (Experimental Example 3).
  • prevention refers to any action that inhibits or delays the onset of neuroinflammatory or degenerative neurological disease by administration of the composition
  • treatment refers to the improvement of symptoms caused by the neuroinflammatory or degenerative neurological disease by the composition. Any action that advantageously changes.
  • compositions comprising the Hedgehog extract or fractions thereof of the present invention may further comprise suitable carriers, excipients or diluents commonly used in the preparation of pharmaceutical compositions.
  • the extract of the young tree or fractions thereof included in the composition is not particularly limited, but may include 0.001% by weight to 99% by weight, preferably 0.01% by weight to 50% by weight, based on the total weight of the composition.
  • the pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers and suppositories. It can have a formulation of, and can be a variety of oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose (at least one compound). lactose), gelatin and the like can be mixed. In addition to the simple excipients, lubricants such as magnesium stearate, talc and the like can also be used.
  • Liquid preparations for oral administration include suspensions, solution solutions, emulsions, and syrups, and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the present invention provides a method for preventing or treating neuroinflammatory or degenerative neurological disease, comprising administering the pharmaceutical composition to a suspicious individual having neuroinflammatory or degenerative neurological disease.
  • the suspicious individual of the neuroinflammatory or degenerative brain neuron disease refers to all animals including humans who may develop or may develop the disease, and the pharmaceutical composition of the present invention is administered to a suspicious individual of the neuroinflammatory or degenerative neurological disease. By doing so, the individual can be treated efficiently.
  • the pharmaceutical composition and neuroinflammatory or degenerative neurological disease are as described above.
  • administration refers to introducing a pharmaceutical composition of the present invention to a subject suspected of neuroinflammatory or degenerative cranial neuropathy by any suitable method, wherein the route of administration is directed to various oral or parenteral routes as long as the target tissue can be reached. It can be administered through.
  • the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.
  • 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. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • the pharmaceutical composition of the present invention is not particularly limited as long as it is an individual for the purpose of neuroinflammatory or degenerative cranial nerve disease, and any one may be applied.
  • monkeys, dogs, cats, rabbits, morphotes, rats, mice, cows, sheep, pigs, goats, and the like can be used for all non-human animals, humans, birds and fish, and the like
  • the pharmaceutical composition is non-oral, It may be administered subcutaneously, intraperitoneally, in pulmonary and nasal, and may be administered by any suitable method, including intralesional administration if necessary for local treatment.
  • Preferred dosages of the pharmaceutical compositions of the present invention vary depending on the condition and weight of the individual, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art.
  • it may be administered by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections, but is not limited thereto.
  • Suitable total daily doses may be determined by the practitioner within the correct medical judgment and are generally in amounts of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / The amount of kg may be administered once to several times daily.
  • the present invention is Vaccinium Bracteatum Thunb.
  • the Hedgehog its extracts, fractions and neuroinflammatory or degenerative neurological diseases are as described above.
  • “Improvement” in the present invention is any action that improves or benefits the symptoms of suspected and onset of diseases, such as neuroinflammatory or degenerative neurological disease, which is prevented or treated by using a composition containing the extract of the young tree or fractions thereof as an active ingredient.
  • the Hedgehog extract of the present invention or a fraction thereof may be added to the food composition for the purpose of preventing or ameliorating neuroinflammatory or degenerative neurological disease.
  • the food composition of the present invention may include the form of pills, powders, granules, acupuncture, tablets, capsules or liquids, etc., there is no particular limitation on the kind of food to which the hedgehog extract of the present invention or a fraction thereof may be added.
  • the hedgehog extract of the present invention or a fraction thereof may be added.
  • the food composition may be added to other components in addition to the extract of the camphor tree or fractions thereof, the kind is not particularly limited.
  • various herbal extracts, food acceptable food additives, natural carbohydrates, and the like may be included as additional ingredients, such as conventional foods, but are not limited thereto.
  • the "food supplement” is a component that can be added to food supplements, it can be added to prepare the health functional food of each formulation and can be used by those skilled in the art as appropriate.
  • food additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners. , pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, but is not limited to the kind of food additives of the present invention by the above examples.
  • Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; And polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol, and as flavoring agents other than those mentioned above, natural flavoring agents (such as taumartin), stevia extract (rebaudioside A, glycyr) Higin and the like) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the food composition of the present invention may include a health functional food.
  • the "health functional food” refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and pills using raw materials or ingredients having useful functions for the human body. Functionality refers to obtaining useful effects on health use such as nutrient control or physiological effects on the structure and function of the human body.
  • the health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art.
  • unlike the general medicine has the advantage that there is no side effect that can occur when taking a long-term use of the drug with food as a raw material, can be excellent in portability.
  • the mixed amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment).
  • the Hedgehog extract of the present invention or a fraction thereof may be added in an amount of 1 to 50% by weight, preferably 5 to 10% by weight of the raw material composition, but is not limited thereto.
  • the amount may be used below the above range.
  • Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcohol drinks and vitamin complexes, and the like, and may include all of the health functional food in a conventional sense.
  • the present invention is a Vaccinium Bracteatum Thunb.
  • the parent tree, extracts and fractions thereof are as described above.
  • the extract of H. julibrissin or a fraction thereof may be used for improving learning ability or memory, and the composition may be a pharmaceutical composition, quasi-drug composition or food composition.
  • the present invention also provides the use of Vaccinium bracteatum Thunb. Extract or fractions thereof for the manufacture of a pharmaceutical composition or food composition for the prevention, improvement or treatment of neuroinflammatory or degenerative neurological disease.
  • the present invention for the preparation of food compositions for improving or improving learning ability or memory, Vaccinium bracteatum Thunb.) extract or fractions thereof.
  • the invention also mosae tree (Vaccinium Provided is a method of enhancing or improving a subject's learning ability or memory by administering a bracteatum Thunb.) extract or a fraction thereof to a subject in need thereof.
  • mosae tree Vaccinium Provided is a method of enhancing or improving a subject's learning ability or memory by administering a bracteatum Thunb.) extract or a fraction thereof to a subject in need thereof.
  • Amyloid beta 25 -35 (A ⁇ 25 -35 ), Dimethyl sulfoxide (DMSO), 30% hydrogen peroxide (H 2 O 2 ), lipopolysaccharide, phosphoric acid, poly-D-lysine, 3- (4,5-dimethyl thiazol-2 -yl) -2,5-diphenyl tetrazolium bromide (MTT), N- (1-naphthyl) ethylenediamine dihydrochloride), sulphanilamide, Tween-20, scopolamine and anti- ⁇ -actin antibodies are described in Sigma Chemical Co. (St. Louis, Mo., USA) was used.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS Fetal bovine serum
  • trypsin-EDTA penicillin / streptomycin mixture
  • GIBCO-BRL Gibbonuclear bovine serum
  • Rabbit anti-rabbit horseradish peroxidase-linked IgG antibodies were from Cell Signaling (Boston, Mass., USA).
  • Rabbit anti-APP, rabbit anti-BACE1, rabbit anti-COX-2 and rabbit anti-iNOS antibodies used Epitomics (Burlingame, CA, USA), TRIZOL, cDNA synthesis kit from Invitrogen (Molecular Probes, OR, USA) .
  • PGE2 ELISA kit (Cayman, MI, USA) was used.
  • the reagents used in the experiment were purchased from the best product.
  • mice 25-30 g
  • 4 weeks old were supplied by Koatech (Gyeonggi, South Korea) and used in the animal breeding room of Sungkyunkwan University pharmacy for more than 1 week.
  • Temperature 23 ⁇ 2 ° C
  • humidity 55 ⁇ 10%
  • contrast cycle (12 hours) were automatically adjusted.
  • Example 2-1 The resultant was extracted in Example 2-1, and extracted twice with 1 L of butanol (BuOH) in the obtained aqueous layer to obtain 6.8 g of a butanol-soluble fraction.
  • the H. extract and fractions were each concentrated in reduced pressure by hydrothermal treatment and used in the experiment.
  • MTT reduction assay was used to measure the survival rate of neurons (SH-SY5Y) by treatment of H. bark extract.
  • the MTT solution was placed in each well to a final concentration of 0.5 mg / ml. After reacting for 2 hours in the incubator and removing the medium and the MTT solution, DMSO was added and stirred. When completely dissolved, the UV absorbance was measured at 540 nm using a microplate reader (Molecular device, USA).
  • the cell absorbance was calculated by substituting the measured absorbance values into the following equation.
  • the production of inflammatory mediator NO was quantitatively measured. Specifically, 2.5 ⁇ 10 5 BV-2 microglia were dispensed into 24-well plates 24 hours before the experiment to add 100 ng / ml of LPS, which is a neuro-inflammatory substance, and the extract of the camphor tree prepared in Example 1 by concentration. After incubating for 24 hours in the incubator, 50 ⁇ l of Greases reagent (1% sulfonilamine / 0.1% N- (1-naphtyl) -ethylenediamine dihydrochloride / 5% phosphoric acid) was added, followed by reaction for 15 minutes. . Then, the microplate reader (Molecular device, USA) was used to measure the neuroinflammatory response inhibitory effect at 540nm wavelength.
  • Greases reagent 1% sulfonilamine / 0.1% N- (1-naphtyl) -ethylenediamine dihydrochloride / 5% phosphoric acid
  • BV-2 microglial cells by a 2.5 ⁇ 10 5 cells were dispensed to a 24 hours test mosae wood extracts prepared from the LPS 100 ng / ml in the above embodiment 1 neuroinflammation causing substances before the 24-well plate at a concentration
  • the reaction was carried out in the incubator for 24 hours, and after 24 hours, the supernatants of the wells treated at the respective concentrations were collected and precipitated for 400 minutes using a centrifuge for 3 minutes, using a microplate using a PGE 2 ELISA kit.
  • UV absorbance at 490 nm was measured using a reader (Molecular device, USA). The measured absorbance values using a quantitative graph of standard curve was calculated PGE 2 generation.
  • the secondary antibody horseradish peroxidase (HRP) -conjugated anti-rabbit and anti-mouse antibody
  • HRP horseradish peroxidase
  • the plate was washed 5 times with TTBS for 10 minutes, and the washed membrane was developed using ECL and x-ray film, and the concentration was analyzed using a quantitative analysis program (Fujifilm, Japan). It was.
  • the RNA was extracted using TRIZOL (Invitrogen) to confirm the expression of mRNA, RT-PCR was performed using the cDNA synthesis kit (Invitrogen). The RT-PCR used primers of iNOS, COX-2 and ⁇ -actin, and the primer sequences are shown in Table 1 below.
  • Proteins were quantified using BCA quantitation kit (Thermo, USA), eluted with 12.5% SDS gel and transferred to PVDF membrane. In order to confirm the expression of the protein, it is confirmed by fluorescence coloration with enhanced chmilumenescence (ECL).
  • ECL enhanced chmilumenescence
  • the membrane is reacted with 5% skim milk powder for 1 hour, and 4 ° C with primary antibodies APP, ⁇ -CTF, BACE1 and ⁇ -actin. After overnight washing with TTBS, the secondary antibodies, horseradish peroxidase (HRP) -conjugated anti-rabbit and anti-mouse antibodies, were labeled at room temperature for 1 hour.
  • HRP horseradish peroxidase
  • the plate was washed 5 times using TTBS for 10 minutes, and the washed membrane was developed using ECL and X-ray film, and the concentration was analyzed using a quantitative analysis program (Fujifilm, Japan) according to the quantitative method. It was.
  • RNA was extracted using TRIZOL (Invitrogen), and RT-PCR was performed using cDNA synthesis kit (Invitrogen).
  • the RT-PCR used primers of BACE1 and ⁇ -actin, and the primer sequences are shown in Table 2 below.
  • BACE1 5'-CATTGGAGGTATCGACCACTCGCT-3 (SEQ ID NO: 7) 5'-CCACAGTCTTCCATGTCCAAGGTG-3 (SEQ ID NO: 8) 624
  • mice were divided into 4 groups, 14 of each group.
  • the first group was the distilled water administration group (control group) containing 10% Tween 20, the second to fourth groups were the hedgehog extract or its butanol soluble fraction 6.25, 12.5 and 25 mg / kg administration group (experimental group).
  • mice in groups 2 to 4 (experiment group) who administered the parent tree extract or its butanol soluble fraction. It was confirmed that the rate of cross action was increased depending on the concentration of the tree extract or its butanol soluble fraction.
  • mice were divided into 5 groups, 14 of each group.
  • the first group is distilled water administration group (control group) containing 10% Tween 20
  • the second group is distilled water and scopolamine administration group (positive control group) containing 10% Tween 20
  • the third to fifth group It was set as the administration group (experimental group) of a tree extract or its soluble fraction (ethyl acetate).
  • Moss extract was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 6.25, 12.5, and 25 mg / kg, and 0.5 mg / kg of scopolamine was injected subcutaneously after 30 minutes.
  • ethyl acetate fraction of H. alba extract was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 12.5, 25 and 50 mg / kg, and after 30 minutes, subcutaneous 0.5 mg / kg of scopolamine Injection.
  • mice were placed in the Y-maze to measure the free entry of mice into A, B and C branches. At this time, a new branch is given to give a point, the percent cross action was calculated by the following equation (2).
  • mice were divided into 5 groups of 11-12 animals per group.
  • the first group is the distilled water administration group (control group) containing 10% Tween 20
  • the second group is the distilled water and A ⁇ 25 -35 administration group (positive control group) containing 10% Tween 20
  • the third to fifth groups are It was set as the administration group (experimental group) of the extract according to the concentration.
  • the H. locust extract was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 6.25, 12.5, and 25 mg / kg, and after 1 hour, A ⁇ 25 -35 6 nmol was added to the left ventricle. Was injected using. For 5 days each group was administered 6.25, 12.5 and 25 mg / kg of the H. locust extract, including 10% Tween 20.
  • mice were placed in the Y-maze one hour after the administration of the extract of each bark, and the free entry of the mice into branches A, B, and C was measured. At this time, a new branch is given to give a point, the percent cross action was calculated by the following equation (2).
  • wood mosae methanol extract 6.25 mg / kg administration group showing a cross-action rate of 12.5 mg / kg group and 25 mg / kg administered group was 71%, 65%, and 64% A ⁇ 25 -35 induced dementia model group (positive Compared to the control group, it was confirmed that the rate of cross action was significantly increased.
  • mice were divided into 4 groups, 14 of each group.
  • the first group was the distilled water administration group (control group) containing 10% Tween 20, and the second to fourth groups were 6.25, 12.5, and 25 mg / kg of the extract of locust tree or its soluble fraction (ethyl acetate, butanol, water), respectively. It was set as the administration group (experimental group).
  • Hedgehog extract or its soluble fraction (ethylacetate, butanol, water) was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 6.25, 12.5 and 25 mg / kg. After 1 hour, the mice were placed in a step-through apparatus into a dark box and trained by applying an electric shock of 0.25 mA for 3 seconds. After 24 hours, the mice were placed in bright boxes again, and the stay time until entering the black boxes was measured as an index of learning and memory. At this time, the cut-off time of the mouse was 300 seconds and compared with the control group.
  • the extract of the tree from the mice of groups 2 to 4 (experimental group) administered the extract or soluble fraction thereof.
  • the residence time increased depending on the concentration of the soluble fraction thereof.
  • mice were divided into 5 groups, 14 of each group.
  • the first group is distilled water administration group (control group) containing 10% Tween 20
  • the second group is distilled water and scopolamine administration group (positive control group) containing 10% Tween 20
  • the third to fifth group It was set as the administration group (experimental group) of a tree extract or its soluble fraction (ethyl acetate).
  • Hedgehog extract or its water soluble fraction was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 6.25, 12.5 and 25 mg / kg, and after 30 minutes subcutaneous 0.5 mg / kg of scopolamine Injection.
  • butanol or ethyl acetate fractions of H. alba extract were dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 12.5, 25 and 50 mg / kg, and after 30 minutes 0.5 mg / kg of scopolamine. was injected subcutaneously.
  • mice were placed in a step-through device into a dark box and trained by applying a 0.25 mA electric shock for 3 seconds. After 24 hours, the mice were placed in bright boxes again to measure the length of time until they entered the black boxes, which were used as indicators of learning and memory about scopolamine induced forgetfulness. At this time, the cut-off time of the mouse was 300 seconds and compared with the control group.
  • mice were divided into 5 groups of 11-12 animals per group.
  • the first group is the distilled water administration group (control group) containing 10% Tween 20
  • the second group is the distilled water and A ⁇ 25 -35 administration group (positive control group) containing 10% Tween 20
  • the third to fifth groups are It was set as the administration group (experimental group) of the Methanol extract by concentration.
  • Methanol methanol extract was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 6.25, 12.5 and 25 mg / kg, and 1 hour later, A ⁇ 25 -35 6 nmol was stereosterically positioned in the left ventricle. Injection was done using the instrument. For 5 days each group was administered 6.25, 12.5 and 25 mg / kg of the H. locust extract, including 10% Tween 20.
  • mice were placed in a step-through apparatus into a dark box and trained by applying an electric shock of 0.5 mA for 3 seconds. After 24 hours, the mice were put back into bright boxes and the time to stay in the black boxes was measured as an indicator of learning and memory for A ⁇ 25 -35 induced dementia. At this time, the cut-off time of the mouse was 300 seconds and compared with the control group.
  • Methanol extract of 6.25 mg / kg, 12.5 mg / kg and 25 mg / kg administered groups showed 169 seconds, 94 seconds, and 62 seconds, respectively, of the A ⁇ 25 -35 induced dementia model group (positive control). Compared to the above, it showed a significant increase in staying time.

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Abstract

La présente invention concerne une composition pharmaceutique et une composition alimentaire contenant un extrait de Vaccinium bracteatum Thunb. ou une fraction de celui-ci comme principe actif pour prévenir, traiter ou améliorer une inflammation des nerfs ou des maladies neurodégénératives. L'extrait de Vaccinium bracteatum Thunb. ou une fraction de celui-ci, selon la présente invention, est dérivé d'un produit naturel qui a été utilisé comme ingrédient en médecine naturelle et, en tant que tel, n'a pas d'effets secondaires, et qui inhibe l'expression de protéine ou de gènes NO, PGE2, iNOS et/ou COX-2, qui sont des facteurs associés à une inflammation, et qui est également très efficace pour augmenter et améliorer la mémoire et la capacité d'apprentissage, et peut donc être avantageusement utilisé pour prévenir ou traiter une inflammation des nerfs ou des maladies neurodégénératives.
PCT/KR2015/008976 2014-08-27 2015-08-27 Composition pharmaceutique contenant un extrait de vaccinium bracteatum thunb. ou une fraction de celui-ci comme principe actif pour prévenir ou traiter une inflammation des nerfs ou des maladies neurodégénératives Ceased WO2016032249A1 (fr)

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KR1020140112667A KR101756943B1 (ko) 2014-08-27 2014-08-27 모새나무(Vaccinium bracteatum Thunb.) 추출물 또는 이의 분획물을 유효성분으로 포함하는 신경염증 또는 퇴행성 뇌신경 질환의 예방 또는 치료용 약학적 조성물
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CN114184713A (zh) * 2021-12-30 2022-03-15 中华全国供销合作总社南京野生植物综合利用研究所 一种乌饭树水提物的鉴定技术及应用
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10925914B2 (en) * 2016-12-01 2021-02-23 Jeonnam Bioindustry Foundation Method for alleviating depression using a health functional food containing Vaccinium bracteatum Thunb fruit extract
CN114184713A (zh) * 2021-12-30 2022-03-15 中华全国供销合作总社南京野生植物综合利用研究所 一种乌饭树水提物的鉴定技术及应用
CN114184713B (zh) * 2021-12-30 2024-04-12 中华全国供销合作总社南京野生植物综合利用研究所 一种乌饭树水提物的鉴定技术及应用
CN114874348A (zh) * 2022-06-14 2022-08-09 常熟理工学院 乌饭树叶多糖VBLP-3b及其制备方法、应用
CN114874348B (zh) * 2022-06-14 2023-02-03 常熟理工学院 乌饭树叶多糖VBLP-3b及其制备方法、应用

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