WO2007091613A1 - Agent prophylactique ou thérapeutique pour la maladie d'alzheimer et aliment/boisson - Google Patents

Agent prophylactique ou thérapeutique pour la maladie d'alzheimer et aliment/boisson Download PDF

Info

Publication number
WO2007091613A1
WO2007091613A1 PCT/JP2007/052151 JP2007052151W WO2007091613A1 WO 2007091613 A1 WO2007091613 A1 WO 2007091613A1 JP 2007052151 W JP2007052151 W JP 2007052151W WO 2007091613 A1 WO2007091613 A1 WO 2007091613A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
disease
alzheimer
fraction
amyloid
Prior art date
Application number
PCT/JP2007/052151
Other languages
English (en)
Japanese (ja)
Inventor
Hiroko Isoda
Hideyuki Shigemori
Junkyu Han
Original Assignee
University Of Tsukuba
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Tsukuba filed Critical University Of Tsukuba
Priority to JP2007557875A priority Critical patent/JPWO2007091613A1/ja
Publication of WO2007091613A1 publication Critical patent/WO2007091613A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Alzheimer's disease preventive or therapeutic agent and food and drink
  • the present invention relates to an agent for preventing or treating Alzheimer's disease, food and drink, and the like. More specifically, the present invention relates to an Alzheimer's disease preventive or therapeutic agent containing at least caffeoylquinic acid (such as di-O-caffeoylquinic acid) having a structure in which two or more caffeic acids are ester-linked, and food and drink. .
  • caffeoylquinic acid such as di-O-caffeoylquinic acid
  • Alzheimer's disease is a progressive neurodegenerative disease whose main symptoms are progressive memory impairment and cognitive impairment.
  • the number of cases has been increasing!
  • ⁇ -amyloid is produced by the gradual degradation of ⁇ (amyloid precursor protein) and is constantly released extracellularly.
  • ⁇ amyloid precursor protein
  • j8 amyloid accumulates and aggregates outside the cell.
  • the process of damaging nerve cells proceeds and Alzheimer's disease develops (see, for example, Non-Patent Document 1).
  • Patent Documents 1 to 3 are disclosed as prior documents related to the present invention, for example.
  • Patent Document 1 discloses a blood glucose level increase inhibitor that also has chlorogenic acid potency
  • Patent Document 2 discloses a drug for treating amyloid diseases including an isolated compound of Uncaria genus plant material.
  • Reference 3 describes a therapeutic or preventive drug for Alzheimer's disease, which comprises a compound obtained by isolating Grapevine japonicum as an active ingredient.
  • Patent Document 1 Japanese Patent Laid-Open No. 2003-34636
  • Patent Document 2 Special Table 2004-514679
  • Patent Document 3 Japanese Patent Laid-Open No. 10-226668
  • Non-Patent Document 1 Matsujinkai Medical Journal 42 (2): 97-109, 2003
  • a substance that suppresses cell damage caused by ⁇ -amyloid may be useful for the prevention or treatment of Alzheimer's disease.
  • the main object of the present invention is to provide a substance useful for the prevention or treatment of Alzheimer's disease.
  • caffeoylquinic acid having a structure in which two or more caffeic acids are ester-linked suppresses cell damage caused by ⁇ -amyloid.
  • an agent for preventing or treating Alzheimer's disease containing at least caffeoylquinic acid having a structure in which two or more caffeic acids are ester-linked and an agent for preventing or treating Alzheimer's disease containing at least the compound.
  • an agent for preventing or treating Alzheimer's disease containing at least caffeoylquinic acid having a structure in which two or more caffeic acids are ester-linked and an agent for preventing or treating Alzheimer's disease containing at least the compound.
  • caffeoylquinic acid having a structure in which two or more caffeic acids are ester-bonded has an action of suppressing cell damage caused by
  • cuff oil quinic acid having a structure in which two or more cuff oxalates are ester-bonded has an action of inducing an increase in expression of phosphodariserate kinase, which is a protein involved in nerve cell protection. Therefore, drugs and foods and drinks containing at least this compound are likely to be useful for the prevention or treatment of Alzheimer's disease.
  • the drug and food and drink according to the present invention have the following advantages.
  • the compound according to the present invention is a plant-derived component, there is a high possibility that it can be applied continuously for a long period of time. In addition, even if applied continuously for a long period of time, there is a high possibility that side effects are few.
  • the compound according to the present invention can be administered to healthy subjects (preliminary preparation before the onset of Alzheimer's disease). (Including the military) supplements' healthy foods and so on for a long period of continuous application, there is a possibility of preventing the onset of Arno, Imah's disease.
  • Alpno-Ima disease has already developed, it can be applied continuously for a long period of time, which may inhibit the progression of Alzheimer's disease. May lead to treatment.
  • the drug and food and drink according to the present invention are highly likely to be useful for the prevention or treatment of Alzheimer's disease.
  • the drug and food and drink according to the present invention have advantages such as high possibility of being continuously applied for a long period of time, low side effects, and high possibility.
  • the compounds according to the present invention include all caffeoylquinic acids having a structure in which two or more cuff succinic acids are ester-bonded.
  • caffeoylquinic acid for example, 3, 4-di-O-power pheoylquinic acid (abbreviation "3, 4-di-CA”), 3,5-di-O-power pheoylquinic acid (abbreviation) "3,5—di-CA”), 4,5-di-O-caffeoylquinic acid (abbreviated "4,5-di-CA”), 3, 4,5-tri-O Abbreviation “3, 4, 5-tri-CA”).
  • the compound according to the present invention can be obtained, for example, by extracting a component with a predetermined plant power and separating and purifying it.
  • plants containing this compound include American pear pods, coffee, apples, grapes, lemons, radishes, onions, pine, turmeric, sunflower, corn, barley, wheat, rice, morroheia and the like.
  • the compound according to the present invention can be obtained by, for example, extracting an effective component of these plant powers using various solvents, or separating and purifying a predetermined effective component from the extracted component by various chromatography. You can get it.
  • the drug according to the present invention only needs to contain at least caffeoylquinic acid having a structure in which two or more caffeic acids are ester-bonded as an active ingredient for preventing or treating Alzheimer's disease.
  • the dosage form of the drug according to the present invention is not particularly limited.
  • oral preparations prowder, fine granules, condyles Granules, tablets, capsules, suspensions, emulsions, syrups, extracts, pills, etc.
  • external preparations ointments, creams, gels, external liquids, eye drops, nasal drops, inhalants
  • injections e.g., injections.
  • the compound according to the present invention is added to an excipient, a binder, a disintegrant, a surfactant, a preservative, a coloring agent, a flavoring agent, a fragrance, a stabilizer, an antiseptic, an oxidation agent.
  • An inhibitor or the like may be appropriately contained.
  • the compound according to the present invention may appropriately contain a substrate, a preservative, an emulsifier, a colorant, a preservative, an anti-oxidation agent and the like.
  • the compound according to the present invention may appropriately contain a solvent, a stabilizer, a solubilizing agent, a suspending agent, a preservative, an isotonic agent, and the like.
  • the food and drink according to the present invention may contain at least caffeoylquinic acid having a structure in which two or more caffeic acids are ester-bonded as an active ingredient for the prevention or treatment of Arno, Imah's disease.
  • the body may be contained in health functional foods (specific health functional foods, nutritional functional foods, etc.), V-healthy health foods and drinks, and other various foods and drinks, or may be blended in various seasonings. Can do. Moreover, you may make it contain in what is temporarily contained in a mouth, for example, dentifrice, dyeing agent, chewing gum, a mouthwash.
  • health functional foods specific health functional foods, nutritional functional foods, etc.
  • V-healthy health foods and drinks and other various foods and drinks
  • other various foods and drinks or may be blended in various seasonings.
  • Can do you may make it contain in what is temporarily contained in a mouth, for example, dentifrice, dyeing agent, chewing gum, a mouthwash.
  • Example 1 a physiologically active ingredient was extracted from the American pear quail (scientific name rcuscuta pentagonaj, hereinafter the same). The extracted components were separated and purified to identify the compounds. Each reagent used in this example was purchased from Wako Pure Chemical Industries, Ltd.
  • the solvent was distilled off under reduced pressure using a rotary evaporator in the same manner as described above to obtain a hexane extract component powder (2.55 g) and a 90% methanol extract component powder (115 g). It was.
  • n-butanol and water are added to the water extraction solution fractionated in the above procedure, and the mixture is stirred and allowed to stand.
  • n-butanol extraction solution layer and water extraction solution layer.
  • the solvent was distilled off under reduced pressure using a rotary evaporator in the same manner as described above to obtain n-butanol extract component powder (40. Og) and water extract component powder (36.4 g). Obtained.
  • each fraction obtained was CP-EA-1 fraction (179mg), CP-EA-2 fraction (212mg), CP-EA-3 fraction (148mg), CP-EA- 4 fractions (1295mg), CP-EA 5 fractions (399mg), CP-EA-6 fractions (314mg), CP-EA-7 fractions (202mg), CP-EA-8 fractions (431mg), CP—EA—9 fractions (101 mg).
  • each fraction obtained is CP-BU-1 fraction (384mg), CP-BU-2 fraction (270mg), same? -: 61;-3 fractions (27811 ⁇ ), same? -: 61;-4 fractions (19511 ⁇ ), same? -: 61;-5 fractions (56 6 mg), CP-BU- 6 fractions (135 mg), CP-BU- 7 fractions (395 mg), CP-BU-8 fractions (215 mg), CP-BU- Nine fractions (41 mg) and CP-BU-10 fractions (185 mg).
  • a Platform LC type manufactured by Waters was used as the ESIMS apparatus.
  • Heavy water shows the residual solvent peak of heavy water ( ⁇ ⁇ 4.8 ppm) and heavy methanol residual solvent peak ( ⁇ ⁇ 3.35 ppm), deuterated methanol shows the residual solvent peak of heavy methanol ( ⁇ ⁇ 3.35 ppm, ⁇ C49.8 ppm), Heavy Chloroform Form uses the residual solvent peak ( ⁇ ⁇ 7.26 ppm) of Heavy Chloroform Form as an internal standard.
  • FIGS. Fig. 8 to Fig. 10 show the measurement results (representative examples) for the fractions (CP—EA—4, CP—BU—5, and CP—BU—4-2—4) that identified strong feooil quinic acid.
  • CP—BU-4-2-4 Di-O-caffeoylquinic acid
  • FIGS. 11 and 12 The fraction (CP-BU-4-2-4) in which the fraction was identified is shown in FIGS. 11 and 12, respectively.
  • FIG. 5 is a spectrum showing the ESIMS measurement results for the fraction in which 3, 4 di-O-force pheoylquinic acid was identified.
  • the horizontal axis of this spectrum represents the mass-electric ratio (mZz), and the vertical axis represents the relative intensity of ions.
  • FIG. 6 is a spectrum showing 1H-NMR measurement results for the fraction in which 3,4 di-O-forced feoylquinic acid was identified.
  • the horizontal axis of this spectrum represents the chemical shift value (unit: pp m (parts per million)), and the vertical axis represents the signal intensity.
  • FIG. 7 is a spectrum showing the 13C-NMR measurement result for the fraction in which 3,4-di- ⁇ -force pheoylquinic acid was identified.
  • the horizontal axis of this spectrum represents the chemical shift value (unit: ⁇ m (parts per million)), and the vertical axis represents the signal intensity.
  • this compound was estimated to be 3,4-di-O-force feoylquinic acid (the compound represented by the chemical formula of “Chemical Formula 1”).
  • FIG. 8 is a spectrum (representative example) showing the ESIMS measurement results for the fraction in which 3,5-di-O-force pheoylquinic acid was identified.
  • the horizontal axis of this spectrum represents the mass-electric ratio (mZz), and the vertical axis represents the relative intensity of ions.
  • FIG. 9 is a spectrum (representative example) showing the 1H-NMR measurement results for the fraction in which 3,5 di-O-forced feoylquinic acid was identified.
  • the horizontal axis of this spectrum represents the chemical shift value (unit: ppm (parts per million)), and the vertical axis represents the signal intensity.
  • the caffeic acid structure portion was almost the same as the spectrum of 3, 4 di-O-forced feoylquinic acid.
  • FIG. 10 is a spectrum showing the 13C-N MR measurement results for the fraction in which 3,5 di-O-forced feoylquinic acid was identified. As described above, the horizontal axis of this spectrum represents the chemical shift value (unit: ppm (parts per million)), and the vertical axis represents the signal intensity.
  • this compound was estimated to be 3,5 di-O-force feoylquinic acid (the compound represented by the chemical formula of “Chemical Formula 2”).
  • FIG. 11 is a spectrum showing the ESIMS measurement results for the fraction in which 4,5 di-O-forced feoylquinic acid was identified. As described above, the horizontal axis of this spectrum represents the mass electrification ratio (mZz), and the vertical axis represents the relative intensity of ions.
  • mZz mass electrification ratio
  • FIG. 12 is a spectrum showing 1H-NMR measurement results for the fraction in which 4,5 di-O-caffeoylquinic acid was identified. As described above, the horizontal axis of this spectrum represents the chemical shift value (unit: ppm (parts per million)), and the vertical axis represents the signal intensity.
  • Example 2 whether or not di-O-forced feoylquinic acid has an effect of suppressing cell damage caused by j8 amyloid was examined by MTT assay.
  • the MTT assay is a method for measuring the relative number of viable cells.
  • MTT (3- (4, 5— dimethylthiazol— 2— yl) —2, 5— diphenyltetrazolium bromide, mitochondrial dehydrogenase (phthalate dehydrogenase) in raw silkworms is reduced to MTT formazan. Therefore, the amount of MTT formazan produced is proportional to the number of viable cells, so after adding MTT reagent to the cultured cells, the absorbance at 550 to 600 nm is measured and the amount of MTT formazan produced is compared to the value. By obtaining, the relative number of viable cells can be measured.
  • ⁇ -amyloid and zirconia-feoylquinic acid were added to cultured cells derived from neuronal cells, followed by cocoon assembly, and the number of viable cells was measured. Then, by measuring the number of surviving cells, it was examined whether di-strength pheoylquinic acid had an action to suppress cell damage caused by
  • SH-SY5Y cells have the property of releasing cell adhesion factors and are easily detached, adhesion factors (Fibrone ctin) were added during culture.
  • ⁇ -amyloid 13 amyloid manufactured by Bachem in Switzerland was dissolved in 100% DMSO, and then diluted to 200 M concentration with PBS containing 1% DMSO (phosphate buffer, the same applies hereinafter).
  • Samples (di-O-forced feoylquinic acid) were prepared by diluting each powder separated and purified in Example 1 to 10% (vZv) with PBS (3 types). Below, sample 3, 4 di-O-forced oleoquinic acid sample 1, 3, 5 zi sample O-forced peuroylquinic acid sample 2, 4, 5 di-O-caffeoylquinic acid sample 3
  • a 96-well plate (manufactured by Falcon) was coated with Fibronectin, and each well was seeded with SH cells at a concentration of 2 X 105 cells / ml at 100 / z L / well, and the cells were incubated at 37 ° C for 12-24 hours. The cells were cultured in a C02 incubator. Next, the medium of each well is removed, cell adhesion is confirmed, the cells are washed and removed once with Assay medium (“OPTI-MEM”, manufactured by Gibco), and then the medium is again removed. ⁇ LZwell was added.
  • Assay medium (“OPTI-MEM”, manufactured by Gibco
  • FIG. 13 is a graph showing the number of viable cells when di-O-forced feoylquinic acid was added to cultured cells in the presence of j8 amyloid.
  • the vertical axis of the graph represents the relative value (Relative value) of the number of viable cells.
  • the numerical values on the vertical axis represent each measured value, and only j8 amyloid is added. It is a value calculated by dividing by the measured value in the case of calorie.
  • S3 is when sample 3 (4,5-dihydro-force enoinorequinic acid) is added
  • the relative value of the number of viable cells is 33 + 8
  • 8 is the relative value of the number of viable cells when sample 3 (4,5-di-4-caffeoylquinic acid) and j8 amyloid are added. Represent each.
  • Example 3 a protemitase analysis was performed on the mechanism of the neuroprotective action of caffeoylquinic acid.
  • Proteomic analysis is generally a method of identifying proteins by developing intracellular proteins by two-dimensional electrophoresis, collecting the target protein, performing mass spectrometry, etc., and performing database analysis. It is. For example, it is possible to perform high-order information analysis such as chemical structure, total amount, expression time, post-translational modification, splicing, and aggregate formation of the target protein.
  • proteomic analysis was conducted to determine whether the expression level of phosphodarisellate kinase (PGK1), which is known as a protein involved in neuroprotection, is changed by caffeoylquinic acid. .
  • PGK1 phosphodarisellate kinase
  • the cell force was sucked out from the medium and washed twice with 10 mL of Tris-Sorbitol.
  • 2 mL of Lysis buffer having the composition shown in Table 1 was added and scraped off with a cell scooter.
  • the cell solution was transferred to an ultracentrifuge tube and left at room temperature for 1 hour while stirring up and down every 15 minutes. The supernatant after ultracentrifugation at 15 ° C. and 46000 rpm for 1 hour was used as a protein extract.
  • BSA bovine plasma albumin
  • Ettan IPGphorll isoelectric focusing system (Amershm Biosiences) was used for the first dimension electrophoresis in this example.
  • the IPG strip used was an 18 cm IPG strip (Immobiline DryStrip) with a pH range of 3-10, and a strip holder was used for swelling of the strip.
  • Ettan Daltsix electrophoresis system (Ame rshm Biosiences) was used for the second dimension SDS-PAGE in this example.
  • the IPG strip after one-dimensional electrophoresis was transferred to a petri dish, 10 mL of equilibration solution 1 having the composition shown in Table 4 was added, and shaken on a shaker for 15 minutes. Thereafter, equilibration solution 1 was discarded, 10 mL of equilibration solution 2 having the composition shown in Table 4 was added, and similarly shaken for 15 minutes on a shaker to equilibrate the IPG strip.
  • Proteins separated on the gel by two-dimensional electrophoresis were stained with a CBB staining solution having the composition shown in Table 6 to detect a protein spot pattern.
  • the gel after electrophoresis was immersed in the fixing solution shown in Table 6 and shaken for 2 hours, immersed in CBB staining solution, stained for 15 minutes, and then shaken for 2 hours with a washing solution having the same composition as the fixing solution to detect protein spots.
  • ImageMaster 2D Elite (Amersham-Pharmacia Biotech) was used for spot analysis!
  • the obtained peptide sequence information was collated with the protein on the database by protein database BLAST search, and the protein of the specific spot was identified. As a result, it was found that the protein of the specific spot was phosphoglycerate kinase (PGK1).
  • Fig. 14 shows the expression pattern of phosphoglycerate kinase (PGK1) in a gel subjected to two-dimensional electrophoresis.
  • Control is the control (expression pattern of PGK1 when caffeoylquinic acid and ⁇ -amyloid solution are not applied), and “ ⁇ ” 3 is the iS amyloid solution.
  • the expression pattern of PGK1 when the caffeoylquinic acid was added ⁇ CA '' is the expression pattern of PGK1 when caffeoylquinic acid was added, and ⁇ CA + A ⁇ '' was the PGK1 expression when caffeoylquinic acid and ⁇ -amyloid were added The expression patterns of are shown respectively.
  • caffeoylquinic acid is a protein phosphoglycol involved in neuronal cell protection.
  • Example 4 the effect of caffeoylquinic acid on the prevention of the onset of Arno-Ima was confirmed at the animal level.
  • This example was performed by a behavioral physiological method using the Morris water maze.
  • the Morris water maze is an experimental device that can measure memory learning for spatial recognition. It fills a circular pool with water and places a platform hidden under the surface of the water as a blame.
  • you put a mouse in the Morris water maze you first find a platform as a result of swimming around in the aquarium. If you repeat this many times, the mouse will remember where the platform is and reduce the time it takes to reach the platform. Learning ability can be determined by measuring the swimming pattern of the mouse (time spent near the platform) and the time to reach the platform.
  • SAM P8 is a mouse in which aging progressed faster due to inbreeding, resulting in a memory 'learning disorder.
  • a Morris water maze having a diameter of 120 cm and a depth of 25 cm shown in Fig. 16 was prepared, and the caffeoylquinic acid-administered group, PBS-administered group, and control group mice were released into the Morris water maze. As shown in Fig. 17, the time taken for the mouse to swim underwater and ride on a transparent platform (flat home) under the surface of the water was measured once a day for 30 days.
  • mice in the caffeoylquinic acid administration group and PBS administration group on the 30th day to get on the flat home the time until the mouse in the caffeoylquinic acid administration group gets on the flat home was compared.
  • Example 4 From the above results, in Example 4, it was found that caffeoylquinic acid had an improving effect on learning memory impairment.
  • FIG. 1 A schematic diagram showing a procedure for extracting a physiologically active ingredient such as the mosquito moth.
  • FIG. 2 Schematic diagram showing the separation and purification procedures for the soluble component of ethyl acetate in the extract of Prunus japonica.
  • FIG. 3 Schematic diagram showing the procedure for separation and purification of n-butanol-soluble components in the extract of the American pear extract.
  • FIG. 4 HPLC chromatogram of CP-BU-4 2 fraction in n-butanol soluble component.
  • FIG. 5 Spectra showing the ESIMS measurement results for the fraction that identified 3, 4-G O-powered pheoylquinic acid.
  • FIG. 6 is a spectrum showing 1H-NMR measurement results for a fraction in which 3, 4 di-O-forced feoylquinic acid was identified.
  • FIG. 7 A spectrum showing 13C-NMR measurement results for a fraction in which 3, 4 di-O-forced feoylquinic acid was identified.
  • FIG. 8 Spectra showing the ESIMS measurement results for the fraction that identified 3,5-G O-forced feoylquinic acid.
  • FIG. 9 is a spectrum showing 1H-NMR measurement results for a fraction in which 3,5 di-O-forced feoylquinic acid was identified.
  • FIG. 10 A spectrum showing the result of 13C-NMR measurement of a fraction in which 3,5 di-O-forced feoylquinic acid was identified.
  • FIG. 11 A spectrum showing the results of ESIMS measurement of a fraction in which 4, 5 GE O-forced feoylquinic acid was identified.
  • FIG. 12 A spectrum showing 1H-NMR measurement results for a fraction in which 4,5 di-O-forced feoylquinic acid was identified.
  • FIG. 13 is a graph showing the number of viable cells when di-strength pheoylquinic acid is added to cultured cells in the presence of ⁇ -amyloid.
  • FIG. 14 is a drawing-substituting photograph showing the expression pattern of phosphodariserate kinase (PGK1) in a gel subjected to two-dimensional electrophoresis in Example 3.
  • PGK1 phosphodariserate kinase
  • FIG. 15 shows a phosphodariserate kinase in a gel subjected to two-dimensional electrophoresis in Example 3.
  • the drawing substitute graph which shows the expression intensity of (PGK1).
  • FIG. 16 is a drawing-substituting photograph of the Morris water maze used in Example 4.
  • FIG. 17 is a drawing-substituting photograph showing a state where the mouse is on a flat platform in Example 4.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Mycology (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Le problème rencontré consistait à obtenir une substance utile pour la prévention ou le traitement de la maladie d'Alzheimer. Pour résoudre le problème, on a utilisé un agent prophylatique ou thérapeutique pour la maladie d'Alzheimer qui comprend au moins un acide cafféoylquinique présentant une structure telle qu'au moins deux acides caféiques sont liés l'un à l'autre par une liaison ester (par exemple, l'acide di-O-cafféoylquinique); et un aliment/une boisson utile pour la prévention ou le traitement de la maladie d'Alzheimer, qui renferme au moins le composé. L'acide cafféoylquinique a pour effet d'inhiber la cytopathie provoquée par la β-amyloïde. Par conséquent, on s'attend à ce qu'un agent ou un aliment/une boisson comprenant au moins le composé soit utile pour la prévention ou le traitement de la maladie d'Alzheimer. De plus, on espère également fortement que l'agent ou l'aliment/la boisson puisse être utilisé en continu sur une durée prolongée et qu'il produise peu d'effets secondaires indésirables.
PCT/JP2007/052151 2006-02-07 2007-02-07 Agent prophylactique ou thérapeutique pour la maladie d'alzheimer et aliment/boisson WO2007091613A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2007557875A JPWO2007091613A1 (ja) 2006-02-07 2007-02-07 アルツハイマー病予防又は治療剤、並びに飲食物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006029255 2006-02-07
JP2006-029255 2006-02-07

Publications (1)

Publication Number Publication Date
WO2007091613A1 true WO2007091613A1 (fr) 2007-08-16

Family

ID=38345208

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/052151 WO2007091613A1 (fr) 2006-02-07 2007-02-07 Agent prophylactique ou thérapeutique pour la maladie d'alzheimer et aliment/boisson

Country Status (2)

Country Link
JP (1) JPWO2007091613A1 (fr)
WO (1) WO2007091613A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2164483A2 (fr) * 2007-06-11 2010-03-24 National Cancer Center Inhibiteur de transglutaminase comprenant de l'acide chlorogénique et son procédé de production
JP2018039797A (ja) * 2016-09-02 2018-03-15 花王株式会社 脳機能改善剤
JP2018145100A (ja) * 2017-03-01 2018-09-20 富士フイルム株式会社 脳由来神経栄養因子産生向上剤及び飲食品
WO2018207790A1 (fr) 2017-05-12 2018-11-15 花王株式会社 AGENT SERVANT À FAVORISER LA DÉCOMPOSITION ET L'EXCRÉTION D'AMYLOÏDES-β

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10226668A (ja) * 1997-02-18 1998-08-25 Wakamoto Pharmaceut Co Ltd ブドウ科植物ヤブガラシより得られる新規生理活性物質
WO2001076614A1 (fr) * 2000-04-10 2001-10-18 Takara Bio Inc. Remedes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006006318A (ja) * 2004-05-21 2006-01-12 Toyo Shinyaku:Kk 味覚修飾剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10226668A (ja) * 1997-02-18 1998-08-25 Wakamoto Pharmaceut Co Ltd ブドウ科植物ヤブガラシより得られる新規生理活性物質
WO2001076614A1 (fr) * 2000-04-10 2001-10-18 Takara Bio Inc. Remedes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HUR J.Y. ET AL.: "Neuroprotective and neurotrophic effects of quinic acids from Aster scaber in PC12 cells", BIOL. PHARM. BULL., vol. 24, no. 8, 2001, pages 921 - 924, XP003024509 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2164483A2 (fr) * 2007-06-11 2010-03-24 National Cancer Center Inhibiteur de transglutaminase comprenant de l'acide chlorogénique et son procédé de production
EP2164483A4 (fr) * 2007-06-11 2013-08-28 Nat Cancer Ct Inhibiteur de transglutaminase comprenant de l'acide chlorogénique et son procédé de production
JP2018039797A (ja) * 2016-09-02 2018-03-15 花王株式会社 脳機能改善剤
JP2022051870A (ja) * 2016-09-02 2022-04-01 花王株式会社 脳機能改善剤
JP7499285B2 (ja) 2016-09-02 2024-06-13 花王株式会社 脳機能改善剤
JP2018145100A (ja) * 2017-03-01 2018-09-20 富士フイルム株式会社 脳由来神経栄養因子産生向上剤及び飲食品
WO2018207790A1 (fr) 2017-05-12 2018-11-15 花王株式会社 AGENT SERVANT À FAVORISER LA DÉCOMPOSITION ET L'EXCRÉTION D'AMYLOÏDES-β
JP2019178130A (ja) * 2017-05-12 2019-10-17 花王株式会社 アミロイドβ分解排出促進剤
CN110621311A (zh) * 2017-05-12 2019-12-27 花王株式会社 淀粉样蛋白β分解排出促进剂

Also Published As

Publication number Publication date
JPWO2007091613A1 (ja) 2009-07-02

Similar Documents

Publication Publication Date Title
JP2024038127A (ja) カンナビジオール製剤及びその使用
Qosa et al. Oleocanthal enhances amyloid-β clearance from the brains of TgSwDI mice and in vitro across a human blood-brain barrier model
Matei et al. Investigating the chemical changes of chlorogenic acids during coffee brewing: Conjugate addition of water to the olefinic moiety of chlorogenic acids and their quinides
JP5816171B2 (ja) 神経変性障害における脳の健康を保護するための化合物、組成物および方法
Watanabe et al. Isolation and characterization of a phenolic antioxidant from the Pacific oyster (Crassostrea gigas)
Martínez‐Mármol et al. Hericerin derivatives activates a pan‐neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory
D'Acunto et al. Metallomics for Alzheimer's disease treatment: Use of new generation of chelators combining metal-cation binding and transport properties
WO2007091613A1 (fr) Agent prophylactique ou thérapeutique pour la maladie d'alzheimer et aliment/boisson
JP7218306B2 (ja) 神経変性疾患を治療するための組成物
US9737495B2 (en) Process for obtaining purified pterostilbene and methods of use thereof
JP2022527329A (ja) 神経疾患を処置するために有用なレトロマー安定化剤としてのアミノグアニジンヒドラゾン
EP3461486B1 (fr) Composition pharmaceutique pour la prévention ou le traitement de la démence et l'amélioration de la fonction cognitive, comprenant de l'acanthoside b issue d'un extrait de salicorne
Cui et al. Brazilin-7-acetate, a novel potential drug of Parkinson's disease, hinders the formation of α-synuclein fibril, mitigates cytotoxicity, and decreases oxidative stress
André et al. 2, 5‐diketopiperazines mitigate the amount of advanced glycation end products accumulated with age in human dermal fibroblasts
JPWO2016006548A1 (ja) ＰＰＡＲγ活性化剤、抗肥満剤及び抗糖尿病剤
La Spina et al. Multiple mechanisms converging on transcription factor EB activation by the natural phenol pterostilbene
Martínez-Mármol et al. Hericerin derivatives from Hericium erinaceus exert BDNF-like neurotrophic activity in central hippocampal neurons and enhance memory
US7935673B2 (en) Polyphenol glycoside isolated from acerola
Pang et al. In vitro and in vivo biological evaluation of newly synthesized multi-target 20 (R)-panaxadiol derivatives for treating Alzheimer's disease
CN111225664A (zh) 包含作为活性成分的蕨素化合物及其衍生物的组合物，用于预防或治疗退行性脑疾病
KR100554343B1 (ko) 감국 추출물 및 이로부터 유래한 화합물을 포함하는아세틸콜린에스터라제 저해용 조성물
KR101944083B1 (ko) 한우 저분자 추출물 또는 한우 유래 펩타이드를 함유하는 대장암 개선, 예방 또는 치료용 조성물
KR20110007370A (ko) 고미신 ｎ을 유효성분으로 포함하는 항암용 조성물
EP2609929A1 (fr) Composition destinée à prévenir ou à traiter la démence
US11820762B2 (en) Compounds as potential therapeutic agents targeting various neurodegenerative diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: 2007557875

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07708183

Country of ref document: EP

Kind code of ref document: A1

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)