WO2018207792A1 - Agent de protection de barrière hémato-encéphalique - Google Patents

Agent de protection de barrière hémato-encéphalique Download PDF

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Publication number
WO2018207792A1
WO2018207792A1 PCT/JP2018/017831 JP2018017831W WO2018207792A1 WO 2018207792 A1 WO2018207792 A1 WO 2018207792A1 JP 2018017831 W JP2018017831 W JP 2018017831W WO 2018207792 A1 WO2018207792 A1 WO 2018207792A1
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Prior art keywords
chlorogenic acids
salts
mass
brain barrier
expression
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English (en)
Japanese (ja)
Inventor
瞳 西村
征輝 山本
幸一 三澤
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Kao Corp
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Kao Corp
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    • 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
    • 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
    • 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
    • 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

  • the present invention relates to a blood brain barrier protective agent.
  • the Blood-Brain Barrier is a mechanism that limits free substance exchange between circulating blood and the brain.
  • BBB protects the brain from harmful substances present in the circulating blood and contributes to maintaining the homeostasis of the brain.
  • the body of the BBB is brain capillary endothelial cells, in which two types of cells, perisite and astrocytes, and two basement membranes exist around the endothelial cells bound by tight junctions.
  • Tight junctions that make up the BBB are composed of transmembrane proteins such as Claudin, Occludin, junctional adhesion molecule (JAM), and proteins present in the cytoplasm such as ZO-1, 2, 3 and Actin. Also called zipper structure.
  • the BBB can limit the movement of substances into the cell gap.
  • BBB breaks down that is, when the permeability of BBB increases, harmful substances in blood vessels leak into the brain and brain tissue is damaged, resulting in various diseases and disorders such as cerebral vascular disorders, inflammation, and neurological disorders. Bring. Therefore, protecting the BBB from failure is effective for the prevention or improvement of those diseases and disorders.
  • Claudin is considered to be the most important for the tight junction structure.
  • Claudin-5 is mainly expressed in the claudin family.
  • Claudin-5 has been reported to be highly expressed in vascular endothelial cells in vertebrates and mainly expressed in brain capillary endothelial cells in the brain (Non-patent Document 1).
  • Non-patent Document 2 deletion of Claudin-5 with siRNA increases the permeability of BBB
  • Non-patent Document 3 Increased BBB permeability and lethality in Claudin-5 knockout mice. From the above, it is considered that the decrease of Claudin-5 in BBB leads to the breakdown of BBB, and it is possible to protect BBB by increasing the expression of Claudin-5 in BBB.
  • HMGB1 High Mobility Group Box 1
  • HMGB1 has been identified as a protein that is mainly present in the cell nucleus and is involved in the stabilization of the structure of chromatin or the transcription reaction of genes, and also plays a role in regulating immunity and inflammation in the cytoplasm and extracellularly.
  • Non-Patent Document 4 In an experimental system using an in vitro blood-brain barrier model, BBB permeability was increased by treating vascular endothelial cells with HMGB1, but the increase in BBB permeability was suppressed by using an anti-HMGB1 antibody together with HMGB1. Has been reported (Non-Patent Document 5).
  • Non-patent Document 6 it has been reported that the morphology of endothelial cells, perisite, and astrocytes constituting BBB was changed by HMGB1 treatment, and permeability was increased.
  • the anti-HMGB1 antibody can suppress brain edema due to traumatic brain injury, and it is considered that the anti-HMGB1 antibody suppresses BBB breakdown as the mechanism (Non-patent Document 7). ). From the above, the increase in HMGB1 in the BBB leads to the breakdown of the BBB, and it is considered that the BBB can be protected by suppressing the expression of HMGB1 in the BBB.
  • Patent Document 1 a drug that prevents, suppresses or ameliorates disease by strengthening the blood brain barrier function
  • Patent Document 2 a prostacyclin receptor agonist or prosta
  • Patent Document 3 a vascular permeability enhancement inhibitor containing a cyclin production promoting substance
  • Patent Document 3 a therapeutic agent for a disease associated with blood-brain barrier disorder containing prothymosin ⁇ or a partial peptide thereof as an active ingredient
  • Chlorogenic acids are one type of coffee polyphenol (CPP), and are mainly mono- and diesters in which phenol groups are bonded to quinic acid at various positions. Chlorogenic acids are known to have antioxidative, anxiolytic, anti-inflammatory, analgesic, and antipyretic effects in rodents, and amyloid ⁇ -induced toxicity and oxidative stress in the central nervous system. It has been reported that it has the effect
  • Non-patent Document 8 It has been reported that when macrophages collected from the abdominal cavity of a mouse are stimulated with lipopolysaccharide (LPS), the expression of HMGB1 increases, but when treated with chlorogenic acids, the increase is suppressed.
  • LPS lipopolysaccharide
  • macrophages are hardly present in the brain, and chlorogenic acids have not been reported so far to pass through the BBB and into the brain. It is still unknown whether HMGB1 expression is suppressed.
  • oral intake of chlorogenic acids increases the expression of Claudin-5 in the body.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2015-78225 (Patent Document 2) Japanese Patent Application Laid-Open No. 2015-134732 (Patent Document 3) Japanese Patent Laid-Open No. 2013-122116 (Patent Document 4) Japanese Patent Application Publication No.
  • Patent Document 1 BMC Cancer, 2006, 6: 186 (Non Patent Literature 2) Journal of Cerebral Blood Flow & Metabolism, 2012, 32: 860-873 (Non-Patent Document 3) Journal of Cell Biology, 2003, 161 (3): 653-660 (Non-Patent Document 4) PNAS, 2013, 110 (51): 20699-20704 (Non-Patent Document 5) Journal of Neuroinflammation, 2016, 13: 194 (Non-Patent Document 6) Stroke, 2011, 42: 1420-1428 (Non-patent document 7) Yakugaku zasshi, 2014, 134 (6): 701-705 (Non-Patent Document 8) Molecular medicine, 2012, 18: 1437-1448
  • the present invention provides a Claudin-5 expression promoter containing chlorogenic acids or salts thereof as an active ingredient. Moreover, this invention provides the brain HMGB1 expression inhibitor which uses chlorogenic acid or its salt as an active ingredient.
  • the present invention also provides a blood brain barrier protective agent comprising chlorogenic acids or salts thereof as an active ingredient.
  • the present invention also provides a preventive or ameliorating agent for lowering the function of the blood brain barrier, comprising chlorogenic acids or salts thereof as an active ingredient.
  • the present invention also provides a preventive or ameliorating agent for diseases or conditions caused by the breakdown of the blood brain barrier, comprising chlorogenic acids or salts thereof as an active ingredient.
  • the present invention provides a substance that promotes the expression of Claudin-5 or suppresses the expression of HMGB1 in the brain to suppress the breakdown of the blood brain barrier.
  • chlorogenic acids can promote Claudin-5 expression, suppress HMGB1 expression in the brain, and thereby protect the blood brain barrier from failure.
  • the expression of Claudin-5 can be promoted and the expression of HMGB1 in the brain can be suppressed.
  • the blood brain barrier can be protected or its breakdown can be effectively suppressed through the promotion of Claudin-5 expression or the suppression of brain HMGB1 expression.
  • the present invention is effective in protecting the blood brain barrier and preventing or ameliorating various conditions or diseases caused by the breakdown of the blood brain barrier.
  • BBB Blood-Brain Barrier
  • Diseases and disorders caused by BBB breakdown include, for example, cerebral hemorrhage or cerebrovascular disorder due to brain infiltration of blood albumin or sodium; encephalopathy due to leukocyte brain infiltration (white matter encephalopathy, etc.); autoimmunity due to transfer of inflammatory cytokines into the brain CNS disorders (optic neuromyelitis, acute disseminated encephalomyelitis, inflammatory demyelinating polyneuritis, etc.); brain infection or anaphylaxis caused by viral or allergic substances in the brain; Occurrence of adverse drug events such as war and abnormal behavior; brain and spinal cord trauma caused by transfer of other harmful substances into the brain, and tremor, delirium, abnormal behavior, drowsiness, consciousness disorder, obsessive compulsive disorder, etc. (See, for example, Patent Document 1, Cell
  • Claudin-5 is a transmembrane protein involved in the construction of tight junctions.
  • Claudin-5 is mainly expressed in the claudin family.
  • Claudin is considered to be the most important. It has been reported that deletion of Claudin-5 increases BBB permeability (Non-patent Document 2), and increases BBB permeability and lethality in Claudin-5 knockout mice (Non-patent Document 3). Thus, decreased Claudin-5 expression leads to BBB failure, while increased Claudin-5 expression strengthens the BBB tight junction and protects the BBB.
  • HMGB1 High Mobility Group Box 1
  • HMGB1 is a protein that exists in the nuclei of various cells, and has been identified as a protein that plays a role in stabilizing the structure of chromatin or in the transcription reaction of genes.
  • HMGB1 is also partially present in the cytoplasm, released to the outside of cells during inflammatory response and infection, functions as an inflammatory cytokine, promotes the inflammatory response, and is taken from the outside of the cell. It has been revealed that it is involved in recognition of embedded nucleic acids and induction of autophagy (Non-Patent Document 4).
  • HMGB1 is blood It is thought to be a factor related to the breakdown of the brain barrier. Therefore, the increase in HMGB1 promotes the breakdown of BBB and causes various diseases or conditions as described above resulting from it.
  • Chlorogenic acids have the action of promoting the expression of Claudin-5 in the brain and suppressing the expression of HMGB1, as shown in the Examples below. So far, there has been no report that chlorogenic acids act on Claudin-5. In addition, until now, there has been no report that chlorogenic acids taken orally act on HMGB1 in the brain protected by BBB. If the expression of Claudin-5 is promoted, the BBB surrounding the brain can be strengthened. Moreover, if the expression of HMGB1 in the brain is suppressed, the action of HMGB1 on the BBB surrounding the brain can be suppressed.
  • chlorogenic acids are effective for promoting Claudin-5 expression, suppressing HMGB1 expression in the brain, protecting the BBB, preventing or ameliorating the decline in BBB function, and preventing or ameliorating a disease or condition resulting from the breakdown of the BBB It is.
  • Claudin-5 refers to human Claudin-5 consisting of an amino acid sequence that is 95% or more identical to the amino acid sequence represented by SEQ ID NO: 1, or a homologue thereof. These include human Claudin-5 (SEQ ID NO: 1) represented by Gene ID: 7122 and mouse Claudin-5 (SEQ ID NO: 2) represented by Gene ID: 12741. These “Claudin-5” are membrane proteins constituting the BBB tight junction, and their increased expression strengthens the BBB tight junction and acts to protect the BBB.
  • Claudin-5 expression refers to Claudin-5 expression in vascular endothelial cells, preferably Claudin-5 expression in brain capillary endothelial cells, more preferably cerebral cortex or hippocampus. Refers to Claudin-5 expression in the surrounding BBB vascular endothelial cells.
  • HMGB1 refers to human HMGB1 consisting of an amino acid sequence 95% or more identical to the amino acid sequence represented by SEQ ID NO: 3, or a homologue thereof. Typical examples thereof include Gene Examples thereof include human HMGB1 (SEQ ID NO: 3) represented by ID: 3146 and mouse HMGB1 (SEQ ID NO: 4) represented by Gene ID: 15289. These “HMGB1” are present in the nucleus of the cell, and their increased expression results in increased permeability of the BBB.
  • in-brain HMGB1 expression refers to the expression of HMGB1 in cells of brain tissue protected by BBB, preferably cells in the cerebral cortex.
  • protection of the blood brain barrier means protecting the BBB from failure.
  • the permeability of the BBB increases, and harmful substances in blood vessels that have been blocked from entering the brain by the BBB so far leak into the brain. Therefore, the failure of the BBB causes a decrease in the function of the BBB.
  • the “disease or condition resulting from the breakdown of the blood-brain barrier (BBB)” refers to a disease or condition caused by the barrier function being impaired by the breakdown of the BBB.
  • BBB blood-brain barrier
  • the “prevention or amelioration of a disease or condition caused by blood-brain barrier (BBB) failure” is preferably intracerebral hemorrhage, cerebrovascular disorder, optic neuromyelitis, leukoencephalopathy, acute disseminated encephalomyelitis One or more selected from the group consisting of inflammatory demyelinating polyneuritis, brain infection, anaphylaxis, brain tumor, brain and spinal cord trauma, tremor, delirium, abnormal behavior, sleepiness, consciousness disorder, and obsessive-compulsive disorder Prevention or amelioration of other diseases or conditions.
  • BBB blood-brain barrier
  • prevention means prevention, suppression or delay of the onset of a disease, symptom or condition in an individual, or reduction of the risk of development of a disease, symptom or condition in an individual.
  • improvement means improvement of a disease, symptom or condition, prevention, suppression or delay of deterioration of the disease, symptom or condition, or reversal, prevention, suppression or delay of progression of the disease, symptom or condition.
  • non-therapeutic means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing a human, more specifically, a doctor or a person who has received instructions from a doctor. It is a concept that does not include a method for performing surgery, treatment, or diagnosis on humans.
  • chlorogenic acids used in the present invention include mono-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA) and 5-caffeoylquinic acid (5-CQA).
  • the chlorogenic acids used in the present invention may be any one or a combination of two or more of the compounds listed above.
  • the chlorogenic acids used in the present invention are preferably one or more monocaffe oils selected from the group consisting of 3-CQA, 4-CQA and 5-CQA. Contains quinic acid, more preferably 5-CQA.
  • the content of 5-CQA in the chlorogenic acids used in the present invention is preferably 15% by mass or more, more preferably 25% by mass or more, and further preferably 35% by mass or more in the total amount.
  • Chlorogenic acids can be extracted from natural products containing them, particularly plants, and can be industrially produced by chemical synthesis. Chlorogenic acids have stereoisomers, and in the present invention, these pure stereoisomers or a mixture of these stereoisomers can be used.
  • the chlorogenic acids used in the present invention can be extracted from the plant containing them.
  • plants containing chlorogenic acids include coffee, cabbage, lettuce, arch chalk, tomato, eggplant, carrot, apple, pear, plum, peach, apricot, cherry, sunflower, morroheia, sweet potato, southern sky leaves, Examples include blueberries, wheat, simmon leaves, pine cones, pine seed husks, ume fruit, dandelions, and vines.
  • the chlorogenic acids can be extracted from raw coffee beans, roasted coffee beans, southern leaves, unripe apples, sunflower seeds, and the like.
  • coffee beans such as green coffee beans and roasted coffee beans are preferably used in the present invention in view of the content of chlorogenic acids and the like.
  • citric acid acidic aqueous solution or hot water from the seeds of coffee Coffee arabica LINNE
  • a green coffee bean extract can be prepared.
  • an extract containing chlorogenic acids may be prepared from roasted coffee beans.
  • the coffee beans medium roasted coffee beans (L value: more than 16.8 and 24.2 or less), shallow roasted coffee beans (L value: more than 24.2 and less than 30.2), fine roasted coffee Beans (L value: more than 30.2) and green coffee beans are preferable, and green coffee beans are more preferable, but deep roasted coffee beans (L value: 16.8 or less) can also be used.
  • the “L value” is a value obtained by measuring the brightness of roasted coffee beans with a color difference meter, with black as L value 0 and white as L value 100.
  • a commercially available raw coffee bean extract, an apple extract, and a sunflower seed extract can be used as a chlorogenic acid raw material.
  • the coffee bean extract used in the present invention preferably has a low caffeine content.
  • the mass ratio of caffeine to chlorogenic acids in the coffee bean extract is preferably 0.05 or less, more preferably 0.03 or less, and even more preferably 0.02 or less.
  • 0.005 or less is more preferable
  • 0.003 or less is more preferable
  • 0.001 or less is more preferable.
  • the lower limit of the ratio of caffeine / chlorogenic acids is not particularly limited, and may be 0.
  • the mass ratio of caffeine to chlorogenic acids is 0.02 or less, and the content of 5-CQA in the total amount of chlorogenic acids (5 -CQA / total chlorogenic acids) is a green coffee bean extract having a mass of 35% by mass or more. More preferable examples include fresh coffee bean extracts having (caffeine / chlorogenic acids) of 0.001 or less and (5-CQA / total chlorogenic acids) of 35% by mass or more.
  • Chlorogenic acids can improve water solubility and increase physiological effectiveness by making them into salts.
  • the salt of chlorogenic acids used in the present invention is preferably a pharmaceutically acceptable salt.
  • Examples of such basic substances for salt formation include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as magnesium hydroxide and calcium hydroxide. Products; inorganic bases such as ammonium hydroxide; basic amino acids such as arginine, lysine, histidine and ornithine; organic bases such as monoethanolamine, diethanolamine and triethanolamine, of which alkali metals or alkaline earths Metal hydroxides are preferred.
  • chlorogenic acid salts examples include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, organic amine salts such as monoethanolamine, diethanolamine and triethanolamine, arginine, lysine and histidine. And basic amino acid salts such as ornithine. These salts of chlorogenic acids can be extracted from the above-mentioned plants containing chlorogenic acids.
  • chlorogenic acids or salts thereof can be used in the form of a plant extract containing them.
  • a plant extract in addition to the aforementioned plant extract, a commercially available chlorogenic acid-containing preparation may be used.
  • flavor holder RC Hasegawa Fragrance Co., Ltd.
  • fresh coffee bean extract P Oryza Oil Chemicals
  • Svetol manufactured by Nurex Inc.
  • OXCH100 manufactured by Toyo Fermentation Co., Ltd.
  • the present invention provides a Claudin-5 expression promoter comprising chlorogenic acids or salts thereof as an active ingredient. Moreover, this invention provides the brain HMGB1 expression inhibitor which uses chlorogenic acid or its salt as an active ingredient.
  • the present invention also provides a blood brain barrier protective agent comprising chlorogenic acids or salts thereof as an active ingredient.
  • the present invention also provides a preventive or ameliorating agent for lowering the function of the blood brain barrier, comprising chlorogenic acids or salts thereof as an active ingredient.
  • the present invention also provides a preventive or ameliorating agent for diseases or conditions caused by the breakdown of the blood brain barrier, comprising chlorogenic acids or salts thereof as an active ingredient.
  • the present invention is caused by Claudin-5 expression promoter, brain HMGB1 expression inhibitor, blood brain barrier protective agent, blood brain barrier function preventive or ameliorating agent, or blood brain barrier breakdown
  • chlorogenic acids or salts thereof for the prevention or improvement of diseases or conditions.
  • the agent may consist essentially of chlorogenic acids or salts thereof.
  • the agent may be a composition containing at least chlorogenic acids or salts thereof. Examples of the composition include pharmaceuticals, quasi-drugs, and foods described later.
  • the present invention relates to diseases or conditions caused by Claudin-5 expression promotion, brain HMGB1 expression suppression, blood-brain barrier protection, prevention or improvement of blood brain barrier function deterioration, or blood-brain barrier breakdown.
  • Use of chlorogenic acids or salts thereof for the prevention or amelioration of in still another aspect, the present invention relates to a disease or condition caused by Claudin-5 expression promotion, brain HMGB1 expression suppression, blood-brain barrier protection, prevention or improvement of blood brain barrier function deterioration, or blood-brain barrier breakdown.
  • a chlorogenic acid or a salt thereof is provided for use in prevention or amelioration.
  • the use according to the present invention may be a therapeutic use or a non-therapeutic use.
  • therapeutic uses include use for those in need of treatment or amelioration of the disease or condition resulting from the above-mentioned BBB failure.
  • Non-therapeutic use refers to use for a person who has not been diagnosed as having a disease or condition caused by BBB failure by a doctor, including healthy subjects, but who wants to prevent a disease or condition caused by BBB failure, such as the elderly Is mentioned.
  • chlorogenic acids or salts thereof can be used for both human and non-human animals.
  • non-human animals include non-human mammals and birds.
  • non-human mammals include apes, other primates, mice, rats, hamsters, dogs, cats, and companion animals.
  • chlorogenic acids or salts thereof are used to promote Claudin-5 expression, cerebral HMGB1 expression suppression, BBB protection, BBB of pharmaceuticals, quasi drugs or foods (including foods for non-human animals), etc. It can be used as an active ingredient for imparting a function of preventing or ameliorating functional deterioration or preventing or ameliorating a disease or condition caused by BBB failure.
  • the drug (including quasi-drugs) promotes Claudin-5 expression, suppresses HMGB1 expression in the brain, protects the BBB, prevents or ameliorates the decline in BBB function, or prevents or ameliorates a disease or condition caused by the breakdown of the BBB And contains chlorogenic acids or salts thereof as an active ingredient for the function.
  • the pharmaceutical may contain a pharmaceutically acceptable carrier, or other active ingredients, pharmacological ingredients, and the like as necessary.
  • the administration form of the drug may be either oral administration or parenteral administration, but oral administration is preferred.
  • the pharmaceutical dosage form is not particularly limited as long as it is a dosage form that can be administered orally or parenterally.
  • injections, suppositories, inhalants, transdermal absorption agents, various external preparations, tablets, capsules, Any of granules, powders, liquids, syrups and the like, and preparations of such various dosage forms are prepared by using chlorogenic acids or salts thereof as a pharmaceutically acceptable carrier (for example, excipient, binder).
  • Extenders disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, filming agents, diluents, etc.), other medicinal ingredients, etc., in accordance with conventional methods Can be prepared.
  • the content of chlorogenic acids or salts thereof in the drug (including quasi-drugs) is not particularly limited, but is preferably 0.01% by mass or more, more preferably 0.00% or more in terms of chlorogenic acids in the total mass. 1% by mass or more, more preferably 0.5% by mass or more, still more preferably 1.0% by mass or more, still more preferably 10% by mass or more, and preferably 95% by mass or less, more preferably 80% by mass. Hereinafter, it is more preferably 60% by mass or less. Further, examples of the content include 0.01 to 95% by mass, 0.01 to 80% by mass, 0.01 to 60% by mass, 0.1 to 95% by mass, and 0.1 to 80% by total mass.
  • Mass% 0.1-60 mass%, 0.5-95 mass%, 0.5-80 mass%, 0.5-60 mass%, 1.0-95 mass%, 1.0-80 mass% 1.0 to 60% by mass, 10 to 95% by mass, 10 to 80% by mass, and 10 to 60% by mass.
  • the food is a food for providing Claudin-5 expression promotion, brain HMGB1 expression suppression, BBB protection, prevention or improvement of BBB function decline, or prevention or improvement of a disease or condition caused by BBB failure. And containing chlorogenic acids or salts thereof as an active ingredient for the function.
  • the food is based on the concept of promoting Claudin-5 expression, suppressing HMGB1 expression in the brain, protecting the BBB, preventing or improving BBB function decline, or preventing or improving a disease or condition caused by BBB failure.
  • Foods for the sick who have indicated that effect, and functional foods such as functional foods for nutrition, foods for specified health use, functional display foods and the like.
  • the food provided by the present invention includes a beverage. Therefore, the food can be paraphrased as food or drink.
  • the food form may be solid, semi-solid or liquid (eg, a beverage).
  • the food include confectionery such as breads, noodles, rice, and cookies, jelly, dairy products, soups, frozen foods, instant foods, processed starch products, processed fish products, other processed foods, seasonings , Nutritional supplements, and beverages such as tea beverages, coffee beverages, fruit beverages, carbonated beverages, milk beverages, jelly-like beverages, and near water, and their raw materials.
  • the food may be a supplement having the form of an orally administered preparation such as a tablet, capsule, granule, powder, solution, or syrup.
  • the food may contain chlorogenic acids or salts thereof and any food material or food-acceptable additive (eg, solvent, softener, oil, emulsifier, preservative, fragrance, sweetener, stabilizer, colorant, ultraviolet light (Absorbers, antioxidants, humectants, thickeners, fixing agents, dispersants, wetting agents, etc.) can be appropriately combined and prepared according to a conventional method.
  • any food material or food-acceptable additive eg, solvent, softener, oil, emulsifier, preservative, fragrance, sweetener, stabilizer, colorant, ultraviolet light (Absorbers, antioxidants, humectants, thickeners, fixing agents, dispersants, wetting agents, etc.
  • the content of chlorogenic acids or salts thereof in the food is not particularly limited, but is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, and more preferably 0.001% by mass or more in terms of chlorogenic acids in the total mass.
  • it is 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 0.5% by mass or more, still more preferably 1% by mass or more, and preferably 50% by mass or less, more preferably Is 20% by mass or less, more preferably 10% by mass or less.
  • examples of the content include 0.0001 to 50% by mass, 0.0001 to 20% by mass, 0.0001 to 10% by mass, 0.001 to 50% by mass, and 0.001 to 20% in the total mass.
  • Mass% 0.001-10 mass%, 0.01-50 mass%, 0.01-20 mass%, 0.01-10 mass%, 0.1-50 mass%, 0.1-20 mass% 0.1 to 10% by mass, 0.5 to 50% by mass, 0.5 to 20% by mass, 0.5 to 10% by mass, 1 to 50% by mass, 1 to 20% by mass, and 1 to 10% by mass %.
  • the present invention provides a method for promoting Claudin-5 expression in a subject.
  • the present invention also provides a method for suppressing HMGB1 expression in the brain of a subject.
  • the present invention also provides a target BBB protection method.
  • the present invention also provides a method for preventing or improving the functional deterioration of the target BBB.
  • the present invention also provides a method for preventing or ameliorating a disease or condition caused by the target BBB failure.
  • the method includes administering to the subject an effective amount of chlorogenic acids or salts thereof.
  • the method may be a therapeutic method or a non-therapeutic method.
  • Targets in the method of the present invention include promotion of Claudin-5 expression, suppression of HMGB1 expression in the brain, protection of BBB, prevention or improvement of BBB function decline, or prevention or improvement of diseases or conditions resulting from BBB breakdown Or animals that need them.
  • BBB BBB
  • BBB BBB
  • it will not specifically limit if it is an animal which has BBB as an animal, The human and non-human animal mentioned above are mentioned, More preferably, it is a human.
  • the effective amount of administration in the method of the present invention can be an amount that can achieve Claudin-5 expression promotion or brain HMGB1 expression suppression in the subject.
  • the effective amount is an amount that can significantly reduce Claudin-5 expression or brain HMGB1 expression in the administration group compared to the non-administration group.
  • the dose and schedule of chlorogenic acids or salts thereof may be appropriately determined by those skilled in the art according to the species, weight, sex, age, condition, or other factors of the subject.
  • the dose of chlorogenic acids or salts thereof according to the present invention is, for example, preferably 1 mg or more, more preferably 5 mg or more, more preferably 15 mg or more, per adult per day, and Preferably it is 10 g or less, More preferably, it is 5 g or less, More preferably, it is 1 g or less.
  • the above dose is preferably administered continuously for several weeks to several months, for example, once a day, divided into 2 times or 3 times or more. Oral administration is preferred.
  • the present invention also includes the following substances, production methods, uses, methods and the like as exemplary embodiments. However, the present invention is not limited to these embodiments.
  • a Claudin-5 expression promoter comprising chlorogenic acids or salts thereof, or a plant extract containing them as an active ingredient.
  • a brain HMGB1 expression inhibitor comprising chlorogenic acids or salts thereof, or a plant extract containing them as an active ingredient.
  • a blood-brain barrier protecting agent comprising chlorogenic acids or salts thereof, or a plant extract containing them as an active ingredient.
  • a preventive or ameliorating agent for lowering the function of the blood brain barrier comprising chlorogenic acids or salts thereof, or a plant extract containing them as an active ingredient.
  • an agent for preventing or ameliorating a disease or condition caused by the breakdown of the blood-brain barrier comprising a chlorogenic acid or a salt thereof, or a plant extract containing them as an active ingredient.
  • the disease or condition resulting from the breakdown of the blood brain barrier is intracerebral hemorrhage, cerebrovascular disorder, optic neuromyelitis, leukoencephalopathy, acute disseminated encephalomyelitis, inflammatory demyelinating polyneuritis,
  • the agent according to [5] which is at least one selected from the group consisting of brain infection, anaphylaxis, brain tumor, brain / spinal cord trauma, tremor, delirium, abnormal behavior, sleepiness, consciousness disorder, and obsessive-compulsive disorder.
  • the chlorogenic acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-ferroyl.
  • [1] to [1] which are at least one selected from the group consisting of ruquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid.
  • the agent according to any one of [6].
  • the agent is a pharmaceutical or a quasi-drug
  • chlorogenic acids are 0.01 to 95% by mass, 0.01 to 80% by mass, 0.01 to 60% by mass, 0.1 to 95% by mass, 0.1-80% by mass, 0.1-60% by mass, 0.5-95% by mass, 0.5-80% by mass, 0.5-60% by mass, 1.0-95% by mass %, 1.0 to 80% by mass, 1.0 to 60% by mass, 10 to 95% by mass, 10 to 80% by mass, or 10 to 60% by mass, and any one of [1] to [7] Item agent.
  • the agent is a food
  • chlorogenic acids are 0.0001 to 50% by mass, 0.0001 to 20% by mass, 0.0001 to 10% by mass, 0.001 to 50% by mass, 0 0.001 to 20% by mass, 0.001 to 10% by mass, 0.01 to 50% by mass, 0.01 to 20% by mass, 0.01 to 10% by mass, 0.1 to 50% by mass, 0.1 To 20% by weight, 0.1 to 10% by weight, 0.5 to 50% by weight, 0.5 to 20% by weight, 0.5 to 10% by weight, 1 to 50% by weight, 1 to 20% by weight, or The agent according to any one of [1] to [7], which is contained in an amount of 1 to 10% by mass.
  • the raw coffee bean extract is Preferably, a raw coffee bean extract having a mass ratio of caffeine to chlorogenic acids of 0.02 or less and a content of 5-caffeoylquinic acid in the total amount of chlorogenic acids of 35% by mass or more, More preferably, it is a raw coffee bean extract in which the mass ratio of caffeine to chlorogenic acids is 0.001 or less, and the content of 5-caffeoylquinic acid in the total amount of chlorogenic acids is 35% by mass or more.
  • the Claudin-5 expression promoter is used for promoting Claudin-5 expression in a person in need of prevention or amelioration of a disease or condition caused by the breakdown of the blood brain barrier.
  • the HMGB1 expression inhibitor in the brain is used for suppressing HMGB1 expression in the brain in a person in need of prevention or amelioration of a disease or condition caused by the breakdown of the blood brain barrier. Use as described.
  • the blood-brain barrier protecting agent is used for blood-brain barrier protection in a person in need of prevention or amelioration of a disease or condition resulting from the breakdown of the blood-brain barrier.
  • the preventive or ameliorating agent for the blood-brain barrier function prevents or reduces the blood-brain barrier function in a person in need of prevention or amelioration of a disease or condition caused by the breakdown of the blood-brain barrier. The use according to [16], which is used for improvement.
  • the disease or condition resulting from the breakdown of the blood brain barrier is cerebral hemorrhage, cerebrovascular disorder, optic neuromyelitis, leukoencephalopathy, acute disseminated encephalomyelitis, inflammatory demyelinating polyneuritis, [17] to [21], which is at least one selected from the group consisting of brain infection, anaphylaxis, brain tumor, brain / spinal trauma, tremor, delirium, abnormal behavior, sleepiness, consciousness disorder, and obsessive-compulsive disorder Use of any one of these.
  • the chlorogenic acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-ferroyl. [13] to [13], which are at least one selected from the group consisting of ruquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid. 22]. The use according to any one of [22].
  • the agent is a pharmaceutical or a quasi-drug
  • chlorogenic acids are 0.01 to 95% by mass, 0.01 to 80% by mass, 0.01 to 60% by mass, 0.1 to 95% by mass, 0.1-80% by mass, 0.1-60% by mass, 0.5-95% by mass, 0.5-80% by mass, 0.5-60% by mass, 1.0-95% by mass %, 1.0 to 80 mass%, 1.0 to 60 mass%, 10 to 95 mass%, 10 to 80 mass%, or 10 to 60 mass%, any one of [13] to [23] Use as described in section.
  • the agent is a food and chlorogenic acids are 0.0001 to 50% by mass, 0.0001 to 20% by mass, 0.0001 to 10% by mass, 0.001 to 50% by mass, 0 0.001 to 20% by mass, 0.001 to 10% by mass, 0.01 to 50% by mass, 0.01 to 20% by mass, 0.01 to 10% by mass, 0.1 to 50% by mass, 0.1 To 20% by weight, 0.1 to 10% by weight, 0.5 to 50% by weight, 0.5 to 20% by weight, 0.5 to 10% by weight, 1 to 50% by weight, 1 to 20% by weight, or The use according to any one of [13] to [23], which is contained in an amount of 1 to 10% by mass.
  • the raw coffee bean extract is Preferably, a raw coffee bean extract having a mass ratio of caffeine to chlorogenic acids of 0.02 or less and a content of 5-caffeoylquinic acid in the total amount of chlorogenic acids of 35% by mass or more, More preferably, it is a raw coffee bean extract in which the mass ratio of caffeine to chlorogenic acids is 0.001 or less, and the content of 5-caffeoylquinic acid in the total amount of chlorogenic acids is 35% by mass or more.
  • [29] Use of chlorogenic acids or salts thereof, or plant extracts containing them for promoting Claudin-5 expression.
  • [31] Use of chlorogenic acids or salts thereof, or plant extracts containing them for protecting the blood-brain barrier.
  • the chlorogenic acids or salts thereof, or a plant extract containing them promotes Claudin-5 expression in a person in need of prevention or amelioration of a disease or condition resulting from the breakdown of the blood brain barrier.
  • the chlorogenic acids or salts thereof, or a plant extract containing them suppresses HMGB1 expression in the brain in a person in need of prevention or amelioration of a disease or condition resulting from the breakdown of the blood brain barrier.
  • the chlorogenic acids or salts thereof, or a plant extract containing them is used to protect the blood brain barrier in a person in need of prevention or amelioration of a disease or condition caused by the breakdown of the blood brain barrier.
  • the chlorogenic acids or salts thereof, or a plant extract containing them reduces blood brain barrier function in a person in need of prevention or amelioration of a disease or condition caused by blood brain barrier breakdown.
  • the disease or condition resulting from the breakdown of the blood-brain barrier is intracerebral hemorrhage, cerebrovascular disorder, optic neuromyelitis, leukoencephalopathy, acute disseminated encephalomyelitis, inflammatory demyelinating polyneuritis, [33] to [37], which is at least one selected from the group consisting of brain infection, anaphylaxis, brain tumor, brain and spinal cord trauma, tremor, delirium, abnormal behavior, sleepiness, consciousness disorder, and obsessive-compulsive disorder Use of any one of these.
  • the chlorogenic acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-ferroyl. [29] to [29] which are at least one selected from the group consisting of ruquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid. 38]. [40] Preferably, the chlorogenic acids or salts thereof, or the plant extract containing them contains 0.01 to 95% by mass, 0.01 to 80% by mass, 0.01 to 60% by mass of the chlorogenic acids.
  • the chlorogenic acids or salts thereof, or a plant extract containing them contains 0.0001 to 50% by mass, 0.0001 to 20% by mass, 0.0001 to 10% by mass of the chlorogenic acids.
  • the daily dose of the above-mentioned chlorogenic acids or salts thereof, or plant extracts containing them, in terms of chlorogenic acids, is preferably 1 mg or more, more preferably 5 mg or more, and even more preferably 15 mg or more.
  • the use according to any one of [29] to [42], wherein the chlorogenic acids or salts thereof, or a plant extract containing them is preferably administered orally.
  • the use according to any one of [29] to [43], wherein the plant extract is preferably a coffee bean extract, more preferably a fresh coffee bean extract.
  • the green coffee bean extract is Preferably, a raw coffee bean extract having a mass ratio of caffeine to chlorogenic acids of 0.02 or less and a content of 5-caffeoylquinic acid in the total amount of chlorogenic acids of 35% by mass or more, More preferably, it is a raw coffee bean extract in which the mass ratio of caffeine to chlorogenic acids is 0.001 or less, and the content of 5-caffeoylquinic acid in the total amount of chlorogenic acids is 35% by mass or more.
  • the chlorogenic acids or salts thereof according to [48] preferably used for protecting the blood brain barrier in a person in need of prevention or amelioration of a disease or condition caused by the breakdown of the blood brain barrier, or Plant extracts containing them.
  • the disease or condition resulting from the breakdown of the blood-brain barrier is intracerebral hemorrhage, cerebrovascular disorder, optic neuromyelitis, leukoencephalopathy, acute disseminated encephalomyelitis, inflammatory demyelinating polyneuritis, [50] to [54], which is at least one selected from the group consisting of brain infection, anaphylaxis, brain tumor, brain and spinal cord trauma, tremor, delirium, abnormal behavior, sleepiness, consciousness disorder, and obsessive-compulsive disorder
  • the chlorogenic acids or salts thereof according to any one of the above, or a plant extract containing them.
  • the chlorogenic acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-ferroyl. [46] to [46], which are at least one selected from the group consisting of ruquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid. 55] The chlorogenic acids or salts thereof according to any one of [55] or a plant extract containing them.
  • the chlorogenic acids are 0.01 to 95% by mass, 0.01 to 80% by mass, 0.01 to 60% by mass, 0.1 to 95% by mass, 0.1 to 80% by mass, 0.1 to 60% by mass, 0.5 to 95% by mass, 0.5 to 80% by mass, 0.5 to 60% by mass, 1.0 to 95% by mass, 1.0 to 80% by mass, Any one of [46] to [56] used in the form of a pharmaceutical or quasi-drug containing 0 to 60% by mass, 10 to 95% by mass, 10 to 80% by mass, or 10 to 60% by mass A chlorogenic acid or a salt thereof according to Item or a plant extract containing them.
  • the chlorogenic acids are 0.0001 to 50% by mass, 0.0001 to 20% by mass, 0.0001 to 10% by mass, 0.001 to 50% by mass, 0.001 to 20% by mass, 0.001 to 10% by mass, 0.01 to 50% by mass, 0.01 to 20% by mass, 0.01 to 10% by mass, 0.1 to 50% by mass, 0.1 to 20% by mass, 1-10% by mass, 0.5-50% by mass, 0.5-20% by mass, 0.5-10% by mass, 1-50% by mass, 1-20% by mass, or 1-10% by mass
  • the chlorogenic acids or salts thereof according to any one of [46] to [56], which are used in the form of food, or a plant extract containing them.
  • the daily dose per adult is preferably 1 mg or more, more preferably 5 mg or more, more preferably 15 mg or more, and preferably 10 g or less, more preferably 5 g or less, in terms of chlorogenic acids.
  • the chlorogenic acids or salts thereof according to any one of [46] to [60] wherein the plant extract is preferably a coffee bean extract, more preferably a fresh coffee bean extract, or Plant extracts containing them.
  • the green coffee bean extract is Preferably, a raw coffee bean extract having a mass ratio of caffeine to chlorogenic acids of 0.02 or less and a content of 5-caffeoylquinic acid in the total amount of chlorogenic acids of 35% by mass or more, More preferably, it is a raw coffee bean extract in which the mass ratio of caffeine to chlorogenic acids is 0.001 or less, and the content of 5-caffeoylquinic acid in the total amount of chlorogenic acids is 35% by mass or more.
  • a method for promoting Claudin-5 expression comprising administering an effective amount of chlorogenic acids or salts thereof, or a plant extract containing them to a subject in need thereof.
  • a method for suppressing HMGB1 expression in the brain comprising administering an effective amount of chlorogenic acids or salts thereof, or a plant extract containing them to a subject in need thereof.
  • a method for protecting the blood brain barrier comprising administering an chlorogenic acid or a salt thereof, or a plant extract containing them in an effective amount to a subject in need thereof.
  • a method for preventing or improving a decrease in blood-brain barrier function comprising administering an effective amount of chlorogenic acids or salts thereof, or a plant extract containing them to a subject in need thereof .
  • a method for preventing or ameliorating a disease or condition resulting from the breakdown of the blood-brain barrier comprising administering an effective amount of chlorogenic acids or salts thereof, or a plant extract containing them to a subject in need thereof Including the method.
  • the disease or condition resulting from the breakdown of the blood-brain barrier is intracerebral hemorrhage, cerebrovascular disorder, optic neuromyelitis, leukoencephalopathy, acute disseminated encephalomyelitis, inflammatory demyelinating polyneuritis, [67]
  • the method of [67] which is at least one selected from the group consisting of brain infection, anaphylaxis, brain tumor, brain / spinal cord trauma, tremor, delirium, abnormal behavior, sleepiness, consciousness disorder, and obsessive-compulsive disorder.
  • the chlorogenic acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-ferroyl.
  • [63] to [63] which is at least one selected from the group consisting of luquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid. 68].
  • the chlorogenic acids or a salt thereof or a salt thereof, or a plant extract containing them is 0.01 to 95% by mass, 0.01 to 80% by mass, 0.01 to 60% by mass, 0.1-95% by mass, 0.1-80% by mass, 0.1-60% by mass, 0.5-95% by mass, 0.5-80% by mass, 0.5-60% by mass %, 1.0-95% by mass, 1.0-80% by mass, 1.0-60% by mass, 10-95% by mass, 10-80% by mass, or 10-60% by mass [63]
  • the chlorogenic acids or a salt thereof or a salt thereof, or a plant extract containing them contains 0.0001 to 50% by mass, 0.0001 to 20% by mass, 0.0001 to 10% by mass, 0.001-50% by mass, 0.001-20% by mass, 0.001-10% by mass, 0.01-50% by mass, 0.01-20% by mass, 0.01-10% by mass %, 0.1-50 mass%, 0.1-20 mass%, 0.1-10 mass%, 0.5-50 mass%, 0.5-20 mass%, 0.5-10 mass%,
  • the effective amount is preferably 1 mg or more, more preferably 5 mg or more, still more preferably 15 mg or more, and preferably 10 g or less, more preferably 5 g or less, in terms of chlorogenic acids per day per adult.
  • the plant extract is preferably a coffee bean extract, more preferably a fresh coffee bean extract.
  • the green coffee bean extract is Preferably, a raw coffee bean extract having a mass ratio of caffeine to chlorogenic acids of 0.02 or less and a content of 5-caffeoylquinic acid in the total amount of chlorogenic acids of 35% by mass or more, More preferably, it is a raw coffee bean extract in which the mass ratio of caffeine to chlorogenic acids is 0.001 or less, and the content of 5-caffeoylquinic acid in the total amount of chlorogenic acids is 35% by mass or more.
  • the amount of activated carbon used relative to the chlorogenic acid content in the filtrate was 0.81 times by mass (g / g).
  • the amount of ion exchange resin used was 0.74 (mL / g) based on the solid content in the crude chlorogenic acid-containing composition. 5) 1038 g of the column treatment solution was filtered with a 0.2 ⁇ m membrane filter, and then ethanol was distilled off with a rotary evaporator to obtain 225 g of a chlorogenic acid-containing solution.
  • the composition of the chlorogenic acid-containing liquid is 22.6% by mass of chlorogenic acids, 0.29% by mass of caffeine, 0.013 by mass ratio (caffeine / chlorogenic acids), 0% by mass of ethanol, and pH of 3 .1.
  • the chlorogenic acid-containing liquid was diluted with distilled water to adjust the chlorogenic acid concentration to 3% by mass. 10 g of the obtained diluted solution was taken in a centrifuge tube, centrifuged at 3000 rpm, 15 ° C. for 60 minutes, and the supernatant was freeze-dried to obtain purified coffee polyphenol (CPP) containing chlorogenic acids.
  • CPP purified coffee polyphenol
  • the content of 5-caffeoylquinic acid (5-CQA) in the total amount of chlorogenic acids is 45.6% by mass, and monocaffeoylquinic acid and monoferuloylquinic acid (3-CQA, 4-
  • the content of 5-CQA in the total amount of CQA, 5-CQA, 3-FQA, 4-FQA and 5-FQA) was 36.9% by mass.
  • Table 1 shows the composition ratio of chlorogenic acids in the CPP.
  • Test Example 1 Inhibition of HMGB1 expression by chlorogenic acids in healthy mice (animal) C57BL / 6J mice (male, 8 weeks old) (CLEA Japan) were used for the test. Mice were housed at room temperature 22 ⁇ 2 ° C., humidity 55 ⁇ 10%, lighting 12-hour cycle (7:00 am to 7:00 pm), and food and water were ad libitum.
  • Chlorogenic acids 1% food group Feed containing 1% by mass of chlorogenic acids (corn oil 10%, casein 20%, cellulose 4%, minerals 3.5%, vitamin 1%, potato starch 59.5%, manufactured CPP obtained in Example 1 (containing chlorogenic acids with the composition shown in Table 1) 2%)
  • RNA degradation inhibitor RNA later solution, Ambion
  • RNeasy registered trademark Plus Universal Mini kit
  • Quantitative PCR was performed using TaqMan (registered trademark) Fast Universal PCR Master Mix (Applied Biosystems) and ABI Prism 7700 (Applied Biosystems) using the obtained cDNA as a template.
  • TaqMan® Gene used for quantitative PCR was HMGB1: Mm00849805_gH, GAPDH: Mm9999999915_g1.
  • the expression level of the HMGB1 gene was corrected by the expression level of GAPDH (Glyceraldehyde-Phosphate Dehydrogenase) gene. From the measured expression level, a relative expression level with an average value of 1 in the control diet group was determined for each group.
  • Test Example 2 Claudin-5 expression increased by chlorogenic acid intake in healthy mice (method) In the same procedure as in Test Example 1, mice of (I) a control diet group, (II) a chlorogenic acid 0.5% diet group, and (III) a chlorogenic acid 1% diet group were reared for one month, respectively. Total RNA was prepared from cerebral cortex and hippocampus and cDNA was synthesized. Quantitative PCR was performed in the same procedure as in Test Example 1 using the obtained cDNA as a template. TaqMan (R) Gene used for quantitative PCR was Claudin-5: Mm00727012_s1, GAPDH: Mm9999999915_g1. The expression level of Claudin-5 gene was corrected by the expression level of GAPDH gene. From the measured expression level, a relative expression level with an average value of 1 in the control diet group was determined for each group.
  • Test Example 3 Claudin-5 Expression Increase and HMGB1 Expression Suppression by Chlorogenic Acid Intake in Aging Acceleration Model Mouse (animal) Aging-promoting model mouse SAMP8 (male, 12 weeks old) and its control (normal aging) mouse SAMR1 (male, 12 weeks old) (Japan SLC) were used for the test. Mice were housed at room temperature 22 ⁇ 2 ° C., humidity 55 ⁇ 10%, lighting 12-hour cycle (7:00 am to 7:00 pm), and food and water were ad libitum.
  • RNA was prepared from mouse cerebral cortex and hippocampus by the same procedure as in Test Example 1, cDNA was synthesized, and quantitative PCR was performed on HMGB1 and Claudin-5 using this as a template.
  • TaqMan (R) Gene used for quantitative PCR was HMGB1: Mm00849805_gH, Claudin-5: Mm00727012_s1, GAPDH: Mm9999999915_g1.
  • the expression levels of HMGB1 and Claudin-5 gene were corrected by the expression level of GAPDH gene. From the measured expression level, a relative expression level with an average value of 1 in the SAMP8 control diet group was determined for each group.
  • the expression level of Claudin-5 is shown in Table 4.
  • the expression level of Claudin-5 gene in the cerebral cortex of the control diet group mice was significantly higher in the normal aging mouse SAMR1 (group IV) than in the aging promotion model mouse SAMP8 (group I).
  • Claudin-5 gene expression levels in the cerebral cortex of the chlorogenic acid 1% diet group (Group II) and the 5-caffeoylquinic acid 0.8% diet group (Group III) were the same as the SAMP8 control diet group (Group I). The value was significantly high compared.
  • the gene expression level of Claudin-5 was significantly higher in the SAMP8 chlorogenic acid 1% diet group (Group II) than in the SAMP8 control diet group (Group I). From these results, it was shown that chlorogenic acids have the action of suppressing the decrease of Claudin-5 expression due to aging and protecting the blood brain barrier by promoting the expression of Claudin-5.
  • HMGB1 The expression level of HMGB1 is shown in Table 5.
  • the gene expression level of HMGB1 in the cerebral cortex was significantly lower in the SAMR1 control diet group (Group IV) than in the SAMP8 control diet group (Group I).
  • the HMGB1 expression level was significantly decreased compared to the SAMP8 control diet group (Group I). Or there was a downward trend. From these results, it was shown that chlorogenic acids have the action of suppressing the HMGB1 gene expression increase due to aging and protecting the blood brain barrier.

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Abstract

L'invention concerne une substance qui permet d'empêcher une rupture de la barrière hémato-encéphalique. Un promoteur d'expression de Claudin-5 qui comprend de l'acide chlorogénique ou un sel de celui-ci en tant que principe actif. Un inhibiteur d'expression de HMGB1 du cerveau qui comprend de l'acide chlorogénique ou un sel de celui-ci en tant que principe actif. Un agent de protection de barrière hémato-encéphalique qui comprend de l'acide chlorogénique ou un sel de celui-ci en tant que principe actif. Un agent pour prévenir ou améliorer un dysfonctionnement de la barrière hémato-encéphalique, ledit agent comprenant de l'acide chlorogénique ou un sel de celui-ci en tant que principe actif.
PCT/JP2018/017831 2017-05-12 2018-05-08 Agent de protection de barrière hémato-encéphalique Ceased WO2018207792A1 (fr)

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WO2020239356A1 (fr) 2019-05-27 2020-12-03 Organes Tissus Regeneration Reparation Remplacement Composition pour la protection et la reparation de la barriere hematoencephalique (bhe)
FR3096579A1 (fr) 2019-05-27 2020-12-04 Organes Tissus Regeneration Reparation Remplacement composition pour la protection et la reparation de la barriere hematoencephalique (BHE)
JP2022534278A (ja) * 2019-05-27 2022-07-28 オルガンズ ティシューズ リジェネレーション リパレーション レムプレースメント － オーティーアール３ 血液脳関門（ｂｂｂ）の保護及び修復のための組成物
JP7578621B2 (ja) 2019-05-27 2024-11-06 オルガンズ ティシューズ リジェネレーション リパレーション レムプレースメント － オーティーアール３ 血液脳関門（ｂｂｂ）の保護及び修復のための組成物

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