WO2015068832A1 - Composition pour prévenir/traiter la démence et/ou améliorer la fonction cognitive, et médicament et aliments l'utilisant - Google Patents

Composition pour prévenir/traiter la démence et/ou améliorer la fonction cognitive, et médicament et aliments l'utilisant Download PDF

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WO2015068832A1
WO2015068832A1 PCT/JP2014/079684 JP2014079684W WO2015068832A1 WO 2015068832 A1 WO2015068832 A1 WO 2015068832A1 JP 2014079684 W JP2014079684 W JP 2014079684W WO 2015068832 A1 WO2015068832 A1 WO 2015068832A1
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dementia
microglia
alkyl group
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泰久 阿野
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キリン株式会社
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    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

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  • the present invention relates to a composition that improves the prevention, treatment, and / or cognitive function of dementia by enhancing the activity of microglia, and a pharmaceutical and functional food using the same.
  • Microglia are activated by infection, trauma and inflammation in the brain, and change to activated microglia, which can be responsible for various physiological functions such as antigen presentation to T cells, bactericidal activity, antitumor activity, tissue repair, etc. Are known. Microglia removes dead cells and foreign bodies due to apoptosis and damage by phagocytosis.
  • Non-patent Document 1 a brain immune system centered on microglia.
  • microglia plays a very important role in maintaining homeostasis and neuronal network in the brain, and has the effect of removing phagocytosis of old synapses and accompanying synapse formation (non-patent literature). 2).
  • Non-patent Document 3 the reactivity of microglia changes in various diseases such as neurological diseases with neurodegeneration such as Alzheimer's disease and Parkinson's disease and cerebral infarction. These diseases that accompany dementia with neurodegeneration are all social problems due to the arrival of an aging society.
  • the number of elderly people with dementia is estimated to be 46,220,000 by the Ministry of Health, Labor and Welfare's research team, and 15% of those aged 65 and over.
  • the increase in elderly people with dementia has become a major social problem, including the development of an environment where elderly people with dementia can live with peace of mind, including medical and nursing care problems.
  • dementia since dementia is difficult to treat when it develops, its prevention is a major issue.
  • dementia refers to a condition in which normal cognitive function once declined sustainably due to an acquired brain disorder, causing problems in daily life and social life. It is a pathological condition accompanied by symptoms such as memory impairment and disorientation, and is caused by organic changes in the brain based on Alzheimer's disease, cerebrovascular disease, and other factors.
  • Alzheimer's dementia is the most common type of dementia along with cerebrovascular dementia and Lewy body disease.
  • amyloid ⁇ deposits called senile plaques are found in the cerebral cortex, and therefore accumulation of amyloid ⁇ in the brain has been considered to be the cause of Alzheimer's disease (Non-Patent Documents). 4). Therefore, it is believed that a substance that reduces the accumulation of amyloid ⁇ in the brain will be a potential therapeutic drug candidate for Alzheimer's disease.
  • no fundamental therapeutic agent has been found for Alzheimer-type dementia.
  • Amyloid ⁇ is produced even in healthy individuals regardless of the presence or age of Alzheimer's disease. However, in normal brain, amyloid ⁇ is properly removed and does not accumulate. In Alzheimer's disease patients, amyloid ⁇ production, deposition, and removal occur in parallel. Therefore, if a substance capable of removing amyloid ⁇ from the brain can be found, it can be used for prevention and treatment of Alzheimer's dementia.
  • Non-Patent Documents 5 and 6 Non-Patent Documents 5 and 6
  • Microglia is also involved in the removal of amyloid ⁇ which has become insoluble and deposited extracellularly. Insolubilized and deposited amyloid ⁇ has undergone opsonization by complement activation. Microglia expresses complement receptors and IgG receptors, and are thought to be involved in phagocytosis of amyloid ⁇ via opsonin (Non-patent Document 7).
  • JP 2010-018631 A International Publication No. 2006/068117 International Publication No. 2006/043671 JP 2013-124237 A
  • An object of the present invention is to provide a pharmaceutical and a food that activates the immune system in the brain and enhances dementia by enhancing microglia activity.
  • Non-patent Document 8 The results of epidemiological studies show that although large amounts of alcohol increase the risk of dementia, small to moderate alcohol consumption does not cause dementia but also prevents dementia. According to a survey on drinking of elderly people and the risk of dementia, assuming that the risk of dementia in a group of people who do not drink is converted to 350 ml of beer, about 1 to 6 drinks per week In the group, the risk of dementia is about 0.4 and less than half (Non-patent Document 8).
  • microglia can be removed even if it is aggregated and insolubilized to form amyloid ⁇ . Therefore, microglia's phagocytosis-removing activity is used as an index to prevent, treat, and treat symptoms.
  • substances that are effective for improvement were searched for substances that are effective for improvement.
  • microglia phagocytosis can be activated, brain waste such as amyloid ⁇ and foreign substances can be removed, synapses of old neurons can be removed, and synapses can be renewed, so that not only Alzheimer's disease but also microglia Other neurodegenerative diseases such as Parkinson's disease, which is said to be involved, can be expected to lead to disease prevention, symptom improvement and treatment.
  • the active ingredient is represented by the formula (I): [Wherein R 1 and R 2 represent a C 1-6 alkyl group or a C 2-6 alkenyl group, and R 3 and R 4 represent a hydroxyl group, a C 1-6 alkyl group, or a C 2-6 alkenyl group. R 3 and R 4 do not represent a hydroxyl group at the same time.
  • an isomerized hop extract obtained by isomerizing a hop extract extracted from hop spikelets contains a substance that enhances microglia activity.
  • Hop (scientific name: Humulus luplus) is a creeping perennial plant of the family Asapidae, and the cocoon that matured on the female flower is known as one of the ingredients of beer. Hops are rich in substances having various functions such as a healthy stomach, a sedative effect, a sleep-and-sleep effect, increased appetite, and improved lipid metabolism. Therefore, it has been used as a crude drug and a folk medicine.
  • the knowledge that the isomerized hop extract contains a substance that enhances the activity of microglia has not been reported so far. Furthermore, no drug has been reported so far that removes foreign substances in the brain by activating microglia to prevent or treat dementia and improve cognitive function.
  • the present inventors are the first to show that an active ingredient contained in isomerized hop extract activates microglia to remove foreign substances in the brain, prevent dementia, improve treatment, and improve cognitive function. I found it.
  • the compound represented by the above chemical formula is a compound contained in an isomerized hop extract and a derivative thereof (Patent Document 1). Therefore, by extracting or synthesizing these compounds, a compound that enhances the activity of microglia and prevents, treats, and improves cognitive function of dementia can be obtained.
  • composition for preventing or treating dementia and / or improving cognitive function of the present invention is characterized in that the active ingredient is contained in an isomerized hop extract.
  • the component contained in the isomerized hop extract contains a component that enhances microglia activity.
  • the compound contained in the isomerized hop extract is an ingredient originally contained in foods such as beer, and can be safely ingested without worrying about side effects.
  • the active ingredient is isohumulones, or a pharmacologically acceptable salt or solvate thereof.
  • the active ingredients contained in the isomerized hop extract are collectively referred to as isohumulones.
  • the humulonic acid contained in the hop spikelets is converted into isohumulone, which is a bitter component of beer, in the brewing process of beer.
  • Isohumulones are known to have various functions such as lipid metabolism improvement. However, the present inventors have found for the first time a function that enhances the activation of microglia and prevents, treats and / or improves the cognitive function of dementia. Isohumulones contained in the isomerized hop extract have a function of preventing and treating dementia and / or improving cognitive function by activating microglia. Therefore, application to medicines and functional foods becomes possible.
  • composition for preventing, treating and / or improving cognitive function of dementia of the present invention is further applied to docosahexaenoic acid (DHA), which is an omega-3 fatty acid, arachidonic acid (ARA), which is an omega-6 fatty acid, and the like. It is characterized by containing a polyunsaturated fatty acid (PUFA) represented.
  • DHA docosahexaenoic acid
  • ARA arachidonic acid
  • PUFA polyunsaturated fatty acid
  • the microglia is synergistically activated by adding PUFA to the composition.
  • PUFA is known to have an action of improving brain development, memory, and learning function
  • the present inventors have found for the first time that isohumulones and DHA which is PUFA act synergistically.
  • isohumulones and DHA which is PUFA act synergistically.
  • both are substances originally contained in food, there is no concern about side effects or the like due to continuous intake.
  • composition for preventing or treating dementia and / or improving cognitive function of the present invention is characterized by acting as a microglia activity enhancer.
  • the composition of the present invention activates microglia in the brain by animal experiments by ingestion. Therefore, it is possible to remove waste products, foreign substances, and dead cells produced in the brain. As a result, not only Alzheimer's disease, but also the prevention of various diseases associated with neurodegeneration and the improvement of symptoms can be expected by removing foreign substances and the like due to enhanced microglia activity.
  • Other neurodegenerative diseases that can be expected to improve symptoms or have therapeutic effects by the composition of the present invention include Creutzfeldt-Jakob disease, Parkinson's disease and the like.
  • the medicament or food for preventing or treating dementia of the present invention and / or improving cognitive function has an active ingredient of formula (I): [Wherein R 1 and R 2 represent a C 1-6 alkyl group or a C 2-6 alkenyl group, and R 3 and R 4 represent a hydroxyl group, a C 1-6 alkyl group, or a C 2-6 alkenyl group. R 3 and R 4 do not represent a hydroxyl group at the same time.
  • the medicament or food for preventing, treating and / or improving cognitive function of dementia according to the present invention is characterized in that the active ingredient is contained in an isomerized hop extract.
  • the compound that prevents or treats dementia by improving microglia activity and / or improves cognitive function is a component contained in foods such as beer. It shows that it can be widely used as a sex food. Alzheimer's disease is said to start accumulating amyloid ⁇ more than 20 years before onset. It can be expected to prevent or delay the onset of Alzheimer's disease by continuously ingesting the functional food containing the composition of the present invention before the onset of Alzheimer's disease.
  • the active ingredient is isohumulones, or a pharmacologically acceptable salt or solvate thereof.
  • isohumulones contained as a bitter component of beer have a high microglia activation ability. Therefore, foods such as beer that originally contain isohumulones are considered to contribute to the prevention, treatment, and improvement of cognitive function of dementia. Furthermore, it is possible to promote the development of foods with enhanced isohumulones and enhanced functions.
  • the medicament or food for preventing, treating and / or improving cognitive function of dementia according to the present invention further comprises PUFA as an active ingredient. It is because it has a synergistic effect by combining with PUFA.
  • the medicament or food for preventing or treating dementia and / or improving cognitive function according to the present invention is characterized in that the active ingredient acts as a microglia activity enhancer.
  • composition of the present invention activates brain microglia. Therefore, it is suggested that foreign substances such as amyloid ⁇ produced in the brain are removed, thus preventing, treating, and improving the symptoms of various neurodegenerative diseases including Alzheimer's disease. I can expect that.
  • composition of the present invention as a functional food as well as a medicine is useful for prevention of dementia, especially Alzheimer type dementia.
  • the figure which shows CD36 expression increase of microglia by an isomerization hop extract.
  • the present inventors have found that isohumulones, which are bitterness components derived from hops, have an action of enhancing microglia activity. Isohumulones have been shown to be useful for the treatment of renal disorders associated with hypertension and for the treatment of diseases that can be treated by the activation of the transcription factor Nrf2, improvement of symptoms, lipid metabolism, and autonomic regulation. (Patent Documents 1 to 4). However, the present inventors have found for the first time that microglial activity is enhanced. Thereby, it is possible to provide compositions, medicines, and foods that improve prevention, treatment, and symptoms of neurodegenerative diseases, particularly dementia, which can be expected to be prevented and improved by enhancing microglia activity.
  • composition refers to the compounds represented by the formulas (I) to (V), isohumulones contained in the isomerized hop extract, or pharmaceutically acceptable salts or solvates thereof.
  • This composition is expected to prevent, treat, and / or improve symptoms associated with neurodegeneration, such as Alzheimer's dementia, Creutzfeldt-Jakob disease, etc., by microglial activation.
  • some of the above formulas (I) to (V) may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like. Including all possible isomers and mixtures thereof.
  • the pharmaceutically acceptable salts of the compounds represented by the formulas (I) to (V) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts. And amino acid addition salts.
  • Examples of the pharmaceutically acceptable acid addition salts of the compounds represented by the formulas (I) to (V) include inorganic acid salts such as hydrochloride, sulfate and phosphate, acetates, maleates, and fumarates.
  • Organic acid salts such as acid salts, citrate salts, methanesulfonate salts, etc.
  • pharmaceutically acceptable metal salts include alkali metal salts such as sodium salts and potassium salts, alkali salts such as magnesium salts and calcium salts, for example.
  • Examples include earth metal salts, aluminum salts, zinc salts, and the like, and pharmaceutically acceptable ammonium salts such as ammonium and tetramethylammonium salts, and pharmaceutically acceptable organic amine addition salts. Examples thereof include addition salts such as morpholine and piperidine.
  • Examples of pharmaceutically acceptable amino acid addition salts include addition salts such as lysine, glycine and phenylalanine. It is. *
  • “medicament” includes compounds represented by formulas (I) to (V) or isohumulones contained in isomerized hop extract as an active ingredient, and includes a carrier, excipient, binder, It can be produced by mixing a diluent or the like. It can be administered orally or parenterally, and when administered orally, it may be in any form such as granules, powders, tablets, pills, capsules, syrups and the like. Examples of parenteral dosage forms include, but are not limited to, external preparations such as injections, drops, and nasal preparations.
  • one or more active ingredients may be further added in addition to the active ingredient according to the present invention.
  • PUFA is said to improve brain development, memory and learning ability.
  • DHA exhibits a synergistic effect on microglia activity when added with an isomerized hop extract.
  • a synergistic effect can be expected by adding a PUFA such as DHA.
  • the compounds represented by the formulas (I) to (V) or pharmaceutically acceptable salts or solvates thereof vary depending on the dosage form, patient age, body weight, nature or severity of the symptoms to be treated, etc., but usually oral, 0.01 mg to 1 g per adult, preferably 0 Administer 05-100 mg once or several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.
  • the “food” is anything other than pharmaceuticals, as long as it is ingestible, there is no particular limitation on the form thereof, and it may be liquid, semi-liquid, or solid, Also includes beverage-like forms.
  • “food” includes health foods, functional foods, foods for specified insurance, dietary supplements, foods with a disease risk reduction label, foods for the sick, and so-called supplements. .
  • Typical foods containing known isomerized hop extract include beverages such as beer, non-alcohol beer, and sparkling liquor. These beverages already contain a certain amount or more of the active ingredient in the present invention. These foods are not simply added with a hop component, but are added through a process of isomerizing the hop component. Therefore, a beverage such as beer can be used as a food containing the active ingredient of the present invention. Furthermore, the effect can be enhanced by adding the active ingredient of the present invention.
  • isohumulones contained as a main component in the isomerized hop extract include isohumulone, isoadhumulone, isocohumulone, isoposthumulone, isoprehumulone, tetrahydroisohumulone, alloisohumulone, paraisohumulone, humunilic acid, hexahydroisohumulone. , Anti-isohumulone, and fupon, etc. are included, but any known one can be used without particular limitation.
  • a brain tissue dispersion is obtained by removing the brain from the mouse and performing papain treatment. After papain reaction was stopped, microglia was reacted using anti-CD11b (Miltenyi Biotec), which is a pan-microglia marker labeled with microbeads, and isolated using the MACS method.
  • anti-CD11b Miltenyi Biotec
  • the cultured microglia cells are cultured for 12 hours in a medium supplemented with various candidate substances. Thereafter, evaluation was carried out by measuring the phagocytic activity of microglia and the expression of CD36, which is a cell surface marker correlated with the activation of microglia, and screening of candidate substances was performed.
  • FIG. 1A it was shown that the phagocytic activity of microglia was enhanced even by treatment with an isomerized hop extract at a very low concentration of 50 nM.
  • CD36 a cell surface marker known to increase in expression when the phagocytic ability of microglia is enhanced.
  • the isolated mouse microglia cells are treated with a medium supplemented with isomerized hop extract to a concentration of 0.05 to 10 ⁇ M for 12 hours.
  • the expression of CD36 in the CD11b positive cells after the treatment was analyzed using an APC-labeled anti-CD36 antibody (eBioscience). The results are shown in FIG. 1B.
  • the brain was removed from the mouse, and microglia was purified as described above.
  • the purified microglia was seeded on a cell culture plate, and then cultured for 12 hours in a medium containing various concentrations of isomerized hop extract.
  • labeled dextran molecular weight 10,000, pHrodoRed dextran, manufactured by MolecularProbe
  • the fluorescence after 60 minutes is micronized. Measured with a plate reader. The result is shown in FIG. 2A.
  • microglia was purified in the same manner as described above, treated with various concentrations of isomerized hop extract, and then fluorescent-labeled latex beads having a diameter of 1 ⁇ m were added to the medium. Three hours later, the number of latex beads incorporated into cells existing per field was counted by a fluorescence microscope, and the average number of beads incorporated per cell was determined. Results are shown in FIG. 2C.
  • microglia treated with isomerized hop extract have enhanced phagocytic activity against various substances such as dextran, Escherichia coli and latex beads. That is, it is recognized that the microglia activated by the isomerized hop extract has enhanced phagocytic ability not only for amyloid ⁇ but also for foreign substances in general.
  • Alzheimer type dementia due to accumulation of amyloid ⁇ but also other neurodegenerative diseases in which the involvement of microglia is suggested, leading to prevention, improvement of symptoms and treatment.
  • neuronal synapse formation promoting action can be expected.
  • ARA which is abundant in eggs and meat, is abundant as phospholipids, and is especially contained in the brain. It is also shown to be an essential fatty acid that is closely related to brain functions such as thinking and memory.
  • omega-3 fatty acids such as DHA and eicopentaneenoic acid (EPA) are abundant in fish and are important for maintaining the fluidity of cell membranes.
  • DHA is said to maintain the flexibility of nerve cell membranes, increase dendrites, promote axon growth, and keep the brain and nervous system normal. It has also been reported that DHA is effective against Alzheimer-type dementia.
  • DHA was added to 0 nM and 125 nM medium in the presence of isomerized hop extract 0 nM and 100 nM to microglia isolated from mice, and the phagocytic ability of microglia was evaluated after culturing for 12 hours. The results are shown in FIG.
  • mice After 6-week-old mice were orally administered isomerized hop extract 4 mg / kg, 20 mg / kg, or only the solvent daily for 4 days, microglia were isolated, and microglia's phagocytic activity CD36 expression analysis was performed to evaluate microglial activation.
  • FIG. 4A shows the results of analyzing the phagocytic ability of microglia collected after oral administration of isomerized hop extract for 4 days using amyloid ⁇ labeled with FAM.
  • FIG. 4B is an analysis of CD36 expression, which is an indicator of activated microglia, by FACS.
  • microglia is observed with the administration of isomerized hop extract. Not only in experiments using cultured cells but also when administered orally, the increase in microglia activation by isomerized hop extract indicates that sufficient effects can be obtained even when ingested as a food. .
  • microglia is activated by treatment with isomerized hop extract.
  • Purified microglia is seeded on a plate, and isomerized hop extract (IHE), trans-iso-N-humulone (tIH), cis-iso-N-humulone (cIH) is added to the medium to a concentration of 200 nM, After culturing for hours, FAM-labeled amyloid ⁇ was added. The uptake of amyloid ⁇ 4 hours after adding amyloid ⁇ was measured by the amount of fluorescence.
  • IHE isomerized hop extract
  • tIH trans-iso-N-humulone
  • cIH cis-iso-N-humulone
  • FIG. 5 shows the fluorescence amount of cells cultured with addition of isohumulone as a ratio to the fluorescence amount of cells cultured with a medium to which only a solvent is added.
  • trans-iso-N-humulone and cis-iso-N-humulone have an effect of enhancing microglia phagocytic ability.
  • trans-iso-N-humulone was found to have a stronger effect of activating microglia than cis-iso-N-humulone.
  • composition of the present invention is a substance originally contained in food, a constant preventive effect can be expected by continuously ingesting it as food. In addition, it would be possible to ingest it continuously as a functional food with enhanced active ingredients.
  • microglia eliminates waste and dead cells by phagocytosing foreign bodies and dead cells in the brain.
  • NNF nerve growth factor
  • BDNF neurotrophic factor
  • activated microglia not only removes waste and dead cells in the brain, but also plays a role in growing and enhancing neural synapses. Therefore, it is considered that by enhancing the activation of microglia, the nerve synapse is enhanced and the cognitive function is also restored.
  • Developed and marketed dementia drugs are mainly drugs that act on neurotransmitter receptors. Therefore, it was difficult to fundamentally treat dementia.
  • a compound capable of eliminating foreign substances can be an unprecedented new type of drug that can enhance neural synapse and restore cognitive function. That is, the composition of the present invention not only removes waste in the brain, but also promotes neurogenesis, so that it can be expected to treat dementia, which has been said to be difficult to treat, and improve symptoms. it can.

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Abstract

　L'invention concerne une composition, un médicament, et des aliments pour prévenir, traiter et améliorer les symptômes de démence. On a découvert qu'un composant contenu dans un extrait de houblon isomérisé active la microglie. L'augmentation de l'activation de la microglie élimine la matière étrangère, les cellules mortes, et d'autres dans le cerveau et permet de fournir une composition, un médicament et des aliments pour prévenir, traiter et améliorer les symptômes de démence. De plus, il a été montré que l'ajout de DHA à ce composant potentialise de manière synergique l'activation de la microglie.
PCT/JP2014/079684 2013-11-11 2014-11-10 Composition pour prévenir/traiter la démence et/ou améliorer la fonction cognitive, et médicament et aliments l'utilisant WO2015068832A1 (fr)

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EP3443973A4 (fr) * 2016-04-12 2019-11-27 Kirin Holdings Kabushiki Kaisha Composition pour améliorer les fonctions de reconnaissance

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