WO2019167297A1 - AMYLOID β PROTEIN PRODUCTION INHIBITOR - Google Patents

AMYLOID β PROTEIN PRODUCTION INHIBITOR Download PDF

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Publication number
WO2019167297A1
WO2019167297A1 PCT/JP2018/024488 JP2018024488W WO2019167297A1 WO 2019167297 A1 WO2019167297 A1 WO 2019167297A1 JP 2018024488 W JP2018024488 W JP 2018024488W WO 2019167297 A1 WO2019167297 A1 WO 2019167297A1
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extract
lavender
rosemary
lemon
orange
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PCT/JP2018/024488
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French (fr)
Japanese (ja)
Inventor
八郎 杉本
充顕 奥田
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グリーン・テック株式会社
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Publication of WO2019167297A1 publication Critical patent/WO2019167297A1/en

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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 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/125—Camphor; Nuclear substituted derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/14—Preparations for removing make-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/10—Washing or bathing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners

Definitions

  • the present invention relates to an amyloid ⁇ protein production inhibitor and a tau protein phosphorylation inhibitor.
  • Patent Document 1 is selected from the group consisting of Red Kidney Beans, Guava, Fermented Guava, Ghetto, Fermented Ghetto, Oregano, Basil, Lemon Verbena, Hermanus, Aosa, Marjoram, Ginnemu, Fermented Ginnemu, Kobimikan and Gymnema Sylvestre. It is disclosed that a plant body of one or more plants or a processed product thereof or an extract thereof has an aggregation inhibitory action on amyloid ⁇ protein and / or a degradation action on aggregated amyloid ⁇ protein. And it is disclosed that the said processed material and extract are used as oral preparations, such as a tablet, a powder, a granule, and parenteral preparations, such as an injection, a drip, a cream, and a suppository.
  • oral preparations such as a tablet, a powder, a granule, and parenteral preparations, such as an injection, a drip, a cream, and a suppository
  • Non-Patent Documents 1 and 2 include, as a technique using plant essential oil, aromatherapy for Alzheimer's disease patients by combining rosemary camphor oil and lemon oil, and authentic lavender oil and orange oil. It has been reported that the function of nerves in the brain is improved through olfactory stimulation and the cognitive function is improved.
  • the present invention relates to an amyloid ⁇ protein production inhibitor, an inhibitor that inhibits tau protein phosphorylation, a method for reducing amyloid ⁇ protein, and a method for inhibiting tau protein phosphorylation.
  • the present inventors have been able to reduce the amount of amyloid ⁇ protein produced in the brain by using a specific essential oil in combination, and also inhibit phosphorylation of tau protein The present inventors have found that this can be done and have completed the present invention.
  • the present invention relates to the following [1] to [10].
  • An amyloid ⁇ protein production inhibitor comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  • a tau protein phosphorylation inhibitor comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  • Agent [4] The agent according to any one of [1] to [3] above, wherein the rosemary extract is rosemary camphor and the lavender extract is authentic lavender.
  • a composition comprising the agent according to any one of [1] to [7].
  • a method for inhibiting phosphorylation of tau protein comprising inhaling one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  • the present invention also includes the following embodiments [11] to [15].
  • [11] A brain-derived neurotrophic factor (BDNF) production promoter comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange .
  • BDNF brain-derived neurotrophic factor
  • [12] Alzheimer's disease, Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive nuclei including the step of administering the agent according to any one of [1] to [7] Paralysis, cerebral cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage and A method for preventing and / or treating a disease selected from ischemic brain injury.
  • ischemic brain injury A method for preventing and / or treating a disease selected from ischemic brain injury.
  • Alzheimer's disease Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal Rosemary for the prevention and / or treatment of diseases selected from leaf degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage
  • diseases selected from leaf degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage
  • Use of one or more extracts selected from the group consisting of lemon, lavender and orange.
  • Alzheimer's disease Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal
  • a prophylactic and / or therapeutic agent for a disease selected from leaf degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage
  • the production inhibitor of amyloid ⁇ protein of the present invention is excellent in the effect of reducing the content of amyloid ⁇ protein itself, and thus can also suppress polymerization, aggregation and accumulation of amyloid ⁇ protein.
  • the phosphorylation inhibitor of tau protein of the present invention is excellent in the effect of inhibiting phosphorylation of tau protein, and thus can also suppress aggregation and accumulation of phosphorylated tau protein. Therefore, the inhibitor of the present invention can exert a preventive or therapeutic effect on diseases associated with amyloid ⁇ protein and phosphorylated tau protein, for example, diseases such as Alzheimer's disease and tauopathy.
  • diseases associated with amyloid ⁇ protein and phosphorylated tau protein for example, diseases such as Alzheimer's disease and tauopathy.
  • BDNF brain-derived neurotrophic factor
  • FIG. 1 shows the results of examining the influence of aromatherapy on cognitive function.
  • FIG. 2 shows the results of examining the effect of aromatherapy on the amount of amyloid ⁇ protein in the brain.
  • FIG. 3 shows the results of examining the effect of aromatherapy on phosphorylation of tau protein in the brain.
  • FIG. 4 shows the results of examining the effect of aromatherapy on BDNF in the brain.
  • FIG. 5 shows the results of examining the influence of aromatherapy on motor function.
  • the production inhibitor of amyloid ⁇ protein and the phosphorylation inhibitor of tau protein of the present invention comprise one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange as active ingredients.
  • these inhibitors may be collectively referred to as the inhibitor of the present invention, and these extracts may be collectively referred to as the extract of the present invention.
  • Alzheimer's disease is a neurodegenerative disease characterized by the formation of senile plaques composed of amyloid ⁇ protein and neurofibrillary tangles composed of tau protein, and brain atrophy accompanied by these changes.
  • Amyloid ⁇ protein causes dysfunction by forming protein aggregates and depositing them in tissues, but amyloid ⁇ protein itself has a cytotoxic effect together with the aggregates, thus inhibiting the production of amyloid ⁇ protein itself This is expected as a treatment for Alzheimer's disease.
  • Phosphorylated tau protein is also known as a protein that deposits in tissues and causes dysfunction. However, tau protein itself is abundant in central neurons and constitutes the neural network of the brain. Inhibition of phosphorylation is also considered effective for the treatment of Alzheimer's disease.
  • factors that increase the risk of onset and progression of Alzheimer's disease include aging, obesity, diabetes, hypertension, hyperlipidemia, lack of sleep, lack of exercise, excessive drinking and smoking, and trauma to the head. . Presuming from these risk factors, the onset and progression of Alzheimer's disease involves amyloid ⁇ protein and tau protein, such as neuronal cell function decline due to a decrease in cerebral blood flow and ability to metabolize sugar and lipid, or neuronal cell damage due to chronic inflammation. There may be routes that are not directly involved. Therefore, in order to suppress the onset and progression of Alzheimer's disease, it is necessary to consider various routes.
  • the present inventors have focused on nerve cells and found that exposure of the extract of the present invention inhibits amyloid ⁇ protein production and tau protein phosphorylation.
  • aroma components stimulate the hypothalamus that regulates the autonomic nervous system and endocrine system via the olfactory nerve, and neurotransmitters such as acetylcholine and noradrenaline are released, thereby relaxing and refreshing.
  • the extract of the present invention acts on nerve cells in the brain via the olfactory nerve or one of the extracts. It is presumed that the part is absorbed from the nasal mucosa and directly acts on nerve cells in the brain, thereby producing effects such as production inhibition / degradation removal of amyloid ⁇ protein and phosphorylation inhibition of tau protein.
  • the extract also increases brain-derived neurotrophic factor (BDNF) and promotes neurogenesis, growth, differentiation and regeneration of neurons.
  • BDNF brain-derived neurotrophic factor
  • the extract of the present invention acts directly on nerve cells as described above, and the function of the nerve cells is indirectly improved by an increase in cerebral blood flow through improvement of the autonomic nervous system.
  • the extract of the present invention is expected to have an inhibitory effect not only on amyloid ⁇ protein and tau protein, which are the factors causing the onset and progression of Alzheimer's disease, but also on all other pathways.
  • the extract since the extract has an inhibitory effect on any of amyloid ⁇ protein, tau protein, and other pathways, it can also exert an effect of suppressing the onset and progression of diseases via these pathways. Be expected. However, these assumptions do not limit the present invention.
  • the extract of the present invention is an extract of one or more kinds of plants selected from the group consisting of rosemary, lemon, lavender and orange, and is obtained by subjecting these plants to artificial treatment.
  • essential oils for example, steam distillate, squeezed liquid, pressed product, solvent extract, supercritical fluid extract
  • these plants may be individually treated or collectively treated.
  • the processing method may be the same or different.
  • the extract of the present invention include, for example, rosemary extract, lemon extract, lavender extract and orange extract, rosemary essential oil, lemon essential oil, lavender essential oil and orange. Embodiments containing the essential oils can be used.
  • Rosemary, lemon, lavender and orange can be used without particular limitation as long as they are known.
  • the production area and variety are not particularly limited.
  • rhizomes, leaves, fruits, seeds, flowers or whole plants can be used, and these can be used as processed products such as cut products, crushed products, and dried products.
  • the extraction method is not particularly limited, and examples thereof include a method in which the aforementioned plant is extracted with a solvent according to a known method and the solvent is distilled off.
  • the extraction solvent examples include lower alcohols (methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, etc.), polyhydric alcohols (ethylene glycol, propylene glycol, 1,3-butylene glycol, etc.), ketones (acetone , Methyl ethyl ketone, etc.), ether (dioxane, methyl ethyl ether, diethyl ether, etc.), halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.), polar solvents (dimethylformamide, dimethyl sulfoxide, etc.), ethyl acetate, toluene, n -Various organic solvents such as hexane and petroleum ether, or water can be used alone or in combination of two or more. When combining, the ratio can be appropriately adjusted.
  • organic solvents such as hexane and petroleum ether,
  • the extraction temperature cannot be set unconditionally depending on the solvent used, plant part / morphology, etc., but from the viewpoint of extraction efficiency, the lower limit may be 4 ° C. and the upper limit may be 150 ° C.
  • the upper limit value and the lower limit value can be appropriately set within the above-described temperature range, for example, 10 ° C., 15 ° C., 20 ° C., 30 ° C., 40 ° C., 60 ° C., 80 ° C., 100 °C, 120 °C, 140 °C etc. can be set as the upper limit value or the lower limit value.
  • the extraction time can be appropriately set according to the amount of raw material used for extraction and the apparatus.
  • the extract obtained by extraction is subjected to one or more treatments selected from the group consisting of filtration, centrifugation, concentration, dilution, ultrafiltration, lyophilization, powdering and fractionation. You may carry out according to a well-known method. If necessary, the treatment can be performed under normal pressure or reduced pressure.
  • the obtained extract may be volatile at temperatures near body temperature.
  • the extract used in the present invention may be one prepared by the known extraction method described above or a commercially available product.
  • Commercially available aroma oil may be used.
  • examples of the rosemary extract include rosemary cineole, rosemary camphor, rosemary berbenone, and the like, but rosemary camphor can be preferably used.
  • examples of lavender include authentic lavender, lavender stoecas, lavender spica, lavender raid van, lavender super, and the like, but authentic lavender can be preferably used.
  • the shape of the extract of the present invention is not particularly limited, and may be any of powder, solid, and liquid. Moreover, when using an individual extract, the shape may be the same or different.
  • the inhibitor of the present invention contains, as an active ingredient, one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  • one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  • rosemary, lemon, lavender and orange The total content of the extract is not particularly limited, and examples thereof include 0.01 to 100% by weight.
  • the content ratio of each extract cannot be set unconditionally depending on the shape of the extract or the extraction method, and can be appropriately adjusted according to common general technical knowledge.
  • An example is shown below.
  • Specific content ratio (volume ratio) of each extract is, for example, rosemary extract / lemon extract / lavender extract / orange extract, 0.1-10 / 0.1-10 / 0.1-10 / 0.1. -10, 1-5 / 1 to 5/1 to 5/1 to 5 are exemplified.
  • examples of the content ratio of the rosemary extract and the lemon extract include 1 to 5/1 and 1 to 3/1.
  • Examples of the content ratio of the lavender extract and the orange extract include 1 to 5/1 and 1 to 3/1.
  • the inhibitor of the present invention inhibits the production of amyloid ⁇ protein and phosphorylation of tau protein, thereby causing Alzheimer's disease, Down's syndrome, tauopathy (eg, dolphins granule dementia, neurofibrillary tangle dementia) , Progressive supranuclear palsy, cerebral cortical degeneration, Pick's disease) and the prevention, amelioration or treatment of symptoms based on the disease. It also has the effect of increasing BDNF, so Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage It can also be used for prevention, improvement or treatment of symptoms such as ischemic brain damage.
  • the extract of the present invention acts on nerve cells in the brain via the olfactory nerve, or a part of the extract is absorbed from the nasal mucosa and taken into the living body.
  • the extract of the present invention may be formulated as it is or prepared into a form that can be used for raw materials such as pharmaceuticals, quasi-drugs, foods and drinks, food additives and cosmetics.
  • raw materials described above known materials are used without particular limitation, and the components and blending amounts are appropriately selected and prepared by a conventional method.
  • Examples of pharmaceuticals and quasi drugs include tablets (including uncoated tablets, sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules) Agents, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, Film agents (e.g., orally disintegrating film, oral mucosa adhesive film), transdermal preparations, ointments, lotions, patches, pellets, nasal agents, transpulmonary agents (inhalants) Oral preparations are mentioned.
  • tablets including uncoated tablets, sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills pills, powders, granules, capsules (soft capsules) Agents, microcapsules), lozenges,
  • foods and beverages and food additives include, for example, breads, cakes, noodles, confectionery, jelly, frozen foods, ice creams, dairy products, soups, edible oils, and other fruit juices. Beverages, carbonated drinks, tea-based drinks, sports drinks, milk drinks, alcoholic drinks, soft drinks and the like can be mentioned. Moreover, the above-mentioned forms of oral administration of pharmaceuticals and quasi drugs are also included.
  • cosmetics include cleaning agents, shampoos, rinses, hair nicks, hair lotions, after shave lotions, body lotions, makeup lotions, cleansing creams, massage creams, emollient creams, aerosol products, fragrances, and baths. .
  • the content of the extract of the present invention varies depending on the dosage form, intake method, carrier and the like, but is usually 0.01 to 100% by weight, preferably 0.1 to 95% by weight in the product.
  • the content of the extract of the present invention means the total content of extracts of rosemary, lemon, lavender and orange.
  • the amount of intake varies depending on the user, symptoms, route of intake, etc., but in the case of oral ingestion, generally, for example, in a human having a body weight of about 60 kg, the dry weight of the extract of the present invention is about 0.01 per day. ⁇ 1000 mg, preferably about 0.1 to 100 mg, more preferably about 0.5 to 50 mg. Moreover, when using by parenteral ingestion, it can set suitably so that the amount of intake when taken orally preferably is taken in in vivo.
  • the above intake may be taken once to several times a day regardless of the form of intake.
  • the extract of the present invention for example, rosemary, lemon, lavender and orange extracts may be divided and ingested. It may be taken either intermittently or intermittently. Specifically, for example, rosemary extract and lemon extract as the first extract, lavender extract and orange extract as the second extract, the first extract in the morning, The second extract may be taken in the evening.
  • the extract of the present invention may be used as an essential oil for aromatherapy, and can also be used in a form that can be spread and diffused at a predetermined place and inhaled.
  • the oil may be distributed and diffused using a diffuser or the like.
  • the distribution / diffusion place is not particularly limited, but it is preferably used, for example, at homes, hospitals, and facilities where the above-mentioned diseases and patients presenting symptoms based on the diseases are present.
  • rosemary extract and lemon extract as the first extract
  • lavender extract and orange extract as the second extract
  • the second extract may be distributed and diffused in the evening using a diffuser or the like in a hospital or facility.
  • a method for reducing amyloid ⁇ protein and a method for inhibiting tau protein phosphorylation which comprises inhaling the extract of the present invention.
  • the extract used here can be used with reference to the section of the extract of the present invention.
  • an inhalation method if the extract of this invention can be inhaled, a well-known inhalation method can be used without limitation.
  • the extract of the present invention acts on nerve cells, as another embodiment of the present invention, one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange are effective.
  • a brain-derived neurotrophic factor (BDNF) production promoter as a component is provided. Since the BDNF production promoter of the present invention has the same active ingredients as the inhibitor of the present invention, the preparation method, shape and use thereof can be referred to the section of the inhibitor of the present invention.
  • BDNF brain-derived neurotrophic factor
  • the BDNF production promoter of the present invention can be suitably used for diseases in which the above action is desired.
  • diseases in which the above action is desired.
  • tauopathy eg, degranular granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cerebral cortex
  • prevention of symptoms such as Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage, ischemic brain damage It can also be used for improvement or treatment.
  • Example 1 We investigated the effect of aromatherapy on cognitive function.
  • SAMP8 / TaSlc mice male, 3 months old, Japan SLC Inc.
  • SAMP8 / TaSlc mice male, 3 months old, Japan SLC Inc.
  • Each was prepared and impregnated into a filter paper having a diameter of 10 cm and placed near individual cages. Treatment with exposure to aroma oil on such a time schedule was defined as one cycle, and this cycle was performed for 4 days a week for 2 months (Aroma group).
  • Figure 1 shows the voluntary alternation behavior rate (%) in the Y-shaped maze test.
  • the rate of spontaneous alternation in each group was approximately 71% (70.8 ⁇ 2.1% in the control group and 70.8 ⁇ 1.9% in the aromatherapy group), and the cognitive function of all individuals was within the normal range.
  • the rate of spontaneous alternation decreased to 52.6 ⁇ 1.9% in the control group and cognitive impairment was observed, but the aromatherapy group maintained the same level as at the start of treatment ( 64.4 ⁇ 2.2%), a significant difference was confirmed between the two groups. This result indicates that aromatherapy prevents or ameliorates cognitive impairment in SAMP8 mice.
  • Example 2 The effect of aromatherapy on the amount of amyloid ⁇ protein in the brain was examined.
  • Example 1 100 mg / kg sodium pentobarbital (Kyoritsu Pharmaceutical) was intraperitoneally administered, the mouse was opened under deep anesthesia, and blood was removed by perfusion with physiological saline from the heart. Later, the brain was removed and the olfactory bulb and hippocampus were collected. To the resulting tissue, add 10 volumes of 2 ⁇ RIPA buffer containing 0.5 mM phenylmethylsulfonyl fluoride (Sigma-Aldrich), 1 ⁇ PhosSTOP (Roche) and 1% protease inhibitor cocktail (Nacalai Tesque). And then centrifuged at 15,000 ⁇ g and 4 ° C. for 60 minutes, and the supernatant was recovered as a protein extract.
  • Example 3 The effect of aromatherapy on tau protein phosphorylation was investigated.
  • tau protein quantification was performed by Western blotting using the hippocampal protein extract prepared in Example 2.
  • the protein extract was mixed with an equal volume of Tris-SDS ⁇ ME sample buffer (Cosmo Bio) and boiled at 100 ° C. for 10 minutes. These samples were electrophoresed on a 5-20% polyacrylamide gel (Wako Pure Chemical Industries) at 200 V for 1 hour. The electrophoresed sample was transferred to a 0.45 ⁇ m polyvinylidene difluoride membrane (Merck Millipore) (conditions: 8 V, 60 minutes).
  • anti-phosphorylated tau AT8 or anti-tau antibody TAU-5 (1: 1 with blocking solution). (1000 dilution) at 4 ° C. overnight. After washing 3 times with TBS-T for 10 minutes, the mixture was incubated with horseradish peroxidase-conjugated anti-mouse Immunoglobulin G (1: 3000 diluted with blocking solution; GE Healthcare) at room temperature for 1 hour.
  • tau protein was detected using a chemiluminescent HRP substrate (Merck Millipore) and analyzed using an image analyzer (ImageQuant LAS4000; GE Healthcare). The results are shown in FIG.
  • FIG. 3 shows that the total tau protein amount detected by TAU-5 did not change between the two, but the phosphorylated tau protein amount detected by AT8 was significantly decreased in the aromatherapy group.
  • Example 4 We investigated the effect of aromatherapy on BDNF.
  • BDNF quantification was performed by Western blotting using the olfactory bulb protein extract prepared in Example 2. The measurement was performed in the same manner as in Example 3.
  • 15-20% tricine gel (Wako Pure Chemical Industries, Ltd.) was used, and anti-BDNF antibody N-20 (1: 200 dilution; Santa Cruz Biotechnology), two primary antibodies.
  • Horseradish peroxidase-conjugated anti-rabbit Immunoglobulin G (1: 3000 dilution; GE3000Healthcare) was used as the next antibody.
  • about 30 kDa was quantified as precursor BDNF and about 14 kDa as mature BDNF. The results are shown in FIG.
  • FIG. 4 shows that both the precursor BDNF and the mature BDNF showed an increasing tendency in the olfactory bulb that receives olfactory stimulation more strongly by aromatherapy. This result suggests that aromatherapy increases the expression level of BDNF.
  • Example 5 We investigated the effects of aromatherapy on motor function.
  • Example 1 the ability of the mouse for coordinated movement was evaluated using a Rotarod treadmill MK-670 (Muromachi Kikai). The mouse was placed on a rotating rod and accelerated to 40 revolutions per minute over 300 seconds, and the time until the mouse fell was recorded for a maximum of 300 seconds. Each mouse was tested twice and the average was calculated. In addition, the grip strength of the limbs of the mouse was evaluated using a mouse grip strength meter MK-380M (Muromachi Kikai). Each mouse was tested three times and the average was calculated. The results are shown in FIG.
  • FIG. 5 time (second) until dropping from the rod is shown in FIG. 5A, and gripping force (g) is shown in FIG. 5B.
  • FIG. 5A in the rotarod test, the time until the mice in the aromatherapy group fell significantly compared to the control mice.
  • FIG. 5B in the grip strength test, the grip strength of the aromatherapy group was 12% stronger than that of the control group.
  • the inhibitor of the present invention is excellent in the action of reducing amyloid ⁇ protein / phosphorylated tau protein in the brain, Alzheimer's disease, Down's syndrome, tauopathy (twelve-granular dementia, neurofibrillary tangle cognition Disease, progressive supranuclear palsy, cerebral cortical degeneration, Pick's disease and the like) and symptoms based on the disease can be suitably used. Also, by increasing BDNF, Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage, ischemic It can also be used for the prevention, amelioration or treatment of symptoms such as brain disorders.

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Abstract

An amyloid β protein production inhibitor containing, as an active ingredient, at least one extract selected from the group consisting of extracts from rosemary, lemon, lavender and orange. A tau protein phosphorylation inhibitor containing, as an active ingredient, at least one extract selected from the group consisting of extracts from rosemary, lemon, lavender and orange. The inhibitors according to the present invention have an excellent effect to reduce amyloid β protein or phosphorylated tau protein in the brain, and therefore can be used suitably for the prevention, amelioration or treatment of diseases including Alzheimer's disease, Down syndrome, tauopathy (e.g., argyrophilic grain dementia, senile dementia of the neurofibrillary tangle type, progressive supranuclear palsy, corticobasal degeneration, Pick disease) and symptoms associated with these diseases. The inhibitors can increase BDNF, and therefore can also be used for the prevention, amelioration or treatment of diseases including dementia with Lewy bodies, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorders, panic disorder, schizophrenia, autism, traumatic nerve injuries and ischemic brain damage and symptoms associated with these diseases.

Description

アミロイドβ蛋白の生成阻害剤Amyloid β protein production inhibitor
　本発明は、アミロイドβ蛋白の生成阻害剤及びタウ蛋白のリン酸化阻害剤に関する。 The present invention relates to an amyloid β protein production inhibitor and a tau protein phosphorylation inhibitor.
　天然物から特定の薬理作用のある物質又は成分を探索して創薬に利用することが、一般に行われている。このように有用な物質又は成分は、しばしば、新たな治療・予防法の開発や発症メカニズム解明の研究などに利用されるが、近年、植物から抽出した精油を用いる手法についても検討が種々行われている。 It is a common practice to search for substances or components having a specific pharmacological action from natural products and use them for drug discovery. Such useful substances or components are often used for the development of new treatment / prevention methods and research for elucidation of the onset mechanism, etc. In recent years, various methods using essential oils extracted from plants have been studied. ing.
　例えば、特許文献１には、レッドキドニービーンズ、グアバ、発酵グアバ、ゲットウ、発酵ゲットウ、オレガノ、バジル、レモンバーベナ、ハマナス、アオサ、マジョラム、ギンネム、発酵ギンネム、コブミカン及びギムネマシルベスタからなる群から選ばれる１以上の植物の植物体もしくはその処理物又はその抽出物に、アミロイドβ蛋白の凝集抑制作用及び／又は凝集アミロイドβ蛋白の分解作用を有することが開示されている。そして、前記処理物や抽出物は、錠剤、散剤、顆粒剤等の経口剤や、注射剤、点滴剤、クリーム剤、坐剤等の非経口剤として用いられることが開示されている。 For example, Patent Document 1 is selected from the group consisting of Red Kidney Beans, Guava, Fermented Guava, Ghetto, Fermented Ghetto, Oregano, Basil, Lemon Verbena, Hermanus, Aosa, Marjoram, Ginnemu, Fermented Ginnemu, Kobimikan and Gymnema Sylvestre. It is disclosed that a plant body of one or more plants or a processed product thereof or an extract thereof has an aggregation inhibitory action on amyloid β protein and / or a degradation action on aggregated amyloid β protein. And it is disclosed that the said processed material and extract are used as oral preparations, such as a tablet, a powder, a granule, and parenteral preparations, such as an injection, a drip, a cream, and a suppository.
　また、非特許文献１及び２には、植物の精油を用いる手法として、ローズマリーカンファーオイルとレモンオイル、及び、真正ラベンダーオイルとオレンジオイルを組み合わせて、アルツハイマー病の患者にアロマテラピーを行うことで、嗅覚刺激を介して脳内の神経の機能が改善し、認知機能が改善したことが報告されている。 In addition, Non-Patent Documents 1 and 2 include, as a technique using plant essential oil, aromatherapy for Alzheimer's disease patients by combining rosemary camphor oil and lemon oil, and authentic lavender oil and orange oil. It has been reported that the function of nerves in the brain is improved through olfactory stimulation and the cognitive function is improved.
特開２０１０－２０２６０６号公報JP 2010-202606 A
　本発明は、アミロイドβ蛋白の生成阻害剤、タウ蛋白のリン酸化を阻害する阻害剤、アミロイドβ蛋白の減少方法及びタウ蛋白のリン酸化阻害方法に関する。 The present invention relates to an amyloid β protein production inhibitor, an inhibitor that inhibits tau protein phosphorylation, a method for reducing amyloid β protein, and a method for inhibiting tau protein phosphorylation.
　本発明者らは、上記目的を達成するために鋭意検討した結果、特定の精油を組み合わせて用いることで、脳内におけるアミロイドβ蛋白の産生量を減少でき、また、タウ蛋白のリン酸化も阻害できることを見出し、本発明を完成するに至った。 As a result of intensive studies to achieve the above object, the present inventors have been able to reduce the amount of amyloid β protein produced in the brain by using a specific essential oil in combination, and also inhibit phosphorylation of tau protein The present inventors have found that this can be done and have completed the present invention.
　即ち、本発明は、下記〔１〕～〔１０〕に関する。
〔１〕　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とする、アミロイドβ蛋白の生成阻害剤。
〔２〕　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とする、タウ蛋白のリン酸化阻害剤。
〔３〕　ローズマリーの抽出物とレモンの抽出物を含む第一抽出物と、ラベンダーの抽出物とオレンジの抽出物を含む第二抽出物を組み合わせてなる、前記〔１〕又は〔２〕記載の剤。
〔４〕　ローズマリー抽出物がローズマリー・カンファーであり、ラベンダー抽出物が真正ラベンダーである、前記〔１〕～〔３〕いずれか記載の剤。
〔５〕　アルツハイマー病、ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の治療又は予防に用いられる、前記〔１〕～〔４〕いずれか記載の剤。
〔６〕　ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、及びピック病から選ばれる疾患の予防に用いられる、前記〔１〕～〔５〕いずれか記載の剤。
〔７〕　レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の予防に用いられる、前記〔１〕～〔５〕いずれか記載の剤。
〔８〕　前記〔１〕～〔７〕いずれか記載の剤を含有してなる、組成物。
〔９〕　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を吸入することを特徴とする、アミロイドβ蛋白の減少方法。
〔１０〕　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を吸入することを特徴とする、タウ蛋白のリン酸化阻害方法。 That is, the present invention relates to the following [1] to [10].
[1] An amyloid β protein production inhibitor comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
[2] A tau protein phosphorylation inhibitor comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
[3] The above-mentioned [1] or [2], comprising a combination of a first extract containing a rosemary extract and a lemon extract, and a second extract containing a lavender extract and an orange extract. Agent.
[4] The agent according to any one of [1] to [3] above, wherein the rosemary extract is rosemary camphor and the lavender extract is authentic lavender.
[5] Alzheimer's disease, Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal [1] used for the treatment or prevention of a disease selected from lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage [4] The agent according to any one of [4].
[6] used for the prevention of diseases selected from Down's syndrome, greasy granular dementia, neurofibrillary tangle dementia, progressive supranuclear paralysis, cerebral cortical degeneration, and Pick's disease [ [1] The agent according to any one of [5].
[7] Disease selected from dementia with Lewy bodies, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage The agent according to any one of the above [1] to [5], which is used for the prevention of.
[8] A composition comprising the agent according to any one of [1] to [7].
[9] A method for reducing amyloid β protein, comprising inhaling one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
[10] A method for inhibiting phosphorylation of tau protein, comprising inhaling one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
　また、本発明は、下記の態様〔１１〕～〔１５〕も包含する。
〔１１〕　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とする、脳由来神経栄養因子(Brain-derived neurotrophic factor：BDNF)の生成促進剤。
〔１２〕　前記〔１〕～〔７〕いずれか記載の剤を投与する工程を含む、アルツハイマー病、ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の予防及び／又は治療方法。
〔１３〕　投与が吸入によるものである、前記〔１２〕記載の方法。
〔１４〕　アルツハイマー病、ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の予防及び／又は治療するための、ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物の使用。
〔１５〕　アルツハイマー病、ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の予防及び／又は治療剤を製造するための、ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物の使用。 The present invention also includes the following embodiments [11] to [15].
[11] A brain-derived neurotrophic factor (BDNF) production promoter comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange .
[12] Alzheimer's disease, Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive nuclei including the step of administering the agent according to any one of [1] to [7] Paralysis, cerebral cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage and A method for preventing and / or treating a disease selected from ischemic brain injury.
[13] The method described in [12] above, wherein administration is by inhalation.
[14] Alzheimer's disease, Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal Rosemary for the prevention and / or treatment of diseases selected from leaf degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage Use of one or more extracts selected from the group consisting of lemon, lavender and orange.
[15] Alzheimer's disease, Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cortical degeneration, Pick's disease, Lewy body dementia, frontotemporal For producing a prophylactic and / or therapeutic agent for a disease selected from leaf degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage Use of one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
　本発明のアミロイドβ蛋白の生産阻害剤は、アミロイドβ蛋白そのものの含有量を減少する効果に優れ、ひいては、アミロイドβ蛋白の重合や凝集、蓄積も抑制することが可能となる。また、本発明のタウ蛋白のリン酸化阻害剤は、タウ蛋白のリン酸化を阻害する効果に優れ、ひいては、リン酸化タウ蛋白の凝集、蓄積も抑制することが可能となる。よって、本発明の阻害剤により、アミロイドβ蛋白やリン酸化タウ蛋白が関連する疾患、例えば、アルツハイマー病やタウオパチーなどの疾患に対して予防あるいは治療効果を奏することが可能となる。また、脳由来神経栄養因子(Brain-derived neurotrophic factor：BDNF)を増加させる傾向もみられたことから、その他の神経変性疾患の予防及び／又は治療にも応用が可能である。 The production inhibitor of amyloid β protein of the present invention is excellent in the effect of reducing the content of amyloid β protein itself, and thus can also suppress polymerization, aggregation and accumulation of amyloid β protein. Further, the phosphorylation inhibitor of tau protein of the present invention is excellent in the effect of inhibiting phosphorylation of tau protein, and thus can also suppress aggregation and accumulation of phosphorylated tau protein. Therefore, the inhibitor of the present invention can exert a preventive or therapeutic effect on diseases associated with amyloid β protein and phosphorylated tau protein, for example, diseases such as Alzheimer's disease and tauopathy. In addition, since a tendency to increase brain-derived neurotrophic factor (BDNF) was also observed, it can be applied to the prevention and / or treatment of other neurodegenerative diseases.
図１は、アロマテラピーによる認知機能に対する影響を調べた結果を示す。FIG. 1 shows the results of examining the influence of aromatherapy on cognitive function. 図２は、アロマテラピーによる脳内のアミロイドβ蛋白量に対する影響を調べた結果を示す。FIG. 2 shows the results of examining the effect of aromatherapy on the amount of amyloid β protein in the brain. 図３は、アロマテラピーによる脳内のタウ蛋白のリン酸化に対する影響を調べた結果を示す。FIG. 3 shows the results of examining the effect of aromatherapy on phosphorylation of tau protein in the brain. 図４は、アロマテラピーによる脳内のBDNFに対する影響を調べた結果を示す。FIG. 4 shows the results of examining the effect of aromatherapy on BDNF in the brain. 図５は、アロマテラピーによる運動機能に対する影響を調べた結果を示す。FIG. 5 shows the results of examining the influence of aromatherapy on motor function.
　本発明のアミロイドβ蛋白の生成阻害剤及びタウ蛋白のリン酸化阻害剤は、ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とするものであり、以降、これらの阻害剤をまとめて本発明の阻害剤、これらの抽出物をまとめて本発明の抽出物とそれぞれ記載することもある。 The production inhibitor of amyloid β protein and the phosphorylation inhibitor of tau protein of the present invention comprise one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange as active ingredients. In the following, these inhibitors may be collectively referred to as the inhibitor of the present invention, and these extracts may be collectively referred to as the extract of the present invention.
　アルツハイマー病は、アミロイドβ蛋白から成る老人斑とタウ蛋白から成る神経原繊維変化の形成、またこれらに伴って進行する脳の萎縮を特徴的病変とする神経変性疾患である。アミロイドβ蛋白は、蛋白凝集体を形成して組織に沈着することによって機能障害を引き起こすが、その凝集体と共にアミロイドβ蛋白自身も細胞毒性作用を有することから、アミロイドβ蛋白そのものの生成を阻害することがアルツハイマー病の治療法として期待されている。また、組織へ沈着して機能障害を引き起こす蛋白質としてはリン酸化タウ蛋白も知られているが、タウ蛋白そのものは中枢神経細胞に多量に存在し、脳の神経ネットワークを構成することから、タウ蛋白のリン酸化を阻害することもアルツハイマー病治療に有効であると考えられている。一方、アルツハイマー病の発症・進行リスクを高める要因としては、加齢、肥満、糖尿病、高血圧、高脂血症、睡眠不足、運動不足、過度の飲酒や喫煙、頭部への外傷なども挙げられる。これらのリスク要因から推察すると、アルツハイマー病の発症・進行には、脳血流量や糖・脂質代謝能の低下による神経細胞機能低下、あるいは慢性炎症による神経細胞障害など、アミロイドβ蛋白やタウ蛋白が直接関与しない経路も存在すると考えられる。よって、アルツハイマー病の発症・進行を抑制するには、様々な経路を考慮する必要がある。このような状況下において、本発明者らは、神経細胞に着目し、本発明の抽出物を曝露させることで、アミロイドβ蛋白の生成やタウ蛋白のリン酸化を阻害することを見出した。従来は、例えば、芳香成分が嗅覚神経を介して自律神経系や内分泌系を調整している視床下部を刺激し、アセチルコリンやノルアドレナリンといった神経伝達物質が放出されることでリラックス効果やリフレッシュ効果等がもたらされて認知機能が向上すると考えられていたが、詳細なる機序は不明なるも、本発明の抽出物が嗅覚神経を介して脳内の神経細胞に作用する、あるいは、抽出物の一部が鼻粘膜から吸収され脳内の神経細胞に直接作用することで、アミロイドβ蛋白の産生抑制・分解除去、タウ蛋白のリン酸化抑制といった効果をもたらすと推察される。 Alzheimer's disease is a neurodegenerative disease characterized by the formation of senile plaques composed of amyloid β protein and neurofibrillary tangles composed of tau protein, and brain atrophy accompanied by these changes. Amyloid β protein causes dysfunction by forming protein aggregates and depositing them in tissues, but amyloid β protein itself has a cytotoxic effect together with the aggregates, thus inhibiting the production of amyloid β protein itself This is expected as a treatment for Alzheimer's disease. Phosphorylated tau protein is also known as a protein that deposits in tissues and causes dysfunction. However, tau protein itself is abundant in central neurons and constitutes the neural network of the brain. Inhibition of phosphorylation is also considered effective for the treatment of Alzheimer's disease. On the other hand, factors that increase the risk of onset and progression of Alzheimer's disease include aging, obesity, diabetes, hypertension, hyperlipidemia, lack of sleep, lack of exercise, excessive drinking and smoking, and trauma to the head. . Presuming from these risk factors, the onset and progression of Alzheimer's disease involves amyloid β protein and tau protein, such as neuronal cell function decline due to a decrease in cerebral blood flow and ability to metabolize sugar and lipid, or neuronal cell damage due to chronic inflammation. There may be routes that are not directly involved. Therefore, in order to suppress the onset and progression of Alzheimer's disease, it is necessary to consider various routes. Under such circumstances, the present inventors have focused on nerve cells and found that exposure of the extract of the present invention inhibits amyloid β protein production and tau protein phosphorylation. Conventionally, for example, aroma components stimulate the hypothalamus that regulates the autonomic nervous system and endocrine system via the olfactory nerve, and neurotransmitters such as acetylcholine and noradrenaline are released, thereby relaxing and refreshing. Although the detailed mechanism is unknown, the extract of the present invention acts on nerve cells in the brain via the olfactory nerve or one of the extracts. It is presumed that the part is absorbed from the nasal mucosa and directly acts on nerve cells in the brain, thereby producing effects such as production inhibition / degradation removal of amyloid β protein and phosphorylation inhibition of tau protein.
　また、前記以外にも、前記抽出物が、脳由来神経栄養因子(Brain-derived neurotrophic factor：BDNF)も増加させ、神経細胞の新生・成長・分化・再生を促進することが分かってきた。これは、本発明の抽出物が前記したように神経細胞に直接作用する以外に、自律神経系の改善を介した脳血流量の増加等によって間接的に神経細胞の機能が改善する等の作用を奏することで、BDNF増加といった効果をもたらすからと推察される。これらより、本発明の抽出物はアルツハイマー病発症・進行の要因であるアミロイドβ蛋白、タウ蛋白だけでなく、その他の諸経路のいずれに対しても阻害効果を有することが期待される。また、前記抽出物は、アミロイドβ蛋白、タウ蛋白、その他の諸経路のいずれに対しても阻害効果を有することから、これらの経路を介した疾患の発症・進行を抑制する効果も奏することが期待される。但し、これらの推測は、本発明を限定するものではない。 In addition to the above, it has been found that the extract also increases brain-derived neurotrophic factor (BDNF) and promotes neurogenesis, growth, differentiation and regeneration of neurons. This is because the extract of the present invention acts directly on nerve cells as described above, and the function of the nerve cells is indirectly improved by an increase in cerebral blood flow through improvement of the autonomic nervous system. It is presumed that the effect of increasing the BDNF by playing From these, the extract of the present invention is expected to have an inhibitory effect not only on amyloid β protein and tau protein, which are the factors causing the onset and progression of Alzheimer's disease, but also on all other pathways. Further, since the extract has an inhibitory effect on any of amyloid β protein, tau protein, and other pathways, it can also exert an effect of suppressing the onset and progression of diseases via these pathways. Be expected. However, these assumptions do not limit the present invention.
　本発明の抽出物は、ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の植物の抽出物であるが、これらの植物に対し人為的な処理を施して得られたものであれば特に限定はなく、例えば、抽出物(エキス)の他、精油(例えば、水蒸気蒸留物、搾汁液、圧搾物、溶剤抽出物、超臨界流体抽出物)も含まれる。また、これらの植物に対して、個別に処理を行ったものであっても、まとめて処理を行ったものでもよい。個別に処理を行う場合は、処理方法が同一でも異なってもよい。本発明の抽出物としては、例えば、ローズマリーの抽出物、レモンの抽出物、ラベンダーの抽出物及びオレンジの抽出物を含む態様の他、ローズマリーの精油、レモンの精油、ラベンダーの精油及びオレンジの精油を含む態様を用いることができる。 The extract of the present invention is an extract of one or more kinds of plants selected from the group consisting of rosemary, lemon, lavender and orange, and is obtained by subjecting these plants to artificial treatment. For example, in addition to the extract (extract), essential oils (for example, steam distillate, squeezed liquid, pressed product, solvent extract, supercritical fluid extract) are also included. In addition, these plants may be individually treated or collectively treated. When processing individually, the processing method may be the same or different. Examples of the extract of the present invention include, for example, rosemary extract, lemon extract, lavender extract and orange extract, rosemary essential oil, lemon essential oil, lavender essential oil and orange. Embodiments containing the essential oils can be used.
　ローズマリー、レモン、ラベンダー及びオレンジとしては、公知のものであれば特に限定なく用いることができる。産地や品種も特に限定されない。 Rosemary, lemon, lavender and orange can be used without particular limitation as long as they are known. The production area and variety are not particularly limited.
　使用される部位については、例えば、根茎、葉、果実、種子、花又は植物全体を使用することができ、これらの裁断物や破砕物、乾燥物等の加工品としても使用することができる。 For the part to be used, for example, rhizomes, leaves, fruits, seeds, flowers or whole plants can be used, and these can be used as processed products such as cut products, crushed products, and dried products.
　抽出方法としては、特に限定はなく、例えば、前記した植物を公知の方法に従って溶媒により抽出し、溶媒を留去する方法が挙げられる。 The extraction method is not particularly limited, and examples thereof include a method in which the aforementioned plant is extracted with a solvent according to a known method and the solvent is distilled off.
　抽出溶媒としては、例えば、低級アルコール(メタノール、エタノール、プロパノール、イソプロピルアルコール、n-ブタノール、イソブチルアルコール等)、多価アルコール(エチレングリコール、プロピレングリコール、１，３－ブチレングリコール等)、ケトン(アセトン、メチルエチルケトン等)、エーテル(ジオキサン、メチルエチルエーテル、ジエチルエーテル等)、ハロゲン化炭化水素(クロロホルム、ジクロロメタン、ジクロロエタン等)、極性溶媒(ジメチルホルムアミド、ジメチルスルホキシド等)のほか、酢酸エチル、トルエン、n-ヘキサン、石油エーテル等の各種有機溶媒、或いは水等を、それぞれ単独で又は２種以上組み合わせて用いることが出来る。組み合わせる際には、その比率は適宜調整することができる。 Examples of the extraction solvent include lower alcohols (methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, etc.), polyhydric alcohols (ethylene glycol, propylene glycol, 1,3-butylene glycol, etc.), ketones (acetone , Methyl ethyl ketone, etc.), ether (dioxane, methyl ethyl ether, diethyl ether, etc.), halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.), polar solvents (dimethylformamide, dimethyl sulfoxide, etc.), ethyl acetate, toluene, n -Various organic solvents such as hexane and petroleum ether, or water can be used alone or in combination of two or more. When combining, the ratio can be appropriately adjusted.
　抽出温度は、用いる溶媒や植物の部位・形態などによって一概には設定することができないが、抽出効率の観点から、下限としては4℃、上限としては150℃を挙げることができる。本発明においては、前記した温度範囲内であれば上限値や下限値を適宜設定することができ、例えば、10℃、15℃、20℃、30℃、40℃、60℃、80℃、100℃、120℃、140℃等を上限値あるいは下限値として設定することができる。抽出時間は、抽出に供する原料の使用量や装置に応じて適宜設定することができる。 The extraction temperature cannot be set unconditionally depending on the solvent used, plant part / morphology, etc., but from the viewpoint of extraction efficiency, the lower limit may be 4 ° C. and the upper limit may be 150 ° C. In the present invention, the upper limit value and the lower limit value can be appropriately set within the above-described temperature range, for example, 10 ° C., 15 ° C., 20 ° C., 30 ° C., 40 ° C., 60 ° C., 80 ° C., 100 ℃, 120 ℃, 140 ℃ etc. can be set as the upper limit value or the lower limit value. The extraction time can be appropriately set according to the amount of raw material used for extraction and the apparatus.
　なお、抽出により得られた抽出物に対しては、ろ過、遠心分離、濃縮、希釈、限外ろ過、凍結乾燥、粉末化及び分画からなる群より選ばれる１種又は２種以上の処理を、公知の方法に従って行ってもよい。また、必要により、常圧下又は減圧下で前記処理を行うことができる。得られた抽出物は、体温付近の温度で揮発性を有するものであってもよい。 The extract obtained by extraction is subjected to one or more treatments selected from the group consisting of filtration, centrifugation, concentration, dilution, ultrafiltration, lyophilization, powdering and fractionation. You may carry out according to a well-known method. If necessary, the treatment can be performed under normal pressure or reduced pressure. The obtained extract may be volatile at temperatures near body temperature.
　本発明で用いる抽出物は、前記した公知の抽出方法によって調製したものであっても、市販品であってもよい。市販のアロマオイルであってもよい。例えば、ローズマリーの抽出物としては、ローズマリー・シネオール、ローズマリー・カンファー、ローズマリー・ベルベノンなどが挙げられるが、ローズマリー・カンファーを好適に用いることができる。また、ラベンダーとしては、真正ラベンダー、ラベンダー・ストエカス、ラベンダー・スピカ、ラベンダー・レイドバン、ラベンダー・スーパーなどが挙げられるが、真正ラベンダーを好適に用いることができる。 The extract used in the present invention may be one prepared by the known extraction method described above or a commercially available product. Commercially available aroma oil may be used. Examples of the rosemary extract include rosemary cineole, rosemary camphor, rosemary berbenone, and the like, but rosemary camphor can be preferably used. Examples of lavender include authentic lavender, lavender stoecas, lavender spica, lavender raid van, lavender super, and the like, but authentic lavender can be preferably used.
　本発明の抽出物の形状は、特に限定されず、粉状、固形状、液状のいずれの形状であっても良い。また、個別の抽出物を用いる場合、その形状は同一でも異なってもよい。 The shape of the extract of the present invention is not particularly limited, and may be any of powder, solid, and liquid. Moreover, when using an individual extract, the shape may be the same or different.
　本発明の阻害剤は、ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とするが、阻害剤中、ローズマリー、レモン、ラベンダー及びオレンジの抽出物の合計含有量は、特に限定されず、例えば、0.01～100重量％が例示される。 The inhibitor of the present invention contains, as an active ingredient, one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange. In the inhibitor, rosemary, lemon, lavender and orange The total content of the extract is not particularly limited, and examples thereof include 0.01 to 100% by weight.
　また、各抽出物の含有量比としては、抽出物の形状や抽出方法によって一概には設定することができず、技術常識に従って適宜調整することができる。以下に一例を示すが、例えば、ローズマリーの含有量を1とする場合、その他は0.01～100の範囲内で適宜調整することができる。具体的な各抽出物の含有量比(体積比)としては、例えば、ローズマリー抽出物／レモン抽出物／ラベンダー抽出物／オレンジ抽出物が、0.1～10／0.1～10／0.1～10／0.1～10、1～5／1～5／1～5／1～5が例示される。また、個々の抽出物を規定する場合、ローズマリー抽出物とレモン抽出物の含有量比としては、1～5／1、1～3／1が例示される。ラベンダー抽出物とオレンジ抽出物の含有量比としては、1～5／1、1～3／1が例示される。 In addition, the content ratio of each extract cannot be set unconditionally depending on the shape of the extract or the extraction method, and can be appropriately adjusted according to common general technical knowledge. An example is shown below. For example, when the content of rosemary is 1, the others can be appropriately adjusted within the range of 0.01 to 100. Specific content ratio (volume ratio) of each extract is, for example, rosemary extract / lemon extract / lavender extract / orange extract, 0.1-10 / 0.1-10 / 0.1-10 / 0.1. -10, 1-5 / 1 to 5/1 to 5/1 to 5 are exemplified. Further, when defining individual extracts, examples of the content ratio of the rosemary extract and the lemon extract include 1 to 5/1 and 1 to 3/1. Examples of the content ratio of the lavender extract and the orange extract include 1 to 5/1 and 1 to 3/1.
　本発明の阻害剤は、アミロイドβ蛋白の生成やタウ蛋白のリン酸化を阻害することにより、アルツハイマー病、ダウン症候群、タウオパチー（例えば、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病）の疾患や前記疾患に基づく症状の予防、改善又は治療に好適に用いることができる。また、BDNFを増加させる作用も有することから、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷、虚血性脳障害等の症状の予防、改善又は治療に用いることも可能である。 The inhibitor of the present invention inhibits the production of amyloid β protein and phosphorylation of tau protein, thereby causing Alzheimer's disease, Down's syndrome, tauopathy (eg, dolphins granule dementia, neurofibrillary tangle dementia) , Progressive supranuclear palsy, cerebral cortical degeneration, Pick's disease) and the prevention, amelioration or treatment of symptoms based on the disease. It also has the effect of increasing BDNF, so Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage It can also be used for prevention, improvement or treatment of symptoms such as ischemic brain damage.
　本発明の阻害剤の形態としては、本発明の抽出物が嗅覚神経を介して脳内の神経細胞に作用する、あるいは、抽出物の一部が鼻粘膜から吸収されて生体内に摂取することができる形態であれば特に限定はなく、そのまま製剤化したり、医薬品、医薬部外品、飲食品、飲食品用添加剤、化粧品等の原材料に用いることが可能な形態に調製してもよい。前記した原材料としては、公知のものが特に限定なく用いられ、その成分及び配合量を適宜選択して常法により調製される。 As the form of the inhibitor of the present invention, the extract of the present invention acts on nerve cells in the brain via the olfactory nerve, or a part of the extract is absorbed from the nasal mucosa and taken into the living body. There is no particular limitation as long as it can be used, and it may be formulated as it is or prepared into a form that can be used for raw materials such as pharmaceuticals, quasi-drugs, foods and drinks, food additives and cosmetics. As the raw materials described above, known materials are used without particular limitation, and the components and blending amounts are appropriately selected and prepared by a conventional method.
　医薬品、医薬部外品としては、例えば、錠剤(素錠、糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む)、丸剤、散剤、顆粒剤、カプセル剤(ソフトカプセル剤、マイクロカプセル剤を含む)、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤(例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤)、エアゾール剤、フィルム剤(例、口腔内崩壊フィルム、口腔粘膜貼付フィルム)、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、ペレット、経鼻剤、経肺剤(吸入剤)等の経口剤又は非経口剤が挙げられる。 Examples of pharmaceuticals and quasi drugs include tablets (including uncoated tablets, sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules) Agents, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, Film agents (e.g., orally disintegrating film, oral mucosa adhesive film), transdermal preparations, ointments, lotions, patches, pellets, nasal agents, transpulmonary agents (inhalants) Oral preparations are mentioned.
　飲食品、飲食品用添加剤としては、例えば、パン類、ケーキ類、麺類、菓子類、ゼリー類、冷凍食品、アイスクリーム類、乳製品、スープ類、食用油等の各種食品の他、果汁飲料、炭酸飲料、茶系飲料、スポーツ飲料、乳飲料、アルコール飲料、清涼飲料等が挙げられる。また、上記した医薬品、医薬部外品の経口投与型の形態も含まれる。 Examples of foods and beverages and food additives include, for example, breads, cakes, noodles, confectionery, jelly, frozen foods, ice creams, dairy products, soups, edible oils, and other fruit juices. Beverages, carbonated drinks, tea-based drinks, sports drinks, milk drinks, alcoholic drinks, soft drinks and the like can be mentioned. Moreover, the above-mentioned forms of oral administration of pharmaceuticals and quasi drugs are also included.
　化粧品としては、洗浄剤、シャンプー、リンス、ヘアートニック、ヘアーローション、アフターシェーブローション、ボディーローション、化粧ローション、クレンジングクリーム、マッサージクリーム、エモリエントクリーム、エアゾール製品、芳香剤又は入浴剤などを例示することができる。 Examples of cosmetics include cleaning agents, shampoos, rinses, hair nicks, hair lotions, after shave lotions, body lotions, makeup lotions, cleansing creams, massage creams, emollient creams, aerosol products, fragrances, and baths. .
　本発明の抽出物の含有量は、剤型、摂取方法、担体等により異なるが、例えば、製品中、通常0.01～100重量％、好ましくは0.1～95重量％である。なお、本明細書において、本発明の抽出物の含有量とは、ローズマリー、レモン、ラベンダー及びオレンジの抽出物の合計含有量のことを意味する。 The content of the extract of the present invention varies depending on the dosage form, intake method, carrier and the like, but is usually 0.01 to 100% by weight, preferably 0.1 to 95% by weight in the product. In the present specification, the content of the extract of the present invention means the total content of extracts of rosemary, lemon, lavender and orange.
　摂取量は、使用者、症状、摂取ルートなどにより差異はあるが、経口摂取の場合、一般的に例えば、体重約60kgのヒトにおいては、本発明の抽出物の乾燥重量として、１日当たり約0.01～1000mg、好ましくは約0.1～100mg、より好ましくは約0.5～50mgである。また、非経口摂取で使用する場合には、好ましくは経口摂取した場合の摂取量が生体内に取り込まれるよう、適宜設定することができる。 The amount of intake varies depending on the user, symptoms, route of intake, etc., but in the case of oral ingestion, generally, for example, in a human having a body weight of about 60 kg, the dry weight of the extract of the present invention is about 0.01 per day. ˜1000 mg, preferably about 0.1 to 100 mg, more preferably about 0.5 to 50 mg. Moreover, when using by parenteral ingestion, it can set suitably so that the amount of intake when taken orally preferably is taken in in vivo.
　摂取方法としては、摂取の形態に関わらず、前記した摂取量を１日１回～数回に分けて摂取すればよい。また、本発明においては、本発明の抽出物として、例えば、ローズマリー、レモン、ラベンダー及びオレンジの抽出物を分割して摂取してもよく、抽出物を分割して摂取する場合には連続的に摂取しても、断続的に摂取してもよい。具体的には、例えば、ローズマリーの抽出物とレモンの抽出物を第一抽出物として、ラベンダーの抽出物とオレンジの抽出物を第二抽出物として分割し、第一抽出物を朝に、第二抽出物を夕方に摂取してもよい。 As an ingestion method, the above intake may be taken once to several times a day regardless of the form of intake. Further, in the present invention, as the extract of the present invention, for example, rosemary, lemon, lavender and orange extracts may be divided and ingested. It may be taken either intermittently or intermittently. Specifically, for example, rosemary extract and lemon extract as the first extract, lavender extract and orange extract as the second extract, the first extract in the morning, The second extract may be taken in the evening.
　また、本発明においては、本発明の抽出物をアロマテラピー用エッセンシャルオイルとして用いてもよく、所定の場所に撒布、拡散して、吸入し得る形態で使用することもできる。該オイルは、拡散器（ディフューザー）等を用いて撒布、拡散してもよい。撒布・拡散場所としては、特に限定されないが、例えば、前記した疾患や前記疾患に基づく症状を呈する患者が存在する家庭、病院、施設などで用いることが好ましい。具体的には、例えば、ローズマリーの抽出物とレモンの抽出物を第一抽出物として、ラベンダーの抽出物とオレンジの抽出物を第二抽出物として分割し、第一抽出物を朝に、第二抽出物を夕方に、それぞれ病院や施設内で拡散器（ディフューザー）等を用いて撒布、拡散してもよい。 Further, in the present invention, the extract of the present invention may be used as an essential oil for aromatherapy, and can also be used in a form that can be spread and diffused at a predetermined place and inhaled. The oil may be distributed and diffused using a diffuser or the like. The distribution / diffusion place is not particularly limited, but it is preferably used, for example, at homes, hospitals, and facilities where the above-mentioned diseases and patients presenting symptoms based on the diseases are present. Specifically, for example, rosemary extract and lemon extract as the first extract, lavender extract and orange extract as the second extract, the first extract in the morning, The second extract may be distributed and diffused in the evening using a diffuser or the like in a hospital or facility.
　また、本発明の一態様として、本発明の抽出物を吸入することを特徴とする、アミロイドβ蛋白の減少方法及びタウ蛋白のリン酸化阻害方法を提供する。ここで用いられる抽出物は、本発明の抽出物の項を参照して用いることができる。また、吸入方法としては、本発明の抽出物を吸入できるのであれば、公知の吸入方法を限定されずに用いることができる。 Also, as one aspect of the present invention, there is provided a method for reducing amyloid β protein and a method for inhibiting tau protein phosphorylation, which comprises inhaling the extract of the present invention. The extract used here can be used with reference to the section of the extract of the present invention. Moreover, as an inhalation method, if the extract of this invention can be inhaled, a well-known inhalation method can be used without limitation.
　またさらに、本発明の抽出物が神経細胞に作用することから、本発明の別の態様として、ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とする、脳由来神経栄養因子(Brain-derived neurotrophic factor：BDNF)の生成促進剤を提供する。本発明のBDNFの生成促進剤は、本発明の阻害剤と有効成分が同じであるため、その調製方法や形状、使用に関しては、本発明の阻害剤の項を参照することができる。 Furthermore, since the extract of the present invention acts on nerve cells, as another embodiment of the present invention, one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange are effective. A brain-derived neurotrophic factor (BDNF) production promoter as a component is provided. Since the BDNF production promoter of the present invention has the same active ingredients as the inhibitor of the present invention, the preparation method, shape and use thereof can be referred to the section of the inhibitor of the present invention.
　BDNFは、神経細胞の新生・成長・分化・再生を促進することから、本発明のBDNFの生成促進剤は、前記作用の発現が望まれる疾患に好適に用いることができる。具体的には、例えば、BDNFを増加させることにより、アルツハイマー病、ダウン症候群、タウオパチー（例えば、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病）の疾患や前記疾患に基づく症状の予防、改善又は治療に好適に用いることができる。また、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷、虚血性脳障害等の症状の予防、改善又は治療に用いることも可能である。 Since BDNF promotes neurogenesis, growth, differentiation, and regeneration of nerve cells, the BDNF production promoter of the present invention can be suitably used for diseases in which the above action is desired. Specifically, for example, by increasing BDNF, Alzheimer's disease, Down's syndrome, tauopathy (eg, degranular granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cerebral cortex It can be suitably used for the prevention, amelioration, or treatment of diseases such as degeneration and Pick disease) and symptoms based on the diseases. In addition, prevention of symptoms such as Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage, ischemic brain damage It can also be used for improvement or treatment.
　以下、実施例により本発明を詳細に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.
実施例１
　アロマテラピーによる、認知機能への影響を調べた。 Example 1
We investigated the effect of aromatherapy on cognitive function.
　具体的には、老化促進・認知機能低下モデル動物であるSAMP8/TaSlcマウス(雄、3ヶ月齢、Japan SLC Inc.)を個別にケージに入れた状態で飼育室にて飼育した(n=8～9)。その際に、夜間(20～8時)に15μLのレモン精油と30μLのローズマリー・カンファー精油の混合物を、日中(8～20時)に30μLの真正ラベンダー精油と15μLのオレンジ精油の混合物を、それぞれ調製して直径10cmの濾紙に含浸させて、個々のケージの近くに載置した。このようなタイムスケジュールでアロマオイルに曝露させて治療を行うことを1サイクルとし、かかるサイクルを週に4日間、2ヶ月にわたって行った(Aroma群)。そして、治療開始前、治療開始1ヵ月後、2ヶ月後に、それぞれ以下に示す空間作業記憶に関するテストを行った。結果を図１に示す。なお、対照としては、アロマオイルに曝露させない以外は同じようにして飼育した対照群(Control群)を用いた。 Specifically, SAMP8 / TaSlc mice (male, 3 months old, Japan SLC Inc.), which are model animals for promoting aging and cognitive decline, were individually housed in cages (n = 8 ~ 9). At that time, mix 15 μL of lemon essential oil and 30 μL rosemary camphor essential oil at night (20-8 o'clock), and 30 μL of authentic lavender essential oil and 15 μL orange essential oil during the day (8-20 o'clock). Each was prepared and impregnated into a filter paper having a diameter of 10 cm and placed near individual cages. Treatment with exposure to aroma oil on such a time schedule was defined as one cycle, and this cycle was performed for 4 days a week for 2 months (Aroma group). The following tests on spatial working memory were performed before the start of treatment, one month after the start of treatment, and two months later. The results are shown in FIG. As a control, a control group (Control group) reared in the same manner except that it was not exposed to aroma oil was used.
＜空間作業記憶に関するテスト＞
　Y字迷路試験(Y-maze test)を用いて評価した。具体的には、同じ大きさの3本のアームが120°で連結されたY字型の装置内を自由に8分間移動させ、進入したアームを順番に記録した。3本のアームに侵入した総回数のうち、3回連続で異なるアームを選択した場合を自発交替行動とし、時間内のアームへの総進入回数及び自発交替行動数をカウントし、以下の式から、自発交替行動率(％)を算出した。なお、自発交替行動率(％)が高いほど、空間作業記憶が高く認知機能が良好であることを示す。
　　　自発交替行動率(％)＝自発交替行動数／(総進入回数-1)×100 <Test on spatial working memory>
Evaluation was made using the Y-maze test. Specifically, we moved freely in a Y-shaped device in which three arms of the same size were connected at 120 ° for 8 minutes, and the arms that entered were recorded in order. Of the total number of intrusions into three arms, if you select a different arm three times in a row, it will be the spontaneous replacement action, count the total number of times of entry into the arm and the number of spontaneous replacement actions in time, from the following formula Spontaneous alternation behavior rate (%) was calculated. The higher the voluntary alternation action rate (%), the higher the spatial working memory and the better the cognitive function.
Spontaneous replacement action rate (%) = number of spontaneous replacement actions / (total entry count-1) x 100
　図１にY字迷路試験における自発交替行動率(％)を示す。治療開始時、各群の自発交替行動率は約71％(対照群で70.8±2.1％、アロマテラピー群で70.8±1.9％)であり、全個体の認知機能は正常範囲であった。そして、治療開始2ヵ月後には、自発交替行動率は対照群では52.6±1.9％に低下し認知機能障害が認められたが、アロマテラピー群は治療開始時とほぼ同じレベルを維持しており(64.4±2.2％)、2つの群に有意差が確認された。この結果は、アロマテラピーがSAMP8マウスの認知機能障害を予防あるいは改善することを示している。 Figure 1 shows the voluntary alternation behavior rate (%) in the Y-shaped maze test. At the start of treatment, the rate of spontaneous alternation in each group was approximately 71% (70.8 ± 2.1% in the control group and 70.8 ± 1.9% in the aromatherapy group), and the cognitive function of all individuals was within the normal range. Two months after the start of treatment, the rate of spontaneous alternation decreased to 52.6 ± 1.9% in the control group and cognitive impairment was observed, but the aromatherapy group maintained the same level as at the start of treatment ( 64.4 ± 2.2%), a significant difference was confirmed between the two groups. This result indicates that aromatherapy prevents or ameliorates cognitive impairment in SAMP8 mice.
実施例２
　アロマテラピーによる、脳内のアミロイドβ蛋白量に対する影響を調べた。 Example 2
The effect of aromatherapy on the amount of amyloid β protein in the brain was examined.
　具体的には、実施例１の治療終了時に、100mg/kgペントバルビタールナトリウム(共立製薬)を腹腔内投与して深麻酔下でマウスを開腹、心臓より生理食塩水で灌流して血液を取り除いた後に脳を摘出し嗅球と海馬を採取した。得られた組織に、0.5mMのフェニルメチルスルホニルフルオライド(Sigma-Aldrich)、1×PhosSTOP(Roche)及び1％プロテアーゼ阻害剤カクテル(ナカライテスク)を含む2×RIPA緩衝液を10倍量添加してホモジネートし、さらに15,000×g、4℃で60分間遠心分離して、上清を蛋白質抽出物として回収した。 Specifically, at the end of the treatment of Example 1, 100 mg / kg sodium pentobarbital (Kyoritsu Pharmaceutical) was intraperitoneally administered, the mouse was opened under deep anesthesia, and blood was removed by perfusion with physiological saline from the heart. Later, the brain was removed and the olfactory bulb and hippocampus were collected. To the resulting tissue, add 10 volumes of 2 × RIPA buffer containing 0.5 mM phenylmethylsulfonyl fluoride (Sigma-Aldrich), 1 × PhosSTOP (Roche) and 1% protease inhibitor cocktail (Nacalai Tesque). And then centrifuged at 15,000 × g and 4 ° C. for 60 minutes, and the supernatant was recovered as a protein extract.
　次に、アミロイドβELISAキット(和光純薬工業)を用いて、海馬中のアミロイドβ42量及びアミロイドβ40量を測定した。結果を図２に示す。 Next, the amount of amyloid β42 and the amount of amyloid β40 in the hippocampus were measured using an amyloid β ELISA kit (Wako Pure Chemical Industries). The results are shown in FIG.
　図２より、記憶機能に関する領域である海馬において、アロマテラピー群で有意にアミロイドβ蛋白量が低下していることが分かった。 2. From FIG. 2, it was found that the amount of amyloid β protein was significantly decreased in the aromatherapy group in the hippocampus, which is a region related to the memory function.
実施例３
　アロマテラピーによる、タウ蛋白のリン酸化に対する影響を調べた。 Example 3
The effect of aromatherapy on tau protein phosphorylation was investigated.
　具体的には、実施例２で調製した海馬蛋白質抽出物を用い、Western blotting法によるタウ蛋白定量を行った。該蛋白質抽出物を等量のTris-SDSβME試料緩衝液(Cosmo Bio)と混合し、100℃で10分間煮沸した。これらの試料を5～20％ポリアクリルアミドゲル(和光純薬工業)上で200Vで1時間電気泳動した。電気泳動した試料を、0.45μmポリビニリデンジフルオリド膜(Merck Millipore)に転写(条件：8V・60分間)した。さらに0.05％Tween20を含むトリス緩衝生理食塩水(TBS-T)に2.5％スキムミルクを溶解したブロッキング液で1時間ブロッキングした後、抗リン酸化タウAT8あるいは抗タウ抗体TAU-5(ブロッキング液で1：1000希釈)で4℃・一晩インキュベートした。TBS-Tで10分間3回洗浄した後、ホースラディッシュペルオキシダーゼ結合抗マウスImmunoglobulin G(ブロッキング液で1：3000希釈；GE Healthcare)で室温・1時間インキュベートした。TBS-Tで10分間3回洗浄した後、化学発光HRP基質(Merck Millipore)を用いてタウ蛋白を検出し、画像分析装置(ImageQuant LAS4000；GE Healthcare)を用いて分析した。結果を図３に示す。 Specifically, tau protein quantification was performed by Western blotting using the hippocampal protein extract prepared in Example 2. The protein extract was mixed with an equal volume of Tris-SDSβME sample buffer (Cosmo Bio) and boiled at 100 ° C. for 10 minutes. These samples were electrophoresed on a 5-20% polyacrylamide gel (Wako Pure Chemical Industries) at 200 V for 1 hour. The electrophoresed sample was transferred to a 0.45 μm polyvinylidene difluoride membrane (Merck Millipore) (conditions: 8 V, 60 minutes). Further, after blocking with a blocking solution prepared by dissolving 2.5% skim milk in Tris-buffered saline (TBS-T) containing 0.05% Tween20, anti-phosphorylated tau AT8 or anti-tau antibody TAU-5 (1: 1 with blocking solution). (1000 dilution) at 4 ° C. overnight. After washing 3 times with TBS-T for 10 minutes, the mixture was incubated with horseradish peroxidase-conjugated anti-mouse Immunoglobulin G (1: 3000 diluted with blocking solution; GE Healthcare) at room temperature for 1 hour. After washing with TBS-T three times for 10 minutes, tau protein was detected using a chemiluminescent HRP substrate (Merck Millipore) and analyzed using an image analyzer (ImageQuant LAS4000; GE Healthcare). The results are shown in FIG.
　図３より、TAU-5によって検出される総タウ蛋白量は両者で変わらなかったが、AT8によって検出されるリン酸化タウ蛋白量はアロマテラピー群において有意に減少していることが分かった。これらの結果は、アロマテラピーが脳におけるアミロイドβ蛋白の産生及びタウ蛋白のリン酸化の阻害によってSAMP8マウスにおける認知機能障害を改善することを示唆している。 FIG. 3 shows that the total tau protein amount detected by TAU-5 did not change between the two, but the phosphorylated tau protein amount detected by AT8 was significantly decreased in the aromatherapy group. These results suggest that aromatherapy improves cognitive dysfunction in SAMP8 mice by inhibiting amyloid β protein production and tau protein phosphorylation in the brain.
実施例４
　アロマテラピーによる、BDNFに対する影響を調べた。 Example 4
We investigated the effect of aromatherapy on BDNF.
　具体的には、実施例２で調製した嗅球蛋白質抽出物を用い、Western blotting法によるBDNF定量を行った。測定は実施例３と同様にして行い、電気泳動には15～20％トリシンゲル(和光純薬工業)を、さらに一次抗体として抗BDNF抗体N-20(1：200希釈；Santa Cruz Biotechnology)、二次抗体としてホースラディッシュペルオキシダーゼ結合抗ウサギImmunoglobulin G(1：3000希釈；GE Healthcare)を用いた。なおWestern blotting法によって検出されるBDNF蛋白質のうち、約30kDaのものを前駆型BDNF、約14kDaのものを成熟型BDNFとして定量した。結果を図４に示す。 Specifically, BDNF quantification was performed by Western blotting using the olfactory bulb protein extract prepared in Example 2. The measurement was performed in the same manner as in Example 3. For electrophoresis, 15-20% tricine gel (Wako Pure Chemical Industries, Ltd.) was used, and anti-BDNF antibody N-20 (1: 200 dilution; Santa Cruz Biotechnology), two primary antibodies. Horseradish peroxidase-conjugated anti-rabbit Immunoglobulin G (1: 3000 dilution; GE3000Healthcare) was used as the next antibody. Of the BDNF proteins detected by Western blotting, about 30 kDa was quantified as precursor BDNF and about 14 kDa as mature BDNF. The results are shown in FIG.
　図４より、アロマテラピーによる嗅覚刺激をより強く受ける嗅球において、前駆型BDNF・成熟型BDNFともに増加傾向がみられた。この結果は、アロマテラピーがBDNFの発現量を増加させることを示唆している。 FIG. 4 shows that both the precursor BDNF and the mature BDNF showed an increasing tendency in the olfactory bulb that receives olfactory stimulation more strongly by aromatherapy. This result suggests that aromatherapy increases the expression level of BDNF.
実施例５
　アロマテラピーによる、運動機能に対する影響を調べた。 Example 5
We investigated the effects of aromatherapy on motor function.
　具体的には、実施例１の治療終了時に、マウスの協調運動の能力を、ロータロッドトレッドミルMK-670(室町機械)を用いて評価した。マウスを回転ロッド上に置き、300秒かけて毎分40回の回転数になるまで加速し、マウスが落下するまでの時間を最大300秒間記録した。各マウスに2回の試験を実施し、その平均を計算した。また、マウスの四肢の握力を、マウス握力計MK-380M(室町機械)を用いて評価した。各マウスに3回の試験を実施し、その平均を計算した。結果を図５に示す。 Specifically, at the end of the treatment in Example 1, the ability of the mouse for coordinated movement was evaluated using a Rotarod treadmill MK-670 (Muromachi Kikai). The mouse was placed on a rotating rod and accelerated to 40 revolutions per minute over 300 seconds, and the time until the mouse fell was recorded for a maximum of 300 seconds. Each mouse was tested twice and the average was calculated. In addition, the grip strength of the limbs of the mouse was evaluated using a mouse grip strength meter MK-380M (Muromachi Kikai). Each mouse was tested three times and the average was calculated. The results are shown in FIG.
　図５では、図５Ａにロッドから落下するまでの時間(秒)を、図５Ｂに握力(g)を示す。図５Ａより、ロータロッド試験では、アロマテラピー群のマウスは、対照マウスと比較して落下するまでの時間が有意に増加した。図５Ｂより、握力強度試験では、アロマテラピー群は対照群と比較して握力が12％強かった。これらの結果は、アロマテラピー群のマウスは、対照群マウスよりも高い運動機能を有することを示唆している。 In FIG. 5, time (second) until dropping from the rod is shown in FIG. 5A, and gripping force (g) is shown in FIG. 5B. From FIG. 5A, in the rotarod test, the time until the mice in the aromatherapy group fell significantly compared to the control mice. From FIG. 5B, in the grip strength test, the grip strength of the aromatherapy group was 12% stronger than that of the control group. These results suggest that the aromatherapy group of mice has a higher motor function than the control group of mice.
　本発明の阻害剤は、脳内のアミロイドβ蛋白・リン酸化タウ蛋白を減少させる作用に優れることから、アルツハイマー病、ダウン症候群、タウオパチー（嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病等）の疾患や前記疾患に基づく症状の予防、改善又は治療に好適に用いることができる。また、BDNFを増加させることにより、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷、虚血性脳障害等の症状の予防、改善又は治療に用いることも可能である。 Since the inhibitor of the present invention is excellent in the action of reducing amyloid β protein / phosphorylated tau protein in the brain, Alzheimer's disease, Down's syndrome, tauopathy (twelve-granular dementia, neurofibrillary tangle cognition Disease, progressive supranuclear palsy, cerebral cortical degeneration, Pick's disease and the like) and symptoms based on the disease can be suitably used. Also, by increasing BDNF, Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve damage, ischemic It can also be used for the prevention, amelioration or treatment of symptoms such as brain disorders.

Claims (10)

  1. 　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とする、アミロイドβ蛋白の生成阻害剤。 An amyloid β protein production inhibitor comprising as an active ingredient one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  2. 　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を有効成分とする、タウ蛋白のリン酸化阻害剤。 A tau protein phosphorylation inhibitor comprising, as an active ingredient, one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  3. 　ローズマリーの抽出物とレモンの抽出物を含む第一抽出物と、ラベンダーの抽出物とオレンジの抽出物を含む第二抽出物を組み合わせてなる、請求項１又は２記載の剤。 The agent according to claim 1 or 2, comprising a combination of a first extract containing a rosemary extract and a lemon extract, and a second extract containing a lavender extract and an orange extract.
  4. 　ローズマリー抽出物がローズマリー・カンファーであり、ラベンダー抽出物が真正ラベンダーである、請求項１～３いずれか記載の剤。 The agent according to any one of claims 1 to 3, wherein the rosemary extract is rosemary camphor and the lavender extract is authentic lavender.
  5. 　アルツハイマー病、ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症、ピック病、レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の治療又は予防に用いられる、請求項１～４いずれか記載の剤。 Alzheimer's Disease, Down's Syndrome, Granular Dementia, Neurofibrillary tangle Dementia, Progressive supranuclear palsy, Cortical degeneration, Pick's disease, Lewy body dementia, Frontotemporal lobar degeneration Any one of claims 1-4, used for the treatment or prevention of a disease selected from depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain injury The agent described.
  6. 　ダウン症候群、嗜銀顆粒性認知症、神経原繊維変化型老年期認知症、進行性核上性麻痺、大脳皮質変性症及びピック病から選ばれる疾患の予防に用いられる、請求項１～５いずれか記載の剤。 Use according to any of claims 1 to 5, which is used for the prevention of diseases selected from Down's syndrome, addiction-granular dementia, neurofibrillary tangle dementia, progressive supranuclear palsy, cerebral cortical degeneration and Pick's disease. Or the agent described.
  7. 　レビー小体型認知症、前頭側頭葉変性症、うつ病、双極性障害、不安障害、パニック障害、統合失調症、自閉症、外的神経損傷及び虚血性脳障害から選ばれる疾患の予防に用いられる、請求項１～５いずれか記載の剤。 For prevention of diseases selected from Lewy body dementia, frontotemporal lobar degeneration, depression, bipolar disorder, anxiety disorder, panic disorder, schizophrenia, autism, external nerve injury and ischemic brain damage The agent according to any one of claims 1 to 5, which is used.
  8. 　請求項１～７いずれか記載の剤を含有してなる、組成物。 A composition comprising the agent according to any one of claims 1 to 7.
  9. 　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を吸入することを特徴とする、アミロイドβ蛋白の減少方法。 A method for reducing amyloid β protein, which comprises inhaling one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
  10. 　ローズマリー、レモン、ラベンダー及びオレンジからなる群より選ばれる１種又は２種以上の抽出物を吸入することを特徴とする、タウ蛋白のリン酸化阻害方法。 A method for inhibiting tau protein phosphorylation, which comprises inhaling one or more extracts selected from the group consisting of rosemary, lemon, lavender and orange.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021063018A (en) * 2019-10-10 2021-04-22 グリーン・テック株式会社 Neurodegenerative disease preventive and/or therapeutic agent

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115884780B (en) * 2020-05-28 2024-07-12 浦项工科大学校产学协力团 A composition containing Hibiscus sabdariffa, herba Rosmarini officinalis and grape seed extract as effective components for preventing or treating neurodegenerative diseases

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011236149A (en) * 2010-05-10 2011-11-24 Ogawa & Co Ltd In-vivo antioxidant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011236149A (en) * 2010-05-10 2011-11-24 Ogawa & Co Ltd In-vivo antioxidant

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ARA KATSUTOSHI: "Wisdom of foods with medicinal plants", NEW FOOD INDUSTRY, vol. 56, no. 2, 2014, pages 91 - 95, ISSN: 0547-0277 *
AYAZ M ET AL.: "Neuroprotective and anti-aging potentials of essential oils from aromatic and medicinal plants", FRONT AGING NEUROSCI., vol. 9, 2017, XP055633940, ISSN: 1663-4365, DOI: 10.3389/fnagi.2017.00168 *
CORNEJO A ET AL.: "Rosmarinic acid prevents fibrillization and diminishes vibrational modes associated to 6 sheet in tau protein linked to Alzheimer's disease", J ENZ INHIB MED CHEM., vol. 32, no. 1, 2017, pages 945 - 953, XP055633910, ISSN: 1475-6366, DOI: 10.1080/14756366.2017.1347783 *
HABTEMARIAM S: "Molecular pharmacology of Rosmarinis and Salvianolic acids : Potential seeds for Alzheimer's and Vascular dementia drugs", INT J MOL SCI., vol. 19, 3 February 2018 (2018-02-03), pages 458, XP055633921, ISSN: 1661-6596, DOI: 10.3390/ijms19020458 *
JIMBO D ET AL.: "Effect of aromatherapy on patients with Alzheimer's disease", PSYCHOGERIATRICS, vol. 9, 2009, pages 173 - 179, XP055038645, ISSN: 1346-3500, doi:10.1111/j.1479-8301.2009.00299.x *
KIMURA YUKI ET AL.: "Effect of aromatherapy on patients with Alzheimer's disease", DEMENTIA JAPAN, vol. 19, 2005, pages 77 - 85, ISSN: 1342-646X *
URAKAMI KATSUYA: "Dementia and aromatherapy", PSYCHIATRY, vol. 27, no. 5, 2015, pages 351 - 354 *
VIDEIRAR ET AL.: "Dose dependent inhibition of BACE-1 by the monoterpenoid 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone in cellular and mouse models of Alzheimer's disease", J NAT PROD, vol. 77, no. 6, 2014, pages 1275 - 1279, XP055633924, ISSN: 0163-3864, DOI: 10.1021/np400903w *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021063018A (en) * 2019-10-10 2021-04-22 グリーン・テック株式会社 Neurodegenerative disease preventive and/or therapeutic agent
JP7499015B2 (en) 2019-10-10 2024-06-13 小林製薬株式会社 Preventive and/or therapeutic agent for neurodegenerative disease

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