WO2021167012A1 - Composition pour la régulation de la fonction neuronale - Google Patents

Composition pour la régulation de la fonction neuronale Download PDF

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WO2021167012A1
WO2021167012A1 PCT/JP2021/006166 JP2021006166W WO2021167012A1 WO 2021167012 A1 WO2021167012 A1 WO 2021167012A1 JP 2021006166 W JP2021006166 W JP 2021006166W WO 2021167012 A1 WO2021167012 A1 WO 2021167012A1
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dementia
treatment
extract
group
cells
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Japanese (ja)
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礒田　博子
一憲 佐々木
義信 新井
内田　晴久
健吾 岩田
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国立大学法人筑波大学
ニッポー株式会社
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Publication of WO2021167012A1 publication Critical patent/WO2021167012A1/fr

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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
    • 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
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61P25/14—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
    • A61P25/20—Hypnotics; Sedatives
    • 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

Definitions

  • the present invention is selected from the group consisting of 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, and 3-o-ferloyl quinic acid, and isoorientin (luteolin-6-C-glucoside). Containing a composition useful as a food or pharmaceutical, comprising any of the above.
  • Polyphenols are natural compounds that are widely present in nature and are known to have various bioactive functions. Among them, chlorogenic acid contained in coffee beans, potatoes and the like has been reported to exhibit physiological activities such as an antioxidant effect, an inhibitory effect on blood glucose elevation, and an anti-obesity effect. In recent years, the effects of chlorogenic acid on nerve function have been studied, and the effects of improving autonomic nerve function, recovering from cerebral fatigue, and improving cognitive function have been reported (Patent Documents 1 to 4).
  • sugar cane contains polyphenols such as chlorogenic acid.
  • Sugarcane uses stems with a high sucrose content as a sugar-making raw material, and the head of the treetop (pointing to the tip of the ear above the 5th leaf thickening zone) is removed at the time of harvesting, and most of it is used as feed for cattle.
  • a method for producing sugarcane polyphenol-containing substances from sugarcane ears has been proposed (Patent Document 5).
  • Non-Patent Document 1 the antioxidant components of the head of sugar cane were identified as chlorogenic acid (5-o-cafe oil quinic acid) and neochlorogenic acid (3-o-cafe oil quinic acid)
  • Non-Patent Document 2 It has also been proposed to produce brown sugar rich in polyphenols by adding the head of sugarcane treetop to the brown sugar raw material
  • Isoorientin is known to be contained in cereals and rooibos tea (an extract of Aspalathus linearis leaves), but it has recently been reported that oral administration improved scopolamine-induced cognitive impairment in mice. (Non-Patent Document 3).
  • the present inventors have for the prevention or treatment of Alzheimer-type dementia having at least caffeic oil quinic acid (such as di-o-caffeic oil quinic acid) having a structure ester-bonded with two or more caffeic acids.
  • caffeic oil quinic acid such as di-o-caffeic oil quinic acid
  • An object of the present invention is to provide a novel material derived from a natural product and useful for regulating nerve function.
  • the present invention provides: [1] At least one selected from the group consisting of 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin, which comprises the following steps. Including, manufacturing method of food material or pharmaceutical material: At least one selected from the group consisting of 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin from the head of sugar cane using an aqueous solvent. The process of obtaining a fraction containing. [2] The production method according to 1, which is a method for producing a food material or a pharmaceutical material containing at least isoorientin.
  • Food or pharmaceutical materials include senile dementia, Alzheimer-type dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumors, dementia caused by chronic subdural hematoma, and normal compressed brain.
  • Treatment of dementia including dementia caused by edema, post-dementia dementia, and Parkinson-type dementia; mild cognitive impairment (MCI), and non-dementia cognitive impairment, including cognitive decline due to aging.
  • Treatment of , And treatment of dementia including bipolar disorder; for any one selected from the group consisting of improved motivation / motivation and improved circadian rhythm disturbance, any one of 1-4.
  • a food composition or a pharmaceutical composition for regulating nerve function which comprises either luteolin or a glycoside thereof.
  • R 1 , R 2 , and R 3 are independently H, cafe oil groups, or ferroyl groups.
  • the composition according to 8 which comprises isoorientin, 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, and 3-o-ferloyl quinic acid.
  • Senile dementia Alzheimer-type dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumors, dementia caused by chronic subdural hematoma, dementia caused by normal pressure cerebral edema, spinal cord Treatment of dementia, including post-dementia dementia and Parkinson-type dementia; Treatment of non-dementia cognitive impairment, including mild cognitive impairment (MCI) and cognitive decline due to aging; Improvement of learning impairment , Improvement of memory impairment; Improvement of learning ability, Improvement of memory ability; Treatment of memory decline; Treatment of cerebral infarction and peripheral neuropathy; Includes attention dementia hyperactivity disorder (ADHD), depression, and bipolar disorder , Treatment of dementia; the composition according to any one of 7 to 10 for any selected from the group consisting of improved motivation / motivation and improved circadian rhythm disorder.
  • ADHD attention dementia hyperactivity disorder
  • depression depression
  • bipolar disorder Treatment of dementia
  • Treatment of dementia the composition according to any one of 7 to 10 for any selected from the group consisting of improved motivation / motivation and improved circadian rhythm disorder.
  • a food or pharmaceutical material containing a component having a nerve function regulating action can be produced from a natural product.
  • the nerve function can be regulated by the food material, the pharmaceutical material, the food composition using them, or the pharmaceutical composition obtained by the present invention.
  • the cell viability of the amyloid ⁇ -treated group was reduced by about 40% compared with the control group, whereas the cell viability of the amyloid ⁇ + sugar cane head extract simultaneous treatment group was compared with that of the amyloid ⁇ alone-treated group. A significant concentration-dependent increase was confirmed.
  • Cellular evaluation of four compounds contained in sugarcane treetop extract A cell viability measurement test and an ATP production test using SH-SY5Y cells were performed. The concentration of each compound was the concentration contained in the treetop extract 50 ⁇ g / mL (3-CQA: 0.50 ⁇ M, 5-CQA: 0.70 ⁇ M, 3-FQA: 0.85 ⁇ M, isoorientin: 0.477 ⁇ M). ..
  • the amounts of dopamine and noradrenaline in the cerebral cortex were significantly increased as compared with the SAMP8 + water administration group.
  • the amounts of acetylcholine and serotonin showed an increasing tendency.
  • Efficiency of component extraction from sugarcane treetop head From 1 g of the dried sugarcane treetop head, components were extracted using ethanol having different concentrations of 20%, 40%, 60%, and 80%, respectively, as extraction solvents. As a result of quantitative analysis, the content of each polyphenol component per 100 parts by weight of the extract was the highest among the samples extracted using 40% ethanol as a solvent. Comparison of bioactivity on nerve cells by sugarcane treetop extract.
  • Each sample obtained by the above method was redissolved in 70% ethanol and used for a cell viability measurement test using a human nerve model SH-SY5Y cell.
  • a concentration-dependent and significant increase in cell viability was confirmed in the amyloid ⁇ (A ⁇ ) + sugar cane head extract treatment group compared with the A ⁇ alone treatment group.
  • the cell viability was highest in the group treated with A ⁇ + sugar cane head extract (solvent 40% ethanol). Effects of four compounds contained in sugarcane treetop extract on nerve cell viability.
  • the n3-CQA, 5-CQA, 3-FQA and ISO dissolved in 70% ethanol were used for the cell viability measurement test using SH-SY5Y cells.
  • 3-CQA, 5-CQA and ISO showed a significant increase in SH-SY5Y cell viability in a concentration-dependent manner. Effect of four compounds contained in sugarcane treetop extract on ATP production in nerve cells. An ATP production test was conducted using SH-SY5Y cells using the above-mentioned four compounds. 3-CQA, 5-CQA and ISO showed a significant increase in the rate of ATP production in SH-SY5Y cells. Effect on gene expression of glycolytic enzymes such as sugar cane treetop extract. To evaluate the effects of four compounds contained in sugar cane head extract or sugar cane head extract on gene expression of enzymes (PGK1, PGAM1, PKM, PC) that catalyze glycolytic reactions. Gene expression analysis in SH-SY5Y cells was performed.
  • ACTB was used as the internal standard. Treatment of sugarcane treetop extract or standard compound for 24 hours significantly increased the expression of PGK1, PGAM1, PKM, and PC as compared with the control group. A mechanism that promotes ATP production in nerve cells, which is suggested by the results of gene expression analysis of glycolytic enzymes. Photograph of neural stem cells (hNSC) derived from human foetation. hNSC floats in a medium for neural stem cell proliferation without adhering to the bottom surface of the flask, and proliferates while forming a spherical cell mass (neurosphere). Gene expression analysis of NES (stem cell marker) at Neurosphere.
  • NES stem cell marker
  • TUBB3 which is a marker for neurons (nerve cells) in human embryo-derived neural stem cells, and astrocytosis or transit amplifying (TA) cells (finite proliferation located between stem cells and differentiated cells)
  • TA transit amplifying
  • GFAP which is a marker for cells
  • PDGFRA which is a marker for oligodendrocytes
  • NES which is a marker for neural stem cells
  • the sugar cane treetop extract-treated group and the compound mixture-treated group showed a large increase in NTRK2 expression even when compared with the ginkgo leaf extract-treated group used as a positive control.
  • the present invention comprises at least one selected from the group consisting of 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin, which comprises the following steps.
  • the present invention relates to a method for producing a food material or a pharmaceutical material, which comprises, as a functional ingredient. At least one selected from the group consisting of 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin from the head of sugar cane using an aqueous solvent. The process of obtaining a fraction containing.
  • the present invention also relates to a food composition or a pharmaceutical composition containing either luteolin or a glycoside thereof, and any of the chlorogenic acids described below as an active ingredient.
  • Food materials or pharmaceutical materials, or food compositions or pharmaceutical compositions related to the present invention (hereinafter, food materials, pharmaceutical materials, food compositions, and pharmaceutical compositions related to the present invention are collectively referred to as "the present invention.” (Sometimes referred to as “composition, etc.”) contains chlorogenic acids as a functional ingredient or an active ingredient.
  • chlorogenic acids refer to compounds represented by the following formulas.
  • R 1 , R 2 , and R 3 are independently H, cafe oil groups, or ferroyl groups, respectively.
  • chlorogenic acids examples include 3-o-cafe oil quinic acid, 4-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, 4-o-ferloyl quina. Acids, 5-o-ferloyl quinicic acid, 3,4-di-o-cafe oil quinic acid, 3,5-di-o-cafe oil quinic acid, and 4,5-di-o-cafe oil quinic acid Is included.
  • composition and the like of the present invention preferably contain at least one selected from the group consisting of the above three compounds as chlorogenic acids, and more preferably contain at least two selected from the group. It is even more preferable that all three are included.
  • the composition and the like of the present invention contain luteolin or a glycoside thereof as a functional ingredient or an active ingredient.
  • the glycoside of luteolin is a compound in which a sugar is glycosidic bonded to luteolin (3', 4', 5,7-tetrahydroxyflavone).
  • sugars include glucose, galactose, fructose, glucuronic acid, rhamnose, xylose, arabinose, apiose, rutinose, gentiobiose, primeberose, and dichitoxose.
  • luteolin glycosides examples include luteolin 4'-o-glucoside, luteolin 4'-o-glucuronide, luteolin 5-glucuronide, luteolin 5-glucoside, luteolin 5-lucinoside, luteolin 5-o-glucuronide, luteolin 6 -Glucocide (isoorientin), luteolin 6-c- ⁇ -d-glucopyranoside 8-c- ⁇ -l-arabinopyranoside, luteolin 6-c-arabinoside, luteolin 7- (2-o-apiosil glucoside) ), Luteolin 7- (2-o-glucuronosyl) glucuronide, luteolin 7- (2-sulfoglucoside), luteolin 7-o-glucoside, luteolin 7-o-galactoside, luteolin 7-o-glucuronide, luteolin 7,4' -Di-o-glucuronide, luteolin 7- [6-o- (2-methylbutyryl)
  • composition and the like of the present invention contain a compound represented by the following formula as luteolin or a glycoside thereof.
  • R 4 and R 5 are H or sugar residues, respectively.
  • composition and the like of the present invention contain at least one selected from the group consisting of the above two compounds as luteolins, and it is more preferable that isoorientin is contained.
  • compositions and the like of the present invention include 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, and 3-o-ferloyl quinic acid as chlorogenic acids. It contains isoorientin, which is a glycoside of luteolin.
  • the composition or the like containing all of these four kinds of components may be the sugarcane treetop extract itself or a composition containing the same as an active ingredient. This application is the first to report that the head of sugarcane treetop contains these four kinds of compounds.
  • the extract containing the four target compounds is dried from 1 g of the dried sugarcane treetop head (including leaves and bark). It can be obtained by weight from 100 mg to 170 mg, more specifically from 130 mg to 140 mg.
  • the amount of 3-o-cafe oil quinic acid contained in the sugarcane treetop extract provided by the present invention can be 0.20 mg or more per 100 g (dry weight) of the extract, regardless of the content of other components. .. By optimizing the extraction conditions, it can be 0.30 mg or more, 0.35 mg or more, or 0.40 mg or more regardless of the content of other components.
  • the amount of 5-o-cafe oil quinic acid contained in the sugarcane treetop extract provided by the present invention can be 1.0 mg or more per 100 g (dry weight) of the extract, regardless of the content of other components. .. By optimizing the extraction conditions, the amount can be 1.5 mg or more, 2.0 mg or more, or 2.5 mg or more regardless of the content of other components.
  • the amount of 3-o-ferloylquinic acid contained in the sugarcane treetop extract provided by the present invention can be 0.10 mg or more per 100 g (dry weight) of the extract, regardless of the content of other components. .. By optimizing the extraction conditions, it can be 0.13 mg or more, 0.16 mg or more, or 0.20 mg or more regardless of the content of other components.
  • the amount of isoorientin contained in the sugarcane treetop extract provided by the present invention can be 0.80 mg or more per 100 g (dry weight) of the extract, regardless of the content of other components.
  • the amount can be 1.0 mg or more, 1.2 mg or more, or 1.4 mg or more regardless of the content of other components.
  • the 3-o-cafe oil quinic acid contained in 100 g (dry weight) of the sugar cane shoot head extract is 0.40 mg or more and 0.60 mg or less, and the 5-o-cafe oil quinic acid is 2.5 mg or more and 3.5 mg or less, 3-o-ferloylquinic acid is 0.20 mg or more and 0.30 mg or less, and isoorientin is 1.4 mg or more and 1.8 mg or less.
  • the sugarcane shoot head may contain 2.1-2.6 mg / g (dry weight) of isoorientin.
  • Isoorientin is also known to be contained in rooibos tea. Extracts from 10 g of dried green rooibos tea leaves in 500 ml of hot water have been reported to contain 26 mg of isoorientin (Food Chemistry 128: 338-347, 2011).
  • compositions and the like of the present invention include 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin 4 It contains a type of compound as an active ingredient, or contains a sugar cane head extract as an active ingredient. According to the studies by the present inventors, treatment with 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, and 3-o-ferloyl quinic acid alone causes NTRK2 expression at the experimental concentrations.
  • TrkB Neurotrophic tyrosine kinase receptor type 2, NTRK2
  • TrkB Neurotrophic tyrosine kinase receptor type 2, NTRK2
  • BDNF brain-derived neurotrophic factor
  • composition or the like of the present invention contains four kinds of compounds, their ratio is not particularly limited as long as it has the desired effect, and for example, 3-o-cafe oil quinic acid: 5-o-cafe oil quinic acid: 3-o-ferloylquinic acid: isoorientin can have a molar ratio of 1: 0.10 to 10: 0.15 to 15: 0.080 to 8.0, 1: 0.30 to 3.0: 0.40 to 4.0: 0.20 to 2.0. It can be 1: 0.60 to 1.5: 0.80 to 2.0: 0.40 to 1.0.
  • the sugarcane treetop head refers to the tip portion of the sugarcane (scientific name: Saccharum officinarum L.) above the fifth leaf thickening zone.
  • the sugarcane treetop head used for producing the composition of the present invention may be the entire sugarcane treetop head, a portion including leaves and bark, and a portion excluding leaves and bark. There may be.
  • the sugarcane treetop head may be raw or dried. Drying can be performed by cold air drying or sun drying.
  • the sugarcane treetop head may be cut, shredded, or crushed to increase extraction efficiency.
  • the means for extraction from the head of the sugar cane treetop is not particularly limited, and extraction may be performed using a liquid extraction solvent, or supercritical extraction or subcritical extraction may be performed using a supercritical fluid or a subcritical fluid. You may.
  • the extraction solvent is preferably a solvent that is effective in extracting luteolin or its glycosides and that is effective in extracting chlorogenic acids.
  • solvents are water, methanol, ethanol, isopropanol, butanol, propylene glycol, butylene glycol, glycerin, acetone, ethyl acetate, and methyl ethyl ketone, and mixtures thereof.
  • Preferred examples are aqueous solvents, such as water, or a mixture of water and any of the groups selected from the group consisting of methanol, ethanol, isopropanol, butanol, propylene glycol, butylene glycol, glycerin.
  • a mixed solvent of water and ethanol is used.
  • the concentration of ethanol can be 5% or more, preferably 10% or more, more preferably 20% or more, and even more preferably 25% or more.
  • the concentration of ethanol can be 95% or less, preferably 90% or less, and more preferably 85% or less. It can be 70% or less.
  • the concentration of ethanol can be 60% or less, preferably 50% or less, more preferably 40% or less, and even more preferably 35% or less.
  • the ethanol concentration of the extraction solvent containing ethanol is indicated, it is a value based on the volume (v / v) unless otherwise specified, and unless otherwise specified, ethanol is water. It is mixed.
  • the extraction operation may be performed at room temperature, but preferably when heated under reflux cooling, the components can be extracted efficiently and quickly.
  • the extraction temperature can be 60 ° C. or higher, preferably 70 ° C. or higher, and more preferably 80 ° C. to 100 ° C. When performed under heating, the extract can be obtained efficiently and with high purity.
  • the extraction may be carried out under pressure and can be carried out at 5 MPa (50 bar) or more, preferably 7.5 MPa (75 bar) or more, and may be 10 MPa (100 bar) or more.
  • heating may be performed in order to efficiently and quickly extract the target component.
  • the temperature can be 25 ° C. or higher, preferably 30 ° C. or higher, more preferably 35 ° C. or higher, and even more preferably 40 ° C. or higher.
  • the ratio of the raw material to the extraction solvent, the extraction time, and the number of repetitions of the extraction operation can be adjusted appropriately in consideration of the extraction efficiency.
  • the fluids include, for example, water, carbon dioxide, ethylene, propylene, ethane, propane, dinitrogen monoxide, chlorodifluoromethane, chlorotrifluoromethane, xenone, ammonia, and methanol and ethanol. Lower alcohols such as can be used. From the viewpoint of safety, it is preferable to use water, ethanol, a mixture thereof, or carbon dioxide.
  • the insoluble residue can be removed, concentrated by a conventional method, and dried by means such as spray drying and freeze drying.
  • extract in the present invention includes an extract extracted from a raw material with a solvent, a concentrate of the extract, a dried product, and a crude product.
  • compositions of the present invention and the like can be used for neural function regulation.
  • Nerve function regulation protects nerve cells from amyloid ⁇ , antioxidants (suppression of environmental stress stimulation), anti-inflammatory (improvement of inflammatory state), increased secretion of neurotransmitters in the brain, promotion of ATP production in nerve cells , Promotion of neurogenesis by proliferation of nerve stem cells, treatment of dementia, improvement of non-dementia cognitive disorder, improvement of learning disorder, improvement of memory disorder, improvement of learning ability, improvement of memory ability, treatment of mental illness, Includes improvement of motivation and motivation, and improvement of disturbance of circadian rhythm.
  • sugarcane shoot head extract was able to reduce the decrease in cell viability due to amyloid ⁇ treatment in SH-SY5Y, which is a cell line derived from human neuroblastoma.
  • composition and the like of the present invention can be expected to have a neuroprotective effect from amyloid ⁇ , and are useful for treating diseases or conditions exacerbated by amyloid ⁇ .
  • Amyloid ⁇ (A ⁇ ) is a peptide consisting of 40 to 42 amino acids, which is toxic to nerve cells and causes cell death. In Alzheimer's disease, A ⁇ aggregates to form insoluble fibrosis, which becomes amyloid and deposits in the brain. Diseases or conditions exacerbated by amyloid ⁇ include Alzheimer's disease.
  • MAP2K4 Mitogen-activated protein kinase 4
  • MAPK14 Mitogen-activated protein kinase 14
  • MAPK8 Mitogen-Activated Protein kinase 8
  • MAPK8 Mitogen-Activated Protein kinase 8
  • SH-SY5Y cells by treatment with amyloid ⁇ , PI3KCA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalyst Subunit Alpha)
  • AKT1 AKT Serine / Threonine Kinase 1
  • PARP1 Poly (ADP-Ribose) Polymerase 1)
  • the above gene clusters respond to stress stimuli on cells and regulate a wide variety of cellular processes such as cell proliferation, growth, differentiation, transformation and apoptosis. Since the expression fluctuations of these amyloid ⁇ -induced genes were improved, the extract used in this experiment suppressed environmental stress stimuli such as oxidative stress (antioxidation, etc.) and caused inflammation in nerve cells. It may be useful for improving the condition (neuroinflammation, etc.) (anti-inflammatory).
  • the sugarcane treetop extract-administered group was compared with the SAMP8 water-administered group from the 5th day after the start of the experiment to the platform. A significant reduction in the arrival time of was observed.
  • a significant increase in the number of crossings across the platform installation site was observed in the sugarcane treetop extract administration group compared with the water administration group, and the staying time in the platform installation area tended to increase. rice field.
  • the compositions of the present invention have an improving effect on cognitive decline, and for example, dementia (senile dementia, Alzheimer-type dementia, cerebrovascular dementia).
  • dementia senile dementia, Alzheimer-type dementia, cerebrovascular dementia.
  • Various diseases such as dementia, post-traumatic dementia, dementia caused by brain tumors, dementia caused by chronic subdural hematoma, dementia caused by normal pressure cerebral edema, dementia after meningitis, and Parkinson-type dementia. It may be useful for the treatment of dementia caused by).
  • the compositions and the like of the present invention may be useful for the treatment of non-dementia cognitive impairment such as mild cognitive impairment (MCI) and deterioration of cognitive function due to aging.
  • MCI mild cognitive impairment
  • the compositions and the like of the present invention may be useful for improving learning or memory disorders (learning and memory disorders associated with brain developmental disorders), improving learning ability, and improving memory ability.
  • the amounts of dopamine and noradrenaline in the cerebral cortex were significantly increased in the sugarcane head extract-administered group of SAMP8 as compared with the SAMP8 water-administered group.
  • the amounts of acetylcholine and serotonin showed an increasing tendency.
  • compositions of the present invention containing sugar cane head extract may be useful for the treatment of diseases or conditions that are ameliorated by increased secretion of transmitters in the brain. Furthermore, since an improving effect on the decrease in dopamine and noradrenaline secretion was confirmed, mental illness including attention deficit hyperactivity disorder (ADHD), depression, and bipolar disorder (manic depression, etc.) It can be useful for the treatment of diseases. In addition, since it was confirmed that it has an improving effect on the decrease in dopamine secretion, it may be useful for improving motivation and motivation.
  • ADHD attention deficit hyperactivity disorder
  • depression depression
  • bipolar disorder manic depression, etc.
  • the composition of the present invention and the like may be useful for improving the disorder of the circadian rhythm (biological clock).
  • the composition can be expected to be safe to use without unnecessarily enhancing the secretion of neurotransmitters in the brain.
  • compositions of the present invention can improve sleep (eg, improve sleep quality, promote non-rem sleep, improve sleep rhythm), or sleep disorders. It can also be expected for the treatment of (for example, insomnia).
  • sugar cane shoot head extract and 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin are used. Increased survival rate in SH-SY5Y.
  • sugar cane shoot head extract, 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, and isoorientin were able to promote the production of ATP.
  • PGK1 phosphoglycerate kinase
  • PGAM1 phosphoglycerate mutase
  • PLM pyruvate kinase
  • PC pyruvate carboxylase
  • compositions of the present invention and the like can be used to promote the production of ATP in nerve cells, and are useful for treating diseases or conditions that are improved by promoting the production of ATP in nerve cells. obtain.
  • it may be useful for the treatment of diseases or conditions that are ameliorated by elevated expression of any gene selected from the group consisting of PGK1, PGAM1, PKM, and PC.
  • TUBB3 Tebulin beta III / Tuj1
  • GFAP Glial fibrillary acidic protein
  • TA transit amplifying
  • ASCL1 and HES1 are basic helix-loop-helix (bHLH) factors that control fate decisions in cell development and differentiation.
  • bHLH basic helix-loop-helix
  • ASCL1 and HES1 are basic helix-loop-helix (bHLH) factors that control fate decisions in cell development and differentiation.
  • the expression level of HES1 is high and the expression level of ASCL1 is kept low in the state where the stem cell property is maintained ( ⁇ dormant state).
  • the expression level of HES1 decreases and the expression level of ASCL1 increases, so that the neural stem cells differentiate into nerve cells.
  • ASCL1 in hNSC was increased and the expression of HES1 was decreased in a treatment concentration-dependent manner by the treatment with the sugarcane treetop extract.
  • hNSCs having formed spheres were treated with sugar cane shoot head extract, and Tuj1 (Tublin beta III) and GFAP-positive cells were detected by immunostaining.
  • Tuj1 Tublin beta III
  • GFAP-positive cells Astrosite (GFAP) was detected.
  • the proportion of neurons (Tuj1-positive cells) did not change, but the proportion of neurons (Tuj1-positive cells) showed a treatment concentration-dependent increase.
  • an extension of the total length of the protrusions of astrocytes was observed under the treatment of sugarcane treetop extract.
  • sugar cane headtop extract can induce neuronal differentiation from neural stem cells (induction of differentiation into neurons can be rephrased as neurogenesis and promotion of neuronal production) and promote astrocyte development. can.
  • the symptoms can be improved by forming a new neural circuit from the newborn neurons produced by the treatment of the sugar cane headtop extract and recovering the lost neuroplasticity.
  • composition and the like of the present invention can be useful for promoting neurogenesis by proliferation of neural stem cells. It may also be useful for the treatment of diseases or conditions that are ameliorated by promoting neurogenesis through the proliferation of neural stem cells.
  • a therapeutic drug for brain tumors must cross the blood-brain barrier, which protects the brain.
  • Conditions that easily cross the blood-brain barrier include (1) small molecular weight, (2) low protein binding rate, and (3) high lipophilicity.
  • Temodar a drug applicable to malignant glioma
  • Temodar has an extremely small molecular weight of 194, so it has the advantage of easily passing through the blood-brain barrier and reaching the affected area.
  • the molecular weights of the four components 3-o-cafe oil quinic acid, 5-o-cafe oil quinic acid, 3-o-ferloyl quinic acid, and isoorientin according to the present invention are 354, 354, 368, and 448, respectively. Is. It has been reported that monocafe oil quinic acid crosses the blood-brain barrier and reaches brain tissue after ingestion. (Fitorick 99: 139-152, 2014)
  • compositions of the present invention can be expected to improve symptoms by effectively improving the TrkB signal, promoting neurogenesis, and suppressing the decrease in nerve cells with aging. More specifically, the compositions of the present invention include diseases in which BDNF-TrkB signal reduction and reduction of nerve cells due to reduction of neurogenesis have been reported, specifically, memory deterioration in aging and Alzheimer's disease. It can be used to treat depression.
  • the term "treatment" for a disease or condition includes reduction of risk of onset, delay of onset, prevention, treatment, suspension of progression, and delay.
  • Treatment includes actions performed by doctors for the purpose of treating illness, and persons other than doctors, such as dietitians (including registered dietitians and sports nutritionists), public health nurses, midwives, nurses, clinical laboratory technicians, and sports. This includes non-therapeutic acts performed by instructors, beauty staff, estheticians, drug manufacturers, drug sellers, food manufacturers, food sellers, etc.
  • the treatment includes actions performed by veterinarians for the purpose of treating non-human animal diseases, and persons other than veterinarians, such as veterinarian nurses, pet animal care managers, servants, zookeepers, and veterinary medicines.
  • Non-therapeutic acts performed by manufacturers, veterinary drug sellers, pet food manufacturers, pet food sellers, etc. Further treatments include recommendations for administration or intake of specific foods, dietary guidance, health guidance, nutritional guidance (nutrition guidance necessary for medical treatment of the sick and injured, and nutritional guidance for maintaining and improving health. ), Food management, and guidance necessary for improving nutrition related to food.
  • the target of the treatment in the present invention includes humans (individuals), and preferably, it is desirable to perform any of the above-mentioned treatments, or a human who needs to be subjected to any of the above-mentioned treatments.
  • the target of the treatment in the present invention may be an animal other than human, and examples thereof include pets such as dogs, cats, rabbits, hamsters, guinea pigs, and squirrels (sometimes referred to as pet animals and companion animals). Examples include domestic animals such as cows and pigs, experimental animals such as mice and rats, and animals bred in zoos and the like.
  • the growth stage of the target non-human animal is not particularly limited, and the target of the treatment of the present invention may be, for example, a puppy, an adult dog, an elderly dog, a kitten, an adult cat, or an elderly cat.
  • composition may be the sugar cane head extract itself, and may contain an active ingredient (for example, sugar cane head extract) and other components.
  • composition of the present invention can be a food composition or a pharmaceutical composition.
  • foods include not only solids but also liquids such as soups, beverages and drinks, unless otherwise specified. Further, unless otherwise specified, not only those intended for humans but also those intended for non-human animals, such as feed and pet food, are included. Furthermore, unless otherwise specified, foods include general foods, health foods, supplements, foods with health claims (foods for specified health use (commonly known as Tokuho), foods with nutritional claims, foods with functional claims), and therapeutic foods (foods with functional claims). Those that serve the purpose of treatment. Those that are cooked based on the menu prepared by a nutritionist, etc. after a doctor puts out a meal sheet.), Dietary foods, ingredient-adjusted foods, salt-reduced foods, nursing foods, calorie-reduced foods , Including diet foods.
  • composition of the present invention is in the form of an oral drug, a health food, or a supplement
  • examples of the dosage form include soft capsules, hard capsules, tablets, pills, powders, granules, and fine granules. , Jelly, tubed, and drinks.
  • the content of the sugarcane treetop extract, which is an active ingredient, in the composition of the present invention can be designed in consideration of the daily intake and dose.
  • the sugarcane treetop extract can be contained as a solid in an amount of 0.2 to 2,000 mg, preferably 0.5 to 1,000 mg, more preferably 1 to 500 mg, and further preferably 2 to 2. It can be 200 mg.
  • the daily dose can be ingested and administered in multiple doses, for example, 2 to 4 doses.
  • composition of the present invention may contain components other than the sugarcane treetop extract as long as the desired effect can be exhibited.
  • Other ingredients may be various food-acceptable additives or pharmaceutically acceptable additives. Examples of this include excipients, antioxidants (antioxidants), flavors, seasonings, sweeteners, colorants, thickeners, color formers, bleachers, preservatives, gum bases, bitterness agents, etc. Enzymes, brighteners, acidulants, emulsifiers, fortifiers, manufacturing agents, binders, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, coagulants and the like.
  • Other components may be functional components other than sugarcane treetop extract.
  • other functional ingredients include amino acids (eg, branched chain amino acids, astaxanthin), unsaturated fatty acids (eg, EPA, DHA), vitamins, trace metals, polyphenols, egg yolk extract, honey.
  • amino acids eg, branched chain amino acids, astaxanthin
  • unsaturated fatty acids eg, EPA, DHA
  • vitamins trace metals
  • polyphenols eg., EPA, DHA
  • EPA unsaturated fatty acids
  • vitamins trace metals
  • polyphenols eg, egg yolk extract
  • honey Processed products, brown sugar, oligosaccharides, dietary fiber, glucosamine, chondroitins, CoQ10, fucoidan, fucoxanthin, astaxanthin, placenta, yeast extract, black vinegar concentrate, plant extract (garlic extract, ginkgo leaf extract, tea extract) Amino acids, bilberry extract, blueberry extract,
  • composition of the present invention can be ingested and administered with a meal, before or after a meal.
  • composition of the present invention can be labeled as being usable for the treatment of the above-mentioned diseases or conditions, and can be labeled as being recommended for ingestion for the above-mentioned subjects.
  • the labeling can be direct or indirect, and examples of direct labeling are descriptions on tangible objects such as the product itself, packages, containers, labels, tags, etc., and examples of indirect labeling are Includes advertising and publicity activities by location or means such as websites, stores, exhibitions, signboards, bulletin boards, newspapers, magazines, television, radio, mailings, e-mails, etc.
  • [Component analysis of sugar cane treetop extract] ⁇ Preparation of sugarcane treetop extract sample> From 1 g of dried sugarcane treetop head (including leaves and bark), components were extracted (number of extractions: 4 times) using an automatic extraction device using 80% ethanol as an extraction solvent. The solution after extraction was concentrated using a rotary evaporator, and then lyophilized to obtain a sample. The obtained sample was redissolved in 100% methanol (concentration: 100 mg / mL) and then sterilized by a 0.22 ⁇ m filter, which was used for chemical analysis using high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • HPLC high performance liquid chromatography
  • sugarcane treetop extract sample A solvent extraction method was used as a method for extracting polyphenol components from sugarcane treetop powder. Specifically, the sugarcane treetop head was soaked in 10 mL of 70% ethanol per 1 g of dried product for 14 days (inverted stirring on the 7th day of extraction), and the components were eluted in the solvent. Then, a sample was obtained by concentrating and drying the extraction solvent sterilized by a 0.22 ⁇ m filter. The sample was dissolved in 70% ethanol and used for the cell test described later.
  • SH-SY5Y cells were used as a human nerve model cell.
  • SH-SY5Y is a cell line derived from human neuroblastoma and is widely used as a model cell for evaluating nerve function.
  • SH-SY5Y cells were seeded in 100 mm sterile petri dishes (BD Falcon, USA) and 15% heat inactivated in 1: 1 (v / v) mixture of Dulbecco's Modified eagle medium and Ham's F-12 medium (Lonza, Japan).
  • the sugarcane treetop extract was added so that its concentration was 10 ⁇ g / mL, 25 ⁇ g / mL, or 50 ⁇ g / mL.
  • the cell viability was evaluated by measuring the absorbance using the MTT method. Specifically, the medium was removed from the wells, 5 mg / ml MTT solution dissolved in PBS was added (100 ⁇ l / well), and the mixture was incubated at 37 ° C. in the presence of 5% CO 2 for 6 hours, and then 10%. Sodium dodecyl sulfate (SDS) was added (100 ⁇ l / well) and incubated at 37 ° C.
  • SDS sodium dodecyl sulfate
  • the concentration of each compound standard was calculated by calculating the content of 50 ⁇ g / mL of sugar cane headtop extract from the quantitative results of HPLC analysis. Specifically, 3-CQA had a concentration of 0.50 ⁇ M, 5-CQA had a concentration of 0.70 ⁇ M, 3-FQA had a concentration of 0.85 ⁇ M, and ISO had a concentration of 0.477 ⁇ M.
  • the standard product of each compound was dissolved in 70% ethanol for the cell test.
  • RT-PCR reverse transcription polymerase chain reactions
  • Superscript III reverse transcriptase kit Invitrogen, USA
  • 2720 Thermal cycler Applied Biosystems, USA
  • TaqMan real time RT PCR amplification reactions using the 7500 Fast Real Time PCR system was carried out to quantify transcripts, and it is a gene involved in the signal pathway involved in the mechanism of action of nerve cell death by amyloid ⁇ treatment as a primer.
  • MAP2K4 Hs00387426_m1
  • MAPK14 Hs01051152_m1
  • MAPK8 Hs01548506_m1
  • PI3KCA Hs00907957_m1
  • AKT1 Hs00178280_m1
  • PARP1 Hs00242302_m1
  • PARP1 Hs00242302_m1
  • PARP1 Hs00242302_m1
  • GAPDH Hs02786624_m1 was used as the internal standard.
  • the obtained values were subjected to a significant difference test (* P ⁇ 0.05, ** P ⁇ 0.01) by the One-way ANOVA method.
  • sugarcane treetop extract sample The polyphenol component was extracted from sugarcane treetop powder in the same manner as in 1-1. Above, and used as a sample. The sample dissolved in Mill-Q was used for the animal test described later.
  • SAMP8 (purchased from Nippon LSC Co., Ltd.) was used as an aging acceleration model. SAMP8 is a model animal of a naturally occurring strain characterized by the onset of early aging-related pathological conditions, and studies on the effects of antioxidant components contained in various foods are being conducted. SAMR1, which indicates normal aging, was used as a control for SAMP8. In this experiment, 16-week-old male mice that began to show aging-like symptoms such as memory impairment were used, and the mice were set in the following three groups: (a) SAMR1 + water-administered group, (b) SAMP8 + water-administered group. (c), SAMP8 + sugar cane head extract administration group.
  • the dose of sugarcane treetop extract was set to 20 mg / kg per day, and oral administration was used as the administration method. After oral administration of samples and water for 30 days to each group, a behavioral test was conducted to evaluate the spatial learning and memory ability of each group. Ten mice in each group were used in this experiment. During the breeding period, water and feed were freely ingested, and the mice were weighed daily.
  • the brain was isolated and collected from the mice, and comprehensive gene expression was analyzed using a microarray and the concentrations of neurotransmitters in the brain (dopamine, noradrenaline, adrenaline, acetylcholine, serotonin) were analyzed by the ELISA method. ..
  • ⁇ Evaluation of spatial learning memory ability by Morris water maze test> After 30 days of continuous administration of sugarcane treetop extract, a Morris water maze test was conducted, which is a behavioral test to evaluate the spatial learning and memory ability of animals.
  • the Morris Water Labyrinth Test is an experimental method to evaluate the learning and memory ability of animals.
  • a transparent escape platform platform
  • mice dropped into the pool were dropped from the water.
  • the experimental device consists of a circular water pool (120 cm in diameter and 45 cm in height), the temperature and depth of the water are set to 23 ⁇ 2 ° C and 30 cm, respectively, and there are four virtual quadrants: north, south, east, and west.
  • a transparent, invisible escape platform (10 cm in diameter) was installed 1 cm below the surface of the water.
  • the mouse uses four visual landmarks on the wall of the pool as clues, allowing the mouse to reach the platform in a short amount of time over time.
  • the spatial learning memory ability of the mouse was evaluated by allowing the mouse to freely search for 60 seconds and measuring the arrival time at the platform. In this test, shortening the arrival time is an index of the learning memory improvement effect.
  • the test was conducted for 8 days, and on the final day of the test, the test was performed with the platform removed, and the mouse stayed in the area where the platform was installed and crossed the position where the platform was installed. The number of times was measured (probe test).
  • the significant difference test between the SAMP8 + water administration group, the SAMP8 + sugar cane head extract administration group and the SAMR1 + water administration group is the two-way ANOVA method (*) for the test results with the 7-day platform installed. According to P ⁇ 0.05), the test results of the probe test on the final day were performed by the One-way ANOVA method (* P ⁇ 0.05).
  • the purified aRNA was fragmented using the Gene Atlas 3'IVT Express Kit, and the Gene Chip MG-430 PM microarray (Affymetrix Inc., Santa Clara, CA, USA) was used at 45 ° C for 16 hours. Hybridization was performed. The chips were then washed and stained with Gene Atlas Fluidics Station 400 (Affymetrix Inc., Santa Clara, CA, USA) and image images scanned by Gene Atlas Imaging Station (Affymetrix Inc., Santa Clara, CA, USA). ..
  • the change in gene expression in the SAMP8 + sugar cane head extract administration group was measured by fold-change (magnification change, control signal value as a control) based on the obtained results. It was calculated as a relative ratio obtained by dividing the signal value of.
  • DAVID URL: https://david.ncifcrf.gov
  • the genes that were up-regulated were categorized as a group related to various biological functions, and among them, cholinergic synapses that release acetylcholine as a neurotransmitter, body temperature regulation, etc. Serotonergic synapses that play an important role in sleep, dopaminergic synapses that play a role in controlling cognitive and voluntary movements and motivating behavior associated with rewards, calcium signaling in nerve cells, long-term potentiation in neurotransmission, It was confirmed that the genes related to circadian rhythm, Alzheimer's disease, etc. were elevated (Fig. 6).
  • ⁇ Analysis of neurotransmitter concentration in the brain by ELISA> After 30 days of continuous administration of sugarcane treetop extract or water and a behavioral test, brain tissue was removed and the cerebral cortex was collected. Brain tissue is dissolved in RIPA buffer (Santa Cruz Biotechnology, USA) containing a protease inhibitor, centrifuged (4 ° C, 1,200 g, 20 min), and the supernatant is collected to obtain total protein for neurotransmission. Dopamine, noradrenaline, adrenaline, acetylcholine and serotonin concentrations were measured using the substance ELISA kit (ImmuSmol SAS, France). The measured value was displayed as the concentration per protein amount (g) of the brain tissue calculated by the BCA method. In addition, the obtained values were subjected to a significant difference test (** P ⁇ 0.01) by the One-way ANOVA method.
  • the solution after extraction was concentrated using a rotary evaporator, and then freeze-dried to obtain a powdery sample (the color is brown for those using 20% ethanol as a solvent, and green for others.
  • the ethanol concentration is high.
  • the green color of the obtained sample was slightly deeper).
  • the total amount (yield) of each extracted sample is shown in the table below (approximately 130 mg to 140 mg from 1 g of raw material).
  • the obtained sample was redissolved in 100% methanol (concentration: 100 mg / mL), sterilized by a 0.22 ⁇ m filter, and then used for quantitative analysis of the components using high performance liquid chromatography (HPLC).
  • control group ii) 3-CQA treatment group
  • iii 5-CQA treatment group
  • 3-FQA treatment group v) ISO treatment group
  • the treatment concentration was 10 ⁇ M.
  • a sample was added to each well so as to be. Samples were incubated at 37 ° C. in the presence of 5% CO 2 for 12, 24, 48 hours and then incubated at room temperature for 30 minutes.
  • ATP reagent Toyo Ink
  • 150 ⁇ L of supernatant from each well was transferred to a 96-well white bottom plate (BD Falcon), and 25 Incubation was performed at ° C for 10 minutes to stabilize luminescence.
  • the ATP production ratio was measured by measuring the emission intensity using a plate reader (Powerscan HT, USA). The obtained values were subjected to a significant difference test (* P ⁇ 0.05, ** P ⁇ 0.01) by the One-way ANOVA method. 6-3.
  • treatment groups for SH-SY5Y As treatment groups for SH-SY5Y, (i) control group, (ii) sugar cane shoot head extract (50 ⁇ g / mL) treatment group, (iii) 3-CQA treatment group, iv) 5-CQA treatment group (v)
  • the ISO treatment group was set, and the treatment concentration of the sugarcane treetop extract sample was set to 50 ⁇ g / mL, and the treatment concentration of each compound sample was set to 10 ⁇ M. After incubating the cells together with the sample in a 60 mm cell culture dish (BD Falcon) at 37 ° C. in the presence of 5% CO 2 for 24 hours, the cells in each treatment group were subjected to ISOGEN kit (Nippon Gene, Japan). mRNA was extracted.
  • RT-PCR reverse transcription polymerase chain reactions
  • PGK1 Hs00943178_g1
  • PGAM1 Hs01652468_g1
  • PKM Hs00761782_s1
  • PC Hs01085875_g1
  • ACTB Hs01060665_g1
  • hNSC human neural stem cells
  • Human embryo-derived neural stem cells (Gibco® life technologies, USA) were used for the purpose of evaluating the effects of samples on neural stem cells (hNSC; human Neural Stem Cell).
  • hNSC was seeded in T75 flasks (BD Falcon, USA) and in KnockOut TM D-MEM / F-12 with 2% StemPro® Neural Supplement, 20 ng / mL bFGF and 20 ng / mL.
  • EGF EGF, 2 mM GlutaMAX TM- I Supplement, 6 units / mL Heparin, and 200 ⁇ M Ascorbic acid, a medium for neural stem cell proliferation (all of which are Gibco® life technologies).
  • Ascorbic acid a medium for neural stem cell proliferation (all of which are Gibco® life technologies).
  • hNSC is cultured in a floating state without adhering to the bottom surface of the flask, and proliferates while forming a spherical cell mass (neurosphere) (Fig. 15).
  • RT-PCR reverse transcription polymerase chain reactions
  • Superscript IV reverse transcriptase kit (Invitrogen, USA) and 2720 Thermal cycler (Applied Biosystems, USA).
  • TaqMan real time RT PCR amplification reactions using the 7500 Fast Real Time PCR system was performed.
  • TUBB3 (Hs00801390_s1), which is a marker for neurons (nerve cells)
  • GFAP Hs00909233_m1
  • TA transit amplifying
  • PDGFRA Hs00998018_m1
  • NES Hs04187831_g1
  • GAPDH Hs02786624_g1
  • HuC / D is a protein that is specifically expressed in the cell body of neurons from the early stage of differentiation, and the proportion of newborn neurons was analyzed by quantifying positive cells together with BrdU.
  • treatment groups for hNSC (i) control group, (ii) 10 ⁇ g / mL sugar cane head extract treatment group, (iii) 25 ⁇ g / mL sugar cane head extract treatment group, (iv) 50 ⁇ g / mL sugar cane A treetop extract treatment group was set.
  • hNSC was seeded at a concentration of 5.0 ⁇ 10 4 cells / mL and incubated at 37 ° C. in the presence of 5% CO 2 for 12 hours to adhere the hNSC to the bottom surface of the slide.
  • BrdU and HuC / D positive cells were detected using immunostaining.
  • the cells were encapsulated using ProLong (trademark registration) Diamind (Thermo Fisher Scientific, USA) and a cover glass. After encapsulation, the slide glass was stored at 4 ° C and used for analysis using a microscope.
  • ASCL1 and HES1 are factors that regulate neural stem cell activation, using real-time RT-PCR.
  • ASCL1 and HES1 are basic helix-loop-helix (bHLH) factors that control fate decisions in cell development and differentiation.
  • bHLH basic helix-loop-helix
  • the expression level of HES1 decreases and the expression level of ASCL1 increases, so that the neural stem cells differentiate into nerve cells.
  • dissociated hNSC was subjected to 6-well play at a concentration of 5.0 ⁇ 10 4 cells / mL. The seeds were seeded and incubated at 37 ° C. in the presence of 5% CO 2 for 12 hours to adhere hNSC to the bottom of the slide.
  • mRNA was extracted using the ISOGEN kit (NipponGene, Japan), and gene expression was analyzed in the same manner as described in the above-mentioned ⁇ Evaluation of the effect of sugar cane shoot head extract on gene expression of differentiation markers in hNSC>.
  • ASCL1 Hs00269932_m1
  • HES1 Hs00172878_m1
  • GAPDH Hs02786624_g1 was used as an internal standard. All primers were purchased from Applied Biosystems (USA). The obtained values were subjected to a significant difference test (* P ⁇ 0.05, ** P ⁇ 0.01) by the One-way ANOVA method.
  • hNSC The dissociated hNSC was seeded in a Tek chamber slide 4 well (Thermo Fisher Scientific, USA) at a concentration of 5.0 ⁇ 10 4 cells / mL. Differentiation of hNSC was performed in KnockOut TM D-MEM / F-12 with 2% StemPro® Neural Supplement, 2 mM GlutaMAX TM- I Supplement, 6 units / mL Heparin, and 200 ⁇ M. It was induced by culturing in a medium for neural stem cell differentiation composed of Ascorbic acid (all of which are Gibco® life technologies) at 37 ° C. in the presence of 5% CO 2 for 7 days. Further, even during the induction of differentiation, the sample was added to the medium so as to have the above-mentioned set concentration.
  • Ascorbic acid all of which are Gibco® life technologies
  • Tuj1 Tublin beta III
  • GFAP-positive cells were detected using immunostaining. Immunostaining was performed in the same manner as described in ⁇ Evaluation of the effect of sugarcane shoot head extract on the generation of newborn neurons from hNSC> above (no degeneration treatment was performed). Rabbit polyclonal anti-GFAP (1: 1000, Novus Biologicals, Centennial, CO) and mouse monoclonal anti-beta III tubulin (Tuj1, 1: 1000, Abcam, UK) were used as primary antibodies.
  • the tissue section on the slide was washed with PBS, and a part of the double-stranded DNA was denatured into short-stranded DNA to expose BrdU and bound to the antibody. It was conducted. Then, permeabilization was performed with PBS containing 0.03% Triton X-100 (PBS-T) for 15 minutes, and the sections were incubated with 10% Normal donkey serum in PBS-T at room temperature for 1 hour to bind non-specific antibodies. Was prevented. Rat monoclonal anti-BrdU (1: 200, Abcam) and Rabbit polyclonal anti-Doublecortin (DCX, 1: 200, Cell signaling technology) were used as primary antibodies, diluted with blocking buffer, and then incubated overnight. rice field. Then, the sections were washed and incubated with a fluorescent dye-labeled specific secondary antibody at room temperature for 2 hours. The slides were encapsulated using FluorSave (Merck Millipore).
  • the stained tissue section was used for image acquisition with a Nikon Ti-Eclipse microscope (Nikon). Confocal images for quantification were acquired with a Zeiss LSM710 laser scanning confocal microscope (Leica). The analysis of the hippocampal dentate gyrus, which is the site of neurogenesis, was performed using ImageJ.
  • TrkB Neurotrophic tyrosine kinase receptor type 2, NTRK2
  • TrkB Neurotrophic tyrosine kinase receptor type 2, NTRK2
  • TrkB is involved in the development and maturation of the central and peripheral nervous systems, and is activated by in vivo factors such as BDNF (brain-derived neurotrophic factor) for nerve cell growth and survival, synaptic development, and neurogenesis in the hippocampus. It has been reported to activate the signal pathways involved.
  • BDNF brain-derived neurotrophic factor
  • Ginkgo biloba extract (Fujifilm Healthcare Laboratory Co., Ltd.) dissolves powder in 70% ethanol, sterilizes 0.22 ⁇ m, prepares a stock solution (100 mg / mL), and then treats group (viii) Ginkgo biloba. It was added to the experimental conditions as an extract (50 ⁇ g / mL). After incubating the cells together with the sample in a 60 mm cell culture dish (BD Falcon) at 37 ° C. in the presence of 5% CO2 for 24 hours, mRNA was used from the cells in each treatment group using the ISOGEN kit (Nippon Gene, Japan). Was extracted.
  • RT-PCR reverse transcription polymerase chain reactions
  • NTRK2 Hs00178811_ma
  • GAPDH Hs02786624_g1
  • All primers were purchased from Applied Biosystems (USA). The obtained values were subjected to a significant difference test (* P ⁇ 0.05, ** P ⁇ 0.01) by the One-way ANOVA method.
  • NTRK2 expression level is a relative value of the control group, and this suggests that these compounds synergistically increase NTRK2 expression in nerve cells when mixed and treated. ..
  • sugar cane treetop extract-treated group and the compound mixture-treated group showed a large increase in NTRK2 expression as compared with the ginkgo biloba extract-treated group. Since signal transduction via TrkB activation plays an important role in promoting synaptic plasticity and neurogenesis (Numakawa et al), sugar cane treetop extract has been reported to have a cognitive function improving effect. Compared with ginkgo biloba extract, which is a plant extract of Synaptic plasticity, it can be expected to improve symptoms by effectively improving TrkB signal, promoting neurogenesis, and suppressing the decrease of nerve cells with aging. Specific diseases include memory loss and depression in aging and Alzheimer's disease (Tapia-Arancibiaet al., 2008; The improvement effect in Erickson et al., 2012) can be expected.
  • the solution after extraction was concentrated using a rotary evaporator and then freeze-dried to obtain a powdery sample (the color of the sample became deeper green as the ethanol concentration increased).
  • the obtained sample was redissolved in 100% methanol (concentration: 50 mg / mL), sterilized by a 0.22 ⁇ m filter, and then used for quantitative analysis of the components using high performance liquid chromatography (HPLC).
  • the related markets will be expanded and new markets will be expanded through the development of new food and pharmaceutical seeds for the purpose of improving and improving cognitive function and the development of products in the form of supplements and the like.
  • Pioneering is expected.
  • the composition of the present invention is derived from food by-products, it is a major innovation in the medical / health market. Is expected to be.

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Abstract

Le problème à résoudre par la présente invention est de fournir une nouvelle substance qui est dérivée de produits naturels et qui est utile pour la régulation de la fonction neurologique. La présente invention concerne un procédé de fabrication d'une substance alimentaire ou d'une substance médicinale qui comprend au moins un élément choisi dans le groupe constitué par l'acide 3-o-caféoylquinique, l'acide 5-o-caféoylquinique, l'acide 3-o-feruloylquinique, et l'isoorientine, le procédé comprenant l'étape suivante : une étape dans laquelle une fraction comprenant au moins un élément choisi dans le groupe constitué par l'acide 3-o-caféoylquinique, l'acide 5-o-caféoylquinique, l'acide 3-o-feruloylquinique et l'isoorientine est obtenue à partir de la partie couronne d'une plante de canne à sucre à l'aide d'un solvant aqueux. Cette composition ou similaire peut être utilisée pour n'importe quel élément choisi dans le groupe constitué par : la promotion de la neurogenèse par la protection des cellules nerveuses contre l'amyloïde-β, une augmentation de la sécrétion des neurotransmetteurs cérébraux, la promotion de la production d'ATP dans les cellules nerveuses, ou la croissance de cellules souches neurales ; le traitement de la démence, notamment la démence sénile, la démence résultant de la maladie d'Alzheimer, la démence vasculaire, la démence post-traumatique, la démence résultant d'une tumeur cérébrale, la démence résultant d'un hématome sous-dural chronique et la démence résultant d'un œdème cérébral à pression normale, de l'hydrocéphalie post-méningitique et de la maladie de Parkinson ; le traitement d'une déficience cognitive non démentielle, notamment un trouble cognitif léger (MCI)) et d'une fonction cognitive réduite liée à l'âge ; l'amélioration des troubles d'apprentissage et des troubles de la mémoire ; l'amélioration de la capacité d'apprentissage et de la capacité de mémoire ; le traitement de la perte de mémoire ; le traitement de l'infarctus cérébral et de la lésion du nerf périphérique ; le traitement de troubles mentaux, notamment le trouble déficitaire de l'attention avec hyperactivité (ADHD), la dépression et le trouble bipolaire ; l'amélioration du dynamisme et de la motivation ; et l'amélioration des perturbations du rythme circadien.
PCT/JP2021/006166 2020-02-18 2021-02-18 Composition pour la régulation de la fonction neuronale WO2021167012A1 (fr)

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