KR20150040618A - Composition for preventing or treating Alzheimer's disease comprising compounds from Kaempferia parviflora - Google Patents
Composition for preventing or treating Alzheimer's disease comprising compounds from Kaempferia parviflora Download PDFInfo
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- KR20150040618A KR20150040618A KR20130119367A KR20130119367A KR20150040618A KR 20150040618 A KR20150040618 A KR 20150040618A KR 20130119367 A KR20130119367 A KR 20130119367A KR 20130119367 A KR20130119367 A KR 20130119367A KR 20150040618 A KR20150040618 A KR 20150040618A
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- dementia
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Images
Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
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- 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)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9068—Zingiber, e.g. garden ginger
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
Abstract
Description
The present invention relates to a pharmaceutical composition comprising 5,7-dimethoxy flavone, 5,7,4'-trimethoxy flavone and 3,5,7,3 ', 4'-pentamethoxy flavone compounds, which are compounds isolated from black ginger, To a composition for preventing or treating Alzheimer ' s dementia.
Cognitive function refers to various intellectual abilities such as memory, language ability, ability to grasp time and space, judgment and abstract thinking ability. Alzheimer's disease (AD) is the most common form of dementia. According to WHO, it is estimated that by 2050, one in every 85 people will be AD patients. AD is characterized by neurofibrillary tangles (NFT) generated inside nerve cells and synaptic functional degeneration and neuronal loss due to exogenous senile plaques.
Currently, Aβ, which is the most potent cause of AD, is produced by abnormal hydrolysis of a precursor protein called amyloid protein precursor (β) and γ-secretase enzyme, which forms a senile plaque when immersed. In addition, Aβ is poisonous and destroys neurons in the cerebrum and cerebral cortex that produce acetylcholine, a neurotransmitter, to reduce the activity of acetylcholine and produce reactive oxygen species (ROS) Causing neuronal apoptosis by inducing damage (Hensley K et < RTI ID = 0.0 > al . , 1994). In normal cases, the N -terminal 15th and 16th amino acids of APP are cleaved by α-secretase, and then shortened by γ-secretase and then released to the outside of the cell without toxicity (Efremov I et al ., 2012).
In addition, in the study of AD treatment, β, γ-secretase, which is the main enzyme involved in Aβ formation, appeared as a main target, but inhibition of γ-secretase was difficult due to side effects due to the Notch pathway involved in this enzyme , Whereas β-secretase does not produce Aβ without any side effects in β-secretase deficient mice, suggesting that β-secretase inhibitor screening is most appropriate for the treatment of AD. BACE1 (β-site APP cleaving enzyme 1), a potent candidate for β-secretase, is an aspartic protease and is distributed at high concentration in neurons. Overexpression of Aβ is reported to result in the formation of Aβ and the formation of the elderly.
Meanwhile, most of the AD medications used in various countries are ACh inhibitor, tacrine, and aricept. In these cases, the side effects of hepatic toxicity are so great that the treatment is often stopped and various side effects are caused.
Therefore, there is a need for research for securing a new therapeutic agent with natural side effects and excellent therapeutic effect from natural products.
Therefore, an object of the present invention is to provide a process for producing a 5,7-dimethoxy flavone, a 5,7,4'-trimethoxy flavone, and a 3,5,7,3 ', 4'-pentamethoxy flavone compound And a pharmaceutical composition for preventing or treating Alzheimer's dementia comprising one compound as an active ingredient.
Still another object of the present invention is to provide a method for producing a 5,7-dimethoxy flavone, which is selected from the group consisting of 5,7-dimethoxy flavone, 5,7,4'-trimethoxy flavone and 3,5,7,3 ' And a health functional food for preventing or ameliorating Alzheimer's dementia comprising any one of the compounds as an active ingredient.
In order to accomplish the above object, the present invention provides a pharmaceutical composition comprising 5,7-dimethoxy flavone, 5,7,4'-trimethoxy flavone and 3,5,7,3 ', 4'-pentamethoxy flavone compound A pharmaceutical composition for preventing or treating Alzheimer ' s dementia comprising any one selected compound as an active ingredient.
In one embodiment of the invention, the compound may be isolated from black ginger.
In one embodiment of the present invention, the compound may have an activity of inhibiting the activity of beta-secretase (BACE1).
In one embodiment of the present invention, the compound may be contained in the composition at a concentration of 10 to 200 uM.
In addition, the present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of 5,7-dimethoxy flavone, 5,7,4'-trimethoxy flavone and 3,5,7,3 ', 4'-pentamethoxy flavone compound The present invention provides a health functional food for preventing or ameliorating Alzheimer ' s dementia comprising a compound of formula (I) as an active ingredient.
In one embodiment of the invention, the compound may be isolated from black ginger.
In one embodiment of the present invention, the compound may have an activity of inhibiting the activity of beta-secretase (BACE1).
In one embodiment of the present invention, the compound may be contained in the composition at a concentration of 10 to 200 uM.
The present invention relates to a pharmaceutical composition comprising any one compound selected from the group consisting of 5,7-dimethoxy flavone, 5,7,4'-trimethoxy flavone and 3,5,7,3 ', 4'-pentamethoxy flavone compound As an active ingredient, to a pharmaceutical composition for preventing or treating Alzheimer ' s dementia. The compounds according to the present invention can selectively and excellently inhibit the activity of beta-secretase, thereby preventing accumulation of beta-amyloid (A [beta]) in brain cells and preventing and treating Alzheimer's dementia Since these compounds are isolated from natural ginger, which is a natural product, and have stability without cytotoxicity, they can be advantageous over long-term use without adverse effects on the human body as compared with the chemical synthesis method which had many side effects. Therefore, the compounds according to the present invention can be used as medicines for the prevention, amelioration or treatment of Alzheimer ' s dementia, health functional foods and the like.
1 shows a structural formula of a compound capable of treating Alzheimer's dementia from black ginger, wherein 1a represents 5,7-dimethoxyflavone, 1b represents a structural formula of 5,7,4'-trimethoxyflavone, 1c is a structural formula of 3,5,7,3 ', 4'-pentamethoxyflavone.
FIG. 2 shows the results of suppressing β-secretase activity of the compounds of the present invention isolated from black ginger.
3 shows the β-secretase inhibitory effect of the compounds according to the present invention isolated from black ginger, wherein 3a represents 5,7-dimethoxyflavone, 3b represents a structural formula of 5,7,4'-trimethoxyflavone, 3c is a structural formula of 3,5,7,3 ', 4'-pentamethoxyflavone.
The present invention is characterized in that compounds isolated from black ginger can be used as a therapeutic agent for preventing or treating Alzheimer's dementia. Specifically, the present invention provides 5,7-dimethoxy flavone, 5,7,4 ' -Trimethoxy flavone, and a 3,5,7,3 ', 4'-pentamethoxy flavone compound as an active ingredient for the prevention or treatment of Alzheimer's dementia And the like.
The compounds having the therapeutic effect of Alzheimer ' s dementia provided by the present invention may each be a compound having the following structural formula.
≪ Formula 1 >
5,7-Dimethoxy flavone structure
(2)
The 5,7,4'-trimethoxy flavone structure
(3)
3,5,7,3 ', 4'-pentamethoxy flavone structure
The compounds represented by the
The compounds represented by the formulas (1) to (3) according to the present invention may be those commercially available or may be those isolated from natural sources or produced by chemical synthesis methods known in the art, preferably from black ginger Separated ones can be used.
Meanwhile, the present inventors have focused on black ginger to study a novel therapeutic agent derived from natural products as a treatment for dementia. As for a conventional study on black ginger, Korean Patent Publication No. 10-2012-0100264 " And its use as an antiviral agent " but it relates to antiviral function, and a paper on black ginger includes antioxidant (Vichtphan S et al ., 2007), anti-inflammatory (Moon H et al ., 2011), anti-tumor (Banjerdpongchai R et al . 2007), anti-ulcerative action (Rujjanawate C et al ., 2007) There is no report on dementia studies.
Accordingly, the inventors of the present invention discovered through experiments that compounds of the above formulas (1) to (3) are effective in treating Alzheimer's dementia while discovering new therapeutic agents that can be used as agents for treating dementia from black ginger. and it is possible to induce dementia treatment efficacy through inhibition of the activity of beat-secrtase.
For reference, the cause of Alzheimer's disease is largely related to the hypothesis (acetylcholine hypothesis) that the synthesis of acetylcholine, a neurotransmitter, is reduced, and ii) accumulation of amyloid peptides in the brain (Tau hypothesis) that amyloid hypothesis induces Alzheimer's disease due to abnormality of hyperphosphorylated tau protein. Among them, amyloid hypothesis is widely supported have.
According to the amyloid hypothesis, the most important cause of Alzheimer's disease is the accumulation of amyloid beta peptide (Aβ), consisting of 40 to 42 amino acids, in brain cells, which causes oxidative damage of neurons constituting neurons It is believed to eventually lead to dementia. Beta-amyloid is produced by proteolysis of the amyloid precursor protein (APP). In relation to the degradation of amyloid precursor proteins, three proteolytic enzymes, alpha-secretase, beta-secretase and gamma-secretase, Cretaceous).
More specifically, the amyloid precursor protein (APP) is a single trans-membrane protein, which contains an extracellular N-terminal domain consisting of 590 to 680 amino acids and an intracellular and a signal transduction sequence of about 55 amino acids, including the cytoplasmic tail. The transcriptional RNA (mRNA) of such an amyloid precursor protein gene forms 8 isoforms through alternative splicing, of which 3 isoforms are predominantly in the brain.
Amyloid precursor protein (APP) is largely undergoes proteolytic processing through two pathways. First, alpha- secrecase cleaves the 17th amino acid of the beta-amyloid domain of the amyloid precursor protein to form a relatively large soluble N-terminal fragment (APPs alpha) and a non-amyloid-like C-terminal fragment (C83) of approximately 10 KDa , And these fragments are further degraded by gamma-secretase to produce non-amyloid-type peptide (P3). As another optional pathway, beta-secrecase cleaves this precursor protein in the beta-amyloid domain of the amyloid precursor protein to produce a short soluble N-terminal fragment (APPs beta) of approximately 100-KDa and an approximately amyloid- C-terminal fragment (C99) of 12-KDa is generated and further C99 fragment is cleaved by gamma-secrecase to produce beta-amyloid. Depending on the region cleaved by gamma-secretase, 40 Beta-amyloid (A [beta] 40) composed of amino acids and beta-amyloid (A [beta] 42) composed of 42 amino acids are produced.
Therefore, in order to prevent accumulation of beta-amyloid (A beta) in brain cells, which is known to cause Alzheimer's disease, which is a representative degenerative brain disease, it is necessary to cause amyloid precursor protein (APP) to be cleaved into amyloidogenic C- Lt; RTI ID = 0.0 > beta-secretase < / RTI >
In addition, beta-secrecase inhibits the activity of beta-secrecase as an enzyme that initiates beta-amyloid production, thereby also preventing all subsequent harmful steps as well as reduction of beta-amyloid, Modification of the gene coding for the secretase has many advantages as a target for the treatment of Alzheimer's disease in that it is clinically safe since there are no serious problems.
With respect to the inhibitor of beta-secretase, hydroxyethylenes having a peptide bond or a compound substituted at the N-terminal with a phenylacetyl group are known, but an enzyme inhibitor having therapeutic activity should have a size of less than 700 Da Because it can exert its effect stably in metabolism in the body, continuous research is needed. In addition, chitosan derivatives, catechins, plant-derived compounds and the like have been reported as inhibitors of beta-secretase as living body-derived substances, but their efficacy has not yet been fully demonstrated.
In this respect, the 5, 7-dimethoxy flavone, 5,7,4'-trimethoxy flavone and 3,5,7,3 ', 4'-pentamethoxy flavone compounds derived from black ginger of the present invention, , And 5,7,4'-trimethoxyflavone exhibited the most excellent activity with an IC 50 of 3.7 × 10 -5 M. In the case of 5,7,4'-trimethoxyflavone, 5,7-dimethoxyflavone and 3,5,7,3', 4'-pentamethoxyflavone FIG IC 50 each 4.9 × 10 -5 M, IC 50 6.0 x 10 <" 5 > M.
In addition, it was confirmed that the compounds of the present invention have specificity for BACE1. According to one embodiment of the present invention, no significant inhibitory effect was observed for chymotrypsin, trypsin and TACE, whereas only for BACE1 Selectively inhibiting activity.
Accordingly, the present inventors have found that 5,7-dimethoxy flavone, 5,7,4'-trimethoxy flavone, and 3,5,7,3 ', 4'-pentamethoxy flavone compounds selectively activate BACE1 Inhibiting activity can prevent and treat Alzheimer ' s dementia.
The composition for preventing or treating Alzheimer's dementia containing the compound of the present invention as an active ingredient is a pharmaceutical composition comprising the above compound as an active ingredient and a pharmaceutically acceptable and physiologically acceptable adjuvant And an auxiliary agent such as an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, a lubricant or a flavoring agent may be used.
The pharmaceutical composition may be formulated into a pharmaceutical composition containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.
The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation into tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included as a mixture. Suitable binders include, but are not limited to, natural sugars such as starch, gelatin, glucose or beta-lactose, natural and synthetic gums such as corn sweeteners, acacia, tracker candles or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include sterile water and sterile water suitable for the living body such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.
In one embodiment of the present invention, the compound of the present invention may be contained in the composition at a concentration of 10 to 200 μM.
The present invention also provides a method of preventing or treating Alzheimer ' s dementia comprising administering to a mammal a compound of the present invention.
The term "mammal " as used herein refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
The term "therapeutically effective amount " as used herein refers to the amount of active ingredient or pharmaceutical composition that elicits a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, The amount that induces the relief of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect. The optimal dosage to be administered can therefore be readily determined by those skilled in the art and will depend upon the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, , Sex and diet, time of administration, route of administration and rate of administration of the composition, duration of treatment, concurrent administration of the drug, and the like. In the treatment method of the present invention, in the case of an adult, it is preferable to administer the compound of the present invention at a dose of 0.01 mg / kg to 250 mg / kg once to several times a day.
In the therapeutic method of the present invention, the composition comprising the compound of the present invention as an active ingredient can be administered orally, rectally, intravenously, intraarterally, intraperitoneally, intramuscularly, intrasternally, transdermally, topically, ≪ / RTI >
The present invention also provides a health functional food for preventing or ameliorating Alzheimer's dementia comprising the compound of the present invention as an active ingredient.
The health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and circles for the purpose of preventing and improving Alzheimer's dementia.
In the present invention, the term " health functional food " refers to foods manufactured and processed using raw materials or ingredients having useful functions in accordance with Law No. 6727 on Health Functional Foods. Or to obtain a beneficial effect in health use such as physiological action.
The health functional foods of the present invention may contain conventional food additives and, unless otherwise specified, whether or not they are suitable as food additives are classified according to the General Rules for Food Additives approved by the Food and Drug Administration, Standards and standards.
Examples of the items listed in the above-mentioned "food additives" include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as persimmon extract, licorice extract, crystalline cellulose, high color pigment and guar gum; L-glutamic acid sodium preparations, noodle-added alkalis, preservative preparations, tar coloring preparations and the like.
For example, the health functional food in the form of tablets may be prepared by granulating a mixture of the compound of the present invention, which is an active ingredient of the present invention, with an excipient, a binder, a disintegrant and other additives in a usual manner, Alternatively, the mixture can be directly compression molded. In addition, the health functional food of the tablet form may contain a mating agent or the like if necessary.
The hard capsule may be prepared by filling a normal hard capsule with a mixture of the active ingredient of the present invention and an additive such as an excipient. The soft capsule may contain the compound of the present invention as an excipient And filling the mixture with a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
The ring-shaped health functional food can be prepared by molding a mixture of a compound of the present invention with an excipient, a binder and a disintegrant in accordance with a conventionally known method and, if necessary, Or the surface may be coated with a material such as starch, talc.
The granular health functional food may be prepared by granulating a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant and the like in a granular form by a conventionally known method and, if necessary, adding a flavoring agent, ≪ / RTI >
The health functional food may be a beverage, a meat, a chocolate, a food, a confectionery, a pizza, a ramen, a noodle, a gum, a candy, an ice cream, an alcoholic beverage, a vitamin complex and a health supplement food.
Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
< Example 1>
From black ginger Isolation and Identification of Compounds Having Alzheimer's Therapeutic Effect
In order to discover a novel therapeutic agent having an effect of treating Alzheimer's dementia, the inventors of the present invention have found that, as a compound of an active ingredient from black ginger, 5,7-dimethoxyflavone, 5,7,4'- trimethoxyflavone, 4'-pentamethoxyflavone was isolated and identified. Black ginger was cut into slices, and three times repeated extraction with hot water reflux extraction method was freeze-dried to obtain crude powdery extract. The yield of the extract was 12.3%. The active ingredients KP-1, KP-2. In order to isolate KP-3, the crude extract was suspended in distilled water and a systemic solvent fraction was carried out. First, fractionation was carried out using chloroform. After concentrating the chloroform fraction, 84.3 g was obtained. The residue was dissolved again in distilled water and fractionated with hexane, followed by fractionation with dichloromethane. 49g of Dichloromethane fraction layer was obtained, and open colunm chromatography was performed using Dichloromethane fraction layer. For the open colunm chromatography, silica7734 was used. The use of developing solvent was adjusted by adjusting the ratio of chloroform: methanol (C: M). Dichloromethane fraction layer was loaded on silica and 56 total fractions were obtained by varying the solvent composition in the ratio of C: M = 50: 1, solvent: C: M = 30: 1. C: M in the ratio of C: M = 20: 1, C: M in the ratio of C: M = 10: = 1: 1 ratio. Of these, 5.6 g of KP-
The structural formulas of 5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone and 3,5,7,3 ', 4'-pentamethoxyflavone isolated by the above method are shown in FIG. 1, respectively. 5,7-dimethoxyflavone, (B) 5,7,4'-trimethoxyflavone, and (C) 3,5,7,3 ', 4'-pentamethoxyflavone.
< Example 2>
The < RTI ID = 0.0 > beta- Secretase ( BACE1 ) Inhibition effect measurement
The anti-Alzheimer's effect of the compounds 5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone and 3,5,7,3 ', 4'-pentamethoxyflavone isolated from black ginger according to the method of Example 1 BACE1 inhibitory effects were investigated. The material used in the experiment was purchased from Pan Vera Co., Ltd. The method is as follows. (10 U / mL) was added to a 384-well plate and incubated at 25 ° C for 60 min. The plate was incubated with a fluorescence microplate reader Ex. 530 nm, Em. After measuring the fluorescence at 590 nm, the inhibition rate was calculated by the following equation.
Inhibition (%) = [1 - ( S - S 0 ) / ( C - C 0 )] 100
C : Fluorescence of control after 60 min of incubation
(enzyme, assay buffer and substrate)
C 0 : Fluorescence of the control at
S : Fluorescence of control after 60 min of incubation
(enzyme, sample solution and substrate)
S 0 : Fluorescence of the tested samples ( S ) at
In order to confirm the enzyme specificity of BACE1 isolated from black ginger, serine proteases such as chymotrypsin and trypsin and α-secretase, a non-amyloidogenic pathway, were investigated.
Trypsin and chymotrypsin inhibitory activity were measured using 0.05 M Tris-HCl buffer (pH 8.2, containing 0.02 M CaCl 2 ) and 1.25 mM z -Arg-pNA and 1.25 mM z- L-Tyr-pNA, respectively. The OD value was measured at 410 nm using a 96-well plate. α-Secretase inhibitory activity was measured by the same method as BACE1 by measuring the fluorescence intensity at 400 nm using fluorescence ELISA Ex 320 and Em 405 nm by reacting recombinant TACE (0.1 ppm in 25 mM Tris butter) Respectively.
To investigate inhibition patterns of enzyme inhibitors, the inhibitory activity of each substrate (250, 500, and 750 nM) was measured and then Dixon plot was constructed.
As a result, as shown in FIG. 2, the inhibitory effect of the black ginger-derived compound on BACE1 activity was shown to have a concentration-dependent inhibition of BACE1 activity. Especially, 5,7,4'-trimethoxyflavone has IC 50 3.7 × 10 -5 M, and 5,7-dimethoxyflavone and 3,5,7,3 ', 4'-pentamethoxyflavone also have IC 50 4.9 × 10 -5 M, IC 50 6.0 x 10 <" 5 > M.
In addition, as shown in FIG. 3, as shown in FIG. 3, it was found that Ki was an inhibitor that inhibits BACE1 in a non-competitive manner with respect to the substrate, indicating that the Ki value is X-intercept. 5,7-dimethoxyflavone, , Ki values of the 7,4'-trimethoxyflavone, 3,5,7,3', 4'- pentamethoxyflavone is 5.1 × 10 -5 Ki, Ki, respectively 3.8 x 10 < -5 > and Ki 5.9 × 10 -5 . In Figure 3, (A) is 5,7-dimethoxyflavone, (B) is 5,7,4'-trimethoxyflavone, and (C) is BACE1 inhibition pattern for 3,5,7,3 ', 4'- pentamethoxyflavone Lt; / RTI >
Further, the enzyme specificity of 5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone and 3,5,7,3 ', 4'-pentamethoxyflavone isolated from black ginger was examined for BACE1. As a result, , It was confirmed that all of the three compounds did not show any significant inhibitory effect on chymotrypsin, trypsin and TACE, and thus they were specific inhibitors of BACE1 having selective specificity for BACE1.
The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
Claims (8)
A pharmaceutical composition for preventing or treating Alzheimer ' s dementia, wherein the compound is isolated from black ginger.
A pharmaceutical composition for preventing or treating Alzheimer's dementia characterized in that the compound has an activity of inhibiting the activity of beta-secretase (BACE1).
The pharmaceutical composition for preventing or treating Alzheimer's dementia, wherein the compound is contained in the composition at a concentration of 10 to 200 uM.
Wherein the compound is isolated from black ginger. The health functional food for preventing or ameliorating Alzheimer's disease.
Wherein said compound has an activity of inhibiting the activity of beta-secretase (BACE1).
Wherein the compound is contained in the composition at a concentration of 10 to 200 uM for the prevention or amelioration of Alzheimer's disease.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20170039457A (en) | 2015-10-01 | 2017-04-11 | 동아대학교 산학협력단 | Composition for preventing or treating diabetes comprising a flavone-based compound from Kaempferia parviflora |
| JP2017178889A (en) * | 2016-03-31 | 2017-10-05 | チズＢｅファクトリー株式会社 | OPH activity enhancer |
| KR20190009897A (en) | 2017-07-20 | 2019-01-30 | 건국대학교 산학협력단 | Composition for preventing and treating alzheimer's disease containing d-limonene |
| JP2021521139A (en) * | 2018-04-13 | 2021-08-26 | ヒョン ユ、スン | Identification of guanine as a virulence factor for Alzheimer's disease, and compositions and methods for inhibiting granine aggregation and treating Alzheimer's disease. |
-
2013
- 2013-10-07 KR KR20130119367A patent/KR20150040618A/en not_active Application Discontinuation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20170039457A (en) | 2015-10-01 | 2017-04-11 | 동아대학교 산학협력단 | Composition for preventing or treating diabetes comprising a flavone-based compound from Kaempferia parviflora |
| JP2017178889A (en) * | 2016-03-31 | 2017-10-05 | チズＢｅファクトリー株式会社 | OPH activity enhancer |
| KR20190009897A (en) | 2017-07-20 | 2019-01-30 | 건국대학교 산학협력단 | Composition for preventing and treating alzheimer's disease containing d-limonene |
| JP2021521139A (en) * | 2018-04-13 | 2021-08-26 | ヒョン ユ、スン | Identification of guanine as a virulence factor for Alzheimer's disease, and compositions and methods for inhibiting granine aggregation and treating Alzheimer's disease. |
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