KR102085358B1 - Composition for preventing or treating neurodegenerative diseases comprising pterosin compounds or derivative thereof - Google Patents

Abstract

The present invention relates to a composition for preventing or treating degenerative brain disease comprising a pterosine compound and derivatives thereof as an active ingredient, and more specifically, to a pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient. A pharmaceutical composition for preventing or treating degenerative brain disease and a food composition for preventing or improving degenerative brain disease. The method of the present invention is to provide a therapeutic agent for preventing or treating degenerative brain disease, a food for improving degenerative brain disease, or a functional food for cognitive functioning, using a pterosine compound and derivatives thereof extracted from bracken. It can be usefully used.

Description

Composition for preventing or treating neurodegenerative diseases comprising pterosin compounds or derivatives thereof

The present invention relates to a composition for preventing or treating degenerative brain disease comprising a pterosine compound and derivatives thereof as an active ingredient, and more specifically, to a pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient. A pharmaceutical composition for preventing or treating degenerative brain disease and a food composition for preventing or improving degenerative brain disease.

This application claims the priority of Korean Patent Application No. 10-2017-0078655, filed June 21, 2017, the entirety of which is a reference of the present application.

Dementia is a syndrome in which severe disorders such as memory, concentration, language and cognition progress progressively over time due to damage and loss of nerve cells, leading to a loss of mental and social ability. The representative cause of the disease is Alzheimer's disease ( Alzheimer's disease). Alzheimer's disease is divided into sporadic and familial types, depending on the cause, which occurs in 5% of elderly people over 65 years and 20% of elderly people over 80 years (Launer et al ., 1999, In: Iqbal et al., (Eds.) Alzheimers Disease and related disorders: Etiology, Pathogenesis and Therapeutics, John Wiley & Sons, New York, NY, USA.pp. 9-15). Pathogenesis is unclear in more than 80% to 90% of cases, but is generally described as amyloid hypothesis and cholinergic hypothesis. The main cause of mutations in genes such as presenilin (PS) types 1 and 2 is 100% symptom in populations under 65 years of age.

According to the Amyloid hypothesis, symptoms of Alzheimer's disease are beta amyloid (hereinafter referred to as Αβ) that forms senile plaques outside the nerve cells of brain tissue and hyperphosphorylation within neurons to form paired helical filaments. Tau protein is recognized as a major causative agent (Querfurth and Laferia, 2010, N Engl J Med, 362: 329-344). Aβ is a protein composed of 40 to 42 amino acids that are formed by the metabolism of amyloid precursor protein (hereinafter APP) to be specifically metabolized by protease enzymes such as β- and γ-secretase. It has been reported to cause toxicity, synapse loss and inflammation (Cappari et al , Neurochem Res, 2008, 33: 526-532), and tau protein binds to microtubules to maintain cell morphology and structure Hyperphosphorylation separates from microtubules and breaks down microtubules and forms neurofibrillary tangles to induce neuronal death (Iqbal et al , Acta Neuropathol, 2009, Acta Neuropathol, 118 (1): 53-69). Has been reported.

Meanwhile, beta-site APP-cleaving enzyme 1, the enzyme that plays the most important role in the production of beta-amyloid, is commonly called BACE (beta-site APP-cleaving enzyme). Two types of BACE-2 are known. Among them, BACE-1 has most of the activity of beta-secretase (about 90%) and is known to play a much more important role than BACE-2 in the production of beta-amyloid (Vassar R., Advanced Drug Delivery Review, 2002, 54: 1589-1602. Therefore, substances that selectively inhibit the activity of BACE-1 is fully recognized the value that can be used as a treatment for Alzheimer's dementia.

Acetylcholine is a neurotransmitter associated with memory and thinking ability, and its concentration decreases in specific areas of the brain of patients with dementia (Tricco et al ., 2012, Syst Rev, 28: 1-31). Therefore, inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity have been used to treat dementia (Alzheimer's Association, Alzheimers Dement, 2012, 8: 131-168).

Alzheimer's disease is known to be about 26 million people worldwide as of 2008 and is expected to grow to more than 100 million by 2050 due to an increase in the elderly population, but the development of fundamental treatments is still slow.

Currently available drugs include acetylcholinesterase activity inhibitors (Aricept, Exelon, Reminyl, etc.) that maintain a constant concentration of acetylcholine and NMDA receptor antagonists (Memantine) that inhibit neuronal cell death by Ca2 +. However, these are used for the purpose of alleviating the progress of symptoms, the situation is urgently required to develop a therapeutic agent showing a stronger therapeutic effect.

The present inventors confirmed that the fern extract contains a pterosine compound and its derivatives. As a result of confirming the effect on the living body, the pterosine compound and its derivatives degenerate by inhibiting the activity of BACE1 and AChE and BChE. The present invention was completed by confirming the therapeutic effect on brain diseases.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative brain disease, which comprises a pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient.

<Formula 1>

Wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are each independently H, OH, alkyl or alcohol having 1 to 4 carbon atoms, or alkyl-O-glucose;

R7 is halogen, H, OH, O-alkyl, O-alkenyl, O-alkynyl, O-alcohol, O-carboxyl, O-ether, O-sulfonic acid (-SO ₃ H), O-cycloalkyl, O-heterocycloalkyl, glucose, and O-glucose.

Another object of the present invention (a) extracting the fern with water or an organic solvent having 1 to 4 carbon atoms; (b) fractionating the extract obtained in step (a) with ethyl-acetate; And (c) isolating and purifying the ethyl-acetate fraction obtained in step (b) by concentration gradient chromatography to provide a method for producing a pterosine compound of claim 1 or a derivative thereof. .

Another object of the present invention is to provide a food composition for preventing or improving degenerative brain disease, which comprises a pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient.

Another object of the present invention is to provide a food composition for improving cognitive function comprising a pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating degenerative brain disease, which comprises a pterosine compound represented by the following formula (1) or a derivative thereof as an active ingredient.

<Formula 1>

Wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are each independently H, OH, alkyl or alcohol having 1 to 4 carbon atoms, or alkyl-O-glucose;

R7 is halogen, H, OH, O-alkyl, O-alkenyl, O-alkynyl, O-alcohol, O-carboxyl, O-ether, O-sulfonic acid (-SO ₃ H), O-cycloalkyl, O-heterocycloalkyl, glucose, and O-glucose.

In order to achieve another object of the present invention, (a) extracting the fern with water or an organic solvent having 1 to 4 carbon atoms; (b) fractionating the extract obtained in step (a) with ethyl-acetate; And (c) isolating and purifying the ethyl-acetate fraction obtained in step (b) by concentration gradient chromatography to provide a method for producing a pterosine compound of claim 1 or a derivative thereof.

In order to achieve another object of the present invention, the present invention provides a food composition for preventing or improving degenerative brain disease, comprising the pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient.

In order to achieve another object of the present invention, there is provided a food composition for improving cognitive function comprising a pterosine compound represented by the formula (1) or a derivative thereof as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating degenerative brain disease, which comprises a pterosine compound represented by Formula 1 or a derivative thereof as an active ingredient.

<Formula 1>

Wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are each independently H, OH, alkyl or alcohol having 1 to 4 carbon atoms, or alkyl-O-glucose;

R7 is halogen, H, OH, O-alkyl, O-alkenyl, O-alkynyl, O-alcohol, O-carboxyl, O-ether, O-sulfonic acid (-SO ₃ H), O-cycloalkyl, O-heterocycloalkyl, glucose, and O-glucose.

As used herein, the term "alkyl" is used to describe a group or portion of a group comprising a straight or branched chain alkyl group containing 1 to 4 carbon atoms; Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl.

As used herein, the term “alkenyl” is a straight or branched monovalent or divalent hydrocarbon having 2-10 carbon atoms (eg C 2 -C 10) and having one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, propenylene, allyl and 1,4-butadienyl.

The term "alkynyl" as used herein is a straight or branched monovalent or divalent hydrocarbon having 2-10 carbon atoms (eg C2-C10) and having one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, ethynylene, 1-propynyl, 1- and 2-butynyl and 1-methyl-2-butynyl.

As used herein, the term "alcohol" is used to describe a straight or branched chain alcohol or alkoxy group having 1 to 4 carbon atoms; Such groups include methanol, ethanol, propanol, butanol and their alkoxy groups. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy.

As used herein, the term "halogen" refers to a halogen atom and may include fluorine, chlorine, bromine, iodine and the like. R7 of the present invention may preferably be chlorine.

The pterosin compounds and derivatives thereof of the present invention are sesquiterpenoids present in ferns, and are characterized in that they are purified from fern extracts. In addition, the pterosine compounds and derivatives thereof of the present invention are not limited thereto, but are not limited thereto, pterosin A, pterosin B, pterosin C, and pterosin D D), pterosin J, pterosin M, pterosin P, pterosin S, pterosin Z, pterosin Pteroside A, pteroside A2, pteroside B, pteroside C, pteroside D, pteroside N ), Pteroside P, pteroside Z, or sulfated pterosin C, preferably the pterosine compounds described in Table 1 of the present invention. Or derivatives.

The pterosine compounds of the invention may also have non-aromatic double bonds and one or more asymmetric centers, which are racemic and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures and cis- or It can occur as a trans-isomer and can include all such isomeric forms. It may preferably comprise cis- or trans-isomer form.

For example, the isomers of pterosine C are (2R, 3S)-pterosine C, (2S, 3S)-pterosine C, (2R, 3R)-pterosine C, (2S, 3R)- May be pterosine C.

Isomers of the pterosides C may be (2S, 3R) -pterosides C, (2R, 3R) -pterosides C.

Isomers of sulfated pterosine C may be (2R, 3S) -sulfated pterosine C, (2S, 3S) -sulfated pterosine C.

Pterosine compounds and derivatives thereof according to the present invention can be isolated from nature or prepared by chemical synthesis of novel compounds known in the art.

Preferably, the pterosine compounds of the present invention and derivatives thereof can be isolated and purified from natural plants. That is, it can be obtained from a plant or part of a plant using a method of extracting and separating conventional materials. Stems, roots or leaves are appropriately dried and macerated to obtain the desired extract, or only dried and extracted with a suitable organic solvent, and the desired extract can be purified using methods known to those skilled in the art. Can be purified. Preferably, the pterosine compounds and derivatives thereof of the present invention can be isolated and purified from ferns.

The fern can be, for example, dense Tad thiazol new (Dennstaedtiaceae) and loop terry dasae (Pteridaceae). Specific examples of such plants include, but are not limited to, Dennstaedtia scandens , Histiopteris incisa , Microlepia speluncae , Pterdium aquilinium bar. Pteridium aquilinum var.latiusculum , Pteridium revolutum , Hypolepis punctata , Ceratopteris thalictroides , Pteris pauriae fauriei ), Pteris dimidiata and Pteris ensiformi . These plants are distributed worldwide and can be found in particular in Wulai Township, Taipei County and Mountain Datun and Taipei City.

Pterosine compounds and derivatives thereof of the present invention can be isolated and purified by methods comprising the following steps:

(a) extracting the fern with water or an organic solvent having 1 to 4 carbon atoms;

(b) fractionating the extract obtained in step (a) with ethyl-acetate or butanol;

(C) separating and purifying the ethyl-acetate fraction or butanol fraction obtained in step (b) by concentration gradient chromatography.

In the step (a) the fern can be used as it is or the whole of the whole body, it can be used to grind the dry body of Cheongho with a grinder to increase the extraction efficiency. As a drying method, both dry, shade, hot air drying, freeze drying and natural drying methods can be used. Preferably hot air drying and lyophilization methods can be used.

The organic solvent having 1 to 4 carbon atoms used for fern extraction may be methanol, ethanol, propanol, isopropanol, butanol, acetone, ether, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, dichloromethane or petroleum ether. In one embodiment of the present invention the fern was extracted with water.

In the step (b), the extract obtained in the step (a) is fractionated and extracted by partition extraction using ethyl-acetate or butanol.

The ethyl-acetate fraction to butanol fraction obtained in step (b) is separated by concentration gradient chromatography. As the chromatography, column chromatography filled with various synthetic resins such as silica gel or activated alumina, high performance liquid chromatography (HPLC), etc. may be used alone or in combination. Preferably, among the fractions obtained in step (b), ethyl-acetate fraction or butanol fraction may be applied to the silica gel column, and various fractions may be obtained while gradually increasing the polarity by adjusting the composition of the eluting solvent. Among the fractions obtained in the above process, the fraction having active activity can be carried out by concentration gradient silica gel chromatography to gradually increase the polarity by adjusting the composition of the eluting solvent. However, extraction and separation and purification of the compounds are not necessarily limited to the above-described methods.

In step (c), the ethyl-acetate fraction or butanol fraction obtained in step (b) is separated and purified by concentration gradient chromatography.

As the chromatography, column chromatography filled with various synthetic resins such as silica gel or activated alumina, high performance liquid chromatography (HPLC), etc. may be used alone or in combination. Preferably, high performance liquid chromatography can be used to isolate and purify the novel compound.

The methods used to separate these compounds are well known in the art. See, eg, Takahashi et al , Phytother. Res, 2004, 18, 573, Sheridan et al, Planta Med., 1999, 65, 271, Nagao et al ., Mutation Research, 1989, 215, 173, Murakami et al ., Chem. Pharm. Bull, 1976, 24, 2241, and Kuraishi et al. , Chem. Pharm. Bull, 1985, 33, 2305. These compounds can also be prepared by chemical synthesis. Non-naturally occurring pterosine compounds can be converted from naturally occurring compounds (see, eg, Banerji et al, Tetrahedron Letters, 1974, 15, 1369, Hayashi et al. , Tetrahedron Letters, 1991, 33, 2509, and McMorris et al. , J. Org. Chem., 1992, 57, 6876), and may be newly synthesized by methods well known in the art.

Synthetic chemical conversion and protecting group methods (protection and deprotection) useful for synthesizing such pterosine compounds are known in the art and described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions etc.

In one embodiment of the present invention, after hot water extraction with fern 200 ~ 500g, hot water extract was added to the first ethyl acetate (EA), and then mixed well. Then, the ethyl acetate extract was dissolved in DMSO, diluted with water, and divided into seven fractions using column chromatography. The divided fractions were analyzed by HPLC to extract the pterosine compounds of Formula 1 and their derivatives. Next, butanol was added to the hot water extract, and the mixture was well mixed and extracted. Then, the butanol extract was dissolved in DMSO, diluted with water, and divided into nine fractions using column chromatography. The divided fractions were analyzed by HPLC to extract the compounds of the present invention (see Example 1).

The degenerative brain disease of the present invention is a disease that causes various symptoms with degenerative changes in the nerve cells of the central nervous system, and most of the disease gradually starts onset, and symptoms appear after long-term normal functioning. Also, once onset, the disease progresses for years or even decades until death, often with a family history.

Specific examples of degenerative brain diseases of the present invention include, but are not limited to, Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy ), Tourette`s Syndrome, Friedrich`s Ataxia, Machado-Joseph`s disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy and Frontotemporal Dementia.

Prevention, treatment or amelioration of degenerative brain disease may prevent, treat or ameliorate the symptoms of the disease, including the following symptoms:

a) behavioral symptoms such as sleep disorders, delirium (including agitation), attacks and progression,

b) psychological symptoms such as hallucinations, delusions, anxiety and depression,

c) motor symptoms, meaning impaired ability to perform motor activity in spite of intact motor function and

d) impaired learning and cognitive impairment, for example impaired ability to learn new information or recall previously learned information (e.g. impaired social memory), aphasia, execution, actual authentication, impairment in executive function, etc. .

The pharmaceutical composition according to the present invention may contain a pterosine compound or a derivative thereof alone or be formulated in a suitable form with a pharmaceutically acceptable carrier and may further contain an excipient or diluent. As used herein, 'pharmaceutically acceptable' refers to a non-toxic composition that, when administered to human beings, is physiologically acceptable and typically does not cause an allergic reaction, such as gastrointestinal disorders, dizziness, or the like.

Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, it may include various drug delivery materials used for oral administration to the peptide formulation. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-parabens and chlorobutanol. The pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent and the like in addition to the above components. Other pharmaceutically acceptable carriers and formulations may be referred to those described in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995.

The compositions of the invention can be administered to any mammal, including humans. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can be.

The pharmaceutical composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.

In the case of preparations for oral administration, the compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like. Can be. For example, oral preparations can be obtained by tablets or dragees by combining the active ingredients with solid excipients and then grinding them, adding suitable auxiliaries and processing them into granule mixtures. Examples of suitable excipients include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, including starch, corn starch, wheat starch, rice starch and potato starch, and the like. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.

Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, PA, 1995, a prescription generally known in all pharmaceutical chemistries.

 The total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol that is administered in multiple doses for long periods of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease. Preferably the preferred total dose of the pharmaceutical composition of the present invention may be about 0.01 to 10,000 mg, most preferably 0.1 to 500 mg per patient body weight per day. However, the dosage of the pharmaceutical composition is determined in consideration of various factors such as the formulation method, route of administration and frequency of treatment, as well as various factors such as the patient's age, weight, health status, sex, severity of the disease, diet and excretion rate. In view of this, one of ordinary skill in the art will be able to determine the appropriate effective dosage of the compositions of the present invention. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.

The present invention may be provided in the form of a food composition for the purpose of preventing or improving degenerative brain disease or the purpose of enhancing cognitive function.

"Pterosine compounds or derivatives thereof" and "degenerative brain diseases" represented by Formula 1 are as described above.

The term "cognition" of the present invention refers to all processes of receiving and storing some information in the brain, finding and using the stored information, and all processes of thinking, saying, remembering, judging, and executing in our lives. Are included in cognition. Cognitive function is the ability of the brain to remember, think, judge, and execute all processes of receiving and storing information and finding and using the stored information. These cognitive functions can be largely divided into attention, language, space-time, memory, and execution (or management). Cognitive function of the present invention includes learning ability, memory ability or concentration.

Food compositions using pterosine compounds or derivatives thereof according to the present invention include all forms of functional foods, nutritional supplements, health foods and food additives. do. These types can be prepared in various forms according to conventional methods known in the art.

For example, as a health food, the composition for food itself of the present invention may be prepared in the form of tea, juice and drink for drinking, or granulated, encapsulated and powdered. In addition, the composition for food of the present invention may be prepared in the form of a composition by mixing with a known substance or active ingredient known to have the effect of reducing body fat, improving cholesterol, lowering blood pressure.

Functional foods also include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruit, canned foods, jams, marmalade, etc.), fish, meat and processed foods (e.g. ham, sausage and conveyor). If), breads and noodles (e.g. udon, soba, ramen, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, malts, dairy products (e.g. butter, cheese), edible vegetable oils, margarine It can be prepared by adding the food composition of the present invention to vegetable protein, retort food, frozen food, various seasonings (for example, miso, soy sauce, sauce, etc.).

The preferred content of the food composition according to the present invention is not limited thereto, but is preferably 0.01 to 50% by weight of the total weight of the finally prepared food. In order to use the food composition of the present invention in the form of a food additive, it may be prepared and used in powder or concentrate form.

In addition, the food composition of the present invention may contain various flavors, natural carbohydrates, and the like as additional components, as in general beverages. The carbohydrates are glucose, glucose such as fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetener, natural sweeteners such as tautin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 ~ 0.04g, preferably about 0.02 ~ 0.03g per 100mL of the composition of the present invention, but is not limited thereto.

The term definitions of the excipients, binders, disintegrants, glidants, copulation agents, flavoring agents, etc. of the present invention are described in documents known in the art and include those having the same or similar functions. Sacrament, Korean College of Pharmacy, 5th Edition, p33-48, 1989).

The "treatment" of the present invention refers generically to ameliorating symptoms of degenerative brain disease or degenerative brain disease related disease or degenerative brain disease related disease, which cures, substantially prevents, or ameliorates the disease. It may include, but is not limited to, alleviating, healing or preventing one or most of the symptoms resulting from a degenerative brain disease or a disease associated with degenerative brain disease.

The term "promoting" of the present invention refers generically to further improving cognitive function, which may include improving cognitive function-related abilities, preferably learning, memory or concentration, as degenerative brain diseases. It may include, but is not limited to, alleviating, healing or enhancing symptoms such as cognitive impairment and degeneration.

Accordingly, the present invention provides a composition for preventing, ameliorating or treating degenerative brain disease, including a pterosine compound and a derivative thereof. The method of the present invention is to provide a therapeutic agent for preventing or treating degenerative brain disease, a food for improving degenerative brain disease, or a functional food for cognitive functioning, using a pterosine compound and derivatives thereof extracted from bracken. It can be usefully used.

1 is a diagram illustrating a process of separating and purifying a compound of the present invention and a derivative thereof.
2 shows the conditions of HPLC for separating single compounds from EA-2 and butanol fractions.
3 shows the 1 H-NMR spectrum of Pteroside N (Compound 16, comp. 15).
Figure 4 shows a 13C-NMR spectrum of Pteroside N (Compound 16, comp. 15).
5 shows the DEPT 1 spectrum of Pteroside N (Compound 16, comp. 15).
6 shows the results of HMBC analysis of pteroside N (compound 16, comp. 15).
FIG. 7 shows the (2S, 3R) -Pterosine C cis isomers (FIGS. A, D), (2R, 3R) -Pterosine C trans isomers (FIGS. B, E), and Pterosine B (FIG. C, FIG. F) BACE1 inhibitory mechanisms and Ki values of Dixon plot (x-axis: new compound concentration, y-axis: 1 / initial reaction rate) graph (a) and Lineweaver plot (x-axis: 1 / substrate concentration, y-axis: 1 / enzyme initial reaction rate) shows the results of the evaluation in the graph (b). Figures A to C show Dixon plots, and Figures D to F show Lineweaver plots.
FIG. 8 shows (2S, 3R) -Pterosine C cis isomers (FIGS. A, D), (2R, 3R) -Pterosine C trans isomers (FIGS. B, E), and Pterosine B (FIG. C, F) ACx inhibitory activity and Ki values of Dixon plot (x-axis: new compound concentration, y-axis: 1 / enzyme initial reaction rate) and lineweaver plot (x-axis: 1 / substrate concentration) , y-axis: 1 / enzyme initial reaction rate) shows the evaluation results in the graph (D, E, F).
FIG. 9 shows (2S, 3R) -Pterosine C cis isomers (FIGS. A, D), (2R, 3R) -Pterosine C trans isomers (FIGS. B, E), and Pterosine B (FIG. C, FIG. The BChE inhibitory mechanism and Ki values of F) were calculated using Dixon plot (x-axis: new compound concentration, y-axis: 1 / enzyme initial reaction rate) graph (A, B, C) and Lineweaver plot (x-axis: 1 / substrate concentration). , y-axis: 1 / enzyme initial reaction rate) shows the evaluation results in the graph (D, E, F).
10 is a lineweaver plot (top) of (2S) -pterosin A (compound 1) to evaluate the BACE1 activity inhibition mechanism and Ki of the new compound (x-axis: 1 / substrate concentration, y-axis: 1 / enzyme initial reaction Rate), and Dixon plot (bottom) to evaluate BACE1 activity inhibition mechanism and Ki (x-axis: new compound concentration, y-axis: 1 / enzyme initial reaction rate).
FIG. 11 shows the results of molecular docking of (2R, 3R) -pteroside C (compound 14), BACE1, AChE, and BChE of the positive control quercetin and berberine, showing the binding energy and binding site of each compound and enzyme. Table.
FIG. 12 shows that (2R, 3R) -Pteroside C (Compound 14) binds to human BACE1 to inhibit BACE1 action. FIG. 12A shows three-dimensional and FIG. 12B shows a planar binding. Green represents a hydrogen bond, pink represents a hydrophobic bond, and purple represents a π-sigma bond.
FIG. 13 shows that (2R, 3R) -Pteroside C (Compound 14) binds to human AChE and inhibits AChE. FIG. 13A shows a three-dimensional structure and FIG. 13B shows a planar binding. Green represents a hydrogen bond, pink represents a hydrophobic bond, and purple represents a π-sigma bond.
FIG. 14 shows the binding of (2R, 3R) -teroside C (compound 14) to human BACE1, FIG. 14A shows a three-dimensional structure, and FIG. 14B shows a planar binding. Green represents a hydrogen bond, pink represents a hydrophobic bond, and purple represents a π-sigma bond.

Hereinafter, the present invention will be described in detail.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Experimental Method

Laboratory equipment

1H NMR and 13C NMR spectra were deuterium chloroform (CDCl3), methanol (CD3OD), dimethyl sulfoxide (DMSO-d8) and Bruker Ascend III 700 spectrometer (Bruker Biospin, Rheinstetten, at 700 MHz with 1H NMR and 175 MHz with 13C NMR). Germany).

Column chromatography was performed with silica gel (70-230 mesh; Merk, Darmstadt, Germany), RP-18 (40-63 mm; Merk) and Sephadex LH-20 (20-100 mm; Sigma, St. Louis, MO, USA) It became. Thin layer chromatography (TLC) was performed pre-coated with Kiesel gel 60 F254 plates (0.25 mm; Merck) and 25 RP-18 F 254s plates (5-10 cm, Merk). Spray reagent was 50% H ₂ SO ₄ . All chemicals and solvents used in column chromatography were in reagent grade and used as received and received.

reagent

Electric Eel Acetylcholine Esterase (AChE, EC3.1.1.7), Equine Serum Butyrylcholine Esterase (BChE, EC3.1.1.8), Acetyl Thiocholine Iodide (ACh), Butyryl Thio Choline chloride (BCh), 5,5'-dithiobis [2-nitrobenzoic acid] (DTNB), quercetin and berberine are described by Sigma-Aldrich Co. (St. Louis, MO, USA). The BACE1 (-sectetase) FRET Assay Kit is available from Pan Vera Co. (Madison, WI, USA). All chemicals and solvents used in column chromatography were in reagent grade and used as received and received.

MTT assay

NIH3T3 cells, a mouse fibroblast cell line, and B16F10 cells, a mouse melanoma cell line, at a concentration of 1 X 10 ³ cells / well, were prepared in a 96 well plate containing DMEM with 10% FBS (fetal bovine serum). Incubated at. Treatment of compounds (pterosin A, pterosin B, pterosin C, pterosin D, pterosin P, pterosin Z, pteroside A, pteroside A2, pteroside B, pteroside C isomers, pteroside D, pteroside N, pteroside P, pteroside Z) And incubated for 24 hours. Thereafter, 100 μL of MTT (0.5 mg / ml PBS) was administered, followed by incubation for 2 hours. Then, the medium was removed from each well and 100 μL of DMSO was added. After incubation for 10 minutes, the absorbance was measured at 570 nm using a microplate reader (SPCTRA MAX 340PC, Molecular Devices, USA). Absorbance is calculated by the formula below as an indicator of the number of surviving cells, and reproducibility was confirmed by three experiments.

 Cell growth rate (%) = OD550 (sample) / OD550 (control)

in vitro  BACE1 Activity Assay

BACE1 fluorescence resonance energy transfer (FRET) assay kit (β-secretase, human recombination) was prepared using Pan Vera Co. (Madison, WI, USA). It was performed according to the manual provided, with minor modifications as described by Jung et al. (Jung et al., Biol Pharm Bull, 2010, 33: 267-272). Quercetin is a positive control.

in vitro  Cholinesterase Activity Assay

The inhibitory activity of the compounds against cholinesterase was measured using the spectrophotometric method developed by Elman et al . (Elman et al ., Biochem Pharmcol, 1961, 7:88). -95). 140 μL sodium phosphate buffer (pH 8.0), 20 μL test sample solution (final concentration 125 μM), 20 μL of AChE or BChE solution were added to the reaction solution, and mixed and incubated at room temperature for 15 minutes. All test samples and positive controls (berberine) were dissolved in 10% analytical grade ethanol. The reaction was initiated with the addition of 10 μL of DTNB and 10 μL of Ach or Bch.

Hydrolysis of Ach or BCh was measured for 15 minutes at 412 nm with a microplate spectrophotometer (Molecular Devices, Inc., Sunnyvale, Calif., USA). Specifically, thio anion (yellow) of dithio compound and nitrobenzoic acid produced from the reaction of thiocholine, which is hydrolyzed and liberated by acetylcholine esterase in DTNB and acetylthiocholine in 96-well microplate Was detected by 412nm UV to measure the enzyme activity. Inhibition was calculated as (1 ≦ S / E) ≦ 100. Where E and S are the respective enzyme activities with or without test sample.

Molecular Docking

In order to confirm the enzyme inhibitory ability of the compounds of the present invention, molecular docking studies for BACE1, AChE and BChE were performed. 2-amino-3- (1r) -1-cyclohexyl-2-[(cyclohexylcarbonyl) amino] ethyl-6-phenoxyquinazolin-3-ium (QUD) was bound to the X-ray crystal structure of human BACE1 to form a complex. AChE is donepezil (E2020) (PDB code: 4EY7), and BChE is N-[(3R) -1- (2,3-dihydro-1H-inden-2-yl) piperidin-3-yl] methyl-N It was complexed with-(2-methoxyethyl) naphthalene-2-carboxamide (3F9) (PDB code: 4TPK). The complex formed was retrieved from the RCSB Protein Databank (https://www.rcsb.org/). Discovery Studio 2017 R2 (BIOVIA, San Diego: Dassault Syst) was used to create 3D structures of docked ligands and to minimize energy.

Docking studies were performed using Dock AutoDock 4.2.6 software. Re-docking experiments were performed on the co-crystallized ligands of the mentioned PDBs to assess the molecular docking setup. The identified docking protocol was then used to dock other compounds. The protein structure remained tight, but the ligands were handled with complete flexibility during docking. Protein and ligand structures were treated with AutoDock Tools (ADT) 1.5.6 prior to docking. Co-crystallized ligand and water molecules were removed from the original PDB. The polar hydrogen atoms merged to assign Kollman and Gasteiger charges to the protein structure. Gasteiger charge was added to the ligand for docking calculations.

The number of rotatable bonds was set and all the torsion could be rotated. For each enzyme, a grid box was created around the co-crystallized ligand to cover the active site of the protein with the AutoGrid program. A grid of size 40 × 40 × 40 × 3 with a 0.375 mm 3 spacing was located around the co-crystallized ligand of each enzyme. Lamarckian genetic algorithm (LGA) was used to search the structure.

The docking protocol consisted of 100 runs, 25 × 10 ⁵ energy assessments and 27,000 iterations. Other docking parameters were set to default values. Docked poses were selected based on scoring function and protein-ligand interaction. We used Discovery Studio 2017 R2 to visualize binding interactions and generate interaction figures.

Statistical analysis

The data show the results of three or more independent experiments as mean ± standard error (mean ± SE).

Example 1 Purification of Compounds of the Invention

Fern hydrothermal extracts were extracted using ethyl acetate and butanol, and then separated into seven fractions, and the fractions of pterosine and novel compounds were separated by HPLC method.

Specifically, the fern extract is washed 200-250 g of fern collected from Gapyeong-gun, Gyeonggi-do, and put in a steaming vessel (OSK-2002, red ginseng doctor, Well sosanaTM, Daewoong Pharma) and steamed for 24 hours by adding 1.5L of water, and then water 3.5 Additional L was aged for 72 hours and refrigerated was used as a hot water extract. After adding the same volume of ethyl acetate (EA) to the hot water extract and mixing well, the EA layer was dried with a rotary evaporator and used as an EA extract. The EA extract was dissolved in a minimum amount of DMSO and diluted with water, where the dilution multiple was diluted to 70% of the original volume of the hydrothermal extract with the expected yield of approximately 70%.

The EA extract was divided into seven fractions using chloroform (CHCl 3) and methanol using silica gel column chromatography. Then, each fraction was analyzed by Prep-HPLC, and fractions 2, 4, 5, 6, and 7 were extracted from pterosine and its derivatives as shown in Table 1. The extraction process is shown in FIG. 1 .

In addition, after extracting the hot water extract with EA and adding the same volume of butanol to the remaining extract and mixed well, the butanol layer was dried by a rotary evaporator and used as Bu extract. The Bu extract was dissolved in a minimum amount of DMSO and diluted with water, where the dilution multiple was diluted to 70% of the original volume of the hydrothermal extract with the expected yield of approximately 70%.

Bu extract was divided into nine fractions using chloroform (CHCl3) and methanol using silica gel column chromatography. Then, as a result of analyzing each fraction by Prep-HPLC, fraction 6 was able to extract the pterosine derivatives as shown in Table 1. The extraction process is shown in FIG. 1 .

The conditions of HPLC for separating single compounds from EA-2 fraction and Bu-6 fraction are as shown in FIG . 2 .

Compound (FIG. 1 comp.) constitutional formula designation 1 (comp. 2 )

(2 S) -pterosin A 2 (comp. 3 )

(2 R) -pterosin B 3

(2 R , 3 S ) -pterosin C
4

(2 S , 3 S ) -pterosin C
5 (comp. 5 )

(2 R , 3 R ) -pterosin C 6 (comp. 4 )

(2 S , 3 R ) -pterosin C 7 (comp. 6 )

(3 R ) -Pterosin D 8 (comp. 7 )

(2 S) -pterosin P
9 (comp. 8 )

pterosin Z
10 (comp. 9 )

(2 S) -pteroside A
11 (comp. 10 )

₍₂ S) -pteroside A 2
12 (comp. 11 )

(2 R) -pteroside B
13 (comp. 12 )

(2 S , 3 R ) -pteroside C
14 (comp. 13 )

(2 R , 3 R ) -pteroside C
15 (comp. 14 )

(3 S) -pteroside D
16 (comp. 15 )

(-)-pteroside N
17 (comp. 16)

(2 S) -pteroside P
18 (comp. 17 )

pteroside Z 19

(2 R , 3 S ) -sulfated pterosin C 20

(2 S , 3 S ) -sulfated pterosin C 21

pterosin J 22

pterosin M 23

pterosin S

Example 2: Cytotoxicity Assessment of Compounds (MTT assay)

In order to determine whether the compounds of the present invention have a toxic effect on the cells was carried out as follows.

As described in the above experimental method, normal cells NIH3T3 (mo use embryo fibroblast cell-line) and cancer cells B16F10 (Mouse mela noma cell-line) were cultured in 96-well plate, and each compound was added to the cell medium by concentration. After 48 hours of incubation and administration of MTT, the absorbance was measured at 550 nm using a microplate reader. Absorbance was calculated by the formula below as an indicator of the number of cells that survived, and reproducibility was confirmed by three experiments.

Cell growth rate (%) = OD550 (sample) / OD550 (control) *? *

Then, LD50 (Lethal Dose 50) value was calculated based on the change in cell proliferation rate.

As a result, as shown in Table 2, the LD50 value of pterosin A in cancer cells was the lowest as 522 ± 25 μM. The LD50 value of pterosin B in normal cells was 3110 ± 130 μM and the LD50 value of pterosin Z in normal cells. Silver 553 ± 37μM, pterosin Z LD50 value of cancer cells was 618 ± 71μM. Apart from this, LD50 values of other compounds in normal cells and cancer cells were found to be greater than 5000 μM.

Through this, Pterosin Z (Compound 9) has a weak cytotoxicity, Pterosin A (Compound 1) was found to have a weak cytotoxicity only in cancer cells, and other compounds were confirmed that there is little cytotoxicity in normal cells and cancer cells.

Example 3: BACE1 inhibitory effect of the compound of the present invention

BACE1 is an enzyme that promotes the production of β-amyloid, a substance that destroys neurons. Thus, in order to confirm the effect of the compounds of Table 1 on the activity of BACE1, in vitro BACE1 activity was measured according to the experimental method was measured IC (inhibition concentrations) 50 value. Each compound was dissolved in 10% DMSO and treated at various concentrations up to 125 μM.

As a result, as shown in Table 3 , Compounds 2, 5, 6, 12, 14, and 15 showed that IC50 values were lower or similar to quercetin.

Among these, quercetin, a positive control, and Compound 2 ((2R) -Pterosin B) with low IC50 values, Compound 5 ((2R, 3R) -Pterosin C), Compound 6 ((2S, 3R) -Pterosin C), and Compound 12 Dixon plot to determine the BACE 1 enzyme activity and Ki of ((2R) -Pteroside B), Compound 14 ((2R, 3R) -Pteroside C), and Compound 15 ((3S) -Pteroside D) ) And an enzyme kinetics experiment using a Lineweaver plot.

As a result, as shown in Table 4 (Enzyme kinetics of the compounds of the present invention based on Dixon plot and Lineweaver plot), BACE1 inhibitory mechanism of Compound 2 is a noncompetitive type, BACE1 inhibitory mechanism of Compound 5 is a mixed type (mixed type) , BACE1 inhibitory mechanism of compound 6 is a noncompetitive type, compound 12 is a non-competitive type, compound 14 is a mixed type, compound 15 is a mixed type. The compounds 2, 5, 6, 12, 14, 15 all showed a very low Ki value and confirmed that the strong binding to BACE1, it was confirmed that it is a very strong inhibitor of BACE1 enzyme activity.

Quercetin ^a positive control for BACE1.

Example 4 Inhibitory Effects of Pterosine Compounds on Cholinesterases

In order to evaluate the anti-Alzheimer's activity of the compounds of Table 1 , by measuring the inhibitory activity against AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) that degrades acetylcholine in the central nervous system according to the experimental method, IC (inhibition) concentrations) 50 values were calculated. Each compound was dissolved in 10% DMSO and treated at various concentrations up to 125 μM.

Cholinesterase is an enzyme that degrades acetylcholine, a neurotransmitter that plays a role in enhancing thinking and memory. Acetylcholine degrading activity is much stronger in AChE than in BChE.

As a result, as shown in Table 5 , each compound was found to have a higher IC 50 value than Berberine, a positive control. Among the compounds, compound 12 showed the lowest IC 50 value in AChE. In addition, Compound 14 showed the lowest IC50 value and Compound 7 showed the highest value in BChE.

As a result, it was confirmed that Compound 12 (pteroside B), Compound 14 (pteroside C), and Compound 2 (Pterosin B) among the pterosine compounds extracted by the method of the present invention have excellent AChE inhibitory activity. In addition, it was confirmed that Compound 5 (pterosin C trans-isomer), Compound 12 (pteroside B) and Compound 18 (pteroside Z) have excellent BChE inhibitory activity.

Among them, the positive control group was berberine and compound 2 ((2R) -Pterosin B) having low IC50 value, compound 5 ((2R, 3R) -Pterosin C), compound 6 ((2R, 3S) -Pterosin C), and compound Enzyme kinetics experiments were conducted using Dixon plots and Lineweaver plots to determine the mechanism of inhibition of AChE and BChE enzyme activity and Ki of 12 ((2R) -Pteroside B). (See FIGS . 8 and 9 )

As a result, as shown in Table 4, AChE, BChE inhibitory mechanism of Compound 2 is a mixed or non-competitive type, respectively, AChE, BChE inhibitory mechanism of Compound 5 is a non-competitive or mixed type, respectively, AChE, BChE inhibitory mechanism of Compound 6 Was mixed or non-competitive type, AChE, BChE inhibitor mechanism of compound 12 was confirmed to be all mixed type. Thus, Compounds 2, 5, 6, and 1 exhibited very low Ki values, which confirmed that they strongly bind AChE and BChE, and were found to be very strong AChE, BChE enzyme activity inhibitors.

Therefore, the pterosine compounds extracted by the method of the present invention have the ability to maintain the level of acetylcholine by inhibiting AChE and BChE activities, which are enzymes that degrade acetylcholine, a neurotransmitter responsible for cognitive functions such as brain thinking, memory, etc. I could confirm that there is.

Berberine ^a : positive control for cholinesterases (AChE and BChE).

SI ^b : selectivity index (BChE / AChE). An indicator that identifies which enzyme, AChE or BChE, is more specific.

Example 4 Docking Results of Compounds in BACE1, AChE and BChE Active Sites

There are several crystal structures in BACE1, AChE and BChE. Among them, human PDB was selected in consideration of the solution of wild type structure, co-crystallized ligand and structure. X-ray crystal structures of BChE, complexed with BACE1, E2020 (PDB code: 4EY7), complexed with QUAD (PDB code: 2WJO), and AChE and 3F9 (PDB code: 4TPK), complexed with were selected.

Docking studies were performed on selected compounds to investigate the binding patterns of the compounds shown in Table 1 and to investigate their structural activity relationships. (2R, 3R) -Pteroside C was found to be a potent inhibitor of BACE1, AChE and BChE following the enzyme inhibition test. Thus, (2R, 3R) -Pteroside C was chosen as representative of the compound for docking. In addition, Quercetin and Berberine, which were used as positive controls in the enzyme inhibition test, were docked.

Docking results are summarized in Fig. Molecular docking simulations showed that (2R, 3R) -pteroside C interacted strongly with the active site residues of BACE1, and the binding energy was -6.77 kcal / mol lower than quercetin -5.68 kcal / mol.

In addition, the binding energy with AChE was -6.85 kcal / mol, higher than -8.61 kcal / mol of berberine, and the binding energy with BChE was -5.99 kcal / mol, slightly higher than -6.67 kcal / mol of berberine.

 This demonstrates the high affinity and tight binding capacity of the compounds of the invention to the active sites of BACE1, AChE and BChE, indicating that the compounds of the invention bind and inhibit the enzymes.

12 to 14 show that (2R, 3R) -teroside C binds to BACE1, AChE, and BChE, respectively.

In conclusion, in vitro enzyme assay and molecular docking tests demonstrated that pterosine and its derivatives have promising inhibition potential against BACE1, AChE and BChE. This suggests the possibility that the compounds of the present invention can be used in the treatment or prevention of dementia through inhibition of BACE1 and AChE activity.

As described above, the method of the present invention uses a pterosine compound and its derivatives extracted from bracken, a therapeutic agent for preventing or treating degenerative brain disease, a food for improving degenerative brain disease, or a functional food for enhancing cognitive function. It can be usefully used to provide.

Claims (10)

A pharmaceutical composition for preventing or treating degenerative brain disease, comprising a pterosine compound represented by Formula 1 as an active ingredient:
[Formula 1]

In the above formula
R 1 and R 2 are each independently H, OH, methyl, hydroxymethyl or methyl-O-glucose;
R3 and R4 are each independently H or OH;
R 5 is H;
R6 is methyl or hydroxymethyl;
R7 is OH or O-glucose;
R8 is methyl.
The method of claim 1, wherein the pterosin compound is pterosin A (pterosin A), pterosin B (pterosin B), pterosin C (pterosin C), pterosin D (pterosin D), ptero new P (pterosin P), program for interrogating new Z (pterosin Z), program for interrogating the side A (pteroside A), program for interrogating the side A ₂ (pteroside A _2), program for interrogating the side B (pteroside B), program for interrogating the side C ( pteroside C), pteroside D, pteroside N, pteroside P, and pteroside Z Pharmaceutical composition for preventing or treating brain diseases.
The pharmaceutical composition of claim 1, wherein the pterosine compound is purified from ferns.
According to claim 1, The degenerative brain disease Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, Spinocer ebellar Atrophy, Tourette syndrome (Tourette`s Syndrome), Friedrich`s Ataxia, Machado-Joseph`sd isease, Lewy Body Dementia, Dysto nia, Progressive nuclear paralysis (Progressive Supranuclear Palsy) and frontal temporal dementia (Frontotemporal Dementia) A pharmaceutical composition for preventing or treating degenerative brain disease, characterized in that any one selected from the group consisting of.
delete delete A food composition for preventing or improving degenerative brain disease, comprising a pterosine compound represented by the following Formula 1 as an active ingredient.
[Formula 1]

In the above formula
R 1 and R 2 are each independently H, OH, methyl, hydroxymethyl or methyl-O-glucose;
R3 and R4 are each independently H or OH;
R 5 is H;
R6 is methyl or hydroxymethyl;
R7 is OH or O-glucose;
R8 is methyl.
The method of claim 7, wherein the pterosin compound is pterosin A (pterosin A), pterosin B (pterosin B), pterosin C (pterosin C), pterosin D (pterosin D), ptero new P (pterosin P), program for interrogating new Z (pterosin Z), program for interrogating the side A (pteroside A), program for interrogating the side A ₂ (pteroside A _2), program for interrogating the side B (pteroside B), program for interrogating the side C ( pteroside C), pteroside D, pteroside N, pteroside P, and pteroside Z Food composition for preventing or improving brain diseases.
According to claim 7, The degenerative brain disease Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette syndrome ( Tourette`s Syndrome, Friedrich`s Ataxia, Machado-Joseph`s disease, Lewy Body Dementia, Dystonia, Progressive Nucleus Paralysis Progressive Supranuclear Palsy) and frontal temporal dementia (Frontotemporal Dementia) is a food composition for preventing or improving degenerative brain disease, characterized in that any one selected from the group consisting of.
Food composition for improving cognitive function comprising a pterosine compound represented by the formula (1) as an active ingredient.
[Formula 1]

In the above formula
R 1 and R 2 are each independently H, OH, methyl, hydroxymethyl or methyl-O-glucose;
R3 and R4 are each independently H or OH;
R 5 is H;
R6 is methyl or hydroxymethyl;
R7 is OH or O-glucose;
R8 is methyl.

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