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WO2012161527A2 - Composition pour la prévention ou le traitement de maladies neurodégénératives, contenant des extraits de bois de santal ou des fractions de ceux-ci comme ingrédients actifs - Google Patents

Composition pour la prévention ou le traitement de maladies neurodégénératives, contenant des extraits de bois de santal ou des fractions de ceux-ci comme ingrédients actifs Download PDF

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Publication number
WO2012161527A2
WO2012161527A2 PCT/KR2012/004103 KR2012004103W WO2012161527A2 WO 2012161527 A2 WO2012161527 A2 WO 2012161527A2 KR 2012004103 W KR2012004103 W KR 2012004103W WO 2012161527 A2 WO2012161527 A2 WO 2012161527A2
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sandalwood
extract
disease
composition
fraction
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WO2012161527A3 (fr
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장춘곤
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Sungkyunkwan University Foundation for Corporate Collaboration
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Sungkyunkwan University Foundation for Corporate Collaboration
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition and a food composition for the prevention or treatment of degenerative cranial nerve disease, including sandalwood extract or a fraction thereof as an active ingredient.
  • the present invention also relates to a method for preventing or treating degenerative neurodegenerative diseases, comprising administering the composition to a subject having or likely to develop a degenerative neurological disease.
  • the present invention also relates to a pharmaceutical composition and food composition for learning or memory enhancement, comprising sandalwood extract or a fraction thereof as an active ingredient.
  • the central nervous system which consists of the brain and spinal cord, is an essential organ that manages all the functions of the human body, from sensory and voluntary or involuntary movements to thinking, memory, emotions, and language. Therefore, neurodegenerative neurological diseases such as stroke, senile dementia and Parkinson's disease, which are represented by Alzheimer's disease, result in irreversible dysfunction of the neural network, resulting in permanent loss of the function of the human body.
  • cerebrovascular dementia due to Alzheimer's dementia and extensive brain lesions caused by stroke or cerebral atherosclerosis accounts for about 90% of all dementia diseases.
  • Other cerebral neurological disorders include Pick's disease, Creutzfeldt-Jakob disease, dementia caused by head injury, and Parkinson's disease.
  • Dementia is a fourth cause of elderly death after cancer, heart disease, and stroke. Dementia is divided into Alzheimer's dementia and vascular dementia.
  • Alzheimer's dementia is a type of dementia commonly observed in the West, and is a disease caused by the accumulation of beta amyloid in certain parts of the brain and the destruction of cholinergic neurons.
  • vascular dementia is a dementia caused by hypertension, stroke, hyperlipidemia, abnormalities in the cerebral blood vessels, and an ischemic condition, resulting in necrosis of the hippocampus and limbic system.
  • the Alzheimer's dementia and vascular dementia may have different causes, but consequently, they have the same mechanism of action by reducing the action of acetylcholine, which is known as a memory transmission neuron, to impair memory.
  • microglia In the central nervous system of the brain, microglia are inherent in the immune system and form a line of defense against bacterial invasion and injury. The microglia can be activated due to various exogenous and endogenous substances, and activated microglia produce and release inflammatory cytokines TNF-a and IL-1 nitrogen monoxide, prostaglandins, superoxides and the like. The production of these substances triggers an immune response in the short term, but their overproduction or continuous production leads to the death of neighboring neurons, which in turn leads to neurodegeneration. In addition, the neurons degenerate into a vicious cycle because substances released by dying neurons reactivate the small neuroglial cells.
  • microglia is associated with various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfeldt-Jakob disease, and multiple sclerosis.
  • Alzheimer's disease Parkinson's disease
  • Huntington's disease Huntington's disease
  • Lou Gehrig's disease Lou Gehrig's disease
  • Creutzfeldt-Jakob disease and multiple sclerosis.
  • NMDA N-methyl-D-aspartic acid
  • 'NMDA' N-methyl-D-aspartic acid
  • 'BZ3' peripheral benzodiazepine
  • N, N-di-n-hexyl-2- (4-fluorophenyl) indole-3-acetamide N, N-di-n-hexyl-2- (4), an agonist for the BZ3 receptor.
  • FGIN-1-27 -fluorophenyl indol-3-aceteamide
  • neurosteroids e.g., pregnenolone sulfate, allopregnanolone
  • acetylcholinesterase is used to modulate choline loss by slowing the rate at which synaptic acetylcholine (ACh) is removed in patients with Alzheimer's disease (AD) and consequently to improve symptoms of Alzheimer's disease (AD). , Suppression of AChE) has been attempted.
  • Acetylcholinesterase is an enzyme that breaks down acetylcholine (ACh), while acetylcholinesterase inhibitors inhibit this degradation process, making acetylcholine longer in the neural cleft. Time remains, thus enhancing neurotransmitter effects, improving cognitive functions such as learning and memory.
  • Acetylcholinesterase (AChE) inhibitors developed to date include 1,2,3,4-tetrahydro-9-acridineamine (1,2,3,4-tetrahydro-9-acridine amine; tacrine (tacrine), THA; 'COGNEX', Donepezil (Done Pezyl, E2020; 'ARICEPT') and Rivastigmine (ENA713; 'Excelon' (EXELON)).
  • the mechanism of action of these drugs works best when the cholinergic nerves are not functionally damaged because they prevent and treat Alzheimer's disease by increasing the concentration of ACh, a neurotransmitter, through the inhibition of AChE activity.
  • the AChE inhibitory drugs have a problem that they are effective only in the early stages of mild or moderate senile dementia.
  • the AChE inhibitors are prone to cholinergic side effects in the peripheral nerves, and have many side effects such as short half-life and liver toxicity (Br. J. Psychiatry, 138, p46, 1981).
  • TAA 9-amino-1,2,3,4-tetrahydroacridine
  • a product that is a mixture of several herbal extracts based on ginseng is disclosed in Korean Patent Publication No. 99-85202 and US Patent No. 6,010,702.
  • the herbal extracts show some medicinal effects on senile dementia, they still do not guarantee a definite and stable effect, and the mechanism of action is different from other conventional dementia treatment agents. It appears to be an incomplete composition.
  • the ginseng component is composed of the main component can cause cardiac palpitation in hypertensive patients or may be a problem in that it can cause homeostatic imbalance.
  • Benzimidazole which inhibits the activation of microglia, is also a neuroinflammatory patient (AIDS, dementia, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Down's syndrome, diffuse Lewy body disease, Huntington's disease, white encephalitis, multiple sclerosis, Parkinson's disease, Pix disease , Alzheimer's disease, stroke seizures, temporal lobe epilepsy and tumors).
  • AIDS AIDS, dementia, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Down's syndrome, diffuse Lewy body disease, Huntington's disease, white encephalitis, multiple sclerosis, Parkinson's disease, Pix disease , Alzheimer's disease, stroke seizures, temporal lobe epilepsy and tumors.
  • the relationship between the activation of microglia and degenerative neuropathy has not been fully understood. However, it is generally believed that the activity of microglia is associated with the development and progression of neurodegenerative diseases. Therefore, suppressing the
  • sandalwood belongs to the Araliaceae danhyang (Santalaceae) is a resource of the directional native to Southeast Asia and Australia, Africa, India, Indonesia, its scent is fragrant and persistent excellence is well known and widely used as a fragrance.
  • Sandalwood is also known for its warm nature, very good taste, and no poison. Sandalwood not only can be used in fragrances, Buddha statues, etc., it is processed into sandalwood oil and is used as expensive cosmetics and soap. Sandalwood oil exhibits strong antiviral and anticancer effects, and about 40 species of sesquiterpene of the santacyclo-type bicyclo ring structure have been isolated from the sandalwood oil.
  • A-santalol the main ingredient contained in the sandalwood oil, has been reported to have physiological activities such as strong analgesic and anti-carcinogenic promotion (Kim et al., Tetragedron., 2006, 62, 6981-6989).
  • dihydrodehydrodiconifetyl alcohol (7S, 8S) -3-methoxy-3 ', 7-epoxy-8,4'-oxyneoligna-4,9,9'-triol, (7'S, 8R, 8' R) -lyonesinol, 2,3-bis [(4-hydroxy-3,5-dimethoxyphenyl) -methyl] -1,4-butanediol, and (-)-secoisolariciresinol have been reported to contain phenolic compounds. Kim et al., Chem. Pharm. Bull., 2005, 53, 641-644), to date, there have been no reports on the effects of learning and memory improvement and the preventive or therapeutic effects on degenerative neurological diseases.
  • sandalwood extract or its fraction inhibits acetylcholinesterase activity and neuroinflammatory response, and prevents learning disorders or memory impairment. While showing a therapeutic effect and confirming the effect of learning or memory enhancement, the present invention was completed.
  • One object of the present invention is to provide a pharmaceutical composition and food composition for the prevention or treatment of degenerative neurological disease, including sandalwood extract or fractions thereof as an active ingredient.
  • Still another object of the present invention is to provide a pharmaceutical composition and food composition for learning or memory enhancement, including sandalwood extract or a fraction thereof as an active ingredient.
  • the pharmaceutical composition and food composition comprising the sandalwood extract or fractions thereof of the present invention are derived from natural products and have no side effects, and effectively inhibit acetylcholinesterase, enhance cognition, learning and memory, and at the same time stimulate the neuroinflammatory response. Blocking may be widely used as a prophylactic and therapeutic agent for degenerative cranial nerve diseases such as dementia, Alzheimer's disease and Parkinson's disease.
  • 1 is a graph showing the inhibitory ability of acetylcholinesterase by sandalwood ethanol crude extract or fractions thereof.
  • Figure 2 is a graph showing the free radical inhibition by sandalwood ethanol crude extract or fractions thereof.
  • Figure 3 is a graph showing the working memory enhancement effect in the Y-maze experiment by sandalwood ethanol crude extract administration.
  • Figure 4 is a graph showing the memory enhancement effect in the passive avoidance experiment by administering sandalwood ethanol crude extract (training trial: trial trial, test trial: trial trial).
  • 5 is a graph showing the scopolamine-induced working memory improvement efficacy in the Y-maze experiment by sandalwood ethanol crude extract administration.
  • FIG. 6 is a graph showing the scopolamine-induced memory improvement efficacy in the passive avoidance experiment by administering sandalwood ethanol crude extract (training trial: trial trial, test trial: trial trial).
  • FIG. 7 is a graph showing the inhibitory effect of acetylcholinesterase by sandalwood ethanol crude extract administration of the whole brain cortex (A) and hippocampus (B).
  • FIG. 8 is a graph showing neuroinflammatory inhibition effect by sandalwood ethanol crude extract treatment on LPS neuroinflammatory induction in BV-2 microglia.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of degenerative neurological disease, including sandalwood extract or a fraction thereof as an active ingredient.
  • sandalwood extract means an extract obtained by extracting a fully dried sandalwood ( Santallvum album ) with a solvent, the extract is an extract, a dilution or concentrate of the extract, a dried product obtained by drying the extract, Or both these modifiers or purified products.
  • the extract is not particularly limited, but is an extract obtained by extracting sandalwood with a solvent selected from the group consisting of water, lower alcohols of C 1 to C 4 and mixed solvents thereof, and preferably ethanol crude extract of sandalwood.
  • the sandalwood extract is dried and dried in small pieces to dry about 1 to 10 times, preferably about 2 to 5 times the volume of water, lower alcohol having 1 to 4 carbon atoms or about 1: 0.1.
  • water having a mixing ratio of 1: 0.2 to 1: 3 and a lower alcohol mixed solvent having 1 to 4 carbon atoms at an extraction temperature of 20 ° C to 100 ° C, preferably 30 ° C to 70 ° C.
  • Extraction method such as hot water extraction, reflux cooling extraction, ultrasonic extraction for about 1 hour to 2 days, preferably 2 hours to 1 day, preferably 1 to 5 times, preferably twice
  • the extract was filtered under reduced pressure and the filtered extract was mixed with water, a lower alcohol having 1 to 4 carbon atoms or a mixed solvent thereof, and then a rotary vacuum concentrator was used at a temperature of 20 ° C. to 100 ° C., preferably 50 ° C. Under reduced pressure at -70 ° C It can be obtained by removing the solvent the crude extract soluble fraction of the water, a lower alcohol or a mixed solvent of 1 to 4 carbon atoms.
  • fraction means the result obtained by the fractionation method of separating a specific component or a specific group from a mixture comprising various components.
  • the fraction is a nonpolar solvent or polar solvent soluble extract obtained by fractionation from sandalwood extract
  • the nonpolar solvent soluble extract is a nonpolar solvent selected from methylene chloride, ethyl acetate, chloroform, hexane, acetone, dichloromethane or carbon tetrachloride, preferably ethyl acetate Contains extracts available for use.
  • sandalwood extract preferably sandalwood ethanol crude extract
  • ethyl acetate is suspended in water and then added to the volume of ethyl acetate in an amount of about 1 to 10 times, preferably about 1 to 5 times, of these suspensions.
  • Each fraction preferably 2 to 4 times, may be separated into an ethyl acetate soluble fraction and a water soluble fraction, and each solvent fraction may be concentrated under reduced pressure with a rotary vacuum concentrator to remove the solvent to obtain each fraction.
  • the polar solvent soluble extract is an extract excluding the nonpolar solvent soluble part from the sandalwood extract, and is selected from water, a lower alcohol having 1 to 4 carbon atoms, and a mixed solvent thereof, preferably water or lower alcohol, more preferably butanol. Contains available extracts.
  • the polar solvent soluble extract is added 1 to 5 times by adding about 1 to 10 times, preferably about 1 to 5 times the volume of butanol to the water-soluble fraction that has undergone the extraction process of the non-polar solvent soluble component,
  • the solvent may be fractionated 2 to 4 times to obtain a butanol soluble fraction and a water soluble fraction, and the solvent fraction may be concentrated under reduced pressure with a rotary vacuum concentrator to remove the solvent to obtain respective extracts.
  • the non-polar solvent soluble fraction and the polar solvent soluble extract are directly subjected to ion exchange chromatography (Ion Exchange Chromatography) to the crude extract in order to prevent exposure from organic solvents harmful to human body, in addition to the extraction separation process.
  • the filler usable as the stationary phase may use SP207, HP20SS or HP 20, but it is preferred to use HP 20 filler.
  • a mobile phase solvent first, water having the highest polarity is transferred, and then a step of substituting with a solvent having a lower polarity is performed, for example, water, a water: methanol mixed solvent, methanol or an additional nonpolar solvent. Through the step of converting to a solvent such as acetone it is possible to obtain the fraction fractionated for each developing solvent.
  • the present inventors obtained an ethanol extract from the dried Santalum album , and fractionated the sandalwood ethanol extract with ethyl acetate, butanol, water or the like to obtain each fraction.
  • the composition of the present invention comprises a sandalwood extract, a nonpolar solvent soluble fraction or a polar solvent soluble fraction obtained by the method described above.
  • the content of the extract or fraction contained in the composition of the present invention is not particularly limited, but it is preferable to include the extract in an amount of 0.1 to 50% by weight based on the total weight of the composition.
  • Sandalwood extract or fractions thereof according to the present invention can be usefully used for the prevention or treatment of degenerative neurological diseases, such as dementia or Alzheimer's disease.
  • degenerative brain nerve disease refers to a disease that causes various symptoms by degenerative changes in neurons of the central nervous system, and impairs cognitive function, learning or memory, or is accompanied by a neuroinflammatory response.
  • neurological diseases include dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (Creutzfeld) Jakob disease (CJD), stroke, multiple sclerosis, learning disabilities, memory impairment.
  • the sandalwood extract or a fraction thereof according to the present invention effectively inhibits.
  • scopolamine effectively inhibits cognition, loss of learning memory, and forgetfulness in mice that caused brain cell (memory) damage. That is, the sandalwood extract or fractions thereof according to the present invention effectively block the degradation of acetylcholine, which is a major neurotransmitter of the cranial nerve, and thus can be usefully used in degenerative cranial nerve disease accompanied by memory loss such as cognitive function and learning function.
  • the amount of NO production was measured to determine whether a neuroinflammatory reaction occurs.
  • the amount of NO was measured about 4 times less than the control group treated with nothing, effectively inhibiting the neuroinflammatory response. That is, the sandalwood extract or a fraction thereof could be usefully used in neurodegenerative diseases accompanied with neuroinflammatory reactions.
  • the invention provides a method of preventing or treating degenerative brain neuropathy, comprising administering to a subject having or at risk of developing a neurodegenerative disease in a pharmaceutically effective amount. To provide.
  • prevention refers to any action that inhibits or delays degenerative brain neuron disease by administration of a composition comprising the sandalwood extract or fractions thereof.
  • treatment used in the present invention means any action that improves or advantageously changes the condition of the disease by administration of the composition comprising the sandalwood extract or a fraction thereof.
  • the term "individual” means all animals, including humans, who have already developed or are likely to develop degenerative neurological disease, and can effectively prevent and treat such diseases by administering the composition of the present invention to an individual. .
  • the composition of the present invention is administered in a pharmaceutically effective amount.
  • ⁇ pharmaceutically effective amount '' refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment in a medical treatment, the effective dose level being the type of subject and its severity, age , Sex, type of inflammatory eye disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent drug use, and other factors well known in the medical arts.
  • the sandalwood extract or a fraction thereof may be administered at a dose of 0.01 to 500 mg / kg, preferably 10 to 100 mg / kg, and the administration may be administered once or several times a day. have.
  • the pharmaceutical composition of the present invention may comprise 0.001 to 50% by weight of the sandalwood extract or a fraction thereof based on the total weight of the composition.
  • compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • composition according to the present invention may be formulated into a pharmaceutical composition including a pharmaceutically acceptable carrier, oral or powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like according to conventional methods. It may be formulated in the form of a dosage form, external preparation, suppositories, and sterile injectable solutions.
  • the pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like. Also included are diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.
  • Oral solid preparations include tablets, pills, powders, granules, capsules and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose or lactose. ), Gelatin, and the like, and may include a lubricant such as magnesium stearate, talc, and the like.
  • Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include water, diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, and the like.
  • Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspending agents, emulsions, lyophilized preparations, suppositories, and non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and ethyl. Injectable esters such as oleate and the like.
  • aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and ethyl.
  • Injectable esters such as oleate and the like.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the present invention provides a pharmaceutical composition for learning or memory enhancement, comprising a sandalwood extract or a fraction thereof as an active ingredient.
  • a sandalwood extract or fractions thereof are as described above, and the active ingredient may be included in a pharmaceutical composition capable of improving learning or memory.
  • learning means the ability or behavior to perceive and change one's own behavior, and includes spatial perception, cognition, concentration, and the like.
  • learning disorder or learning disability refers to a variety of causes, such as depression, anxiety, obsessive compulsion, social and environmental factors (faxia, poverty, Defective home, stress), etc. "learning" ability is compared to the normal state means a low state, including spatial perception, cognitive decline, concentration, children's academic achievement, and the like.
  • memory refers to the ability to acquire new information, learned experience, and knowledge obtained from the surrounding environment, encode and store it in a specific region of the brain, and recall it again. Means.
  • memory disorder refers to a state in which the "memory” is lower than the normal person due to various causes such as trauma, attention deficit, aging, disease, Amnesia, concentration disorders, loss of spatial perception, slowing learning, loss of cognition.
  • the present invention provides a food composition for the prevention or improvement of degenerative cranial nerve disease, comprising a sandalwood extract or a fraction thereof as an active ingredient.
  • the food composition may be used alone or in combination with a general food as a health functional food.
  • health functional food of the present invention means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to Act No. 6767 of the Health Functional Food Act, and "functional” means It means ingestion for the purpose of obtaining useful effects on health use such as nutrient control or physiological action on the structure and function of the human body.
  • the food composition of the present invention may include a conventional food additive, and the suitability as the "food additive", unless otherwise specified, according to the General Regulations and General Test Methods of the Food Additives approved by the Food and Drug Administration It is determined by the standard and the standard.
  • the food additive of the "food additive revolving" is not particularly limited, but chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, cinnamon acid, natural additives such as color pigment, licorice extract, crystalline cellulose, high pigment, guar gum, Mixed preparations, such as a sodium L- glutamate preparation, a noodle addition alkali agent, a preservative preparation, and a tar pigment preparation, etc. are contained.
  • the food composition of the present invention comprises 0.01 extract of sandalwood extract or a fraction thereof based on the total weight of the composition for the purpose of preventing or improving degenerative neurological diseases such as dementia, Alzheimer's disease, learning disorders or memory impairment, or for the purpose of learning or memory enhancement. To 95% by weight, preferably 1 to 80% by weight.
  • the food composition may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like.
  • the dietary supplement in the form of tablets, sandalwood extract or fractions thereof granulate the mixture with excipients, binders, disintegrants, and other additives in a conventional manner, and then compression-molded with a lubricant or the like, The mixture may be directly compression molded.
  • the health functional food in the form of tablets may contain a mating agent and the like, if necessary, may be coated with a suitable coating agent.
  • Hard capsules of the health functional foods in the form of capsules may be prepared by filling a conventional hard capsule with a sandalwood extract or a fraction thereof and a mixture of additives such as excipients or granules or peeled granules thereof.
  • a mixture of an extract or a fraction thereof and an additive such as an excipient may be prepared by filling a capsule base such as gelatin.
  • the soft capsule agent may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
  • the dietary supplement in cyclic form may be prepared by molding a mixture of sandalwood extract or a fraction thereof with additives such as excipients, binders, disintegrants, etc. It may also be welcoming with starch, talc or any suitable material.
  • the health functional food in the form of granules may be prepared by granulating a mixture of the sandalwood extract or its fractions with additives such as excipients, binders, disintegrants, etc. Can be.
  • 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, 5 revised edition, p33-48, 1989).
  • the present invention provides a food composition for learning or memory enhancement, comprising sandalwood extract or a fraction thereof as an active ingredient.
  • the sandalwood extract or a fraction thereof is as described above, the active ingredient may be included in a food composition that can enhance learning or memory.
  • the food composition is not particularly limited, as described above, and may be used alone, for example, as a health functional food or as a food additive.
  • Acetylthiocholine iodine, DPPH (1.1-diphenyl-2-picrylhydrazyl), LPS (lipopolysaccharide), Tween-20, and DTNB were purchased from Sigma-Aldrich Chemistry Co., and sandalwood was used in the market. , Korea). In addition, the reagents used in the experiment were purchased from the best product.
  • ICR male mice 25-30g
  • 4 weeks old were supplied by Koatech (Gyeonggi, Korea) and used in the animal breeding room of Sungkyunkwan University pharmacy for more than 1 week.
  • Temperature 23 ⁇ 2 ° C.
  • humidity 55 ⁇ 10%
  • contrast cycle (12 hours) were automatically adjusted.
  • Mouse BV-2 microglia were cultured under inactivated 10% fetal bovine serum (FBS) and antibiotics containing DMEM (dulbecco's modified eagle's medium, Hyclone, Thermo, USA) medium.
  • FBS fetal bovine serum
  • DMEM fetal bovine serum
  • the incubator was maintained at 37 ° C. and gas was mixed with 95% air and 5% CO 2 to provide adequate conditions for cell culture.
  • the cells were incubated 2.5 ⁇ 10 5 cells in 24-well plates 24 hours before the experiment.
  • LPS was determined to be 100ng / ml, and fractions of white charcoal were dissolved in 50% DMSO and used at a final concentration of 0.1% or less.
  • the dried sandalwood ( Santalum album ) was purchased from Gyeongdong market (Seoul, Korea) and used. After drying the sandalwood completely, 1kg of sandalwood was extracted three times at 85 ° C. in 4.5L of 50% ethanol, and then concentrated under reduced pressure with a vacuum condenser (EYELA, N-1000, Japan), and then lyophilized. 351 g of extract was obtained.
  • the sandalwood butanol soluble extract obtained in Example 3 was fractionated and the egg layer was concentrated to give 36 g of water soluble fraction.
  • the sandalwood extract was concentrated under reduced pressure by hydrothermal treatment to obtain an extract.
  • the whole brain of the mouse was uniformly ground using a homogenizer, and diluted to a concentration of 2 mg / ml in 0.1M, pH 7.4 phosphorylated solution, and used as an enzyme sample.
  • the sandalwood ethanol crude extract is sufficiently diluted in phosphorylated solution to a final concentration of 5 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml, 200 ⁇ g / ml and 400 ⁇ g / ml, and then 1.5 ml
  • An aliquot was mixed with 2.6 ml of phosphorylated solution, and 20 ⁇ l of 75 mM acetylthiocholine iodide and 100 ⁇ l of Ellman reagent were added, and reacted at room temperature for 30 minutes. 400 ⁇ l of enzyme sample was added thereto and measured at 412 nm (FIG. 1). . At this time, the measured absorbance value was converted into the
  • FIG. 1 is a graph showing the inhibitory ability of acetylcholinesterase by sandalwood ethanol crude extract or fractions thereof, wherein the activity of acetylcholinesterase inhibitory activity of sandalwood ethanol crude extract was increased in a dose-dependent manner, and it was 5 ⁇ g / ml and 25 ⁇ g / ml. , Acetylcholinesterase inhibitory activity of 7.14, 14.66, 26.46, 34.44, 51.98 and 59.13%, respectively, at concentrations of 50 ⁇ g / ml, 100 ⁇ g / ml, 200 ⁇ g / ml and 400 ⁇ g / ml.
  • the acetylcholinesterase inhibitory ability of the sandalwood butanol soluble fraction increased dose-dependently, at concentrations of 5 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml, 200 ⁇ g / ml and 400 ⁇ g / ml. It showed 0.65, 5.62, 7.26, 8.84, 13.41 and 41.58% inhibition of acetylcholinesterase, respectively.
  • the acetylcholinesterase inhibitory activity of the soluble fraction of sandalwood ethyl acetate was 44.18 at concentrations of 5 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml, 200 ⁇ g / ml and 400 ⁇ g / ml, respectively. It showed 38.63, 17.81, 0.86, 1.33 and 0% acetylcholinesterase inhibitory activity.
  • Acetylcholinesterase inhibitory ability of the sandalwood soluble fraction was 1.79, 1.64, 2.21 at concentrations of 5 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml, 200 ⁇ g / ml and 400 ⁇ g / ml, respectively. , 3.62, 6.35 and 4.53% showed the inhibitory ability of acetylcholinesterase.
  • DPPH 2,2-diphenyl-1-picrylhydrazyl, Sigma D9132
  • Sandalwood ethanol crude extract was diluted in ethanol at concentrations of 5 ⁇ g / ml, 10 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 200 ⁇ g / ml.
  • 1.8 mL of DPPH was added to 200 ⁇ l of the sample, mixed well for 10 seconds, and reacted at room temperature for 30 minutes. The mixture was measured at 517 nm (FIG. 2). At this time, the measured absorbance value was converted into the inhibitory capacity using the following equation (2).
  • Inhibitory Capacity (%) [(Control O.D.- Test Group O.D.) / Control O.D.] ⁇ 100
  • Figure 2 is a graph showing the free radical inhibition ability by the sandalwood ethanol crude extract or fractions thereof, the free radical scavenging ability of the sandalwood ethanol crude extract increased dose-dependently, 1 ⁇ g / ml, 5 ⁇ g / ml, 10 ⁇ g /
  • the free radical scavenging ability of 4.21, 15.2, 27.04, 68.10, 100, 100 and 100% was shown at the concentrations of ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 200 ⁇ g / ml, respectively.
  • the free radical scavenging ability of the sandalwood butanol soluble fraction increased dose-dependently, with 1 ⁇ g / ml, 5 ⁇ g / ml, 10 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 200 ⁇ g / ml At the concentrations of 4.22, 6.46, 12.93, 20.23, 26.34, 33.16 and 33.35%, respectively, the free radical scavenging ability was shown.
  • the free radical scavenging ability of the soluble fraction of sandalwood ethylacetate increased dose-dependently, with 1 ⁇ g / ml, 5 ⁇ g / ml, 10 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 200 Free radical scavenging ability of 0, 0, 0.08, 2.66, 10.50, 23.93 and 46.36% was shown at the concentration of ⁇ g / ml, respectively.
  • Free radical scavenging activity of the sandalwood soluble fraction increased dose-dependently, with 1 ⁇ g / ml, 5 ⁇ g / ml, 10 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 200 ⁇ g / ml.
  • the free radical scavenging ability was 1.89, 3.78, 6.86, 11.65, 18.77, 23.81 and 30.80% at the concentration of.
  • mice were divided into 4 groups, 10 of each group.
  • the first group was a distilled water administration group containing 10% Tween 20, the second group, the third group, and the fourth group were 25 mg / kg, 50 mg / kg and 100 mg / kg administration group sandalwood ethanol crude extract, respectively.
  • Sandalwood ethanol crude extract was dissolved in distilled water containing 10% Tween 20 and orally administered to the mice at doses of 0 mg / kg, 25 mg / kg, 50 mg / kg and 100 mg / kg, and after 1 hour, the mice were placed in the Y-maze. The mice were freely inserted into the A, B and C branches, respectively, and measured (FIG. 3). At this time, a new branch is given one point (actual change), the percent cross action was calculated by the following equation (3).
  • Figure 3 is a graph showing the working memory enhancement effect in the Y-maze experiment by sandalwood ethanol crude extract administration, the control mice showed a 58% cross-action on the test day, 58% sandalwood ethanol crude extract 25mg / kg administration group The 50 mg / kg group showed 67%, which increased the crossover behavior of mice by 9%, and the 100 mg / kg group showed 71%, which increased the crossover behavior by 13%.
  • mice were divided into 4 groups, 10 of each group.
  • the first group was a distilled water administration group containing 10% Tween 20, the second group, the third group, and the fourth group were 25 mg / kg, 50 mg / kg and 100 mg / kg administration group sandalwood ethanol crude extract, respectively.
  • Sandalwood ethanol crude extract was dissolved in distilled water containing 10% Tween 20 and orally administered to the mice at doses of 0 mg / kg, 25 mg / kg, 50 mg / kg and 100 mg / kg, and after 1 hour, the mice were subjected to step-through ( Step into the device into a dark box was trained by applying an electric shock of 0.2 mA (2 seconds). After 24 hours, the mice were placed in the bright box again and the stay time until entering the black box was measured as an indicator of learning and memory (FIG. 4). At this time, the cut-off time of the mouse was set to 300 seconds and compared with the control group.
  • Figure 4 is a graph showing the memory enhancement effect in the passive avoidance experiment by administering sandalwood ethanol crude extract, the control mice showed a stay time of 49 seconds on the test day, the sandalwood ethanol crude extract 25mg / kg administration group was 94 seconds The time was increased by 45 seconds, the 50mg / kg group showed 138 seconds, the mice stayed 89 seconds longer (p ⁇ 0.05), and the 100mg / kg group showed 169 seconds, increasing the settling time by 120 seconds.
  • sandalwood ethanol crude extract can significantly increase the learning and memory of the mouse (p ⁇ 0.01).
  • mice were divided into 5 groups, 10 of each group.
  • the first group (control) is distilled water administration group containing 10% Tween 20
  • the second group is distilled water and scopolamine administration group containing 10% Tween 20
  • group 3 to 5 are sandalwood ethanol crude extract, respectively 25 mg / kg, 50 mg / kg and 100 mg / kg administration group.
  • Sandalwood ethanol crude extract was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 0 mg / kg, 25 mg / kg, 50 mg / kg and 100 mg / kg, and after 30 minutes 0.5 mg / of scopolamine kg was injected subcutaneously. After 1 hour, the mice were placed in a Y-maze to measure the free entry of mice into A, B and C branches (FIG. 5). At this time, a new branch is given to give a point, the percent cross action was calculated by the following equation (4).
  • FIG. 5 is a graph showing the scopolamine-induced working memory improvement efficacy in the Y-maze experiment by sandalwood ethanol crude extract administration, the control group represented 64%, the spatial memory was maintained, the scopolamine administration control group 52 % Cross-behavior was significantly induced (p ⁇ 0.05), 58% of sandalwood ethanol crude extract 25mg / kg group showed a 6% increase in cross-action compared to scopolamine-treated control group, and 50mg / kg group 60% was shown to increase the mouse's crossover behavior by 8% compared to the scopolamine dose control. In addition, the 100 mg / kg administration group was 62% compared to the scopolamine administration control group to increase the crossover behavior of the mice 10% (p ⁇ 0.05).
  • mice were divided into 5 groups, 10 of each group.
  • the first group (control) is a distilled water administration group containing 10% Tween 20
  • the second group is a distilled water and scolpolamine administration group containing 10% Tween 20
  • Groups 3 to 5 are sandalwood ethanol crude extract, respectively 25 mg / kg, 50 mg / kg and 100 mg / kg administration group.
  • Sandalwood ethanol crude extract was dissolved in distilled water containing 10% Tween 20 and orally administered to mice at doses of 0 mg / kg, 25 mg / kg, 50 mg / kg and 100 mg / kg, and after 30 minutes 0.5 mg / of scopolamine kg was injected subcutaneously. After 30 minutes, the mice were placed in a step-through device into a dark box and trained by applying an electric shock of 0.4 mA (2 seconds). After 24 hours, the mice were placed in bright boxes again to measure the length of stay until they entered the black boxes, which were used as indicators of learning and memory for scopolamine-induced forgetfulness (FIG. 6). At this time, the cut-off time of the mouse was 300 seconds and compared with the control group.
  • Figure 6 is a graph showing the scopolamine-induced memory improvement effect in the passive avoidance experiment by administering sandalwood ethanol crude extract, the control group was 150 seconds memory was maintained, the scopolamine control group was 59 seconds on the test day Forgetfulness was significantly induced (p ⁇ 0.01), and the sandalwood ethanol crude extract 25mg / kg group showed 36 seconds, reducing the stay time by 23 seconds compared to the scopolamine-administered control group, and the 63mg 50kg / kg group. In comparison with the scopolamine administered control group, the residence time of the mice was increased by 4 seconds. In addition, compared with the scopolamine-administered control group, the 100 mg / kg administration group exhibited 136 seconds, significantly increasing the staying time of the mice by 77 seconds (p ⁇ 0.01).
  • sandalwood ethanol crude extract can effectively prevent memory damage.
  • mice were divided into 5 groups, 10 of each group.
  • the first group (control) is a distilled water administration group containing 10% Tween 20
  • the second group is a distilled water and scolpolamine administration group containing 10% Tween 20
  • the third to fifth groups are scopolamine and Sandalwood ethanol crude extract 25mg / kg, 50mg / kg and 100mg / kg administration group.
  • the whole cerebral cortex and hippocampus of the mouse were removed, homogenized in 200 mM 0.1 mM phosphorylated solution at pH 7.4, and centrifuged at 10,000 g for 10 minutes to use the supernatant as a sample.
  • FIG. 7 is a graph showing the inhibitory effect of acetylcholinesterase inhibitory effect by the administration of sandalwood ethanol crude extract of the whole cortex (A) and hippocampus (B), the total brain cortex and hippocampus control group 1.70 in the acetylcholinesterase inhibitory effect experiment It showed the activity of acetylcholinesterase of mmol / min / mg / brain and 2.29 mmol / min / mg / brain, and the scopolamine control group showed 2.71 mmol / min / mg / brain and 3.47 mmol / min / mg / brain.
  • the activity of acetylcholinesterase was significantly increased (1.01 mmol / min / mg / brain and 1.18 mmol / min / mg / brain) than that of the control group (p ⁇ 0.001, respectively).
  • 25mg / kg sandalwood ethanol crude extract showed 2.75mmol / min / mg / brain and 3.46mmol / min / mg / brain to increase acetylcholinesterase by scopolamine 0.05mmol / min / mg / brain, respectively
  • 0.01mmol / min / mg / brain increased or decreased
  • 50mg / kg sandalwood ethanol crude extract showed 2.38mmol / min / mg / brain and 2.91mmol / min / mg / brain to increase acetyl increased by scopolamine Cholinesterase was reduced by 0.33 mmol / min / mg / brain and 0.56 mmol / min / mg / brain, respectively (p ⁇ 0.001).
  • the sandalwood ethanol crude extract 100mg / kg administration group showed 2.07mmol / min / mg / brain and 2.23mmol / min / mg / brain to increase the acetylcholinesterase increased by scopolamine 0.64mmol / min / mg / brain, respectively. And 1.24 mmol / min / mg / brain reduction (p ⁇ 0.01 and p ⁇ 0.001).
  • sandalwood ethanol crude extract can significantly inhibit the activity of acetylcholinesterase in mice increased by scopolamine.
  • the cells were dispensed 2.5 ⁇ 10 5 cells in a 24-well plate 24 hours before the experiment to add 100ng / ml of LPS, which is a neuroinflammatory agent, and the sandalwood ethanol crude extract prepared in Example 2 according to the concentration. Reaction was carried out for 24 hours in each of 50 ⁇ l of Griess reagent (1% sulfonilamine / 0.1% N- (1-naphtyl) -ethylenediamine dihydrochloride / 5% phosphoric acid), followed by reaction for 15 minutes and microplate. The effect of inhibiting neuroinflammatory response was measured at 540 nm using a reader (Molecular device, USA) (FIG. 8).
  • FIG. 8 shows the results of neuronal inflammation inhibition by sandalwood ethanol crude extract
  • BV-2 microglia showed a significant increase of about 51-fold NO in LPS-induced NO and 14 ⁇ M in control.
  • NO induced by LPS was inhibited by dose-dependent treatment of crude sandalwood ethanol crude extract, and dose-dependently inhibited neuroinflammation.

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Abstract

La présente invention concerne une composition pharmaceutique et une composition alimentaire pour prévenir ou traiter des maladies neurodégénératives, contenant des extraits de bois de santal ou des fractions de ceux-ci comme ingrédients actifs, et un procédé de prévention ou de traitement de maladies neurodégénératives, comprenant une étape d'administration desdites compositions à un individu qui souffre d'une maladie neurodégénératives ou susceptible d'être atteint d'une maladie neurodégénérative. En outre, la présente invention concerne une composition pharmaceutique et une composition alimentaire contenant des extraits de bois de santal ou des fractions de ceux-ci comme ingrédients actifs pour améliorer la capacité d'apprentissage ou la mémoire. Lesdits extraits de bois de santal ou leurs fractions peuvent effectivement inhiber l'activité acétyl cholinestérase et les réactions de neuro-inflammation, présentent des effets de prévention ou de traitement des troubles de l'apprentissage ou de la mémoire en présentant également des effets d'amélioration de la capacité d'apprentissage ou de la mémoire. Par conséquent, lesdits extraits de bois de santal ou leurs fractions peuvent être largement utilisés comme agents pour la prévention ou le traitement de maladies neurodégénératives, ou dans une composition permettant d'améliorer la capacité d'apprentissage ou la mémoire.
PCT/KR2012/004103 2011-05-24 2012-05-24 Composition pour la prévention ou le traitement de maladies neurodégénératives, contenant des extraits de bois de santal ou des fractions de ceux-ci comme ingrédients actifs Ceased WO2012161527A2 (fr)

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