KR20190036373A - Pharmaceutical compositions for prevention and treatment of neurological diseases including black chokeberry extract - Google Patents
Pharmaceutical compositions for prevention and treatment of neurological diseases including black chokeberry extract Download PDFInfo
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- KR20190036373A KR20190036373A KR1020170125502A KR20170125502A KR20190036373A KR 20190036373 A KR20190036373 A KR 20190036373A KR 1020170125502 A KR1020170125502 A KR 1020170125502A KR 20170125502 A KR20170125502 A KR 20170125502A KR 20190036373 A KR20190036373 A KR 20190036373A
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- disease
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- soluble fraction
- black chokeberry
- ethanol extract
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Polymers & Plastics (AREA)
- Nutrition Science (AREA)
- Veterinary Medicine (AREA)
- Food Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Botany (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
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- Alternative & Traditional Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
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Abstract
Description
본 발명은 블랙쵸크베리 추출물을 포함하는 뇌질환 예방 또는 치료용 약학 조성물에 관한 것으로, 보다 상세하게는 퀸산을 함유하는 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for preventing or treating cerebral diseases including black chokeberry extract, and more particularly, to a pharmaceutical composition for preventing or treating cerebral diseases including water-soluble fractions of black chokeberry ethanol extract containing quinic acid .
빠른 의학기술의 발달로 인간의 수명이 연장되고, 고령화 사회로 접어들면서 퇴행성 뇌질환은 사회적 문제로 대두 되고 있다. 노령화 과정에서 발생하는 뇌 질환의 장애는 지속적으로 증가하며, 경제적, 사회적 부담을 증가시키고 있다. 이러한 이유로 뇌질환치료제의 약물개발은 매우 중요다. 퇴행성 뇌질환 중 대표적인 알츠하이머 병(Alzheimer disease, AD)과 치매는 진행성 기억 상실로 특징지어지는 신경 변성 질환이다. AD는 병인 학적으로 복잡하며 β-아밀로이드 펩타이드의 축적, β-아밀로이드의 축적, 과산화된 타우, 자유 라디칼 및 염증 반응과 같은 인자들로 인해 발생되는 것으로 알려져 있다. 최근 보고에 따르면 AD 환자의 신경 병리학적 변화는 전형적으로 뇌에서 β-아밀로이드 펩타이드 축적 후의 해마 퇴화가 주요 원인의 하나로 밝혀졌다. As the development of rapid medical technology prolongs the life span of human beings, degenerative brain disease becomes a social problem as it enters into an aging society. The obstacles of brain diseases that occur in the aging process are continuously increasing, increasing the economic and social burdens. For this reason, development of medicines for treating brain diseases is very important. Alzheimer's disease (AD) and dementia, a typical degenerative brain disease, are neurodegenerative diseases characterized by progressive memory loss. AD is pathologically complex and is known to be caused by factors such as accumulation of β-amyloid peptides, accumulation of β-amyloid, peroxidated tau, free radicals, and inflammatory responses. Recent reports indicate that neuropathologic changes in AD patients are typically one of the major causes of hippocampal degeneration following β-amyloid peptide accumulation in the brain.
β-아밀로이드는 알츠하이머 환자의 뇌에서 발견된 물질로 아밀로이드플라크의 주성분이 되는 펩타이드이며, 신경세포의 사멸을 유도하는 주요 인자이다. β-아밀로이드의 생성 경로가 다양하게 알려져 있으나, 그 중에서 다량의 과다염증반응 축적을 유발할 수 있다. β-amyloid is a substance found in the brain of Alzheimer's patients and is a major component of the amyloid plaque and is a major factor in inducing the death of nerve cells. The production pathway of β-amyloid is known to be various, but a large amount of inflammatory reaction accumulation can be induced among them.
생체 내 염증반응은 자극원에 대한 생체 내 방어기전 중의 하나로 세포의 손상억제와 괴사상태의 세포를 제거함과 동시에 조직재생을 유도하는 데 그 목적이 있다. 하지만, 리포폴리사카라이드(Lipopolysaccharide, LPS)와 같은 분자는 분자수준에서 만성 염증유발 사이토카인(pro-inflammatory cytokines) 및 유도성 산화질소(NO), 유도형 일산화질소화 효소(iNOS), 시클로옥시게나아제 2(COX-2) 및 종양 괴사 인자 알파(TNF-α)와 같은 염증성 인자의 과발현을 유도한다. 특히, 신경세포와 교세포로 이루어진 신경계에서 미세아교세포(microglia)가 염증반응에 관여하며, LPS와 같은 자극원 등으로부터 과잉반응을 초래하는 경우 상기의 인자를 과발현하여 신경세포의 사멸을 유도할 수 있다. 매해 50,000명 이상이 퇴행성 뇌질환에 대헤 새롭게 진단을 받고 있으나, 많은 연구에도 불구하고 병인의 기전에 대한 명확한 원인을 규명하지 못하였다[Arevalo et al., Mov. Disord. 1997, 12, 277-284].The in vivo inflammatory response is one of the in vivo defense mechanisms against the stimulus source. It is intended to inhibit cell damage and to remove the necrotic cells and induce tissue regeneration. However, molecules such as Lipopolysaccharide (LPS) are known to act as proinflammatory cytokines and inducible nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase Induce overexpression of inflammatory factors such as cytogenase 2 (COX-2) and tumor necrosis factor alpha (TNF-a). In particular, in the nervous system composed of nerve cells and glia, microglia are involved in the inflammatory reaction, and when they cause an over-reaction from stimulating sources such as LPS, they overexpress the above factors and induce the death of nerve cells have. More than 50,000 people are newly diagnosed with degenerative brain disease each year, but despite many studies, they have not been able to elucidate the precise cause of the etiology [Arevalo et al., Mov. Disord. 1997, 12,277-284].
현재 치료방법은 대증적 치료제를 이용하고 있고, 대표적으로는 도파민 (dopamine)의 전구체인 L-3,4-디하이드록시페닐알라닌(L-DOPA), 모노아민 옥시다제 억제제 그리고 도파민 수용체 길항제(아고니스트) 등이 있다. 그러나 이러한 방법들은 병의 진행을 지연시켜 줄 뿐 근원적인 치료가 되지 않으며, 장기간의 복용에 따른 부작용과 합병증을 동반한다. 이에, 부작용이 적고, 항염증 효과와 신경세포 사멸의 효과가 있는 신규한 뇌질환 치료제의 개발이 절실히 요구되고 있다. Currently, treatment methods are based on the use of a proactive therapeutic agent. Representative examples include dopamine precursors such as L-3,4-dihydroxyphenylalanine (L-DOPA), monoamine oxidase inhibitors and dopamine receptor antagonists ). However, these methods delay the progression of the disease but do not lead to the underlying treatment, and are associated with long-term side effects and complications. Therefore, there is an urgent need to develop a novel therapeutic agent for brain diseases, which has few side effects and has an anti-inflammatory effect and neuronal cell death effect.
본 발명이 해결하고자 하는 첫 번째 과제는 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.퀸A first object of the present invention is to provide a pharmaceutical composition for preventing or treating brain diseases, which comprises a water-soluble fraction of an extract of black chokeberry ethanol.
본 발명이 해결하고자 하는 두 번째 과제는 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물의 제조방법을 제공하는 것이다. A second object of the present invention is to provide a method for preparing a pharmaceutical composition for preventing or treating brain diseases, which comprises a water-soluble fraction of an extract of black chokeberry ethanol.
상기한 과제를 달성하기 위하여, 본 발명은 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating brain diseases, which comprises a water-soluble fraction of an extract of black chokeberry ethanol.
본 발명에 있어서, 상기 수용성 분획물은 하기 화학식 1로 표시되는 퀸산을 포함하는 것일 수 있다.In the present invention, the water-soluble fraction may comprise quinic acid represented by the following general formula (1).
[화학식 1][Chemical Formula 1]
본 발명에 있어서, 상기 뇌질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 간질, 인지장애, 치매, 신경세포 손상성 뇌질환, 퇴행성 뇌질환, 우울증, 불면증 및 불안증으로 구성된 군 중에서 선택되는 어느 하나 이상일 수 있다. In the present invention, the brain disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, cognitive disorder, dementia, neuronal cell damage brain disease, degenerative brain disease, depression, insomnia and anxiety It can be more than one.
본 발명에 있어서, 상기 뇌질환은 염증반응으로 인해 생성된 β-아밀로이드 축적으로 유발된 뇌질환일 수 있다. In the present invention, the brain disease may be a brain disease caused by accumulation of [beta] -amyloid produced by an inflammatory reaction.
본 발명에 있어서, 상기 조성물은 뇌신경보호 및 항염증 효과를 가지는 것일 수 있다.In the present invention, the composition may have neuroprotective and anti-inflammatory effects.
또한, 본 발명은 (1) 블랙쵸크베리를 에탄올에 침지하여 에탄올 추출물을 얻는 단계; 및 (2) 상기 블랙쵸크베리 에탄올 추출물로부터 수용성 분획물을 얻는 단계;를 포함하는 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물의 제조방법을 제공한다. The present invention also provides a method for producing a black chokeberry, comprising the steps of: (1) immersing black chokeberry in ethanol to obtain an ethanol extract; And (2) obtaining a water-soluble fraction from the black chokeberry ethanol extract. The present invention also provides a method for preparing a pharmaceutical composition for preventing or treating cerebral diseases, which comprises the step of extracting a water-soluble fraction of a black chokeberry ethanol extract.
또한, 본 발명은 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or ameliorating brain diseases comprising a water-soluble fraction of an ethanol extract of black chokeberry.
본 발명에 따른 퀸산을 포함하는 블랙쵸크베리 에탄올 추출물의 수용성 분획물은 미세아교세포(microglia) 내 발생하는 염증 반응을 완화시킬 수 있으며, 동시에 신경세포를 보호하여 β-아밀로이드의 축적에 의한 신경세포 사멸을 억제할 수 있으므로, 염증반응 또는/및 신경세포 사멸에 의해 유발되는 뇌질환, 특히, 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 간질, 인지장애, 치매, 신경세포 손상성 뇌질환, 퇴행성 뇌질환, 우울증, 불면증 및 불안증 등을 예방 또는 치료하는데 사용할 수 있다. The water-soluble fraction of the black chokeberry ethanol extract containing quinic acid according to the present invention can alleviate the inflammatory reaction occurring in the microglia and at the same time protects the nerve cells, It is possible to prevent brain diseases caused by inflammatory reaction and / or nerve cell death, in particular, brain diseases caused by Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, cognitive disorders, dementia, Diseases, depression, insomnia, anxiety, and the like.
도 1은 본 발명에 따른 블랙쵸크베리 에탄올 추출물의 수용성 분획물에 의한 신경보호작용 메카니즘을 도식화하여 나타낸 것이다.
도 2A는 본 발명에 따른 실시예 1이 BV2의 세포독성에 미치는 영향을 평가한 것으로서, BV2를 각각 실시예 1로 무처리, 0, 30, 100, 300, 1000 및 2000 ㎍/mL의 농도로 처리한 뒤 48시간 뒤에 세포독성을 평가한 결과이고, 도 2B는 LIVE/DEAD Cell Viability Assays kit로 염색한 세포를 현미경으로 관찰한 결과이다.
도 3은 본 발명에 따른 실시예 1이 LPS 유도 일산화질소 생성 저해에 미치는 영향을 평가한 것으로서, BV2를 각각 실시예 1로 무처리, 0, 30, 100, 300 및 1000 ㎍/mL의 농도 및 LPS(500 ng/mL) 처리한 뒤, 일산화질소 생성 억제 효과를 평가하였다.
도 4는 본 발명에 따른 실시예 1이 염증성 사이토카인 생성 저해에 미치는 영향을 평가한 것이다. (A) iNOS, (B) COX-2, (C) IL-1β 및 (D) TNF-α.
도 5는 본 발명에 따른 실시예 1의 처리에 의한 알츠하이머병 마우스모델의 해마영역에서 염증 발현 억제 효과를 확인한 것이다. (A)는 H&E 염색을 통한 조직학적 변화 분석 결과이며, (B)는 염증지표 면역화학적 분석 결과이다.
도 6은 실시예 1 및 실시예 2의 세포독성 및 신경보호 효과를 확인한 것이다. 도 6A는 실시예 1 및 실시예 2 처리된 세포의 형태를 현미경으로 관찰한 결과이고, 도 6B는 실시예 1의 세포독성을 평가한 결과이며, 도 6C는 실시예 2의 세포독성을 평가한 결과이다. 도 6D는 β-아밀로이드 처리에 의한 세포사멸에 대한 실시예 1의 처리에 의한 신경세포보호 효과이며, 도 6E는 β-아밀로이드 처리에 의한 세포사멸에 대한 실시예 2의 처리에 의한 신경세포보호 효과이다.
도 7은 본 발명에 따른 실시예 1의 지표성분을 LC/MS로 확인한 결과이다. 1 is a schematic representation of the neuro-protective action mechanism of the water-soluble fraction of the black chokeberry ethanol extract according to the present invention.
FIG. 2A shows the effect of Example 1 according to the present invention on the cytotoxicity of BV2, and BV2 was measured in the same manner as in Example 1 except that the concentration was 0, 30, 100, 300, 1000 and 2000 占 퐂 / mL FIG. 2B is a microscopic observation of cells stained with the LIVE / DEAD Cell Viability Assay kit. FIG.
FIG. 3 is a graph showing the effect of Example 1 according to the present invention on the inhibition of LPS-induced nitric oxide production. BV2 was measured as the concentration of 0, 30, 100, 300 and 1000 占 퐂 / mL in Example 1, After treatment with LPS (500 ng / mL), the inhibitory effect on the production of nitrogen monoxide was evaluated.
Figure 4 shows the effect of Example 1 according to the present invention on inflammatory cytokine production inhibition. (A) iNOS, (B) COX-2, (C) IL-1β and (D) TNF-α.
FIG. 5 is a graph showing the effect of suppressing the inflammatory effect in the hippocampal region of the mouse model of Alzheimer's disease by the treatment of Example 1 according to the present invention. (A) is the result of histological change analysis by H & E staining, and (B) is the result of immunochemical analysis of inflammation index.
Fig. 6 shows the cytotoxicity and neuroprotective effects of Example 1 and Example 2. Fig. FIG. 6A is a result of microscopic observation of the morphology of cells treated with Example 1 and Example 2. FIG. 6B is a result of evaluating the cytotoxicity of Example 1, and FIG. 6C is a graph showing the cytotoxicity of Example 2 Results. FIG. 6D is a protective effect of the neuronal cell by the treatment of Example 1 against apoptosis by the? -Amyloid treatment. FIG. 6E is a graph showing the effect of the treatment of Example 2 on the cell death by? -Amyloid treatment to be.
7 shows the result of LC / MS analysis of the indicator component of Example 1 according to the present invention.
생체 내 염증 반응은 자극원에 대한 생체 내 방어 기전중의 하나로서, 세포의 손상 억제와 괴사상태의 세포를 제거함과 동시에 조직재생을 유도하는데에 목적이 있다. 신경세포와 교세포로 이루어진 신경계에서 미세아교세포는 염증 반응에 관여하며, LPS와 같은 자극원 등으로부터 과잉반응을 초래하는 경우, 염증성 사이토카인, 산화질소(NO), 일산화질소화 효소(iNOS), 시클로옥시게나아제 2(COX-2) 및 종양 괴사 인자 알파(TNF-α) 등과 같은 염증성 인자가 과발현 된다. The in vivo inflammatory response is one of the defense mechanisms in vivo against the stimulus source. It is aimed at inhibiting the cell damage and removing the cells in the necrotic state and inducing tissue regeneration. In the nervous system consisting of nerve cells and glia, microglial cells are involved in the inflammatory reaction. In case of causing excessive reaction from stimulating sources such as LPS, inflammatory cytokines, nitric oxide (NO), nitric oxide synthase (iNOS) Inflammatory factors such as cyclooxygenase 2 (COX-2) and tumor necrosis factor alpha (TNF-alpha) are overexpressed.
산화질소(NO)는 세포 내에서 nitric oxide synthase (NOS) 효소에 의해 생성된다. 특히 inducible NOS (iNOS)는 뇌에 존재하는 소교세포와 성상세포에서 작용하는 효소이다. 평소에는 매우 낮은 농도로 존재하다가 세포가 활성되는 경우에 발현되고, 결과적으로 뇌 NO 농도를 현저히 (약 100 배) 증가시킨다. 퇴행성 뇌질환 환자의 뇌에서는 이렇게 증가된 iNOS의 발현이 휴식상태로 되돌아가지 못하고 NO를 장기적, 지속적으로 생성한다. 그러므로 iNOS를 비롯한 염증성 인자를 제어하고, 신경세포를 보호하는 조성물은 알츠하이머병을 비롯한 퇴행성 뇌질환의 예방 및 치료에 사용될 수 있을 것이다. Nitric oxide (NO) is produced by the nitric oxide synthase (NOS) enzyme in the cell. In particular, inducible NOS (iNOS) is an enzyme that acts on microglia and astrocytes in the brain. It is usually present at very low concentrations and is expressed when cells are activated, resulting in a significant increase in brain NO concentration (about 100 times). In the brains of patients with degenerative brain disease, this increased expression of iNOS fails to return to resting state and produces NO over a long period of time. Thus, compositions that control inflammatory factors, including iNOS, and protect neurons may be used in the prevention and treatment of degenerative brain diseases including Alzheimer's disease.
본 발명의 발명자들은 블랙쵸크베리(Arobia melanocarpa) 열매의 에탄올 추출물의 수용성 분획물을 유효성분으로 포함하는 조성물이 항염증 효과와 신경세포 사멸 효과가 있음을 확인하여 본 발명을 완성하게 되었다. The inventors of the present invention have completed the present invention by confirming that the composition containing the water-soluble fraction of the ethanol extract of Arobia melanocarpa fruit as an active ingredient has an anti-inflammatory effect and a neuronal cell death effect.
이하, 본 발명을 더욱 상세하게 설명한다. Hereinafter, the present invention will be described in more detail.
본 발명은 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating brain diseases comprising a water-soluble fraction of an extract of black chokeberry ethanol.
본 발명에 있어서, 상기 블랙쵸크베리 에탄올 추출물의 수용성 분획물은 하기 화학식 1로 표시되는 퀸산을 포함하는 것일 수 있다:In the present invention, the water-soluble fraction of the black chokeberry ethanol extract may contain quinic acid represented by the following formula (1)
[화학식 1][Chemical Formula 1]
본 발명에 의하면, 상기 뇌질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 간질, 인지장애, 치매, 신경세포 손상성 뇌질환, 퇴행성 뇌질환, 우울증, 불면증 및 불안증으로 구성된 군 중에서 선택되는 어느 하나 이상일 수 있으나, 이에 제한되는 것은 아니며, 염증반응으로 인해 생성된 β-아밀로이드 축적으로 유발된 뇌질환일 수 있다. According to the present invention, the brain disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, cognitive disorders, dementia, neuronal cell damage brain diseases, degenerative brain diseases, depression, insomnia and anxiety But not limited to, a brain disease caused by the accumulation of [beta] -amyloid produced by the inflammatory reaction.
본 발명에 의하면, 상기 조성물은 뇌신경보호 및 항염증 효과를 나타내는 것일 수 있다. According to the present invention, the composition may exhibit neuroprotective and anti-inflammatory effects.
본 발명의 약학조성물은 환자의 연령, 체중 및 상태와 투여경로를 비롯한 각종 요인에 따라 투여량은 결정될 수 있다. The dosage of the pharmaceutical composition of the present invention can be determined according to various factors including the age, weight and condition of the patient and administration route.
또한, 본 발명은 (1) 블랙쵸크베리를 에탄올에 침지하여 에탄올 추출물을 얻는 단계; 및 (2) 상기 블랙쵸크베리 에탄올 추출물로부터 수용성 분획물을 얻는 단계;를 포함하는 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물의 제조방법을 제공한다. The present invention also provides a method for producing a black chokeberry, comprising the steps of: (1) immersing black chokeberry in ethanol to obtain an ethanol extract; And (2) obtaining a water-soluble fraction from the black chokeberry ethanol extract. The present invention also provides a method for producing a pharmaceutical composition for preventing or treating cerebral diseases, which comprises a water-soluble fraction of a black chokeberry ethanol extract.
본 발명에 의하면, 상기 블랙쵸크베리 에탄올 추출물의 수용성 분획물로부터 뇌질환 예방 또는 치료 효과를 나타내는 바람직한 유효성분을 수득하기 위하여 크로마토그래피법 또는/및 재결정법 등을 이용하여 분리 및 정제할 수 있다. 본 발명에 있어서, 상기 블랙쵸크베리 에탄올 추출물의 수용성 분획물의 바람직한 유효성분은 퀸산을 포함하는 것일 수 있다. According to the present invention, it is possible to separate and purify from water-soluble fractions of the above-mentioned black chokeberry ethanol extract using a chromatographic method and / or a recrystallization method in order to obtain a preferable active ingredient showing the effect of preventing or treating brain diseases. In the present invention, the preferred active ingredient of the water-soluble fraction of the black chokeberry ethanol extract may be one comprising quinic acid.
본 발명에서는 블랙쵸크베리 에탄올 추출물의 수용성 분획물로부터 분리된 퀸산이 블랙초크베리 에탄올 추출물 또는 블랙쵸크베리 에탄올 추출물의 수용성 분획물보다 염증성 인자 발생을 저해하는 효과가 우수하며, 신경보호 효과가 우수함을 확인하였다. In the present invention, quinic acid isolated from the water-soluble fraction of the black chokeberry ethanol extract is superior to the water-soluble fraction of the black chokeberry ethanol extract or the black chokeberry ethanol extract and has excellent neuroprotective effect .
본 발명에 의하면, 상기 (1) 단계는 블랙쵸크베리 열매를 70 내지 100 부피% 에탄올 수용액에 침지하는 것일 수 있으며, 바람직하게는 에탄올 100%에 침지하는 것일 수 있다. 상기 침지는 6시간 내지 48시간일 수 있다. 침지액은 여과하여 상등액만을 회수한다. According to the present invention, the step (1) may be to immerse the black chokeberry fruit in an aqueous 70 to 100% by volume ethanol solution, preferably 100% ethanol. The immersion may be from 6 hours to 48 hours. The immersion liquid is filtered to recover only the supernatant.
다음으로, 상기 에탄올 추출물의 수용성 분획물을 얻는다. 바람직하게는 상기 회수된 에탄올 추출물을 농축한 다음 물에 현탁시키고, 분리하여 수용성 성분만을 분리하여 수득될 수 있다. Next, a water soluble fraction of the ethanol extract is obtained. Preferably by concentrating the recovered ethanol extract, suspending it in water and separating it to isolate only water-soluble components.
본 발명에 의하면, 뇌질환 예방 또는 치료에 특히 바람직한 상기 블랙쵸크베리 에탄올 추출물의 수용성 분획물의 유효성분은 퀸산일 수 있다. 본 발명은 뇌질환 예방 또는 치료에 특히 바람직한 유효성분을 수득하기 위해 상기 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 정제하는 단계를 더 포함할 수 있다. 상기 정제는 크로마토그래피법 또는/및 재결정법을 이용할 수 있으나, 이에 한정되는 것은 아니며, 통상적으로 생약성분으로부터 단일 성분을 분리하기 위한 방법이면 제한은 없다. According to the present invention, the active ingredient of the water-soluble fraction of the above-mentioned black chokeberry ethanol extract which is particularly preferable for prevention or treatment of brain diseases can be queen acid. The present invention may further comprise the step of purifying the water-soluble fraction of the black chokeberry ethanol extract to obtain an effective ingredient particularly preferable for preventing or treating brain diseases. The purification may be performed by chromatography or / and recrystallization, but is not limited thereto, and there is no particular limitation on a method for separating a single component from a herbal composition.
또한, 본 발명은 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 개선용 식품 조성물을 제공한다. The present invention also provides a food composition for preventing or ameliorating brain diseases comprising a water-soluble fraction of an ethanol extract of black chokeberry.
상기 블랙쵸크베리 에탄올 추출물의 수용성 분획물은 사용목적 및 사용방법에 따라 그 함량을 조절하여 포함할 수 있으며, 바람직하기로는 0.001 내지 10 중량%로 함유될 수 있다. The water-soluble fraction of the black chokeberry ethanol extract may be contained in an amount of 0.001 to 10% by weight, depending on the purpose and method of use.
이하, 바람직한 실시예를 들어 본 발명을 더욱 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이에 의하여 제한되지 않는다는 것은 당업계의 통상의 지식을 가진자에게 자명할 것이다. Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. It will be apparent, however, to those skilled in the art that these embodiments are for further explanation of the present invention and that the scope of the present invention is not limited thereby.
실시예Example
시약: 세포배양에 주요시약은 Gibco BRL(Carlsbad, CA, USA)사에서 구매하여 사용하였다. 면역항체반응을 위한 실험에서 쓰이는 항체는 iNOS, COX-2, TNF-α 이며, Santa Cruz Biotechnology(Dallas, TX, USA)사의 것을 사용하였다. 면역화학적염색 방법을 위해서 Vector Laboratories(Burlingame, CA, USA)사의 VECTASTAIN ABC Kit를 사용하였고, 이외의 시약은 Sigma-Aldrich(St. Louis, MO, USA)사에서 구매하여 사용하였다.Reagents: The main reagents for cell culture were purchased from Gibco BRL (Carlsbad, CA, USA). Antibodies used in the immunoassay were iNOS, COX-2, and TNF-α, and those from Santa Cruz Biotechnology (Dallas, TX, USA) were used. For immunochemical staining, VECTASTAIN ABC Kit from Vector Laboratories (Burlingame, CA, USA) was used. Other reagents were purchased from Sigma-Aldrich (St. Louis, Mo., USA).
통계학적 분석Statistical analysis
모든 결과는 최소 세 번의 독립적인 실험 (n ≥ 3)의 평균 ± 표준 오차 (SE)로 표현하였다. 그룹간의 차이는 Student's t-test 와 one-way analysis of variance (ANOVA)를 사용하였다. Tukey's test(GraphPad Prism ver. 4.00 for Windows, La Jolla, CA, USA)는 다중 비교에 사용하였다. P-value < 0.05는 통계적으로 유의하다고 간주된다. All results were expressed as mean ± standard error (SE) of at least three independent experiments (n ≥ 3). Student's t-test and one-way analysis of variance (ANOVA) were used. Tukey's test (GraphPad Prism ver. 4.00 for Windows, La Jolla, CA, USA) was used for multiple comparisons. P-value <0.05 is considered statistically significant.
실시예 1.Example 1.
건조된 블랙쵸크베리 열매 100 g을 분쇄하였다. 1000 mL의 무수 에탄올을 첨가하여 25℃에서 24시간 동안 정치하였다. 24시간 후, 상등액만을 걸러내고 저온감압 장치를 사용하여 농축하였다. bath의 온도를 60℃로 유지하여 에탄올을 완전히 제거하였다. 조농축물은 증류수 50 ml에 용해시킨 뒤, 용해물을 -60 ℃에서 분말화하였다. 100 g of the dried black chokeberry fruit was pulverized. 1000 mL of anhydrous ethanol was added and allowed to stand at 25 DEG C for 24 hours. After 24 hours, only the supernatant was filtered out and concentrated using a low-temperature decompression apparatus. The temperature of the bath was maintained at 60 캜 to completely remove ethanol. The crude concentrate was dissolved in 50 ml of distilled water, and the lysate was pulverized at -60 ° C.
실시예 2. Example 2.
실시예 1의 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 고성능 액체 크로마토그래피(HPLC)법으로 분리하여 지표성분인 퀸산을 단일 성분으로 수득하였다.The water-soluble fraction of the black chokeberry ethanol extract of Example 1 was separated by a high performance liquid chromatography (HPLC) method to obtain an indicator component of quinic acid as a single component.
HPLC 분석은 광다이오드 어레이 검출기에 연결된 sunfire C18 ODS 4.6×150 mm 컬럼(Waters Corporation, USA)을 사용하여 수행하였다. 이동상은 아세토니트릴 0.1%(v/v)과 포름산 0.1%(v/v)을 함유하는 물을 유속 1 mL/min으로 사용하였다. LC/MS를 측정하여 지표성분인 퀸산(MW 192.7)을 확인하였으며, 이를 하기 도 7에 나타내었다. 실시예 1은 퀸산을 약 0.023 mg/mg 함유하는 것으로 나타났다. HPLC analysis was performed using a sunfire C18 ODS 4.6 x 150 mm column (Waters Corporation, USA) connected to a photodiode array detector. The mobile phase was water at a flow rate of 1 mL / min of water containing 0.1% (v / v) acetonitrile and 0.1% (v / v) formic acid. LC / MS was measured to confirm the indicator component, quinic acid (MW 192.7), which is shown in FIG. Example 1 showed that it contained about 0.023 mg / mg of quinic acid.
시험예 1. 세포독성 테스트Test Example 1. Cytotoxicity test
본 발명에 따른 실시예 1이 BV2 세포에 미치는 세포독성을 평가하였다. 구체적으로, 한국세포주 은행으로부터 BV2 세포주를 구매하여 실험에 사용하였다. 배양세포는 10 % fetal bovine serum(FBS)과 1% penicillin-streptomycin(PS) 첨가한 DMEM에서 배양조건(37 ℃, 5% CO2)를 통해 세포수를 유지하였다. 세포 독성의 확인은 무처리군을 대조군으로, 실시예 1을 다양한 농도(30, 100, 300, 1000 및 2000 ㎍/mL)로 처리한 후 48시간 뒤 MTT 처리방법과 LIVE/DEAD Cell Viability Assays kit(ThermoFisher 사)를 활용하여 현미경으로 관찰하여 분석하였다. The cytotoxicity of Example 1 according to the present invention to BV2 cells was evaluated. Specifically, BV2 cell line was purchased from Korean Cell Line Bank and used for the experiment. Cells were maintained in culture conditions (37 ° C, 5% CO 2 ) in DMEM supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (PS). To confirm the cytotoxicity, the cells were treated with various concentrations (30, 100, 300, 1000 and 2000 / / mL) of Example 1 as a control group and 48 hours later with MTT treatment and LIVE / DEAD Cell Viability Assays kit (ThermoFisher), and analyzed with a microscope.
도 2A는 BV2 세포를 각각 실시예 1로 무처리, 0, 30, 100, 300, 1000 및 2000 ㎍/mL의 농도로 처리한 뒤 48시간 뒤에 세포 독성을 평가한 것이다. 도 2B는 세포독성의 시험을 보다 정확히 판단하기 위하여 LIVE/DEAD Cell Viability Assays kit로 염색한 세포를 현미경으로 관찰한 결과이다. 세포의 생존시에만 녹색의 형광을 나타내고 있는 바, 본 발명의 실시예 1에 따른 블랙쵸크베리 에탄올 추출물의 수용성 분획물은 세포 독성이 없음을 확인하였다. Fig. 2A shows the cytotoxicity of BV2 cells treated with untreated, 0, 30, 100, 300, 1000 and 2000 占 퐂 / mL, respectively, in Example 1 and 48 hours later. FIG. 2B is a result of microscopic observation of cells stained with the LIVE / DEAD Cell Viability Assay kit to more accurately determine the cytotoxicity test. And the green fluorescence was exhibited only at the time of cell survival. Thus, it was confirmed that the water-soluble fraction of the black chokeberry ethanol extract according to Example 1 of the present invention was not cytotoxic.
시험예 2. NO 생성 저해효과 테스트 Test Example 2. NO production inhibitory effect test
BV2 세포에서 본 발명에 따른 실시예 1의 처리가 LPS 유도 NO 생성에 미치는 영향을 평가하였다. 구체적으로 BV2 세포(5×104 세포)을 준비하고, 실시예 1로 무처리, 0, 30, 100, 300 및 1000 ㎍/mL의 농도 및 LPS(500 ng/mL) 처리한 뒤, LPS 500 ng/mL를 48시간 처리하여 유도 NO 생성에 대해 griess 용액에 반응시켜 수치적 해석을 하였다. 반응은 시험이 종료된 세포의 상등액을 100 μL 씩 새로운 용기로 옮겨 동량의 Griess reagent를 처리 한 후 30분간 암소에서 반응시켰다. 수치적 해석은 520 nm에서 ELISA reader로 측정한 수치를 무처리군을 음성대조군으로 지정하고 LPS 처리군의 증가수치를 양성대조군화 하여 비교분석하였으며, sodium nitrate 표준곡선으로 생성량을 수치화하였다. The effect of the treatment of Example 1 according to the present invention on the production of LPS-induced NO was evaluated in BV2 cells. Specifically, BV2 cells (5 × 10 4 cells) were prepared and treated with LPS (500 ng / mL) at a concentration of 0, 30, 100, 300 and 1000 μg / ng / mL was treated for 48 hours to react with the griess solution for induced NO production. The reaction was carried out by transferring the supernatant of the cells that had been tested to 100 μL into a new container, treating the same amount of Griess reagent, and reacting in a dark place for 30 minutes. Numerical analysis was performed by comparing the values measured with an ELISA reader at 520 nm as a negative control group, by comparing the increase of the LPS treatment group with that of the positive control group, and by quantifying the amount of sodium nitrate standard curve.
도 3에 나타낸 바와 같이, 본 발명의 실시예 1의 농도의존적으로 NO 생성이 저해된 것이 관찰되었다. As shown in Fig. 3, it was observed that the NO production was inhibited in a concentration-dependent manner in Example 1 of the present invention.
시험예 3. 염증성 사이토카인 생성 저해 평가Test Example 3. Assessment of inflammatory cytokine production inhibition
BV2 세포에서 본 발명에 따른 실시예 1의 처리가 염증성 사이토카인 생성 저해에 미치는 영향을 평가하기 위하여 mRNA 수준에서 변화를 분석하였다. 구체적으로, Total RNA는 TRI reagent 시약의 사용법을 따라 세포를 용해하여 분리하였다. 측정된 mRNA의 발현은 PCR 역전사 효소를 갖는 thermocycler를 사용하여 수행하였다. 간단히 하게, first-strand cDNA는 SuperScript II reverse transcriptase 제조사의 프로토콜을 따라 합성하였다. Real-time PCR와 thermocycler를 이용하여 cDNA를 증폭시켰다. Real-time PCR은 다음과 같은 조건으로 실행하였다 : Initial denaturation(10min, 95C), denaturation 40 cycle(30s, 95C), annealing(30s, 60C) 그리고 extension (30s, 72C). Primer sequence는 다음과 같다: iNOS(5-CAG GAG GAG AGA GAT CCG ATT-3 and 5-GCA TTA GCA TGG AAG CAA AGA-3); COX-2 (5-CTG GTC GGT TTG ATG CTA-3 and 5-CGA GTC GTT CTG CCA ATA-3); IL-1β (5-TAC CAG TTG GGG AAC TCT GC-3 and 5-TGG AAA AGC GGT TTG TCT TC-3); TNF-α (5-TGG GAG TAG ACA AGG TAC AAC-3 and 5-CAT CTT CTC AAA ATT CGA GTG-3); GAPDH (5-TGT CAT CAT ATC TGG CAG GTT-3 and 5-GGC CTT CCG TGT TCC TAC-3).Changes in mRNA levels were analyzed in BV2 cells to assess the effect of the treatment of Example 1 according to the present invention on inflammatory cytokine production inhibition. Specifically, total RNA was isolated by dissolving cells according to the usage of TRI reagent reagent. Expression of the measured mRNA was performed using a thermocycler with PCR reverse transcriptase. To simplify, the first-strand cDNA was synthesized following the protocol of SuperScript II reverse transcriptase manufacturer. CDNA was amplified using real-time PCR and thermocycler. Real-time PCR was performed under the following conditions: Initial denaturation (10 min, 95 ° C),
도 4에 나타낸 바와 같이, 본 발명에 따른 실시예 1의 처리는 iNOS, COX-2, IL-1β 및 TNF-α의 생성을 효과적으로 저해하는 것이 관찰되었다. As shown in Fig. 4, it was observed that the treatment of Example 1 according to the present invention effectively inhibited the production of iNOS, COX-2, IL-1 [beta] and TNF- [alpha].
시험예 4. in-vivo 테스트Test Example 4. In-vivo test
본 발명에 따른 실시예 1의 in-vivo 효과를 확인하였다. ICR계 수컷 마우스(체중 20~30g)를 실험에 사용하였다. 마우스는 물과 사료(AIN 93G formula)를 자유롭게 식이 할 수 있도록 개별적으로 보관하였다. 모든 마우스는 통제된 환경(실내온도 24±2 ℃; 습도 40±2%; 명암 사이클 12 시간)에 보관하였다. 모든 실험과 동물 관리는 동국대학교의 지침(IACUC-2014-005)에 따라 수행하였다. 마우스(6 주령, n=30)을 세 그룹으로 무작위로 나누었다. 미처리 그룹(대조군)은 생리 식염수를 투여하였다. LPS 유발 뇌손상 군(LPS)은 250 g/kg의 LPS를 단일 복강 i.p) 주사를 받았다. 실험군은 식염수에 실시예 1(50 mg/kg/day)을 투여한 뒤, 1시간 이후 LPS를 투약하였다. 실시예 1은 7일 동안 매일 구강투여 하였다. 실시된 동물은 7일 후 희생한 뒤, 뇌를 해부하였다. The in-vivo effect of Example 1 according to the present invention was confirmed. ICR male mice (body weight 20-30 g) were used in the experiments. Mice were individually kept in water and feed (AIN 93G formula) for free feeding. All mice were kept in a controlled environment (room temperature 24 ± 2 ° C;
마우스의 LPS 유도 손상성 뇌의 해마영역을 조직화학적(Histochemistry) 분석 및 면역조직화학적(immunohistochemistry) 분석을 통해 염증인자의 변화를 분석하였다. 구체적으로, 마우스의 뇌를 차가운 PBS로 세척하고 2% 포르말린으로 고정하였다. 각 절반의 조각을 파라핀에 끼워 넣고 5μm 슬라이스로 연속 section을 만들었다. 조제된 부분은 자일렌으로 수세하고, 에탄올 농도별(70%, 80% 그리고 90%)로 수화시켰다. section은 헤마톡실린&에오신(H&E)와 크레실 바이올렛으로 염색을 하였다. 일부 section은 iNOS, COX-2, IL-1와 TNF- 4C primary antibody를 16시간 동안 배양하였다. 면역염색법은 VECTASTAIN ABC Kit 내 시험정보에 따라 수행하였다.Histochemistry analysis and immunohistochemistry analysis of the hippocampal area of the injured brain of the LPS induced mouse were performed to analyze the changes of inflammatory factors. Specifically, mouse brains were washed with cold PBS and fixed with 2% formalin. Each half piece was inserted into a paraffin and a continuous section was made with a 5 μm slice. The prepared portion was washed with xylene and hydrated by ethanol concentration (70%, 80% and 90%). The sections were stained with hematoxylin & eosin (H & E) and cresyl violet. Some sections were incubated with iNOS, COX-2, IL-1 and TNF-4C primary antibodies for 16 h. Immunostaining was performed according to the test information in the VECTASTAIN ABC Kit.
본 발명에 따른 실시예 1의 처리는 LPS로 유도한 염증 발현 동물모델의 해마영역에서 조직 손상을 억제한 결과를 확인하였으며, 이를 도 5에 나타내었다. 도 5A는 해마영역(hippocampus)에서 LPS 유도에 의한 손상영역이 CA1(Cornu Ammonis 1)영역과 DG(the dentate gyrus)영역에서 나타난 것을 H&E 염색법으로 확인한 결과이며, 도 5B는 실시예 1의 처리에 의해 LPS로 유도된 염증 발현 동물모델의 해마영역에서 염증지표가 유의성 있게 감소된 것을 보여주는 결과이다. The treatment of Example 1 according to the present invention confirmed the inhibition of tissue damage in the hippocampal region of an inflammatory animal model induced by LPS, which is shown in Fig. FIG. 5A is a result obtained by H & E staining method in which a damaged region caused by LPS induction in the hippocampus appears in the region of CA1 (Cornu Ammonis 1) and DG (the dentate gyrus). FIG. Lt; RTI ID = 0.0 > inflammatory < / RTI >
시험예 5. 퀸산의 약리활성 평가Test Example 5. Evaluation of pharmacological activity of quinic acid
마우스 태아로부터 뇌를 적출하여 신경세포를 분리한 뒤, neurobasal medium과 1% L-glutamine,1% PS 그리고 B27를 첨가하여 배양하였다. 세포독성의 확인은 무처리군을 음성대조군으로, β-아밀로이드(aβ) (20uM)을 처리군을 양성대조군으로, 실험군은 실시예 1 및 실시예 2를 각각 β-아밀로이드 처리와 동시에 처리한 뒤 48시간 배양하고 MTT 처리방법과 LIVE/DEAD Cell Viability Assays kit(ThermoFisher 사)를 활용하여 현미경으로 관찰하여 분석하였다. Neurons were isolated from mouse embryos and cultured with neurobasal medium, 1% L-glutamine, 1% PS and B27. The cytotoxicity was confirmed by treatment with β-amyloid (aβ) (20 μM) as a negative control group, negative control group as a negative control group, and β-amyloid treatment with Example 1 and Example 2 as an experimental group The cells were cultured for 48 hours and analyzed by MTT and LIVE / DEAD Cell Viability Assays kit (ThermoFisher).
도 6A는 실시예 1 및 실시예 2 처리된 세포의 형태를 현미경으로 관찰한 결과이다. 신경세포에 SDS를 처리한 경우 세포사멸이 나타나는 반면, 실시예 1 및 실시예 2를 함께 처리한 경우 세포사멸이 일어나지 않았다. 특히, 실시예 2의 처리는 더 많은 형광이 관찰되었으며, 신경세포 보호 효과가 뛰어난 것으로 확인되었다. 도 6B 및 6C는 각각 실시예 1 및 실시예 2 처리된 군의 세포독성을 그래프로 나타낸 것으로, 모두 세포독성이 없는 것으로 나타났다. FIG. 6A is a microscopic observation of the morphology of cells treated in Example 1 and Example 2. FIG. Cell death was observed when the neurons were treated with SDS, whereas when the cells of Example 1 and Example 2 were treated together, apoptosis did not occur. In particular, the treatment of Example 2 showed more fluorescence and was found to be superior in nerve cell protection effect. Figures 6B and 6C are graphs depicting the cytotoxicity of the treated groups of Example 1 and Example 2, respectively, showing no cytotoxicity.
도 6D는 β-아밀로이드 처리에 의한 세포사멸에 대한 실시예 1의 처리에 의한 신경세포보호 효과이며, 도 6E는 β-아밀로이드 처리에 의한 세포사멸에 대한 실시예 2의 처리에 의한 신경세포보호 효과이다. FIG. 6D is a protective effect of the neuronal cell by the treatment of Example 1 against apoptosis by the? -Amyloid treatment. FIG. 6E is a graph showing the effect of the treatment of Example 2 on the cell death by? -Amyloid treatment to be.
실시예 1은 100 μM 농도 수준에서 β-아밀로이드 처리에 의한 세포사멸로부터 신경세포를 100% 보호하였으나, 실시예 2는 더 낮은 농도인 10 μM 농도 수준에서 β-아밀로이드 처리에 의한 세포사멸로부터 신경세포를 100% 보호하였다. Example 1 showed 100% protection of neurons from cell death by β-amyloid treatment at a concentration of 100 μM, whereas Example 2 showed that at a concentration of 10 μM, which is a lower concentration, cell death by β- Was 100% protected.
Claims (10)
상기 수용성 분획물은 하기 화학식 1로 표시되는 퀸산을 포함하는 것인, 뇌질환 예방 또는 치료용 약학적 조성물:
[화학식 1]
Wherein the water-soluble fraction comprises quinic acid represented by the following formula (1):
[Chemical Formula 1]
상기 뇌질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 간질, 인지장애, 치매, 신경세포 손상성 뇌질환, 퇴행성 뇌질환, 우울증, 불면증 및 불안증으로 구성된 군 중에서 선택되는 어느 하나 이상인, 뇌질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
Wherein the brain disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, cognitive disorders, dementia, neuronal cell damage brain diseases, degenerative brain diseases, depression, insomnia, A pharmaceutical composition for preventing or treating.
상기 뇌질환은 염증반응으로 인해 생성된 β-아밀로이드 축적으로 유발된 뇌질환인, 뇌질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
A pharmaceutical composition for preventing or treating brain diseases, wherein the brain disease is a brain disease caused by accumulation of? -Amyloid produced by an inflammatory reaction.
상기 조성물은 뇌신경보호 및 항염증 효과를 가지는 것인, 뇌질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
Wherein the composition has neuroprotective and anti-inflammatory effects.
(2) 상기 블랙쵸크베리 에탄올 추출물로부터 수용성 분획물을 얻는 단계;를 포함하는 블랙쵸크베리 에탄올 추출물의 수용성 분획물을 포함하는 뇌질환 예방 또는 치료용 약학적 조성물의 제조방법.(1) immersing black chokeberry in ethanol to obtain an ethanol extract; And
(2) obtaining a water-soluble fraction from the black chokeberry ethanol extract; and (2) a water-soluble fraction of the black chokeberry ethanol extract.
상기 수용성 분획물은 하기 화학식 1로 표시되는 퀸산을 포함하는 것인, 뇌질환 예방 또는 치료용 약학적 조성물의 제조방법:
[화학식 1]
Wherein the water-soluble fraction comprises quinic acid represented by the following formula (1): < EMI ID =
[Chemical Formula 1]
상기 뇌질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 간질, 인지장애, 치매, 신경세포 손상성 뇌질환, 퇴행성 뇌질환, 우울증, 불면증 및 불안증으로 구성된 군 중에서 선택되는 어느 하나 이상인, 뇌질환 예방 또는 치료용 약학적 조성물의 제조방법.The method according to claim 6,
Wherein the brain disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, cognitive disorders, dementia, neuronal cell damage brain diseases, degenerative brain diseases, depression, insomnia, Or a pharmaceutically acceptable salt thereof.
상기 수용성 분획물은 하기 화학식 1로 표시되는 퀸산을 포함하는 것인, 뇌질환 예방 또는 또는 개선용 식품 조성물:
[화학식 1]
Wherein the water-soluble fraction comprises quinic acid represented by the following formula (1):
[Chemical Formula 1]
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| WO2022088656A1 (en) * | 2020-11-02 | 2022-05-05 | 山东理工大学 | Application of polyphenolic extract of aronia melanocarpa leaves in preparation of antidepressant drug |
| IT202200000581A1 (en) * | 2022-01-17 | 2023-07-17 | Univ Degli Studi Di Verona | Quinic acid for use in the treatment of mood disorders |
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