KR101771679B1 - Pharmaceutical Composition for Improving, Preventing or Treating Degenerative Disease comprising Ginsenoside Rg18 - Google Patents
Pharmaceutical Composition for Improving, Preventing or Treating Degenerative Disease comprising Ginsenoside Rg18 Download PDFInfo
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- KR101771679B1 KR101771679B1 KR1020160073271A KR20160073271A KR101771679B1 KR 101771679 B1 KR101771679 B1 KR 101771679B1 KR 1020160073271 A KR1020160073271 A KR 1020160073271A KR 20160073271 A KR20160073271 A KR 20160073271A KR 101771679 B1 KR101771679 B1 KR 101771679B1
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Abstract
Description
본 발명은 진세노사이드 Rg18을 포함하는 신경퇴행성 질환 개선, 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for improving, preventing or treating a neurodegenerative disease comprising ginsenoside Rg18.
알츠하이머병과 같은 퇴행성 뇌질환은 은 60세 이상의 고령인구에서 주로 발병되기 때문에 매우 빠른 속도로 진행되고 있는, 우리나라 인구의 고령화 문제와, 환자 본인뿐만 아니라 그 가족과 사회, 국가에 심각한 심리적 고통과 경제적 부담을 줄 수 있는 점을 고려할 때 이러한 질환들의 발병기 의 규명을 위한 연구는 필수적이다. 또한 이 같은 연구가 선행되어야만 증상개선이나 질환의 발전 속도를 늦추는 정도에 그치고 있는 현 시점에서의 질병의 예방이나 질병의 개선효과제의 시급성을 요한다.Degenerative brain diseases, such as Alzheimer's disease, are aggravated by the aging of the Korean population and the serious psychological pain and economic burden on the family, society, and the state as well as the patients themselves, , It is necessary to study the mechanism of the onset of these diseases. In addition, such studies require the urgency of prevention of diseases or improvement of diseases at present, which is only to slow down the development of symptoms or diseases.
알츠하이머병 병의 원인으로는 외부적 요인과 내부적 요인으로 나누어 볼 수 있는데, 연령, 유전적 원인, 환경적 영향에 의한 독성물질 등이 외부적 원인으로 거론되고 있으며, 내부적 원인으로는 아세틸콜린(acetylcholine) 농도 저하로 인한 신경전달의 감소, 사이토카인(cytokine) 등에 의한 신경염 (neuroinflammation) 발생, 아밀로이드-베타 및 과인산화된 타우단백질(tau protein)의 응집에 의한 세포독성, 산화스트레스에 의한 활성산소의 신경세포 사멸 등이 알려져 있다. 이러한 경세포의 사멸은 여러 뇌질환에 공통된 근본적인 병리로 지적되고 있어 세포사멸을 유발하는 요인과 분자기전에 대한 연구가 심층적으로 이루어지고 있다. 하지만, 기존에 개발된 분해효소제라든가, 광범위한 세포사멸억제제는 부작용과 더불어 임상효과가 감소하는 현실이다.Causes of Alzheimer's disease can be classified into external and internal factors. Age, genetic cause, toxic substances due to environmental effects are considered as external causes, and internal causes include acetylcholine ), Neuroinflammation caused by cytokines, cytotoxicity by aggregation of amyloid-beta and hyperphosphorylated tau protein, oxidative stress induced by oxidative stress, And nerve cell death are known. Since the death of such mature cells is indicated as a fundamental pathology common to various brain diseases, studies on factors causing cell death and molecular mechanisms have been in-depth. However, the existing degradative enzymes or a wide range of cell death inhibitors have a side effect and a reduced clinical effect.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
본 발명자들은 신경퇴행성 질환의 신규 소재를 개발하고자 노력하였다. 그 결과, 인삼(Panax ginseng) 뿌리로부터 분리된 진세노사이드 Rg18의 뇌염증 및 신경세포 사멸의 억제효과를 최초로 확인함으로써 본 발명을 완성하였다.The present inventors have sought to develop new materials for neurodegenerative diseases. As a result, the present invention was completed by first confirming the inhibitory effect of ginsenoside Rg18 isolated from Panax ginseng root on brain inflammation and neuronal cell death.
따라서, 본 발명의 목적은 신경퇴행성 질환의 개선, 예방 또는 치료용 식품 및 약제학적 조성물을 제공하는 데 있다.Accordingly, it is an object of the present invention to provide a food and pharmaceutical composition for improving, preventing or treating neurodegenerative diseases.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 다음의 화학식 1로 표시되는 진세노사이드 Rg18 또는 이의 염의 신경퇴행성 질환억제 용도를 제공한다:According to one aspect of the present invention, there is provided a neurodegenerative disease-suppressing use of ginsenoside Rg18 or a salt thereof represented by the following formula 1:
화학식 1
본 발명자들은 신경퇴행성 질환의 신규 소재를 개발하고자 노력하였다. 그 결과, 인삼(Panax ginseng) 뿌리로부터 분리된 진세노사이드 Rg18의 뇌염증 및 신경세포 사멸의 억제효과를 최초로 확인하였다.The present inventors have sought to develop new materials for neurodegenerative diseases. As a result, the inhibitory effect of ginsenoside Rg18 isolated from Panax ginseng root on brain inflammation and neuronal cell death was first confirmed.
상기 진세노사이드 Rg18은 분광학적 구조분석결과는 다음과 같다:The spectroscopic structure analysis results of the ginsenoside Rg18 are as follows:
(a) 백색; (b) 화학식: C48H82O18; (c) 파지티브 FAB-MS에서 m/z 969[M+Na]+ 및 HRFAB-MS에서 m/z 969.5415로, 분자량은 969.5399로 예측됨; (d) IR Vmax cm-1(Kbr)은 3365 및 1631로 확인됨(이 등, Chem. Pharm. Bull. 63, 927-934 ,2015).(a) white; (b) a compound of the formula: C 48 H 82 O 18 ; (c) m / z 969 [M + Na] + and HRFAB-MS at m / z 969.5415 in the positive FAB-MS, molecular weight predicted 969.5399; (d) IR Vmax cm -1 (Kbr) was confirmed to be 3365 and 1631 (Lee et al., Chem. Pharm. Bull. 63, 927-934, 2015).
본 발명의 진세노사이드 Rg18은 인삼(Panax ginseng)의 뿌리으로부터 분리할 수 있다. 상기 인삼은 수삼, 백삼, 홍삼 및 태극삼을 모두 포함하나, 이에 한정되지 않는다.The ginsenoside Rg18 of the present invention can be isolated from the roots of Panax ginseng . The ginseng includes, but is not limited to, ginseng, white ginseng, red ginseng, and taekguk ginseng.
본 발명의 다른 양태에 따르면, 본 발명은 상기 진세노사이드 Rg18을 유효성분으로 포함하는 신경퇴행성 질환의 개선, 예방 또는 치료용 조성물을 제공한다.According to another aspect of the present invention, there is provided a composition for improving, preventing or treating a neurodegenerative disease comprising the ginsenoside Rg18 as an active ingredient.
본 명세서에서 용어 ‘유효성분으로 포함하는’이란 하기의 진세노사이드 Rg18의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 본 발명은 천연식물재료인 인삼으로부터 추출한 조성물로서 과량 투여하여도 인체에 부작용이 없으므로 진세노사이드 Rg18이 본 발명의 조성물에 포함된 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.As used herein, the term "comprising as an active ingredient" means an amount sufficient to achieve the efficacy or activity of the following ginsenoside Rg18. The present invention is a composition extracted from ginseng, which is a natural plant material. Since the ginsenoside Rg18 is not adversely affected by the human body even when administered in an excessive amount, the quantitative upper limit of the composition of the present invention can be selected by a person skilled in the art within a suitable range.
본 명세서에서 용어 ‘신경퇴행성 질환’은 신경세포의 기능 감소 또는 소실에 의해 운동조절능력, 인지기능, 지각기능, 감각기능 및 자율신경의 기능 이상을 의미하며, ‘퇴행성 뇌질환’과 동일한 의미이다. 상기 신경퇴행성 질환은 임상적 특징으로 분류할 수 있다. 주요 증상으로 진행성 인지기능 장애를 나타내는 질환에는, 알츠하이머병, 치매(전두측두치매, 루이치매), 피질기저퇴행증(corticobasal degeneration) 등이 있고, 진행성 운동실조를 나타내는 질환에는 파킨슨병, 다계통위축증(multiple system atrophy), 헌팅턴병, 진행성핵상마비(progressive supranuclear palsy) 등이 있다. 근력저하 및 근위축 증상을 나타내는 신경퇴행성 질환으로는 루게릭병, 원발성측삭경화증, 척수근위축병 등이 있다.As used herein, the term 'neurodegenerative disease' refers to the ability to regulate exercise, cognitive function, sensory function, sensory function, and autonomic dysfunction due to a decrease or loss of function of neurons, which is synonymous with 'degenerative brain disease' . The neurodegenerative diseases can be classified into clinical features. Diseases that present progressive cognitive impairment as the main symptom include Alzheimer's disease, dementia (frontal temporal dementia, Louie dementia), corticobasal degeneration, and the diseases exhibiting progressive ataxia include Parkinson's disease, multiple system atrophy multiple system atrophy, Huntington's disease, and progressive supranuclear palsy. Neurodegenerative diseases that show muscle weakness and atrophic symptoms include Lou Gehrig's disease, primary sidewalk sclerosis, and spinal muscular atrophy.
본 발명의 신경퇴행성 질환의 개선, 예방 또는 치료용 약제학적 조성물은 뇌염증 및 신경세포사멸의 억제 활성을 갖는다.The pharmaceutical composition for improving, preventing or treating neurodegenerative diseases of the present invention has an activity of inhibiting brain inflammation and neuronal cell death.
본 발명의 일 구현예에 따르면, 상기 조성물은 소교세포(microglia cell)의 염증성 사이토카인의 분비를 감소시킨다.According to one embodiment of the present invention, the composition reduces secretion of inflammatory cytokines of microglia cells.
하기 실시예에서 입증된 바와 같이, 본 발명의 진세노사이드 Rg18은 LPS에 의해 증가된 염증성 사이토카인(MCP-1, IL-6, IL-1β 및 TNFα)의 분비를 억제하는 효과를 갖는다. 본 발명의 이러한 효과는 종래의 진세노사이드 Rb1보다 특정 농도 범위에서 우수한 효과를 나타내었다.As demonstrated in the following examples, the ginsenoside Rg18 of the present invention has the effect of inhibiting the secretion of inflammatory cytokines (MCP-1, IL-6, IL-1 [beta] and TNF [alpha]) increased by LPS. This effect of the present invention is superior to the conventional ginsenoside Rb1 in a specific concentration range.
본 발명의 일 구현예에 따르면, 상기 조성물은 COX-2(prostaglandin-endoperoxide synthase 2), PGE2(prostaglandin E2) 및 TNF-α(tumor necrosis factor-alpha) 단백질의 발현을 감소시킨다.According to one embodiment of the present invention, the composition reduces the expression of prostaglandin-endoperoxide synthase 2 (COX-2), prostaglandin E2 (PGE 2 ) and tumor necrosis factor-alpha (TNF-alpha).
하기 실시예에서 입증된 바와 같이, 본 발명의 진세노사이드 Rg18은 염증을 매개하는 대표적인 효소인 COX-2 단백질의 발현을 감소시켰고, 상기 COX-2에 의해 생성되며 면역억제 작용을 하는 PGE2 단백질의 발현도 감소시켰다. 또한, 급성기 반응에 유도되는 사이토카인인 TNF-α의 발현을 감소시켰다.To, ginsenoside Rg18 true of the present invention sikyeotgo reduce the typical enzyme expression of COX-2 protein in mediating inflammation, it is generated by the COX-2 PGE 2 protein to the immunosuppressive action. As demonstrated in Example . In addition, the expression of TNF-a, a cytokine induced in the acute phase response, was reduced.
본 발명의 일 구현예에 따르면, 상기 조성물은 STAT-1(Signal transducer and activator of transcription 1)의 활성을 감소시킨다.According to one embodiment of the present invention, the composition reduces the activity of STAT-1 (signal transducer and activator of transcription 1).
하기 실시예에서 입증된 바와같이 본 발명의 진세노사이드 Rg18은 INF-α, INF-γ와 같은 염증 매개 물질 및 세포 스트레스에 관여하는 Stat-1의 인산화를 억제하여 활성을 감소시켰다.As demonstrated in the following examples, the ginsenoside Rg18 of the present invention inhibited the inflammation mediators such as INF- ?, INF-? And the phosphorylation of Stat-1 involved in cell stress, thereby reducing the activity.
본 발명의 일 구현예에 따르면, 상기 β-아밀로이드에 의한 신경세포의 사멸을 억제한다.According to one embodiment of the present invention, the inhibition of neuronal cell death by the? -Amyloid is suppressed.
하기 실시예에서 입증된 바와 같이, 본 발명의 진세노사이드 Rg18은 β-아밀로이드에 의한 신경세포의 사멸을 10-20% 억제하였다. 이러한 효과는 진세노사이드 Rg18가 β-아밀로이드에 의해 감소된 Erk 및 Akt의 인산화를 회복시켰다.As demonstrated in the following examples, the ginsenoside Rg18 of the present invention inhibited the death of [beta] -amyloid by 10-20%. This effect restored the phosphorylation of Erk and Akt reduced by β-amyloid by ginsenoside Rg18.
본 발명의 일 구현예에 따르면, 상기 조성물은 OH-1(Heme oxygenase) 및 Nrf2[Nuclear factor (erythroid-derived 2)-like 2]단백질의 발현을 증가시킨다.According to one embodiment of the present invention, the composition increases the expression of OH-1 (Heme oxygenase) and Nrf2 (Nuclear factor (erythroid-derived 2) -like 2] proteins.
하기 실시예에서 입증된 바와 같이, 본 발명의 진세노사이드 Rg18은 항산화 작용을 갖는 HO-1 및 Nrf2의 단백질 발현을 증가시켰다.As demonstrated in the following examples, the ginsenoside Rg18 of the present invention increased protein expression of HO-1 and Nrf2 with antioxidant activity.
본 발명의 조성물은 식품 조성물, 기능성 식품 조성물 또는 약제학적 조성물이다.The composition of the present invention is a food composition, a functional food composition or a pharmaceutical composition.
본 발명의 조성물은 식품 조성물로 제공될 수 있다. 본 발명의 진세노사이드 Rg18을 유효성분으로 포함하는 신경퇴행성 질환의 예방, 치료 또는 개선용 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 진세노사이드 Rg18뿐 만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등)] 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 진세노사이드 Rg18 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다.The composition of the present invention can be provided as a food composition. When the composition for preventing, treating or ameliorating a neurodegenerative disease comprising the ginsenoside Rg18 of the present invention as an active ingredient is prepared from a food composition, not only ginsenoside Rg18 as an active ingredient, And includes, for example, proteins, carbohydrates, fats, nutrients, flavoring agents, and flavoring agents. Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavors (saccharin, aspartame, etc.) may be used as flavorings. For example, when the food composition of the present invention is prepared as a drink, it additionally contains citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry juice, jujube extract, licorice extract, etc. in addition to the ginsenoside Rg18 of the present invention .
본 발명의 진세노사이드 Rg18을 유효성분으로 포함하는 신경퇴행성 질환의 예방, 치료 또는 개선용 기능성 식품 조성물로 제조될 수 있다. 본 발명의 조성물이 기능성 식품 조성물로 제조되는 경우, 식품 제조 시 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분으로서 진세노사이드 Rg18 이외에 향미제 또는 천연 탄수화물을 추가 성분으로 포함시킬 수 있다. 예를 들어, 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등); 디사카라이드(예컨대, 말토스, 수크로오스 등); 올리고당; 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등); 및 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)을 포함한다. 향미제로서 천연 향미제(예컨대, 타우마린, 스테비아 추출물 등) 및 합성 향미제(예컨대, 사카린, 아스파르탐 등)을 이용할 수 있다.Or a functional food composition for preventing, treating or ameliorating a neurodegenerative disease comprising the ginsenoside Rg18 of the present invention as an active ingredient. When the composition of the present invention is prepared with a functional food composition, it includes components that are conventionally added in food production, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, when it is made of a drink, a flavoring agent or a natural carbohydrate may be added as an additional ingredient in addition to ginsenoside Rg18 as an active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (e.g., dextrin, cyclodextrin and the like); And sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Natural flavoring agents (e.g., tau marin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) may be used as flavorings.
본 발명의 진세노사이드 Rg18을 유효성분으로 포함하는 신경퇴행성 질환의 예방, 치료 또는 개선용 조성물은 약제학적 조성물로 제조될 수 있다. 본 발명의 조성물은 (a) 상술한 본 발명의 진세노사이드 Rg18의 약제학적 유효량; 및 (b) 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물이다. 본 명세서에서 용어 “약제학적 유효량”은 상술한 진세노사이드 Rg18의 효능 또는 활성을 달성하는 데 충분한 양을 의미한다.The composition for preventing, treating or ameliorating a neurodegenerative disease comprising the ginsenoside Rg18 of the present invention as an active ingredient can be prepared from a pharmaceutical composition. The composition of the present invention comprises (a) a pharmaceutically effective amount of the ginsenoside Rg18 of the present invention described above; And (b) a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to achieve the efficacy or activity of the ginsenoside Rg18 described above.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 일반적인 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . Typical dosages of the pharmaceutical compositions of this invention are in the range of 0.001-100 mg / kg on an adult basis.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(a) 본 발명의 진세노사이드 Rg18은 뇌염증 및 신경세포의 사멸을 억제하는 효과를 제공한다.(a) The ginsenoside Rg18 of the present invention provides an effect of suppressing brain inflammation and nerve cell death.
(b) 본 발명은 인삼 유래 진세노사이드 Rg18의 신규한 용도를 규명한 발명으로, 식품 조성물, 기능성 식품 조성물 또는 약제학적 조성물에 활용가능하다.(b) The present invention is a new invention of ginsenoside Rg18 derived from ginseng, which can be applied to food compositions, functional food compositions or pharmaceutical compositions.
도 1은 신규한 진세노사이드인 진세노사이드 18의 화학식을 나타낸다.
도 2a 내지 2d는 염증성 사이토카인의 분비에 대한 진세노사이드 Rg18의 억제 효과를 나타낸다.
도 3은 염증 매개 효소인 COX-2의 발현에 대한 진세노사이드 Rg18의 억제 효과를 나타낸다.
도 4는 COX-2의 다운스트림인 프로스타글란딘 E2의 발현에 대한 진세노사이드 Rg18의 억제 효과를 나타낸다.
도 5는 급성기 반응에 의해 유도되는 TNF-α(Tumor Necrosis Factor-alpha)의 발현에 대한 진세노사이드 Rg18의 억제 효과를 나타낸다.
도 6은 염증 매개 물질 및 세포 스트레스 반응에 관여하는 Stat-1 전사인자의 발현에 대한 진세노사이드 Rg18의 억제 효과를 나타낸다.
도 7은 진세노사이드 Rg18의 세포독성 및 β-아밀로이드에 의한 세포사멸 억제 효과를 나타낸다.
도 8a 내지 8b는 β-아밀로이드를 처리하는 경우에 세포 생존 기전의 하나인 Erk 및 Akt의 인산화에 대한 진세노사이드 Rg18의 회복 효과를 나타낸다.
도 9a 내지 9c는 β-아밀로이드를 처리하는 경우에 진세노사이드 Rg18의 뉴런 세포사멸 억제 효과를 나타낸다.Figure 1 shows the formula of the novel ginsenoside ginsenoside 18.
Figures 2a-2d show inhibitory effects of ginsenoside Rg18 on the secretion of inflammatory cytokines.
Figure 3 shows the inhibitory effect of ginsenoside Rg18 on the expression of COX-2, an inflammatory mediator.
Figure 4 shows the inhibitory effect of ginsenoside Rg18 for expression of prostaglandin downstream of COX-2
Figure 5 shows the inhibitory effect of ginsenoside Rg18 on the expression of TNF-alpha (Tumor Necrosis Factor-alpha) induced by acute phase response.
Figure 6 shows the inhibitory effect of ginsenoside Rg18 on the expression of Stat-1 transcription factors involved in inflammatory mediators and cellular stress responses.
Fig. 7 shows the cytotoxicity of ginsenoside Rg18 and the effect of suppressing apoptosis by? -Amyloid.
Figures 8A-8B show the recovery effect of ginsenoside Rg18 on phosphorylation of Erk and Akt, one of the cell survival mechanisms in the treatment of [beta] -amyloid.
FIGS. 9A to 9C show the neuronal cell death suppression effect of ginsenoside Rg18 when? -Amyloid is treated.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예: 뇌신경세포 사멸 억제효과Example: Effect of inhibiting neuronal cell death
1) 뇌염증 억제활성1) Brain inflammation inhibitory activity
가) 염증 사이토카인 분비 억제효과A) Inhibitory effect of inflammatory cytokine secretion
BV2 마우스 소교(microglia) 세포를 DMEM(Dulbecco's Modified Eagle Medium) 배지에 10% 우태아혈성(Fetal bovine serum; FBS), 1% 항생제를 첨가하여 100 ㎜ 디쉬에 접종한 후, 37℃, 5% CO2 항온반응기에서 배양하였다. 염증 반응 유도하기 위해 5×105 cells/웰로 6 웰 플레이트에 접종한 후 FBS 무첨가배지로 추가 배양하였다. 16시간 이상 배양 후 LPS(Lipopolysaccharide, 2 ㎍/㎖)을 처리하고 NGA를 농도별로 처리하여 24시간 배양하였다. LPS로 염증반응을 유도한 6 웰 플레이트에서 상층액 1 ㎖을 수거하고 차가운 PBS(Phosphate Buffered Saline)로 세척한 후 세포를 수확하였다. 수확한 세포를 2000 rpm으로 원심분리를 실시한 후, 상층액을 버리고 침전물에 단백질 용해 완충액 50 ㎕을 첨가하여 얼음 위에서 30분 동안 정치시켰다. 다시 13,000 rpm에서 원심분리를 실시하여 상층액을 단백질로 사용하였다. 1 ㎖ 수확한 상층액을 다시 원심분리를 실시하여 상층액을 ELISA(Enzyme-linked Immunosorbent Assay) 분석에 사용하였다. 멀티플렉스 ELISA 어레이 키트를 이용하여 다양한 염증인자 사이토카인의 단백질 양을 측정하였다. 실험방법은 특정 항체가 포획된 QPLEX 키트(Quansys Biosciences, Utah, USA)를 이용하고 그 매뉴얼 방식대로 실험을 진행하였다. 이때 사용된 키트는 MCP-1, IL-6, IL-1β 및 TNFα이며 결과는 도 2a 내지 2d와 같다.BV2 mouse microglia cells were inoculated into a 100 mm dish containing 10% fetal bovine serum (FBS) and 1% antibiotic in DMEM (Dulbecco's Modified Eagle Medium) medium, 2 < / RTI > incubator. To induce an inflammatory reaction, the cells were inoculated in a 6-well plate at 5 × 10 5 cells / well and further cultured in an FBS-free medium. After culturing for more than 16 hours, LPS (Lipopolysaccharide, 2 ㎍ / ㎖) was treated and treated with NGA for 24 hours. 1 ml of the supernatant was collected in a 6-well plate induced by LPS and washed with cold PBS (Phosphate Buffered Saline), and the cells were harvested. The harvested cells were centrifuged at 2000 rpm, and the supernatant was discarded. 50 μl of protein lysis buffer was added to the precipitate, and the mixture was allowed to stand on ice for 30 minutes. The supernatant was centrifuged at 13,000 rpm and the supernatant was used as a protein. 1 ml of the harvested supernatant was centrifuged again and the supernatant was used for ELISA (Enzyme-linked Immunosorbent Assay) analysis. Multiplex ELISA array kit was used to measure the amount of protein of various inflammatory cytokines. Experimental procedures were performed using the QPLEX kit (Quansys Biosciences, Utah, USA) in which the specific antibody was captured. The kits used were MCP-1, IL-6, IL-1 [beta] and TNF [alpha], and the results are shown in FIGS.
실험결과 NGA는 LPS로 유도한 염증 사이토카인의 분비를 억제하였다. LPS 2 ㎍/㎖을 처리한 BV-2 세포에서 2배 이상 증가되었던 TNF-α의 단백질양이 NGA를 농도별(1, 5, 10, 50 및 100 ㎍/㎖)로 처리하였을 때, 농도 의존적으로 감소하는 경향을 나타내었으며, 특히 10 ㎍/㎖ 이상부터는 양성 대조군으로 사용된 Rb1(10μM)보다 더 좋은 효능을 나타내었다. IL-6도 LPS에 의해 5배 이상 증가되었는데, NGA가 농도의존적으로 감소시키는 효능을 나타내었고, IL-1β도 농도 의존적으로 감소시킴을 확인 하였다.NGA inhibited the secretion of inflammatory cytokines induced by LPS. When NGA was treated with concentrations of 1, 5, 10, 50 and 100 ㎍ / ㎖, the amount of TNF-α protein, which was increased more than twice in BV-2 cells treated with 2 ㎍ / (10 ㎍ / ㎖) than that of Rb1 (10 ĩM) used as a positive control. IL-6 was also increased by LPS more than 5-fold, indicating that NGA was dose-dependently reduced and IL-1β was also dose-dependent.
나) 염증관련 단백질 인자의 발현 억제 확인B) Inhibition of expression of inflammatory protein factors
염증성 매개인자의 단백질 발현에 미치는 영향을 확인하기 위하여 상층액은 ELISA에 이용하고 세포는 용해하여 웨스턴블럿(Western blot)에 사용하였다. 염증반응을 유도한 세포에서 용해 완충액으로 단백질을 추출하고, 브래드포드법을 이용하여 단백질을 정량하였다. 50 ㎍의 단백질을 DTT(Dithiothreitol)가 포함된 로딩 완충액과 1:1로 혼합한 후 10% SDS-PAGE 겔에 로딩하고 니트로셀룰로오스(nitrocellulose) 막에 전송하여 블라팅(blotting)하였다. 이때 사용한 항체는 COX-2(Cell signaling technology, MA, USA), PGE2(Enzo life science, NY, USA), TNF-α(NOVUS a bioteche brand, CO, USA), stat1(Cell signaling Technology, MA, USA) 및 P-stat1(Cell signaling Technology, MA, USA)이고, 2차 항체는 항-래빗 HRP 컨쥬게이티드 항체(Santa Cruz Biotechnology, Texas, USA)를 사용하였다.To confirm the effect of inflammatory mediators on protein expression, supernatants were used for ELISA and cells were lysed and used for Western blotting. Proteins were extracted from the cells induced by the inflammation reaction with a lysis buffer, and proteins were quantified using the Bradford method. 50 의 of the protein was mixed with loading buffer containing DTT (Dithiothreitol) at a ratio of 1: 1, loaded on a 10% SDS-PAGE gel, transferred to nitrocellulose membrane and blotted. The antibodies used were COX-2 (Cell signaling technology, MA, USA), PGE 2 (Enzo life science, NY, USA), TNF-α (NOVUS a bioteche brand, Rabbit HRP conjugated antibody (Santa Cruz Biotechnology, Texas, USA) was used as the secondary antibody.
COX-2(Cyclooxygenase-2)는 프로스타글란딘-엔도페록사이드 합성효소(prostaglandin-endoperoxide synthase)로 알려져 있으며 프로스타사이클린(prostacyclin) 및 트롬복산(thromboxane) 형성에 중요한 역할을 하는 효소이다. 즉 염증을 매개하는 효소로서 염증확인 하는데 사용하는 대표적인 효소이다(Seibert K et al, Role of inducible cyclooxygenase (COX-2) in inflammation. Receptors. 1994 4(1):17-23). 본 연구에서는 방출된 단백질뿐 아니라 세포내재성 염증인자도 확인하고자 세포를 이용하여 확인하였다. 그 결과, LPS에 의해 2배 이상 증가되었던 COX-2의 발현량이 NGA를 10, 50 및 100 μM 처리하였을 때 농도 의존적으로 감소시킴을 확인하였다(도 3).COX-2 (Cyclooxygenase-2), known as prostaglandin-endoperoxide synthase, is an enzyme that plays an important role in the formation of prostacyclin and thromboxane. (COX-2) in inflammation. [4] (1): 17-23), which is an enzyme that mediates inflammation and is used to identify inflammation (Seibert K et al., Role of inducible cyclooxygenase (COX-2) In this study, we used cells to identify not only released proteins but also intracellular inflammatory factors. As a result, it was confirmed that the expression level of COX-2, which was increased more than twice by LPS, decreased in a concentration-dependent manner when NGA was treated at 10, 50 and 100 μM (FIG.
프로스타글란딘 E2 (PGE2)는 내재성 인자로서 생체 내에서 다양한 생리약리작용을 한다. 특히, 평활근수축, 면역억제 등과 같은 작용을 한다고 알려져 있으며 COX-2에 의해 생성(Vigano T et al, COX2 and synthesis of PGE2 in human bronichial smooth-muscle cells. Am J Respir Crit Care Med, 1997 155(3):864-8)되므로 앞 연구에서 NGA가 COX-2의 발현량을 억제하였기 때문에, PGE2 발현량에 미치는 영향을 확인하고자 하였다. PGE2 ELISA 키트를 사용하여 BV2 배양 후 상층액을 이용하여 측정하였다. 그 결과 도 4에서와 같이 LPS에 의해 8배 정도 증가되었던 PGE2는 NGA 50, 100 μM에서 는 유의적으로 감소하는 경향을 나타내었다.Prostaglandin E 2 (PGE 2 ) is an endogenous factor and has a variety of physiological actions in vivo. In particular, it is known to act like smooth muscle contraction and immunosuppression and is produced by COX-2 (Vigano et al, COX2 and synthesis of PGE2 in human bronchial smooth-muscle cells. ): 864-8). Therefore, the effect of NGA on the amount of PGE 2 expression was confirmed by inhibiting the amount of COX-2 expressed in the previous study. PGE 2 ELISA kit was used to measure BV2 after incubation with supernatant. As a result, as shown in FIG. 4, PGE 2, which was increased 8-fold by LPS, was significantly decreased at
TNF-α는 종앙 괴사 인자(tumor necrosis factor)알파로서 급성기 반응(acute phase response)에 유도되는 사이토카인이다. TNF-α의 비정상적인 조절은 알츠하이머, 패혈증 등 연관된 다른 질병을 유도하기에 초기에 TNF-α의 억제는 면역반응 조절에 중요한 역할을 한다 (Cheng X et al, Targetig TNF-α: a therapuetic strategy for Alzhemier ’s disease. Drug Discov Today 2014 .19(11) 1822-7.). 본 연구에서 세포내의 TNF-α의 발현을 검사한 결과, 1.5배 이상 증가되었던 TNF-α의 양이 NGA에 의해 농도 의존적으로 감소 효능을 확인하였으며 50 μM 및 100 μM에서는 유의적인 감소를 나타내었다(도 5).TNF-α is a tumor necrosis factor alpha, a cytokine that is induced in the acute phase response. Inhibition of TNF-α plays an important role in regulating the immune response (Cheng X et al, Targetig TNF-α: a therapuetic strategy for Alzheimer's disease), in order to elicit other related diseases such as Alzheimer's and sepsis 's disease. Drug Discov Today 2014 .19 (11) 1822-7.). In this study, the expression of TNF-α in the cells was examined by the NGA-induced decrease in TNF-α level, which was increased more than 1.5-fold, and decreased significantly at 50 μM and 100 μM 5).
Stat-1 전사 인자는 INF-α 및 INF-γ과 같은 염증 매개 물질 및 세포스트레스에 반응에 관여하는 중요한 인자이다. 염증자극이나 세포 스트레스에 의한 Stat-1의 Tyr701 잔기 및 Set727(맞습니다) 잔기의 인산화는 Stat-1이 이합체화(dimerization)되고 핵 안으로 이동(translocation)한 후 DNA와 반응하거나 p38 MAPK 의존 경로로 반응하게 된다(Cho JW et al, Curcumin attenuates the expression of IL-1beta, IL-6, INF-α as well as cyclin E in INF-α treated HcCaT cells. International journal of molecular medicine 19(2007)169-474). 본 연구에서는 NGA가 이러한 염증 매개 키나아제인 STAT-1의 발현을 어떻게 조절하는지 확인하기 위하여 웨스턴 블럿으로 발현량을 확인하였다. 그 결과, LPS에 의해 1.8배 정도 증가한 STAT-1의 인산화(phosphorylation)은 NGA 50 μM 및 100 μM에서 대조군 수준과 유사한 수준의 발현량을 확인하여, NGA가 Stat-1의 활성화 조절에 관여한다는 것을 확인하였다(도 6).Stat-1 transcription factors are important factors involved in the response to inflammatory mediators such as INF-α and INF-γ and cellular stress. Phosphorylation of the Tyr701 and Set727 residues of Stat-1 by inflammatory or cellular stress dimerizes Stat-1 and translocates into the nucleus before reacting with DNA or by p38 MAPK-dependent pathway In this study, we investigated the effects of IL-1beta, IL-6, INF-α as well as cyclin E on INF-α treated HcCaT cells and curcumin attenuates the expression of IL-1beta, 19 (2007) 169-474. . In this study, we used Western blot to determine the expression level of NGA to regulate the expression of STAT-1, an inflammatory mediator. As a result, the phosphorylation of STAT-1 increased by 1.8-fold by LPS was observed at a level similar to that of the control group at 50 μM and 100 μM of NGA, indicating that NGA was involved in the regulation of STAT-1 activation (Fig. 6).
2) 신경세포에서의 β-아밀로이드에 의한 신경세포사멸 보호 효능2) Effect of β-amyloid on nerve cell death protection in neurons
가) 뇌신경세포 보호 효능 A) Neuroprotective effect
뇌에서의 소교 세포는 외부자극이 들어왔을 때 염증 매개 물질 및 다양한 작용을 통해 뉴런세포를 보호한다. 하지만 이러한 염증반응이 외부자극에 의해 계속 이루어지면 오히려 뉴런 세포를 사멸하는 물질을 매개하여 뉴런 세포를 자멸 하게 한다(Lee J et al, Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells. Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11. J Biol Chem. 2001 276(35):32596-65). 본 연구에서는 NGA가 소교세포의 염증 작용을 억제하는 것을 확인 한 후, 그렇다면 뉴런 세포에는 어떠한 영향을 미치는지 확인하고자 하였다. SH-SY5Y 세포를 이용하여 응집화(aggregation)된 β-아밀로이드(beta amyloid)로 세포사멸을 유도하고, NGA가 이러한 세포사멸을 억제하는지 확인하였다.Microglia in the brain protect neurons through inflammatory mediators and a variety of actions when external stimuli come in. However, when the inflammatory reaction is continued by external stimuli, neuronal cells are destroyed by mediating neuronal cell death substances (Lee J et al, Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells. Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11. J Biol Chem. 2001 276 (35): 32596-65). In this study, we investigated the effect of NGA on the neuronal cells after confirming the inhibition of the inflammatory action of microglial cells. Amyloid (beta amyloid) aggregated with SH-SY5Y cells induced apoptosis and NGA inhibited apoptosis.
실험방법은 SH-SY5Y를 3.5×105 cells/㎖로 96 웰 플레이트에 시딩(seeding)한 후, 4일 동안 응집화 시킨 β-아밀로이드1-42(American peptide company, CA, USA)를 25 μM 처리한 후 24시간 추가 배양하였다. 이후, MTT를 이용하여 세포 생존능를 측정하였다. 그 결과, NGA만 처리하였을때는 독성을 나타내지 않았으며, β-아밀로이드에 의해 55% 감소되었던 세포 생존능은 NGA를 농도별로 처리하였을 때 농도 의존적으로 증가하였고, 특히 50 및 100 μM에서 각각 71% 및 73%로 증가하는 것을 확인하였다(도 7).The experimental method was as follows: SH-SY5Y was seeded into a 96-well plate at 3.5 × 10 5 cells / ml, β-amyloid 1-42 (American peptide company, CA, USA) After the treatment, the cells were further cultured for 24 hours. Cell viability was then measured using MTT. As a result, the cell viability which was 55% reduced by β-amyloid was not toxic when treated with NGA only, and increased by 50% and 100 μM when NGA was treated by concentration, % (Fig. 7).
(나) 세포사멸 억제 관련 키나아제의 발현 확인(B) Confirmation of expression of kinase inhibiting apoptosis
NGA의 β-아밀로이드에 의한 세포사멸 억제의 기전을 확인하고자 대표적인 세포 생존의 기전중 하나인 Erk의 활성을 확인하였다. 그 결과, β-아밀로이드에 의해 감소되었던 Erk의 인산화가 NGA에 의해 회복되는 것을 확인하였고, Erk 억제제인 PD98059를 처리하였을 때 감소되는 것을 확인하여 Erk가 NGA의 세포사멸억제 효능에 관여하는 것을 확인하였다(도 8a).In order to confirm the mechanism of cell death suppression by β-amyloid in NGA, the activity of Erk, which is one of representative cell survival mechanisms, was confirmed. As a result, it was confirmed that phosphorylation of Erk which was reduced by β-amyloid was restored by NGA, and decreased when treated with PD98059, which is an Erk inhibitor, confirming that Erk is involved in the inhibitory effect of NGA on apoptosis (Fig. 8A).
Akt 경로는 외부자극이 있을 때 세포사멸이나 성장을 촉진하는 신호전단 경로 중 하나로 다운스트림(downstream)에 아폽토시스(apoptosis)나 세포사멸에 관여하는 단백질을 조절하게 된다. 본 연구에서는 NGA가 β-아밀로이드에 의해 유도된 세포 사멸을 억제하는 효능이 어떠한 기전인지 확인하고자 Akt의 인산화을 확인한 결과 β-아밀로이드에 의해 감소되었던 akt의 인산화가 NGA에 의해 증가되는 것을 확인하였고, akt의 업스트림(upstream) 신호인 PI3 키나아제의 억제제인LY294002를 NGA와 같이 처리하였을 때 변화가 없는 것을 확인하여 NGA는 PI3K-Akt 신호전달에 의해 뉴런세포의 사멸을 억제하는 것을 확인할 수 있었다(도 8b).The Akt pathway regulates proteins involved in apoptosis or apoptosis downstream in one of the signaling pathways that stimulate apoptosis or growth in the presence of external stimuli. In this study, we investigated the effect of NGA on the inhibition of β-amyloid-induced apoptosis by confirming the phosphorylation of Akt and found that the phosphorylation of Akt, which was reduced by β-amyloid, was increased by NGA. (Fig. 8B), it was confirmed that NGA inhibited neuronal cell death by PI3K-Akt signal transduction by confirming that there was no change when LY294002, which is an upstream signal of PI3 kinase, was treated with NGA, .
(다) NGA의 항산화기전을 통한 β-아밀로이드 유도 뉴런 세포사멸 억제 효능 검증(C) Antioxidative mechanism of NGA inhibits β-amyloid-induced neuronal apoptosis
헴 산소화효소(Heme oxygenase; HO)는 헴의 분해대사과정에 관여하는 효소로, 헴을 분해하여 담록소(biliverdin), 유리 철(free iron) 및 일산화탄소(carbon monoxide)를 생성시키는 효소이다. 이는 강력한 항산화 작용으로 산화적 손상 모델에서 세포보호작용을 한다고 밝혀져 있다. HO-1은 이중 하나의 효소로 저산소상태, UV 방사선, 카드뮴과 같은 중금속, 활성산소종(ROS)등 다양한 산화적 스트레스성 자극에 반응하여 생체방어 기능을 갖는 것으로 알려져 있다(Myricetin ameliorates brain injury and neurological deflicitis via Nrf2 activation after experimental stroke in middle-aged rats. Food Funct. 2016). 본 연구에서는 β-아밀로이드에 의한 세포사멸 기전 중 알려져 있는 산화적 스트레스를 NGA가 방어하는지 확인하고자 HO-1을 확인하였으며 산화적 스트레스의 대표적인 방어 기작으로 알려져 있는 Nrf2(nuclear factor E2-related factor 2)의 발현량을 측정하였다. 그 결과, NGA를 농도별로 처리하였을 때, 농도 의존적으로 HO-1의 증가를 확인하였고, Nrf2의 핵 분획(nuclear fraction)으로의 이동이 증가되는 것을 확인하였다(도 9a 내지 9b). KEAP1(Kelch-like ECH-associated protein 1)은 항산화 작용을 하는 Nrf2와 상호작용하여 자극이 없는 경우에는 세포질에서 Nrf2와 결합하여 Nrf2의 작용을 억제한다. 본 연구에서는 NGA에 증가되었던 KEAP1 유전자의 발현이 45분 이후에 감소되는 것을 확인하였다(도 9c).Heme oxygenase (HO) is an enzyme involved in the degradation process of heme, and is an enzyme that decomposes heme to produce biliverdin, free iron and carbon monoxide. It has been shown that the strong antioxidant activity has a cytoprotective action in the oxidative damage model. It is known that HO-1 is a biosynthetic enzyme in response to various oxidative stress stimuli such as hypoxia, UV radiation, heavy metals such as cadmium, and reactive oxygen species (ROS) (Myricetin ameliorates brain injury and neurological deflicitis via Nrf2 activation after experimental stroke in middle-aged rats. In this study, HO-1 was identified to determine whether NGA inhibits oxidative stress in β-amyloid-induced apoptosis. Nrf2 (nuclear factor E2-related factor 2), a typical defense mechanism of oxidative stress, Was measured. As a result, when NGA was treated at different concentrations, an increase in HO-1 was observed in a concentration-dependent manner, and it was confirmed that migration of Nrf2 to the nuclear fraction was increased (FIGS. 9A to 9B). KEAP1 (Kelch-like ECH-associated protein 1) interacts with Nrf2, an antioxidant, that binds to Nrf2 in the cytoplasm in the absence of stimulation to inhibit the action of Nrf2. In this study, it was confirmed that the expression of KEAP1 gene increased in NGA after 45 minutes (FIG. 9C).
결 론conclusion
뇌에 존재하는 다양한 세포(glia, neuron 등)를 조절하여 뇌신경 세포 보호효과를 나타내는 신규 진세노사이드를 발굴하였고 이는 뇌에서의 소교세포의 과활성화(overactivation)를 조절하여 과활성화되었을 때 신경세포를 사멸시키는 작용을 억제하고, 직접적으로 뉴런 세포의 세포사멸도 억제하는 두가지 효능을 모두 갖는 신규 진세노사이드이다.We found a new ginsenoside that protects brain cells by controlling various cells (glia, neuron, etc.) in the brain. It regulates the overactivation of microglia in the brain, It is a novel ginsenoside that has both the two effects of suppressing the killing action and directly inhibiting the cell death of neuron cells.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (10)
화학식 1
A pharmaceutical composition for improving, preventing or treating neurodegenerative diseases comprising, as an active ingredient, ginsenoside Rg18 or a salt thereof represented by the following formula
Formula 1
The composition of claim 1, wherein the ginsenoside Rg18 is derived from Panax ginseng root.
The use according to claim 1, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, corticobasal degeneration, Parkinson's disease, multiple system atrophy, Huntington's disease, eukaryotic paralysis, Lou Gehrig's disease, primary lateral sclerosis and spinal muscular atrophy ≪ / RTI >
2. The composition of claim 1, wherein said composition reduces the secretion of inflammatory cytokines of microglia cells.
The method of claim 1, wherein the composition is COX-2 (prostaglandin-endoperoxide synthase 2), PGE 2 (prostaglandin E2) , and TNF-α (tumor necrosis factor- alpha) composition, comprising a step of reducing the expression of the protein.
2. The composition of claim 1, wherein the composition reduces the activity of STAT-1 (Signal transducer and activator of transcription 1).
The composition of claim 1, wherein the composition inhibits the death of neuronal cells by beta -amyloid.
2. The composition of claim 1, wherein the composition increases the expression of OH-1 (Heme oxygenase) and Nrf2 (erythroid-derived 2) -like 2] proteins.
A food composition for improving or preventing neurodegenerative diseases, which comprises, as an active ingredient, ginsenoside Rg18 or a salt thereof represented by the general formula (1) of claim 1.
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