KR102294270B1 - Composition comprising Dendranthema boreale extract for improving cognitive functio - Google Patents
Composition comprising Dendranthema boreale extract for improving cognitive functio Download PDFInfo
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- KR102294270B1 KR102294270B1 KR1020190161356A KR20190161356A KR102294270B1 KR 102294270 B1 KR102294270 B1 KR 102294270B1 KR 1020190161356 A KR1020190161356 A KR 1020190161356A KR 20190161356 A KR20190161356 A KR 20190161356A KR 102294270 B1 KR102294270 B1 KR 102294270B1
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Abstract
본 발명은 산국 추출물(Dendranthema boreale)을 유효성분으로 포함하는 인지능력 개선 및 퇴행성 뇌질환 예방 또는 치료용 조성물에 관한 것이다.
보다 상세하게는 본 발명의 산국 추출물은 기억력 저하 예방 효과, 아세틸콜린에스터라제 저해 효과, 아밀로이드 단백질 섬유화 저해 효과, 산화질소 생성 저해 효과 및 NMDA 수용체 저해 효과가 우수하므로 인지능력 개선 및 퇴행성 뇌질환 예방 또는 치료용 조성물로 유용하게 이용될 수 있다.The present invention relates to a composition for improving cognitive ability and preventing or treating degenerative brain disease, comprising an extract of wild ginseng (Dendranthema boreale) as an active ingredient.
More specifically, the sanguk extract of the present invention has excellent memory loss prevention effect, acetylcholinesterase inhibitory effect, amyloid protein fibrosis inhibitory effect, nitric oxide production inhibitory effect, and NMDA receptor inhibitory effect, so it improves cognitive ability and prevents degenerative brain disease Or it may be usefully used as a composition for treatment.
Description
본 발명은 산국 추출물을 유효성분으로 포함하는 인지능력 개선 및 퇴행성 뇌질환 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for improving cognitive ability and preventing or treating degenerative brain disease, comprising an extract of wild ginseng as an active ingredient.
기억에 대한 전반적인 기능을 인지능이라 하는데 이러한 인지능력의 저하는 학습저하 및 삶의 질 저하 등을 초래하기 때문에 현대사회에 큰 문제로 대두 되고 있다. 현재 뇌 손상 및 치매, 알츠하이머 등과 같은 인지능 저하에 대한 질병이 현대사회의 급격한 고령화로 증가하는 추세를 보이고 있다. 이와 같은 질병들은 자기유지나 사회생활에 심한 장애를 초래할 정도로 기억력, 사고력, 이해력, 계산능력, 학습능력, 언어 및 판단력 등 전체적이고 복합적인 지적 기능의 저하가 발생하게 된다. The overall function of memory is called cognitive intelligence, and this decline in cognitive ability is emerging as a major problem in modern society because it leads to deterioration in learning and quality of life. Currently, diseases related to cognitive decline, such as brain damage, dementia, and Alzheimer's disease, are on the rise due to the rapid aging of modern society. These diseases cause deterioration of overall and complex intellectual functions such as memory, thinking ability, comprehension, calculation ability, learning ability, language and judgment to the extent that it causes severe impairment in self-maintenance or social life.
퇴행성 뇌질환(degenerative brain diseases)은 노화에 따른 신경퇴화, 유전적 요인 등으로 인해 뇌신경세포가 사멸하거나, 뇌신경세포의 기능이 상실되어 발병하는 것으로 알려져 있다. 퇴행성 뇌질환 발병에 대한 정확한 원인은 밝혀지지 않았으며 원인 규명을 위한 연구가 활발히 진행되고 있다. 퇴행성 뇌질환으로 알츠하이머병(Alzheimer's disease), 파킨슨병(Parkinson's disease), 헌팅톤병(Huntington's disease), 다발성경화증 (Multiple sclerosis) 및 근위축성 측색 경화증(Amyotrophic lateral sclerosis) 등이 알려져 있다.It is known that degenerative brain diseases are caused by the death of brain nerve cells or loss of function of brain nerve cells due to neurodegeneration according to aging, genetic factors, and the like. The exact cause of the onset of degenerative brain disease is not known, and research is being actively conducted to identify the cause. Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are known as degenerative brain diseases.
최근 노인 인구가 증가하면서 인지능력 저하 및 퇴행성 뇌질환에 대한 문제가 심각한 사회문제로 대두되고 있으며 이에 인지능력 개선 및 알츠하이머병을 비롯한 퇴행성 뇌질환에 대하여 해당 분야에서는 최근 인체 적합성을 가진 천연물 소재를 이용한 치료제 개발이 발전 중에 있으며, 또한 부작용이 적은 신소재의 개발이 필요한 실정이다. With the recent increase in the elderly population, the problems of cognitive decline and degenerative brain disease are emerging as serious social problems. The development of therapeutic agents is in progress, and there is a need to develop new materials with fewer side effects.
한편 산국(Dendranthema boreale)은 들국화의 한 종류로서 개국화라고도 한다. 한국, 중국 북부, 일본에 분포하고, 산지에서 자라며 높이는 약 1m로 뿌리줄기는 길게 뻗으며 줄기는 모여 나고 곧추선다. 흰 털이 나며 가지가 많이 갈라지고 뿌리에 달린 잎은 꽃이 필 때 마른다. 줄기에 달린 잎은 어긋나고 긴 타원형의 달걀 모양이며 길이 5∼7cm, 나비 4∼7cm이다. 깃꼴로 깊게 갈라지고 가장자리에 날카로운 톱니가 있으며 잎자루는 길이 1∼2cm이다. 꽃은 9∼10월에 노란색으로 피는데, 두화(頭花)는 지름 1.5cm 정도로서 가지와 줄기 끝에 산형(傘形) 비슷하게 달린다. 총포는 길이 약 4mm이고, 포조각은 3∼4줄로 늘어서며 바깥조각은 줄 모양이거나 좁은 긴 타원 모양이다. 화관은 통 모양이며 끝이 5갈래로 갈라진다. 열매는 수과(瘦果)로서 10∼11월에 익으며 길이 1mm 정도이다. 꽃은 진정·해독·소종 등의 효능이 있어 두통과 어지럼증에 사용한다. 관상용으로 심으며 어린순은 나물로 먹는다. On the other hand, Dendranthema boreale is a kind of wild chrysanthemum and is also called Gaekgwa. Distributed in Korea, northern China, and Japan, it grows in mountainous areas and is about 1m high, with long rhizomes, and the stems gather and stand upright. It has white hairs, branches are divided a lot, and the leaves on the roots dry out when the flowers bloom. The leaves on the stem are alternate phyllotaxis, long oval egg-shaped, 5-7cm long and 4-7cm wide. It is deeply divided in pinnate shape, has sharp saw teeth on the edge, and the petiole is 1~2cm long. The flowers bloom in yellow from September to October. The head flower is about 1.5cm in diameter and hangs like a umbel at the ends of branches and stems. The gun is about 4mm long, and the gun pieces are arranged in 3-4 lines, and the outer pieces are line-shaped or narrow long oval shape. The corolla is cylindrical and the tip is divided into 5 parts. The fruit is aqueous and ripens from October to November and is about 1mm long. The flowers have soothing, detoxifying, and small swelling effects, so they are used for headaches and dizziness. It is planted for ornamental purposes and the young shoots are eaten as greens.
본 발명자들은 인지능력 개선 및 퇴행성 뇌질환 예방, 치료제를 개발하기 위하여 연구하던 중 산국이 기억력 저하 예방 효과, 아세틸콜린에스터라제 저해 효과, 아밀로이드 단백질 섬유화 저해 효과, 산화질소 생성 저해 효과 및 NMDA 수용체 저해 효과가 우수함을 확인함으로써 상기 산국 추출물을 인지능력 개선 및 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물의 유효성분으로 유용하게 사용될 수 있음을 밝혀 본 발명을 완성하였다.The present inventors were conducting research to improve cognitive ability, prevent degenerative brain disease, and develop therapeutic agents, while sanguin was studied to prevent memory loss, acetylcholinesterase inhibitory effect, amyloid protein fibrosis inhibitory effect, nitric oxide production inhibitory effect, and NMDA receptor inhibition. By confirming that the effect is excellent, the present invention was completed by revealing that the sanguk extract can be usefully used as an active ingredient in a pharmaceutical composition for improving cognitive ability and preventing or treating degenerative brain disease.
본 발명의 목적은 산국 추출물(Dendranthema boreale)을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating degenerative brain disease comprising an extract of sanguk (Dendranthema boreale) as an active ingredient.
또한, 본 발명의 다른 목적은 산국 추출물을 유효성분으로 포함하는 인지능력 개선용 약학적 조성물을 제공하는 것이다.In addition, it is another object of the present invention to provide a pharmaceutical composition for improving cognitive ability comprising an extract of wild ginseng as an active ingredient.
또한, 본 발명의 또 다른 목적은 산국 추출물을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a food composition for preventing or improving degenerative brain disease comprising an extract of wild ginseng as an active ingredient.
또한, 본 발명의 또 다른 목적은 산국 추출물을 유효성분으로 포함하는 인지능력 개선용 식품조성물을 제공하는 것이다. In addition, another object of the present invention is to provide a food composition for improving cognitive ability comprising an extract of wild ginseng as an active ingredient.
상기의 목적을 달성하기 위하여, In order to achieve the above object,
본 발명은 산국 추출물(Dendranthema boreale)을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating degenerative brain disease comprising an extract of sanguk (Dendranthema boreale) as an active ingredient.
또한, 본 발명은 산국 추출물을 유효성분으로 포함하는 인지능력 개선용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for improving cognitive ability comprising an extract of wild ginseng as an active ingredient.
또한, 본 발명은 산국 추출물을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving degenerative brain disease, comprising the extract of wild ginseng as an active ingredient.
또한, 본 발명은 산국 추출물을 유효성분으로 포함하는 인지능력 개선용 식품조성물을 제공한다.In addition, the present invention provides a food composition for improving cognitive ability comprising the extract of wild ginseng as an active ingredient.
본 발명에 따른 산국 추출물은 우수한 기억력 저하 예방 효과, 아세틸콜린에스터라제 저해 효과, 아밀로이드 단백질 섬유화 저해 효과, 산화질소 생성 저해 효과 및 NMDA 수용체 저해 효과를 가진다.Sanguk extract according to the present invention has an excellent memory loss prevention effect, acetylcholinesterase inhibitory effect, amyloid protein fibrosis inhibitory effect, nitric oxide production inhibitory effect, and NMDA receptor inhibitory effect.
도 1은 산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 Y-maze 시험을 수행한 결과를 나타낸 도이다.
도 2는 산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 수동회피시험을 수행한 결과를 나타낸 도이다.
도 3은 산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 수중미로시험을 수행한 결과를 나타낸 도이다.
도 4는 마우스 해마에서 ERK/CREB 발현을 웨스턴블랏을 통해 분석한 결과를 나타낸 도이다.
도 5는 산국 추출물의 아세틸콜린에스터라제 저해 활성을 나타낸 도이다.
도 6은 산국 추출물의 아밀로이드 단백질 섬유화 저해 활성을 나타낸 도이다.
도 7은 산국 추출물의 BV2세포에서의 산화질소 저해 활성을 나타낸 도이다.
도 8은 산국 추출물의 BV2세포에서의 세포 증식 효과를 나타낸 도이다. 1 is a diagram showing the results of performing the Y-maze test to confirm the memory loss prevention effect of wild ginseng extract.
Figure 2 is a view showing the results of performing a passive avoidance test to confirm the effect of preventing memory deterioration of wild ginseng extract.
Figure 3 is a view showing the results of performing the water maze test to confirm the memory loss prevention effect of wild ginseng extract.
4 is a diagram showing the results of analysis of ERK/CREB expression in mouse hippocampus through western blot.
Figure 5 is a diagram showing the acetylcholinesterase inhibitory activity of sanguk extract.
Figure 6 is a diagram showing the amyloid protein fibrosis inhibitory activity of sanguk extract.
Figure 7 is a diagram showing the nitric oxide inhibitory activity in BV2 cells of sanguk extract.
8 is a diagram showing the cell proliferation effect in BV2 cells of the extract of wild ginseng.
이하, 첨부된 도면을 참조하여 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다. Hereinafter, the present invention will be described in detail as an embodiment of the present invention with reference to the accompanying drawings. However, the following embodiments are presented as examples of the present invention, and when it is determined that detailed descriptions of well-known techniques or configurations known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted, and , the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the scope of equivalents interpreted therefrom and the description of the claims to be described later.
또한, 본 발명에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서, 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, the terms used in the present invention (terminology) are terms used to properly express the preferred embodiment of the present invention, which may vary according to the intention of the user or operator, or customs in the field to which the present invention belongs. Accordingly, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 발명에서 사용되는 모든 기술용어는 달리 정의되지 않는 이상 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 도입된다.Unless otherwise defined, all technical terms used in the present invention have the meanings commonly understood by those skilled in the art in the relevant field of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. The contents of all publications herein incorporated by reference are incorporated herein by reference.
본 발명은 산국 추출물(Dendranthema boreale)을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating degenerative brain disease comprising an extract of sanguk (Dendranthema boreale) as an active ingredient.
상기 퇴행성 뇌질환은 알츠하이머병(Alzheimer disease), 픽병(Pick disease), 파킨슨병(Parkinson's disease), 루게릭병(amyotrophic lateral sclerosis) 및 헌팅턴병(Huntington's disease) 중에서 선택된 어느 하나일 수 있다.The degenerative brain disease may be any one selected from Alzheimer's disease, Pick disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.
본 발명에 있어서, 상기 산국 추출물은 산국의 지상부, 꽃 또는 잎 중에서 선택된 어느 하나의 부위를 사용하여 추출될 수 있으나, 상술한 부위들 중에서도 산국의 지상부로부터 추출된 추출물이 기억력 저하 예방 효과, 아세틸콜린에스터라제 저해 효과, 아밀로이드 단백질 섬유화 저해 효과, 산화질소 생성 저해 효과 및 NMDA 수용체 저해 효과가 더 우수할 수 있다.In the present invention, the wild ginseng extract can be extracted using any one part selected from the above-mentioned parts, flowers or leaves of wild ginseng. The esterase inhibitory effect, the amyloid protein fibrosis inhibitory effect, the nitric oxide production inhibitory effect, and the NMDA receptor inhibitory effect may be superior.
본 발명에서 사용되는 용어 "추출물(extract)"은 산국을 적절한 추출용매로 추출하고 용매를 증발시켜 농축한 제제를 의미하는 것으로, 이에 제한되지는 않으나, 추출처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 이들의 조정제물 또는 정제물일 수 있다. 상기 산국 추출물은 통상의 기술분야에 공지된 일반적인 추출방법, 분리 및 정제방법을 이용하여 제조할 수 있다. 상기 추출방법으로는, 이에 제한되지는 않으나, 바람직하게 열탕 추출, 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 방법을 사용할 수 있다.As used in the present invention, the term "extract" refers to a preparation obtained by extracting wild yeast with an appropriate extraction solvent and evaporating the solvent, and is not limited thereto, but is not limited thereto, but an extract obtained by extraction treatment, a dilution of the extract, or It may be a dried product obtained by drying a concentrate or an extract, a crude product or a purified product thereof. The sanguk extract can be prepared using a general extraction method, separation and purification method known in the art. The extraction method is not limited thereto, but preferably methods such as hot water extraction, hot water extraction, cold extraction, reflux cooling extraction, or ultrasonic extraction may be used.
본 발명에 따른 추출물은 당업계에 공지된 추출 및 분리방법을 사용하여 천연으로부터 추출 및 분리하여 수득한 것을 사용할 수 있으며, 본 발명에서 정의된 "추출물"은 적절한 용매를 이용하여 산국으로부터 추출한 것이며, 예를 들어, 조추출물, 극성용매 가용 추출물 또는 비극성용매 가용 추출물을 모두 포함한다. 상기 산국으로부터 추출물을 추출하기 위한 적절한 용매로는 약학적으로 허용되는 유기용매라면 어느 것을 사용해도 무방하며, 물 또는 유기용매를 사용할 수 있으며, 이에 제한되지는 않으나, 예를 들어, 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있다. The extract according to the present invention may be obtained by extraction and separation from nature using extraction and separation methods known in the art, and "extract" as defined in the present invention is extracted from wild country using an appropriate solvent, For example, crude extracts, polar solvent-soluble extracts, or non-polar solvent-soluble extracts are included. As a suitable solvent for extracting the extract from the acid country, any pharmaceutically acceptable organic solvent may be used, and water or an organic solvent may be used, but is not limited thereto, for example, purified water, methanol ( methanol), ethanol, propanol, isopropanol, alcohol having 1 to 4 carbon atoms, including butanol, acetone, ether, benzene, chloroform ( Various solvents such as chloroform), ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or in combination.
추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있다. 또한, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. As the extraction method, any one of methods such as hot water extraction method, cold extraction method, reflux cooling extraction method, solvent extraction method, steam distillation method, ultrasonic extraction method, elution method, compression method, etc. can be selected and used. In addition, the desired extract may be further subjected to a conventional fractionation process, and may be purified using a conventional purification method.
본 발명의 추출물의 제조방법에는 제한이 없으며, 공지되어 있는 어떠한 방법도 이용될 수 있다. 예를 들면, 본 발명의 조성물에 포함되는 추출물은 상기한 열수 추출 또는 용매 추출법으로 추출된 1차 추출물을, 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말상태로 제조할 수 있다. There is no limitation on the method for preparing the extract of the present invention, and any known method may be used. For example, the extract included in the composition of the present invention may be prepared in a powder state by an additional process such as distillation under reduced pressure and freeze-drying or spray-drying the primary extract extracted by the hot water extraction or solvent extraction method described above.
본 발명에서 사용되는 용어 “조성물(composition)”은 본 발명의 산국 추출물에 희석제 또는 담체와 같은 다른 화학 성분들을 혼합한 혼합물을 의미한다.As used herein, the term “composition” refers to a mixture in which other chemical components such as a diluent or carrier are mixed with the extract of the present invention.
본 발명에서 사용되는 용어 “담체(vehicle)”는 세포 또는 조직 내로의 화합물의 부가를 용이하게 하는 화합물로 정의된다. 예를 들어, 디메틸술폭사이드(DMSO)는 생물체의 세포 또는 조직 내로의 많은 유기 화합물들의 투입을 용이하게 하는 통상 사용되는 담체이며, 이에 제한되지는 않는다.As used herein, the term “carrier” is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, but not limited to, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of living organisms.
본 발명에서 사용되는 용어 “희석제(diluent)”는 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키게 되는 물에서 희석되는 화합물로 정의된다. 버퍼 용액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상적으로 사용되는 버퍼 용액은 포스페이트 버퍼 식염수이며, 이는 인간 용액의 염상태를 모방하고 있기 때문이다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형하는 일은 드물다.As used herein, the term “diluent” is defined as a compound that not only stabilizes the biologically active form of the target compound, but is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.
본 발명에서, 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 퇴행성 뇌질환의 발생 및 이로 인한 합병증을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any action that suppresses or delays the occurrence of degenerative brain disease and complications resulting therefrom by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용된 용어 "치료"란 상기 약학적 조성물의 투여에 의해 퇴행성 뇌질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다. 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면, 대한의학협회 등에서 제시된 자료를 참조하여 본원의 조성물이 효과가 있는 질환의 정확한 기준을 알고, 개선, 향상 및 치료된 정도를 판단할 수 있을 것이다.As used herein, the term "treatment" refers to any action that improves or beneficially changes the symptoms of the suspected and onset subject of degenerative brain disease by administration of the pharmaceutical composition. Those of ordinary skill in the art to which the present invention pertains, with reference to the data presented in the Korean Medical Association, etc., know the exact criteria of the disease for which the composition of the present application is effective, and can determine the degree of improvement, improvement and treatment will be.
본 발명에서 사용되는 모든 기술용어는 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다.Unless otherwise defined, all technical terms used in the present invention have the meanings commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention.
본 발명의 약학 조성물에는 유효성분 이외에 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 면역성을 증가시킬 수 있다. The pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient. The adjuvant may be used without limitation as long as it is known in the art, and for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
본 발명에 따른 약학 조성물은 유효성분을 약학적으로 허용된 담체에 혼입시킨 형태로 제조될 수 있다. 여기서, 약학적으로 허용된 담체는 제약 분야에서 통상 사용되는 담체, 부형제 및 희석제를 포함한다. 본 발명의 약학 조성물에 이용할 수 있는 약학적으로 허용된 담체는 이들로 제한되는 것은 아니지만, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition according to the present invention may be prepared in a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories or sterile injection solutions according to conventional methods, respectively. .
제제화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 그러한 고형 제제는 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카르보네이트, 수크로스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 일반적으로 사용되는 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수용성용제, 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As the base of the suppository, witepsol, tween 61, cacao butter, laurin, glycerogelatin, etc. may be used.
본 발명에 따른 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
상기 약학 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화될 수 있다.The pharmaceutical composition may be formulated in various oral or parenteral dosage forms.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경질, 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 추가로 포함할 수 있다. 또한, 상기 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다.Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). In addition, the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid. or disintegrants such as sodium salts thereof or effervescent mixtures and/or absorbents, coloring, flavoring and sweetening agents. The formulation may be prepared by conventional mixing, granulating or coating methods.
비경구 투여용 제형의 대표적인 것은 주사용 제제이며, 주사용 제제의 용매로서 물, 링거액, 등장성 생리식염수 또는 현탁액을 들 수 있다. 상기 주사용 제제의 멸균 고정 오일은 용매 또는 현탁 매질로서 사용할 수 있으며 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있다. 상기 주사용 제제는 올레산과 같은 지방산을 사용할 수 있다. A typical example of a formulation for parenteral administration is an injection formulation, and examples of a solvent for the injection formulation include water, Ringer's solution, isotonic saline, or suspension. The sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose. The injection preparation may use a fatty acid such as oleic acid.
또한, 본 발명은 산국 추출물을 유효성분으로 포함하는 인지능력 개선용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for improving cognitive ability comprising an extract of wild ginseng as an active ingredient.
본 발명에서 인지능력 개선용 약학적 조성물은 기억력 장애 개선 또는 기억력 증진용 조성물과 동일한 의미로 사용될 수 있다.In the present invention, the pharmaceutical composition for improving cognitive ability may be used in the same meaning as the composition for improving memory impairment or improving memory.
또한, 본 발명은 산국 추출물을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving degenerative brain disease, comprising the extract of wild ginseng as an active ingredient.
상기 식품조성물의 종류에는 통상적으로 제조 및/또는 판매되는 것이라면 특별히 제한하지 않는다. 예를 들면, 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 등이 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료인 형태로 사용할 수 있고 통상적인 의미에서의 건강기능식품을 모두 포함한다.The type of the food composition is not particularly limited as long as it is conventionally manufactured and/or sold. For example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes, etc. It can be used in the form of pills, powders, granules, needles, tablets, capsules or beverages, and includes all health functional foods in a conventional sense.
상기 건강 음료 조성물은 본 발명에 따른 산국 추출물을 함유하는 것 외에는 액체성분에는 특별한 제한은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.The health drink composition is not particularly limited in the liquid component except for containing the extract according to the present invention, and may contain various flavoring agents or natural carbohydrates as an additional component like a conventional beverage.
통상적으로, 건강기능식품에 포함되는 산국 추출물의 양은 전체 식품 중량의 0.1~50 중량%, 바람직하게는 1~40 중량%로 포함될 수 있다.Typically, the amount of sanguk extract contained in the health functional food may be included in an amount of 0.1 to 50% by weight, preferably 1 to 40% by weight of the total food weight.
또한, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용할 수도 있다.In addition, in the case of long-term intake for the purpose of health and hygiene or health control, it may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
또한, 본 발명은 산국 추출물을 유효성분으로 포함하는 인지능력 개선용 식품조성물을 제공한다.In addition, the present invention provides a food composition for improving cognitive ability comprising the extract of wild ginseng as an active ingredient.
이하 하기 실시예를 통해 본 발명을 보다 상세히 설명한다. 그러나 하기 실시예는 본 발명의 기술적 사상의 내용과 범위를 쉽게 설명하기 위한 예시일 뿐, 이에 의해 본 발명의 기술적 범위가 한정되거나 변경되는 것은 아니다. 또한 이러한 예시에 기초하여 본 발명의 기술적 사상의 범위 안에서 다양한 변형과 변경이 가능함은 당업자에 의해 용이하게 결정될 수 있다.Hereinafter, the present invention will be described in more detail by way of Examples. However, the following examples are only examples for easily explaining the content and scope of the technical idea of the present invention, and thereby the technical scope of the present invention is not limited or changed. In addition, it can be easily determined by those skilled in the art that various modifications and changes are possible within the scope of the technical spirit of the present invention based on these examples.
<실시예 1><Example 1>
산국 추출물 제조production of wild ginseng extract
<1-1> 산국 조추출물의 제조<1-1> Preparation of wild country crude extract
산국의 지상부, 꽃 또는 잎을 85 ℃에서 환류냉각장치를 사용하여 70% 에탄올로 추출한 후 감압농축기에서 용매를 제거하고 추출물을 확보하였다. After extracting the above-ground parts, flowers, or leaves of sanguk with 70% ethanol using a reflux condenser at 85 °C, the solvent was removed in a vacuum concentrator and the extract was obtained.
상기 추출물은 하기의 동물실험 및 아세틸콜린에스테라제 저해능, Thioflavin T 분석 및 NMDAR 제어능 분석에 사용하였으며, 가속용매추출장치에서 메탄올을 이용하여 추출하고 농축기를 이용해 용매를 제거하여 BV2에서의 산화질소저해능(항염 활성) 및 세포증식율 분석에 사용하였다.The extract was used for the following animal experiments, acetylcholinesterase inhibitory ability, Thioflavin T analysis, and NMDAR control ability analysis. It was used for the analysis of inhibitory ability (anti-inflammatory activity) and cell proliferation rate.
<1-2> 산국 잎 조추출물의 제조<1-2> Preparation of crude extract of wild ginseng leaves
산국 잎을 85 ℃에서 환류냉각장치를 사용하여 70% 에탄올로 추출한 후 감압농축기에서 용매를 제거하고 추출물을 확보하여 NMDAR 저해효과 분석에 사용하였다. After extracting the sanguk leaves with 70% ethanol using a reflux condenser at 85 °C, the solvent was removed in a vacuum concentrator, and the extract was obtained and used for the analysis of the NMDAR inhibitory effect.
<실험예 1><Experimental Example 1>
스코폴라민(Scopolamine) 유도 기억력 감퇴 동물모델을 이용한 산국 추출물의 기억력 저하 예방 효과 확인Scopolamine-induced memory loss Confirmation of memory loss prevention effect of wild ginseng extract using animal model
<1-1> 동물모델의 제작<1-1> Production of animal models
산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 4주령 수컷 ICR 마우스를 확보하여 1주일동안 순화한 후 실험에 사용하였다. 사육기간동안 사료와 물은 자유섭취하게 하였으며 사육실 온도는 23 ± 1℃, 습도 50 ± 5 %, 조명시간 07:00~19:00 (12시간 주기)로 환경을 유지하여 사육하였다.In order to confirm the memory loss prevention effect of sanguk extract, 4-week-old male ICR mice were obtained, acclimatized for 1 week, and then used in the experiment. Feed and water were allowed to be freely consumed during the breeding period, and the breeding room temperature was 23±1℃,
실험군당 총 7-10 수의 실험동물을 사용하였으며, 실험군은 산국 지상부 추출물을 경구 투여하고, 양성대조군은 도네페닐 5 mg/Kg를 경구 투여한 후 30분 뒤 스코폴라민 1 mg/Kg 를 복강 투여한 후 30분 뒤 행동실험을 진행하였다.A total of 7-10 experimental animals were used per experimental group, and the experimental group was orally administered an extract of wild ginseng extract, and the positive control group was orally administered 5 mg/Kg of donephenyl, followed by intraperitoneal administration of
<1-2> Y-maze test 결과<1-2> Y-maze test result
스코폴라민 유도 기억력 감퇴 동물모델에서 산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 Y-maze test를 실시하였다. A Y-maze test was performed to confirm the effect of scopolamine-induced memory decline in animal models of wild ginseng extract for memory loss prevention.
구체적으로는 Y-maze test법에 의해 변경행동력(alternation behavior)을 아래의 산출식에 의해 산출하였다.Specifically, by the Y-maze test method, alteration behavior was calculated by the formula below.
[식 1][Equation 1]
변경행동력 (%)= (실제 변경/총 출입횟수-2)×100Changed Action (%)= (Actual Change/Total Number of Access -2)×100
그 결과 도 1에 나타낸 바와 같이, 정상인 NOR군의 자발적 변경행동력은 81.4 ± 1.1%로 측정되었으며 스코폴라민의 투여로 인한 기억력이 손상된 대조군은 자발적 변경행동력이 48.5 ± 0.8%로 나타나, NOR군과 비교하여 유의적으로 감소하였음을 확인하였다. As a result, as shown in FIG. 1, the spontaneous altering behavior of the normal NOR group was measured to be 81.4 ± 1.1%, and the control group whose memory was impaired due to the administration of scopolamine showed 48.5 ± 0.8% of the spontaneous altering behavior, compared with the NOR group. Thus, it was confirmed that there was a significant decrease.
한편, 산국 추출물을 50, 100 또는 200 ㎎/kg 용량으로 경구 투여한 후 스코폴라민을 복강 투여한 실험군에서는 자발적 변경행동력이 각각 57.2 ± 0.6%, 62.0 ± 0.7%, 70.3 ± 0.9%로 나타나 대조군과 비교하여 유의적으로 증가하는 것을 확인하였다. On the other hand, in the experimental group in which scopolamine was administered orally after oral administration of sanguk extract at a dose of 50, 100 or 200 mg/kg, the spontaneous altering behavior was 57.2 ± 0.6%, 62.0 ± 0.7%, and 70.3 ± 0.9%, respectively, in the control group. It was confirmed that there was a significant increase compared to .
<1-3> 수동회피실험 (Passive avoidance test)<1-3> Passive avoidance test
산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 스코폴라민 (1 ㎎/kg, i.p.)을 투여한 기억력 감퇴 동물모델을 이용하여 수동회피 측정 장치를 이용하여 확인하였으며 수동회피실험을 통해 retention trial을 측정하였다.In order to confirm the memory loss prevention effect of wild ginseng extract, it was confirmed using a passive avoidance measuring device using an animal model of memory loss administered with scopolamine (1 mg/kg, ip), and a retention trial was measured through a manual avoidance experiment. did.
그 결과 도 2에 나타낸 바와 같이, 실험 둘째 날 시행한 시험에서 정상인 NOR군의 step-through latency는 33.1 ± 4.6초, 스코폴라민의 투여로 인한 기억력이 손상된 대조군은 25.3 ± 5.0초로 NOR군과 비교하여 유의적으로 감소하였으나, 산국 추출물을 50, 100 또는 200 ㎎/kg 용량으로 경구 투여한 후 스코폴라민을 복강 투여한 실험군에서 step-through latency는 각각 105.0 ± 7.8초, 176.6 ± 8.1초, 230.7 ± 11.8초로 나타나 대조군과 비교하여 유의적으로 증가함을 확인하였다. As a result, as shown in Figure 2, the step-through latency of the normal NOR group in the test conducted on the second day of the experiment was 33.1 ± 4.6 seconds, and the control group, whose memory was impaired due to administration of scopolamine, was 25.3 ± 5.0 seconds, compared with the NOR group. Although significantly decreased, step-through latency was 105.0 ± 7.8 seconds, 176.6 ± 8.1 seconds, and 230.7 ± It was confirmed that it appeared as 11.8 seconds and significantly increased compared to the control group.
<1-4> 수중미로실험 (Morris water-maze test)<1-4> Morris water-maze test
스코폴라민 유도 기억력 감퇴 동물모델에서 산국 추출물의 기억력 저하 예방 효과를 확인하기 위하여 수중미로실험을 실시하여 플랫폼이 있던 구역에 머무르는 시간을 측정하였다.In order to confirm the effect of sanguk extract to prevent memory deterioration in scopolamine-induced memory loss animal model, an underwater maze experiment was conducted to measure the time spent in the area where the platform was.
그 결과 도 3a에 나타낸 바와 같이, Morris 수중미로 학습에서 4일째에는 플랫폼에 도달하는데 소요되는 시간이 집단 간 유의성 있는 차이를 보였다. 이에 측정일에 따른 그룹간의 사후검정 결과, 2일째부터 스코폴라민 투여군에서 Normal군에 비해 학습능력이 현저히 저하되었으며 마찬가지로 산국 추출물 200 ㎎/kg 투여군에서도 학습수행에 유의한 증진 효과가 관찰되었다. 즉 2일째부터 플랫폼에 도달하는 소요시간이 스코폴라민 투여군에 비해 통계적으로 유의하게 감소하였으며, 양성대조군인 DNPZ 투여군 역시 비슷한 수준으로 감소하는 것을 확인하였다. As a result, as shown in Fig. 3a, on the 4th day in the Morris water maze learning, the time required to reach the platform showed a significant difference between groups. As a result of the post-hoc test between groups according to the measurement day, the learning ability was significantly decreased in the scopolamine-administered group compared to the normal group from the second day, and similarly, a significant improvement effect on learning performance was observed in the group administered with
또한 도 3b에 나타낸 바와 같이, Morris 수중미로 학습에서 마지막 날인 제 5일째 기억검사를 시행하기 위해 플랫폼을 제거한 후 60초간 자유 수영을 시행하고 이를 Ethovision program을 통하여 총시간 중 플랫폼에 있었던 4분원에 머무는 시간을 측정하고 플랫폼에 머무르는 정도에 대한 집단별 사후검정 결과, NOR군은 14.8 ± 0.6초인 반면 스코폴라민 투여군은 10.1 ± 0.9초로 유의하게 감소하였고, 산국 추출물 200 ㎎/kg 투여군에서는 12.9 ± 0.6초로 스코폴라민 손상군에 비해 유의성 있는 증가를 확인하였다. 양성대조군인 DNPZ군 역시 12.9 ± 0.8초로 증가하는 것을 확인하였으며, 이는 산국 추출물이 장기 및 공간 기억을 개선하는 것을 의미한다. In addition, as shown in Figure 3b, after removing the platform to perform the memory test on the 5th day, the last day in Morris water maze learning, free swimming was performed for 60 seconds, and this was done through the Ethovision program to stay in the quadrant that was on the platform during the total time. As a result of the group post-hoc test on the time measurement and the degree of staying on the platform, the NOR group was 14.8 ± 0.6 seconds, whereas the scopolamine administered group significantly decreased to 10.1 ± 0.9 seconds, and in the 200 mg/kg wild ginseng extract group, it was 12.9 ± 0.6 seconds. A significant increase was confirmed compared to the scopolamine injured group. It was confirmed that the positive control group, DNPZ group, also increased to 12.9 ± 0.8 sec, which means that the extract of wild ginseng improved long-term and spatial memory.
<실험예 2><Experimental Example 2>
ERK/CREB 단백질 발현양 확인ERK/CREB protein expression level confirmation
기억과 관련된 기전의 하나인 ERK/CREB 경로에서의 기억개선 효과를 확인하기 위하여 웨스턴블랏을 실시하였다. Western blot was performed to confirm the memory improvement effect in the ERK/CREB pathway, which is one of the mechanisms related to memory.
구체적으로 실험동물을 희생한 후 적출한 해마를 차가운 Lysis buffer로 균질화하고 이후 4 ℃에서 20분간 원심분리하여 상등액을 취하고 BCA protein assay kit로 단백질 함량을 정량한 뒤 40 ㎍의 단백질을 SDS-PAGE에서 전기영동하였다. 전개시킨 gel을 PVDF 멤브레인으로 옮긴 후 5% skim milk로 비특이적인 결합을 blocking 시켰다. 1차 항체를 1:1000 희석배율로 처리하여 overnight 시키고 0.1% Tween-20이 첨가된 PBST로 세척 후 2차 항체를 상온에서 1시간 붙인 다음 다시 PBST로 세척하여 ECL 용액과 반응시켜 LAS mini4000으로 촬영하였다.Specifically, after sacrificing the experimental animals, the harvested hippocampus was homogenized with cold lysis buffer, and then centrifuged at 4 °C for 20 minutes to take the supernatant and quantify the protein content with the BCA protein assay kit. electrophoresis. After the developed gel was transferred to the PVDF membrane, non-specific binding was blocked with 5% skim milk. The primary antibody was treated at a dilution ratio of 1:1000 and left overnight. After washing with PBST containing 0.1% Tween-20, the secondary antibody was applied at room temperature for 1 hour, washed again with PBST, reacted with ECL solution, and photographed with LAS mini4000. did.
그 결과 도 4에 나타낸 바와 같이 스코폴라민을 투여한 대조군에서는 단백질의 발현양이 감소하는 것이 확인되었으나 산국 추출물 200 ㎎/kg 투여군에서는 감소되었던 단백질이 증가하는 것을 확인하였다. 따라서 본 발명의 산국 추출물이 ERK/CREB 경로를 통해 기억 개선효과를 가짐을 확인하였다.As a result, as shown in FIG. 4 , it was confirmed that the expression level of the protein was decreased in the control group administered with scopolamine, but the decreased protein was increased in the group administered with sanguk extract 200 mg/kg. Therefore, it was confirmed that the wild yeast extract of the present invention has an effect of improving memory through the ERK/CREB pathway.
<실험예 3><Experimental Example 3>
산국 지상부 추출물의 아세틸콜린 분해효소(AchE) 저해활성 확인Acetylcholine degrading enzyme (AchE) inhibitory activity of wild pickled radish extract
상기 실험예 1의 동물실험에 사용한 것과 동일한 산국 지상부 추출물을 인산 완충용액 (100 mM, pH 8.0)으로 200 ㎍/㎖의 농도가 되도록 희석하고 희석한 시료 1.5 ㎖, 완충용액 1.5 ㎖, 75 mM acetylthiocholine iodide 용액 20 ㎕ 및 Ellman 시약 (buffered Ellman's reagent: 10mM DTNB (5.5'-dithiobis- (2-nitrobenzoic acid)) 및 17.85 mM NaHCO3로 구성된 용액) 100㎕를 혼합하여 25℃에서 10분간 반응 후, 제조된 AchE시료를 첨가하고 30초 간격으로 410nm에서 흡광도를 측정 (5분간 측정)하였다. 이때, 대조군으로는 아세틸콜린에스터라제 시료를 첨가하지 않고 saline을 첨가한 반응액을 사용하였으며 acetylthiocholine iodide를 첨가하지 않고 반응시켜 흡광도를 측정하였다.The same as that used in the animal experiment of Experimental Example 1, the same as that used in the animal experiment, was diluted with a phosphate buffer solution (100 mM, pH 8.0) to a concentration of 200 μg/ml, diluted sample 1.5 ml, buffer solution 1.5 ml, 75
상기와 같이 처리하여 검색 대상물질과 효소활성 측정용 시약 사이의 비특이적 반응은 일어나지 않음을 확인하였으며, 검색 대상물질을 첨가하지 않은 반응액의 아세틸콜린에스터라제 활성도를 100%으로 하여 각 검색 대상물질을 첨가한 반응액의 아세틸콜린에스터라제 활성 저해도를 확인하였다. It was confirmed that a non-specific reaction between the search target substance and the reagent for measuring enzyme activity did not occur by the treatment as described above. The degree of inhibition of acetylcholinesterase activity of the reaction solution to which was added was confirmed.
그 결과 도 5에 나타낸 바와 같이, 산국 추출물 투여군에서 용량 의존적으로 아세틸콜린에스터라제 활성을 억제하였으며 IC50값은 6.617 μg/ml이고, 양성대조군으로 사용한 도네페질의 IC50값은 0.083 μg/ml로 나타나 기억력 개선 작용기전은 아세틸콜린에스터라제 활성 억제로 인한 것임을 확인하였다.As a result, as shown in Figure 5, in Country of origin extract treated group dose-dependently acetylcholinesterase inhibited activity IC 50 value was 6.617 μg / ml, donepezil IC 50 value used as the positive control is 0.083 μg / ml As a result, it was confirmed that the mechanism of action for improving memory is due to inhibition of acetylcholinesterase activity.
<실험예 4><Experimental Example 4>
산국 지상부 추출물의 아밀로이드 단백질 섬유화 억제 효과 확인(Thioflavin T assay)Confirmation of the amyloid protein fibrosis inhibitory effect of wild pickled radish extract (Thioflavin T assay)
Thioflavin T(ThT)는 benzothiazole dye로 아밀로이드 단백질의 양을 확인하는데 형광의 농도를 이용한다. 이에 Beta-amyloid(Aβ1-42)의 균질한 구조를 깨기 위하여 수소 결합을 깨는 1,1,1,3,3,3-hexafluoro-2-propanol(HFIP)에 1 ㎎/㎖ 농도로 녹여 37℃에서 6시간 둔 후 100 ㎕씩 분주하여 4℃에 보관하며 실험에 사용하였다. 그 후 PBS에 건조한 Aβ1-42를 50 μM, ThT를 1 mM 농도로 녹이고, ThT는 사용 전 0.22 μm 필터 후 사용하였다. Aβ1-42를 ThT 용액과 시료와 혼합하였고 최종 ThT 용액의 농도는 45 μM로 하였으며 대조군으로 자유 Aβ1-42를 사용하였으며 10분 뒤 Ex 450 nm, Em 480 nm에서 흡광도를 측정하였다.Thioflavin T (ThT) is a benzothiazole dye that uses the concentration of fluorescence to check the amount of amyloid protein. Therefore, in order to break the homogeneous structure of Beta-amyloid (Aβ1-42), it was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at a concentration of 1 mg/ml and dissolved at 37℃ After 6 hours in the refrigerator, 100 μl of each was dispensed and stored at 4° C. for use in the experiment. After that, 50 μM of dried Aβ1-42 and 1 mM of ThT were dissolved in PBS, and ThT was used after 0.22 μm filter before use. Aβ1-42 was mixed with the ThT solution and the sample, and the final ThT solution concentration was 45 μM. Free Aβ1-42 was used as a control. After 10 minutes, absorbance was measured at Ex 450 nm and Em 480 nm.
그 결과 도 6에 나타낸 바와 같이, Aβ1-42를 단독 처리한 군의 ThT 형광값이 665.3 ± 4.5%로 나타난 반면, 산국 추출물을 처리한 군은 168.4 ± 2.3%로 Aβ1-42 단독 처리한 군과 비교하여 유의하게 감소하였고 양성대조군으로 사용한 curcumin 역시 239.3 ± 4.5%로 유의하게 감소하는 것을 확인하여 산국 추출물이 Aβ1-42 단백질의 섬유화를 억제하는 것을 확인하였다. As a result, as shown in FIG. 6 , the ThT fluorescence value of the group treated with Aβ1-42 alone was 665.3 ± 4.5%, whereas the group treated with sanguk extract was 168.4 ± 2.3%, compared with the group treated with Aβ1-42 alone. Comparatively, it was significantly reduced, and curcumin used as a positive control was also significantly reduced to 239.3 ± 4.5%, confirming that sanguk extract inhibited the fibrosis of Aβ1-42 protein.
<실험예 5><Experimental Example 5>
산국 지상부 추출물의 산화질소(NO) 생성저해 활성 및 세포 증식 효과 확인Confirmation of nitric oxide (NO) production inhibitory activity and cell proliferation effect of wild ginseng extract
먼저, 48 웰 플레이트에 BV2 microglia cell을 seeding한 후 CO2 배양기에서 24시간 배양한 뒤 시료처리하고 2시간 후 LPS (0.5 ㎍/㎖)를 처리하였다. 그 후 다시 24시간 후 반응된 media 50 ㎕를 96 웰 플레이트에 취해 1% sulfanilamide 및 0.1% NED (N-1-napthylnethylenediamine dihydrochloride)를 각 50 ㎕가하여 520 nm에서 흡광도를 측정하였다.First, after seeding BV2 microglia cells in a 48-well plate, the samples were cultured for 24 hours in a CO 2 incubator, and then treated with LPS (0.5 μg/ml) after 2 hours. Then, after 24 hours, 50 μl of the reacted media was taken in a 96-well plate, and 50 μl of each of 1% sulfanilamide and 0.1% NED (N-1-napthylnethylenediamine dihydrochloride) was added to measure the absorbance at 520 nm.
상기와 같은 과정으로, 처리된 표준물질로부터 얻어진 검량선을 적용하여 nitrite 함량 (μM)을 산출하였고, 상등액을 제거하고 남은 세포에 대해 MTT 시약을 처리하여 1시간동안 CO2 배양기에서 반응시킨 후 540 nm에서 흡광도를 측정하여 세포증식효과를 분석하였다. In the same manner as above, the nitrite content (μM) was calculated by applying the calibration curve obtained from the treated standard material, the supernatant was removed and the remaining cells were treated with MTT reagent and reacted in a CO 2 incubator for 1 hour at 540 nm By measuring the absorbance in the cell proliferation effect was analyzed.
그 결과 도 7에 나타낸 바와 같이 산국 지상부 추출물은 LPS로 유도된 BV2 세포에서 농도 의존적으로 산화질소의 생성을 저해하였으며, 도 8에 나타낸 바와 같이 25 ㎍/㎖의 처리농도 이하에서는 비교적 높은 세포증식효과를 나타내었다.As a result, as shown in FIG. 7 , the above extract of wild pickled radish inhibited the production of nitric oxide in a concentration-dependent manner in LPS-induced BV2 cells. was shown.
<실험예 6><Experimental Example 6>
산국 추출물의 NMDA 수용체에 대한 저해 효과 확인Confirmation of inhibitory effect on NMDA receptor of wild ginseng extract
4°C에서 1 mg 단백질에 해당하는 뇌피질막 균질액을 5 nM [3H]CGP39653와 함께 5mM Tris-HCl(pH7.7), 10mMEDTA-Tris와 함께 본 발명의 산국 추출물을 포함 또는 포함하지 않는 조건에서 60 분간 배양하였으며, 비특이적 결합을 100 μM L-glutamate 존재 하에 결정하였다. 배양 후, 시료를 진공 하에 glass fiber filters (GF/B, Whatman)로 신속히 여과하고, 48-sample cell harvester (Brandel)를 사용하여 ice-cold incubation buffer로 여러 차례 세척한 후 여과액은 건조시키고 a scintillation cocktail (Formula 989, Packard)을 사용하여 scintillation counter (LS series, Beckman)에서 radioactivity를 계산하였다. 상기 실험 결과는 control radioligand specific binding에 대한 % 저해율로서 나타내었으며 standard reference compound는 CGS 19755을 사용하였다.At 4 °C, the cortical membrane homogenate corresponding to 1 mg protein was prepared with or without 5 mM Tris-HCl (pH7.7) with 5 nM [3H]CGP39653 and 10 mM MEDTA-Tris with or without the wild ginseng extract of the present invention. Conditions were incubated for 60 minutes, and non-specific binding was determined in the presence of 100 μM L-glutamate. After incubation, the sample was quickly filtered with glass fiber filters (GF/B, Whatman) under vacuum, washed several times with ice-cold incubation buffer using a 48-sample cell harvester (Brandel), and the filtrate was dried and a Radioactivity was calculated in a scintillation counter (LS series, Beckman) using a scintillation cocktail (Formula 989, Packard). The experimental results were shown as % inhibition for control radioligand specific binding, and CGS 19755 was used as a standard reference compound.
그 결과 하기 표 1에 나타낸 바와 같이 산국 꽃 및 지상부 추출물을 50 ㎍/㎖ 농도에서 처리한 결과 27~28%의 저해효과를 나타내었으며 표 2에 나타낸 바와 같이 산국 잎 추출물을 25, 50, 100, 200 ㎍/㎖의 농도로 처리한 결과에서는 14.7 ~45.2%의 NMDA 수용체에 대한 저해효과를 확인하였다. As a result, as shown in Table 1 below, as a result of treating wild ginseng flower and above-ground part extract at a concentration of 50 μg/ml, an inhibitory effect of 27 to 28% was exhibited. In the result of treatment with a concentration of 200 ㎍ / ㎖ confirmed the inhibitory effect on the NMDA receptor of 14.7 ~ 45.2%.
Claims (8)
상기 산국 지상부의 70% 에탄올 추출물은 기억력 저하 예방 효과, 아세틸콜린에스터라제 저해 효과, 아밀로이드 단백질 섬유화 저해 효과, 산화질소 생성 저해 효과 및 NMDA 수용체 저해 효과를 갖는 것을 특징으로 하는 알츠하이머치매(Alzheimer's dementia) 예방 또는 치료용 약학적 조성물.The method of claim 1,
Alzheimer's dementia, characterized in that the 70% ethanol extract of the above-ground part of the wild country has a memory loss prevention effect, an acetylcholinesterase inhibitory effect, an amyloid protein fibrosis inhibitory effect, an nitric oxide production inhibitory effect, and an NMDA receptor inhibitory effect. A pharmaceutical composition for prophylaxis or treatment.
A food composition for improving memory, comprising 70% ethanol extract of the above-ground part of the wild country as an active ingredient.
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| MPTP에 의해 유도된 생쥐의 신경독성에 대한 산국 추출물의 항산화 작용, 대한동의생리학회, 27(1), pp.49-56(2013.) 1부.* |
| 콜린 에스테라제 저해효과 보유 식물 추출물 탐색, Korean J. Plant Res. 31(5):433-452(2018) |
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