KR101631589B1 - Pharmaceutical composition for preventing or treating neurodegenerative diseases comprising compounds isolated from Daphne genkwa extract - Google Patents
Pharmaceutical composition for preventing or treating neurodegenerative diseases comprising compounds isolated from Daphne genkwa extract Download PDFInfo
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- KR101631589B1 KR101631589B1 KR1020110123848A KR20110123848A KR101631589B1 KR 101631589 B1 KR101631589 B1 KR 101631589B1 KR 1020110123848 A KR1020110123848 A KR 1020110123848A KR 20110123848 A KR20110123848 A KR 20110123848A KR 101631589 B1 KR101631589 B1 KR 101631589B1
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
본 발명은 팥꽃나무 추출물로부터 분리된 화합물인 겐콰닌 N(Genkwanine N) 또는 유안후아신(Yuanhuacine), 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 신경퇴행성 질환 예방 또는 치료용 약학적 조성물에 관한 것이다. 보다 구체적으로 본 발명은 팥꽃나무의 유기용매 추출물로부터 분리된 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 치료용 약학적 조성물, Nurr1 기능 장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물, Nurr1 활성화 조성물 및 상기 Genkwanine N 또는 Yuanhuacine을 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 개선용 기능성 식품 첨가물에 관한 것이다.
본 발명의 팥꽃나무 추출물로부터 분리한 화합물은 천연물 유래 화합물로서 별다른 부작용을 나타내지 않으면서도, 신경손상에 의한 Nurr1 단백질 활성 억제를 회복시키는데 우수한 효과를 나타냄으로써 Nurr1 단백질의 활성 억제로 인해 유발되는 파킨슨병을 비롯한 신경퇴행성 질환을 예방 또는 치료할 수 있다.The present invention relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising, as an active ingredient, Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof, . More particularly, the present invention relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof, isolated from an organic solvent extract of Red Bean Blossom as an active ingredient, a pharmaceutical composition for treating Nurr1 dysfunction , A Nurr1 activating composition, and a functional food additive for preventing or ameliorating a neurodegenerative disease comprising Genkwanine N or Yuanhuacine as an active ingredient.
The compound of the present invention isolated from the red bean curd extract has excellent effects in restoring the inhibition of Nurr1 protein activity due to nerve damage without showing any side effects as a natural product compound. Thus, it is possible to prevent Parkinson's disease caused by inhibition of Nurr1 protein activity Can be prevented or treated.
Description
본 발명은 팥꽃나무 추출물로부터 분리된 화합물인 겐콰닌 N(Genkwanine N) 또는 유안후아신(Yuanhuacine), 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 신경퇴행성 질환 예방 또는 치료용 약학적 조성물에 관한 것이다. 보다 구체적으로 본 발명은 팥꽃나무의 유기용매 추출물로부터 분리된 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 치료용 약학적 조성물, Nurr1 기능 장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물, Nurr1 활성화 조성물 및 상기 Genkwanine N 또는 Yuanhuacine을 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 개선용 기능성 식품 첨가물에 관한 것이다.
The present invention relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising, as an active ingredient, Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof, . More particularly, the present invention relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof, isolated from an organic solvent extract of Red Bean Blossom as an active ingredient, a pharmaceutical composition for treating Nurr1 dysfunction , A Nurr1 activating composition, and a functional food additive for preventing or ameliorating a neurodegenerative disease comprising Genkwanine N or Yuanhuacine as an active ingredient.
신경퇴행성 질환(neurodegenerative diseases)은 신경세포가 퇴화하고, 기능을 잃고, 그리고 종종 사멸하는 경우의 증상들과 관련된다. 이들은 주로 진행성이기 때문에, 신경퇴행성 질환의 결과는 종종 대단히 파괴적이다. 신경퇴행성 질환을 가진 환자들은 인지(cognitive) 또는 운동(motor) 능력에 있어서의 극심한 퇴화를 겪을 수 있다. 결과적으로, 그들의 삶의 질 및 삶에 대한 기대는 현저히 감소될 수 있다. 인간에게 있어서, 이들 질환은 파킨슨병(Parkinson's disease; PD), 알츠하이머병(Alzheimer's disease; AD), 루게릭병(amyotrophic lateral sclerosis; ALS), 헌팅턴병(Huntington's disease; HD), 전측두엽 치매(Fronto-Temporal Dementia), 피질-기저핵 퇴행증(Cortico Basal Degeneration), 진행성 핵상마비(progressive supranuclear palsy; PSP), 및 다른 질병들을 포함한다.
Neurodegenerative diseases are associated with symptoms of neuronal degeneration, loss of function, and often death. Because they are primarily progressive, the consequences of neurodegenerative diseases are often very devastating. Patients with neurodegenerative diseases may experience extreme degeneration in cognitive or motor ability. As a result, their quality of life and their expectations for life can be significantly reduced. In humans, these diseases include Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Fronto-Temporal dementia Dementia, Cortico Basal Degeneration, progressive supranuclear palsy (PSP), and other diseases.
한편 상당수의 신경퇴행성 질환에는 Nurr1(nuclear receptor related 1) 단백질이 관련된 것으로 알려져 있다. 상기 Nurr1은 NR4A2(nuclear receptor subfamily 4, group A, member 2)라고도 알려져 있는 핵수용체 관련 1 단백질을 의미하며, 이는 사람의 NR4A2 유전자에 의해 암호화되는 것으로 알려져 있다. 비록, 상기 Nurr1 단백질은 고아 핵 수용체(orphan nuclear receptor)로서, 아직까지는 상기 단백질에 대한 리간드가 규명되어 있지 않지만, 상기 Nurr1은 세포 내 전사인자의 핵 수용체 패밀리에 속하는 단백질로서, 뇌에서 도파민 시스템(dopaminergic system)을 유지하는 핵심적인 역할을 수행함이 규명되었다. 상기 Nurr1 또는 NR4A2 유전자에 이상이 발생하면, 도파민 시스템의 기능이 손상되어 파킨슨병을 유발시킬 뿐만 아니라, 류마티스 관절염, 정신분열증, 조울증 등의 광범위한 염증성 및 신경성 질환의 원인이 되는 것으로 알려져 있다.On the other hand, a number of neurodegenerative diseases are known to involve Nurr1 (nuclear receptor related 1) protein. The Nurr1 refers to a nuclear receptor-related protein, also known as NR4A2 (
상기 Nurr1의 기능장애에 의하여 유발되는 대표적인 신경퇴행성 질환인 파킨슨병은 근육운동을 통제하는 뇌신경세포에 영향을 미치는 만성 진행성 신경질환으로서, 중뇌의 흑질(substantia nigra) 부위에 신경전달물질인 도파민을 만들어내는 세포가 갑자기 손상되거나, 퇴화되거나 또는 그 수가 크게 감소할 경우에 발생하는데, 상기 도파민은 신체의 운동을 용이하게 하기 위해 세포 사이에서 신호를 전달하기 위한 중요한 화학물질이기 때문에, 전형적으로 나타나는 떨림증(tremor), 경직(rigidity), 운동완서(bradykinesia), 자세의 불안정(postural instability) 및 언어능력 손상과 같은 운동성 질환 증상이 야기된다. 이처럼 도파민 생성세포가 손상되는 원인은 명확히 밝혀져 있지 않으나, 뇌의 동맥경화증, 일산화탄소 중독, 약물, 부갑상선 기능저하증 등에 의한 대사성, 외상성 뇌염 후유증 등이 관여하는 것으로 연구되고 있다.Parkinson's disease, which is a representative neurodegenerative disease caused by the dysfunction of Nurr1, is a chronic progressive neurological disease affecting the neuronal cell that regulates muscle movement, and it produces dopamine which is a neurotransmitter in the substantia nigra region of the midbrain Dopamine is an important chemical for transferring signals between cells in order to facilitate the movement of the body, so that the typical symptoms of dysphagia such as tremor, rigidity, bradykinesia, postural instability, and impaired language ability. The cause of dopaminergic cell damage is not clear yet, but it has been studied that it involves metabolic diseases such as cerebral arteriosclerosis, carbon monoxide poisoning, drugs, hypoparathyroidism, and traumatic encephalopathy complications.
이같은 파킨슨병의 치료를 위한 약물로서, 엘도파(l-dopa) 제제, 도파민 수용체 작용제, 항콜린 약제, 엘데프릴(Eldepryl=depreyl) 등이 알려져 있으며, 이들 약물들 대부분은 원인적인 치료가 아니라 증상을 조절하는 역할을 하는 것이며, 따라서 꾸준하게 지속적인 약물의 복용을 필요로 한다. 그러나, 이러한 약물들의 장기 투여는 약물 부작용의 문제점을 야기하게 된다. 예를 들어, 항콜린 약제들은 자율신경계 이상이나 정신기능의 이상 등이 나타날 수 있어 고령의 환자들에게 지속적으로 투여하는 것에 한계가 있다. 또한, 엘도파 제제의 경우 장기간 동안의 복용에 따라 점차적으로 효과가 떨어지고, 몸이 뒤틀리고 손이나 발이 저절로 움직이는 이상운동이 생기는 등의 부작용이 발생하게 된다.As drugs for the treatment of Parkinson's disease, there are known l-dopa drugs, dopamine receptor agonists, anticholinergic drugs, and Eldepryl = depreyl. Most of these drugs are not causal treatment, And therefore requires continuous and continuous drug use. However, the long-term administration of these drugs causes problems of drug side effects. For example, anticholinergic agents may have autonomic nervous system abnormalities or mental dysfunctions, which limits the continuous administration to older patients. In addition, in the case of the eldopa agent, side effects such as a gradual decrease in the effect due to long-term use, twisting of the body, abnormal movement in which the hands or feet move spontaneously occur, and the like.
이러한 부작용을 방지하기 위하여, 천연물로부터 유래한 파킨슨병의 치료제를 개발하려는 노력이 활발히 진행되고 있다. 예를 들어, 특허공개 제2001-0081188호에는 신경보호작용을 갖는 황금(Scutellariae Radix) 추출물을 유효성분으로 포함하는 파킨슨병 및 노인성 치매를 포함하는 뇌질환 등의 신경계 질환의 예방 및 치료용 조성물이 개시되어 있고, 특허공개 제2004-0012396호에는 백강잠 101A(Beauveria Bassiana 101A)의 추출물을 포함하는 파킨슨병 및 중풍과 같은 퇴행성 뇌질환 치료용 조성물이 개시되어 있으며, 특허공개 제2004-0029072호에는 웽구앙구오(wenguanguo) 껍질로부터 얻은 추출물을 포함하는 파킨슨병 치료용 약학적 조성물이 개시되어 있고, 특허공개 제2010-0060123호에는 생강 추출물 또는 쇼가올을 포함하는 파킨슨병의 예방 또는 치료용 약학적 조성물이 개시되어 있으며, 특허공개 제2010-0060949호에는 복숭아 잎 추출물을 유효성분으로 포함하는 파킨슨병 등의 질환의 예방 또는 치료에 사용되는 신경세포 보호용 조성물이 개시되어 있고, 특허공개 제2011-0013466호에는 포도씨 추출물 또는 이로부터 유래되는 하나 이상의 화합물을 유효성분으로 포함하는 파킨슨병 치료용 약학적 조성물이 개시되어 있다. 그러나, 이들 천연물로부터 유래된 성분은 부작용이 없는 대신 파킨슨병의 치료효율이 낮다는 단점이 있었다.
In order to prevent such side effects, efforts to develop a therapeutic agent for Parkinson's disease derived from natural products have been actively conducted. For example, Japanese Patent Application Laid-Open No. 2001-0081188 discloses a composition for prevention and treatment of neurological diseases such as Parkinson's disease comprising senescent protective action of Scutellariae Radix as an active ingredient and brain diseases including senile dementia And Patent Document No. 2004-0012396 discloses a composition for treating degenerative brain diseases such as Parkinson's disease and stroke including an extract of Beauveria Bassiana 101A. In Patent Publication No. 2004-0029072, Discloses a pharmaceutical composition for treating Parkinson's disease comprising an extract from a wenguanguo skin, and Patent Publication No. 2010-0060123 discloses a pharmaceutical composition for preventing or treating Parkinson's disease comprising ginger extract or showol And Patent Publication No. 2010-0060949 discloses a composition for preventing or preventing diseases such as Parkinson's disease comprising peach leaf extract as an active ingredient, And a composition for protecting nerve cells used in the treatment is disclosed, in Patent Publication No. 2011-0013466 discloses is a pharmaceutical composition for treating Parkinson's Disease disclosed comprising at least one compound derived from grape seed extract or an active ingredient therefrom. However, the components derived from these natural products have a disadvantage in that the treatment efficiency of Parkinson's disease is low, without side effects.
이에, 본 발명자들은 팥꽃나무(Daphne genkwa)의 줄기 및 뿌리로부터 유래된 추출물이 천연물로부터 유래되어 부작용이 없으면서도, Nurr1을 활성화시킴으로써, 도파민성 신경세포의 분화, 성장 및 유지를 증진시키고, 그 결과 Nurr1 기능장애에 의해 유발되는 파킨슨병을 비롯한 다양한 신경퇴행성 질환에 대한 치료효과가 우수함을 확인하였다. 나아가, 상기 팥꽃나무 추출물의 활성성분을 분석하여 추출물 중 Genkwanine N 및 Yuanhuacine 화합물이 Nurr1 단백질 활성화에 우수한 효과가 있음을 확인하고, 본 발명을 완성하게 되었다.
Thus, the present inventors have found that the extract derived from the stem and root of red bean flower (Daphne genkwa) is derived from a natural product, thereby enhancing the differentiation, growth and maintenance of dopaminergic neurons by activating Nurr1 without side effects, It has been confirmed that the therapeutic effect on various neurodegenerative diseases including Parkinson's disease induced by Nurr1 dysfunction is excellent. Further, by analyzing the active components of the above-mentioned red bean curd extract, it was confirmed that Genkwanine N and Yuanhuacine compounds among the extracts had an excellent effect on Nurr1 protein activation, thereby completing the present invention.
본 발명의 하나의 목적은 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 신경퇴행성 질환(neurodegenerative diseases)의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 목적은 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 Nurr1 기능 장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by Nurr1 dysfunction comprising Genkwanine N or Yuanhuacine or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 Genkwanine N 또는 Yuanhuacine을 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 개선용 기능성 식품 첨가물을 제공하는 것이다.Another object of the present invention is to provide a functional food additive for preventing or ameliorating a neurodegenerative disease comprising Genkwanine N or Yuanhuacine as an active ingredient.
본 발명의 또 다른 목적은 Genkwanine N 또는 Yuanhuacine을 유효성분으로 포함하는 Nurr1 활성화 조성물을 제공하는 것이다.
Another object of the present invention is to provide a Nurr1 activating composition comprising Genkwanine N or Yuanhuacine as an active ingredient.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 신경퇴행성 질환(neurodegenerative diseases)의 예방 또는 치료용 약학적 조성물을 제공한다.In one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising Genkwanine N or Yuanhuacine or a pharmaceutically acceptable salt thereof as an active ingredient do.
본 발명의 Genkwanine N은 하기 화학식 1로 표시되는 테르페노이드, 구체적으로는 다이테르펜 에스테르 화합물로서, 당업자에게 공지된 방법에 따라 제조될 수 있다. 예를 들어, Genkwanine N이 포함되어 있는 것으로 당업계에 공지된 식물로부터 극성 또는 비극성 용매를 사용하여 분리 정제할 수 있다. 또는 상업적으로 시판되는 화합물을 구입하거나 합성하여 제조할 수 있다. 바람직하게는 팥꽃나무로부터 추출, 분리할 수 있다.Genkwanine N of the present invention is a terpenoid represented by the following formula (1), specifically, a diterpene ester compound, which can be prepared by a method known to a person skilled in the art. For example, Genkwanine N can be isolated and purified from plants known in the art using polar or non-polar solvents. Or can be prepared by purchasing or synthesizing commercially available compounds. Preferably, it can be extracted and separated from red bean flower.
본 발명의 Yuanhuacine은 하기 화학식 2로 표시되는 테르페노이드, 구체적으로는 다이테르펜 에스테르 화합물로서, 당업자에게 공지된 방법에 따라 제조될 수 있다. 예를 들어, Yuanhuacine이 포함되어 있는 것으로 당업계에 공지된 식물로부터 극성 또는 비극성 용매를 사용하여 분리 정제할 수 있다. 또는 상업적으로 시판되는 화합물을 구입하거나 합성하여 제조할 수 있다. 바람직하게는 팥꽃나무로부터 추출, 분리할 수 있다.Yuanhuacine of the present invention is a terpenoid represented by the following formula (2), specifically, a diterpene ester compound, and can be prepared according to a method known to a person skilled in the art. For example, Yuanhuacine may be isolated and purified from plants known in the art using polar or non-polar solvents. Or can be prepared by purchasing or synthesizing commercially available compounds. Preferably, it can be extracted and separated from red bean flower.
본 발명의 용어 "팥꽃나무(Daphne genkwa)"는 쌍떡잎식물 도금양목 팥꽃나무과의 낙엽관목을 의미한다. 조기꽃나무, 이팥나무라고도 하며, 주로 바닷가 근처에서 성장하며, 한의학에서는 이뇨, 수종, 신장염 등의 증상을 치료하는데 사용한다.The term " Daphne genkwa "of the present invention means a deciduous shrub of a dicotyledonous plant-bearing potato bean. It is also known as early flowering tree and red bean tree. It grows mainly near the sea. In Oriental medicine, it is used to treat symptoms such as diuretic, species and nephritis.
본 발명의 용어 "팥꽃나무 추출물"은 팥꽃나무로부터 수득한 추출물을 의미하는데, 바람직하게는 팥꽃나무의 줄기 또는 뿌리로부터 수득한 추출물을 의미하며, 보다 바람직하게는 팥꽃나무의 줄기 또는 뿌리를 유기용매 추출하여 수득한 추출물을 의미하고, 구체적으로는 팥꽃나무의 줄기 또는 뿌리를 C1 내지 C5의 저급 알킬알콜로 추출하여 수득한 추출물을 의미한다. 공지된 바에 의하면, 팥꽃나무 추출물은 크게 쿠마린(coumarins)류, 플라보노이드(flavonoids)류, 리그난(lignans)류, 테르페노이드(terpenoids)류 및 이 외 화합물의 크게 5가지 종류의 화합물을 포함하며 총 화합물의 수는 수백 가지에 이른다[Xu, W.-C. et al ., Chem . Biodiversity, 2011, 8: 1215-1233].The term " red bean berry leaf extract "of the present invention means an extract obtained from red bean bloom, preferably an extract obtained from the stem or root of red bean bloom. More preferably, the stem or root of red bean bloom is an organic solvent Refers to an extract obtained by extracting, specifically, Means an extract obtained by extracting the stem or root of red bean flower with a C1 to C5 lower alkyl alcohol. It has been known that the red bean berry extract largely comprises five major classes of compounds: coumarins, flavonoids, lignans, terpenoids and other compounds, The number of compounds is in the hundreds [Xu, W.-C. meat al . , Chem . Biodiversity , 2011, 8: 1215-1233].
본 발명의 일실시예에 의하면, 팥꽃나무의 줄기 및/또는 뿌리 분쇄물을 건조중량의 약 2 내지 20배, 바람직하게는 약 3 내지 5배에 달하는 부피의 물, 메탄올, 에탄올, 부탄올 등의 C1 내지 C5의 저급 알킬알콜 등의 유기용매를 용매로 사용하여 3 내지 5시간 동안 침지하고 여과하여 고형분과 1차 액상성분을 분리하고, 상기 고형분을 동일한 방법으로 침지하고 여과하여 2차 액상성분을 수득하여 혼합하였다. 이후 상기 혼합물을 감압 농축시키고 잔사를 동결건조하여 팥꽃나무 추출물을 수득하였다. 상기 팥꽃나무 추출물은 상기 Genkwanine N 또는 Yuanhuacine 화합물을 포함할 수 있다.According to one embodiment of the present invention, the stem and / or roots of the red bean tree are washed with water in a volume of about 2 to 20 times, preferably about 3 to 5 times the dry weight, methanol, ethanol, The solvent is immersed in an organic solvent such as C1 to C5 lower alkyl alcohol as a solvent for 3 to 5 hours and filtered to separate the solid component and the primary liquid component and the solid component is immersed in the same manner and filtered to obtain a secondary liquid component And mixed. Thereafter, the mixture was concentrated under reduced pressure, and the residue was lyophilized to obtain a red bean berry extract. The red bean berry extract may contain the Genkwanine N or Yuanhuacine compound.
본 발명의 또 다른 실시예에 의하면, 상기 수득한 팥꽃나무 추출물을 헥산, 에틸 아세테이트, 부탄올, 또는 증류수 등의 유기용매의 혼합용매를 이용하여 각 용매의 분획층을 분리하여 수득하고, 크로마토그래피 등의 당업계에 공지된 분리방법을 이용하여 각각의 분획으로부터 활성성분을 고순도로 분리 정제할 수 있다. 상기 팥꽃나무 추출물의 헥산 분획은 본 발명의 Genkwanine N 또는 Yuanhuacine 화합물을 포함할 수 있다.According to another embodiment of the present invention, the obtained red bean berry extract is obtained by separating a fraction layer of each solvent using a mixed solvent of an organic solvent such as hexane, ethyl acetate, butanol, or distilled water, Can be separated and purified from each fraction in high purity by using a separation method known in the art. The hexane fraction of the red bean berry extract may contain the Genkwanine N or Yuanhuacine compound of the present invention.
본 발명자들은 부작용이 없으면서도, Nurr1 기능장애에 의해 유발되는 파킨슨병을 비롯한 다양한 질환을 예방 또는 치료하는 효과가 우수한 천연물 유래의 성분을 규명하기 위하여, 다양한 천연물로부터 수득한 다양한 형태의 추출물을 대상으로 연구를 수행한 결과, 팥꽃나무(Daphne genkwa)의 유기용매 추출물이 Nurr1 활성도를 증가시킬 수 있음을 확인하였다(도 1).The inventors of the present invention have conducted studies on various kinds of extracts obtained from various natural products in order to identify the components derived from natural products which are excellent in preventing or treating various diseases including Parkinson's disease caused by Nurr1 dysfunction without side effects As a result of the study, it was confirmed that the organic solvent extract of Daphne genkwa can increase Nurr1 activity (Fig. 1).
또한, 본 발명자들은 상기 Nurr1 활성도를 증가시키는 팥꽃나무 추출물이 신경세포 사멸을 유도하는 것으로 알려진 화합물(예를 들어, 6-OHDA 등)에 의한 신경세포 손상을 예방하는 효과를 나타냄을 확인하였다(도 2). 뿐만 아니라, 랫트 뇌의 도파민성 신경세포를 사멸시킨 동물모델에 팥꽃나무 추출물을 혼합한 사료로 급이시킨 결과, 사멸된 도파민성 신경세포에 의해 손상된 신경기능이 서서히 개선됨을 확인할 수 있었다(도 3).In addition, the inventors of the present invention have confirmed that the extract of Bacillus subtilis, which increases the Nurr1 activity, has an effect of preventing neuronal cell damage by a compound known to induce neuronal cell death (for example, 6-OHDA) 2). In addition, it was confirmed that the animal model that killed the dopaminergic neurons of the rat brain was fed to a mixture of the red bean flour extract and that the damaged nerve function was gradually improved by the killed dopaminergic neurons (FIG. 3 ).
이와 같이, 본 발명자는 팥꽃나무 추출물이 Nurr1 단백질 활성도를 증가시킴으로써, Nurr1 단백질의 활성에 의하여 직접적으로 영향을 받는 도파민성 신경세포의 손상에 의하여 유발되는 다양한 질환, 예를 들어, 파킨슨병 및 파킨슨병 이외의 Nurr1의 기능장애에 의해 유발되는 다양한 질환의 예방 또는 치료에 효과를 나타냄을 확인하였다.As described above, the present inventors have found that the bean curd tree extract increases the activity of Nurr1 protein, and thus can inhibit various diseases caused by damage of dopaminergic neurons directly affected by the activity of Nurr1 protein, such as Parkinson's disease and Parkinson's disease It was confirmed that the compounds of the present invention are effective in preventing or treating various diseases caused by other dysfunctions of Nurr1.
본 발명자들은 팥꽃나무 추출물 중 Nurr1 당백질을 활성화 하는 활성분획 및 활성성분을 분석한 결과, 팥꽃나무의 헥산 또는 에틸 아세테이트 분획물이 Nurr1 단백질 활성화에 효과를 보임을 확인하였고(도 4), 그 중 Genkwanine N 및 Yuanhuacine 화합물이 Nurr1 단백질 활성화에 우수한 효과를 나타냄을 확인하였다(도 5). Nurr1 단백질은 중추신경계의 특정한 신경세포군에서 도파민성 표현형의 확립과 유지에 관여하며, Nurr1의 발현 감소가 파킨슨병을 비롯한 신경퇴행성 질환에 관여한다는 것이 밝혀졌는 바[Chu, Y. et al., J. Comp . Neurol., 2006, 494(3): 495-514], 상기 팥꽃나무의 헥산 또는 에틸 아세테이트 분획물 및 Genkwanine N 또는 Yuanhuacine이 Nurr1 단백질 활성도를 증가시킴으로써, Nurr1 단백질의 활성에 의하여 직접적으로 영향을 받는 도파민성 신경세포의 손상에 의하여 유발되는 다양한 질환, 예를 들어, 파킨슨병 및 파킨슨병 이외의 Nurr1의 기능장애에 의해 유발되는 다양한 질환의 예방 또는 치료에 효과를 나타냄을 알 수 있다.As a result of analysis of the active fractions and the active components of Nurr1 glycoprotein in the red bean curd extract, it was confirmed that hexane or ethyl acetate fraction of the red bean curd tree had an effect on Nurr1 protein activation (Fig. 4). Among them, Genkwanine N and Yuanhuacine compounds showed excellent effects on Nurr1 protein activation (Fig. 5). Nurr1 protein is involved in the establishment and maintenance of the dopaminergic phenotype in specific neuronal cell populations of the central nervous system and it has been shown that decreased expression of Nurr1 is involved in neurodegenerative diseases including Parkinson's disease [Chu, Y. et al ., J. Comp . Neurol ., 2006, 494 (3): 495-514], the hexane or ethylacetate fractions of the red bean tree and Genkwanine N or Yuanhuacine increase the Nurr1 protein activity, The present invention is effective for the prevention or treatment of various diseases caused by nerve cell damage, for example, various diseases caused by dysfunction of Nurr1 other than Parkinson's disease and Parkinson's disease.
따라서, Nurr1의 활성화에 효과를 가지는 본 발명의 Genkwanine N 및 Yuanhuacine 화합물은 파킨슨병을 비롯한 신경퇴행성 질환의 예방 또는 치료에 유용하게 사용될 수 있다. 본 발명의 용어 "신경퇴행성 질환"이란 신경세포가 퇴화하고, 기능을 잃고, 그리고 사명하는 경우 나타나는 증상들과 관련된 질환을 의미한다. 주로 진행성이어서 그 결과는 매우 파괴적이고, 상기 질환을 가진 환자들은 인지 또는 운동 능력에 있어서 극심한 퇴화를 겪을 수 있다. 상기 신경퇴행성 질환은 특별히 이에 제한되지 않으나, 파킨슨병(Parkinson's disease; PD), 알츠하이머병(Alzheimer's disease; AD), 루게릭병(amyotrophic lateral sclerosis; ALS), 헌팅턴병(Huntington's disease; HD), 전측두엽 치매(Fronto-Temporal Dementia), 피질-기저핵 퇴행증(Cortico Basal Degeneration), 진행성 핵상마비(progressive supranuclear palsy; PSP)를 포함한다.
Therefore, the Genkwanine N and Yuanhuacine compounds of the present invention which have an effect on the activation of Nurr1 can be effectively used for the prevention or treatment of neurodegenerative diseases including Parkinson's disease. The term "neurodegenerative disease" of the present invention means a disease associated with symptoms that occur when a nerve cell degenerates, fails to function, and is commissioned. The results are very destructive because they are primarily progressive, and patients with the disease may experience severe degeneration in cognition or athletic performance. The neurodegenerative diseases include but are not limited to Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) (Fronto-Temporal Dementia), Cortico Basal Degeneration, and progressive supranuclear palsy (PSP).
본 발명의 약학적 조성물은 상기 화학식 1의 Genkwanine N 또는 화학식 2의 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염의 형태로 사용될 수 있다. 본 발명의 용어 "약학적으로 허용가능한 염"은 상기 화합물의 원하는 생물학적 및/또는 생리학적 활성을 보유하고 있고, 원하지 않는 독물학적 효과는 최소한으로 나타내는 모든 염을 의미한다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알콜(예, 글리콜 모노메틸 에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다. 이때, 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 히드로브롬산, 인산, 질산, 황산, 주석산 등을 사용할 수 있고, 유기산으로는 메탄 술폰산, p-톨루엔 술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 히드로아이오딕산 등을 사용할 수 있으며, 이들에 제한되지 않는다.The pharmaceutical composition of the present invention can be used in the form of Genkwanine N of Formula 1 or Yuanhuacine of Formula 2, or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salts" of the present invention means all salts which possess the desired biological and / or physiological activity of the compounds and which exhibit minimal undesired toxicological effects. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, tartaric acid and the like can be used. Examples of the organic acid include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, Citric acid, lactic acid, glycollic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. But are not limited to these.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is preferable to produce sodium, potassium or calcium salt particularly, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
상기 화학식 1의 Genkwanine N 또는 화학식 2의 Yuanhuacine 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, Genkwanine N 또는 Yuanhuacine 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 거의 포함한다. 예를 들어 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며 당업계에서 알려진 염의 제조방법을 통하여 제조될 수 있다.
A pharmaceutically acceptable salt of Genkwanine N of
본 발명의 다른 실시양태에 의하면, 본 발명은 상기 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하고 약학적으로 허용가능한 담체를 포함하는 신경퇴행성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.According to another embodiment of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising the above-mentioned Genkwanine N or Yuanhuacine or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier Gt;
본 발명에서 용어 "약학적으로 허용가능한 담체"란 생물체를 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 말한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 하나 이상의 성분을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다.
As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate the organism and does not interfere with the biological activity and properties of the administered compound. Examples of the pharmaceutical carrier which is acceptable for the composition to be formulated into a liquid solution include sterilized and sterile water suitable for the living body such as saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added.
본 발명의 또 다른 실시양태에 의하면, 본 발명은 상기 약학적 조성물을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 신경퇴행성 질환을 예방 또는 치료하는 방법을 제공한다.According to another embodiment of the present invention, the present invention provides a method for preventing or treating a neurodegenerative disease, comprising the step of administering the pharmaceutical composition to a subject in need thereof.
본 발명의 용어 "개체"란 신경퇴행성 질환이 발병하였거나 발병할 수 있는 인간을 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 신경퇴행성 질환을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나, 기존의 신경퇴행성 질환 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다.The term "individual" as used herein refers to all animals including humans who have developed or are capable of developing neurodegenerative diseases, and the neurodegenerative diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to individuals. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with a conventional therapeutic agent for neurodegenerative diseases, and may be administered sequentially or simultaneously with conventional therapeutic agents.
본 발명의 용어 "투여"란 적절한 방법으로 환자에게 소정의 물질을 도입하는 것을 의미하며 상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물 이외에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로스, 또는 락토즈, 젤라틴 등을 섞어 조제한다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면, 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 그러나 경구 투여시, 천연물로부터 유래된 상기 팥꽃나무 추출물의 활성성분은 소화로 인하여 손실될 수 있으므로, 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화 하는 것이 바람직하다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The term "administering" of the present invention means introducing a predetermined substance into a patient in an appropriate manner, and the administration route of the composition can be administered through any conventional route as long as it can reach the target tissue. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain, in addition to the composition, at least one excipient such as starch, calcium carbonate, sucrose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to water and liquid paraffin, . However, at the time of oral administration, the active ingredient of the red bean berry extract derived from a natural product may be lost due to digestion. Therefore, it is preferable that the oral composition is formulated so as to coat the active agent or protect it from decomposition at the top. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
또한, 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
상기 조성물은 약학적으로 유효한 양으로 단일 또는 다중 투여될 수 있다. 본 발명의 용어 "약학적으로 유효한 양"이란 의학적 예방 또는 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 예방 또는 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율, 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.
The composition may be administered in single or multiple doses in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prophylactic or therapeutic treatment, and the effective dose level will depend on the severity of the disease, Including the age, weight, health, sex, sensitivity of the patient to the drug, the time of administration of the composition of the present invention used, the route of administration and the rate of release, the duration of the treatment, Factors and factors well known in the medical arts.
또 하나의 양태로서, 본 발명은 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 Nurr1 기능 장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases caused by Nurr1 dysfunction comprising Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 "Nurr1(nuclear receptor related 1)"은 NR4A2(nuclear receptor subfamily 4, group A, member 2)라고도 알려져 있는 핵수용체 관련 1 단백질을 의미하며, 이는 사람의 NR4A2 유전자에 의해 암호화되는 것으로 알려져 있다. 또한 상당수의 신경퇴행성 질환에는 관련된 것으로 알려져 있다. 비록, 상기 Nurr1 단백질은 고아 핵 수용체(orphan nuclear receptor)로서, 아직까지는 상기 단백질에 대한 리간드가 규명되어 있지 않지만, 상기 Nurr1은 세포 내 전사인자의 핵 수용체 패밀리에 속하는 단백질로서, 뇌에서 도파민 시스템(dopaminergic system)을 유지하는 핵심적인 역할을 수행함이 규명되었다. 상기 Nurr1 기능 장애에 의해 유발되는 질환은 이에 제한되지 않으나 파킨슨병(Parkinson's disease; PD), 알츠하이머병(Alzheimer's disease; AD), 루게릭병(amyotrophic lateral sclerosis; ALS), 헌팅턴병(Huntington's disease; HD), 전측두엽 치매(Fronto-Temporal Dementia), 피질-기저핵 퇴행증(Cortico Basal Degeneration), 진행성 핵상마비(progressive supranuclear palsy; PSP) 등의 신경퇴행성 질환과 도파민 기능장애로 유발되는 류마티스 관절염, 정신분열증, 조울증 등의 광범위한 염증성 질환을 포함한다.
In the present invention, "Nurr1 (nuclear receptor related 1) " refers to a nuclear receptor-related 1 protein known as NR4A2 (
또 하나의 양태로서, 본 발명은 Genkwanine N 또는 Yuanhuacine을 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 개선효과를 나타내는 기능성 식품 첨가물을 제공한다.In another aspect, the present invention provides a functional food additive exhibiting the effect of preventing or improving neurodegenerative diseases comprising Genkwanine N or Yuanhuacine as an active ingredient.
본 발명의 조성물은 천연물인 팥꽃나무 추출물로부터 분리된 화합물로 안정성이 이미 확인되었으므로, 평소의 식습관에 따라 장기간 동안 상식할 경우, 파킨슨병을 포함하는 다양한 신경퇴행성 질환을 예방함은 물론 발병된 상기 질환의 증상을 개선시키는 효과를 나타낼 수 있다.The composition of the present invention is a compound isolated from a natural product, an adzuki bean floris, and its stability has already been confirmed. Therefore, when the food is habitual for a long period of time according to usual eating habits, various neurodegenerative diseases including Parkinson's disease are prevented, The symptoms of the disease can be improved.
본 발명에서 용어 "예방"은 상기 화학식 1의 Genkwanine N 또는 화학식 2의 Yuanhuacine 화합물을 유효성분으로 포함하는 조성물을 이용하여 Nurr1 단백질을 활성화하여 신경퇴행성 질환의 발병을 억제 또는 지연시키는 모든 행위를 말한다.The term "prophylactic" in the present invention refers to all actions that inhibit or delay the onset of a neurodegenerative disease by activating Nurr1 protein using a composition comprising Genkwanine N of
본 발명에서 용어 "개선"은 상기 화학식 1의 Genkwanine N 또는 화학식 2의 Yuanhuacine 화합물을 유효성분으로 포함하는 조성물을 이용하여 Nurr1 단백질을 활성화하여 신경퇴행성 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, the term "improvement" means activation of Nurr1 protein by using a composition comprising Genkwanine N of
본 발명의 Genkwanine N 또는 Yuanhuacine 화합물을 식품 첨가물로 사용하는 경우, 식품 또는 음료에 상기 화합물을 그대로 첨가하거나 또는 다른 식품 첨가물과 함께 조합하여 사용할 수 있다. 본 발명의 식품 첨가물을 식품 또는 음료의 제조시에 첨가할 경우, 이의 첨가량은 특별히 이에 제한되지 않으나, 최종적인 식품의 중량에 대하여 1 내지 5 중량%, 바람직하게는 1 내지 3 중량%의 첨가량으로 첨가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 첨가량은 상기 범위 이하일 수 있으며, 안전성 면에서 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When the Genkwanine N or Yuanhuacine compound of the present invention is used as a food additive, the compound may be added to the food or beverage as it is or in combination with other food additives. When the food additive of the present invention is added at the time of the production of a food or beverage, the addition amount thereof is not particularly limited, but may be in the range of 1 to 5% by weight, preferably 1 to 3% by weight, Can be added. However, in the case of long-term intake for the purpose of health and hygiene, or for the purpose of controlling health, the added amount 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 exceeding the above range.
아울러, 상기 식품 또는 음료의 종류는 특별히 이에 제한되지 않으나, 통상적인 의미에서의 식품 또는 음료를 모두 포함하고, 바람직하게는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 포함한다.The type of the food or beverage is not particularly limited, but includes foods or beverages in a conventional sense, preferably meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, etc. Noodles, gums, dairy products including ice cream, various soups, drinks, tea, drinks, alcoholic beverages and vitamin complexes.
이때, 본 발명의 팥꽃나무 추출물로부터 분리한 화합물을 포함하는 식품 첨가물을 식품에 첨가할 경우에는, 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜 등의 보조성분과 함께 첨가될 수 있고, 상기 보조성분의 함량은 특별히 이에 제한되지 않으나, 최종적인 식품의 중량에 대하여 0.01 내지 0.1 중량%임이 바람직하다.At this time, when the food additive containing the compound isolated from the bean curd tree extract of the present invention is added to the food, various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and its salts, , A protective colloid thickener, a pH adjusting agent, a stabilizer, a preservative, glycerin, and an alcohol, and the content of the auxiliary component is not particularly limited, but is preferably 0.01 to 0.1 By weight.
또한, 본 발명의 팥꽃나무 추출물로부터 분리한 화합물을 포함하는 식품 첨가물을 음료에 첨가할 경우에는, 통상의 음료와 같이 여러 가지 감미제 또는 천연 탄수화물 등을 추가 성분으로 포함할 수 있다. 이때, 상기 감미제는 특별히 이에 제한되지 않으나, 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있고, 상기 천연 탄수화물은 특별히 이에 제한되지 않으나, 단당류(예를 들어, 포도당, 과당 등), 이당류(예를 들어, 말토스, 수크로스 등), 다당류(예를 들어, 덱스트린, 사이클로덱스트린 등), 또는 당알콜(예를 들어, 자일리톨, 소르비톨, 에리트리톨 등) 등을 사용할 수 있으며, 상기 천연 탄수화물의 함량은 특별히 이에 제한되지 않으나, 최종 음료제품 100 ml 당 약 0.01 내지 0.04 g 바람직하게는 약 0.02 내지 0.03 g의 비율로 포함됨이 바람직하다.
In addition, when the food additive containing the compound isolated from the bean curd tree extract of the present invention is added to beverages, it may contain various sweeteners or natural carbohydrates as an additional ingredient such as ordinary beverages. The sweetener may be a natural sweetening agent such as tau Martin or stevia extract or a synthetic sweetening agent such as saccharine or aspartame. The natural carbohydrate is not limited to monosaccharides (E.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), polysaccharides (e.g., dextrin, cyclodextrin etc.), or sugar alcohols (e.g., xylitol, sorbitol, erythritol ). The content of the natural carbohydrate is not particularly limited, but is preferably about 0.01 to 0.04 g, and preferably about 0.02 to 0.03 g per 100 ml of the final beverage product.
또 하나의 양태로서, 본 발명은 Genkwanine N 또는 Yuanhuacine, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 Nurr1 활성화 조성물을 제공한다.In another aspect, the present invention provides a Nurr1 activating composition comprising Genkwanine N or Yuanhuacine, or a pharmaceutically acceptable salt thereof, as an active ingredient.
본 발명의 Nurr1 단백질은 고아 핵 수용체(orphan nuclear receptor)로서, 아직까지는 상기 단백질에 대한 리간드가 규명되어 있지 않지만, 상기 Nurr1은 세포 내 전사인자의 핵 수용체 패밀리에 속하는 단백질로서, 뇌에서 도파민 시스템(dopaminergic system)을 유지하는 핵심적인 역할을 수행함이 규명되었다. 또한 Nurr1 단백질의 이상에 의해 도파민 시스템의 장애를 유발하고 신경퇴행성 질환의 원인이 될 수 있음이 알려져 있어, Nurr1은 신경퇴행성 질환 관련 단백질 타겟으로 연구되고 있다. 따라서, 본 발명의 Genkwanine N 또는 Yuanhuacine 화합물은 Nurr1 기능 연구용 등으로 사용 가능하나 이에 제한되지는 않는다.
The Nurr1 protein of the present invention is an orphan nuclear receptor and has not yet been identified as a ligand for the protein. However, the Nurr1 protein belongs to the nuclear receptor family of intracellular transcription factors, dopaminergic system in the brain. It is also known that the abnormality of Nurr1 protein causes the disorder of dopamine system and may be a cause of neurodegenerative diseases. Therefore, Nurr1 is being studied as a neurodegenerative disease related protein target. Therefore, the Genkwanine N or Yuanhuacine compound of the present invention can be used for Nurr1 function research, but not limited thereto.
본 발명의 팥꽃나무 추출물로부터 분리한 화합물은 천연물 유래 화합물로서 별다른 부작용을 나타내지 않으면서도, 신경손상에 의한 Nurr1 단백질 활성 억제를 회복시키는데 우수한 효과를 나타냄으로써 Nurr1 단백질의 활성 억제로 인해 유발되는 파킨슨병을 비롯한 신경퇴행성 질환을 예방 또는 치료할 수 있다.
The compound of the present invention isolated from the red bean curd extract has excellent effects in restoring the inhibition of Nurr1 protein activity due to nerve damage without showing any side effects as a natural product compound. Thus, it is possible to prevent Parkinson's disease caused by inhibition of Nurr1 protein activity Can be prevented or treated.
도 1은 팥꽃나무 메탄올 추출물의 농도에 따른 Nurr1 단백질 활성도의 변화를 루시퍼라제 분석을 통하여 나타낸 그래프이다.
도 2는 6-OHDA(6-hydroxydopamine)에 의해 유도되는 신경세포 사멸에 대한 팥꽃나무 추출물의 농도에 따른 억제효과를 나타낸 그래프이다.
도 3은 팥꽃나무 메탄올 추출물의 파킨슨 동물모델에서의 치료효과를 나타낸 그래프이다.
도 4는 팥꽃나무의 다양한 용매 추출물에 의한 Nurr1 단백질 활성도 변화를 나타낸 그래프이다.
도 5는 팥꽃나무 추출물로부터 분리된 Genkwanine N과 Yuanhuacine 화합물의 농도에 따른 Nurr1 단백질 활성도 증가를 나타낸 그래프이다.FIG. 1 is a graph showing the change in Nurr1 protein activity according to the concentration of methanol extract of red bean japonica, through analysis of luciferase.
FIG. 2 is a graph showing the inhibitory effect of 6-OHDA (6-hydroxydopamine) -induced neuronal cell death on the concentration of red bean flour extract.
Fig. 3 is a graph showing the therapeutic effect of methanol extract of red bean flour from Parkinson's animal model.
4 is a graph showing changes in Nurr1 protein activity by various solvent extracts of red bean flour.
FIG. 5 is a graph showing the increase of Nurr1 protein activity according to the concentrations of Genkwanine N and Yuanhuacine compounds isolated from the red bean curd extract.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예Example
1: One:
팥꽃나무Red bean flower
추출물의 제조 Preparation of extract
팥꽃나무(Daphne genkwa)의 줄기 1,260.93 g과 뿌리 1,487.17 g을 세절한 다음, 13 L 메탄올에 4시간 동안 침지하고, 여과하여 고형분과 1차 액상성분을 분리하였다. 상기 분리된 고형분을 다시 13 L 메탄올에 4시간 동안 침지하고, 여과하여 2차 액상성분을 수득하였다. 상기 수득한 1차 액상성분과 2차 액상성분을 혼합하고, 상기 혼합물을 감압하에서 농축시킨 다음, 잔사를 동결건조하여 172.71 g의 팥꽃나무 추출물을 제조하였다.
1,260.93 g of the stem of Daphne genkwa and 1,487.17 g of the root were separated and then immersed in 13 L of methanol for 4 hours and filtered to separate the solid component and the primary liquid component. The separated solid was again immersed in 13 L of methanol for 4 hours and filtered to obtain a second liquid component. The obtained primary liquid component and secondary liquid component were mixed and the mixture was concentrated under reduced pressure. The residue was lyophilized to obtain 172.71 g of red bean berry extract.
실시예Example
2: 2:
팥꽃나무Red bean flower
추출물로부터 다양한 용매에 의한 활성성분의 분리 Isolation of Active Ingredients from Extracts by Various Solvents
상기 실시예 1에서 수득한 팥꽃나무 뿌리 및 줄기를 메탄올 추출하여 감압농축하여 건조시킨 추출물에 다양한 용매를 차례로 가하여 각 용매에 대한 분획의 Nurr1 단백질 활성에 대한 효과를 확인하였다. 이때, 사용된 용매는 헥산(hexane), 에틸 아세테이트(ethyl acetate; EtOAc), 증류수(distilled water; dH2O), 및 부탄올(butanol; BuOH)이다.The extracts of methanol extract of red bean rhizome roots and stems obtained in Example 1 were concentrated under reduced pressure and then dried. Various solvents were added to the extract in order to confirm the effect of the fraction on the Nurr1 protein activity for each solvent. In this case, the solvent used is hexane, ethyl acetate (EtOAc), distilled water (dH 2 O), and butanol (BuOH).
먼저 건조 팥꽃나무 추출물을 2 L의 증류수와 헥산의 1:1 혼합용매에 녹여 분획하여 헥산 층을 얻었다. 남은 증류수 층에 다시 2 L의 증류수와 에틸 아세테이트의 1:1 혼합용매를 가하여 분획하여 에틸 아세테이트 층을 얻고, 동일한 방법으로 부탄올 층과 증류수 층을 수득하였다. 상기 분리 수득한 각 용매 층의 분획에 대하여 Nurr1 활성실험을 실시한 결과, 헥산 및 에틸 아세테이트 분획이 높은 활성을 갖는 것을 확인하였다. 따라서, 해당 활성 분획에 대한 대량분리를 진행하기 위하여 실시예 1의 방법과 유사하게 팥꽃나무 뿌리, 줄기 건조시료 2.75 kg을 메탄올 용매에 13 L씩 2회 반복하여 냉침하고 농축하여 172.71 g의 메탄올 추출물을 수득하였다. 이 중 30.1 g을 증류수에 현탁하여 헥산, 에틸 아세테이트 순으로 분획하였다. 두 분획 중 더 높은 활성을 가진 것으로 확인된 헥산 분획물(3 g)을 실리카겔 컬럼 크로마토그래피를 이용하여 헥산과 에틸 아세테이트의 구배(gradient) 혼합용매(10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10)로 용리시켜 총 50개의 분획을 얻었다. 이 중 헥산:에틸 아세테이트의 1:2 용매조건에서 용리된 32 내지 38 분획(268 mg)에서 Nurr1 활성이 관찰되었다. 따라서, 상기 32 내지 38 분획을 모아 감압 농축하고, 85% 아세토니트릴 조건으로 역상 실리카겔 프렙 TLC(reverse phase silica gel prep TLC)를 실시하여 총 11개의 밴드를 얻었다. 이 중 밴드 6(Rf=0.44)과 밴드 8(Rf=0.33)에서 Nurr1 활성화가 관찰되어, 상기 두 개의 밴드로부터 메탄올로 활성물질을 추출하고 감압 농축하여 각각 B6과 B8의 두 화합물을 얻었다. 최종적으로 80% 아세토니트릴(0.025% 트리플루오로아세트산; trifluoroacetic acid; TFA)을 용출액으로하여 ODS HPLC를 수행하여 이 두 화합물로부터 99% 이상의 순도로 두 가지의 활성성분 겐콰닌 N(Genkwanine N)과 유안후아신(Yuanhuacine)을 단일물질로 성공적으로 분리하였다.
First, the dried red bean bloom extract was dissolved in 2 L of distilled water and hexane 1: 1 mixed solvent and fractionated to obtain a hexane layer. To the remaining distilled water layer, 2 L of distilled water and a 1: 1 mixed solvent of ethyl acetate were added and the fractions were fractionated to obtain an ethyl acetate layer, and a butanol layer and a distilled water layer were obtained in the same manner. As a result of the Nurr1 activity test on the separated solvent layer fractions, it was confirmed that the hexane and ethyl acetate fractions had high activity. Thus, in order to proceed mass separation of the active fractions, 2.75 kg of red bean sprout root and stem dried sample was repeated twice with 13 L each in methanol solvent, followed by concentrating with 172.71 g of methanol extract ≪ / RTI > 30.1 g thereof was suspended in distilled water and fractionated in the order of hexane and ethyl acetate. The hexane fraction (3 g), identified as having higher activity in both fractions, was purified by silica gel column chromatography using a gradient mixture of hexane and ethyl acetate (10: 1, 5: 1, 2: 1, 1: : 1, 1: 2, 1: 5, 1:10) to obtain a total of 50 fractions. Nurrl activity was observed in 32 to 38 fractions (268 mg) eluted at 1: 2 solvent conditions of hexane: ethyl acetate. Thus, the 32 to 38 fractions were collected, concentrated under reduced pressure, and subjected to reversed phase silica gel prep TLC (TLC) under 85% acetonitrile to obtain a total of 11 bands. Among them, Nurr1 activation was observed in band 6 (Rf = 0.44) and band 8 (Rf = 0.33). Active substances were extracted from the two bands by methanol and concentrated under reduced pressure to obtain two compounds, B6 and B8. Finally, ODS HPLC was carried out using 80% acetonitrile (0.025% trifluoroacetic acid; TFA) as an eluent to obtain two active compounds, Genkwanine N and Yuanhuacine was successfully isolated as a single substance.
실시예Example
3: 3:
Nurr1Nurr1
단백질 활성에 대한 For protein activity
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
GLA4 유전자가 결합할 수 있는 염기서열(5'-CTCGGAGGACAGTACTCCG-3, 서열번호 1)이 8회 반복된 유전자를 리포터 유전자인 루시퍼라제에 결합시킨 벡터를 합성한 후, Nurr1-LBD를 포함한 DNA와 베타-갈락토시다제(β-galactosidase)를 가진 DNA 등 3종의 플라스미드 DNA를 BE(2)C 세포에 주입(transfection)한 뒤 6시간 후, 팥꽃나무 추출물을 1 내지 200 ppm의 농도로 처리하였다. 이렇게 처리한 세포를 20시간 동안 37℃, 5% 이산화탄소 배양기에서 배양한 후, 루시퍼라제 분석을 수행하였다(도 1).(5'-CTCGGAGGACAGTACTCCG-3, SEQ ID NO: 1), to which a reporter gene, luciferase, has been synthesized, and then a DNA containing Nurr1-LBD and a beta Three plasmid DNAs, such as DNA with β-galactosidase, were transfected into BE (2) C cells, and after 6 hours, the red bean berry extract was treated at a concentration of 1 to 200 ppm . The cells thus treated were cultured in a 5% carbon dioxide incubator at 37 DEG C for 20 hours, and then subjected to luciferase analysis (FIG. 1).
도 1은 팥꽃나무 메탄올 추출물의 농도에 따른 Nurr1 단백질 활성도의 변화를 루시퍼라제 분석을 통하여 나타낸 그래프이다. 대조군으로는 0.1% DMSO를 사용하였고, 이때의 활성에 배수로 활성도의 증가를 나타내었다. 팥꽃나무 추출물을 20 ppm의 농도로 처리하였을 때, 최대의 활성을 나타내었고 이때의 값은 대조군의 약 3배에 달하였다. 도 1에서 보듯이, 인간 유래 신경모세포(neuroblast)인 BE(2)C 세포에서 팥꽃나무 추출물에 의한 Nurr1 단백질의 활성이 증가함을 확인하였다.
FIG. 1 is a graph showing the change in Nurr1 protein activity according to the concentration of methanol extract of red bean japonica, through analysis of luciferase. As a control, 0.1% DMSO was used, and the activity at this time was increased by a multiple of the activity. The maximum activity of the extracts of Aspergillus oryzae at 20 ppm was about 3 times that of the control group. As shown in FIG. 1, it was confirmed that the activity of Nurr1 protein was increased by BE (2) C cells, which are human neuroblasts,
실시예Example
4: 4:
SHSH
--
SY5YSY5Y
세포에 대한 For cells
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
인간 유래 신경모세포종(neuroblastoma)인 SH-SY5Y 세포를 5×105 세포수/웰의 세포농도로 24-웰 플레이트에 분주하고, 24시간 동안 이산화탄소 배양기에서 배양하였다. 상기 배양된 세포에 세포사멸을 유도하는 6-OHDA(6-hydroxydopamine)(50 μM)를 단독으로 또는 서로 다른 농도(5 내지 20 ppm)의 팥꽃나무 추출물과 함께 처리하고, 다시 24시간 동안 37℃, 5% 이산화탄소 배양기에서 배양하였다. 24시간 경과 후, MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 용액을 1 mg/ml의 농도로 각 웰에 처리하고, 1시간 동안 5% 이산화탄소 배양기에 보관한 다음, MTT 추출용액(extraction solution)을 가하였다. 이어 37℃에 24시간 동안 보관하고, 570 nm에서 흡광도를 측정하였다(도 2).Division of the SH-SY5Y cells, derived from human neuroblastoma (neuroblastoma) in 24-well plates at a cell concentration of 5 × 10 5 cells / well, and cultured in a carbon dioxide incubator for 24 hours. The cultured cells were treated with 6-OHDA (6-hydroxydopamine) (50 μM) alone or in combination with different concentrations (5 to 20 ppm) of red bean berry extract for inducing apoptosis, , And cultured in a 5% carbon dioxide incubator. After 24 hours, MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution was treated at a concentration of 1 mg / ml in each well and incubated for 1 hour in a 5% And MTT extraction solution was added thereto. It was then stored at 37 DEG C for 24 hours and absorbance was measured at 570 nm (FIG. 2).
도 2는 6-OHDA에 의해 유도되는 신경세포 사멸에 대한 팥꽃나무 추출물의 농도에 따른 효과를 나타내는 그래프이다. 도 2에서 보듯이, 6-OHDA에 의해 유도되는 신경세포 사멸이 팥꽃나무 추출물에 의해 저해되어 팥꽃나무 추출물 처리군의 세포 생존률이 대조군의 70% 이상의 수준까지 회복되는 것을 확인하였다.
FIG. 2 is a graph showing the effects of 6-OHDA-induced neuronal cell death on the concentration of the red bean flour extract. As shown in FIG. 2, it was confirmed that 6-OHDA-induced neuronal cell death was inhibited by the extract of red bean japonica, and the cell survival rate of the treated group was recovered to 70% or more of the control group.
실시예Example
5: 신경세포를 손상시킨 5: Damaged neurons
랫트에In rats
대한 About
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
6주령 SD 랫트(코아텍 사)의 중뇌의 흑질 부위에 존재하는 도파민성 신경세포를 특이적으로 사멸시키기 위하여, 정위고정성 도구(stereotaxic tool)를 이용하여 뇌의 AP(-4.3), ML(-1.8), DV(-8.2) 부위와 AP(-5.0), ML(-1.8), DV(-8.2) 부위에 6-OHDA(1 μg/μl)를 1 μl/min의 속도로 4 μg을 직접 주입하였다. 이때, 데시프라민(desipramine)을 25 mg/kg의 용량으로 상기 6-OHDA 투여 30분 전에 투함으로써, 도파민성 신경세포 이외의 세포사는 억제시켰다.In order to specifically kill dopaminergic neurons in the midbrain black part of 6-week-old SD rats (COATEC), the brain AP (-4.3), ML (1 μg / μl) at a rate of 1 μl / min to the DV (-8.2) and AP (-5.0), ML (-1.8) and DV Direct injection. At this time, desipramine was injected 30 minutes before the administration of the 6-OHDA at a dose of 25 mg / kg to inhibit cell death other than dopaminergic neurons.
이후, 팥꽃나무 추출물의 1일 투여량이 500 mg/kg이 되도록 상기 추출물이 혼합된 사료를 상기 랫트에게 2주일간 급이시켰다. 이때, 대조군으로는 상기 추출물이 혼합되지 않은 먹이를 급이시킨 랫트를 사용하였다.Then, the mixture containing the above extract was fed to the rats for 2 weeks so that the daily dose of the red bean berry extract was 500 mg / kg. At this time, as a control group, rats to which the extract had not been mixed were used.
약물학적 시험의 오차를 보강하기 위한 비약물학적 검사방법인 스텝 테스트(stepping test)를 수행하였다. 구체적으로, 길이 90 cm의 탁자 위에서 손으로 쥐의 세 다리를 제어한 상태에서 탁자면 위를 15초 동안 이동시키며 제어되지 않은 다리가 탁자 표면을 딛는 수를 각 다리별로 3회 반복하여 측정하였다. 상기 스텝 테스트의 측정 시점은 6-OHDA를 주입하기 3일 전, 6-OHDA 주입 후 2주, 4주 및 6주가 경과된 시점이었다(도 3).We conducted a stepping test, which is a non - pharmacological test method, to reinforce the error of pharmacological test. Specifically, the three legs of a mouse were controlled by hand on a table having a length of 90 cm, and the number of unregulated legs on the table surface was measured by repeating the above procedure three times for each leg. The measurement of the step test was performed three days before the injection of 6-OHDA and two, four and six weeks after the 6-OHDA injection (FIG. 3).
도 3은 도파민성 신경세포가 사멸된 랫트에 대한 팥꽃나무 추출물의 효과를 스텝 테스트를 통하여 확인한 결과를 나타낸 그래프이다. 도 3에서 보듯이, 팥꽃나무 추출물이 투여된 랫트는 투여되지 않은 랫트에 비하여 스텝 수가 증가함을 알 수 있었다.
FIG. 3 is a graph showing the results of a step test to examine the effect of a red bean curd extract on rats in which dopaminergic neurons were killed. As shown in FIG. 3, it was found that the rats administered with the red bean flour extract increased the number of steps compared to the untreated rats.
실시예Example
6: 다양한 용매에 의한 6: by various solvents
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
상기 실시예 2에서 다양한 용매를 이용하여 수득한 팥꽃나무 추출물의 분획물의 Nurr1 단백질 활성에 대한 효과를 실시예 3에 기재된 방법과 유사한 방법에 따라 확인하였다. 용매로는 헥산(hexane), 에틸 아세테이트(ethyl acetate; EtOAc), 증류수(distilled water; dH2O), 및 부탄올(butanol; BuOH)을 사용하였다.The effect of the fraction of red bean berry extract obtained using various solvents in Example 2 on the Nurr1 protein activity was confirmed by a method similar to that described in Example 3. As the solvent, hexane, ethyl acetate (EtOAc), distilled water (dH 2 O), and butanol (BuOH) were used.
도 4에 나타낸 바와 같이, 헥산 분획물에서 강한 Nurr1 단백질 활성화 효과가 나타났으며, 1 ppm의 헥산 분획물은 Nurr1 단백질의 활성을 380%까지 증가시켰다.
As shown in Fig. 4, the hexane fraction exhibited a strong Nurr1 protein activation effect and the 1 ppm hexane fraction increased the activity of the Nurr1 protein by 380%.
실시예Example
7: 활성성분 Genkwanine N과 Yuanhuacine의 효과 7: Effect of active ingredients Genkwanine N and Yuanhuacine
실시예 3과 유사한 방법으로, Nurr1 단백질의 활성에 대한 Genkwanine N과 Yuanhuaicine 효과의 농도의존성을 실험하고 그 결과를 도 5에 나타내었다.The concentration dependency of Genkwanine N and Yuanhuaicine effect on the activity of Nurr1 protein was tested in a similar manner to Example 3 and the results are shown in FIG.
도 5에 나타낸 바와 같이, Genkwanine N과 Yuanhuaicine은 두가지 화합물 모두 0.3 ppm에서 300%가 넘는 활성을 보였고, 특히 0.01 ppm 즉, 각각에 대하여 16 nM과 15 nM의 낮은 나노몰랄 수준의 농도에서도 Nurr1 단백질의 활성을 각각 60 및 70% 향상시켰다.
As shown in Fig. 5, Genkwanine N and Yuanhuaicine both showed activity of more than 300% at 0.3 ppm, especially 0.01 ppm, that is, at a low nano-moral level of 16 nM and 15 nM, Activity was improved by 60 and 70%, respectively.
<110> Korea Research Institute of Bioscience and Biotechnology <120> Pharmaceutical composition for preventing or treating neurodegenerative diseases comprising compounds isolated from Daphne genkwa extract <130> PA110885/KR <160> 1 <170> KopatentIn 2.0 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> GAL4 gene <400> 1 ctcggaggac agtactccg 19 <110> Korea Research Institute of Bioscience and Biotechnology <120> Pharmaceutical composition for or treating neurodegenerative Daphne genkwa extract <130> PA110885 / KR <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> GAL4 gene <400> 1 ctcggaggac agtactccg 19
Claims (12)
Parkinson's disease (PD) comprising a terpenoid compound selected from the group consisting of Genkwanine N and Yuanhuacine, or a pharmaceutically acceptable salt thereof as an active ingredient, A pharmaceutical composition for preventing or treating.
A pharmaceutical composition for preventing or treating rheumatoid arthritis comprising, as an active ingredient, a terpenoid compound selected from the group consisting of Genkwanine N and Yuanhuacine, or a pharmaceutically acceptable salt thereof. Composition.
상기 겐콰닌 N(Genkwanine N) 또는 유안후아신(Yuanhuacine)은 팥꽃나무 추출물로부터 분리된 화합물인 약학적 조성물.
3. The method of claim 2,
Wherein said Genkwanine N or Yuanhuacine is a compound isolated from an adzuki bean flour extract.
상기 겐콰닌 N(Genkwanine N) 또는 유안후아신(Yuanhuacine)은 팥꽃나무 추출물로부터 분리된 화합물인 약학적 조성물.
The method according to claim 1,
Wherein said Genkwanine N or Yuanhuacine is a compound isolated from an adzuki bean flour extract.
약학적으로 허용가능한 담체를 추가로 포함하는 것인 약학적 조성물.
The method according to claim 1,
Wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
상기 조성물은 Nurr1의 활성을 증가시키는 것인 약학적 조성물.
The method of claim 1,
Wherein said composition increases the activity of Nurrl.
상기 조성물은 Nurr1의 활성을 증가시키는 것인 약학적 조성물.
3. The method of claim 2,
Wherein said composition increases the activity of Nurrl.
약학적으로 허용가능한 담체를 추가로 포함하는 것인 약학적 조성물.
3. The method of claim 2,
Wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
A functional food additive for preventing or ameliorating Parkinson's disease (PD) comprising, as an active ingredient, a terpenoid compound selected from the group consisting of Genkwanine N and Yuanhuacine.
상기 겐콰닌 N(Genkwanine N) 또는 유안후아신(Yuanhuacine)은 팥꽃나무 추출물로부터 분리된 화합물인 기능성 식품 첨가물.
10. The method of claim 9,
Wherein the Genkwanine N or Yuanhuacine is a compound isolated from the red bean berry extract.
A functional food additive for preventing or ameliorating rheumatoid arthritis comprising, as an active ingredient, a terpenoid compound selected from the group consisting of Genkwanine N and Yuanhuacine.
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| KR1020110123848A KR101631589B1 (en) | 2011-11-24 | 2011-11-24 | Pharmaceutical composition for preventing or treating neurodegenerative diseases comprising compounds isolated from Daphne genkwa extract |
| PCT/KR2011/009110 WO2012138034A1 (en) | 2011-04-06 | 2011-11-28 | Pharmaceutical composition for the prevention or treatment of a neurodegenerative disease, comprising a daphne genkwa extract or a compound isolated therefrom |
| US14/009,526 US9034916B2 (en) | 2011-04-06 | 2011-11-28 | Pharmaceutical composition for the prevention or treatment of a neurodegenerative disease, comprising a Daphne genkwa extract or a compound isolated therefrom |
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| KR101964889B1 (en) * | 2017-11-17 | 2019-04-02 | 한국생명공학연구원 | Composition for preventing or treating neurodegenerative diseases comprising diterpenoid compound |
| KR20230133466A (en) * | 2022-03-11 | 2023-09-19 | 경희대학교 산학협력단 | Composition for treatment of neuroinflammatory disease comprising daphne genkwa |
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| KR101426307B1 (en) * | 2011-04-06 | 2014-08-05 | 한국생명공학연구원 | Composition Comprising Extract of Daphne genkwa as Active Ingradient |
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| WO2018088862A1 (en) | 2016-11-14 | 2018-05-17 | 한국생명공학연구원 | Pharmaceutical composition for preventing or treating neurodegenerative diseases which includes flower extract of daphne genkwa or fractions thereof as active ingredient |
| EP3539550A4 (en) * | 2016-11-14 | 2020-06-24 | Korea Research Institute of Bioscience and Biotechnology | Pharmaceutical composition for preventing or treating neurodegenerative diseases which includes flower extract of daphne genkwa or fractions thereof as active ingredient |
| US10792323B2 (en) | 2016-11-14 | 2020-10-06 | Korea Research Institute Of Bioscience And Biotechnology | Pharmaceutical composition for preventing or treating neurodegenerative diseases which includes flower extract of daphne genkwa or fractions thereof as active ingredient |
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