KR20220139737A - Composition including Menaquinone-7 as an active ingredient for treatment or prevention of neurodegenerative diseases - Google Patents
Composition including Menaquinone-7 as an active ingredient for treatment or prevention of neurodegenerative diseases Download PDFInfo
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- KR20220139737A KR20220139737A KR1020210046092A KR20210046092A KR20220139737A KR 20220139737 A KR20220139737 A KR 20220139737A KR 1020210046092 A KR1020210046092 A KR 1020210046092A KR 20210046092 A KR20210046092 A KR 20210046092A KR 20220139737 A KR20220139737 A KR 20220139737A
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- amyloid
- menaquinone
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Abstract
Description
메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 약학적으로 또는 식품학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 치료, 개선 또는 예방용 조성물과, 이를 위해 사용되는 메나퀴논-7에 관한 것이다. 보다 구체적으로 본 발명은 아밀로이드 생성 및 응집에 대한 메나퀴논-7의 항-아밀로이드 효과 (anti-amyloidogenic effect)에 기초한 퇴행성 신경질환의 치료, 예방, 또는 개선에 관한 것이다. A composition for the treatment, improvement or prevention of neurodegenerative diseases comprising menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically or pharmaceutically acceptable salt thereof as an active ingredient, and menaquinone- It's about 7. More specifically, the present invention relates to the treatment, prevention, or improvement of neurodegenerative diseases based on the anti-amyloidogenic effect of menaquinone-7 on amyloid production and aggregation.
대표적인 퇴행성 신경질환인 알츠하이머병 (Alzheimer's disease, AD)은 점진적으로 기억력이 감퇴되고 인지력이 상실되는 증상을 나타내는 병이며 인간의 평균수명이 길어짐에 따라 그 발병률도 현저히 증가하고 있다. 알츠하이머 병의 병리학적 특징 중 하나로 신경세포의 외부에 축적되는 노인성 반점 (senile plaques)을 들 수 있다. 노인성 반점을 구성하는 중요한 구성물질로 베타-아밀로이드 (beta-amyloid 또는 amyloid-β, Aβ) 단백질이 알려져 있으며, 이것은 전구 물질인 아밀로이드 전구체 단백질 (amyloid precursor protein, APP)의 대사 과정에서 생성된다. APP는 제1유형 막 당단백질 (Type 1 membrane glycoprotein)로서 단백질 분해효소인 알파-시크리타제 (α-secretase), 베타-시크리타제 (β-secretase), 그리고 감마-시크리타제 (γ-secretase)에 의해서 특이적으로 대사 된다. Alzheimer's disease (AD), a typical degenerative neurological disease, is a disease showing symptoms of progressive memory loss and cognitive loss. One of the pathological features of Alzheimer's disease is senile plaques that accumulate on the outside of nerve cells. As an important constituent of senile plaque, beta-amyloid (beta-amyloid or amyloid-β, Aβ) protein is known, and it is produced during the metabolic process of amyloid precursor protein (APP), a precursor. APP is a Type 1 membrane glycoprotein and is a proteolytic enzyme alpha-secretase (α-secretase), beta-secretase (β-secretase), and gamma-secretase (γ-secretase). is specifically metabolized by
베타-아밀로이드 형성에 중요한 역할을 하는 베타-시크리타제는 베타 위치 APP 절단 효소 (β-site APP-cleaving enzyme, BACE)라고도 지칭되며, BACE1과 BACE2가 있고, 이 중에 BACE1가 베타-시크리타제의 대부분의 활성 (약 90%)을 가지고 있어 베타-아밀로이드 생성에 가장 중요한 역할을 담당한다.Beta-secretase, which plays an important role in the formation of amyloid, is also referred to as beta-site APP-cleaving enzyme (BACE), and includes BACE1 and BACE2, of which BACE1 is the majority of beta-secretase. It has the activity (about 90%) of beta-plays the most important role in the production of amyloid.
베타-시크리타제 (BACE1)에 의해 잘려진 APP는 β-secretase derived secreted form of APP (sAPPβ)라 불리는 N 말단 도메인 (N-terminal domain)과, β-secretase derived secreted C-terminal fragment of APP (CTFβ) (C99)라 불리는 세포질 도메인 (cytoplasmic domain)으로 나눠진다 (sAPPβ 와 CTFβ 를 합해서 90 kDa 내외). 이렇게 생성된 sAPPβ는 세포 밖으로 분비되고, C99는 다시 감마-시크리타제에 의해 잘려 베타-아밀로이드 (4 kDa)로 생성된다. 따라서 베타-시크리타제 (BACE1)의 활성을 억제하는 물질은 베타-아밀로이드의 생성을 저해하여 알츠하이머병을 비롯한 베타-아밀로이드 축적으로 인한 퇴행성 신경질환에 대한 치료 또는 예방 효과를 나타낼 것으로 기대된다. APP cleaved by beta-secretase (BACE1) includes an N-terminal domain called β-secretase derived secreted form of APP (sAPPβ) and a β-secretase derived secreted C-terminal fragment of APP (CTFβ). It is divided into a cytoplasmic domain called (C99) (sAPPβ and CTFβ combined are around 90 kDa). sAPPβ thus produced is secreted out of the cell, and C99 is cleaved again by gamma-secretase to produce beta-amyloid (4 kDa). Therefore, substances that inhibit the activity of beta-secretase (BACE1) inhibit the production of beta-amyloid and are expected to exhibit therapeutic or preventive effects on neurodegenerative diseases caused by beta-amyloid accumulation, including Alzheimer's disease.
알츠하이머병의 기존 치료제로는 콜린성 신경계 가설에 근거하여 개발된 아세틸콜린에스테라제 (acetylcholinesterase) 억제제인 타크린 (tacrine), 도네페질 (donepezil), 리바스티그민 (rivastigmine), 갈란타민 (galantamine)과, 글루타메이트 (glutamate)가 작용하는 NMDA 수용체의 길항제인 메만틴 (memantine) 등을 들 수 있다. 그러나 현재 시판 중이거나 개발 중인 약물의 대부분은 알츠하이머 환자의 증상을 개선 시켜 삶의 질을 높이는 약물이며, 발병 초기에 일시적인 임상증상개선 효과에 그치는 것들이 대부분이고 부작용까지 나타나고 있어 실제 이용에 문제점이 많다.Existing treatments for Alzheimer's include acetylcholinesterase inhibitors tacrine, donepezil, rivastigmine, and galantamine developed based on the cholinergic nervous system hypothesis. , and memantine, which is an antagonist of NMDA receptors on which glutamate acts, and the like. However, most of the drugs currently on the market or under development are drugs that improve the symptoms of Alzheimer's patients and improve the quality of life.
본 발명자들은 알츠하이머병 발명 원인에 근거한 근본적인 치료에 목표를 두어 치료제를 개발하고자 노력 하였으며 베타-아밀로이드 단백질의 생성을 억제하거나 응집을 저해하거나 또는 분해할 수 있는 약물을 개발하기 위해 연구 하였다. 또한, APP의 비정상적인 대사로 인하여 베타-아밀로이드가 다량 생성되어 뇌세포 독성을 일으키고 이에 따라 AD를 비롯한 퇴행성 신경질환이 발병하므로 이러한 베타-아밀로이드 생성에 관여하는 효소인 베타-시크리타제를 조절하는 치료제 개발을 목표로 연구하였다. 또한, 기존 치료제는 주로 아세틸콜린에스터라제 억제 효과만을 가지고 있을 뿐, 베타-아밀로이드의 형성 억제 또는 이미 형성된 베타-아밀로이드 응집체의 분해 기능은 없었다.The present inventors tried to develop a therapeutic agent with the goal of a fundamental treatment based on the cause of the invention of Alzheimer's disease, and studied to develop a drug capable of inhibiting the production of beta-amyloid protein, inhibiting aggregation, or degrading it. In addition, due to abnormal metabolism of APP, a large amount of beta-amyloid is produced, which causes brain cell toxicity, which leads to the onset of neurodegenerative diseases including AD. was studied with the aim of In addition, existing therapeutic agents mainly only have an inhibitory effect on acetylcholinesterase, but have no function of inhibiting the formation of beta-amyloid or degrading the already formed beta-amyloid aggregates.
일 양상은 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 예방 또는 치료용 약학 조성물에 관한 것이다. One aspect relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
다른 일 양상은 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 예방 또는 개선용 식품 조성물에 관한 것이다. Another aspect relates to a food composition for preventing or improving neurodegenerative diseases comprising menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
다른 일 양상은 뇌내 베타-아밀로이드 축적을 저해하기 위해 사용되는 퇴행성 뇌질환 예방, 개선, 또는 치료용 메나퀴논-7에 관한 것이다.Another aspect relates to menaquinone-7 for preventing, ameliorating, or treating degenerative brain disease, which is used to inhibit the accumulation of beta-amyloid in the brain.
(1) 메나퀴논-7 (Menaquinone-7), 이의 유도체, 또는 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 예방 또는 치료용 약학 조성물. (1) Menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising a pharmaceutically acceptable salt thereof as an active ingredient.
(2) 상기 (1)의 퇴행성 신경질환은 베타-아밀로이드 응집 또는 집적을 주된 원인으로 하는 질환인 것인 약학 조성물. (2) The neurodegenerative disease of (1) is a pharmaceutical composition that is a disease mainly caused by beta-amyloid aggregation or aggregation.
(3) 상기 (1)의 메나퀴논-7은 베타-아밀로이드 생성을 억제 또는 베타-아밀로이드 응집을 저해하는 것인 약학 조성물. (3) The menaquinone-7 of (1) is beta- inhibiting amyloid production or beta- a pharmaceutical composition to inhibit amyloid aggregation.
(4) 상기 (1)의 메나퀴논-7은 베타-시크리타제 활성을 저해하는 것인 약학 조성물. (4) The menaquinone-7 of (1) is a pharmaceutical composition that inhibits beta-secretase activity.
(5) 상기 (1)의 퇴행성 신경질환은 알츠하이머병 (Alzheimer's disease, AD), 대뇌 아밀로이드 맥관병증 (Cerebral amyloid angiopathy), 전신성 아밀로이드증 (systematic amyloidosis), 루게릭병 (Amyotrophic lateral sclerosis 또는 Lou Gehrig disease), 헌팅턴병 (Huntington's disease), 니만-픽병 (Niemann-Pick Disease), 더취 (Dutch)형 아밀로이드증, 아밀로이드성 뇌졸중 (stroke), 파킨슨병 (Parkinson's disease), 경도 인지 장애 (Mild cognitive impairment), 노쇠 (Senility), 치매 (Dementia), 루이 소체 치매 (Lewy Body Dementia) 다경색 치매 (Multi-infarct dementia), 다운 증후군 (Down's syndrome), 뇌졸중 관련 치매 (Dementia associated with stroke), 파킨슨 질환 관련 치매 (Dementia associated with Parkinson's disease) 또는 베타-아밀로이드 관련 치매 (Dementia associated with beta-amyloid)의 예방 또는 치료용 약학 조성물. (5) The neurodegenerative disease of (1) is Alzheimer's disease (AD), cerebral amyloid angiopathy, systemic amyloidosis, Lou Gehrig disease (Amyotrophic lateral sclerosis or Lou Gehrig disease), Huntington's disease, Niemann-Pick disease, Dutch amyloidosis, amyloid stroke, Parkinson's disease, mild cognitive impairment, senility , Dementia, Lewy Body Dementia Multi-infarct dementia, Down's syndrome, Dementia associated with stroke, Dementia associated with Parkinson's disease) or beta-amyloid-related dementia (Dementia associated with beta-amyloid) for the prevention or treatment of a pharmaceutical composition.
(6) 상기 (1)의 퇴행성 신경질환은 알츠하이머병, 대뇌 아밀로이드 맥관병증, 전신성 아밀로이드증, 루게릭병, 헌팅턴병, 및 니만-픽병으로 이루어진 군으로부터 선택되는 것인 약학 조성물. (6) The neurodegenerative disease of (1) above is Alzheimer's disease, cerebral amyloid angiopathy, systemic amyloidosis, Lou Gehrig's disease, Huntington's disease, and a pharmaceutical composition selected from the group consisting of Niemann-Pick disease.
(7) 상기 (1)의 퇴행성 신경질환은 퇴행성 뇌질환인 것인 약학 조성물. (7) The degenerative neurological disease of (1) is a pharmaceutical composition that is a degenerative brain disease.
(8) 상기 (1)의 퇴행성 뇌질환은 뇌내 베타-아밀로이드 축적을 주된 원인으로 하는 질환인 것인 약학 조성물. (8) The degenerative brain disease of (1) in the brain is a pharmaceutical composition that is a disease mainly caused by the accumulation of beta-amyloid.
(9) 상기 (1)의 퇴행성 신경질환은 알츠하이머병인 것인 약학 조성물. (9) The neurodegenerative disease of (1) above is Alzheimer's disease, a pharmaceutical composition.
(10) 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 예방 또는 개선용 식품 조성물. (10) A food composition for preventing or improving neurodegenerative diseases comprising menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
(11) 상기 (10)에서 베타 위치 APP 절단 효소 1 (β-site APP-cleaving enzyme 1, BACE1)의 활성을 저해하는 것인 약학 조성물. (11) A pharmaceutical composition that inhibits the activity of beta-site APP-cleaving enzyme 1 (β-site APP-cleaving enzyme 1, BACE1) in (10).
(12) 베타-시크리타제 억제제로서 사용되는 메나퀴논-7. (12) Menaquinone-7 used as a beta-secretase inhibitor.
(13) 상기 (12)에서 베타-시크리타제를 억제하여, 베타-아밀로이드 생성 억제, 베타-아밀로이드의 응집 저해, 또는 베타-아밀로이드 생성 억제 및 베타-아밀로이드의 응집 저해를 위해 사용되는 것인 메나퀴논-7.(13) In (12) above, by inhibiting beta-secretase, beta-amyloid production inhibition, beta-amyloid aggregation inhibition, or beta-amyloid production inhibition and beta- menaquinone used for inhibiting aggregation of amyloid -7.
(14) 상기 (12)에서 뇌내 베타-아밀로이드 축적을 저해하여 퇴행성 뇌질환 예방, 개선, 또는 치료 용도로 사용되는 것인 메나퀴논-7. (14) In (12) above, menaquinone-7, which is used for preventing, improving, or treating degenerative brain diseases by inhibiting intracerebral beta-amyloid accumulation.
일 양상은 메나퀴논-7을 유효성분으로 포함하는 조성물은 베타-아밀로이드 생성을 억제하거나, 및/또는 베타-아밀로이드의 응집을 저해하는 효과를 나타낸다. 따라서, 퇴행성 뇌질환을 비롯한 퇴행성 신경질환에 대한 예방, 치료, 완화, 개선을 위한 약학 조성물 또는 식품 조성물 및 이의 용도로 사용하기 위한 메나퀴논-7을 제공할 수 있다. 예컨대 상기 조성물은 알츠하이머병을 비롯한 뇌내 베타-아밀로이드 축적과 관련한 질환을 앓고 있거나, 앓을 수 있는 환자에 대한 의약품, 보조제, 건강 식품 또는 기능성 식품으로 이용될 수 있다. In one aspect, a composition comprising menaquinone-7 as an active ingredient exhibits an effect of inhibiting beta-amyloid production, and/or inhibiting beta-amyloid aggregation. Therefore, it is possible to provide a pharmaceutical composition or food composition for the prevention, treatment, alleviation, and improvement of neurodegenerative diseases, including degenerative brain diseases, and menaquinone-7 for use therefor. For example, the composition may be used as a pharmaceutical, adjuvant, health food or functional food for patients suffering from or may suffer from diseases related to accumulation of beta-amyloid in the brain, including Alzheimer's disease.
도 1은 메나퀴논-7의 세포 생존력 및 베타-아밀로이드 생성에 미치는 영향을 확인한 도이다. 도 1A는 메나퀴논-7의 세포 독성유무를 확인한 도이다. 도 1B는 메나퀴논-7의 베타-아밀로이드 생성 억제에 대한 효과를 확인한 도이다.
도 2는 메나퀴논-7의 베타-시크리타제 발현에 대한 효과를 확인한 도이다. 도 2A는 sAPPβ 발현에 대한 효과를 나타내고, 도 2B는 베타-시크리타제 발현에 대한 효과를 나타낸다.
도 3은 메나퀴논-7의 알파-시크리타제 발현에 대한 효과를 확인한 도이다. 도 3A는 sAPPα 발현에 대한 효과를 나타내고, 도 3B는 알파-시크리타제 (ADAM10) 발현에 대한 효과를 나타낸다.
도 4는 메나퀴논-7의 베타-아밀로이드 응집 억제에 대한 효과를 확인한 도이다. 1 is a view confirming the effect of menaquinone-7 on cell viability and beta-amyloid production. 1A is a diagram confirming the presence or absence of cytotoxicity of menaquinone-7. 1B is a diagram confirming the effect of menaquinone-7 on the inhibition of beta-amyloid production.
2 is a view confirming the effect of menaquinone-7 on the beta-secretase expression. Figure 2A shows the effect on sAPPβ expression, Figure 2B shows the effect on beta-secretase expression.
3 is a diagram confirming the effect of menaquinone-7 on alpha-secretase expression. Figure 3A shows the effect on sAPPα expression, Figure 3B shows the effect on alpha-secretase (ADAM10) expression.
4 is a view confirming the effect of menaquinone-7 on the inhibition of beta-amyloid aggregation.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
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 전체가 참고로 통합된다.All technical terms used in the present invention, unless otherwise defined, have the same meaning as 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. The contents of all publications herein incorporated by reference are hereby incorporated by reference in their entirety.
일 양상은 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 예방 또는 치료용 약학 조성물을 제공한다. One aspect provides a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 명세서에서 사용된 용어 "퇴행성 신경질환(neurodegenerative disease)"은 노화와 깊은 관련을 가지면서, 정상적인 노화의 과정과는 달리 급속하게 신경계의 일부 또는 뇌 전체에 비정상적인 신경세포의 죽음이 일어나 뇌와 척수의 기능이 상실되어 인지 능력, 보행-운동 능력 등이 감소하는 질환을 의미한다. 예컨대 중추신경계의 뇌와 척수 세포가 퇴화 또는 소실 등의 이유로 인해 표현적인 기능장애로 나타나는 질환을 의미한다. As used herein, the term "neurodegenerative disease" is closely related to aging, and, unlike the normal process of aging, rapid death of abnormal nerve cells occurs in part of the nervous system or the entire brain, resulting in brain and spinal cord It refers to a disease in which cognitive ability, walking-motor ability, etc. are reduced due to loss of function. For example, it refers to a disease in which the brain and spinal cord cells of the central nervous system show expressive dysfunction due to degeneration or loss.
본 명세서에서 사용된 용어 "퇴행성 뇌질환(degenerative brain disease)"은 퇴행성 신경질환의 하나로서, 나이가 들어감에 따라 뇌에서 발생하는 질환을 말한다. 현재까지 잘 알려지지 않은 원인으로 뇌에서 특정 뇌세포군이 서서히 그 기능을 잃고 뇌신경계의 정보전달에 가장 중요한 뇌신경세포의 사멸, 뇌신경세포와 뇌신경세포 사이의 정보를 전달하는 시냅스의 형상이나 기능상의 문제 또는 뇌신경의 전기적 활동성의 이상적 증가나 감소로 인하여 야기되는 것으로 알려져 있다.As used herein, the term "degenerative brain disease" is one of neurodegenerative diseases, and refers to a disease that occurs in the brain as people age. Due to unknown causes, a specific group of brain cells gradually loses their function in the brain, and the death of cranial nerve cells, which is the most important for information transmission in the cranial nervous system, problems with the shape or function of synapses that transmit information between cranial nerve cells and cranial nerve cells, or It is known to be caused by an ideal increase or decrease in electrical activity of cranial nerves.
일 구체 예에서, 상기 퇴행성 신경질환은 베타-아밀로이드의 응집 또는 집적 등을 주된 원인으로 하는 모든 퇴행성 신경질환을 포함할 수 있다. In one embodiment, the neurodegenerative disease may include all neurodegenerative diseases mainly caused by aggregation or aggregation of beta-amyloid.
일 구체 예에서, 상기 퇴행성 신경질환은 알츠하이머병 (Alzheimer's disease, AD), 대뇌 아밀로이드 맥관병증 (Cerebral amyloid angiopathy), 전신성 아밀로이드증 (systematic amyloidosis), 루게릭병 (Amyotrophic lateral sclerosis 또는 Lou Gehrig disease), 헌팅턴병 (Huntington's disease), 니만-픽병 (Niemann-Pick Disease), 더취 (Dutch)형 아밀로이드증, 아밀로이드성 뇌졸중 (stroke), 파킨슨병 (Parkinson's disease), 경도 인지 장애 (Mild cognitive impairment), 노쇠 (Senility), 치매 (Dementia), 루이 소체 치매 (Lewy Body Dementia) 다경색 치매 (Multi-infarct dementia), 다운 증후군 (Down's syndrome), 뇌졸중 관련 치매 (Dementia associated with stroke), 파킨슨 질환 관련 치매 (Dementia associated with Parkinson's disease) 또는 베타-아밀로이드 관련 치매 (Dementia associated with beta-amyloid)일 수 있으나, 이에 한정되는 것은 아니다.In one embodiment, the neurodegenerative disease is Alzheimer's disease (AD), cerebral amyloid angiopathy, systemic amyloidosis, Lou Gehrig disease (Amyotrophic lateral sclerosis or Lou Gehrig disease), Huntington's disease ( Huntington's disease, Niemann-Pick disease, Dutch amyloidosis, amyloid stroke, Parkinson's disease, mild cognitive impairment, senility, dementia Dementia, Lewy Body Dementia Multi-infarct dementia, Down's syndrome, Dementia associated with stroke, Dementia associated with Parkinson's disease or beta-amyloid-associated dementia (Dementia associated with beta-amyloid), but is not limited thereto.
일 구체 예에서, 상기 퇴행성 신경질환은 알츠하이머병, 대뇌 아밀로이드 맥관병증, 루게릭병, 헌팅턴병, 및 니만-픽병으로 이루어진 군으로부터 선택되는 것일 수 있다. In one embodiment, the neurodegenerative disease may be selected from the group consisting of Alzheimer's disease, cerebral amyloid angiopathy, Lou Gehrig's disease, Huntington's disease, and Niemann-Pick's disease.
알츠하이머병 (Alzheimer's disease)은 뇌세포가 점진적으로 파괴되어 기억과 인지능이 점차로 상실되고 결국은 사망으로 이어지는 질환이다. 이 병이 있는 환자는 기억력이 서서히 감퇴될 뿐만 아니라, 현재 자기가 처한 상황을 정확히 이해하는 능력을 상실하게 되며, 학습능력, 언어능력 및 판단능력이 감퇴하고 나아가 자기 자신을 보살피는 능력까지 상실하는 치매(dementia)에 이르게 된다. 알츠하이머병에 걸린 환자의 뇌는 점차로 그 손상이 심해지면서 중추신경계는 물론 자율신경계의 기능까지 침해되어 전반적인 건강상태가 악화된다. 알츠하이머병에 걸린 환자의 뇌조직에는 베타-아밀로이드 (Aβ)라는 플라크 (senile plaques)가 축적되고 뇌세포에는 신경섬유성 엉킴 (neurofibrillary tangle, NFT)이 나타나며, 이로 인해 뇌조직 전반에 걸쳐 광범위한 퇴행성 위축이 일어난다. Alzheimer's disease is a disease in which brain cells are gradually destroyed, leading to a gradual loss of memory and cognitive ability, and eventually death. Patients with this disease not only gradually lose their memory, but also lose the ability to accurately understand their current situation, their learning ability, language ability and judgment ability, and even the ability to take care of themselves. leads to dementia. As the brain of patients with Alzheimer's disease is gradually damaged, the functions of the central nervous system as well as the autonomic nervous system are infringed and the overall health condition deteriorates. In the brain tissues of patients with Alzheimer's disease, senile plaques called beta-amyloid (Aβ) accumulate and neurofibrillary tangles (NFTs) appear in brain cells, resulting in extensive degenerative atrophy throughout the brain tissue. this happens
예를 들어, 상기 알츠하이머병은 알츠하이머 질환으로 야기되는 치매, 즉, 베타-아밀로이드이 뇌조직에 침착되어 발병하는 치매를 포함하며, 베타-아밀로이드의 침착으로 야기된 치매라면 본원 발명의 권리범위에 포함된다.For example, the Alzheimer's disease includes dementia caused by Alzheimer's disease, that is, dementia caused by deposition of beta-amyloid in brain tissue, and dementia caused by deposition of beta-amyloid is included in the scope of the present invention. .
대뇌 아밀로이드 맥관병증 (Cerebral amyloid angiopathy)은 피질과 연수막의 뇌혈관 벽에 아밀로이드가 침착되는 질환이다. 대뇌 아밀로이드 맥관병증은 뇌엽성 뇌출혈, 치매, 일과성 허혈발작, 간질발작 등을 일으킨다. 알츠하이머병에서 뇌 아밀로이드 혈관병증의 빈도가 80-90 %에 달한다는 연구결과들도 있으며, 알츠하이머병과 깊이 연관되는 것으로 생각된다. Cerebral amyloid angiopathy (Cerebral amyloid angiopathy) is a disease in which amyloid deposits on the walls of blood vessels in the brain in the cortex and leptomeningeal membrane. Cerebral amyloid angiopathy causes lobar cerebral hemorrhage, dementia, transient ischemic attacks, and epileptic seizures. There are also studies that the frequency of brain amyloid angiopathy in Alzheimer's disease reaches 80-90%, and it is thought to be deeply related to Alzheimer's disease.
전신성 아밀로이드증 (systematic amyloidosis)은 몸 전체에 걸쳐 아밀로이드 (amyloid) 단백질이 조직이나 장기에 지나치게 쌓여서 조직이나 장기의 기능 장애를 일으키는 질환을 총칭한다.Systemic amyloidosis is a generic term for diseases in which amyloid protein accumulates excessively in tissues or organs throughout the body, leading to dysfunction of tissues or organs.
본 명세서에서 사용된 용어 "아밀로이드 (Amyloid)"는 수용성 단백질이 다양한 생화학적 조선에서 비수용성 특성을 나타냄으로써 단백질간 특이적 상호작용에 의해 형성된 섬유상 구조물을 말한다. 위에서 언급한 다양한 퇴행성 신경질환에서 관찰되는 공통된 단백질 응집물에 해당한다. As used herein, the term “amyloid” refers to a fibrous structure formed by specific interactions between proteins by showing water-soluble proteins exhibiting water-insoluble properties in various biochemical vessels. It corresponds to a common protein aggregate observed in the various neurodegenerative diseases mentioned above.
일 구체 예에서, 상기 퇴행성 신경질환은 뇌내 베타-아밀로이드 축적과 관련된 질환일 수 있다. In one embodiment, the neurodegenerative disease may be a disease related to the accumulation of beta-amyloid in the brain.
일 구체 예에서, 상기 조성물은 베타-아밀로이드 생성을 억제할 수 있다. In one embodiment, the composition may inhibit beta-amyloid production.
일 구체 예에서, 상기 조성물은 베타-아밀로이드의 응집을 저해할 수 있다. In one embodiment, the composition may inhibit aggregation of beta-amyloid.
본 명세서에서 "메나퀴논-7 (Menaquinone-7, MK-7)"은 하기 화학식 1로 나타내어지는 화합물을 지칭한다. As used herein, "menaquinone-7 (Menaquinone-7, MK-7)" refers to a compound represented by the following formula (1).
[화학식 1][Formula 1]
본 명세서에서 사용된 용어 "유도체(derivative)"는 상기 화합물의 구조 일부를 다른 원자나 원자단으로 치환하여 얻어지는 화합물을 말한다. 상기 "치환"은 유기 화합물 중의 하나 이상의 수소 원자를 다른 원자단으로 치환하여 유도체를 형성한 경우 수소 원자 대신에 도입되는 것을 말하고, "치환기"는 도입된 원자단을 말한다. 치환기는 예를 들면, 히드록시기, 할로겐 원자(예, 불소(F), 염소(Cl), 브롬(Br), 및 요오드(I)), C2 내지 C10 알케닐기, C2 내지 C10 알키닐기, C1 내지 C10 헤테로알킬기, C6 내지 C10 아릴기, C6 내지 C10 헤테로아릴기, C1 내지 C10의 알콕시, 니트로기, 시아노기, 아미노기, 카르복실기나 그의 염, 술포닐기, 술파모일(sulfamoyl)기, 술폰산기나 그의 염, 인산이나 그의 염, 또는 이들의 조합일 수 있다.As used herein, the term "derivative" refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms. The "substitution" refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and "substituent" refers to an introduced atomic group. The substituent is, for example, a hydroxyl group, a halogen atom (eg, fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)), a C 2 to C 10 alkenyl group, a C 2 to C 10 alkynyl group. , C 1 to C 10 heteroalkyl group, C 6 to C 10 aryl group, C 6 to C 10 heteroaryl group, C 1 to C 10 alkoxy, nitro group, cyano group, amino group, carboxyl group or a salt thereof, sulfonyl group, It may be a sulfamoyl group, a sulfonic acid group or a salt thereof, phosphoric acid or a salt thereof, or a combination thereof.
상기 메나퀴논-7 또는 그의 유도체는 그의 이성질체를 포함한다. 상기 이성질체는 구조 이성질체 또는 입체이성질체일 수 있다.The menaquinone-7 or its derivative includes isomers thereof. The isomers may be structural isomers or stereoisomers.
본 명세서에서 사용된 용어 "용매화물(solvate)"은 유기 또는 무기 용매에 용매화된 화합물을 말한다. 상기 용매화물은 예를 들어, 수화물이다.As used herein, the term “solvate” refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.
본 명세서에서 사용된 용어 "염" 화합물의 무기산염, 유기산염, 또는 금속염의 부가염을 말한다. 상기 무기산염은 염산염, 브롬산염, 인산염, 황산염, 또는 이황산염일 수 있다. 상기 유기산염은 포름산염, 아세트산염, 프로피온산염, 젖산염, 옥살산염, 주석산염, 말산염, 말레인산염, 구연산염, 푸마르산염, 베실산염, 캠실산염, 에디실염, 트리클로로아세트산, 트리플루오로아세트산염, 벤조산염, 글루콘산염, 메탄술폰산염, 글리콜산염, 숙신산염, 4-톨루엔술폰산염, 갈룩투론산염, 엠본산염, 글루탐산염, 메탄술폰산, 에탄술폰산, 벤젠술폰산, p-톨루엔술폰산, 또는 아스파르트산염일 수 있다. 상기 금속염은 칼슘염, 나트륨염, 마그네슘염, 스트론튬염, 또는 칼륨염일 수 있다. 상기 염은 약학적으로 또는 식품학적으로 허용가능한 염일 수 있다. As used herein, the term “salt” refers to an addition salt of an inorganic, organic, or metal salt of a compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or aspartate It may be an acid. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt. The salt may be a pharmaceutically or food acceptable salt.
본 명세서에서 사용된 용어 "이의 약학적으로 허용가능한 염" 또는 "이의 식품학적으로 허용가능한 염"은 일반적으로 안전하며, 무독성이고, 생물학적으로도 다른 측면으로도 부적합하지 않아 약학적 및 식품학적 조성물의 제조에 사용가능함을 지칭한다. As used herein, the term "pharmaceutically acceptable salt thereof" or "food acceptable salt thereof" is generally safe, non-toxic, and is not biologically or otherwise unsuitable for pharmaceutical and food pharmaceutical compositions. indicates that it can be used in the manufacture of
다른 일 양상은 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 예방 또는 개선용 식품 조성물을 제공한다. Another aspect provides a food composition for preventing or improving neurodegenerative diseases comprising menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 우유, 요플레 등의 각종 낙농제품, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등의 식음료, 빵, 쵸코렛, 캔디류, 과자류 등의 스낵류를 포함하여, 통상적인 의미에서의 식품을 모두 포함한다. There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include various dairy products such as milk and yogurt, beverages, tea, drinks, alcoholic beverages and vitamin complexes, and snacks such as bread, chocolate, candy, and confectionery. It includes all foods in the sense of phosphorus.
상기 식품 조성물은 보조식품, 건강기능식품으로도 제공될 수 있다. The food composition may be provided as a supplement or a health functional food.
상기 조성물 중 메나퀴논-7은 약학적으로 또는 식품학적으로 유효한 함량으로 포함될 수 있다. 예를 들어, 상기 조성물 중 메나퀴논-7은 0.001 내지 1000 nM의 농도로 존재할 수 있다. 예를 들어, 상기 조성물 중 메나퀴논-7은 5 nM, 10 nM, 25 nM, 30nM, 40 nM, 50 nM, 60 nM, 75 nM, 100 nM, 200 nM 또는 이들 수치를 상한 또는 하한으로 하는 범위로 존재할 수 있다. 예를 들어, 상기 조성물 중 메나퀴논-7은 1 내지 10 M의 농도로 존재할 수 있다. 예를 들어, 상기 조성물 메나퀴논-7은 5 nM 내지 200 nM, 또는 10 nM 내지 100 nM 으로 존재할 수 있다. 예를 들어, 상기 조성물 중 메나퀴논-7은 퇴행성 신경질환 예방, 치료, 또는 개선을 위해 필요한 1일 투여량의 전부, 1/2, 또는 1/3의 양으로 포함될 수 있다. In the composition, menaquinone-7 may be included in an effective amount pharmaceutically or foodologically. For example, menaquinone-7 in the composition may be present in a concentration of 0.001 to 1000 nM. For example, menaquinone-7 in the composition is 5 nM, 10 nM, 25 nM, 30 nM, 40 nM, 50 nM, 60 nM, 75 nM, 100 nM, 200 nM, or a range using these values as upper or lower limits can exist as For example, menaquinone-7 in the composition may be present in a concentration of 1 to 10 M. For example, the composition menaquinone-7 may be present in an amount of 5 nM to 200 nM, or 10 nM to 100 nM. For example, menaquinone-7 in the composition may be included in an amount of all, 1/2, or 1/3 of the daily dose required for the prevention, treatment, or improvement of neurodegenerative diseases.
상기 조성물은 약학적으로 또는 식품학적으로 허용가능한 첨가제 또는 담체를 더 포함하는 것일 수 있다. 이러한 첨가제 또는 담체는 조성물 100 중량부당 예컨대 0.001 내지 90 중량부의 범위에서 적절하게 선택될 수 있다.The composition may further include a pharmaceutically or food-acceptable additive or carrier. Such additives or carriers may be appropriately selected, for example, in the range of 0.001 to 90 parts by weight per 100 parts by weight of the composition.
상기 조성물은 약학적으로 또는 식품학적으로 허용가능한 첨가제 또는 담체를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. The composition may be prepared in a unit dose form by formulating using a pharmaceutically or food acceptable additive or carrier, or may be prepared by internalizing in a multi-dose container.
상기 약학 또는 식품 조성물 중에 포함될 수 있는 첨가제는 부형제, 붕해제, 결합제, 활택제, 또는 그 조합일 수 있다. 상기 부형제는 미결정 셀룰로오스, 유당, 또는 저치환도 히드록시셀룰로오스 등으로 예시 될 수 있으나, 이에 한정되는 것은 아니다. 상기 붕해제는 전분글리콜산 나트륨, 또는 무수인산일수소 칼슘 등으로 예시 될 수 있으나, 이에 한정되는 것은 아니다. 상기 결합제는 폴리비닐피롤리돈, 저치환도 히드록시프로필셀룰로오스, 또는 히드록시프로필셀룰로오스 등으로 예시 될 수 있으나, 이에 한정되는 것은 아니다. 상기 활택제는 스테아린산 마그네슘, 이산화규소, 또는 탈크 등으로 예시 될 수 있으나, 이에 한정되는 것은 아니다.The additive that may be included in the pharmaceutical or food composition may be an excipient, a disintegrant, a binder, a lubricant, or a combination thereof. The excipient may be exemplified by microcrystalline cellulose, lactose, or low-substituted hydroxycellulose, but is not limited thereto. The disintegrant may be exemplified by sodium starch glycolate, or anhydrous calcium monohydrogen phosphate, but is not limited thereto. The binder may be exemplified by polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, or hydroxypropyl cellulose, but is not limited thereto. The lubricant may be exemplified by magnesium stearate, silicon dioxide, or talc, but is not limited thereto.
상기 조성물은 경구 또는 비경구 투여 제형으로 제형화될 수 있다. 경구 투여 제형은 과립제, 산제, 액제, 정제, 캅셀제, 건조시럽제, 또는 그 조합일 수 있다. 비경구 투여 제형은 주사제 또는 피부외용제일 수 있다. 피부외용제는 크림, 겔, 연고, 피부 유화제, 피부 현탁액, 경피전달성 패치, 약물 함유 붕대, 또는 로션, 등으로 예시 될 수 있으나, 이에 한정되는 것은 아니다.The composition may be formulated as an oral or parenteral dosage form. Oral dosage forms may be granules, powders, solutions, tablets, capsules, dry syrups, or a combination thereof. The parenteral dosage form may be an injection or an external preparation for skin. The external preparation for skin may be exemplified as a cream, gel, ointment, skin emulsifier, skin suspension, transdermal patch, drug-containing bandage, or lotion, but is not limited thereto.
상기 조성물의 투여는 당업계에 알려진 방법에 의하여 투여될 수 있다. 예를 들면, 정맥내, 근육내, 경구, 경피 (transdermal), 점막, 코안 (intranasal), 기관내 (intratracheal) 또는 피하 투여와 같은 경로로, 임의의 수단에 의하여 개체로 직접적으로 투여될 수 있다. 상기 투여는 전신적으로 또는 국부적으로 투여될 수 있다. Administration of the composition may be administered by a method known in the art. For example, it can be administered directly to a subject by any means, such as intravenous, intramuscular, oral, transdermal, mucosal, intranasal, intratracheal or subcutaneous administration. . The administration may be systemically or locally.
상기 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사 등은 소망하는 치료, 예방 또는 개선에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 일 구체 예에 따르면, 상기 조성물의 1일 투여량은 0.001 내지 10 g/㎏일 수 있다.A suitable dosage of the composition varies depending on factors such as formulation method, administration mode, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity of the patient, and usually skilled in the art. A physician or the like can readily determine and prescribe an effective dosage for the desired treatment, prevention or improvement. According to one embodiment, the daily dose of the composition may be 0.001 to 10 g / kg.
예를 들어, 퇴행성 신경질환 예컨대 알츠하이머성 치매 치료를 위한 뇌 조직 재생용 약제학적 조성물의 투여량은 유효성분의 흡수도, 불활성률 및 병용되는 약물을 고려하여 결정할 수 있으며, 1일 유효성분을 기준으로 하였을 때 0.1 mg/kg(체중) 내지 500 mg/kg(체중), 0.1 mg/kg(체중) 내지 400 mg/kg(체중) 또는 1 mg/kg(체중) 내지 300 mg/kg(체중)으로 투여할 수 있으며, 1회 또는 수회로 나누어 투여할 수 있으나, 이에 한정되는 것은 아니다.For example, the dosage of the pharmaceutical composition for brain tissue regeneration for the treatment of degenerative neurological diseases such as Alzheimer's dementia can be determined in consideration of the absorption of the active ingredient, the inactivation rate, and the drug used in combination, based on the daily active ingredient 0.1 mg/kg (body weight) to 500 mg/kg (body weight), 0.1 mg/kg (body weight) to 400 mg/kg (body weight), or 1 mg/kg (body weight) to 300 mg/kg (body weight) may be administered, and may be administered once or dividedly into several doses, but is not limited thereto.
다른 일 양상은 다른 일 양상은 뇌내 베타-아밀로이드 축적을 저해하기 위해 사용되는 퇴행성 뇌질환 예방, 개선, 또는 치료용 메나퀴논-7을 제공한다. Another aspect provides menaquinone-7 for preventing, ameliorating, or treating degenerative brain disease, which is used to inhibit beta-amyloid accumulation in the brain.
또 다른 일 양상은 메나퀴논-7을 유효성분으로 포함하는 조성물을 개체에게 투여하는 단계를 포함하는 개체의 퇴행성 신경질환을 예방, 개선 또는 치료하기 위한 방법을 제공한다. Another aspect provides a method for preventing, improving or treating a neurodegenerative disease of an individual comprising administering to the individual a composition comprising menaquinone-7 as an active ingredient.
본 명세서에서 사용되는 용어 "예방"은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸리기 쉬운 경향이 있는 개체에서 질환 또는 질병의 발생을 억제하는 것을 의미한다.As used herein, the term "prevention" refers to inhibiting the development of a disease or disorder in an individual who has not been diagnosed with the disease or disease, but is prone to the disease or disease.
본 명세서에서 사용되는 용어 "치료"는 개체에서 (a) 질환 또는 질병의 발전의 억제 (b) 질환 또는 질병의 경감 및 (c) 질환 또는 질환의 제거를 의미한다.As used herein, the term “treatment” refers to (a) inhibiting the development of a disease or disorder in a subject, (b) alleviating the disease or disorder, and (c) eliminating the disease or disorder.
본 명세서에서 사용되는 용어 "개선"은 개체에서 질환 또는 질병의 증세가 호전되는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action in which a disease or symptom of a disease is improved in an individual.
본 명세서에서 사용되는 용어 "개체"는 본 발명의 상기 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간을 포함한 원숭이, 소, 말, 돼지, 양, 개, 고양이, 래트, 마우스, 침팬지 등의 포유동물을 의미한다.As used herein, the term "individual" refers to monkeys, cows, horses, pigs, sheep, dogs, cats, rats, mice, chimpanzees, etc. means a mammal of
본 명세서에서 사용된 용어 "유효성분으로 포함"은 메나퀴논-7의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. As used herein, the term “including as an active ingredient” means including an amount sufficient to achieve the efficacy or activity of menaquinone-7.
예를 들어, 퇴행성 신경질환 예컨대 알츠하이머성 치매 치료를 위한 뇌 조직 재생용 약제학적 조성물 내 유효성분의 함량은 0.001 중량% 내지 99.9 중량%, 0.1 중량% 내지 99 중량% 또는 1 중량% 내지 50 중량%일 수 있으나, 이에 한정되는 것은 아니며, 조성물의 사용태양 및 사용방법에 따라 바람직한 함량으로 적절히 조절하여 사용될 수 있다.For example, the content of the active ingredient in the pharmaceutical composition for brain tissue regeneration for the treatment of degenerative neurological diseases such as Alzheimer's dementia is 0.001 wt% to 99.9 wt%, 0.1 wt% to 99 wt%, or 1 wt% to 50 wt% may be, but is not limited thereto, and may be appropriately adjusted to a desired content according to the usage aspect and method of use of the composition.
일 구체 예에서, 약학 조성물 전체 중량을 기초로 1 내지 80 중량%의 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 포함할 수 있다. In one embodiment, the pharmaceutical composition may contain 1 to 80% by weight of menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutical composition.
일 구체 예에서, 식품 조성물 전체 중량을 기초로 1 내지 80 중량%의 메나퀴논-7, 이의 유도체, 또는 이의 용매화물, 또는 이의 식품학적으로 허용가능한 염을 포함할 수 있다. In one embodiment, based on the total weight of the food composition, 1 to 80% by weight of menaquinone-7, a derivative thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof may be included.
또한, 조성물 중에서는 상기 유효성분 이외에 공지의 치매 치료 효과가 있는 것으로 당업계에 알려진 퇴행성 신경질환 치료제, 일 예로 타크린 (tacrine), 도네페질 (donepezil), 리바스티그민 (rivastigmine), 갈란타민 (galantamine)등의 물질을 추가적으로 포함할 수 있다.In addition, in the composition, in addition to the active ingredient, a therapeutic agent for degenerative neurological disease known in the art to have a known therapeutic effect on dementia, for example, tacrine, donepezil, rivastigmine, galantamine ( galantamine) and the like may be additionally included.
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 through examples. However, these examples are for illustrative purposes of the present invention, and the scope of the present invention is not limited to these examples.
제조예 1. 아밀로이드 전구체 단백질 (APP)를 과발현하는 형질주입 세포주 (APP-CHO 세포 사용)의 세포배양Preparation Example 1. Cell culture of a transfected cell line overexpressing amyloid precursor protein (APP) (using APP-CHO cells)
실험에 사용한 APP-CHO 세포주는 10% FBS가 함유된 RPMI 배지를 이용하여 37℃, 5% CO2 incubator에서 배양하였으며, 배지는 3일마다 교환해 주었다.The APP-CHO cell line used in the experiment was cultured in an RPMI medium containing 10% FBS at 37° C., 5% CO 2 in an incubator, and the medium was exchanged every 3 days.
제조예 2. 메나퀴논-7의 제조 Preparation Example 2. Preparation of menaquinone-7
메나퀴논-7은 ㈜지에프퍼멘텍에서 제조한것을 제공받아 사용하였다. Menaquinone-7 was supplied and used by GF Fermentec.
시험예 1. 메나퀴논-7의 세포독성 평가Test Example 1. Cytotoxicity evaluation of menaquinone-7
APP-CHO 세포에 대한 메나퀴논-7의 세포독성을 검사하기 위하여 MTT 기반 세포 독성 분석 (MTT-based cytotoxicity assay)을 실시하였다. 약물이 처리된 세포를 24시간 배양한 후, 5 mg/ml 농도의 MTT 시약 (3-(4,5-dimethyl thiaxo-2-yl)-2,5-diphenyltetrazolium bromide)을 넣고 3시간 배양하였다. 배지를 제거하고 DMSO를 넣어 30분간 용해시킨 후 Emax precision microplate reader (Molecular Devices, CA, USA)를 이용하여 540 nm에서 흡광도를 측정하였다. 동일한 방법으로 실시하되 메나퀴논-7을 처리하지 않은 군 (THF 처리)을 대조군으로 하였다.In order to examine the cytotoxicity of menaquinone-7 to APP-CHO cells, an MTT-based cytotoxicity assay was performed. After culturing the drug-treated cells for 24 hours, MTT reagent (3-(4,5-dimethyl thiaxo-2-yl)-2,5-diphenyltetrazolium bromide) at a concentration of 5 mg/ml was added and cultured for 3 hours. After removing the medium, adding DMSO and dissolving for 30 minutes, the absorbance was measured at 540 nm using an Emax precision microplate reader (Molecular Devices, CA, USA). In the same manner, but not treated with menaquinone-7 (THF treatment) was used as a control group.
도 1A는 메나퀴논-7의 세포 독성유무를 확인한 도이다. 1A is a diagram confirming the presence or absence of cytotoxicity of menaquinone-7.
도 1A에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 세포 생존력 (cell viability) (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 1A , the horizontal axis represents the concentration (nM) of menaquinone-7, and the vertical axis represents cell viability (expressed as a percentage of the control group).
도 1A에서와 같이 메나퀴논-7은 75 nM까지 독성이 나타나지 않았다. As shown in FIG. 1A, menaquinone-7 did not show toxicity up to 75 nM.
시험예 2. 메나퀴논-7의 베타-아밀로이드 생성 억제 평가 (ELISA)Test Example 2. Beta-amyloid production inhibition evaluation of menaquinone-7 (ELISA)
APP-CHO 세포를 96 well plate에 seeding을 한 후 메나퀴논-7을 처리하였다. 동일한 방법으로 실시하되 메나퀴논-7을 처리하지 않은 군 (THF 처리)을 대조군으로 하였다.APP-CHO cells were seeded in 96 well plates and treated with menaquinone-7. In the same manner, but not treated with menaquinone-7 (THF treatment) was used as a control group.
24시간 후 생성되어 상등액 (supernatant)으로 유리된 베타-아밀로이드 (Aβ)를 Human Aβ40 ELISA kit (Invitrogen)를 이용하여 측정하였다. Beta-amyloid (Aβ) produced after 24 hours and released as a supernatant was measured using a Human Aβ40 ELISA kit (Invitrogen).
도 1B는 메나퀴논-7의 베타-아밀로이드 생성 억제에 대한 효과를 확인한 도이다. 1B is a diagram confirming the effect of menaquinone-7 on the inhibition of beta-amyloid production.
도 1B에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 베타-아밀로이드 (amyloid-β, Aβ)의 생성량 (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 1B , the horizontal axis indicates the concentration (nM) of menaquinone-7, and the vertical axis indicates the amount of beta-amyloid (amyloid-β, Aβ) produced (expressed as a percentage of the control group).
도 1B에서와 같이 메나퀴논-7은 농도의존적으로 베타-아밀로이드 생성을 억제하였다. As shown in FIG. 1B, menaquinone-7 inhibited beta-amyloid production in a concentration-dependent manner.
시험예 3. 메나퀴논-7의 베타-아밀로이드 생성 억제 평가 (western blot analysis)Test Example 3. beta-amyloid production inhibition evaluation of menaquinone-7 (western blot analysis)
웨스턴 블랏 분석 (western blot analysis)을 이용하여 베타-시크리타제 (β-secretase), sAPPβ, 알파-시크리타제 (α-secretase) (ADAM10), sAPPα의 수준 변화를 측정하였다. 동일한 방법으로 실시하되 메나퀴논-7을 처리하지 않은 군 (THF 처리)을 대조군으로 하였다.Changes in the levels of beta-secretase, sAPPβ, α-secretase (ADAM10), and sAPPα were measured using western blot analysis. In the same manner, but not treated with menaquinone-7 (THF treatment) was used as a control group.
60mm dish에 배양한 세포들에 메나퀴논-7을 다양한 농도로 24시간 처리한 후 PBS로 세척하고 트립신 (trypsin)을 넣어 3분간 배양한 다음 떼어내어 EP튜브로 옮겼다. 1000 x g에서 원심분리를 통해 cell pellet을 만든 후 상등액을 제거하고 Lysis buffer 50μl를 넣었다. 30분 동안 -20℃에서 용해시켜 단백질을 추출한 후 SMARTTM BCA kit(Intron, Korea)를 이용하여 정량하였다. 추출한 단백질에 sample loading buffer를 넣고 100℃끓는 물에 10분 동안 끓인 후 사용할 때까지 -20℃에 보관 했다. 7.5% gel 또는 15% Acrylamide gel로 전기영동을 통해 단백질을 분리한 후 PVDF membrane으로 옮겼다. PVDF membrane의 항체에 대한 비특이적 결합을 차단하기 위하여 blocking buffer (5% skin milk in PBS) 용액에서 1시간 동안 반응 시킨 후 Tween 20을 함유한 PBS 용액 (0.1% PBST)으로 15분간 3번 세척 후 각 검증 단백질에 대한 1차 항체를 첨가하여 4℃에서 12시간 반응시켰다. 사용한 1차 항체는 다음과 같다. Cells cultured in a 60 mm dish were treated with menaquinone-7 at various concentrations for 24 hours, washed with PBS, incubated with trypsin for 3 minutes, and then removed and transferred to an EP tube. After making a cell pellet through centrifugation at 1000 x g, the supernatant was removed and 50 μl of lysis buffer was added. Proteins were extracted by dissolution at -20°C for 30 minutes, and then quantified using SMART TM BCA kit (Intron, Korea). Sample loading buffer was added to the extracted protein, boiled in 100°C boiling water for 10 minutes, and stored at -20°C until use. Proteins were separated by electrophoresis using 7.5% gel or 15% acrylamide gel, and then transferred to a PVDF membrane. After reacting for 1 hour in blocking buffer (5% skin milk in PBS) solution to block non-specific binding of PVDF membrane to antibody, washed 3 times for 15 minutes with PBS solution (0.1% PBST) containing
anti-β-secretase (1:1000; Abcam, MA, USA), anti-sAPPβ (1:1000; IBL-America, Minneapolis, MN, USA), anti-sAPPα (1:1,000; IBL-America, USA), anti-ADAM10 (1:1000; Abcam, Cambridge, UK) 및 anti-α-tubulin (1:20,000; Sigma Aldrich). anti-β-secretase (1:1000; Abcam, MA, USA), anti-sAPPβ (1:1000; IBL-America, Minneapolis, MN, USA), anti-sAPPα (1:1,000; IBL-America, USA) , anti-ADAM10 (1:1000; Abcam, Cambridge, UK) and anti-α-tubulin (1:20,000; Sigma Aldrich).
PBST 용액으로 15분간 3번 세척한 다음 2차 항체 (5% skin milk in PBS)로 1시간 반응시켰다. 이어서 ECL-spray (Advanta, CA, USA)로 반응시킨 후 G:Box iChemiXT Imager (Syngene, Cambridge, UK) 상에서 단백질을 확인하였다. After washing 3 times for 15 minutes with PBST solution, it was reacted with a secondary antibody (5% skin milk in PBS) for 1 hour. Then, after reaction with ECL-spray (Advanta, CA, USA), the protein was confirmed on a G:Box iChemiXT Imager (Syngene, Cambridge, UK).
(1) 메나퀴논-7의 베타-시크리타제 발현에 미치는 효과(1) Effects of menaquinone-7 on beta-secretase expression
메나퀴논-7이 베타-아밀로이드 생성을 억제하는 것이 베타-시크리타제를 억제함에 기인한 것인지 알아보기 위해 베타-시크리타제 및 그로 인해 생성되는 단편인 sAPPβ의 변화를 웨스턴 블랏 실험법으로 확인하였다. In order to determine whether menaquinone-7 inhibits beta-amyloid production due to inhibition of beta-secretase, changes in beta-secretase and sAPPβ, a fragment produced thereby, were confirmed by Western blot experimentation.
도 2는 메나퀴논-7의 베타-시크리타제 발현에 대한 효과를 확인한 도이다. 도 2A는 sAPPβ 발현에 대한 효과를 나타내고, 도 2B는 베타-시크리타제 발현에 대한 효과를 나타낸다. 2 is a view confirming the effect of menaquinone-7 on the beta-secretase expression. Figure 2A shows the effect on sAPPβ expression, Figure 2B shows the effect on beta-secretase expression.
도 2A에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 sAPPβ 발현량 (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 2A , the horizontal axis indicates the concentration (nM) of menaquinone-7, and the vertical axis indicates the sAPPβ expression level (expressed as a percentage of the control group).
도 2B에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 베타-시크리타제 발현량 (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 2B , the horizontal axis indicates the concentration (nM) of menaquinone-7, and the vertical axis indicates the beta-secretase expression level (expressed as a percentage of the control group).
도 2에서와 같이 메나퀴논-7의 농도의존적으로 sAPPβ와 베타-시크리타제의 양이 감소하였다. As shown in FIG. 2, the amounts of sAPPβ and beta-secretase were decreased in a concentration-dependent manner of menaquinone-7.
(2) 메나퀴논-7의 알파-시크리타제 발현에 미치는 효과(2) Effects of menaquinone-7 on alpha-secretase expression
메나퀴논-7이 베타-아밀로이드 생성을 억제하는 것이 알파-시크리타제를 활성화함에 기인한 것인지 알아보기 위해 알파-시크리타제 (ADAM10) 및 그로 인해 생성되는 단편인 sAPPα의 변화를 웨스턴 블랏 실험법으로 확인하였다. In order to examine whether menaquinone-7 inhibits beta-amyloid production due to activation of alpha-secretase, changes in alpha-secretase (ADAM10) and the resulting fragment, sAPPα, were confirmed by Western blot experimentation. .
도 3은 메나퀴논-7의 알파-시크리타제 발현에 대한 효과를 확인한 도이다. 도 3A는 sAPPα 발현에 대한 효과를 나타내고, 도 3B는 알파-시크리타제 (ADAM10) 발현에 대한 효과를 나타낸다.3 is a diagram confirming the effect of menaquinone-7 on alpha-secretase expression. Figure 3A shows the effect on sAPPα expression, Figure 3B shows the effect on alpha-secretase (ADAM10) expression.
도 3A에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 sAPPα 발현량 (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 3A , the horizontal axis indicates the concentration (nM) of menaquinone-7, and the vertical axis indicates the sAPPα expression level (expressed as a percentage of the control group).
도 3B에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 알파-시크리타제 (ADAM10) 발현량 (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 3B , the horizontal axis indicates the concentration (nM) of menaquinone-7, and the vertical axis indicates the expression level of alpha-secretase (ADAM10) (expressed as a percentage with respect to the control group).
도 3에서와 같이 메나퀴논-7이 고농도에서는 알파-시크리타제 (ADAM10)와 sAPPα를 미미하게 증가시켰으나 통계적 유의성은 없었다. As shown in FIG. 3, menaquinone-7 slightly increased alpha-secretase (ADAM10) and sAPPα at a high concentration, but there was no statistical significance.
시험예 4. 메나퀴논-7의 베타-아밀로이드 응집 억제 평가 (ThT assay)Test Example 4. Beta-amyloid aggregation inhibition evaluation of menaquinone-7 (ThT assay)
단량체에서 올리고머 및 피브릴 (fibril)로의 베타-아밀로이드 (Aβ)의 응집은 신경 독성을 유도하고 신경세포 사멸을 유발하는 것으로 알려져 있다. 따라서, 메나퀴논-7이 Aβ의 피브릴로의 자기 응집 (self-aggregation)을 억제할 수 있는지 평가하기 위해 티오플라빈 T 시험 (ThT assays)을 통해서 베타-아밀로이드 단량체 (Aβ monomer)의 양을 측정하였다. Aggregation of beta-amyloid (Aβ) from monomers to oligomers and fibrils is known to induce neurotoxicity and induce neuronal cell death. Therefore, to evaluate whether menaquinone-7 can inhibit the self-aggregation of Aβ into fibrils, the amount of beta-amyloid monomer (Aβ monomer) was measured through thioflavin T assays (ThT assays). measured.
베타-아밀로이드를 96well plate에 최종농도가 10 mM 되도록 분주한 후 다양한 농도의 메나퀴논-7과 혼합하여 37℃에서 24시간 반응시켰다. 그 후 티오플라빈 T 시험 용액 (ThT solution) (thioflavin with 100 mM glycine, pH 8.5)를 넣어 최종농도가 3 μM이 되도록 추가하고 20분 반응시킨 후 형광양을 442 excitation, 485 emission를 측정하는 형광측정기로 측정하였다. 동일한 방법으로 실시하되 메나퀴논-7을 처리하지 않은 군 (THF 처리)을 대조군으로 하였다.Beta-amyloid was aliquoted to a final concentration of 10 mM in a 96-well plate, mixed with menaquinone-7 at various concentrations, and reacted at 37° C. for 24 hours. Then, thioflavin T test solution (ThT solution) (thioflavin with 100 mM glycine, pH 8.5) was added so that the final concentration was 3 μM, and after 20 minutes of reaction, the amount of fluorescence was measured 442 excitation and 485 emission. It was measured with a measuring instrument. In the same manner, but not treated with menaquinone-7 (THF treatment) was used as a control group.
도 4는 메나퀴논-7의 베타-아밀로이드 응집 억제에 대한 효과를 확인한 도이다. 4 is a view confirming the effect of menaquinone-7 on the inhibition of beta-amyloid aggregation.
도 4에서 가로축은 메나퀴논-7의 농도 (nM)를 나타내고, 세로축은 ThT 형광 측정 결과 (대조군에 대한 백분율로 표시함)을 나타낸다. In FIG. 4 , the horizontal axis represents the concentration (nM) of menaquinone-7, and the vertical axis represents the ThT fluorescence measurement result (expressed as a percentage of the control group).
도 4에서와 같이 베타-아밀로이드 (Aβ)와 메나퀴논-7의 배양은 농도의존적으로 베타-아밀로이드 응집을 감소 시켰다. As shown in FIG. 4, the incubation of beta-amyloid (Aβ) and menaquinone-7 reduced beta-amyloid aggregation in a concentration-dependent manner.
예를 들어, 도 4에서 메나퀴논-7은 75 nM에서 베타-아밀로이드의 응집을 현저히 감소시켰다 (약 80%까지 감소시킴). 그러나 베타-아밀로이드 생성 억제 효과와는 달리 25 nM와 50 nM에서는 베타-아밀로이드 응집 억제 효과가 나타나지 않았다. For example, in FIG. 4, menaquinone-7 significantly reduced the aggregation of beta-amyloid at 75 nM (reduced by about 80%). However, unlike the beta-amyloid production inhibitory effect, the beta-amyloid aggregation inhibitory effect was not observed at 25 nM and 50 nM.
통계분석 statistical analysis
모든 자료와 도면은 평균 ± 표준 편차로 표현된다. 둘 또는 그 이상의 그룹 비교는 일원 분산 분석 (ANOVA)에 이어 Tukey의 사후 테스트 (SPSS 버전 17.0)에 의해 평가되었다. 차이는 P <0.05에서 통계적으로 유의 한 것으로 간주되었습다.All data and figures are expressed as mean ± standard deviation. Comparisons of two or more groups were assessed by one-way analysis of variance (ANOVA) followed by Tukey's post hoc test (SPSS version 17.0). Differences were considered statistically significant at P < 0.05.
본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로, 상기 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.Those of ordinary skill in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
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| US20140031432A1 (en) * | 2010-08-06 | 2014-01-30 | Ampere Life Sciences, Inc. | Treatment of mitochondrial diseases with vitamin k |
| WO2016131993A2 (en) * | 2015-02-20 | 2016-08-25 | Vitak B.V. | Vitamin k and capillary function |
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| US20140031432A1 (en) * | 2010-08-06 | 2014-01-30 | Ampere Life Sciences, Inc. | Treatment of mitochondrial diseases with vitamin k |
| WO2016131993A2 (en) * | 2015-02-20 | 2016-08-25 | Vitak B.V. | Vitamin k and capillary function |
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