KR102583195B1 - Composition Comprising Quinovic Acid for Preventing or Treating of Neurodegenerative Disease - Google Patents
Composition Comprising Quinovic Acid for Preventing or Treating of Neurodegenerative Disease Download PDFInfo
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- KR102583195B1 KR102583195B1 KR1020200172462A KR20200172462A KR102583195B1 KR 102583195 B1 KR102583195 B1 KR 102583195B1 KR 1020200172462 A KR1020200172462 A KR 1020200172462A KR 20200172462 A KR20200172462 A KR 20200172462A KR 102583195 B1 KR102583195 B1 KR 102583195B1
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- acid
- amyloid beta
- disease
- brain
- quinoba
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
본 발명은 퀴노바산을 포함하는 조성물로, 본 발명의 조성물을 섭취 또는 투여할 경우, 퇴행성 뇌질환을 예방, 개선 및 치료할 수 있으며, 인지기능을 증진시킬 수 있는 효과가 있다. The present invention is a composition containing quinoba acid, and when ingested or administered, the composition of the present invention can prevent, improve, and treat degenerative brain diseases and has the effect of improving cognitive function.
Description
본 발명은 퀴노바산을 포함하는 퇴행성 뇌질환 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating degenerative brain diseases containing quinobaic acid.
우리나라 전체 인구 중 65세 이상 인구가 차지하는 고령화율이 2019년 기준 15.36%를 기록하였다. 이에 따라 퇴행성 질환의 대표적 질환인 알츠하이머성 치매를 앓는 인구가 급속도로 늘어나고 있다. 중앙치매센터가 발간한 '대한민국 치매 현황 2019' 보고서에 따르면, 국내 65세 이상 노인 인구 중 75만 488명이 치매환자로 추정되며 치매 유병률은 10.16%에 달한다. 이는 노인 10명 중 1명이 치매를 앓는 꼴이며, 향후 치매환자가 2024년에는 100만명, 2039년에는 200만명, 2050년에는 300만 명을 넘어설 것으로 예상되고 있다.The aging rate, which accounts for the population aged 65 or older among the total population in Korea, was 15.36% as of 2019. Accordingly, the number of people suffering from Alzheimer's dementia, a representative degenerative disease, is rapidly increasing. According to the 'Status of Dementia in Korea 2019' report published by the Central Dementia Center, 750,488 people aged 65 or older in Korea are estimated to have dementia, and the prevalence of dementia is 10.16%. This means that 1 in 10 elderly people suffer from dementia, and the number of dementia patients is expected to exceed 1 million in 2024, 2 million in 2039, and 3 million in 2050.
알츠하이머성 치매 등 퇴행성 뇌질환을 일으키는 원인으로 크게 두 가지 단백질의 활동이 주목 받고 있다. 상기 두 가지 단백질은 아밀로이드 베타(amyloid-β) 단백질의 응집에 의한 아밀로이드 플라크(amyloid plaque)와 타우 단백질이 응집해 형성되는 타우 탱글(tau tangle)이다. 상기 아밀로이드 베타가 뇌에 쌓이게 되면, 시냅스가 점차 사라져서 결국 기억을 잃는다. 따라서 아밀로이드 베타가 쌓였을 때 나타나는 반응들을 억제할 수 있는 물질이 있다면, 퇴행성 뇌질환을 예방 또는 치료하는 좋은 치료제로 사용될 수 있을 것이다.The activity of two proteins is receiving attention as a cause of degenerative brain diseases such as Alzheimer's dementia. The above two proteins are amyloid plaques formed by the aggregation of amyloid-β protein and tau tangles formed by the aggregation of tau proteins. When the amyloid beta accumulates in the brain, synapses gradually disappear and eventually memory is lost. Therefore, if there is a substance that can suppress the reactions that occur when amyloid beta accumulates, it could be used as a good treatment to prevent or treat degenerative brain diseases.
일 양상은 퀴노바산을 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One aspect is to provide a pharmaceutical composition for preventing or treating degenerative brain diseases containing quinobaic acid.
다른 양상은 퀴노바산을 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품 조성물을 제공하는 것이다. Another aspect is to provide a food composition for preventing or improving degenerative brain diseases containing quinoba acid.
또 다른 양상은 퀴노바산을 포함하는 인지기능 증진용 식품 조성물을 제공하는 것이다.Another aspect is to provide a food composition for improving cognitive function containing quinobic acid.
일 양상은 퀴노바산을 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One aspect is to provide a pharmaceutical composition for preventing or treating degenerative brain diseases containing quinobaic acid.
상기 퀴노바산은 생약성분 중 하나로, 식물들로부터 추출할 수 있는 성분일 수 있고, 화학식 C30H46O5 인 화합물로 화학구조는 하기 화학식 1일 수 있다. The quinobaic acid is one of the herbal ingredients and may be a component that can be extracted from plants. It is a compound with the chemical formula C 30 H 46 O 5 and its chemical structure may be the following formula 1.
상기 퇴행성 뇌질환은 아밀로이드 베타(Amyloid Beta, Aβ)가 축적되는 것을 통해 나타나는 것일 수 있고, 콜레스테롤이 뇌의 피질과 해마에 축적되므로 나타나는 것일 수 있으며, 산화 스트레스로 인해 나타나는 것일 수 있다. 또한, 퇴행성 뇌질환은 뇌의 염증이 나타나는 것일 수 있다.The degenerative brain disease may be caused by accumulation of amyloid beta (Aβ), may be caused by cholesterol accumulating in the brain cortex and hippocampus, or may be caused by oxidative stress. Additionally, degenerative brain disease may be caused by brain inflammation.
일 구체예에 있어서, 상기 퇴행성 뇌질환은 파킨슨 병(parkinson's disease), 헌팅턴병(huntington's disease), 알츠하이머병(alzheimer's disease), 경도인지 장애(mild cognitive impairment), 노인성 치매(senile dementia), 루게릭병(amyotrophic lateral sclerosis), 투렛 증후군(tourette syndrome), 근육긴장이상(dystonia), 진행성 핵상안근마비(progressive supranuclear ophthalmoplegia) 및 전두측두치매(frontotemporal dementia(FTD))로 구성된 군으로부터 선택되는 어느 하나인 것 일 수 있다. In one embodiment, the degenerative brain disease is Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, Lou Gehrig's disease ( Any one selected from the group consisting of amyotrophic lateral sclerosis, Tourette syndrome, dystonia, progressive supranuclear ophthalmoplegia, and frontotemporal dementia (FTD). You can.
본 발명에서 '예방'은 퇴행성 뇌질환이 발생하는 것을 지연시키거나 억제하는 모든 행위를 의미한다. 상기 예방은 뇌의 해마와 피질에 신경 염증을 억제하는 것일 수 있고, 콜레스테롤 축적을 억제하는 것일 수 있으며, ROS를 감소시키는 것일 수 있다. In the present invention, 'prevention' refers to all actions that delay or suppress the occurrence of degenerative brain disease. The prevention may include suppressing neuroinflammation in the hippocampus and cortex of the brain, suppressing cholesterol accumulation, and reducing ROS.
본 발명에서 '치료'는 퇴행성 뇌질환의 증상이 호전되도록 하거나 이롭게 되도록 하는 모든 행위를 의미한다. 상기 치료는 뇌의 해마와 피질에 신경 염증을 완화하는 것일 수 있고, 콜레스테롤 축적을 완화하는 것일 수 있으며, ROS를 감소하는 것일 수 있다. 또한, 공간 인지능력 및 장기 기억을 회복하는 것일 수 있다. In the present invention, 'treatment' refers to any action that improves or benefits the symptoms of a degenerative brain disease. The treatment may be alleviating neuroinflammation in the hippocampus and cortex of the brain, alleviating cholesterol accumulation, and reducing ROS. Additionally, it may restore spatial cognitive abilities and long-term memory.
본 발명에서 상기 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용할 수 있다. 상세하게는 제형화 할 경우 통상 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제로는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하나, 이에 한정되는 것은 아니다. 이러한 고형 제제는 상기 퀴노바산을 포함하는 조성물 또는 이의 약학적으로 허용 가능한 염에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 비경구 투여를 위한 제제는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제 및 과제를 포함한다. 비수성 용제 및 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로솔, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등을 사용할 수 있다. In the present invention, the pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. there is. In detail, it can be prepared using commonly used diluents or excipients such as fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc. Such solid preparations can be prepared by mixing the composition containing quinobaic acid or a pharmaceutically acceptable salt thereof with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and preparations. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, wethepsol, macrosol, Tween 61, cacao, laurin, glycerogelatin, etc. can be used.
본 발명의 조성물의 적합한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The appropriate dosage of the composition of the present invention varies depending on the patient's condition and weight, degree of disease, drug form, and time, but can be appropriately selected by a person skilled in the art.
다른 양상은 퀴노바산을 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품 조성물을 제공하는 것이다. Another aspect is to provide a food composition for preventing or improving degenerative brain diseases containing quinoba acid.
일 구체예에 있어서, 상기 퇴행성 뇌질환은 파킨슨 병(parkinson's disease), 헌팅턴병(huntington's disease), 알츠하이머병(alzheimer's disease), 경도인지 장애(mild cognitive impairment), 노인성 치매(senile dementia), 루게릭병(amyotrophic lateral sclerosis), 투렛 증후군(tourette syndrome), 근육긴장이상(dystonia), 진행성 핵상안근마비(progressive supranuclear ophthalmoplegia) 및 전두측두치매(frontotemporal dementia(FTD))로 구성된 군으로부터 선택되는 어느 하나인 것을 일 수 있다. In one embodiment, the degenerative brain disease is Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, Lou Gehrig's disease ( Any one selected from the group consisting of amyotrophic lateral sclerosis, Tourette syndrome, dystonia, progressive supranuclear ophthalmoplegia, and frontotemporal dementia (FTD). You can.
본 발명에서 '퀴노바산', '퇴행성 뇌질환' 및 '예방'에 관한 설명은 상기에 기재되어있는 것과 동일하다. In the present invention, the descriptions of 'quinobaic acid', 'degenerative brain disease', and 'prevention' are the same as those described above.
본 발명에서 '개선'은 퇴행성 뇌질환의 증상을 완화하거나, 퇴행성 뇌질환의 진행을 억제하는 모든 행위를 의미한다. In the present invention, 'improvement' refers to any action that alleviates the symptoms of a degenerative brain disease or inhibits the progression of a degenerative brain disease.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로써 퀴노바산 외에, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함할 수 있다. 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어, 말토오스, 수크로오스, 올리고당 등; 및 폴리사카라이드, 예를 들어, 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 향미제로서 천연 향미제[타우마틴, 스테비아 추출물(예를 들어, 레바우디오시드 A, 글리시르히진 등)] 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is manufactured as a food composition, in addition to quinoacid as an active ingredient, it may contain ingredients commonly added during food production, such as proteins, carbohydrates, fats, nutrients, seasonings, and May contain flavoring agents. Examples of carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
예를 들어, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 퀴노바산 외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액 및/또는 감초 추출액 등이 추가로 포함될 수 있다.For example, when the food composition of the present invention is manufactured as a drink, in addition to the quinoba acid of the present invention, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, Eucommia extract, jujube extract and/or licorice extract, etc. Additional items may be included.
또한, 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. In addition, the food composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may contain salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있으며, 이러한 첨가제의 비율은 본 발명의 식품 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택될 수 있으나, 이에 한정되는 것은 아니다.These ingredients can be used independently or in combination, and the ratio of these additives can be selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
일 구체예에 따르면 상기 식품 조성물은 건강기능식품, 기능성 음료, 야채주스, 발효유일 수 있으나 이에 제한되지 않는다. According to one embodiment, the food composition may be health functional food, functional beverage, vegetable juice, or fermented milk, but is not limited thereto.
또 다른 양상은 퀴노바산을 포함하는 인지기능 증진용 식품 조성물을 제공하는 것이다.Another aspect is to provide a food composition for improving cognitive function containing quinobic acid.
본 발명에서 '인지기능'은 무엇을 알아차리고 함축적인 사고로 깨닫게 되는 지적인 과정을 총칭하는 것으로, 공간을 인지하는 것일 수 있고, 학습 능력, 판단 능력 및 기억력 등을 포함하는 것일 수 있다. In the present invention, 'cognitive function' is a general term for the intellectual process of noticing something and realizing it through implicit thinking, and may include recognizing space, learning ability, judgment ability, and memory.
본 발명에서 '증진'은 인지기능이 향상되는 것을 의미하는 것으로, 공간 인지 능력, 학습 능력, 판단 능력 및 기억력 등의 향상을 의미하는 것일 수 있다. In the present invention, 'enhancement' means improvement in cognitive function, and may mean improvement in spatial cognitive ability, learning ability, judgment ability, and memory.
본 발명에서 '퀴노바산', '식품 조성물'에 관한 설명은 상기에 기재되어 있는 것과 동일하다. In the present invention, the description of ‘quinoba acid’ and ‘food composition’ is the same as that described above.
본 발명의 퀴노바산을 포함하는 조성물을 섭취 또는 투여할 경우, 퇴행성 뇌질환을 예방, 개선 및 치료할 수 있으며, 인지기능을 증진시킬 수 있다. When ingesting or administering a composition containing quinoba acid of the present invention, degenerative brain diseases can be prevented, improved, and treated, and cognitive function can be improved.
도 1은 퀴노바산(Quinovic acid: QA) 처리 농도에 따른 세포의 생존도를 비교한 데이터이다.
도 2는 아밀로이드 베타(Amyloid Beta: Aβ)처리 후, 퀴노바산의 처리 농도에 따른 세포 생존도를 비교한 데이터이다.
도 3의 A는 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 유리 콜레스테롤의 양을 확인한 데이터이고, B는 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 처리에 따른 총 콜레스테롤의 양을 확인한 데이터이다.
도 4는 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따라 콜레스테롤 축적과 관련된 요인의 변화를 확인한 데이터로, A는 HMGCR, B는 p53의 발현을 확인한 것이다.
도 5는 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 ROS(Reactive Oxygen Species)의 변화를 확인한 데이터이다.
도 6은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 GSH(glutathione)의 변화를 확인한 데이터이다.
도 7은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 GSH: GSSG(산화 GSH)의 비율을 나타낸 데이터이다.
도 8은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 Nrf2의 변화를 확인한 데이터이다.
도 9는 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 HO-1의 변화를 확인한 데이터이다.
도 10은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 GFAP의 변화를 확인한 데이터이다.
도 11은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 Iba-1의 변화를 확인한 데이터이다.
도 12는 신경염증 완화 여부를 보기 위해 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 IL-1β의 변화를 확인한 데이터이다.
도 13은 신경염증 완화 여부를 보기 위해 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 p-Jnk의 변화를 확인한 데이터이다.
도 14는 신경염증 완화 여부를 보기 위해 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 p-NF-κB의 변화를 확인한 데이터이다.
도 15는 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 미토콘드리아 세포사멸 마커인 Bax의 변화를 확인한 데이터이다.
도 16은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 미토콘드리아 세포사멸 마커인 Bcl-2의 변화를 확인한 데이터이다.
도 17은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 미토콘드리아 세포사멸 마커인 Cyt-C의 변화를 확인한 데이터이다.
도 18은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 미토콘드리아 세포사멸 마컨인 Casp-3의 변화를 확인한 데이터이다.
도 19는 니슬 소체(Nissl body)를 염색하여 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따른 뇌의 밀도를 본 데이터이다.
도 20은 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따라 시냅스 조절 마커인 PSD-95의 변화를 확인한 데이터이다.
도 21인 뇌의 피질과 해마에서 아밀로이드 베타 및 퀴노바산 투여에 따라 시냅스 조절 마커인 SYP의 변화를 확인한 데이터이다.
도 22는 아밀로이드 베타 및 퀴노바산 투여에 따라 마우스의 플랫폼을 찾아내는 시간을 훈련 받는 5일간 기록한 데이터이다.
도 23은 5일간 훈련 받은 후, 6일차에 아밀로이드 베타 및 퀴노바산 투여에 따라 마우스의 플랫폼을 찾아내는 시간을 나타내는 데이터이다.
도 24는 6일차에 프로브 테스트(Probe test)시 아밀로이드 베타 및 퀴노바산 투여에 따라 마우스가 플랫폼이 있었던 사분면에 머물렀던 시간을 나타낸 데이터이다.
도 25는 6일차에 프로브 테스트(Probe test)시 아밀로이드 베타 및 퀴노바산 투여에 따라 마우스가 플랫폼이 있었던 자리를 교차한 횟수를 나타낸 데이터이다.
도 26은 Y 미로 실험시 아밀로이드 베타 및 퀴노바산 투여에 따라 마우스가 새로운 공간을 파악하고 순차적으로 미로에 들어간 상대적 빈도를 나타낸 것이다. Figure 1 shows data comparing cell viability according to quinovic acid (QA) treatment concentration.
Figure 2 shows data comparing cell viability according to the treatment concentration of quinoba acid after amyloid beta (Aβ) treatment.
A in Figure 3 is data confirming the amount of free cholesterol in the brain cortex and hippocampus following amyloid beta and quinoba acid administration, and B is the amount of total cholesterol in the brain cortex and hippocampus following amyloid beta and quinoba acid treatment. This is data that confirmed .
Figure 4 shows data confirming changes in factors related to cholesterol accumulation in the brain cortex and hippocampus following administration of amyloid beta and quinobic acid, with A confirming the expression of HMGCR and B confirming the expression of p53.
Figure 5 shows data confirming changes in ROS (Reactive Oxygen Species) in the brain cortex and hippocampus following amyloid beta and quinoba acid administration.
Figure 6 shows data confirming changes in GSH (glutathione) following administration of amyloid beta and quinoacid in the brain cortex and hippocampus.
Figure 7 is data showing the ratio of GSH: GSSG (oxidized GSH) in the brain cortex and hippocampus according to amyloid beta and quinobic acid administration.
Figure 8 shows data confirming changes in Nrf2 following administration of amyloid beta and quinoacid in the brain cortex and hippocampus.
Figure 9 shows data confirming changes in HO-1 in the brain cortex and hippocampus following amyloid beta and quinoba acid administration.
Figure 10 shows data confirming changes in GFAP following administration of amyloid beta and quinoacid in the brain cortex and hippocampus.
Figure 11 shows data confirming changes in Iba-1 in the brain cortex and hippocampus following amyloid beta and quinoba acid administration.
Figure 12 shows data confirming changes in IL-1β following amyloid beta and quinoba acid administration in the brain cortex and hippocampus to see whether neuroinflammation is alleviated.
Figure 13 shows data confirming changes in p-Jnk following administration of amyloid beta and quinoacid in the brain cortex and hippocampus to see whether neuroinflammation is alleviated.
Figure 14 shows data confirming changes in p-NF-κB following administration of amyloid beta and quinoacid in the brain cortex and hippocampus to see whether neuroinflammation is alleviated.
Figure 15 shows data confirming changes in Bax, a mitochondrial apoptosis marker, following administration of amyloid beta and quinoacid in the brain cortex and hippocampus.
Figure 16 shows data confirming changes in Bcl-2, a mitochondrial apoptosis marker, following administration of amyloid beta and quinoacid in the brain cortex and hippocampus.
Figure 17 shows data confirming changes in Cyt-C, a mitochondrial apoptosis marker, in the brain cortex and hippocampus following amyloid beta and quinoba acid administration.
Figure 18 shows data confirming changes in Casp-3, a mitochondrial apoptosis marker, following administration of amyloid beta and quinoacid in the brain cortex and hippocampus.
Figure 19 shows data showing brain density according to amyloid beta and quinoba acid administration in the brain cortex and hippocampus by staining Nissl bodies.
Figure 20 shows data confirming changes in PSD-95, a synaptic regulation marker, in the brain cortex and hippocampus following administration of amyloid beta and quinoacid.
Figure 21 is data confirming changes in SYP, a synaptic regulation marker, in the brain cortex and hippocampus following administration of amyloid beta and quinoacid.
Figure 22 shows data recorded for 5 days during which the mouse was trained to find the platform according to the administration of amyloid beta and quinobic acid.
Figure 23 is data showing the time for mice to find the platform according to amyloid beta and quinoba acid administration on the 6th day after training for 5 days.
Figure 24 is data showing the time the mouse stayed in the quadrant where the platform was located according to the administration of amyloid beta and quinoba acid during the probe test on the 6th day.
Figure 25 is data showing the number of times the mouse crossed the platform location according to the administration of amyloid beta and quinobic acid during the probe test on the 6th day.
Figure 26 shows the relative frequency with which mice identified a new space and sequentially entered the maze according to the administration of amyloid beta and quinoacid during the Y maze experiment.
이하 하나 이상의 구체예를 실시예를 통해 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, one or more embodiments will be described in more detail through examples. However, these examples are intended to illustrate one or more embodiments and the scope of the present invention is not limited to these examples.
실험예 1. 약물준비Experimental Example 1. Drug preparation
동물 실험에서는 인간 Aβ(1-42) 펩타이드(Sigma Chemicals Co.에서 구입)를 멸균 식염수 용액에서 1mg/ml의 저장 농도로 만들고, 37℃에서 배양하여 응집시켜 마우스 당 5μl씩 투여하였다. In animal experiments, human Aβ(1-42) peptide (purchased from Sigma Chemicals Co.) was made to a storage concentration of 1 mg/ml in sterile saline solution, incubated at 37°C for aggregation, and administered at 5 μl per mouse.
세포실험에서는 올리고머 Aβ(1-42)(Oligomeric amyloid-beta: AβO)는 논문[Ali, T.; Yoon, G.H.; Shah, S.A.; Lee, H.Y.; Kim, M.O. Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Scientific reports 2015, 5, 11708, doi: 10.1038/srep11708.]에 개시된 대로 준비하였다. 간단히 설명하자면, Aβ(1-42) 펩타이드는 100% 헥사플루오소프로판올(HFIP; Hexafluoroisopropanol)에 용해하였다. 그 후, HFIP를 진공에서 증발시키고 디메틸설폭사이드(DMSO) 첨가하여 5mM 현탁액을 생성하였다. 5mM HFIP가 처리된 Aβ(1-42) 현탁액을 페놀 레드가 없는 F-12 배양 배지(Gibco by Life Technologies, USA에서 구입)를 100μM로 처리하여 5℃에서 24시간동안 배양하였다. 배양된 용액을 4℃에서 10분간 14,000rpm으로 원심 분리하고 AβO를 포함하는 상청액을 수집하였다. 세포 처리를 위해 AβO는 최종농도 5μM로 사용하였다.In cell experiments, oligomeric Aβ(1-42) (Oligomeric amyloid-beta: AβO) was tested in the paper [Ali, T.; Yoon, G.H.; Shah, S.A.; Lee, H.Y.; Kim, M.O. Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. It was prepared as described in [Scientific reports 2015, 5, 11708, doi: 10.1038/srep11708.]. Briefly, the Aβ(1-42) peptide was dissolved in 100% hexafluoroisopropanol (HFIP). Afterwards, HFIP was evaporated in vacuum and dimethyl sulfoxide (DMSO) was added to produce a 5mM suspension. Aβ(1-42) suspension treated with 5mM HFIP was treated with 100μM phenol red-free F-12 culture medium (purchased from Gibco by Life Technologies, USA) and cultured at 5°C for 24 hours. The cultured solution was centrifuged at 14,000 rpm for 10 minutes at 4°C, and the supernatant containing AβO was collected. For cell treatment, AβO was used at a final concentration of 5 μM.
퀴노바산(QA: Quinocvic acid)은 논문[Saleem, S.; Jafri, L.; ul Haq, I.; Chang, L.C.; Calderwood, D.; Green, B.D.; Mirza, B. Plants Fagonia cretica L. and Hedera nepalensis K. Koch contain natural compounds with potent dipeptidyl peptidase-4 (DPP-4) inhibitory activity. J. Ethnopharmacol. 2014, 156, 26-32, doi: 10.1016/j.jep.2014.08.017.]에 보고된 대로 분리하였다. 분리한 퀴노바산을 동물 실험에서는 멸균된 식염수에 용해시켜 50mg/kg으로 복강주사(intraperitoneal, IP)로 투여하고, 세포실험에서는 DMSO에 용해시켜 사용하였다.Quinocvic acid (QA) was described in the paper [Saleem, S.; Jafri, L.; ul Haq, I.; Chang, L. C.; Calderwood, D.; Green, B. D.; Mirza, B. Plants Fagonia cretica L. and Hedera nepalensis K. Koch contain natural compounds with potent dipeptidyl peptidase-4 (DPP-4) inhibitory activity. J. Ethnopharmacol. It was isolated as reported in [2014, 156, 26-32, doi: 10.1016/j.jep.2014.08.017.]. In animal experiments, the isolated quinoba acid was dissolved in sterilized saline and administered by intraperitoneal (IP) injection at 50 mg/kg, and in cell experiments, it was dissolved in DMSO.
실험예 2. 세포 배양Experimental Example 2. Cell culture
인간 신경 모세포종 SH-SY5Y 세포(한국 세포주 은행에서 구매)는 1% 페니실린-스트렙토마이신과 10% 우태아 혈청(FBS)이 보충된 MEM+F12(1:1)에서 37℃, 5% CO2 조건으로 배양하였다. 세포가 60-70% 포화되었을 때 실험에 사용하였다.Human neuroblastoma SH-SY5Y cells (purchased from the Korean Cell Line Bank) were grown in MEM+F12 (1:1) supplemented with 1% penicillin-streptomycin and 10% fetal bovine serum (FBS) at 37°C and 5% CO 2 conditions. It was cultured. Cells were used for experiments when they were 60-70% confluent.
실험예 3. MTT 어세이Experimental Example 3. MTT Assay
세포의 생존력 및 용량 최적화 수준을 평가하기 위하여, MTT(3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 분석을 사용하였다. SH- SY5Y 세포는 1% 페니실린-스트렙토마이신 및 10% FBS로 증강된 웰 당 100ml MEM+F12(1:1) 배지가 들어있는 96 웰 플레이트에 웰 당 2x104 개 세포를 접종하여 성장시켰다. 세포는 37℃, 5% CO2 조건으로 배양되었고, 배지는 정기적으로 교체하였다. 배지 포화도 60-70%에서 배지를 변경하였고, 세포는 적정 용량을 확인하기 위해 퀴노바산(0, 5, 10, 30, 55, 70, 85, 100 및 115μM)을 다른 농도로 단독 처리하거나 5μM의 AβO와 동시처리하고 24시간동안 37℃에서 배양하였다. DMSO의 최종농도는 각 웰당 0.25% 미만으로 유지되게 하였다. To evaluate cell viability and dose optimization level, MTT (3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used. SH-SY5Y cells were grown by seeding 2x10 cells per well in a 96-well plate containing 100ml MEM+F12 (1:1) medium per well supplemented with 1% penicillin-streptomycin and 10% FBS. Cells were cultured at 37°C and 5% CO 2 conditions, and the medium was replaced regularly. The medium was changed at 60-70% media saturation, and cells were treated with different concentrations of quinoacid (0, 5, 10, 30, 55, 70, 85, 100, and 115 μM) alone or 5 μM to determine the appropriate dose. was co-treated with AβO and incubated at 37°C for 24 hours. The final concentration of DMSO was maintained below 0.25% for each well.
대조 배양 웰은 유지 배지를 포함하거나 0.2% DMSO(Vehicle Control)를 첨가하였습니다. 배양 후, 웰 당 10μL의 MTT를 첨가하고 4시간 동안 배양하였다. 형성된 포르마잔은 배지를 제거하고 10~15분 더 배양한 후 100μL의 DMSO를 첨가하여 용해하였다. 흡광도는 마이크로 플레이트 리더 ApoTox-Glo™(Promega, Madison, WI, USA)를 사용하여 550-570nm에서 측정하였다. 실험은 3회 수행하였다. Control culture wells contained maintenance medium or added 0.2% DMSO (Vehicle Control). After incubation, 10 μL of MTT was added per well and cultured for 4 hours. The formed formazan was dissolved by removing the medium, culturing for another 10 to 15 minutes, and adding 100 μL of DMSO. Absorbance was measured at 550-570 nm using a microplate reader ApoTox-Glo™ (Promega, Madison, WI, USA). The experiment was performed three times.
실험예 4: 마우스 준비 Experimental Example 4: Mouse preparation
8주령된 C57BL/6J 수컷 마우스(약 25-30g)를 Samtako Bio Korea에서 구입하였다. 마우스를 21~25℃, 12시간 명암주기로 물과 음식을 자유 섭취할 수 있는 환경을 제공하여 일주일 동안 순응기간을 가졌다. 순응기간을 가진 마우스를 한 그룹당 12마리씩으로, 식염수를 처리한 대조군, Aβ와 멸균 식염수 처리군, Aβ와 퀴노바산 처리군으로 나눴다. 연구의 모든 실험은 대한민국 경상대학교(GNU) 생명 과학 및 응용 생명 과학과의 동물 윤리위원회(IACUC)의 지침과 원칙을 따랐다. Eight-week-old C57BL/6J male mice (approximately 25-30 g) were purchased from Samtako Bio Korea. Mice were provided with an environment where they could freely consume water and food at 21-25°C with a 12-hour light/dark cycle, and an acclimatization period was conducted for one week. Mice that had an acclimatization period were divided into 12 mice per group, a saline-treated control group, Aβ and sterile saline-treated group, and Aβ and quinobaic acid-treated group. All experiments in the study followed the guidelines and principles of the Animal Ethics Committee (IACUC) of the Department of Life Sciences and Applied Life Sciences, Gyeongsang National University (GNU), Republic of Korea.
실험예 5: 마우스 모델과 약물 투여Experimental Example 5: Mouse model and drug administration
Aβ(1-42) 뇌실내(i.c.v: intracerebroventricular) 투여의 경우, 마우스를 체중 100g 당 0.5ml Rompum: Zoletil로 마취시키고, 응집된 Aβ(1-42) 및 식염수를 해밀턴 미세 주사기(Hamilton micro syringe)를 사용하여 마우스의 뇌실내(i.c.v)로 5ul/5min을 투여하였다.For Aβ(1-42) intracerebroventricular (i.c.v) administration, mice were anesthetized with 0.5 ml Rompum:Zoletil per 100 g body weight, and aggregated Aβ(1-42) and saline were injected using a Hamilton micro syringe. 5ul/5min was administered intracerebroventricularly (i.c.v) to the mouse using .
퀴노바산은 마우스에 Aβ(1-42)를 투여한 다음날부터 50mg/kg로 3주간 격일로 복강주사 하였다. Quinobaic acid was injected intraperitoneally every other day for 3 weeks at 50 mg/kg starting the day after Aβ (1-42) was administered to mice.
실험예 6. 동물 행동 분석Experimental Example 6. Animal behavior analysis
공간 학습과 기억력은 Aβ(1-42)를 뇌실내로 주입한 후 14~20일 후 모리스 수중 미로(Morris water maze: MWM)와 Y미로를 사용하여 조사하였다. 실험하는 동안 동물의 경로는 자동 추적 시스템 소프트웨어(SMART, Panlab Harward-Apparatus, Bioscience Company, Holliston, USA)를 사용하여 기록하였다. Spatial learning and memory were examined using the Morris water maze (MWM) and Y maze 14 to 20 days after intracerebroventricular injection of Aβ(1-42). The animal's path during the experiment was recorded using automatic tracking system software (SMART, Panlab Harward-Apparatus, Bioscience Company, Holliston, USA).
모리스 수중 미로(MWM) 실험을 하기 위해서, 직경 100cm, 깊이 40cm로, 불투명한 물로 채워진 원형 풀에 직경 10cm, 높이 14cm인 투명한 플랫폼을 원형 풀의 4분면 중 한 곳에 임의로 띄어놓았다. 마우스는 실험 시작 하루 전날 플랫폼 없이 60초 동안 수영을 하여 수영장에 처음 적응시켰다.To conduct the Morris water maze (MWM) experiment, a transparent platform with a diameter of 10 cm and a height of 14 cm was randomly placed in one of the four quadrants of the circular pool, 100 cm in diameter and 40 cm deep, filled with opaque water. Mice were first acclimatized to the swimming pool the day before the start of the experiment by swimming for 60 seconds without a platform.
장기기억(reference memory)을 테스트하기 위해서, 마우스는 1일에 3개의 트레일 세션(120초/시행)으로 5일동안 훈련하였다. 플랫폼은 각 시험마다 다른 사분면으로 위치를 변경하여 배치하였다. 동물은 사분면 중 하나의 중앙에 배치하고 플랫폼을 찾도록 하였다. 허용된 시간을 초과한 마우스는 수동으로 플랫폼이 있는 곳으로 안내하여 10초동안 머물게 하였다. 6일차에 마우스 그룹 간의 공간 기억 보유를 분석하기 위해서 플랫폼을 제거하고, 마우스를 사분면 중 하나에서 60초동안 플랫폼을 찾도록 하는 프로브 시험(probe test)을 하였다. 플랫폼이 있었던 사분면에서 소요된 시간과 플랫폼의 위치를 교차한 횟수를 기록하고 분석하였다. To test long-term memory (reference memory), mice were trained for 5 days with 3 trail sessions per day (120 seconds/trial). The platform was relocated and placed in a different quadrant for each test. The animal was placed in the center of one of the quadrants and asked to find the platform. Mice that exceeded the allowed time were manually guided to the platform and allowed to stay there for 10 seconds. To analyze spatial memory retention between mouse groups on day 6, the platform was removed and a probe test was conducted in which mice were asked to find the platform in one of the quadrants for 60 seconds. The time spent in the quadrant where the platform was located and the number of times the platform's location was crossed were recorded and analyzed.
Y-미로(Y-Maze)는 마우스의 인지 및 작업 기억을 테스트하기 위해 자발적인 행동 변화(탐사 행동/ 새로운 팔 미로 탐색 선호도)를 평가하기 위해 사용하였다. 실험에 사용된 Y 미로는 팔의 길이가 75cm, 넓이 15cm, 높이 10cm이며, 팔 가운데 각도가 120°인 Y자형 미로를 사용하였다.The Y-Maze was used to assess spontaneous behavioral changes (exploration behavior/preference to explore a novel arm maze) and to test the mice's cognitive and working memory. The Y maze used in the experiment was a Y-shaped maze with an arm length of 75 cm, a width of 15 cm, and a height of 10 cm, and the angle in the center of the arm was 120°.
동물들은 미로의 팔 중 한쪽에 풀어놓고, 8분 동안 자유롭게 탐색할 수 있게 하였다. 실험은 하루 3번 수행되었고, 각 실험마다 마우스는 다른 팔에 배치되어 시작되었다. 마우스 신체 진입의 85%가 성공적인 진입으로 기록되었다. 자발적인 행동 변화의 %는 하기와 같은 식으로 분석되었다.Animals were released into one of the arms of the maze and allowed to explore freely for 8 minutes. The experiment was performed three times a day, and each experiment started with the mouse placed in a different arm. 85% of mouse body entries were recorded as successful. The percentage of spontaneous behavioral change was analyzed as follows.
[식 1][Equation 1]
100x[(연속적으로 3개의 다른 팔에 차례로 진입한 횟수)/(총 팔의 진입한 횟수 -2)]100x[(Number of times you enter 3 different arms in a row)/(Total number of times you enter each arm -2)]
실험예 7. 조직 수집과 샘플 준비 Experimental Example 7. Tissue collection and sample preparation
행동 평가를 마치고, 마지막 i.p 주사 후, 동물을 마취시켰다. 생화학적 분석을 위해 즉시 뇌를 제거하고 피질과 해마 부위를 드라이아이스에서 분리하여 -80℃에 보관하였다. 단백질 추출을 위해 두뇌 영역을 pro-prep(단백질 추출 용액)에서 균질화한 다음 4℃에서 30분동안 13,000rpm으로 원심분리한 후, 상층액을 수집하였다. After behavioral assessment and final i.p. injection, animals were anesthetized. For biochemical analysis, the brain was immediately removed, and the cortex and hippocampus were separated on dry ice and stored at -80°C. For protein extraction, the brain region was homogenized in pro-prep (protein extraction solution) and then centrifuged at 13,000 rpm for 30 minutes at 4°C, and the supernatant was collected.
면역 조직 화학적 및 형태학적 분석을 위해 마우스를 0.9% 식염수로 경심 관류(transcardial perfusion)를 시킨 후, 4% 파라포름알데히드(PFA: paraformaldehyde)로 재관류시켰다. 뇌를 제거하고 4℃에서 72시간 동안 차가운 파라포름알데히드에 담가 고정시킨 다음 뇌가 튜브 바닥에 가라앉을 때까지 20% 수크로스에 옮겼다. 뇌 조직을 O.C.T(TissueTek O.C.T. Compound Medium, Sakura Finetek USA, Inc., Torrance, CA, USA) 에서 동결시켰다. CM 3050C 저온 유지 장치(Leicam, Germany)를 사용하여 14μm 관상 평면 조직 절편을 얻고 양전하 젤라틴 코팅 슬라이드에 해동시켰다. For immunohistochemical and morphological analysis, mice were transcardially perfused with 0.9% saline and then reperfused with 4% paraformaldehyde (PFA). Brains were removed, fixed in cold paraformaldehyde for 72 hours at 4°C, and then transferred to 20% sucrose until the brains settled to the bottom of the tube. Brain tissue was frozen in O.C.T (TissueTek O.C.T. Compound Medium, Sakura Finetek USA, Inc., Torrance, CA, USA). 14-μm coronal plane tissue sections were obtained using a CM 3050C cryostat (Leicam, Germany) and thawed on positively charged gelatin-coated slides.
실험예 8. 면역 블롯팅과 면역 형광법Experimental Example 8. Immunoblotting and immunofluorescence
면역 블롯팅과 면역 형광법은 논문 [Khan, M.S.; Muhammad, T.; Ikram, M.; Kim, M.O. Dietary Supplementation of the Antioxidant Curcumin Halts Systemic LPS-Induced Neuroinflammation-Associated Neurodegeneration and Memory/Synaptic Impairment via the JNK/NF-kappaB/Akt Signaling Pathway in Adult Rats. Oxidative medicine and cellular longevity 2019, 2019, 7860650, doi: 10.1155/2019/7860650. 및 Alam, S.I.; Rehman, S.U.; Kim, M.O. Nicotinamide Improves Functional Recovery via Regulation of the RAGE/JNK/NF-kappaB Signaling Pathway after Brain Injury. J Clin Med 2019, 8, doi: 10.3390/jcm8020271.]에 설명된 대로 수행하였다. 면역 블롯팅의 경우, β-액틴 발현을 모든 실험에 대한 내부 대조군으로 사용하였다. 레이저 스캐닝 공초점 현미경(FluoView FV 1000 MPE)을 사용하여 면역 형광 시각화를 수행하였다. 두 기술의 데이터는 컴퓨터 기반 Image J 소프트웨어와 GraphPad Prism(버전 7.0)을 사용하여 평가하였다. 값은 평균±평균 오차(standard errors of the mean: SEM)로 나타내었다. 면역 블롯팅과 면역 형광법에 사용된 항체는 하기 표 1과 같다.Immunoblotting and immunofluorescence were performed in the paper [Khan, M.S.; Muhammad, T.; Ikram, M.; Kim, M.O. Dietary Supplementation of the Antioxidant Curcumin Halts Systemic LPS-Induced Neuroinflammation-Associated Neurodegeneration and Memory/Synaptic Impairment via the JNK/NF-kappaB/Akt Signaling Pathway in Adult Rats. Oxidative medicine and cellular longevity 2019, 2019, 7860650, doi: 10.1155/2019/7860650. and Alam, S.I.; Rehman, S.U.; Kim, M.O. Nicotinamide Improves Functional Recovery via Regulation of the RAGE/JNK/NF-kappaB Signaling Pathway after Brain Injury. J Clin Med 2019, 8, doi: 10.3390/jcm8020271.] was performed as described. For immunoblotting, β-actin expression was used as an internal control for all experiments. Immunofluorescence visualization was performed using a laser scanning confocal microscope (FluoView FV 1000 MPE). Data from both techniques were evaluated using computer-based Image J software and GraphPad Prism (version 7.0). Values are expressed as mean ± standard errors of the mean (SEM). Antibodies used in immunoblotting and immunofluorescence are listed in Table 1 below.
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실험예 9. 니슬 염색법Experimental Example 9. Nissl staining method
니슬 염색은 뇌 조직 신경 형태 및 병리를 분석하기 위하여 수행하였다. 간단히 말해서, 뇌 절편을 PBS(0.01M)에서 15분동안 두 번 세척한 다음 몇 방울의 빙하 아세트산으로 증가된 결정 0.5% 크레실 바이올렛 염색액에서 8-10분동안 배양하였다. 조직을 증류수로 세척하고 에틸알코올(70, 95, 100%)로 15분 동안 분화시켰다. 탈수 후, 조직을 자일렌(xylene)으로 각각 3분동안 2회 세척하고, 비형광 봉입제(mounting medium)로 덮었다. 형광 현미경으로 면역 조직 화학적 분석을 수행하고, TIF 이미지를 캡처하였다. 또한, 뇌의 피질-전체 영역과 해마-전체 영역에서 살아남은 뉴런의 수를 Image J 소프트웨어를 사용하여 분석하였다. Nissl staining was performed to analyze brain tissue neuronal morphology and pathology. Briefly, brain sections were washed twice for 15 min in PBS (0.01 M) and then incubated for 8–10 min in crystalline 0.5% cresyl violet staining solution augmented with a few drops of glacial acetic acid. Tissues were washed with distilled water and differentiated with ethyl alcohol (70, 95, 100%) for 15 minutes. After dehydration, the tissue was washed twice with xylene for 3 minutes each and covered with non-fluorescent mounting medium. Immunohistochemical analysis was performed by fluorescence microscopy, and TIF images were captured. Additionally, the number of surviving neurons in the cortex-wide region and hippocampus-wide region of the brain was analyzed using Image J software.
실험예 10. 콜레스테롤, GSH 및 ROS 어세이Experimental Example 10. Cholesterol, GSH and ROS assay
뇌 균질물의 총 콜레스테롤 및 유리 콜레스테롤 수치는 분석 키트(ab65390, Abcam)를 사용하여, 분석 키트의 매뉴얼을 사용하여 정량화하였다. 글루타치온(GSH) 수준 및 GSH/산화 GSH(GSSG) 비율은 형광측정 GSH 분석 키트(Bio-Vsion Inc., Milpitas, CA, USA, cat. No. K264-100)로 측정하였다. Total cholesterol and free cholesterol levels in brain homogenates were quantified using an assay kit (ab65390, Abcam) using the assay kit's manual. Glutathione (GSH) levels and GSH/oxidized GSH (GSSG) ratio were measured with a fluorometric GSH assay kit (Bio-Vsion Inc., Milpitas, CA, USA, cat. No. K264-100).
ROS 수준은 논문[Ikram, M.; Saeed, K.; Khan, A.; Muhammad, T.; Khan, M.S.; Jo, M.G.; Rehman, S.U.; Kim, M.O. Natural Dietary Supplementation of Curcumin Protects Mice Brains against Ethanol-Induced Oxidative Stress- Mediated Neurodegeneration and Memory Impairment via Nrf2/TLR4/RAGE Signaling. Nutrients 2019, 11, doi: 10.3390/nu11051082.]에 설명된 대로 실험하였다. 간단히 정리하면, 마우스 뇌의 균질물을 얼음이 냉각된 Locke의 완충액(1:20)에 희석하여 5.0mg/조직/ml의 최종 농도 용액을 얻었다. 형광을 얻기 위해 1ml 용액(Locke's buffer, pH7.4 및 균질한 0.2ml)을 10ml의 5mM 디클로로디하이드로플루오레세인 다이아세테이트(dichlorodihydrofluorescein diacetate: DCFH-DA)(Santa Cruz Biotechnology, CAS #4091-99-0)와 함께 30분동안 배양하였다. DCFH-DA는 디클로로플루오레세인(dichlorofluorescein:DCF)으로 산화되어 형광생성물을 생성하였다. 분석의 형광 강도는 96웰 형광 마이크로 플레이트 리더 ApoTox-Glo™(Triplex Assay, Promega, Madison, WI, USA))을 사용하여 측정되었다(콜레스테롤:Ex/Em=535/587nm, GSH:Ex/Em=340/420nm 및 ROS:Ex/Em= 484/530nm).ROS levels were evaluated in the paper [Ikram, M.; Saeed, K.; Khan, A.; Muhammad, T.; Khan, M.S.; Jo, M.G.; Rehman, S.U.; Kim, M.O. Natural Dietary Supplementation of Curcumin Protects Mice Brains against Ethanol-Induced Oxidative Stress- Mediated Neurodegeneration and Memory Impairment via Nrf2/TLR4/RAGE Signaling. The experiment was performed as described in Nutrients 2019, 11, doi: 10.3390/nu11051082. Briefly, the mouse brain homogenate was diluted in ice-cold Locke's buffer (1:20) to obtain a final concentration solution of 5.0 mg/tissue/ml. To obtain fluorescence, 1ml solution (Locke's buffer, pH7.4 and 0.2ml homogenate) was mixed with 10ml of 5mM dichlorodihydrofluorescein diacetate (DCFH-DA) (Santa Cruz Biotechnology, CAS #4091-99- 0) and incubated for 30 minutes. DCFH-DA was oxidized to dichlorofluorescein (DCF) to generate a fluorescent product. The fluorescence intensity of the assay was measured using a 96-well fluorescence microplate reader ApoTox-Glo™ (Triplex Assay, Promega, Madison, WI, USA) (cholesterol:Ex/Em=535/587nm, GSH:Ex/Em= 340/420nm and ROS:Ex/Em=484/530nm).
실험예 11. 통계학적 분석Experimental Example 11. Statistical Analysis
면역 블롯 밴드(X선 스캔 필름)와 면역 형광 이미지 밀도는 Image J로 분석하였으며, 모든 실험 결과는 Turkey's post hoc test에 이어 one way analysis of variance(ANOVA)를 사용하였고, GraphPad Prism 소프트웨어(ver.7.0, 캘리포니아 주 샌디에고)에 의해 통계적으로 평가하였다. 결과는 평균±평균 오차(standard errors of the mean: SEM)으로 표시하였다. Immunoblot band (X-ray scan film) and immunofluorescence image density were analyzed with Image J, and all experimental results were analyzed using Turkey's post hoc test followed by one way analysis of variance (ANOVA), and GraphPad Prism software (ver.7.0). , San Diego, California). Results were expressed as mean ± standard errors of the mean (SEM).
* p≤0.05(대조군의 경우) 및 # p≤0.05(퀴노빅 산 처리 군의 경우)로 표시된 통계적 차이는 둘 다 Aβ 독성 그룹과 비교할 때 유의한 것으로 간주하였다.Statistical differences indicated by *p≤0.05 (for control group) and #p≤0.05 (for quinobic acid treated group) were both considered significant when compared to the Aβ toxicity group.
실시예 1. 퀴노바산 처리량에 따른 세포 생존력Example 1. Cell viability according to quinobic acid treatment amount
퀴노바산 처리량에 따른 세포의 생존력을 확인하기 위해서, SH-SY5Y 세포에 퀴노바산을 처리하였을 때 세포의 생존율을 확인하였다. 도 1을 보면, 퀴노빅 산 처리시 100μM까지는 퀴노바산을 처리하지 않은 대조군과 유의한 차이가 없었으나, 퀴노빅 산 115μM 처리시에는 퀴노바산을 처리하지 않은 대조군보다 세포 생존도가 떨어지는 것을 확인하였다.In order to confirm the viability of cells according to the amount of quinoba acid treated, the viability of cells was confirmed when SH-SY5Y cells were treated with quinoba acid. Looking at Figure 1, when treated with quinobic acid up to 100 μM, there was no significant difference from the control group not treated with quinobic acid, but when treated with 115 μM quinobic acid, cell viability was lower than the control group not treated with quinobic acid. Confirmed.
도 2를 보면 알 수 있듯, 아밀로이드 베타(Aβ, Amyloid Beta) 5μM 처리시, 세포의 생존율이 현저히 줄어드는 것을 확인하였으며, 아밀로이드 베타와 함께 퀴노바산을 처리시 퀴노바산 55μM 내지 85μM까지는 처리량에 비례하여 세포 생존도가 높아지며, 100μM 부터는 세포 생존도가 베타 아밀로이드만 처리한 세포와 유의미한 차이가 없다는 것을 확인하였다.As can be seen in Figure 2, it was confirmed that when treated with 5 μM of amyloid beta (Aβ), the survival rate of cells was significantly reduced, and when treated with quinoba acid together with amyloid beta, the amount of quinoba acid from 55 μM to 85 μM was proportional to the treatment amount. This increases cell viability, and it was confirmed that from 100 μM, cell viability was not significantly different from cells treated only with beta amyloid.
실시예 2. 뇌 콜레스테롤 억제 효과 확인Example 2. Confirmation of brain cholesterol inhibition effect
아밀로이드 베타 및 퀴노바산을 주입하였을 때, 뇌의 피질(cortex)과 해마(hippocampus)에서 콜레스테롤 및 유리 콜레스테롤의 변화를 알아보기 위해 콜레스테롤 어세이를 실행하였다. 그 결과 도3과 같이, 아밀로이드 베타를 투여하였을 때, 뇌의 피질과 해마에서 유리 콜레스테롤 및 총 콜레스테롤의 양이 증가하는 것을 확인하였으며, 아밀로이드 베타와 퀴노바산을 투여시 정상 쥐와 같이 유리 콜레스테롤 및 총 콜레스테롤의 양이 감소하는 것을 확인하였다. When amyloid beta and quinobaic acid were injected, a cholesterol assay was performed to determine changes in cholesterol and free cholesterol in the brain cortex and hippocampus. As a result, as shown in Figure 3, it was confirmed that when amyloid beta was administered, the amount of free cholesterol and total cholesterol increased in the brain cortex and hippocampus, and when amyloid beta and quinoba acid were administered, free cholesterol and total cholesterol increased like normal rats. It was confirmed that the amount of total cholesterol decreased.
도4와 같이, p53의 발현량과 HMGCR의 발현량이 아밀로이드 베타 투여시 뇌의 피질과 해마에서 증가하는 것을 확인하였고, 되는 p53의 발현량과 HMGCR의 발현량이 아밀로이드 베타 및 퀴노바산을 투여하였을 때는 감소하는 것을 확인하였다.As shown in Figure 4, it was confirmed that the expression level of p53 and HMGCR increased in the brain cortex and hippocampus when amyloid beta was administered, and the expression level of p53 and HMGCR decreased when amyloid beta and quinoacid were administered. confirmed.
p53은 콜레스테롤 대사를 변화시키기 위해 HMGCR(3-hydroxy-3-methyl-grytaryl coenzyme A reductase)을 포함한 MVA(mevalonate) 경로의 중요한 효소 활성을 조절하므로, 상기 결과를 통해 p53 및 HMGCR의 억제를 통해 콜레스테롤 축적을 억제한다는 것을 확인하였다.Since p53 regulates important enzymatic activities of the mevalonate (MVA) pathway, including 3-hydroxy-3-methyl-grytaryl coenzyme A reductase (HMGCR), to change cholesterol metabolism, the above results suggest that cholesterol metabolism can be achieved through inhibition of p53 and HMGCR. It was confirmed that accumulation was suppressed.
실시예 3. 산화스트레스에 대한 세포 보호 효과 확인Example 3. Confirmation of cell protection effect against oxidative stress
도 5와 같이, ROS assay를 통해 아밀로이드 베타로부터 발생한 ROS 수치가 아밀로이드 베타와 퀴노바산을 투여한 마우스의 뇌에서는 현저히 감소하는 것을 확인하였다.As shown in Figure 5, through ROS assay, it was confirmed that ROS levels generated from amyloid beta were significantly reduced in the brains of mice administered amyloid beta and quinoba acid.
뇌의 활성산소를 제거해주는 글루타치온(GSH: glutathione)의 양은 도 6를 보면 알 수 있듯이, 아밀로이드 베타를 주입하였을 때는 감소하였다가 아밀로이드 베타 및 퀴노바산을 주입한 마우스에서는 글루타치온이 증가하는 것을 확인하였다. 또한 도7에 나타난 바와 같이, 아밀로이드 베타 투여시 글루타치온의 환원된 형태(GSH)와 산화된 형태(GSSG)의 비율이 감소하는 반면, 아밀로이드 베타 및 퀴노바산을 투여시 GSH와 GSSG의 비율이 다시 증가하는 것을 확인하였다. As can be seen in Figure 6, the amount of glutathione (GSH: glutathione), which removes free radicals from the brain, decreased when amyloid beta was injected, but glutathione was confirmed to increase in mice injected with amyloid beta and quinoacid. . Additionally, as shown in Figure 7, when amyloid beta is administered, the ratio of glutathione's reduced form (GSH) and oxidized form (GSSG) decreases, whereas when amyloid beta and quinobaic acid are administered, the ratio of GSH and GSSG decreases again. It was confirmed that it was increasing.
도 8 및 도 9는 면역형광법을 통해 나타난 결과로, 아밀로이드 베타 투여로 인해 산화스트레스가 발생하였을 때, Nrf-2 및 HO-1이 감소하는 것을 확인하였다. 또한, 아밀로이드 베타 및 퀴노바산 투여시 Nrf 및 HO-1이 증가되는 것을 확인하였다.Figures 8 and 9 show the results shown through immunofluorescence, confirming that when oxidative stress occurred due to amyloid beta administration, Nrf-2 and HO-1 decreased. In addition, it was confirmed that Nrf and HO-1 increased when amyloid beta and quinoba acid were administered.
따라서, 도 5 내지 도 9의 결과를 통해서 아밀로이드 베타로 인해 증가한 산화스트레스가 퀴노바산으로 인해 감소 또는 억제된다는 것을 확인하였다.Therefore, through the results of Figures 5 to 9, it was confirmed that oxidative stress increased due to amyloid beta was reduced or suppressed by quinoba acid.
실시예 4. 신경 염증 완화 효과 확인Example 4. Confirmation of neuroinflammation alleviating effect
뇌의 콜레스테롤 축적으로 인해 발생한 산화스트레스는 뇌에서 염증을 일으킨다. 따라서 퀴노바산이 염증을 억제하는 것을 확인하기 위해서 면역 블롯팅을 통해 뇌의 염증 지표들을 확인하였다. Oxidative stress caused by cholesterol accumulation in the brain causes inflammation in the brain. Therefore, to confirm that quinobaic acid suppresses inflammation, inflammatory indicators in the brain were confirmed through immunoblotting.
그 결과 도 10 내지 도 11에 나타난 것과 같이, GFAP 및 Iba-1가 아밀로이드 베타 투여하였을 때 증가하였다는 것과 퀴노바산을 투여했을 때 감소하는 것을 확인하였다. 상기 결과를 통해서 아밀로이드 베타에 의해 신경교식증(astrogliosis)과 소교세포증(microgliosis)이 증가한다는 것과 아밀로이드 베타에 의해 증가된 신경교식증(astrogliosis)과 소교세포증(microgliosis)이 퀴노바산에 의해 감소한다는 것을 확인하였다.As a result, as shown in Figures 10 and 11, it was confirmed that GFAP and Iba-1 increased when amyloid beta was administered and decreased when quinoba acid was administered. The above results show that astrogliosis and microgliosis are increased by amyloid beta, and that astrogliosis and microgliosis increased by amyloid beta are decreased by quinoacid. confirmed.
또한, 도 12 내지 도 14와 같이 아밀로이드 베타를 통해 IL-1β, p-Jnk 및 p-NF-κB가 증가하는 것과, 아밀로이드 베타와 퀴노바산을 처리하였을 때 IL-1β, p-Jnk 및 p-NF-κB가 감소하는 것을 확인하였다.In addition, as shown in Figures 12 to 14, IL-1β, p-Jnk, and p-NF-κB increase through amyloid beta, and when treated with amyloid beta and quinoba acid, IL-1β, p-Jnk, and p -NF-κB was confirmed to decrease.
이를 통해 퀴노바산이 아밀로이드 베타로 인해 발생한 신경염증을 완화하는 효과가 있다는 것을 확인하였다.Through this, it was confirmed that quinobaic acid is effective in alleviating neuroinflammation caused by amyloid beta.
실시예 5. 미토콘드리아 이상기능으로 인한 신경퇴행과 세포 사멸 억제 효과 확인 Example 5. Confirmation of the effect of suppressing neurodegeneration and cell death due to abnormal mitochondrial function
신경퇴행성 질환에서 미토콘드리아의 이상기능은 잘 알려진 징후이다. 따라서 미토콘드리아 이상 기능에 퀴노바산의 효과를 알아보기 위해 면역 블롯팅과 니슬 염색법을 실행하였다.Mitochondrial dysfunction is a well-known symptom in neurodegenerative diseases. Therefore, immunoblotting and Nissl staining were performed to investigate the effect of quinovanic acid on mitochondrial abnormal function.
그 결과는 도 15 내지 도 19로 나타내었다.The results are shown in Figures 15 to 19.
도 15 내지 도 16을 보면, 아밀로이드 베타를 투여하였을 때, 뇌에서 세포사멸 전구체(pro-paoptotic)인 Bax 단백질은 증가하고, 세포사멸을 억제하는 Bcl-2가 감소하는 것을 확인하였다. 또한, 아밀로이드 베타와 퀴노바산을 투여하였을 때, Bax 단백질은 감소하고 Bcl-2는 증가하는 것을 확인하였다.15 to 16, it was confirmed that when amyloid beta was administered, Bax protein, which is a pro-apoptotic precursor, increased in the brain, and Bcl-2, which inhibits apoptosis, decreased. Additionally, when amyloid beta and quinoba acid were administered, it was confirmed that Bax protein decreased and Bcl-2 increased.
도 17 내지 도 18을 보면, 아밀로이드 베타를 투여했을 때, 미토콘드리아 기능을 악화시키는 싸이토크롬-C(cytochrome-C)가 증가한다는 것과 세포사멸이 유발되어 카스파제-3(Caspase-3)이 증가한다는 것을 확인하였다. 또한, 아밀로이드 베타와 퀴노바산을 투여하였을 때, 싸이토크롬-C 및 카스파제-3이 대조군과 비슷할 정도까지 감소하는 것을 확인하였다. 17 to 18, when amyloid beta is administered, cytochrome-C, which worsens mitochondrial function, increases and apoptosis is induced, resulting in an increase in caspase-3. It was confirmed that it does. In addition, when amyloid beta and quinoba acid were administered, it was confirmed that cytochrome-C and caspase-3 decreased to a level similar to that of the control group.
니슬 염색법을 해본 결과, 도 19와 같이 아밀로이드 베타만 투여하였을 때는 뇌의 밀도가 현저히 감소하는 반면, 아밀로이드 베타와 퀴노바산을 투여한 경우 뇌의 밀도 감소가 아밀로이드 베타 투여시보다 확연히 줄어드는 것을 확인하였다. As a result of Nissl staining, as shown in Figure 19, when only amyloid beta was administered, the brain density was significantly reduced, whereas when amyloid beta and quinoba acid were administered, the decrease in brain density was confirmed to be significantly reduced compared to when amyloid beta was administered. .
따라서, 퀴노바산을 투여시 아밀로이드 베타에 의해 미토콘드리아의 이상기능이 억제되는 것과 그로 인한 세포 사멸효과가 억제되고, 뇌의 퇴행성 진행이 억제되는 것을 확인하였다.Therefore, it was confirmed that when quinoba acid was administered, the abnormal function of mitochondria due to amyloid beta was suppressed, the resulting cell death effect was suppressed, and the degenerative progression of the brain was suppressed.
실시예 6. 시냅스 및 기억 기능 장애에 대한 효과 확인Example 6. Confirmation of effects on synaptic and memory dysfunction
SYP(Synaptophysin)과 PSD-95(postsynaptic density protein 95)를 확인하기 위해, 면역블롯팅을 하였다. To confirm SYP (Synaptophysin) and PSD-95 (postsynaptic density protein 95), immunoblotting was performed.
그 결과 도 20 내지 도 21과 같이 아밀로이드 베타를 투여한 마우스에서는 PSD-95와 SYP가 감소된 반면, 아밀로이드 베타와 퀴노바산을 투여한 마우스에서는 아밀로이드 베타만 투여한 마우스 대비 PSD-95와 SYP가 증가한 것을 확인하였다. As a result, as shown in Figures 20 and 21, PSD-95 and SYP were decreased in mice administered amyloid beta, while PSD-95 and SYP were decreased in mice administered amyloid beta and quinovanic acid compared to mice administered only amyloid beta. An increase was confirmed.
도 22 내지 도 25에 나타나 듯, MWM(Morris water maze) 테스트를 통해 아밀로이드 베타와 퀴노바산을 투여한 마우스가 아밀로이드 베타만 투여한 마우스 대비 플랫폼을 찾는 학습 효과가 3일차부터 차이가 났으며, 플랫폼을 찾아 탈출하는 시간이 현저히 줄었다. 또한, 프로브 테스트에서 원래 플랫폼이 있었던 사분면과 플랫폼의 자리를 돌아다닌 횟수가 현저히 증가한 것을 확인하므로, 아밀로이드 베타로 인한 학습능력 및 공간 기억의 퇴화가 퀴노바산에 의해 억제된다는 것을 확인하였다. As shown in Figures 22 to 25, through the MWM (Morris water maze) test, the learning effect of mice administered amyloid beta and quinovanic acid to find the platform was different from the third day onwards compared to mice administered only amyloid beta. The time to find the platform and escape has been significantly reduced. In addition, in the probe test, it was confirmed that the number of trips to the quadrant where the platform was originally located and the number of times the patient moved around the platform seat significantly increased, confirming that the deterioration of learning ability and spatial memory caused by amyloid beta is suppressed by quinoacid.
또한, 도 26 내지 27에 나타나 있듯이 Y 미로 테스트를 통해서 아밀로이드 베타를 투여한 마우스는 새로운 공간에 대한 호기심이 낮은 반면, 아밀로이드 베타 및 퀴노바산을 투여한 마우스는 새로운 공간에 들어가며 새로운 공간에 대한 호기심이 나타나는 것을 확인하였고, 이를 통해 공간을 운용하는 기억이 활성화 된다는 것을 확인하였다. In addition, as shown in Figures 26 and 27, mice administered amyloid beta through the Y maze test had low curiosity about new spaces, while mice administered amyloid beta and quinoacid entered the new space and showed curiosity about the new space. It was confirmed that this appears, and through this, it was confirmed that memory for operating space is activated.
Claims (5)
상기 퀴노바산은 식물로부터 정제된 것이며,
상기 퀴노바산의 농도는 5 내지 95μM인 것이고,
상기 퇴행성 뇌질환은 파킨슨 병(parkinson's disease), 헌팅턴병(huntington's disease), 알츠하이머병(alzheimer's disease), 경도인지장애(mild cognitive impairment), 노인성 치매(senile dementia), 루게릭병(amyotrophic lateral sclerosis), 투렛 증후군(tourette syndrome), 근육긴장이상(dystonia), 진행성 핵상안근마비 (progressive supranuclear ophthalmoplegia) 및 전두측두치매 (frontotemporal dementia(FTD))로 구성된 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 것인,
퇴행성 뇌질환 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for preventing or treating degenerative brain diseases containing Quinovic acid;
The quinobaic acid is purified from plants,
The concentration of the quinoba acid is 5 to 95 μM,
The degenerative brain diseases include Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, and Tourette's disease. Characterized by being selected from the group consisting of tourette syndrome, dystonia, progressive supranuclear ophthalmoplegia, and frontotemporal dementia (FTD),
Pharmaceutical composition for preventing or treating degenerative brain diseases.
상기 퀴노바산은 식물로부터 정제된 것이며,
상기 퀴노바산의 농도는 5 내지 95μM인 것이고,
상기 퇴행성 뇌질환은 파킨슨 병(parkinson's disease), 헌팅턴병(huntington's disease), 알츠하이머병(alzheimer's disease), 경도인지장애(mild cognitive impairment), 노인성 치매(senile dementia), 루게릭병(amyotrophic lateral sclerosis), 투렛 증후군(tourette syndrome), 근육긴장이상(dystonia), 진행성 핵상안근마비 (progressive supranuclear ophthalmoplegia) 및 전두측두치매 (frontotemporal dementia(FTD))로 구성된 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 것인,
퇴행성 뇌질환 예방 또는 개선용 식품 조성물.
A food composition for preventing or improving degenerative brain diseases containing Quinovic acid;
The quinobaic acid is purified from plants,
The concentration of the quinoba acid is 5 to 95 μM,
The degenerative brain diseases include Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, and Tourette's disease. Characterized by being selected from the group consisting of tourette syndrome, dystonia, progressive supranuclear ophthalmoplegia, and frontotemporal dementia (FTD),
Food composition for preventing or improving degenerative brain diseases.
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