KR20140021902A - Composition for antiinflammatory and inflammatory neurodegenerative diseases comprising olive oil extract - Google Patents
Composition for antiinflammatory and inflammatory neurodegenerative diseases comprising olive oil extract Download PDFInfo
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- KR20140021902A KR20140021902A KR1020120088401A KR20120088401A KR20140021902A KR 20140021902 A KR20140021902 A KR 20140021902A KR 1020120088401 A KR1020120088401 A KR 1020120088401A KR 20120088401 A KR20120088401 A KR 20120088401A KR 20140021902 A KR20140021902 A KR 20140021902A
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- olive oil
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- oil extract
- inflammatory
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- 238000007619 statistical method Methods 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
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Abstract
Description
본 발명은 감람유 추출물을 유효 성분으로 포함하는 것을 특징으로 하는 항염증제 및 염증성 신경 퇴행성 질환용 조성물에 관한 것이다. 본 발명의 조성물은 BV-2 미세아교세포에 있어서 LPS-유발 유도성 질소 산화물 합성(iNOS) 단백질 발현 및 NO 생산을 완전히 약화시킬 수 있으므로 효율적인 항염증제 및 신경퇴행성 질환의 치료제로 효과적으로 사용될 수 있다.
The present invention relates to an anti-inflammatory agent and an inflammatory neurodegenerative disease composition comprising an olive oil extract as an active ingredient. The composition of the present invention can completely attenuate LPS-induced inducible nitrogen oxide synthesis (iNOS) protein expression and NO production in BV-2 microglia and thus can be effectively used as an effective anti-inflammatory and therapeutic agent for neurodegenerative diseases.
일반적으로 신경염증은 뇌허혈, 알쯔하이머 질환, 파킨슨병, 헌팅톤 질환 및 근위축성 측색 경화증 등의 다양한 신경학적 및 신경퇴행성 질환의 발병에 수반되어 있다 (Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001;2:734-744). 뇌에 고유한 면역 세포인 미세아교 세포(microglia)는 전염증성 사이토카인, 산화 질소(NO) 및 기타 신경독 인자의 생산을 통하여 뇌염증에 있어서 특히 중요한 역할을 수행한다. 활성화된 미세아교세포로부터 종양 괴사 인자 (TNF-α) 와 인터류킨 IL-6 등의 사이토카인 분비 자극에 의해 신경 뉴우런을 직접적으로 손상시킬 수 있다(Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS. Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. J Neurochem 2001;77:182-189.). In general, neuroinflammation is accompanied by the development of various neurological and neurodegenerative diseases, such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Neurosci 2001; 2: 734-744). Microglia, immune cells unique to the brain, play a particularly important role in encephalitis through the production of proinflammatory cytokines, nitric oxide (NO) and other neurotoxin factors. Neuronal neurons can be directly damaged by stimulating cytokine secretion such as tumor necrosis factor (TNF-α) and interleukin IL-6 from activated microglia (Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS.Molecular consequences of activated microglia in the brain: overactivation induces apoptosis.J Neurochem 2001; 77: 182-189.).
따라서, 미세아교세포의 세포신호전달 억제는 신경염증성 질환의 개선을 초래할 수 있다.Thus, inhibition of cell signaling by microglia can lead to an improvement in neuroinflammatory diseases.
리포폴리사카라이드(LPS)는 생체 및 시험관내 연구에 있어서 적극적인 모델 면역자극제로서 널리 사용되어 왔다. 이전의 연구에 의하면, LPS는 미세아교세포를 자극하여 유도성 질소 산화물 합성(iNOS), NO 및 인터류킨(IL)-1, IL-6 및 종양 괴사 인자 (TNF-α) 등의 사이토카인 류를 생산하는 것이 제안되었다(Gayle DA, Ling Z, Tong C, Landers T, Lipton JW, Carvey PM. Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitricoxide. Brain Res Dev Brain Res 2002;133:27-35.).Lipopolysaccharide (LPS) has been widely used as an active model immunostimulator in vivo and in vitro studies. Previous studies have shown that LPS stimulates microglia to release cytokines such as inducible nitric oxide synthesis (iNOS), NO and interleukin (IL) -1, IL-6 and tumor necrosis factor (TNF-α). It has been proposed to produce (Gayle DA, Ling Z, Tong C, Landers T, Lipton JW, Carvey PM.Lipopolysaccharide (LPS) -induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitricoxide Brain Res Dev Brain Res 2002; 133: 27-35.).
관련 선행특허로 대한민국특허공개번호 제1020120011981호는 항염증 효과를 갖는 잠분 추출물 및 이를 포함하는 피부 외용제 조성물에 관한 것으로, 잠분 추출물은 헴 옥시게나제- 1과 시르투인1의 발현을 증대시켜 항염증 효과를 갖는다는 것이 기재되어 있다. In related prior patents, Korean Patent Publication No. 1020120011981 relates to a extract of Jambun having an anti-inflammatory effect and an external composition for skin containing the same, and the extract of Jambun increases the expression of heme oxygenase-1 and sirtuin1. It is described that it has an inflammatory effect.
본 발명은 상기의 필요성에 의하여 안출된 것으로서 본 발명의 목적은 항염증성 조성물을 제공하는 것이다.The present invention has been made in view of the above necessity, and an object of the present invention is to provide an anti-inflammatory composition.
본 발명의 다른 목적은 염증성 신경퇴행성 질환의 치료 또는 예장용 조성물을 제공하는것이다.Another object of the present invention is to provide a composition for the treatment or prophylaxis of inflammatory neurodegenerative diseases.
상기의 목적을 달성하기 위하여 본 발명은 감람유 추출물을 유효 성분으로 하는 염증성 신경 퇴행성 질환 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating inflammatory neurodegenerative diseases, which comprises an olive oil extract as an active ingredient.
본 발명의 일 구현예에 있어서, 상기 조성물은 유도성 질소 산화물 합성(iNOS) 및 NO 생산을 약화시키는 것이 바람직하나 이에 한정되지 아니한다.In one embodiment of the invention, the composition is preferably, but not limited to, inductive nitrogen oxide synthesis (iNOS) and attenuate NO production.
본 발명의 다른 구현예에 있어서, 상기 조성물은 미세아교세포에서 미세아교세포 활성을 억제하는 것이 바람직하나 이에 한정되지 아니한다.In another embodiment of the present invention, the composition is preferably, but not limited to, inhibiting microglia activity in microglia.
본 발명의 또 다른 구현예에 있어서, 상기 조성물은 TNF-α 활성을 억제하는 것이 바람직하나 이에 한정되지 아니한다.In another embodiment of the present invention, the composition is preferably, but not limited to, inhibiting TNF-α activity.
또 본 발명은 감람유 추출물을 유효 성분으로 하는 염증성 신경 퇴행성 질환 완화용 식품 조성물을 제공한다.In another aspect, the present invention provides a food composition for inflammatory neurodegenerative disease alleviation comprising an olive oil extract as an active ingredient.
또 본 발명은 감람유 추출물을 유효 성분으로 하는 항염증용 약학 조성물을 제공한다.The present invention also provides an anti-inflammatory pharmaceutical composition comprising an olive oil extract as an active ingredient.
또 본 발명은 감람유 추출물을 유효 성분으로 하는 항염증용 기능성 식품 조성물을 제공한다.The present invention also provides an anti-inflammatory functional food composition comprising the olive oil extract as an active ingredient.
또 본 발명은 감람유 추출물을 유효 성분으로 하는 항산화용 조성물을 제공한다.The present invention also provides an antioxidant composition comprising the olive oil extract as an active ingredient.
본 발명의 감람유 추출물을 유효 성분으로 포함하는 약제학적 조성물은 상기 유효 성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.A pharmaceutical composition comprising the olive oil extract of the present invention as an active ingredient may be prepared using a pharmaceutically acceptable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant may include an excipient, a disintegrant, a sweetener, and a binder. , Coating agents, expanding agents, lubricants, lubricants or flavoring agents may be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The pharmaceutical composition may be formulated into a pharmaceutical composition containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.
상기 약제학적 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해,유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당,옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. 액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있다.The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation in the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included as a mixture. Suitable binders include, but are not limited to, natural and synthetic gums such as natural sugars, corn sweeteners such as starch, gelatin, glucose or beta-lactose, acacia, trackercance or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include sterile water and sterile water suitable for the living body such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.
또한, 본 발명은 상기 감람유추출물을 포함하는 식품 조성물을 제공한다.The present invention also provides a food composition comprising the olive oil extract.
본 발명에 따른 식품 조성물은 상기 약제학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 알코올 음료류, 비타민 복합제, 건강보조 식품류 등이 있다.The food composition according to the present invention can be formulated in the same manner as the above pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meats, chocolates, foods, confectionery, pizza, ramen noodles, gums, ice cream, alcoholic beverages, vitamin complexes, .
본 발명은 상기 조성물을 포함하는 건강기능식품을 제공한다.The present invention provides a health functional food comprising the composition.
본 발명은 또한 결핵 예방 및 치료용 의약 또는 식품의 제조를 위한 상기 감람유추출물을 유효 성분으로 포함하는 조성물의 용도를 제공한다. 상기 감람유추출물을 유효 성분으로 포함하는 본 발명의 조성물은 결핵 예방 및 치료와 관련된 질환의 예방 또는 치료용 의약 또는 식품의 제조를 위한 용도로 이용될 수 있다.The invention also provides the use of a composition comprising said olive oil extract as an active ingredient for the manufacture of a medicament or food for the prevention and treatment of tuberculosis. The composition of the present invention comprising the olive oil extract as an active ingredient may be used for the manufacture of a medicament or food for the prevention or treatment of diseases related to the prevention and treatment of tuberculosis.
또한 본 발명은 포유동물에게 치료상 유효량의 감람유추출물을 투여하는 것을 포함하는 결핵 질환의 예방 또는 치료 방법을 제공한다.The present invention also provides a method for preventing or treating tuberculosis disease comprising administering to a mammal a therapeutically effective amount of olive oil extract.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다. The term "mammal " as used herein refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
여기에서 사용된 용어 "치료상 유효량"은 연구자, 수의사, 의사 또는 기타 임상의에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 치료상 유효 투여량 및 투여횟수는 원하는 효과에 따라 변화될 것임은 당업자에게 자명하다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. As used herein, the term "therapeutically effective amount " refers to the amount of active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, This includes an amount that induces relief of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect. Thus, the optimal dosage to be administered can be readily determined by those skilled in the art and will vary with the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, The age, body weight, sex, diet, time of administration, route of administration and fraction of the composition, duration of treatment, concurrent medication, and the like.
본 발명에 있어서의 약제조성물 중 유효성분인 감람유 추출물의 투여량은 환자의 연령, 성별, 증상, 투여방법 또는 예방목적에 따라, 체중 kg 당 6 내지 30㎎을 일일 1회 내지 3회 분복할 수 있다. 특이 증상을 나타내는 환자에 대한 투여용량 수준은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여 시간, 투여 방법, 배설율, 질환의 중증도 등에 따라 당업자가 투여량을 변화시킬 수도 있다.The dose of the olive oil extract, which is an active ingredient in the pharmaceutical composition of the present invention, may be divided into 6 to 30 mg / kg body weight once or three times a day according to the age, sex, symptoms, administration method or prevention purpose of the patient. have. Dosage levels for patients with specific symptoms may vary by those skilled in the art depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, severity of disease, and the like.
본 발명의 치료방법에서 본 발명의 감람유추출물을 유효 성분으로 포함하는 조성물은 경구, 직장, 정맥내,동맥내, 복강내, 근육내, 흉골내, 경피, 국소, 안구내 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있다.
In the treatment method of the present invention, the composition comprising the olive oil extract of the present invention as an active ingredient is conventionally used through oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular or intradermal routes. It may be administered in a phosphorous manner.
이하 본 발명을 설명한다.Hereinafter, the present invention will be described.
본 발명자들은 감람유 추출물에 대한 항염증 효과를 규명하고자, LPS 자극 동안 미세아교세포의 활성화에 대한 감람유 추출물의 잠재적인 항염증 효과를 탐색한 결과, 이들이 유도성 질소 산화물 합성(iNOS) 및 NO 생산을 완전히 약화시킬 수 있으므로 효율적인 항염증제 및 신경퇴행성 질환의 치료제로 효과적으로 사용될 수 있음을 발견하고 본 발명을 완성하기에 이르렀다.In order to elucidate the anti-inflammatory effects of olive oil extracts, the present inventors explored the potential anti-inflammatory effects of olive oil extracts on the activation of microglial cells during LPS stimulation, and as a result they induced inducible nitric oxide synthesis (iNOS) and NO production. It has been found that the present invention can be effectively used as an effective anti-inflammatory agent and a therapeutic agent for neurodegenerative diseases since it can be completely weakened, thereby completing the present invention.
본 발명은, 상기 감람유 추출물의 항염증제로서의 사용 가능성에 대하여 예의 연구하였고, 후술하는 바와 같이 감람유 추출물은 신경퇴행성 질환의 치료에 유용하게 사용될 수 있음을 밝혀내었다.The present invention has been intensively studied for the use of the olive oil extract as an anti-inflammatory agent, and as described below, the olive oil extract was found to be useful for the treatment of neurodegenerative diseases.
감람유 추출물이 항염증성 시약으로 사용될 수 있는지를 찾아내기 위하여, 본 발명자들은 미세아교세포 작용을 억제하는 세포 및 분자 상의 메카니즘을 연구하였다. To find out whether olive oil extracts can be used as anti-inflammatory reagents, the present inventors have studied mechanisms on cells and molecules that inhibit microglial action.
본 발명자들은 처음으로 감람유 추출물이 BV-2 미세아교세포에 있어서 미세아교세포 활성 및 LPS-유발 TNF-α, iNOS 단백질 발현 및 NO 생산을 억제할 수 있음을 발견하였다. 미세아교세포의 활성화는 염증성 사이토카인 류 및 NO를 방출하고, 이어서 이웃하는 방관자 뉴우런의 세포사멸을 유발한다. 다양한 자극원에 의해 활성화된 미세아교세포로부터의 과도한 NO 및 사이토카인 생산은 독성을 가질 수 있으며 신경 세포 치사를 매개할 수 있음이 제시된 바 있다. 염증성 신경퇴행 질환의 실험 모델에 있어서 가장 널리 사용되는 LPS는 전염증성 사이토카인류의 상당한 상승과 이어지는 NO 방출과 함께 미세아교세포의 활성화를 유도한다(Hou RC, Chen HL, Tzen JT, Jeng KC. Effect of sesame antioxidants on LPS-induced NO production by BV2 microglial cells. Neuroreport 2003;14:1815-1819.).The inventors have found for the first time that olive oil extracts can inhibit microglial activity and LPS-induced TNF-α, iNOS protein expression and NO production in BV-2 microglia. Activation of microglia releases inflammatory cytokines and NO, which in turn causes apoptosis of neighboring bystander neurons. Excessive NO and cytokine production from microglia activated by various stimulators has been shown to be toxic and mediate neuronal lethality. LPS, most widely used in experimental models of inflammatory neurodegenerative diseases, induces activation of microglia with significant elevation of proinflammatory cytokines and subsequent NO release (Hou RC, Chen HL, Tzen JT, Jeng KC. Effect of sesame antioxidants on LPS-induced NO production by BV2 microglial cells. Neuroreport 2003; 14: 1815-1819.).
본 발명자들의 결과는 상당히 증가된 NO 수준을 나타내었고(도 1 참조), TNF-α의 사이토카인을 현저히 유발하였으며 (도 5 참조), 감람유 추출물 전처리는 BV-2 미세아교세포에 있어서 NO, 및 TNF-α 생산을 상당히 완화시켰다(도 1, 4 및 5 참조). 이들 결과로부터, 감람유 추출물이 LPS-유도 미세아교세포 활성화에 대하여 항염증성 작용을 갖는 것이 명백하다. 감람유 추출물 80 ug/ml을 In vitro에서 항산화를 측정한 결과 농도 의존적으로 free radical 소거능력이 60%이상으로 현저하게 항산화 효과가 있음을 밝혔다(도 3).Our results showed significantly increased NO levels (see FIG. 1), which significantly induced the cytokine of TNF-α (see FIG. 5), and olive oil extract pretreatment resulted in NO in BV-2 microglia, and TNF-α production was significantly alleviated (see FIGS. 1, 4 and 5). From these results, it is clear that the olive oil extract has an anti-inflammatory action on LPS-induced microglia activation. 80 ug / ml of olive oil extract was measured in vitro and found to have a significant antioxidant effect of more than 60% free radical scavenging ability in a concentration-dependent manner (Fig. 3).
NO는 NOS 패밀리(family) 아이소자임에 의해 발생하여 L-아르기닌을 L-시트룰린 및 NO로 전환시키는 것으로 알려져 있다(Nathan C. Inducible nitric oxide synthase: what difference does it make? J Clin Invest 1997;100:2417-2423.). iNOS 레벨은 미세아교세포에서 정상적으로 낮으나, iNOS는 LPS 처리를 포함하는 다양한 자극원에 응답하여 고도로 상승되게 조절될 수 있다.NO is known to be caused by the NOS family isozyme to convert L-arginine to L-citrulline and NO (Nathan C. Inducible nitric oxide synthase: what difference does it make? J Clin Invest 1997; 100: 2417-2423.). iNOS levels are normally low in microglia, but iNOS can be regulated to be highly elevated in response to various stimuli, including LPS treatment.
일부 신경 독소 또는 LPS는 iNOS의 상승-조절을 유도하고, 이어지는 미세아교세포에서 NO 생산을 유도하는 반면, iNOS를 직접 억제할 경우 LPS-매개 미세아교세포의 활성화가 효율적으로 감소되었다(Hald A, Lotharius J. Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 2005;193:279-290.).Some neurotoxins or LPS induce up-regulation of iNOS and induce NO production in subsequent microglia, whereas direct inhibition of iNOS effectively reduces the activation of LPS-mediated microglia (Hald A, Lotharius J. Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 2005; 193: 279-290.).
본 발명자들은 80 ug/ml 감람유 추출물이 BV-2 세포에 있어서 LPS-유발 iNOS 단백질 발현 및 NO 생산을 완전히 약화시킬 수 있음을 밝혀내었다 (도 1, 4 참조).We have found that 80 ug / ml olive oil extract can completely attenuate LPS-induced iNOS protein expression and NO production in BV-2 cells (see FIGS. 1, 4).
축적된 결과들에 의하면 iNOS 및 많은 염증성 사이토카인류가 NF-kB를 포함하는 전자 인자들에 의해 조절됨을 나타낸다(Christman JW, Blackwell TS, Juurlink BH. Redox regulation of nuclear factor kappa B:therapeutic potential for attenuating inflammatory responses. Brain Pathol 2000;10:153-162.).Accumulated results indicate that iNOS and many inflammatory cytokines are regulated by electron factors including NF-kB (Christman JW, Blackwell TS, Juurlink BH.Redox regulation of nuclear factor kappa B: therapeutic potential for attenuating inflammatory responses.Brain Pathol 2000; 10: 153-162.).
결론적으로, 이러한 연구 결과는 미세아교세포에 있어서 항염 효과를 가지며, 감람유 추출물이 NO 생산 및 BV-2 미세아교세포에 있어서 LPS에 의해 유발되는 iNOS 단백질 발현과 TNF-α의 분비를 억제하였음을 나타낸다. 감람유 추출물의 작용 기전이 완전히 밝혀지지는 않았으나, 상기 결과는 감람유 추출물이 염증관련 신경퇴행성 질환의 유력한 치료제가 될 수 있음을 의미한다.In conclusion, these findings indicate that the anti-inflammatory effect in microglia and olive oil extract inhibited NO production and LN-induced iNOS protein expression and TNF-α secretion in BV-2 microglia. . Although the mechanism of action of olive oil extract is not fully understood, the results indicate that olive oil extract may be a potent therapeutic agent for inflammation-related neurodegenerative diseases.
본 발명의 감람유 추출물의 급성 독성 실험 및 결과는 하기와 같다.Acute toxicity test and results of the olive oil extract of the present invention are as follows.
6 내지 7주령 된 비설치류 비글견을 대상으로 본 발명의 감람유 추출물을 경구 투여하여 24시간 내의 개체 사망율을 조사하였으며, 이때 암컷은 6 내지 8㎏인 개체를, 수컷은 7 내지 9㎏인 개체를 각각 8마리 사용하였다. 그 결과, 5g/kg 까지 죽은 개체가 발생하지 않아, 본 발명의 감람유 추출물은 kg당 5g까지도 급성독성을 관찰할 수 없을 만큼 안전하므로, 감람유 추출물의 세포 독성은 다른 임상적으로 이용되는 천연물 추출물에 비하여 매우 낮다.
Oral administration of the olive oil extract of the present invention was carried out in 6 to 7 week old non-rodent beagle dogs to investigate the mortality rate within 24 hours, wherein females were 6 to 8 kg and males were 7 to 9 kg. 8 animals each. As a result, dead individuals do not occur up to 5 g / kg, the olive oil extract of the present invention is safe enough to observe acute toxicity even up to 5 g per kg, the cytotoxicity of the olive oil extract to other clinically used natural product extracts Very low compared to
본 발명에 사용된 통계적 분석은 시험 데이터는 평균 SEM으로 나타냈다. 데이터는 먼저 일방향분산분석(one-way factorial analysis of variance, ANOVA)를 사용하여 분석하였다. 이어서, Student's t-test 또는 Turkey's test를 수행하여 처리된 시료와 비교하였다. p<0.05가 유의한 것으로 판단하였다.Statistical analysis used in the present invention showed the test data as the average SEM. The data were first analyzed using one-way factorial analysis of variance (ANOVA). Then, Student's t-test or Turkey's test was performed and compared with the treated samples. p <0.05 was determined to be significant.
본 발명에 따른 감람유 추출물을 포함하는 제약 조성물은 BV-2 세포에 있어서 LPS-유발 유도성 질소 산화물 합성(iNOS) NO 생산을 완전히 약화시킬 수 있고, 또한, 감람유 추출물에 의한 iNOS 단백질 발현이 약화하였음을 밝혀내었으며, 이들 결과는 감람유 추출물이 효율적인 항염증제 및 신경퇴행성 질환의 치료제로 사용될 수 있음을 제시한다.
The pharmaceutical composition comprising the olive oil extract according to the present invention can completely attenuate LPS-induced inducible nitrogen oxide synthesis (iNOS) NO production in BV-2 cells and also attenuate iNOS protein expression by the olive oil extract. These results suggest that olive oil extract can be used as an effective anti-inflammatory and therapeutic agent for neurodegenerative diseases.
도 1은 LPS-활성화시킨 BV-2 미세아교세포에 있어서 NO 생산에 미치는 감람유 추출물의 효과를 나타내는 그래프도.
도 2은 농도 의존적으로 감람유 추출물에 대한 MTT 세포독성시험
도 3은 ESR에 DPPH 방법에 의한 감람유 추출물의 항산화 효과를 나타내는 그래프도
도 4는 BV-2 미세아교 세포에 있어서 iNOS 및 TNF-α의 LPS-유도 단백질 발현에 미치는 감람유 추출물의 효과를 나타내는 그래프도
도 5은 배양된 BV-2 세포에 있어서 사이토카인 TNF-α에 미치는 감람유 추출물의 억제 효과를 나타내는 그래프도.1 is a graph showing the effect of olive oil extract on NO production in LPS-activated BV-2 microglia.
Figure 2 MTT cytotoxicity test for olive oil extract concentration-dependently
3 is a graph showing the antioxidant effect of olive oil extract by the DPPH method on ESR
4 is a graph showing the effect of olive oil extract on LPS-induced protein expression of iNOS and TNF-α in BV-2 microglial cells
5 is a graph showing the inhibitory effect of olive oil extract on cytokine TNF-α in cultured BV-2 cells.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
본 발명의 실시예에서 사용되는 대장균(Escherichia coli) 111:B4로 부터의 LPS는 시그마사(Sigma, St. Louis, Missouri, USA). 로부터 구입하였다. 안티-액틴, 안티-TNF-α 및 안티-iNOS 항체들은 Santa Cruz Biotechnology Inc. (Santa Cruz, California, USA)로 부터 구매하였다.
LPS from Escherichia coli 111: B4 used in the examples of the present invention is Sigma (Sigma, St. Louis, Missouri, USA). Purchased from Anti-actin, anti-TNF-α and anti-iNOS antibodies are described in Santa Cruz Biotechnology Inc. (Santa Cruz, California, USA).
실시예Example 1: One: 감람유Olive oil 추출물의 분리 및 정제 Isolation and Purification of Extracts
수용액을 5 L의 에틸아세테이트로 2회 추출하였다. 추출된 에틸아세테이트 분획을 증발시키고 건조시킨 분말(1 g)을 에탄올(5 ml)에 녹였다. 모든 실험에 있어서, 최종 농도의 DMSO는 0.1%를 초과하지 않도록 첨가하였다.
The aqueous solution was extracted twice with 5 L of ethyl acetate. The extracted ethyl acetate fractions were evaporated and dried (1 g) was dissolved in ethanol (5 ml). For all experiments, the final concentration of DMSO was added not to exceed 0.1%.
실시예Example 2:산화 질소 에세이 2: Nitric Oxide Essay
감람유 추출물이 BV-2 미세아교세포에서 LPS-유도 NO 생산을 억제하는지의 여부에 대하여 알아보고자 시험을 하였다. NO의 생산은 배양 배지 중의 질산염의 축적에 의해 측정하였다. 세포 상층액을 LPS 처리 24 시간 후에 수집하여 동일 용적의 Griess 시약 (1% 술파닐아마이드, 0.1% 나프틸에틸렌디아민 디하이드로클로라이드 및 2.5% 인산)과 혼합하였다. 흡광도는 플레이트 판독기(VersaMax; Molecular Devices, USA). 를 사용하여 540 nm에서 판독하였다. 질산 나트륨을 표준으로 사용하여 질산염의 농도를 계산하여 M으로 나타내었다.To determine whether olive oil extracts inhibit LPS-induced NO production in BV-2 microglia. The production of NO was measured by the accumulation of nitrates in the culture medium. The cell supernatant was collected 24 hours after LPS treatment and mixed with the same volume of Griess reagent (1% sulfanamide, 0.1% naphthylethylenediamine dihydrochloride and 2.5% phosphoric acid). Absorbance was measured by a plate reader (VersaMax; Molecular Devices, USA). Read at 540 nm. Sodium nitrate was used as the standard and the concentration of nitrate was calculated and expressed in M.
NO 생산에 대한 감람유 추출물의 효과를 결정하기 위하여, BV-2 세포들을 감람유 추출물을 30 분 동안 처리하고, LPS (1 ug/ml)를 첨가한 후, 24 시간 후에 질산염의 농도를 배양배지 중에서 측정하였다. LPS 첼린지에 앞서 감람유 추출물로 전처리한 배양물 중의 NO의 양은 각각 42% (20 ug/ml 감람유 추출물), 73% (40 ug/ml 감람유 추출물) 및 94% (80 ug/ml 감람유 추출물) 감소하였다. (도 1 참조).To determine the effect of olive oil extract on NO production, BV-2 cells were treated with olive oil extract for 30 minutes, LPS (1 ug / ml) was added and the concentration of nitrate was measured in culture medium after 24 hours. It was. The amount of NO in cultures pretreated with olive oil extract prior to LPS challenge was reduced by 42% (20 ug / ml olive oil extract), 73% (40 ug / ml olive oil extract) and 94% (80 ug / ml olive oil extract), respectively. It was. (See Figure 1).
도 1은 LPS-활성화시킨 BV-2 미세아교세포에 있어서 NO 생산에 미치는 감람유 추출물의 효과를 나타내는 그래프도이다. BV-2 세포들을 LPS 처리(0.5 g/ml)에 앞서 정해진 농도로 30분 동안 감람유 추출물로 전처리하였다. LPS처리 24 시간 후에 세포 배지 중의 질산염 레벨을 그리스 반응(Griess reaction)에 의해 결정하였다. 감람유 추출물은 BV-2 미세아교 세포에 있어서 농도-의존 방식으로 NO의 LPS-유도 생산을 상당히 감소시킨 반면, 모든 값은 3회의 독립적인 실험의 평균 SEM을 나타냈다. *p<0.05 및 **LPS 단독에 비하여 p<0.01.1 is a graph showing the effect of olive oil extract on NO production in LPS-activated BV-2 microglia. BV-2 cells were pretreated with olive oil extract for 30 minutes at the concentrations specified prior to LPS treatment (0.5 g / ml). 24 hours after LPS treatment, nitrate levels in the cell medium were determined by a Greries reaction. Olive oil extract significantly reduced LPS-induced production of NO in a concentration-dependent manner in BV-2 microglial cells, while all values represented the mean SEM of three independent experiments. * p <0.05 and ** p <0.01 compared to LPS alone.
세포 생존능 분석 결과 세포 증식이나 세포독성이 본 연구에서 상기 농도의 LPS 또는 감람유 추출물의 실험적 처리에 의해 영향을 받지 않은 것으로 나타났다 (도 2 참조)
Cell viability analysis showed that cell proliferation or cytotoxicity was not affected by the experimental treatment of LPS or olive oil extracts of this concentration in this study (see FIG. 2).
실시예Example 3:사이토카인에 미치는 3: affecting cytokines 감람유Olive oil 추출물의 영향 Effect of Extract
효소면역분석 (ELISA) 및 웨스턴 블롯 분석Enzyme Immunoassay (ELISA) and Western Blot Analysis
BV-2 배양물 중의 TNF-α 의 단백질 수준은 상업적인 ELISA 키트 (R&D Systems, USA)를 제조원의 지시에 따라 측정하였다. TNF-α의 양은 배양 상층액을 사용하여 결정하였다. 450 nm에서의 흡광도는 플레이트 판독기에서 판독하고 사이토카인은 pg/ml로 나타내었다. iNOS, TNF-α의 발현은 웨스턴 블롯 분석에 의해 결정하였다. 다양한 실험 조건에서 성장한 BV-2 세포를 PBS로 2회 세척하고, 이어서 RIPA 완충액(PBS, 1% Nonidet P-40, 0.5% 소듐 데옥시콜레이트, 0.1% SDS, 0.1 mg/ml 페닐메틸설포닐 플루오리드, 30 mg/ml 아프로티닌 및 1 mM Na3VO4)에 용해시켰다. 추가의 세포 용해물의 제조물은 PVDF 멤브레인으로 전기이동시키고, 증강된 ECL 화학발광 키트(GE Healthcare, USA)에 의한 단백질 검출을 상기한 바에 따라 수행하였다(참조문헌: Cho HS, Kim S, Lee SY, Park JA, Kim SJ, Chun HS, Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neuroxoxicology 2008;29:656-662.).Protein levels of TNF-α in BV-2 cultures were measured according to manufacturer's instructions with a commercial ELISA kit (R & D Systems, USA). The amount of TNF-α was determined using the culture supernatant. Absorbance at 450 nm was read in a plate reader and cytokines were expressed in pg / ml. Expression of iNOS, TNF-α was determined by Western blot analysis. BV-2 cells grown under various experimental conditions were washed twice with PBS, followed by RIPA buffer (PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS, 0.1 mg / ml phenylmethylsulfonyl fluorine). Reed, 30 mg / ml aprotinin and 1 mM Na 3 VO 4 ). Preparation of additional cell lysates was electrophoresed to PVDF membrane and protein detection by enhanced ECL chemiluminescence kit (GE Healthcare, USA) was performed as described above (Cho HS, Kim S, Lee SY). , Park JA, Kim SJ, Chun HS, Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neuroxoxicology 2008; 29: 656-662.).
BV-2 세포에 있어서 감람유 추출물 및 LPS의 처리 후에 TNF-α 단백질 생산의 조정 능력(modulation)을 조사하기 위하여 ELISA 분석을 수행하고, 그 결과를 도 5에 나타내었다.ELISA analysis was performed to investigate the modulation of TNF-α protein production after treatment of olive oil extract and LPS in BV-2 cells, and the results are shown in FIG. 5.
도 3은 배양된 BV-2 세포에 있어서 사이토카인 및 iNOS의 단백질 발현에 미치는 감람유 추출물의 억제 효과를 나타내는 도면이다. 24 시간 자극 동안 LPS 및 감람유 추출물에 대한 BV-2 세포의 반응을 ELISA에 의해 정량화하였다. 감람유 추출물은 LPS-자극 BV-2 세포 모두에서 IL-1 및 TNF-α 생산을 상당히 감소시켰다. 값은 4회의 독립적인 실험의 평균 SEM으로 나타냈다. *LPS 단독에 비하여 p<0.05. iNOS 단백질의 발현은 16 시간 LPS-자극시킨 세포에서 웨스턴 블롯 분석에 의해 평가하였다. 감람유 추출물 전처리는 iNOS의 LPS-유도 상승 조절을 농도 의존적으로 상당히 억제하였다. 상대 농도계 밀도는 미처리 대조군의 값에 대한 비율로 평가하였다. *LPS 단독에 비교하여 p<0.05.3 is a diagram showing the inhibitory effect of olive oil extract on the protein expression of cytokines and iNOS in cultured BV-2 cells. The response of BV-2 cells to LPS and olive oil extracts during 24 h stimulation was quantified by ELISA. Olive oil extract significantly reduced IL-1 and TNF-α production in both LPS-stimulated BV-2 cells. Values are shown as mean SEM of four independent experiments. * P <0.05 compared to LPS alone. Expression of iNOS protein was assessed by Western blot analysis in 16 hour LPS-stimulated cells. Olive oil extract pretreatment significantly inhibited iNOS LPS-induced upregulation. Relative densitometer density was assessed as a percentage of the value of the untreated control. * P <0.05 compared to LPS alone.
도 4에 나타낸 바와 같이, INOS 및 TNF-α의 LPS-유도 생산에 대한 감람유 추출물의 억제 효과는 상당하였다. 감람유 추출물은 TNF-α 생산을 65% 감소시켰다. iNOS 단백질의 레벨은 웨스턴블롯 분석에 의해 검출하였다.As shown in FIG. 4, the inhibitory effect of olive oil extract on LPS-induced production of INOS and TNF-α was significant. Olive oil extract reduced TNF-α production by 65%. Levels of iNOS protein were detected by Western blot analysis.
도 4에 나타낸 바와 같이, 감람유 추출물 전처리는 iNOS 단백질 발현을 농도 의존적 방식으로 일관된 감소를 유도하였다. 농도계 분석에 의하면 LPS 처리전에 감람유 추출물(10-80 ug/ml)으로 전처리한 배양물에 있어서 iNOS 단백질 레벨이 각각 42%(40 ug/ml 감람유 추출물), 및 63% (80 ug/ml 감람유 추출물) 감소하였음을 나타낸다.As shown in FIG. 4, olive oil extract pretreatment induced a consistent decrease in iNOS protein expression in a concentration dependent manner. Densitometer analysis indicated that iNOS protein levels were 42% (40 ug / ml olive oil extract) and 63% (80 ug / ml olive oil extract, respectively) in cultures pretreated with olive oil extract (10-80 ug / ml) prior to LPS treatment. ) Decreases.
이상에서 살펴 본 바와 같이, 본 발명의 감람유 추출물을 포함하는 조성물은 BV-2 세포에 있어서 LPS-유발 유도성 질소 산화물 합성(iNOS) mRNA 발현 및 NO 생산을 완전히 약화시킬 수 있으므로 효율적인 항염증제 및 신경퇴행성 질환의 치료제로 효과적으로 사용될 수 있다.As described above, the composition comprising the olive oil extract of the present invention can completely attenuate LPS-induced inducible nitric oxide synthesis (iNOS) mRNA expression and NO production in BV-2 cells, so efficient anti-inflammatory and neurodegenerative It can be effectively used as a therapeutic agent for diseases.
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