KR102035109B1 - A composition comprising Micrandilactone C for preventing or treating neurological disease - Google Patents
A composition comprising Micrandilactone C for preventing or treating neurological disease Download PDFInfo
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Abstract
본 발명은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염을 포함하는 신경계 질환의 예방, 개선 또는 치료용 약학적 조성물 및 식품 조성물에 관한 것이다.
본 발명의 미크란디락톤 C (Micrandilactone C)은 신경세포 사멸을 억제하고, 미세아교세포의 활성을 억제하며, 염증에 의한 신경손상 회복 효과를 보이며, 신경계 질환에 의한 운동 장애에 대한 회복 효과를 보임으로써, 신경계 질환의 예방, 개선 또는 치료용 약학적 조성물 또는 식품 조성물로 유용하게 이용할 수 있다.The present invention relates to pharmaceutical compositions and food compositions for the prevention, amelioration or treatment of diseases of the nervous system, including the microcrandilactone C or a pharmaceutically acceptable salt thereof.
Microcrandilactone C of the present invention inhibits neuronal cell death, inhibits the activity of microglia, shows the effect of restoring nerve damage by inflammation, and shows a restoring effect on motor disorders caused by neurological diseases. By this, it can be usefully used as a pharmaceutical composition or food composition for the prevention, improvement or treatment of neurological diseases.
Description
본 발명은 신경계 질환의 예방, 개선 또는 치료용, 약학적 조성물 또는 식품 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition or a food composition for preventing, ameliorating or treating a neurological disease.
중추신경계(central nervous system, CNS)는 신경세포(neuron)와 신경교세포(neuroglia)로 이루어져 있다. 신경교세포는 뇌 속에 가장 많이 분포되어 있는 세포로서 전체 뇌세포의 90%, 부피로 뇌 전체의 50%를 차지하고 있다. 이 세포들은 그 자체로는 신경 충격을 생성시키지 못하지만 신경원들이 고유의 기능을 수행하는데 도움을 주며, 뇌 조직이 손상되었을 때 이를 회복시키는데도 매우 중요한 기능을 하는 것으로 알려져 있다. 상기 신경교세포는 다시 별아교세포(astrocytes), 미세아교세포(microglia) 및 희소돌기아교세포(oligodendrocytes)의 세 종류로 구성되어 있다.Central nervous system (CNS) is composed of neurons (neuron) and glial cells (neuroglia). Glial cells are the most distributed in the brain, accounting for 90% of the brain cells and 50% of the brain. These cells, by themselves, do not produce nerve impulses, but they help neurons perform their own functions and are also very important for repairing damaged brain tissue. The glial cells are composed of three types of astrocytes, microglia and oligodendrocytes.
이들 중에서 미세아교세포(microglia)는 미세교세포, 또는 소교세포로도 불리며 중추신경계에 상재하는 면역세포로서 전체 뇌 세포의 5-10%를 차지한다.Among these, microglia are also called microglia, or microglia, and occupy 5-10% of all brain cells as immune cells located in the central nervous system.
상기 미세아교세포는 중추신경계에서 일차 방어라인으로서 기능한다. 미세아교세포는 중추신경계에서 염증 매개자의 주요 세포 내 공급원이다. 미세아교세포는 일산화질소(nitric oxide, NO), 반응성 산소종(reactive oxygen species, ROS), 전염증성 사이토카인(pro-inflammatory cytokines) 및 프로스타글란딘(prostaglandin)을 생산함으로써 신경염증에 관여한다. 활성화된 미세아교세포는 손상된 신경조직 영역으로 이동하여 미생물 및 세포파편(cell debris)을 포식하고 파괴한다.The microglia serve as the primary line of defense in the central nervous system. Microglia are the major intracellular source of inflammatory mediators in the central nervous system. Microglia are involved in neuroinflammation by producing nitric oxide (NO), reactive oxygen species (ROS), pro-inflammatory cytokines and prostaglandin. Activated microglial cells migrate to damaged neural tissue regions to prey and destroy microorganisms and cell debris.
그러나 염증세포로서의 미세아교세포의 역할은 항상 유익한 것만은 아니다. 조절되지 않은 미세아교세포의 활성화와 지속적인 과도한 신경염증은 신경퇴행성 질환(neurodegenerative diseases)을 포함하는 다양한 중추신경계 병리의 원인으로 여겨지고 있다. 즉, 기능적으로 활성화된 미세아교세포는 염증매개물질을 생성 및 분비하여 신경세포 사멸을 초래하는 것으로 알려져 있다.But the role of microglia as inflammatory cells is not always beneficial. Unregulated microglia activation and sustained excessive neuroinflammation are thought to be responsible for a variety of central nervous system pathologies, including neurodegenerative diseases. That is, functionally activated microglia are known to produce and secrete inflammatory mediators resulting in neuronal cell death.
즉, 중추신경계에 존재하는 면역세포인 미세아교세포는 다양한 외인성, 내인성 물질로 인해 활성화될 수 있으며, 활성화된 미세아교세포는 염증성 사이토카인인 TNF-α 및 IL-1β, 일산화질소, 프로스타글란딘, 초과산화물 등의 물질을 생산, 방출한다. 이러한 물질들의 생성은 단기적으로는 면역반응을 유발하지만, 그 과도한 생산이나 지속적인 생산은 근접한 신경세포들의 사멸을 유도하여 결국 신경퇴행을 비롯한 신경계 질환을 유발한다는 것이다. 또 사멸 중인 신경세포가 방출하는 물질들이 미세아교세포의 활성을 다시 유발하게 되므로, 신경퇴행은 지속적인 악순환에 빠지게 된다. 실제로 미세아교세포의 활성이 알츠하이머병(Alzheimer’s Disease, AD), 파킨슨병(Parkinson’s Disease, PD), 헌팅턴병(Huntington’s Disease, HD), 루게릭병(Amyotrophic Lateral Sclerosis, ALS), 크로이츠펠트야콥병(Creutzfelt-Jakob Disease, CJD), 다발성경화증(Multiple Sclerosis, MS), 뇌졸중(Stroke), 염증성 및 신경병증성 통증(Inflammatory and Neuropathic pain) 등의 다양한 신경계 질환과 관계가 있음이 보고되었다. That is, microglia, which are immune cells present in the central nervous system, can be activated due to various exogenous and endogenous substances, and activated microglia are inflammatory cytokines TNF-α and IL-1β, nitric oxide, prostaglandin, excess Produces and releases substances such as oxides. The production of these substances causes an immune response in the short term, but their overproduction or continuous production leads to the death of neighboring neurons, eventually leading to neurodegenerative diseases including neurodegeneration. In addition, the neurons degenerate into a vicious cycle because substances released by dying neurons reactivate microglia. In fact, the activity of microglia is known as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Creutzfelt-Jakob It has been reported to be associated with various neurological diseases such as Disease, CJD), Multiple Sclerosis (MS), Stroke, Inflammatory and Neuropathic pain.
미크란디락톤 C (Micrandilactone C)는 하기 화학식 1의 구조를 가지는 화합물이다. Micrandilactone C is a compound having the structure of
[화학식 Ⅰ][Formula I]
위 미크란디락톤 C와 관련하여서는 항-HIV 효과에 대해 연구된 바가 있으나, 이외에 다른 의약 용도와 관련되어서 지금까지 연구된 바가 없다. The anti-HIV effect has been studied in relation to gastric dilactone C, but has not been studied so far in relation to other medicinal uses.
본 발명자들은 신경계 질환에 효과가 있는 개별 물질들에 대한 연구개발을 수행하여, 위 미크란디락톤 C가 신경계 질환의 예방, 개선 또는 치료에 우수한 효과를 보임을 확인하고 본 발명을 완성하였다. The present inventors conducted research and development on individual substances that are effective for neurological diseases, confirming that gastric dilactone C shows an excellent effect on preventing, ameliorating or treating neurological diseases, and completed the present invention.
본 발명의 목적은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 신경계 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of diseases of the nervous system, including the microcrandilactone C (Micrandilactone C) or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명의 목적은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염을 포함하는 신경계 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.It is also an object of the present invention to provide a food composition for preventing or ameliorating a neurological disease, including microcrandilactone C or a pharmaceutically acceptable salt thereof.
본 발명자들은 신경계 질환의 치료에 적합한 치료 물질들에 대해 검색을 수행하던 중, 미크란디락톤 C (Micrandilactone C)가 신경 염증을 감소시키고, 미세아교세포 활성을 억제하며, 뇌신경세포를 보호하며, 신경계 질환에 의한 운동 장애 등에 대한 개선 효과가 있음을 확인하고 본 발명을 완성하였다. The inventors of the present invention have been searching for therapeutic agents suitable for the treatment of diseases of the nervous system, while microcandilactone C reduces nerve inflammation, inhibits microglial activity, protects brain nerve cells, and the nervous system. It was confirmed that there is an improvement effect on the movement disorder due to the disease and completed the present invention.
본 발명은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 신경계 질환 예방 또는 치료용 약학적 조성물에 관한 것이다. The present invention micro dilactone It relates to a pharmaceutical composition for preventing or treating neurological diseases comprising C (Micrandilactone C) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 미크란디락톤 C (Micrandilactone C)는 신경 세포 사멸을 억제하고, 미세아교세포의 활성을 억제하며, 염증에 의한 신경 손상 회복 효과를 나타내며, 신경계 질환에 의해 발생하는 운동 장애의 개선 효과를 나타냄으로써 신경계 질환의 예방 또는 치료용 약학적 조성물로 유용하게 이용될 수 있다.Microcrandilactone C of the present invention inhibits neuronal cell death, inhibits the activity of microglia, exhibits the effect of restoring nerve damage by inflammation, and improves motor disorders caused by neurological diseases. By showing it can be usefully used as a pharmaceutical composition for the prevention or treatment of diseases of the nervous system.
본 발명에 있어서 미크란디락톤 C (Micrandilactone C)는 하기 화학식 Ⅰ의 구조를 가지는 화합물이다 : In the present invention, microcrandilactone C is a compound having the structure of Formula I:
[화학식 Ⅰ][Formula I]
본 발명의 유효성분인 미크란디락톤 C (Micrandilactone C)는 화학 합성에 의해 제조된 화합물이거나 오미자속 추출물로부터 분리될 수 있다. 예를 들어, Chem. Pharm . Bull. 63, 746-751 (2015)에 개시된 방법에 따라 천연물로부터 분리될 수 있다. 일 실시양태에 있어서 위 미크란디락톤 C (Micrandilactone C)는 오미자 뿌리로부터 분리될 수 있다. 구체적으로, 세절한 오미자 뿌리를 물, C1-C4의 저급 알코올, 또는 이들의 혼합물로 추출하고, 이의 분획화 및 컬럼크로마토그래피 분리를 통해 미크란디락톤 C (Micrandilactone C) 의 분리 및 동정이 가능하다. Microcrandilactone C, an active ingredient of the present invention, may be a compound prepared by chemical synthesis or isolated from Schizandra chinensis extract. For example, Chem. Pharm . Bull. 63 , 746-751 (2015) can be separated from natural products according to the method disclosed. In one embodiment gastric Mikandilactone C may be isolated from Schisandra roots. Specifically, the fine schizandra roots are extracted with water, lower alcohols of C 1 -C 4 , or mixtures thereof, and separation and identification of microcrandilactone C are achieved through fractionation and column chromatography separation thereof. It is possible.
또한, 상업적으로 제조되어 판매되는 미크란디락톤 C (Micrandilactone C) 라면 제한없이 사용 가능하다. In addition, any commercially available and commercially available microcrandilactone C may be used without limitation.
본 발명에 있어서 미크란디락톤 C (Micrandilactone C)는 약제학적으로 허용 가능한 염의 형태로 존재할 수 있다. In the present invention, microcrandilactone C may be present in the form of a pharmaceutically acceptable salt.
본 발명에 있어서 “약제학적으로 허용 가능한 염”은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하는데, 통상적으로 금속염, 유기 염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기 염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될 수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다.In the present invention, "pharmaceutically acceptable salt" refers to a salt that can be used pharmaceutically even among salts in which a cation and an anion are bound by an electrostatic attraction. Salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), aluminum salt, or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylenediamine Salts and the like; Salts with inorganic acids can be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like; Salts with organic acids can be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; Salts with basic amino acids can be salts with arginine, lysine, ornithine and the like; Salts with acidic amino acids can be salts with aspartic acid, glutamic acid and the like.
본 발명에 있어서 신경계 질환은 신경세포, 예컨대 뇌세포의 사멸 또는 퇴화가 일시적 또는 오랜 기간에 걸쳐 진행됨으로써 신경 기능의 손실이 일어나고 이에 의해 인지기능, 감각기능, 운동기능, 전신기능의 저하가 일어나는 상태 또는 증상을 의미한다. In the present invention, the neurological disease is a condition in which neuronal cells, such as brain cells, die or degenerate over a long period of time, resulting in loss of nerve function, thereby degrading cognitive function, sensory function, motor function, and systemic function. Or symptoms.
예를 들어, 상기 신경계 질환은 뇌졸중(stroke), 치매(dementia), 알츠하이머병(Alzheimer's disease), 파킨슨병(Parkinson's disease), 헌팅턴병(Huntington's disease), 피크병(Pick disease), 크로이펠츠-야콥병(Creutzfeld-Jacob disease), 전두측두치매(frontotemporal dementia), 루이치매(dementia with Lewy bodies), 근육위축가쪽경화증(amyotrophic lateral sclerosis; 루게릭병), 피질기저퇴행증(corticobasal degeneration), 다계통위축병(multiple system atrophy), 진행성핵상마비(progressive supranuclearpalsy), 신경계 자가면역질환(neurological autoimmunedisease), 다발성 경화증(multiple sclerosis), 염증성 및 신경병증성 통증(inflammatory and neuropathic pain) 및 뇌혈관질환(neuro vascular disease)으로 이루어진 그룹으로부터 선택된 어느 하나 이상일 수 있다. For example, the neurological disease may include stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick disease, and Creutzfeldt-Jakob disease. Creutzfeld-Jacob disease, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis (Lou Gehrig's disease), corticobasal degeneration, multiple system atrophy ( multiple system atrophy, progressive supranuclearpalsy, neurological autoimmunedisease, multiple sclerosis, inflammatory and neuropathic pain, and neurovascular disease At least one selected from the group consisting of.
보다 바람직하게 위 신경계 질환은 신경 퇴행성 질환일 수 있으며, 예를 들어 치매, 알츠하이머병, 파킨슨병, 헌팅턴병 및 다발성 경화증으로 이루어진 그룹으로부터 선택되는 어느 하나 이상일 수 있다. More preferably, the stomach nervous system disease may be a neurodegenerative disease, for example, any one or more selected from the group consisting of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis.
보다 바람직하게, 신경계 질환은 헌팅턴병, 파킨슨병 또는 다발성경화증일 수 있다. More preferably, the nervous system disease may be Huntington's disease, Parkinson's disease or multiple sclerosis.
본 발명에서 언급되는 예방은 본 발명의 조성물의 투여에 의해 염증의 증상을 억제시키거나 발병을 지연시키는 모든 행위를 의미하며, 치료는 본 발명의 조성물의 투여에 의해 염증에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.Prophylaxis as referred to in the present invention means any action that inhibits or delays the onset of inflammation by administration of the composition of the present invention, and the treatment improves or benefits the symptoms of inflammation by administration of the composition of the present invention. Means any behavior that changes.
본 발명은 조성물의 총 중량에 대하여 0.01 내지 50중량%으로 미크란디락톤 C (Micrandilactone C)를 포함하는 것이 바람직하나, 이에 한정되지 않는다. The present invention preferably includes, but is not limited to, Mikrandandilactone C at 0.01 to 50% by weight relative to the total weight of the composition.
본 발명의 조성물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제 및 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. The compositions of the present invention may be administered in various formulations, oral and parenteral, in actual clinical administration. When formulated, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants commonly used.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형 제제는 본 발명의 약학적 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스, 락토오스 및 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘, 스티레이드, 탈크 같은 윤활제도 사용될 수 있다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등이 포함될 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and the like, which may be used in the pharmaceutical compositions of the present invention at least one excipient such as starch, calcium carbonate, sucrose, It is prepared by mixing lactose and gelatin. In addition to the simple excipients, lubricants such as magnesium, styrene, and talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제가 포함된다. 비수성용제와 현탁용제로는 프로필레글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 61, 카카오지, 라우린지, 글리세롤 및 젤라틴 등이 사용될 수 있다. 본 발명의 약학적 조성물은 비경구 투여시 피하주사, 정맥주사 또는 근육 내 주사를 통하여 투여될 수 있다. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used. The pharmaceutical composition of the present invention may be administered by subcutaneous injection, intravenous injection or intramuscular injection during parenteral administration.
본 발명의 약학적 조성물의 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르며, 당업자에 의해 적절하게 선택될 수 있다. 예컨대, 다양한 경로로, 예를 들면, 경구, 복강 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다. 바람직한 효과를 위해서 본 발명의 미크란디락톤 C (Micrandilactone C)는 1일 0.01 내지 1,000 mg/kg, 바람직하게 1일 0.1 내지 500 mg/kg으로 투여하는 것이 바람직하다. 투여는 하루에 한 번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 다만, 상기 투여량의 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the severity of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. For example, it can be administered by various routes, for example by oral, intraperitoneal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections. For preferred effects, the microcrandilactone C of the present invention is preferably administered at 0.01 to 1,000 mg / kg per day, preferably 0.1 to 500 mg / kg per day. Administration may be administered once a day or may be divided several times. However, the above dosage amount is not intended to limit the scope of the present invention.
본 발명의 조성물은 신경계 질환 예방 또는 치료를 위하여 단독으로, 또는 수술, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy and biological response modifiers for the prevention or treatment of neurological diseases.
또한 본 발명은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염을 포함하는 신경계 질환의 예방 또는 개선용 식품 조성물을 제공한다. In another aspect, the present invention provides a food composition for preventing or ameliorating a neurological disease, including microcrandilactone C or a pharmaceutically acceptable salt thereof.
본 발명의 식품 조성물은 건강기능식품으로서 사용될 수 있다. 상기 "건강기능식품"이라 함은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The food composition of the present invention can be used as a dietary supplement. The term "health functional food" means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body under the Act on Health Functional Food, and "function" means a structure and function of the human body. It means the ingestion for the purpose of obtaining a useful effect for health use such as nutrient control or physiological action.
본 발명의 식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. The food composition of the present invention may include a conventional food additive, and the suitability as the "food additive" is applicable according to the General Regulations and General Test Law of the Food Additives approved by the Ministry of Food and Drug Safety unless otherwise specified. Judge according to the standards and standards for the item.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류들을 들 수 있다.Examples of the items listed in the "Food Additive Revolution" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid, natural additives such as color pigments, licorice extracts, crystalline cellulose, high color pigments, guar gum, Mixed preparations, such as a sodium L- glutamate preparation, an addition of an alkali, a preservative preparation, and a tar pigment preparation, are mentioned.
본 발명의 식품 조성물은 조성물 총 중량에 대하여 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염을 0.01 내지 95 중량%, 바람직하게는 1 내지 80 중량%로 포함할 수 있다. The food composition of the present invention may include 0.01 to 95% by weight, preferably 1 to 80% by weight of microcrandilactone C or a pharmaceutically acceptable salt thereof based on the total weight of the composition.
또한, 본 발명의 식품 조성물은 신경계 질환의 예방 및/또는 개선을 목적으로, 정제, 캡슐, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.In addition, the food composition of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like, for the purpose of preventing and / or improving neurological diseases.
예를 들어, 상기 정제 형태의 건강기능식품은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염, 부형제, 결합제, 붕해제, 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한, 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.For example, the nutraceutical in the form of tablets may be prepared by granulating conventionally the method with microcrandilactone C or a mixture thereof with pharmaceutically acceptable salts, excipients, binders, disintegrants, and other additives. Next, the lubricant may be added by compression molding, or the mixture may be directly compression molded. In addition, the health functional food in the form of tablets may contain a mating agent and the like, if necessary, may be coated with a suitable coating agent.
캡슐 형태의 건강기능식품 중 경질캡슐제는 통상의 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염, 및 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캡슐제는 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염 및 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캡슐기제에 충진하여 제조할 수 있다. 상기 연질캡슐제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.In capsule dietary supplements, the hard capsules are filled with conventional microcrandilactone C or pharmaceutically acceptable salts thereof, and mixtures with additives such as excipients or granules or granulated granules thereof. The soft capsule may be prepared by filling a capsule base such as gelatin with a mixture of additives such as microcrandilactone C or a pharmaceutically acceptable salt and excipient thereof. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
환 형태의 건강기능식품은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다.The dietary supplement in cyclic form can be prepared by molding a mixture of microcrandilactone C or its pharmaceutically acceptable salts, excipients, binders, disintegrants, etc., if necessary, and containing sucrose or other It is also possible to coat the skin with a suitable coating or starch, talc or a suitable substance.
과립형태의 건강기능식품은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용 가능한 염, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다. 과립형태의 건강기능식품은 12호 (1680 μm), 14호 (1410 μm) 및 45호 (350 μm) 체를 써서 다음 입도시험을 할 때에 12호체를 전량 통과하고 14호체에 남는 것이 전체량의 5.0 %이하이고 또 45호체를 통과하는 것은 전체량의 15.0 %이하일 수 있다.The health functional food in the form of granules can be prepared into granules in a suitable manner by preparing a mixture of microcrandilactone C or pharmaceutically acceptable salts, excipients, binders, disintegrating agents, etc. A mating agent and the like. For the health functional food in the form of granules, No. 12 (1680 μm), No. 14 (1410 μm) and No. 45 (350 μm) were used for the next particle size test. Less than 5.0% and passing through the 45 can be less than 15.0% of the total amount.
상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함한다 (대한약전 해설편, 문성사, 한국약학대학협의회, 제 5 개정판, p33-48, 1989).The term definitions of the excipients, binders, disintegrants, glidants, copulation agents, flavoring agents, etc. are described in the literature known in the art and include those having the same or similar functions (Korean Pharmacopoeia, Munseongsa, Korea Pharmacy University Council, 5th edition, p33-48, 1989).
상기 식품의 종류에는 특별한 제한이 없다. 본 발명의 추출물을 첨가할 수 있는 식품의 예로는 음료, 껌, 비타민 복합제, 드링크제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the kind of food. Examples of foods to which the extract of the present invention may be added include beverages, gums, vitamin complexes, drinks, and the like, and include all health functional foods in a conventional sense.
본 발명은 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염을 대상체에 투여하는 단계를 포함하는 신경계 질환의 치료방법을 제공한다.The present invention provides a method for treating a neurological disease, comprising administering to a subject a microcrandilactone C or a pharmaceutically acceptable salt thereof.
본 발명에서 “미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염”, “신경계 질환”, 및 “투여” 등의 용어는 상기에서 설명한 바와 동일하다.In the present invention, terms such as “Micrandilactone C or a pharmaceutically acceptable salt thereof”, “nerve system disease”, and “administration” are the same as described above.
상기 대상체는 동물을 말하며, 전형적으로 본 발명의 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염을 이용한 치료로 유익한 효과를 나타낼 수 있는 포유동물일 수 있다. 이러한 대상체의 바람직한 예로 인간과 같은 영장류가 포함될 수 있다. 또한 이와 같은 대상체들에는 신경계 질환의 증상을 갖거나 이와 같은 증상을 가질 위험이 있는 대상체들이 모두 포함될 수 있다.The subject refers to an animal and can typically be a mammal that can exhibit a beneficial effect with treatment with the microcrandilactone C of the present invention or a pharmaceutically acceptable salt thereof. Preferred examples of such subjects may include primates, such as humans. In addition, such subjects may include all subjects with or at risk of having a symptom of a neurological disease.
본 발명은 또한 신경계 질환의 치료를 위한 약제의 제조에서 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염의 모두의 용도를 제공한다. The present invention also provides the use of both microcrandilactone C or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neurological diseases.
본 발명은 또한 신경계 질환의 치료에 사용하기 위한 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염을 포함하는 조성물을 제공한다. The present invention also provides compositions comprising microcrandilactone C or a pharmaceutically acceptable salt thereof for use in the treatment of neurological diseases.
본 발명은 또한 신경계 질환의 치료를 위한 미크란디락톤 C (Micrandilactone C) 또는 이의 약제학적으로 허용가능한 염의 용도를 제공한다. The present invention also provides the use of microcrandilactone C or a pharmaceutically acceptable salt thereof for the treatment of diseases of the nervous system.
본 발명의 미크란디락톤 C (Micrandilactone C)은 신경세포 사멸을 억제하고, 미세아교세포의 활성을 억제하며, 염증에 의한 신경손상을 회복시키며, 신경계 질환에 의한 운동 장애등에 대해 회복 효과를 보임으로써 신경계 질환의 예방, 개선 또는 치료에 우수한 효과를 나타낸다. Microcrandilactone C of the present invention inhibits neuronal cell death, inhibits the activity of microglia, restores nerve damage caused by inflammation, and exhibits a restorative effect on movement disorders caused by neurological diseases. It has an excellent effect on the prevention, improvement or treatment of neurological diseases.
도 1은 미크란디락톤 C (Micrandilactone C)의 1H-NMR 스펙트럼 결과를 나타낸다.
도 2는 미크란디락톤 C (Micrandilactone C)의 13C-NMR 스펙트럼 결과를 나타낸다.
도 3은 lipopolysaccharid (LPS) 또는 IL-4가 처리된 미세아교세포에서 미크란디락톤 C (Micrandilactone C) 처리에 의한 신경에서의 염증 반응 억제의 효과로 iNOS 발현 억제 및 Arginase-1 발현의 증진을 확인한 결과를 나타낸다.
도 4는 LPS가 처리된 미세아교세포에서 미크란디락톤 C (Micrandilactone C) 처리에 의한 염증 반응 억제의 기전 및 효과로 MAPKs (JNK, ERK 및 p38), NF-κB 및 STAT3의 발현 감소를 확인한 결과를 나타낸다.
도 5는 3-propionic acid (3-NPA)에 의한 헌팅턴병 동물 모델에서 미크란디락톤 C (Micrandilactone C) 투여에 의한 신경학적 회복 효과, 생존율 증진 및 체중 증진 효과를 확인한 결과를 나타낸다.
도 6은 3-NPA에 의한 헌팅턴병 동물 모델에서 미크란디락톤 C (Micrandilactone C) 투여에 의한 신경세포 사멸 억제 효능을 확인한 결과를 나타낸다.
도 7은 3-NPA에 의한 헌팅턴병 동물 모델에서 미크란디락톤 C (Micrandilactone C) 투여에 의한 미세아교세포의 활성화 억제 효과를 나타낸다.
도 8은 3-NPA에 의한 헌팅턴병 동물 모델에서 미크란디락톤 C (Micrandilactone C) 투여에 의한 신경 염증 관련 신호 기작 억제 효과를 확인한 결과를 나타낸다.
도 9는 3-NPA에 의한 헌팅턴병 동물 모델에서 미크란디락톤 C (Micrandilactone C) 투여에 의한 염증 관련 매개 인자들의 발현 억제 효과를 확인한 결과를 나타낸다. Figure 1 shows the 1 H-NMR spectrum of the microcrandilactone C (Micrandilactone C).
Figure 2 shows the 13 C-NMR spectrum results of Micrandilactone C.
Figure 3 confirms the inhibition of iNOS expression and the enhancement of Arginase-1 expression by the effect of inhibiting the inflammatory response in the neuron by the treatment of micrandilactone C in lipopolysaccharid (LPS) or IL-4 treated microglia Results are shown.
Figure 4 confirms the decrease in the expression of MAPKs (JNK, ERK and p38), NF-κB and STAT3 as a mechanism and effect of inhibiting the inflammatory response by microrandilactone C (Micrandilactone C) treatment in LPS-treated microglia Indicates.
FIG. 5 shows the results of confirming the neurological recovery effect, the survival rate improvement, and the weight gain effect by the administration of microcrandilactone C in Huntington's disease animal model by 3-propionic acid (3-NPA).
Figure 6 shows the results of confirming the neuronal cell death inhibition effect by the administration of the Mikrandandilactone C (Micrandilactone C) in Huntington's disease animal model by 3-NPA.
Figure 7 shows the inhibitory effect of microglial activation by microcrandilactone C administration in Huntington's disease animal model by 3-NPA.
Figure 8 shows the results confirming the inhibitory effect of neuronal inflammation-related signaling mechanisms by administration of microdilactone C (Micrandilactone C) in Huntington's disease animal model by 3-NPA.
Figure 9 shows the results confirming the effect of inhibiting the expression of inflammation-related mediators by administration of Mikranandilactone C in Huntington's disease animal model by 3-NPA.
이하, 하기 실시예 및 실험예에 의해 본 발명을 보다 상세하게 설명한다. 그러나, 하기 실시예는 본 발명의 범위를 제한하는 것은 아니며, 이는 본 발명의 이해를 돕기 위한 것으로 해석되어야 할 것이다.Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. However, the following examples are not intended to limit the scope of the present invention, which will be construed as to aid the understanding of the present invention.
<< 제조예Production Example > > 미크란디락톤Microdilactone C ( C ( MicrandilactoneMicrandilactone C)의 제조 C) manufacture
음지에서 건조하고, 세절한 오미자(Schisandra chinensis) 뿌리 1.72 kg을 70% 수용성 에탄올(20 L)에 침지하고 2일씩 3회에 걸쳐서 반복하여 추출하였다. 추출액을 회전감압농축기(Rotary Evaporator)로 40˚C에서 농축하여 70% 에탄올 추출물 235.75 g을 얻었다(수율 13.7%). 70% 에탄올 추출물을 증류수에 현탁 시킨 후에 에틸 아세테이트(EtOAc)와 부탄올을 이용하여 순차적으로 용매분획을 실시하였다. 에틸아세테이트 분획물(48.09 g)은 n-hexane-EtOAc-MeOH-H2O 혼합물(9:1:0:0, 4:1:0:0, 3:2:0:0, 2:3:0:0, 0:1:0:0, 0:9:1:0.1, 0:8:2:0.2, 그리고 0:7:3:0.3, 최종적으로 100% MeOH)을 용출액으로 하는 실리카겔 칼럼크로마토그래피 실시에 의해 17 개의 분획물(E1-E17)로 세분화하였다. 이중 분획물 E14 (7.73 g)에 대해 n-hexane-EtOAc-MeOH 혼합액(6:3:1)을 용출용매로 하는 실리카겔 칼럼크로마토그래피를 실시하여 8개의 소분획물(E14-1-E14-8)로 나누었다. 소분획물 E14-4 (1.04 g)에 대해 세파데스(Sephadex) LH-20 칼럼크로마토그래피를 실시하여 미크란디락톤 C (Micrandilactone C) 220 mg을 분리하였다. 분리된 미크란디락톤 C (Micrandilactone C)의 화학구조는 NMR 자료 분석과 기존에 보고된 자료[Li et al., Chem. Commun., 23, 2936-2938 (2005)]와의 비교를 통해서 동정하였다.Dried in the shade, 1.72 kg of shredded Schisandra chinensis roots were soaked in 70% aqueous ethanol (20 L) and extracted three times over two days. The extract was concentrated at 40 ° C. with a rotary evaporator to obtain 235.75 g of 70% ethanol extract (yield 13.7%). After 70% ethanol extract was suspended in distilled water, solvent fractionation was performed sequentially using ethyl acetate (EtOAc) and butanol. Ethyl acetate fraction (48.09 g) was mixed with n-hexane-EtOAc-MeOH-H 2 O mixture (9: 1: 0: 0, 4: 1: 0: 0, 3: 2: 0: 0, 2: 3: 0 Silica gel column chromatography using: 0, 0: 1: 0: 0, 0: 9: 1: 0.1, 0: 8: 2: 0.2, and 0: 7: 3: 0.3, finally 100% MeOH) The run was subdivided into 17 fractions (E1-E17). Double fraction E14 (7.73 g) was subjected to silica gel column chromatography using n-hexane-EtOAc-MeOH mixed solution (6: 3: 1) as an eluting solvent. Divided. Sepadex LH-20 column chromatography was performed on subfraction E14-4 (1.04 g) to isolate 220 mg of microcrandilactone C. The chemical structure of the isolated microcrandilactone C was analyzed by NMR data and previously reported data [Li et al., Chem. Commun., 23, 2936-2938 (2005)].
그 결과를 아래 표 1, 도 1 및 도 2에 나타내었다. The results are shown in Table 1 below, FIGS. 1 and 2.
<실시예 1> LPS 또는 IL-4 처리 면역세포 모델에서의 면역 조절 효과 확인 Example 1 Confirmation of Immune Regulatory Effects in LPS or IL-4 Treated Immune Cell Models
면역세포 모델은 미세아교세포(microglia) 세포주인 BV2 세포주를 사용하였다. 세포주는 100 mm plates에 배양액[Dulbecco’s modified Eagle’s medium (DMEM, Gibco, Grand Island, New York, USA), 10% fetal bovine serum (FBS, Gibco) 및 1% penicillin/streptomycin (P/S, Gibco)]를 첨가하여 37°C 및 5% CO2로 유지되는 배양기(incubator)안에서 배양되었으며, 3일 간격으로 배양액을 교체하였다. The immune cell model used a BV2 cell line, which is a microglia cell line. Cell lines were cultured on 100 mm plates (Dulbecco's modified Eagle's medium (DMEM, Gibco, Grand Island, New York, USA), 10% fetal bovine serum (FBS, Gibco) and 1% penicillin / streptomycin (P / S, Gibco)). It was incubated in an incubator maintained at 37 ° C and 5% CO 2 by the addition of the culture medium was replaced every three days.
위 BV2 세포주를 이용하여 미크란디락톤 C의 면역 조절 효과를 확인하였다. 구체적으로, 50 ng/ml의 Lipopolysaccharides (LPS, 0127:B8; Sigma, 미국)를 4시간 동안 BV2 세포에 처리하여 세포를 자극하거나 0.1 ng/ml의 interleukin (IL)-4를 24시간 동안 BV2 세포에 처리하여 세포를 자극하였다. micrandilactone C 투여군의 경우 위와 같이 LPS 또는 IL-4로 자극하기 1시간 전에 세포독성을 나타내지 않는 적정 농도로 0.05 μM, 0.5 μM 또는 5 μM를 전처리하였다. micrandilactone C 는 Chem . Pharm . Bull. 63, 746-751 (2015)에 기재된 분리 방법에 의해 제조된 것을 사용하였다. 정상대조군에는 Phosphate-buffered saline (PBS)를 투여하였다. Using the above BV2 cell line was confirmed the immunomodulatory effect of microrandilatone C. Specifically, 50 ng / ml Lipopolysaccharides (LPS, 0127: B8; Sigma, USA) were treated with BV2 cells for 4 hours to stimulate cells or BV2 cells with 0.1 ng / ml interleukin (IL) -4 for 24 hours. Treated to stimulate cells. In the case of micrandilactone C-administered group, 0.05 μM, 0.5 μM, or 5 μM were pretreated at an appropriate concentration not showing
위와 같은 LPS 또는 IL-4의 신경 염증 자극에 의한 세포의 활성화 및 염증 사이토카인 발현 변화의 분석을 웨스턴 블랏을 수행하였다. Western blot was performed to analyze the activation of cells and changes in inflammatory cytokine expression caused by neurological stimulation of LPS or IL-4.
구체적으로, 6 well plates에 1.0×106개의 세포를 각각의 well에 분주하고, 위 설명된 바와 같이 시험군에 대하여 LPS 또는 IL-4로 자극하기 1시간 전에 micrandilactone C를 전처리하였고 대조군에 대해서는 LPS 또는 IL-4만을 투여하였다. LPS로 4시간과 IL-4로 24시간 각각 자극시킨 후에 세포를 각각 수집하여 단백질 용해 완충액(protein lysis buffer;10 mM 트리스, 0.5 mM EDTA, 0.25 M 수크로스) 50 μl를 넣고 세포막을 터트려 단백질을 분리하였다. 분리된 단백질은 소혈청알부민을 사용한 Bradford (Bio-Rad, Hercules, CA, USA) 방법을 이용하여 각 개체의 단백질을 정량한 뒤 20 μg의 단백질을 10% SDS-PAGE (Sodium Dodecyl Sulfate-polyacrylamidegel electrophoresis)에 의해 분리하여 PVDF (polyvinylidene difluoride) 멤브레인(membrane, Gendepot, Barker, TX, USA)으로 이동시켰다. PVDF 멤브레인은 5% 탈지유(skimmed milk, BD Biosciences, San Jose, CA, USA)에서 1시간 동안 블로킹시켰다. TBST로 수세한 후 1차 항체[토끼 항-inducible nitric oxide synthases (iNOS), arginase-1 (1:500; Santa Cruz Biotechnology, Santa Cruz, CA, USA), 토끼 항-phospho (p)-signal transducer and activator of transcription (STAT), nuclearfactor kappa B p65 (NF-κB p65), p-c-JUN N-terminal kinase (JNK), p-extracellular signal-regulated kinase (ERK) 및 p-p38 (1:1,000; ell Signaling Technology, Beverly, MA, USA)]를 3% 탈지유에 희석시켜 4℃에서 하루 동안 반응시켰다. 그리고 TBST로 10분씩 3회 수세하고 2차 항체와 함께 상온에서 1시간 동안 반응시켰다. 2차 항체(Vector Laboratories) 반응 후 TBST에 수세하고 ECL system (Santa Cruz Biotechnology, Santa Cruz, CA, USA)으로 단백질의 변화를 측정하였다. 단백질의 변화 및 정량 분석은 이미지 장비 ChemiDoc XRS+ (Bio-Rad)를 이용하였다. 각 단백질의 발현 수준은 토끼 항-glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 1:5,000; Cell Signaling Technology)로 표준화하였다.Specifically, 1.0 × 10 6 cells were dispensed into each well in 6 well plates, pretreated with
그 결과를 도 3 및 도 4에 나타내었다. The results are shown in FIGS. 3 and 4.
도 3은 본원 발명에 따른 미크란디락톤 C 처리에 따른 면역 조절 효과를 보여준다. 구체적으로, 미크란디락톤 C 처리는 LPS 또는 IL-4 처리 면역세포 모델 모두에서 M1형 미세아교세포의 마커인 iNOS의 발현을 현저히 억제하고(도 3A 및 C), M2형 미세아교세포의 마커인 arginase-1의 단백질 발현을 현저히 증가시킴(도 3B 및 C)을 보여주었다. Figure 3 shows the immunomodulatory effect of microrandiractone C treatment according to the present invention. Specifically, microdilactone C treatment significantly inhibits the expression of iNOS, a marker of M1 microglia in both LPS or IL-4 treated immune cell models (FIGS. 3A and C), and is a marker of M2 microglia. It was shown to significantly increase the protein expression of arginase-1 (FIGS. 3B and C).
도 4는 미크란디락톤 C의 면역 기전 조절능을 보여준다. 구체적으로, LPS 처리 면역세포 모델에 APKs (p-JNK(도 4의 A 및 B), p-ERK(도 4의 A 및 C) 및 p-p38(도 4의 A 및 D)), NF-κB p65(도 4의 A 및 E) 및 p-STAT3(도 4의 A 및 F)의 염증 관련 마커의 발현이 모두 억제되는 것이 확인되었다. Figure 4 shows the immune mechanism regulation of microdilactone C. Specifically, APKs (p-JNK (A and B in FIG. 4), p-ERK (A and C in FIG. 4) and p-p38 (A and D in FIG. 4)), NF- Expression of inflammatory markers of κB p65 (A and E in FIG. 4) and p-STAT3 (A and F in FIG. 4) was both suppressed.
위 결과를 통해서 본원 발명에 따른 micrandilactone C가 신경 면역 조절에 우수한 효과가 있음이 확인되었다. Through the above results, it was confirmed that micrandilactone C according to the present invention has an excellent effect on neuro immune regulation.
<< 실시예Example 2> 2> 헌팅턴병Huntington's disease 동물 모델에서의 운동 장애 개선 효과 확인 Identify the effects of improving motor impairment in animal models
헌팅턴병 동물 모델에서 micrandilactone C의 신경보호 효능을 확인하기 위해, 신경독성물질인 3-NPA를 이용하여 헌팅턴병의 동물모델을 제조하였다. In order to confirm the neuroprotective effect of micrandilactone C in the Huntington's disease animal model, an animal model of Huntington's disease was prepared using the neurotoxic substance 3-NPA.
구체적으로, C57BL/6J 계통의 수컷 생쥐(Narabiotec Co., Ltd., Seoul, Republic of Korea; weight, 20-23 g; age, 8-9 weeks; Seed mice were originated from Taconic Biosciences Inc., Cambridge, IN, USA)를 명암주기(light on 08:00 to 20:00)와 일정한 온도(23±2 ℃)가 유지되는 실험환경에서, 사료와 물을 자유롭게 공급하며 사육하였다. 상기 동물들은 실험 1주일 전에 실험환경에 적응시켰다. Specifically, male mice of C57BL / 6J strain (Narabiotec Co., Ltd., Seoul, Republic of Korea; weight, 20-23 g; age, 8-9 weeks; Seed mice were originated from Taconic Biosciences Inc., Cambridge, IN, USA) were fed with free feed and water in an experimental environment in which the light cycle (light on 08:00 to 20:00) and constant temperature (23 ± 2 ℃) were maintained. The animals were adapted to the experimental environment one week before the experiment.
동물모델은 상기 마우스에 3-NPA(3-Nitropropionic Acid) (Sigma, 미국)를 생리식염수 100 ㎕에 희석하여 24시간 간격으로 5회(70 mg/kg)에 걸쳐서 복강으로 투여하였다. Sham군은 생리식염수를 투여하였으며, 3-NPA+micrandilactone C 투여군은 micrandilactone C (1.25 또는 2.5 mg/kg)를 3-NPA를 투여하기 1시간 전부터 매일 1회씩 5일간 안와정맥으로 투여하였다. Micrandilactone C 단독투여군은 생리식염수와 micrandilactone C (2.5 mg/kg)를 투여하였다. The animal model was administered to the mouse intraperitoneally by diluting 3-NPA (3-Nitropropionic Acid) (Sigma, USA) in 100 μl of physiological saline over 5 hours (70 mg / kg) at 24 hour intervals. Sham group was treated with saline, and 3-NPA + micrandilactone C group was administered micrandilactone C (1.25 or 2.5 mg / kg) to orbital vein once daily for 5 days from 1 hour before 3-NPA. Micrandilactone C alone group was administered saline and micrandilactone C (2.5 mg / kg).
3-NPA에 의해 나타나는 특이적인 신경학적인 행동변화를 매일 1회씩 관찰하였다. 행동변화의 기준은 활동성 감소, 뒷다리 움켜쥠, 뒷다리 근육긴장이상, 흉추 후만 자세 및 정상자세로의 회복력으로 구분하였으며, 각각은 정도에 따라서 0, 1 및 2 단계로 나누어 측정하였다. 점수가 높을수록 신경학적 행동증상이 심함을 뜻한다. 또한, 생존율과 몸무게는 3-NPA를 마지막(5회째)으로 투여하고 24시간 후 확인하였다.Specific neurological behavioral changes caused by 3-NPA were observed once daily. The criteria for behavioral change were categorized into decreased activity, hind limb grasping, hind limb dystonia, postoperative thoracic vertebral posture and resilience to normal posture. Higher scores indicate more severe neurological behavioral symptoms. Survival and weight were also determined 24 hours after the last (5th) administration of 3-NPA.
그 결과를 도 5에 나타내었다. The results are shown in FIG.
도 5의 A는 신경학적 행동 변화를 확인한 결과, B는 생존율 변화를 확인한 결과, C는 체중 변화를 확인한 결과를 나타낸다. 도 5의 A에서 확인되는 바와 같이 micrandilactone C의 투여는 농도 의존적으로 신경학적 행동 변화에 긍정적 영향을 주어 우수한 운동 장애 개선 효과를 나타내었다. 3-NPA군에서 운동장애의 정도는 Sham군에 비하여 9.0 ± 0.4로 뚜렷하게 증가하였으나, micrandilactone C 1.25와 2.5 mg/kg 전투여군에서 각각 4.0 ± 0.4와 4.8 ± 0.2로 감소하였다. 5A confirms the change in neurological behavior, B confirms the change in survival rate, and C indicates the change in weight. As confirmed in A of FIG. 5, the administration of micrandilactone C had a positive effect on neurological behavioral changes in a concentration-dependent manner, and showed an excellent motor disorder improvement effect. The degree of dyskinesia in the 3-NPA group was significantly increased to 9.0 ± 0.4 compared to the Sham group, but decreased to 4.0 ± 0.4 and 4.8 ± 0.2 in micrandilactone C 1.25 and 2.5 mg / kg combat groups, respectively.
또한, 도 5의 B 및 C에서 확인되는 바와 같이 생존율 및 체중 변화 측면에서 우수한 회복 효과를 나타내었다. 생존율은 3-NPA군에서 42.9%였으나, micrandilactone C 1.25 또는 2.5 mg/kg 전투여군에서 각각 54.1%와 71.4%로 개선되었으며, 체중은 3-NPA군에서 Sham군에 비하여 뚜렷이 감소하였으나, micrandilactone C에 의하여 유의하게 영향을 받지는 않았다. In addition, as shown in B and C of Figure 5 showed an excellent recovery effect in terms of survival rate and weight change. Survival was 42.9% in the 3-NPA group, but improved to 54.1% and 71.4% in the micrandilactone C 1.25 or 2.5 mg / kg combat group, respectively, and the body weight was significantly decreased in the 3-NPA group compared to the Sham group, but not in the micrandilactone C group. It was not significantly affected.
위 결과를 통해서 본원 발명에 따른 micrandilactone C가 헌팅턴병을 비롯한 다양한 신경계 질환에 대해 운동 기능 장애를 개선함으로써 예방, 개선 및 치료 효과를 나타낼 수 있음을 확인하였다. Through the above results, it was confirmed that micrandilactone C according to the present invention can prevent, improve and treat effects by improving motor dysfunction for various neurological diseases including Huntington's disease.
<< 실시예Example 3> 3> 헌팅턴병Huntington's disease 동물 모델에서의 In animal models micrandilactonemicrandilactone C의 신경세포사멸 억제 효능 확인 Inhibition of neuronal cell death of C
상기 실시예 2에서 제조된 동물 모델을 이용하여 조직 절편을 제작하였다. 구체적으로, 3-NPA에 의한 세포사멸 및 미세아교세포의 활성화를 micrandilactone C가 억제하는지 검증하기 위해서, 3-NPA를 마지막으로 투여하고 24 시간 후에 4% 파라포름알데하이드(PFA, paraformaldehyde)를 사용하여 관류 고정하고 뇌를 적출한 후 동일 고정액에 담가 4℃에서 하루 이상 더 고정시킨 다음 30% 수크로스(sucrose)로 바꾸어 4℃에서 3일 동안 보관하였다. 동결절편기(Leica Cryostat CM3050S, 독일)를 이용하여 줄무늬체(선조체, striatum)를 포함한 부위를 뇌의 부위를 30 ㎛ 두께로 관상절단(coronal section)하여 PBS나 동결보존액에 담가 냉동고에 보관하였다. Tissue sections were prepared using the animal model prepared in Example 2 above. Specifically, to verify that micrandilactone C inhibits apoptosis and microglia activation by 3-NPA, 4% paraformaldehyde (PFA, paraformaldehyde) was used 24 hours after the last administration of 3-NPA. After perfusion fixation and brain extraction, the solution was immersed in the same fixation solution at 4 ° C for at least one day, and then changed to 30% sucrose and stored at 4 ° C for 3 days. Using a freezing section (Leica Cryostat CM3050S, Germany) was used to coronal sections of the brain region (30 striatum thick) containing the streaks (stratum, striatum) and soaked in PBS or cryopreservation solution and stored in the freezer.
그리고 나서, 이의 Cresyl violet 염색 또는 Fluoro Jade C 염색을 수행하였다. Cresyl violet 염색방법은 동결 절편을 슬라이드에 올려 건조시킨 후 cresyl violet 염색용액에 5분간 담가 신경세포의 핵을 염색시킨 다음 70%, 80%, 95% 및 100% 에탄올에 순서대로 1분씩, 그리고 자일렌(xylene)에 3분간 담근 후 커버 글라스로 덮었다. 이후 세포손상 정도를 측정하기 위해서 NIH Image J 프로그램을 이용하여 정량하였다. Then, Cresyl violet staining or Fluoro Jade C staining was performed. The cresyl violet staining method involves placing frozen sections on slides and drying them, immersing in the cresyl violet staining solution for 5 minutes to stain the nuclei of neurons, and then sequencing in 70%, 80%, 95% and 100% ethanol for 1 minute and then xyl. It was dipped in xylene for 3 minutes and covered with a cover glass. Then, to measure the degree of cell damage was quantified using the NIH Image J program.
또한, Fluoro Jade C 염색 방법을 수행하였다. 구체적으로, 동결 절편을 70% 에탄올에 3분, 0.06% 과망간산칼륨 용액에 20분 및 0.001% Fluoro Jade C (Millipore, Billerica, MA, USA) 용액에 10분간 담근 후 슬라이드에 올려 건조시키고 자일렌(xylene)에 2분간 담근 후 커버 글라스로 덮어서 관찰하였다. Fluoro Jade C staining was also performed. Specifically, the frozen sections were immersed in 70% ethanol for 3 minutes, 0.06% potassium permanganate solution for 20 minutes and 0.001% Fluoro Jade C (Millipore, Billerica, MA, USA) solution for 10 minutes, then placed on a slide and dried and xylene ( xylene) for 2 minutes and covered with a cover glass for observation.
또한, 세포자멸사 기전의 주요 인자인 cleaved caspase-3의 단백질 발현을 확인하기 위하여, 위 실시예 1에서와 동일한 방법으로 분리된 뇌조직에 대해 웨스턴 블롯을 수행하여 cleaved caspase-3 단백질의 발현 변화를 확인하였다. In addition, in order to confirm the protein expression of cleaved caspase-3, which is a major factor in the apoptosis mechanism, Western blot was performed on the isolated brain tissue in the same manner as in Example 1 to change the expression of cleaved caspase-3 protein. Confirmed.
위 결과를 도 6에 나타내었다. The above results are shown in FIG. 6.
3-NPA에 의한 운동기능장애가 운동기능을 담당하는 뇌의 부위인 줄무늬체(striatum)의 신경세포사멸과 연관이 있는지를 확인하기 위해서, 3-NPA를 마지막으로 투여한 후 24시간 후에 줄무늬체를 포함하는 동결절편을 사용하여 cresyl violet 염색을 수행한 결과를 도 6의 A에 나타내었다. 3-NPA군에서 줄무늬체의 신경세포사멸의 정도(염색되지 않은 부분의 면적)는 유의하게 증가하였으나, micrandilactone C를 전투여한 군에서는 농도 의존적으로 신경세포사멸의 정도가 감소하였다. To determine whether motor dysfunction caused by 3-NPA is associated with neuronal cell death in the striatum, the part of the brain responsible for motor function, the striated body was administered 24 hours after the last administration of 3-NPA. The result of performing cresyl violet staining using the containing frozen section is shown in A of FIG. 6. In the 3-NPA group, the extent of neuronal cell death (unstained area) of striae was significantly increased, but the concentration of neuron cell death was decreased in the concentration-dependent group in the micrandilactone C-treated group.
또한, 도 6의 B 및 C에서 확인되는 바와 같이 신경세포사멸의 정도가 뚜렷이 확인된 생쥐의 비율을 확인한 결과, 3-NPA군에서는 85.7%였으나, micrandilactone C 1.25와 2.5 mg/kg 전투여군에서는 각각 71.4% 및 55.5%로 감소하였으며, 신경세포사멸의 정도가 뚜렷이 확인된 줄무늬체의 면적을 비교한 결과 3-NPA군에서 전체 줄무늬체 면적의 82.7%였지만, micrandilactone C 1.25와 2.5 mg/kg 전투여군에서는 60.2%와 42.7%로 감소하였다. In addition, as confirmed in B and C of FIG. 6, the ratio of the mice whose neuronal cell death was clearly confirmed was 85.7% in the 3-NPA group, but micrandilactone C 1.25 and 2.5 mg / kg in the fighting group, respectively. 71.4% and 55.5% of the striated cells showed significant neuronal cell death, compared with 82.7% of the total striated area in the 3-NPA group, but micrandilactone C 1.25 and 2.5 mg / kg combat group In 60.2% and 42.7%.
또한, 도 6의 D 및 E에서 확인되는 바와 같이, 신경세포사멸의 정도를 재확인하기 위하여 Fluoro Jade C 염색을 시행하고 정량화한 결과, Fluoro Jade C에 의하여 염색된 세포의 수는 줄무늬체 조직절편 당 3-NPA군에서 약 43.6 개였으나, micrandilactone C 2.5 mg/kg 전투여군에서는 약 39.6개로 감소하였다. In addition, as confirmed in D and E of FIG. 6, in order to reconfirm the degree of neuronal cell death, Fluoro Jade C staining was performed and quantified. As a result, the number of cells stained with Fluoro Jade C was increased per stripe tissue section. In the 3-NPA group, it was about 43.6, but in micrandilactone C 2.5 mg / kg combat group, it was reduced to about 39.6.
또한, 도 6의 F에서 확인되는 바와 같이, 세포자멸사 기전의 주요 인자인 cleaved caspase-3의 단백질 발현을 확인하기 위하여 웨스턴블롯 분석을 시행한 결과, cleaved caspase-3의 단백질 발현의 정도는 3-NPA군에서 증가되었으나, micrandilactone C 투여군에서 감소되었다.In addition, as confirmed in FIG. 6F, Western blot analysis was performed to confirm the protein expression of cleaved caspase-3, which is a major factor in the apoptosis mechanism, and the degree of protein expression of cleaved caspase-3 was 3- It was increased in the NPA group but decreased in the micrandilactone C group.
위 결과들에서 확인되는 바와 같이, micrandilactone C의 투여는 줄무늬체의 신경 세포 사멸을 억제함으로써 헌팅턴병을 비롯한 다양한 신경계 질환에서의 신경 손상에 대한 예방, 개선 및 치료 효과를 나타낸다. As can be seen from the above results, administration of micrandilactone C has the effect of preventing, ameliorating and treating nerve damage in various neurological diseases including Huntington's disease by inhibiting neuronal cell death of striated body.
<< 실시예Example 4> 4> 헌팅턴병Huntington's disease 동물모델에서 In animal models micrandilactonemicrandilactone C의 미세아교세포의 활성화 억제 효과 확인 Inhibition of activation of microglial cells of C
상기 실시예 3에서 제조된 조직을 이용하여 면역 조직화학적 염색을 수행하였다. Immunohistochemical staining was performed using the tissue prepared in Example 3.
구체적으로, 미세아교세포의 마커인 Iba-1 (ionized calcium-binding adapter molecule-1)에 대한 항체를 이용하여 면역조직화학적 염색을 시행하였다. 동결 절편을 블로킹 솔루션[10 ml의 PBS에 200 μg 소혈청알부민(BSA, Bovin serum albumin, Sigma-Aldrich, St. Louis, MO, USA), 500 μl Fetal bovine serum (FBS, Gibco, Grand Island, New York, USA), 500 μl Normal goat serum (NGS, Vector Laboratories, Burlingame,California, USA) 및 10 μl Triton X-100 (Sigma-Aldrich)을 넣었다.]을 넣은 플레이트에 담가 1시간 동안 반응시켰다. 그 다음 PBS로 수세한 후 1차 항체[토끼 항-Iba-1 (1:1,000, WAKO, Osaka, Japan)]를 블로킹 솔루션에 희석한 용액으로 교체하고 12시간 반응시켰다. 그리고 PBS로 수세한 후 2차 면역혈청으로 바이오틴화 토끼 IgG 항체(1:200; Vector Laboratories), 아비딘-바이오틴화 겨자무과산화효소(horseradish peroxidase)-복합체(1:200; Vector Laboratories) 및 3,3'-diamino-benzidine (Sigma-Aldrich)을 이용하였다. Specifically, immunohistochemical staining was performed using an antibody against Iba-1 (ionized calcium-binding adapter molecule-1), a marker of microglia. Frozen sections were blocked in blocking solution [200 μg bovine serum albumin (BSA, Bovin serum albumin, Sigma-Aldrich, St. Louis, MO, USA), 500 μl Fetal bovine serum (FBS, Gibco, Grand Island, New) York, USA), 500 μl Normal goat serum (NGS, Vector Laboratories, Burlingame, California, USA) and 10 μl Triton X-100 (Sigma-Aldrich) were added thereto. After washing with PBS, the primary antibody (Rabbit anti-Iba-1 (1: 1,000, WAKO, Osaka, Japan)) was replaced with a solution diluted in a blocking solution and reacted for 12 hours. And washed with PBS and then biotinylated rabbit IgG antibody (1: 200; Vector Laboratories), avidin-biotinated horseradish peroxidase-complex (1: 200; Vector Laboratories) and 3, with secondary immune serum. 3'-diamino-benzidine (Sigma-Aldrich) was used.
또한, 실시예 1에서와 동일한 방법으로 웨스턴 블랏을 통해 Iba-1의 발현 변화를 확인하였다. In addition, the expression change of Iba-1 was confirmed by Western blot in the same manner as in Example 1.
그 결과를 도 7에 나타내었다. The results are shown in FIG.
도 7의 A는 면역조직화학적 염색 결과를 나타낸다. 신경세포사멸은 미세아교세포(microglia)의 활성화를 동반하는데 micrandilactone C의 투여는 Iba-1의 면역반응성을 크게 감소하였다. 7A shows the immunohistochemical staining results. Neuronal cell death was accompanied by activation of microglia, and administration of micrandilactone C significantly reduced the immune response of Iba-1.
또한, 도 7의 B에서 확인되는 바와 같이, 웨스턴 블랏을 통해 확인한 결과에서도 동일한 결과가 확인됨을 알 수 있었다. In addition, as confirmed in FIG. 7B, the same result was confirmed in the result confirmed through the Western blot.
위 결과들에서 확인되는 바와 같이, micrandilactone C의 투여는 미세아교세포의 활성화를 억제함으로써 헌팅턴병을 비롯한 다양한 신경계 질환에서의 신경 손상에 대한 예방, 개선 및 치료 효과를 나타낸다. As can be seen from the above results, administration of micrandilactone C shows the effect of preventing, ameliorating and treating nerve damage in various neurological diseases including Huntington's disease by inhibiting the activation of microglia.
<< 실시예Example 5> 5> 헌팅턴병Huntington's disease 동물모델에서 In animal models micrandilactonemicrandilactone C의 염증관련 Inflammation of C 신호기전Signaling 억제 효과 확인 Confirm inhibitory effect
위 실시예 1에서와 동일한 방법으로 분리된 뇌조직에 대해 웨스턴 블롯을 수행하여 염증 관련 신호 기전의 억제 효과를 확인하였다. Western blot was performed on brain tissue isolated in the same manner as in Example 1 to confirm the inhibitory effect of inflammation-related signaling mechanisms.
또한, 실시예 4의 면역조직화학적 염색과 동일한 방법으로, pSTAT3+ 및 CD11b+에 대해서 면역조직화학적 염색을 수행하였다. In addition, immunohistochemical staining was performed on pSTAT3 + and CD11b + in the same manner as in immunohistochemical staining of Example 4.
그 결과를 도 8에 나타내었다. The results are shown in FIG.
도 8의 A 내지 E는 염증 관련 인자로 p-STAT3와 p-JNK, p-EKR 및 p-p38의 단백질 발현을 확인한 결과를 나타낸다. 그 결과, 3-NPA군에서 증가(각각 0.7, 0.7, 0.7 및 0.8)하였으나 micrandilactone C 전투여군에서 감소하였다(각각 0.4, 0.5, 0.4 및 0.5). 8A to 8E show the results of confirming protein expression of p-STAT3 and p-JNK, p-EKR, and p-p38 as inflammation-related factors. As a result, it increased in the 3-NPA group (0.7, 0.7, 0.7 and 0.8, respectively) but decreased in micrandilactone C combat group (0.4, 0.5, 0.4 and 0.5, respectively).
위 인자들 중 가장 뚜렷한 차이를 보였던 p-STAT3의 발현과 미세아교세포의 활성화를 확인하기 위하여 면역조직화학적 염색을 수행한 결과를 도 8의 F 내지 H에 나타내었다. 그 결과, 3-NPA군에서 p-STAT3의 발현이 CD11b+세포에서 증가되었으며, micrandilactone C 전투여군에는 감소되는 것이 확인되었다. The results of immunohistochemical staining in order to confirm the expression of p-STAT3 and activation of microglial cells, which showed the most significant difference among the above factors, are shown in FIGS. As a result, the expression of p-STAT3 was increased in CD11b + cells in the 3-NPA group and decreased in the micrandilactone C fighting group.
위 결과들에서 확인되는 바와 같이, micrandilactone C의 투여는 염증 관련 신호 기전을 억제함으로써 헌팅턴병을 비롯한 다양한 신경계 질환에서의 신경 손상에 대한 예방, 개선 및 치료 효과를 나타낸다.As confirmed in the above results, administration of micrandilactone C exhibits the effect of preventing, ameliorating and treating neurological damage in various neurological diseases including Huntington's disease by inhibiting inflammation-related signaling mechanisms.
<< 실시예Example 6> 6> 헌팅턴병Huntington's disease 동물모델에서 In animal models micrandilactonemicrandilactone C의 염증관련 Inflammation of C 매개인자의Mediator 발현 Expression 억제 효과Inhibitory effect 확인 Confirm
3-NPA에 의한 염증성 매개인자의 분비 및 염증기작의 활성화를 micrandilactone C가 억제하는지 검증하기 위하여 실시간 PCR 분석을 이용하여 유전자의 발현을 확인하였다. 조직은 3-NPA를 마지막으로 투여하고 12시간 후에 뇌를 적출한 후 줄무늬체(striatum)를 분리하여 동결 보관하였다. 분리한 조직은 트리졸(Trizol, Invitrogen, Carlsbad, CA, USA) 1 ml을 넣고 분쇄기로 조직을 으깬 후 공지된 메뉴얼에 따라 추출하였다(Bioline, London, UK). cDNA를 합성하기 위해 0.5 μg의 Oligo dT, 0.5 mM dNTP mix, 5x first-strand buffer,RNase out,5 mM dithiothreitol (DTT), 및 M-MLV 역전사효소를 포함하는 반응 혼합물(reaction mixture) 중에서 1 μg의 총 RNA를 37℃에서 1시간 동안 반응시켰다. Real time-PCR 분석은 제조사의 메뉴얼에 따라 수행되었다(Applied Biosystems, Foster City, CA, USA). PCR 프라이머 서열은 하기 표 2와 같다. cDNA 4 μl와 하기 표 2에 기재된 염증성 매개인자인 IL-1β, IL-6, TNF-α, MCP-1, COX-2 및 iNOS에 대한 프라이머를 각각 1 μl 및 2x SYBR Green PCR Master Mix (Applied Biosystems) 5 μl를 섞어 실시간 PCR 장비(Applied Biosystems 7500)를 이용하여 분석하였다. 계산은 Fold-induction은 2-ΔCT 방법을 이용하였으며, PCR 증폭은 적어도 세 번 수행하였다. 위 분석에 사용된 서열을 아래 표 2에 나타내었다. Gene expression was confirmed using real-time PCR analysis to verify whether micrandilactone C inhibits the secretion and activation of inflammatory mediators of inflammatory mediators by 3-NPA. Tissues were brain-extracted 12 hours after the last administration of 3-NPA, and streatum were isolated and stored frozen. The separated tissue was added to 1 ml of Trizol (Trizol, Invitrogen, Carlsbad, CA, USA), crushed tissue in a grinder and extracted according to a known manual (Bioline, London, UK). 1 μg in a reaction mixture comprising 0.5 μg of Oligo dT, 0.5 mM dNTP mix, 5x first-strand buffer, RNase out, 5 mM dithiothreitol (DTT), and M-MLV reverse transcriptase to synthesize cDNA Of total RNA was reacted at 37 ° C. for 1 hour. Real time-PCR analysis was performed according to the manufacturer's manual (Applied Biosystems, Foster City, CA, USA). PCR primer sequences are shown in Table 2 below. 4 μl of cDNA and primers for the inflammatory mediators IL-1β, IL-6, TNF-α, MCP-1, COX-2 and iNOS listed in Table 2, respectively, 1 μl and 2 × SYBR Green PCR Master Mix (Applied Biosystems) 5 μl was mixed and analyzed using a real-time PCR instrument (Applied Biosystems 7500). Fold-induction was performed using the 2- ΔCT method and PCR amplification was performed at least three times. The sequences used in the above analysis are shown in Table 2 below.
위 RT-PCR 분석 결과를 도 9에 나타내었다. The RT-PCR analysis results are shown in FIG. 9.
미세아교세포가 활성화되고 염증기전이 활성화되면, 염증과 관련한 매개인자의 발현도 증가하게 된다. 도 9의 A 내지 F에서 확인되는 바와 같이, 이러한 염증 매개 인자로 대표적인 사이토카인(IL-1β, IL-6, TNF-α), 케모카인MCP-1, COX-2 및 iNOS의 mRNA의 발현은 micrandilactone C 투여에 의하여 현저히 감소됨이 확인되었다. When microglia are activated and the inflammatory mechanism is activated, the expression of mediators associated with inflammation is also increased. As shown in Figures A to F, the expression of mRNAs of cytokines (IL-1β, IL-6, TNF-α), chemokines MCP-1, COX-2 and iNOS, which are representative of these inflammation mediators, are micrandilactone It was found to be markedly reduced by C administration.
위 결과들에서 확인되는 바와 같이, micrandilactone C의 투여는 염증 매개 인자들의 발현을 억제함으로써 헌팅턴병을 비롯한 다양한 신경계 질환에서의 신경 손상에 대한 예방, 개선 및 치료 효과를 나타낸다.As confirmed in the above results, administration of micrandilactone C exhibits the effect of preventing, ameliorating and treating neurological damage in various neurological diseases including Huntington's disease by inhibiting the expression of inflammatory mediators.
제제예Formulation example 1. 의약품의 제조 1. Manufacturing of Medicines
1.1 1.1 산제의Powder 제조 Produce
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
1.2 정제의 제조1.2 Preparation of Tablets
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
1.3 캡슐제의 제조1.3 Preparation of Capsules
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 정제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare tablets.
1.4 1.4 액제의Liquid 제조 Produce
정제수를 가하여 전체 1,00 ml로 맞추었다. 통상의 액제의 제조방법에 따라 상기의 성분을 혼합한 다음, 갈색병에 충전하고 멸균시켜 액제를 제조한다.Purified water was added to make a total of 1,00 ml. According to the conventional method for preparing a liquid, the above components are mixed, and then filled into a brown bottle and sterilized to prepare a liquid.
제제예Formulation example 2. 건강기능식품의 제조 2. Manufacturing of dietary supplements
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강기능식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강기능식품 제조방법에 따라 상기의 성분을 혼합한 다음, 통상의 방법에 따라 건강기능식품 조성물 제조(예, 영양캔디 등)에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixtures is a composition that is relatively suitable for the health functional food, the composition is mixed in a preferred embodiment, but the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method. Then, it can be used for the manufacture of the nutraceutical composition (eg, nutrition candy, etc.) according to a conventional method.
제제예Formulation example 3. 건강기능성 음료의 제조 3. Preparation of Health Functional Beverage
통상의 건강기능성 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강기능성 음료 조성물 제조에 사용한다. After mixing the above components in accordance with the conventional method for preparing a health functional beverage, the mixture was heated by stirring at 85 ℃ for about 1 hour, the resulting solution was filtered and obtained in a sterilized 2 L container, sealed and sterilized and then stored in a refrigerator. It is used to prepare the health functional beverage composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용 용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.
<110> University-Industry Cooperation Group of Kyung Hee University <120> A composition comprising Micrandilactone C for preventing or treating neurological disease <130> P17-109-KHU <160> 14 <170> KoPatentIn 3.0 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-1 beta Forward primer <400> 1 ttgtggctgt ggagaagctg t 21 <210> 2 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-1 beta Reverse primer <400> 2 aacgtcacac accagcaggt t 21 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-6 Forward primer <400> 3 tccatccagt tgccttcttg g 21 <210> 4 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> IL-6 Reverse primer <400> 4 ccacgatttc ccagagaaca tg 22 <210> 5 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> TNF-alpha Forward primer <400> 5 agcaaaccac caagtggagg a 21 <210> 6 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> TNF-alpha Reverse primer <400> 6 gctggcacca ctagttggtt gt 22 <210> 7 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MCP-1 Forward primer <400> 7 cttctgggcc tgctgttca 19 <210> 8 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MCP-1 Reverse primer <400> 8 ccagcctact cattgggatc a 21 <210> 9 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> COX-2 Forward primer <400> 9 cagtatcaga accgcattgc c 21 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> COX-2 Reverse primer <400> 10 gagcaagtcc gtgttcaagg a 21 <210> 11 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> iNOS Forward primer <400> 11 ggcaaaccca aggtctacgt t 21 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> iNOS Reverse primer <400> 12 tcgctcaagt tcagcttggt 20 <210> 13 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> GAPDH Forward primer <400> 13 aggtcatccc agagctgaac g 21 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> GAPDH Reverse primer <400> 14 caccctgttg ctgtagccgt at 22 <110> University-Industry Cooperation Group of Kyung Hee University <120> A composition comprising Micrandilactone C for preventing or treating neurological disease <130> P17-109-KHU <160> 14 <170> KoPatentIn 3.0 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-1 beta Forward primer <400> 1 ttgtggctgt ggagaagctg t 21 <210> 2 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-1 beta Reverse primer <400> 2 aacgtcacac accagcaggt t 21 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-6 Forward primer <400> 3 tccatccagt tgccttcttg g 21 <210> 4 <211> 22 <212> DNA <213> Artificial Sequence <220> IL-6 Reverse primer <400> 4 ccacgatttc ccagagaaca tg 22 <210> 5 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> TNF-alpha Forward primer <400> 5 agcaaaccac caagtggagg a 21 <210> 6 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> TNF-alpha Reverse primer <400> 6 gctggcacca ctagttggtt gt 22 <210> 7 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MCP-1 Forward primer <400> 7 cttctgggcc tgctgttca 19 <210> 8 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MCP-1 Reverse primer <400> 8 ccagcctact cattgggatc a 21 <210> 9 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> COX-2 Forward primer <400> 9 cagtatcaga accgcattgc c 21 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> COX-2 Reverse primer <400> 10 gagcaagtcc gtgttcaagg a 21 <210> 11 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> iNOS Forward primer <400> 11 ggcaaaccca aggtctacgt t 21 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> iNOS Reverse primer <400> 12 tcgctcaagt tcagcttggt 20 <210> 13 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> GAPDH Forward primer <400> 13 aggtcatccc agagctgaac g 21 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> GAPDH Reverse primer <400> 14 caccctgttg ctgtagccgt at 22
Claims (10)
상기 미크란디락톤 C (Micrandilactone C)는 하기 화학식 Ⅰ의 구조를 가지는 것인 파킨슨질환, 헌팅턴병 또는 다발성경화증의 예방 또는 치료용 약학적 조성물:
The microdilactone C (Micrandilactone C) is a pharmaceutical composition for the prevention or treatment of Parkinson's disease, Huntington's disease or multiple sclerosis having the structure of formula (I):
상기 미크란디락톤 C (Micrandilactone C)는 하기 화학식 Ⅰ의 구조를 가지는 것인 파킨슨질환, 헌팅턴병 또는 다발성경화증의 예방 또는 개선용 식품 조성물:
The method of claim 6,
The microdilactone C (Micrandilactone C) is a food composition for the prevention or improvement of Parkinson's disease, Huntington's disease or multiple sclerosis having the structure of formula (I):
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| KR20230139049A (en) | 2022-03-25 | 2023-10-05 | 경희대학교 산학협력단 | Composition for preventing or treating neurodegenerative diseases comprising polyamidoamine dendrimer and triamcinolone acetonide |
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| KR20160147132A (en) * | 2015-06-11 | 2016-12-22 | 경희대학교 산학협력단 | A composition comprising the Leaves of Schisandra chinensis for preventing or treating Parkinson's disease or neurodegenerative disease |
| KR101860401B1 (en) * | 2015-08-06 | 2018-05-23 | 경희대학교 산학협력단 | A composition comprising the stem of Schisandra chinensis for preventing or treating neurological disease |
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| KR102279883B1 (en) | 2018-03-12 | 2021-07-22 | 경희대학교 산학협력단 | A composition comprising Micrandilactone C for preventing or treating inflammatory disease |
| KR20230139049A (en) | 2022-03-25 | 2023-10-05 | 경희대학교 산학협력단 | Composition for preventing or treating neurodegenerative diseases comprising polyamidoamine dendrimer and triamcinolone acetonide |
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