KR100799884B1 - Composition for preventing or improving the ischemia damage compring an extract of epimedium koreanum - Google Patents
Composition for preventing or improving the ischemia damage compring an extract of epimedium koreanum Download PDFInfo
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- KR100799884B1 KR100799884B1 KR1020060022721A KR20060022721A KR100799884B1 KR 100799884 B1 KR100799884 B1 KR 100799884B1 KR 1020060022721 A KR1020060022721 A KR 1020060022721A KR 20060022721 A KR20060022721 A KR 20060022721A KR 100799884 B1 KR100799884 B1 KR 100799884B1
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Abstract
본 발명은 삼지구엽초 추출물을 포함하는 허혈성 뇌혈관질환 예방 또는 개선용 조성물에 관한 것으로, 보다 상세하게는 뇌허혈에 민감하다고 알려져 있는 해마조직 CA1 영역의 신경세포 손상을 효과적으로 예방할 뿐만 아니라, 인체에 부작용을 발생시키지 않는 무해한 삼지구엽초 추출물을 포함하는 허혈성 뇌혈관질환 예방 또는 개선용 조성물을 제공할 수 있다. The present invention relates to a composition for preventing or improving ischemic cerebrovascular disease, including trilobite leaf extract, and more particularly, to effectively prevent neuronal cell damage in the CA1 region of hippocampus known to be sensitive to cerebral ischemia, and to prevent side effects on the human body. It is possible to provide a composition for preventing or improving ischemic cerebrovascular disease, including harmless trigeminal vinegar extract.
삼지구엽초, 허혈성 뇌혈관질환, 치매, 알츠하이머, 기억력 Trilobite leaf, ischemic cerebrovascular disease, dementia, Alzheimer's disease, memory
Description
도 1은 삼지구엽초 추출물의 세포 사멸 방지효과를 PC12 배양세포에 저산소환경을 가하여 락테이트 디하이드로게나제(LDH)을 측정한 것이다.Figure 1 is a measure of lactate dehydrogenase (LDH) by applying a hypoxic environment to PC12 cultured cells to prevent cell death of trifoliate vinegar extract.
도 2는 실험동물에 허혈-재관류를 실시하였을 때 정상군(A 및 B) 및 용매(물)투여군(C 및 D)의 해마조직을 악시오팟 현미경(Axiphot microscope)으로 관찰한 것이다.FIG. 2 shows the hippocampal tissues of the normal group (A and B) and the solvent (water) administration group (C and D) when subjected to ischemia-reperfusion, using an axiphot microscope.
도 3은 삼지구엽초 추출물을 허혈-재관류 실시 일주일 전부터 매일 50mg/kg 또는 100㎎/㎏으로 실험동물에 경구 투여한 후 4일 후에 동물을 희생하여 해마조직을 크레실 바이올렛(cresyl violet)으로 염색하여 관찰한 것이다. Figure 3 is orally administered to the experimental animals at 50 mg / kg or 100 mg / kg daily from a week before the ischemia-reperfusion the trigeminal foliar extract to sacrifice the animals and stain the hippocampus tissue with cresyl violet (cresyl violet) Observed.
도 4는 삼지구엽초 추출물을 허혈-재관류 실시 일주일 전부터 매일 50㎎/㎏ 또는 100mg/kg을 실험동물에 투여한 다음 4일 후에 동물을 희생하여 신경세포의 생존율을 측정한 것이다. Figure 4 shows the survival rate of neurons by sacrificing the animals 4 days after the administration of 50 mg / kg or 100 mg / kg daily to a week before the ischemia-reperfusion the trigeminal leaf extract.
[산업상 이용분야][Industrial use]
본 발명은 신경세포 보호 효능을 갖는 삼지구엽초 추출물을 포함하는 조성물에 관한 것으로, 식품 또는 의약 조성물로 사용될 수 있다. The present invention relates to a composition comprising tricotyledonous extract having a neuroprotective effect, and may be used as a food or pharmaceutical composition.
[종래기술][Private Technology]
최근 통계청이 발표한 2005년 총인구 중에서 65세 이상 노령인구의 비율은 9.1%를 차지하고 있고, 14세 이하 유년인구의 비중은 점차 줄어들고 있으며, 65세 이상 인구의 비중은 지난 2000년에 7.2%를 기록하여 이미 고령화 사회에 진입하였다. 또한, 2003년 기준으로 우리나라 평균수명은 77.5세로 노령인구가 급격하게 증가되고 있다.Of the total population released in 2005, the National Statistical Office recently made up 9.1% of the population aged 65 and over, and the proportion of young people aged 14 and younger is decreasing. The proportion of the population aged 65 and over is 7.2% in 2000. Has already entered an aging society. In addition, as of 2003, the average life expectancy of Korea is 77.5 years, and the elderly population is rapidly increasing.
한편 통계청이 발표한 우리나라 1인당 GNI는 2004년 14,162달러였으며, 매년 10% 이상 증가하고 있어 삶의 질이 점차 나아지고 있다고 할 수 있다. 따라서, 과거 주요한 사망원인인 전염성 질병 사망자 수가 급격하게 줄어들고 있으며, 이와는 반대로 암, 뇌혈관질환, 당뇨병 등의 퇴행성 질환이 꾸준히 증가하고 있다. 뇌혈관질환은 우리나라 사망에 2위를 차지하는 질환으로써 뇌에 공급되는 혈류의 감소로 인하여 나타난다.Meanwhile, Korea's GNI per capita, announced by the National Statistical Office, was $ 14,162 in 2004, and is increasing by more than 10% annually. Accordingly, the number of deaths from infectious diseases, which are the major causes of death, has declined sharply in the past, and conversely, degenerative diseases such as cancer, cerebrovascular diseases, and diabetes have been steadily increasing. Cerebrovascular disease is the second largest cause of death in Korea and is caused by a decrease in blood flow to the brain.
허혈성 질환은 뇌의 혈류가 감소되어 산소와 포도당의 공급이 이루어지지 않아, 해마 CA1 영역에 지연성 신경세포사(delayed neuronal death)가 유발되어 발생되는 질환이다(Kirino, Brain Res., 239, pp57-69, 1982; Petito et al., Neurology, 37, pp1281-1286, 1987; Pulsinelli et al., Ann. Neurol ., 11, pp491-498, 1982). 또한, 상기 허혈성 뇌질환은 뇌졸중이나 심장마비와 같은 병리학적 상황에서 뇌에 혈액이 공급되지 않음으로써 유발되는 것으로 알려져 있다(Nedergaard, Acta . Neurol . Scand ., 77, pp81-101, 1988; White et al., Neurology, 43, pp1656-1665, 1993). Ischemic disease is a disease caused by delayed neuronal death in the hippocampus CA1 region due to a decrease in blood flow in the brain and lack of oxygen and glucose (Kirino, Brain Res ., 239 , pp57-). 69, 1982; Petito et al., Neurology , 37 , pp1281-1286, 1987; Pulsinelli et al., Ann. Neurol . , 11 , pp491-498, 1982). In addition, the ischemic brain disease is known to be caused by the lack of blood supply to the brain in pathological conditions such as stroke or heart attack (Nedergaard, Acta . Neurol . Scand . , 77 , pp81-101, 1988; White et. al., Neurology , 43 , pp 1656-1665, 1993).
일시적인 뇌허혈 및 재관류(reperfusion)에 의해 발생되는 해마 CA1영역에서의 지연성 신경세포사의 원인은 세포 내로 칼슘의 과다유입(Hara et al., Brain Res. Bull., 29, pp659-665, 1992; Nedergaard, Acta . Neurol . Scand ., 77, pp81-101, 1988), 프리 라디칼(free radical) 관련 신경세포 손상 및 글루타메이트-수용체 매개 신경세포 손상이라고 알려져 있다(Won et al., Neurosci . Lett ., 301, pp139-142, 2001). 즉, 뇌허혈이 발생되면 신경세포의 탈분극이 일어나고, 시냅스의 글루타메이트(glutamate)가 유리되어 세포 외 글루타메이트의 농도가 증가한다. 또한, ATP(Adenosine Triphosphate)의 감소로 인해 발생하는 능동수송의 역전은 세포 외 글루타메이트의 축적을 가속시킨다. 세포 외 글루타메이트의 축적은 NMDA(N-methyl-D-aspartic Acid), AMPA(α-amino-3-hydroxy-5-methyl-4 -isoxazole-propionic acid) 및 메타보트로픽 글루타메이트 수용체(metabotropic glutamate receptor)의 연속적인 활성을 유도하여, 칼슘의 세포 내 과다 유입을 초래한다(Olney et al., Science, 244, pp1360-1362, 1989). 칼슘의 세포 내 유입은 특히 칼슘 의존성 프로테아제, 리파제 및 모듈레이터의 활동을 촉발시키고, 결국 프리 라디칼을 포함하는 세포 독성분자가 생성되어 DNA 및 세포막 등의 세포 구조물을 파괴하여 신경세포사가 유발하는 것으로 알려져 있다. The cause of delayed neuronal death in the hippocampal CA1 region caused by transient cerebral ischemia and reperfusion is caused by the influx of calcium into cells (Hara et al., Brain Res. Bull. , 29 , pp659-665, 1992; Nedergaard , Acta . Neurol . Scand . , 77 , pp81-101, 1988), known as free radical-related neuronal damage and glutamate-receptor mediated neuronal damage (Won et al., Neurosci . Lett . , 301) . , pp 139-142, 2001). That is, when cerebral ischemia occurs, depolarization of neurons occurs, and glutamate of synapses is released, thereby increasing the concentration of extracellular glutamate. In addition, the reversal of active transport caused by the reduction of Adenosine Triphosphate (ATP) accelerates the accumulation of extracellular glutamate. Accumulation of extracellular glutamate is characterized by N-methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4 -isoxazole-propionic acid (AMPA), and metabotropic glutamate receptor (MTA). Induces a continuous activity of calcium, leading to an influx of calcium into the cells (Olney et al., Science , 244 , pp1360-1362, 1989). Intracellular influx of calcium triggers the activity of calcium-dependent proteases, lipases and modulators, and in turn leads to the generation of cytotoxic molecules, including free radicals, that break down cellular structures such as DNA and cell membranes, causing neuronal death. .
최근 뇌신경세포도 재생한다고 보고되고 있으나, 재생이 어렵다는 조직학적 특성상 치료보다는 예방이 중요하다. 일단 뇌혈관질환에 이환되면 비가역적인 신경세포 손상으로 인해, 운동능력 저하, 성적능력 저하, 기억력 감퇴 등을 유발하는 것으로 알려져 있어, 예방의 중요성이 강조되고 있다. 따라서, 뇌신경세포를 보호할 수 있는 물질을 지속적으로 섭취하여 이러한 뇌혈관질환을 예방하는 것이 무엇보다 중요하다고 할 수 있다.Recently, nerve cells have been reported to regenerate, but the prevention is more important than the treatment due to the histological characteristics of regeneration difficult. Once cerebrovascular disease, irreversible nerve cell damage is known to cause a decrease in motor performance, sexual performance, memory loss, etc., the importance of prevention is emphasized. Therefore, it can be said that it is important to prevent such cerebrovascular diseases by continuously ingesting substances that can protect the nerve cells of the brain.
뇌혈관질환은 치료에 대한 효용이 적은 관계로 천연물 유래의 물질로부터 활성 성분을 찾으려는 노력이 진행중에 있다.Cerebrovascular disease is less effective for treatment, and efforts are underway to find active ingredients from natural-derived materials.
본 발명은 인체에 독성이 없고 신경세포 보호 효과가 현저한 삼지구엽초 추출물을 포함하는 허혈성 뇌혈관질환의 예방 또는 개선을 위한 의약 조성물을 제공하는 것을 목적으로 한다. It is an object of the present invention to provide a pharmaceutical composition for the prevention or improvement of ischemic cerebrovascular disease, including trichophytic vinegar extract, which has no toxicity to the human body and has a significant neuroprotective effect.
또한 본 발명은 삼지구엽초 추출물을 포함하는 허혈성 뇌혈관질환의 예방 또는 개선을 위한 식품 조성물을 제공하는 것을 목적으로 한다. In addition, an object of the present invention is to provide a food composition for the prevention or improvement of ischemic cerebrovascular disease, including trilobite vinegar extract.
본 발명은 상기 목적을 달성하기 위하여, 신경세포 보호 효능을 갖는 삼지구엽초 추출물을 유효성분으로 포함하는 허혈성 뇌혈관질환 예방 또는 개선용 조성물을 제공한다. The present invention provides a composition for the prevention or improvement of ischemic cerebrovascular disease comprising tricotyledonous extract having an effect of nerve cell protection as an active ingredient in order to achieve the above object.
또한 본 발명은 신경세포 보호 효능을 갖는 삼지구엽초 추출물을 유효성분으로 포함하는 허혈성 뇌혈관질환 예방 또는 개선용 의약 조성물을 제공한다. In another aspect, the present invention provides a pharmaceutical composition for preventing or improving ischemic cerebrovascular disease comprising tricotyledonous extract as an active ingredient having neuroprotective effect.
본 발명은 신경세포 보호 효능을 갖는 삼지구엽초 추출물을 유효성분으로 포 함하는 허혈성 뇌혈관질환 예방 또는 개선용 식품 조성물을 제공한다. 본 발명의 식품 조성물의 예로는 식품, 식품첨가제, 또는 음료를 들 수 있다. The present invention provides a food composition for preventing or ameliorating ischemic cerebrovascular disease, including tricotyledonous extract having an effect of protecting nerve cells as an active ingredient. Examples of the food composition of the present invention include food, food additives, or beverages.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 삼지구엽초(Epimedium koreanum)는 다년생 초본으로 높이 30cm 내외, 산지 숲 속 그늘에서 자라며, 잎은 호생하고 3개씩 3회 갈라져서 가지가 3개이고 잎이 9개인데, 이 때문에 삼지구엽초라는 이름이 붙었다. 소엽은 난형이고 끝이 뾰족하며 가장자리에 털 같은 잔톱니가 있다. 꽃은 황백색, 홍자색으로 총상 화서를 이루며 밑을 향해 달린다. 본초강목에서 삼지구엽초의 사용은 전초는 강장, 강정, 이뇨, 창종, 건망증, 음위 등에 약용으로 쓰이며 음양곽이라고 부르기도 한다.Trilobite leaf ( Epimedium) of the present invention koreanum ) is a perennial herb and grows in the shade of mountain forests around 30cm in height. The leaves are regenerated and split three times, and three branches and nine leaves are named. The lobules are ovate, pointed at the end, and have hairy cogs on the edges. The flower is yellowish white and reddish purple, and it runs in the form of gunshot inflorescence. Trichophytium is used as a medicinal herb in tonic, gangjeong, diuretic, emphysema, forgetfulness, and vulgaris.
본 발명의 삼지구엽초 추출물은 용매추출물, 분획추출물 또는 이들의 액상물을 건조한 분말일 수 있다. Tricuspid foliar extract of the present invention may be a dry powder of a solvent extract, a fraction extract or a liquid thereof.
본 발명의 추출용매는 물; 메탄올, 에탄올 등의 탄소수 1 내지 4의 저급알콜; 에틸아세테이트 등의 극성용매; 헥산, 디클로로메탄의 비극성용매; 또는 이들의 혼합용매일 수 있다. 본 발명의 바람직한 추출용매는 50 내지 100%의 메탄올 또는 에탄올 등의 탄소수 1 내지 4의 저급 알콜이며, 더욱 바람직하게는 70 내지 100% 메탄올 또는 메탄올 수용액이다. Extraction solvent of the present invention is water; Lower alcohols having 1 to 4 carbon atoms such as methanol and ethanol; Polar solvents such as ethyl acetate; Nonpolar solvents of hexane and dichloromethane; Or a mixed solvent thereof. Preferred extraction solvents of the present invention are lower alcohols having 1 to 4 carbon atoms, such as 50 to 100% methanol or ethanol, and more preferably 70 to 100% methanol or aqueous methanol solution.
본 발명의 삼지구엽초 추출물은 하기와 같이 수득될 수 있다. Tricuspid leaf extract of the present invention can be obtained as follows.
본 발명의 삼지구엽초 추출물은 수확하여 건조시킨 삼지구엽초의 잎과 뿌리부위를 세절하여 건조 중량의 약 1 내지 15배 바람직하게는 약 2 내지 7배 부피의 용매를 이용하여 추출할 수 있다. 상기 용매를 이용하여 50 내지 90℃의 추출온도에서, 1 내지 12시간, 바람직하게는 약 1 내지 5시간 동안 추출할 수 있다. 상기 추출물의 추출방법으로는 통상의 용매를 이용한 추출방법을 모두 적용할 수 있으며, 예를 들면, 침지, 초음파 추출, 및 환류 추출 등의 추출방법을 이용할 수 있다.The trigeminal leaf vinegar extract of the present invention can be extracted using a solvent having a volume of about 1 to 15 times the dry weight, preferably about 2 to 7 times the dry weight, by slicing the leaves and root portions of the trigeminal vinegar harvested and dried. The solvent may be used for extraction for 1 to 12 hours, preferably about 1 to 5 hours, at an extraction temperature of 50 to 90 ° C. As the extraction method of the extract, any extraction method using a conventional solvent may be applied. For example, an extraction method such as dipping, ultrasonic extraction, and reflux extraction may be used.
또한, 상기 삼지구엽초 추출물은 추가로 통상의 분획 공정을 더욱 수행할 수 있다. 추출물의 분획제조방법의 예는 Harborne J.B. Phytochemical methods: A guide to modern techniques of plant analysis, 3rd Ed., pp6-7, 1998에 기재되어 있으며, 이에 한정되는 것은 아니다.In addition, the trigeminal leaf vinegar extract may further perform a conventional fractionation process. Examples of fractionation methods of extracts are described in, but not limited to, Harborne JB Phytochemical methods: A guide to modern techniques of plant analysis, 3 rd Ed., Pp 6-7, 1998.
상기 수득된 추출액 또는 분획물을 농축 및 동결건조하여 수분이 완전히 제거된 분말상의 삼지구엽초 추출물을 수득할 수 있다.The obtained extract or fractions may be concentrated and lyophilized to obtain a powdery trichophytic herb extract from which moisture is completely removed.
본 발명은 상기 삼지구엽초 추출물을 포함하는 뇌허혈성 질환의 예방 또는 개선을 위한 의약 또는 식물 조성물을 제공한다.The present invention provides a medicament or plant composition for the prevention or improvement of cerebral ischemic disease comprising the trigeminal leaf herb extract.
상기 허혈성 뇌혈관질환은 알츠하이머병, 치매 또는 뇌졸중일 수 있다. 본 발명의 삼지구엽초 추출물은 저빌을 마취시켜 온목동맥을 결찰하여 뇌허혈을 유발시킨 후, 신경세포를 염색하여 효능을 측정하는 실험 및 부신유래의 신경세포주인 PC12 세포를 저산소환경에 노출시켜 세포로부터 방출되는 락테이트 디하이드게나제 농도를 측정하여 효능을 측정하는 실험 모두에서 뇌허혈에 의한 신경세포사를 현저히 억제하였으며, 우수한 신경세포 보호효과를 나타내었다 (Koo BS, Lee WC, Chung KH, Ko JH, Kim CH. A water extract of Curcuma longa L. (Zingiberaceae) rescues PC12 cell death caused by pyrogallol or hypoxia/reoxygenation and attenuates hydrogen peroxide induced injury in PC12 cells. Life Sci. 2004 Sep 24;75(19):2363-75). The ischemic cerebrovascular disease may be Alzheimer's disease, dementia or stroke. Trilobite leaf extract of the present invention anesthetize gerbils to induce cerebral ischemia by ligation of allergic arteries, and then staining nerve cells to measure their efficacy and exposing PC12 cells, which are adrenal derived neuronal cell lines to hypoxic environment, to be released from cells. In all experiments measuring the effect of lactate dehydrogenase concentration, it significantly inhibited neuronal cell death caused by cerebral ischemia and showed an excellent neuronal protective effect (Koo BS, Lee WC, Chung KH, Ko JH, Kim). CH.A water extract of Curcuma longa L. (Zingiberaceae) rescues PC12 cell death caused by pyrogallol or hypoxia / reoxygenation and attenuates hydrogen peroxide induced injury in PC12 cells.Life Sci. 2004 Sep 24; 75 (19): 2363-75) .
본 발명의 뇌허혈성 질환의 예방 또는 개선용 조성물은, 조성물 총 중량에 대하여 상기 추출물을 0.001 내지 99.99중량%, 바람직하게는 0.1 내지 90 중량%로 포함한다.The composition for preventing or improving cerebral ischemic disease of the present invention comprises 0.001 to 99.99% by weight, preferably 0.1 to 90% by weight, based on the total weight of the composition.
본 발명의 삼지구엽초 추출물을 포함하는 의약 조성물 또는 식품 조성물은 그 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.The pharmaceutical composition or food composition comprising the tricotyledonous extract of the present invention may further include appropriate carriers, excipients and diluents commonly used in the preparation thereof.
본 발명에 따른 추출물을 포함하는 건강기능식품 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 현탁제, 에멀젼, 시럽 등의 경구형 제형물로 사용될 수 있다. 추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럼제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러가지 부형제 예를 들면, 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.The dietary supplement composition comprising the extract according to the present invention may be used in oral formulations, such as powders, granules, tablets, suspensions, emulsions, and syrups, respectively, according to conventional methods. Carriers, excipients and diluents that may be included in the composition comprising the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose And methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solvents, emulsions, and serums.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.
본 발명의 추출물의 바람직한 투여량은 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 바람직하게는 본 발명의 추출물은 1일 0.0001 내지 1000mg/kg으로, 보다 효과적이기 위해서는 0.01 내지 100mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. Preferred dosages of the extracts of the present invention vary depending on the condition and weight, extent of disease, drug form, route of administration and duration, but may be appropriately selected by those skilled in the art. Preferably the extract of the present invention is 0.0001 to 1000mg / kg per day, in order to be more effective it is good to administer at 0.01 to 100mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
본 발명의 상기 조성물은 식품으로 사용될 수 있다. 본 명세서에서 식품이라 함은 통상적인 의미로서, 식품, 식품 첨가제, 및 음료를 모두 포함하는 의도이다. The composition of the present invention can be used as food. As used herein, the term "food" is intended to include all foods, food additives, and beverages.
본 발명의 삼지구엽초 추출물을 첨가할 수 있는 식품으로는 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있다. 추가로, 본 발명에서 식품에는 특수영양식품(예, 조제유류, 영,유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류(예, 라면류, 국수류 등), 건강보조식품, 조미식품(예, 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류(예, 스넥류), 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 김치, 절임식품(각종 김치류, 장아찌 등), 음료(예, 과실,채소류 음료, 두유류, 발효음료류 등), 천연조미료(예, 라면 스프 등)을 포함하나 이에 한정되지 않는다. 상기 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다. Examples of the food to which the tricotyledonous extract of the present invention can be added include various foods, beverages, gums, teas, vitamin complexes, and health functional foods. In addition, the food in the present invention includes special nutritional products (e.g., prepared oils, infants, baby food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g. ramen, noodles, etc.), health supplements, seasoned foods ( For example, soy sauce, miso, red pepper paste, mixed soy sauce), sauces, confectionery (e.g. snacks), dairy products (e.g. fermented milk, cheese, etc.), other processed foods, kimchi, pickles (various kimchi, pickles, etc.), beverages ( Examples include, but are not limited to, fruits, vegetable drinks, soy milk, fermented beverages, and the like, and natural seasonings (eg, ramen soup). The food, beverage or food additives may be prepared by a conventional manufacturing method.
또한, 뇌허혈성 질환의 예방 또는 개선의 효과를 목적으로 하는 식품 조성물에 있어서, 상기 추출물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 포함할 수 있으며, 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1g의 비율로 포함할 수 있다. In addition, in the food composition aimed at the effect of preventing or improving cerebral ischemic disease, the amount of the extract may include 0.01 to 15% by weight of the total food weight, the beverage composition is 0.02 to 5 based on 100 ml g, preferably 0.3 to 1 g.
상기 음료 조성물은 상기 추출물외에 다른 추가 성분을 포함할 수 있으며, 예를 들면 각종 향미제 또는 천연 탄수화물 등을 들 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 수크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100㎖ 당 일반적으로 약 1 내지 20g, 바람직하게는 5 내지 12g이다. 그밖에 본 발명의 추출물들은 천연 과일 주스, 과일 쥬스 음료, 야채 음료의 제조를 위한 과육을 추가로 함유할 수 있다.The beverage composition may include additional components in addition to the extract, for example, various flavors or natural carbohydrates. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably 5 to 12 g per 100 ml of the composition of the present invention, in addition, the extracts of the present invention are pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. It may further contain.
상기 외에 본 발명의 추출물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분을 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하지 않지만, 본 발명의 추출물 100 중량부 당 0 내지 20 중량부 범위에서 선택될 수 있다.In addition to the above, the extract of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. These components can be used independently or in combination. The proportion of such additives is not so critical, but may be selected in the range of 0 to 20 parts by weight per 100 parts by weight of the extract of the present invention.
이하, 본 발명의 바람직한 실시예를 기재한다. 다만, 하기의 실시예는 본 발명의 바람직한 일 실시예일뿐, 본 발명의 보호범위가 하기 실시예로 한정되는 것은 아니다.Hereinafter, preferred embodiments of the present invention are described. However, the following examples are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited to the following examples.
실시예Example 1: 삼지구엽초 추출물의 제조 1: Preparation of Trichophyte Leaf Extract
건조상태의 삼지구엽초(강원도 철원) 100g을 곱게 마쇄한 후, 여기에 100% 메탄올 600㎖을 가하고, 74℃에서 5시간 동안 침지하였다. 진공회전증발기를 이용하여 추출액중 메탄올을 완전히 제거하고 농축한 다음 동결건조기를 이용하여 48시간 동안 수분을 완전히 제거하여 삼지구엽초 추출물 분말(8.74g)을 수득하였으며, 수득된 추출물의 1/10을 10㎖의 물에 녹인 것을 원액(98㎎ 추출물/㎖ 물)으로 하여 실험에 사용하였다.After trituration of 100 g of dried trigeminal vinegar (Cheorwon, Gangwon-do) finely, 600 ml of 100% methanol was added thereto, followed by immersion at 74 ° C. for 5 hours. Methanol in the extract was completely removed using a vacuum rotary evaporator and concentrated, followed by complete removal of moisture for 48 hours using a lyophilizer to obtain Trichophyte leaf powder (8.74 g), and 1/10 of the extract obtained was 10 It was used for the experiment as a stock solution (98 mg extract / ml water) that was dissolved in ml of water.
실시예Example 2: 삼지구엽초 추출물의 2: Trichophyllum Extract 뇌허혈시Cerebral ischemia 신경세포 보호효능 측정 Nerve cell protective effect
뇌허혈에 의한 신경세포사의 예방 및 개선효과를 측정하기 위하여 체중 65-75g 인 수컷 몽골리안 저빌(Mongolian gerbil, Harlan, USA)을 마취시켜 온목동맥(common carotid artery)을 결찰하여 뇌허혈을 유발시켰다. 그 후, 신경세포 염색 으로 확인하는 방법을 이용하였다. 또한,부신 유래의 PC12 세포주를 이용하여 저산소환경을 유도한 다음 락테이트 디하이드로게나제 농도를 측정하는 방법의 두 가지 방법으로 상기 실시예 1의 삼지구엽초 추출물의 효능을 검증하였다.In order to measure the prevention and improvement of neuronal cell death by cerebral ischemia, male Mongolian gerbil (Harlan, USA), weighing 65-75 g, was anesthetized and ligated into the common carotid artery to induce cerebral ischemia. Then, the method of confirming by neuronal staining was used. In addition, the efficacy of the Trichophyte herb extract of Example 1 was verified by two methods of inducing a hypoxic environment using an adrenal derived PC12 cell line and then measuring lactate dehydrogenase concentration.
2-1: 2-1: 락테이트Lactate 디하이드로게나제Dehydrogenase (in vitro) 농도 측정을 통한 삼지구엽초 추출물의 (in vitro) of Trichophytium Echo Extract by Concentration Measurement 뇌허혈시Cerebral ischemia 신경세포 보호 효능 측정 Nerve cell protection efficacy measurement
PC12 세포를 이용하여 CoCl2를 투여하여 저산소환경을 통한 신경세포손상을 유도한 후, 신경세포의 손상 유무를 확인하기 위해 배양세포에서 세포밖의 배양액으로 분비되는 락테이드 디하이드게나제(LDH) 농도를 측정하였다. PC12 cell을 7% fetal calf serum, 7% horse serum, 100 ug/ml streptomycin, 100 unit/ml penicillin이 들어 있는 배지에 37℃, 이산화탄소가 6% 있는 환경에서 배양하였으며, LDH의 측정은 손상 및 파괴된 세포로부터 거의 분비가 완료되는 20 시간에 세포배양액을 채취하여 마이크로플레이트 리더로 측정하여 도 1에 나타냈다.Lactide dehydrogenase (LDH) is secreted from the cultured cells into extracellular culture to induce neuronal damage through hypoxic environment by injecting CoCl 2 using PC12 cells. The concentration was measured. PC12 cells were cultured in a medium containing 7% fetal calf serum, 7% horse serum, 100 ug / ml streptomycin and 100 unit / ml penicillin at 37 ° C and 6% carbon dioxide. Cell culture medium was collected at 20 hours when the secretion was almost completed, and the result was shown in FIG. 1 by measuring with a microplate reader.
실시예 1에서 얻은 삼지구엽초 추출물을 상기 PC12 세포주에 배양액, 10, 50, 100, 500, 1000 및 5000 μM으로 각각 처리한 다음, 30분 후에 150μM의 CoCl2를 처리하였다. PC12 세포는 37℃에서 20시간 동안 배양한 후 세포 배양액을 수득하였고, 배양액내의 락테이트 디하이드게나제의 농도를 종셍 바이오테그(Zhong Sheng Biotech) 표준시약으로 한 베크만(Beckman) DU-640 흡광광도계를 이용하여 효소 역학적(enzyme dynamic) 방법(Hou et al. J. Neurosci. Res., 74, pp123-133, 2003; Yamakawa et al. Neurol. Res., 23, pp522-530, 2001)으로 측정하였다. The tricotyledonous extract obtained in Example 1 was treated with the culture medium, 10, 50, 100, 500, 1000 and 5000 μM, respectively, and then treated with 150 μM CoCl 2 after 30 minutes. PC12 cells were cultured at 37 ° C. for 20 hours to obtain cell culture medium, and Beckman DU-640 Absorbance Spectrometer using lactate dehydrogenase concentration in the culture medium as Zhong Sheng Biotech standard. Was measured by enzyme dynamic method (Hou et al. J. Neurosci. Res., 74, pp123-133, 2003; Yamakawa et al. Neurol. Res., 23, pp522-530, 2001). .
실험결과, 도 1에 도시한 바와 같이 삼지구엽초를 처치한 군에서 용매만을 처리한 다음 저산소환경을 유발한 대조군에 비하여 락테이트 디하이드로게나제의 분비율이 농도의존적으로 감소하였다. 이로써, 삼지구엽초 추출물은 신경세포 보호효과 및 개선효과가 있음을 확인할 수 있었다. As a result, as shown in FIG. 1, the treatment rate of the triglyceride vinegar decreased the concentration of lactate dehydrogenase in the group treated with the solvent only and then compared to the control group that induced the hypoxic environment. As a result, it was confirmed that the trigeminal leaf vinegar extract has a neuroprotective effect and an improvement effect.
2-2. 동물실험을 통한 삼지구엽초 추출물의 2-2. Trichophytium Leaf Extract through Animal Experiment 뇌허혈시Cerebral ischemia 신경세포 보호 효능 측정 Nerve cell protection efficacy measurement
저빌을 이용한 동물실험을 통하여 삼지구엽초 추출물의 신경세포사 억제효과를 확인하였다. Animal experiments using gerbils confirmed the neuronal cell death inhibitory effect of Trichophytium foliar extract.
2-2-1. 실험동물의 사육 2-2-1. Breeding of Experimental Animals
체중 65 내지 75g의 수컷 몽골리안 저빌(Mongolian gerbil, Meriones unguiculatus, Halan, USA) 40 마리를 사용하였으며, 실험동물은 오전 7시부터 오후 7시까지 빛을 가하는 일정한 명암주기 하에서 온도 23 ± 2℃, 상대습도 55 ± 10%에서 사육하였다. 음식과 물은 자유로이 섭취하게 하였다. 40 male Mongolian gerbil ( Meriones unguiculatus, Halan, USA), weighing 65-75 g, were used. Experimental animals were subjected to a temperature of 23 ± 2 ° C. under constant light and dark cycles from 7 am to 7 pm. Breeding at a humidity of 55 ± 10%. Food and water were taken freely.
2-2-2. 삼지구엽초 추출물의 뇌허혈시 신경세포 보호 효능 검정 2-2-2. Evaluation of Neuroprotective Effect of Trigeminal Leaf Herb Extract in Brain Ischemia
실험동물에 실시예 1의 삼지구엽초 추출물을 증류수에 용해한 것을 허혈유발 일주일 전부터 매일 식도용 바늘을 이용하여 0.5 ㎖ 경구투여(용량은 체중 ㎏ 당 50 mg 또는 100 ㎎이 되도록 투여)하였다. 실험동물은 질소와 산소가 7 : 3으로 혼합된 가스에 3% 이소플루란(isoflurane , Baxtor, USA)으로 전신마취하였고, 동 일한 가스에 2.5% 이소플루란으로 마취를 유지하면서 수술을 수행하였다. 목 부위의 털을 깎고 소독한 다음 절개를 하여 양쪽 온목동맥을 노출시키고, 동맥류 클립(aneurysm clip, Staelting, USA)을 이용하여 5분 동안 결찰하여 허혈을 일으킨 후, 클립을 제거하여 재관류시켰다. 이 때 각 실험군은 검안경(ophthalmoscope)을 이용하여 망막중심동맥(central artery of retina)의 혈액 순환 유무를 관찰하여 완전한 온목동맥의 폐쇄를 확인하였다. 허혈을 유발시키는 동안 직장 내 체온계를 삽입하여 체온을 측정하였으며, 실험동물의 온도에 따라 자동으로 조절되는 온열 패드를 사용하여 체온을 정상 체온인 37 ± 0.3℃로 일정하게 유지시켰다. The trigeminal leaf vinegar extract of Example 1 was dissolved in distilled water in experimental animals 0.5 ml orally administration (e.g., 50 mg or 100 mg / kg body weight) using an esophageal needle every day from one week before ischemia induction. The animals were subjected to general anesthesia with 3% isoflurane (isoflurane, Baxtor, USA) in a gas mixture of nitrogen and oxygen 7: 3, and the operation was performed while maintaining anesthesia with 2.5% isoflurane in the same gas. . Both hairs of the neck were cut and disinfected, and then incision was made to expose both warm arteries, ligation was performed for 5 minutes using an aneurysm clip (aneurysm clip, Staelting, USA), and then the clips were removed and reperfused. At this time, each experimental group confirmed the complete occlusion of the entire artery by observing the blood circulation of the central artery of retina using an ophthalmoscope. The body temperature was measured by inserting a rectal thermometer during induction of ischemia, and the body temperature was kept constant at a normal body temperature of 37 ± 0.3 ° C by using a heating pad which is automatically adjusted according to the temperature of the experimental animal.
실험군은 뇌허혈 유발 4일 후에 티오펜탈 소듐(thiopental sodium, 유한양행, 한국)을 체중 1 ㎏ 당 각각 30㎎의 용량으로 복강 내 주사하여 마취시킨 다음, 1,000㎖ 당 헤파린 1,000IU를 함유한 4 ℃의 생리식염수를 좌심실로 주입하여 관류 세척하였다. 관류 세척이 끝난 동물은 바로 4℃의 4% 파라포름알데하이드(in 0.1 M phosphate buffer; PB, pH 7.4)로 관류 고정을 하였다. The experimental group was anesthetized by intraperitoneal injection of thiopental sodium at 30 mg / kg body weight 4 days after induction of cerebral ischemia, and then at 4 ° C. containing 1,000 IU per 1,000 ml. Physiological saline was injected into the left ventricle and washed perfusion. After the perfusion wash, the animals were directly perfused with 4% paraformaldehyde (in 0.1 M phosphate buffer; PB, pH 7.4) at 4 ° C.
관류 고정이 끝난 동물을 뼈절단기를 이용하여 머리뼈공간을 열어 뇌를 적출한 다음, 동일 고정액에서 6 시간동안 후고정하였다. 후고정이 끝난 뇌는 30% 슈크로스 용액(in 0.1 M phosphate buffer)에 넣어 바닥에 가라앉을 때까지 침강 시킨 후, 슬라이드 마이크로톰(sliding microtome, Reichert-Jung, Germany)으로 조직을 30㎛ 두께로 잘라 보존액(storing solution)이 들어있는 6웰 플레이트에 넣어 사용시까지 4℃에서 보관하였다. After perfusion fixation, the animals were opened by using a bone cutter to remove the brain, and then fixed in the same fixative for 6 hours. After fixation, the brain was settled in a 30% sucrose solution (in 0.1 M phosphate buffer) until it settled to the bottom, and the tissue was cut into a 30 μm thickness using a sliding microtome (Reichert-Jung, Germany). 6-well plate containing a storage solution (storing solution) was stored at 4 ℃ until use.
각 조직절편 중에서 해마형성체(hippocampal formation)가 잘 나와 있는 조 직을 선택하고, 조직에 묻어있는 보존액을 없애기 위해 0.01M PBS로 10분씩 3회 세척하였다. 이를 젤라틴 입힌 슬라이드에 도말하여 37℃에서 충분히 건조시킨 다음 증류수에 잠시 담가 둔 후, 2% 크레실 바이오렛 아세테이트(cresyl violet acetate, Sigma, USA) 용액에 1분간 염색하였다. 조직은 흐르는 물에 충분히 세척하여 슬라이드에 묻어 있는 과량의 염료를 제거하고, 증류수에 잠시 담근 후 50%, 70%, 80%, 90%, 95% 및 100% 용액을 거쳐 탈수 및 과량의 크레실 바이올렛을 세척하였다. 조직에서 니슬소체(Nissle body)가 보이는 것을 확인한 후, 자일렌(Junsei, Japan)에 담가 투명화한 다음 카나다 발삼(Canada Balsam, Kanto, Japan)으로 봉입하였다. Of each tissue section, a tissue having a well-formed hippocampal formation was selected, and washed three times with 0.01 M PBS for 10 minutes to remove the preservative solution from the tissue. It was smeared onto gelatinized slides, dried sufficiently at 37 ° C., and then immersed in distilled water for a while, and then stained with a 2% cresyl violet acetate (Sigma, USA) solution for 1 minute. The tissue is washed thoroughly with running water to remove excess dye from the slides, briefly immersed in distilled water, and then dehydrated and excess cresyl through 50%, 70%, 80%, 90%, 95% and 100% solutions. Violet was washed. After confirming that the tissue was visible in the Nissle body (Nissle body), immersed in xylene (Junsei, Japan) and made transparent and then encapsulated in Canada Balsam (Kanto, Japan).
대조군은 삼지구엽초 추출물을 녹이는데 이용된 증류수를 투여한 것을 제외하고는 상기와 동일한 방법으로 준비하였으며, 정상군은 삼지구엽초 추출물을 투여하지 아니하였으며, 허혈-재관류 수술을 시행하지 아니한 것을 제외하고는 상기와 동일한 방법으로 준비하였다.The control group was prepared in the same manner as above except for the administration of distilled water used to dissolve the trigeminal vinegar extract, except that the normal group was not administered the trigeminal vinegar extract and did not undergo ischemia-reperfusion surgery. It prepared in the same manner as above.
각 조직들은 디지털 카메라(Axiocam, Cal Zeiss, Germany)가 부착되어 있는 악시오팟 현미경(Axiphot microscope, Carl Zeiss, Germany)으로 전체 해마 영역을 25배로, CA1 영역을 200배로 하여 사진 촬영하여 대조군 및 정상군은 도 2에, 삼지구엽초 추출물을 투여한 실험군은 도 3에 나타냈다. Each tissue was photographed using the Axiphot microscope (Carl Zeiss, Germany) with a digital camera (Axiocam, Cal Zeiss, Germany) at 25 times the total hippocampal area and 200 times the CA1 area. The group is shown in Figure 2, the experimental group administered with the three trichophytium extract is shown in Figure 3.
상기 도 2 및 도 3의 A, C는 전체 해마 영역의 사진이며, B 및 D는 해마의 CA1 영역을 나타낸다. 정상군, 대조군, 삼지구엽초를 50㎎/㎏, 100㎎/㎏ 투여한 경우에 대하여 보라색으로 염색된 부분을 이미지 분석기(Optimas 6.5, USA) 프로그 램을 사용하여 신경세포를 계수하여 도 4에 나타냈다. 각 군에 대한 유의성의 검증을 위하여 일원분산분석(one-way ANOVA test)을 수행하였으며, 데이터는 평균과 표준평균오차로 표시하였다. 특히, 도 2 및 3은 각 군 중에서 가장 일반적인 부분을 골라 악시오팟 현미경(Axiophot microscope, Carl Zeiss, Germany)을 이용하여 사진 촬영하였다.2 and 3, A and C are photographs of the entire hippocampal region, and B and D represent CA1 regions of the hippocampus. In the normal group, the control group, and trigeminal vinegar when 50 mg / kg and 100 mg / kg were administered, purple stained portions were shown in FIG. 4 by counting nerve cells using an image analyzer (Optimas 6.5, USA) program. . One-way ANOVA test was performed to verify the significance of each group, and data were expressed as mean and standard mean error. In particular, FIGS. 2 and 3 were taken with the most common portion of each group using an axiophot microscope (Carlises Zeiss, Germany).
2-2-3. 실험결과 2-2-3. Experiment result
도 1에서 나타나듯이, 50 내지 100 ㎎/㎏의 삼지구엽초 추출물을 투여한 경우 PC12 세포에서의 락테이트 디하이드로게나제의 생성량이 적은 것으로 관찰됨에 따라 본 발명의 추출물을 투여하는 경우 신경세포 보호의 효과가 있음을 알 수 있었다. As shown in Figure 1, when administration of the tricotyledonous extract of 50 to 100 mg / kg was observed that the production of lactate dehydrogenase in PC12 cells is small, the nerve cell protective It was found to be effective.
또한, 도 2에서는 정상군은 해마의 전영역에서 신경세포가 진하게 염색되는 것을 관찰할 수 있었던 반면에, 대조군은 해마의 CA1영역에서 허혈에 의해 세포가 죽어 염색된 세포가 거의 관찰되지 않았다. In addition, in FIG. 2, the normal group was able to observe the deep staining of nerve cells in the whole area of the hippocampus, whereas in the control group, cells stained by ischemia in the CA1 region of the hippocampus were hardly observed.
한편 도 3의 50㎎/㎏ 및 100㎎/㎏의 삼지구엽초 추출물을 투여한 실험군에서는 해마의 전영역에서 세포가 진하게 염색되는 것을 확인할 수 있어, 삼지구엽초가 신경세포사를 현저히 억제시킴을 확인할 수 있었다.On the other hand, in the experimental group administered the triglobin vinegar extract of 50mg / kg and 100mg / kg of Figure 3 it can be confirmed that the cells in the whole area of the hippocampus stained dark, trigeminal vinegar significantly inhibited neuronal cell death was confirmed. .
또한, 도 4의 허혈-재관류 실시 후 삼지구엽초 추출물의 농도에 따른 신경세포의 사멸정도를 신경세포 계수로 확인한 결과에서도, 대조군에서는 정상군에 비하여 해마의 CA1 영역세포가 약 11.3 % 정도 관찰되었으나, 삼지구엽초 추출물을 투여한 군에서는 대조군에 비하여 높은 신경세포 생존율이 관찰되었다. 50㎎/㎏의 삼지구엽초 추출물을 투여한 경우 정상군에 비교했을 때 31%의 세포가 관찰되었으며, 도 3A 및 3B에서 나타난 바와 같이 해마 CA1 영역의 내측에 세포가 많이 죽는 것이 관찰되었다(도 3A, B 그리고 4). 반면 100㎎/㎏의 용량으로 투여하는 경우 정상군에 비해 73%의 세포가 관찰되었으며, 도 3C 및 3D에서 나타난 바와 같이CA1 영역의 모든 부분에서 비슷한 수의 세포가 관찰되었다(도 3C, D 그리고 4). 또한 이들 용량으로 투여시에 어떠한 부작용도 관찰되지 않았다. In addition, even in the results of confirming the neuronal cell death according to the concentration of tricotyledonous extract after the ischemia-reperfusion of FIG. 4 by the neuronal cell count, the CA1 region cells of the hippocampus were observed about 11.3% compared to the normal group in the control group. The neuronal survival rate was higher in the group administered with Trifolium vinegar extract than the control group. Thirty-one percent of cells were observed when 50 mg / kg of Trichophyte herb extract was administered compared to the normal group, and as shown in FIGS. 3A and 3B, many cells were observed to die inside the hippocampus CA1 region (FIG. 3A). , B and 4). On the other hand, when administered at a dose of 100 mg / kg, 73% of cells were observed compared to the normal group, and similar numbers of cells were observed in all parts of the CA1 region as shown in FIGS. 3C and 3D (FIGS. 3C, D and 4). In addition, no side effects were observed upon administration at these doses.
실시예Example 3. 3. 급성독성실험Acute Toxicity Test
6 주령의 특정병원체부재(specific pathogen-free, SPF) SD(Sprague-Dawley, Harlan, USA)계 랫트(대한실험동물, 대한미국)를 사용하여 급성독성실험을 실시하였다. 각 그룹당 5마리씩의 동물에 본 발명의 삼지구엽초 추출물을 50 mg/kg, 100㎎/㎏, 200㎎/㎏, 400mg/kg의 용량으로 1회 경구투여 하였다. 실험 물질 투여 후 동물의 폐사여부, 임상증상 및 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적 검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강 장기의 이상여부를 관찰하였다. Acute toxicity test was performed using 6-week-old specific pathogen-free (SPF) SD rats (Sprague-Dawley, Harlan, USA). Five animals of each group were orally administered to the trigeminal vinegar extract of the present invention at a dose of 50 mg / kg, 100 mg / kg, 200 mg / kg, and 400 mg / kg. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal organs and thoracic organ abnormalities.
실험 결과, 실험 물질을 투여한 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사 및 부검 소견 등에서도 독성변화는 관찰되지 않았다. 이상의 결과, 본 발명의 삼지구엽초 추출물은 랫드에서 각각 400㎎/㎏ 까지도 독성변화를 나타내지 않았으며, 경구투여 최소치사량 (LD50)은 400㎎/㎏ 이상인 안전한 물질로 판단되었다. As a result, no significant clinical symptoms or dead animals were noted in all animals treated with the test substance, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings. As a result, the trigeminal leaf herb extract of the present invention did not show toxic changes up to 400 mg / kg in rats, respectively, and the minimum lethal dose (LD 50 ) was determined to be a safe substance of 400 mg / kg or more.
[표 1]TABLE 1
삼지구엽초 투여에 따른 농도별 각종 장기의 무게 및 조직부검소견Weight and Tissue Autopsy Findings of Various Organs by Concentration Following Administration
[표 2]TABLE 2
삼지구엽초 투여에 따른 농도별 혈액생화학치 및 혈구형태의 변화Changes in Blood Biochemistry and Hemocytosis According to Concentration of Trilobite Leaf
상기 실험결과로 부터, 뇌허혈에 의한 신경세포사를 억제하며 동물실험에서 농도별로 투여하였을 경우에도 병리학적 소견이 발견되지 않았으며, 장기의 무게변화도 없고, 혈액화학치에도 큰 변화가 없어 무해하여, 이를 포함하는 조성물은 뇌허혈성 질환의 예방 및 개선을 위한 건강기능식품으로 유용하게 사용될 수 있다. From the above experimental results, pathological findings were not found even when administered in different concentrations in animal experiments by inhibiting neuronal cell death by cerebral ischemia, and there was no change in weight of organs and no significant change in blood chemistry. The composition comprising the same may be usefully used as a dietary supplement for the prevention and improvement of cerebral ischemic disease.
제제예Formulation example 1. One. 산제의Powder 제조 Produce
삼지구엽초 추출물 분말 20 mg Tricuspid leaf extract powder 20 mg
유당 100 mg
탈크 10 mg Talcuk 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다. The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예Formulation example 2. 정제의 제조 2. Preparation of Tablets
삼지구엽초 추출물 분말 10 mg Tricuspid
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg Magnesium stearate 2 mg
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.
제제예Formulation example 3. 캡슐제의 제조 3. Preparation of Capsule
삼지구엽초 추출물 분말 10 mg Tricuspid
결정성 셀룰로오스 3 mg
락토오스 14.8 mg Lactose 14.8 mg
마그네슘 스테아레이트 0.2 mg Magnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전 하여 캡슐제를 제조한다. According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예Formulation example 4. 4. 액제의Liquid 제조 Produce
삼지구엽초 추출물 분말 20 mg Tricuspid leaf extract powder 20 mg
이성화당 10 g Isomerized sugar 10g
만니톨 5 g 5 g of mannitol
정제수 적량 Appropriate amount of purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다. According to the conventional method of preparing a liquid solution, each component is added and dissolved in purified water, lemon flavor is added to the mixture, and then the above ingredients are mixed, purified water is added to adjust the total amount to 100 ml, and then filled in a brown bottle. The solution is prepared by sterilization.
제제예Formulation example 5. 식품의 제조 5. Manufacture of food
삼지구엽초 추출물 분말 1000 ㎎ Tricuspid leaf extract powder 1000 mg
비타민 혼합물 적량 Proper amount of vitamin mixture
비타민 A 아세테이트 70 ㎍ 70 ㎍ Vitamin A Acetate
비타민 E 1.0 ㎎ Vitamin E 1.0 mg
비타민 B1 0.13 ㎎ Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎ Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎ Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍ 0.2 ㎍ of vitamin B12
비타민 C 10 ㎎
비오틴 10 ㎍ Biotin 10 ㎍
니코틴산아미드 1.7 ㎎ Nicotinamide 1.7 mg
엽산 50 ㎍
판토텐산 칼슘 0.5 ㎎ Calcium pantothenate 0.5 mg
무기질 혼합물 적량 Mineral mixture
황산제1철 1.75 ㎎ Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎ Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎ Magnesium Carbonate 25.3 mg
제1인산칼륨 15 ㎎ Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎ Dibasic calcium phosphate 55 mg
구연산칼륨 90 ㎎ Potassium Citrate 90 mg
탄산칼슘 100 ㎎
염화마그네슘 24.8 ㎎ Magnesium Chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 식품 조성물 제조에 사용할 수 있다. Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above components are mixed according to a conventional food production method. Granules may be prepared and used to prepare food compositions according to conventional methods.
상술한 바와 같이, 본 발명의 삼지구엽초 추출물은 부신유래의 세포주 및 뇌허혈에 민감하다고 알려져 있는 해마조직 CA1 영역의 신경세포의 손상을 효과적으로 예방할 뿐만 아니라, 뇌허혈에 의한 신경세포사를 억제하며 인체에 부작용을 발생시키지 않는 무해한 뇌허혈성 질환의 예방 및 개선을 위한 건강 기능식품으로 유용하게 사용될 수 있다.As described above, the trigeminal leaf vinegar extract of the present invention not only effectively prevents damage to nerve cells in the CA1 region of the hippocampus known to be sensitive to adrenal-derived cell lines and cerebral ischemia, but also inhibits neuronal cell death caused by cerebral ischemia and has side effects on the human body. It can be usefully used as a dietary supplement for the prevention and improvement of harmless cerebral ischemic disease that does not occur.
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