KR102451200B1 - Composition for preventing or treating cognitive disorder or psychiatric disorder comprising extracts of Dracocephalum moldavica - Google Patents
Composition for preventing or treating cognitive disorder or psychiatric disorder comprising extracts of Dracocephalum moldavica Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A—HUMAN NECESSITIES
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- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환 예방, 개선 또는 치료용 조성물에 관한 것으로, 본 발명의 상기 향청란 추출물을 포함하는 조성물은 PDE10A 억제 및 CREB 인산화 활성화를 통한 스코폴라민 투여 건망증 모델 및 MK-801 투여 조현병 모델에서 인지기능 개선 효과를 나타냄을 확인함에 따라, 알츠하이머병, 조현병, 건망증 또는 헌팅턴병 등 인지기능 장애 또는 정신질환의 예방, 치료 또는 개선용 조성물 및 PDE10A 억제제로 유용할 수 있다.The present invention relates to a composition for preventing, improving, or treating cognitive dysfunction or mental disease, comprising an extract of Dracocephalum moldavica as an active ingredient, and the composition comprising the extract of the present invention exhibits inhibition of PDE10A and activation of CREB phosphorylation. For the prevention, treatment or improvement of cognitive dysfunction or mental disorders such as Alzheimer's disease, schizophrenia, forgetfulness, or Huntington's disease, as it has been confirmed that scopolamine-administered forgetfulness model and MK-801-administered schizophrenia model show cognitive function improvement effects compositions and PDE10A inhibitors.
Description
본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating cognitive dysfunction or mental disease, comprising an extract of Dracocephalum moldavica as an active ingredient.
조현병(schizophrenia, 정신분열증)은 자기 자신이나 외부세계에 대한 부적절한 이해, 사고의 혼란, 현실감이 결여된 행동 장애 등을 특징으로 하는 심각한 정신질환으로서, 전세계 인구 중 1%에서 발생한다. 양성증상(환각, 망상 등), 음성증상(무욕증, 사회성 결여 등), 인지기능 장애, 정서 장애 등의 증상이 1개월 이상 동안 대부분의 특정 징후가 지속되거나, 일부 증후가 6개월 이상 지속되는 경우 정신 질환으로 간주한다.Schizophrenia (schizophrenia) is a serious mental disorder characterized by an inappropriate understanding of oneself and the outside world, confusion of thinking, and a lack of realism, affecting 1% of the world's population. Positive symptoms (hallucinations, delusions, etc.), negative symptoms (asexuality, lack of social skills, etc.), cognitive dysfunction, emotional disorder, etc. cases are considered mentally ill.
포스포디에스테라제 타입 10A (phosphodiesterase10A; PDE10A)는 뇌 내의 선조체(striatum) 부위에 주로 위치하며 cAMP와 cGMP의 가수분해를 매개하는 효소로 알려져 있다. 많은 연구자들이 PDE10A를 도파민 신경계와 관련되어 있는 정신질환인 조현병의 치료타깃으로 제시하고 있으며, PDE10A를 억제함으로써 조현병 개선이 가능함을 확인한 연구결과가 보고된 바 있다. 따라서 다국적 제약사에 의해 차세대 조현병 치료제로서 PDE10A 억제제 개발이 이루어지고 상황이다. 다른 연구에 의하면 수면 부족 유도로 장기 공포 기억을 유발한 랫드에서 개선 효과가 알려진 바가 있으나 기억력 감퇴 모델에서의 개발은 이루어진 바가 없다. 따라서 스코폴라민 투여로 유도한 기억력 감퇴 모델에서 PDE10A 억제를 통한 인지기능 장애 예방 및 치료 효과와 집중력 및 조현병 등의 정신질환 개선 효과를 확인하는 연구가 필요하다.Phosphodiesterase type 10A (phosphodiesterase10A; PDE10A) is mainly located in the striatum in the brain and is known as an enzyme that mediates the hydrolysis of cAMP and cGMP. Many researchers have suggested PDE10A as a therapeutic target for schizophrenia, a mental disorder related to the dopaminergic nervous system, and research results have been reported confirming that schizophrenia can be improved by inhibiting PDE10A. Therefore, the development of PDE10A inhibitors as a next-generation treatment for schizophrenia is being made by multinational pharmaceutical companies. According to other studies, the improvement effect was known in rats that induced long-term fear memory by induction of sleep deprivation, but the development of a memory loss model has not been made. Therefore, it is necessary to study the effect of preventing and treating cognitive dysfunction through PDE10A inhibition and improving concentration and mental disorders such as schizophrenia in a model of memory loss induced by scopolamine administration.
MK-801은 N-methyl-D-aspartate(NMDA) 수용체의 길항제 중 하나로 정신분열 증상을 유도하기 위해 사용되는 약물이다. 뇌의 해마에서 글루타메이트(glutamate) 수용체인 NMDA의 활성은 칼슘(Ca2+)의 세포 내 유입을 조절함으로써 신경전달과 학습에 관여하며, MK-801은 NMDA 채널의 펜시클리딘(phencyclidine) 부위에 결합하여 칼슘의 세포 내 유입을 억제하고 흥분성 손상을 유도함으로써 궁극적으로 정신분열과 매우 유사한 상태를 유발한다. MK-801 is one of the antagonists of the N-methyl-D-aspartate (NMDA) receptor and is a drug used to induce schizophrenia symptoms. The activity of NMDA, a glutamate receptor, in the hippocampus of the brain is involved in neurotransmission and learning by regulating the influx of calcium (Ca 2+ ) into cells, and MK-801 is located in the phencyclidine site of the NMDA channel. It binds and inhibits the influx of calcium into cells and induces excitatory damage, ultimately leading to a state very similar to schizophrenia.
한편, 향청란(Dracocephalum moldavica)은 중앙아시아, 중국 북부, 동유럽 및 중부 유럽에 서식하는 다년생의 식물로서, 일반적으로 몰다비카용머리(Moldavian dragonhead) 혹은 Moldavian balm이라고 부른다. 전통적으로 편두통 및 심혈관계 질병 치료에 동아시아 지역에서 사용되어왔으며, 항산화 및 항염증과 같은 약리학적 효과가 있음이 알려진 바 있다. 그러나, 지금까지 향청란 추출물의 인지기능 장애 또는 정신질환의 치료 및 개선에 대해서는 전혀 시사 또는 개시된 바가 없다.On the other hand, Dracocephalum moldavica is a perennial plant inhabiting Central Asia, Northern China, Eastern Europe and Central Europe, and is generally called Moldavian dragonhead or Moldavian balm. It has been traditionally used in East Asia for the treatment of migraines and cardiovascular diseases, and has been known to have pharmacological effects such as antioxidant and anti-inflammatory effects. However, there has been no suggestion or disclosure at all for the treatment and improvement of cognitive dysfunction or mental disease of the Hyangcheongran extract so far.
이에 본 발명자들은 천연물로부터 새로운 조현병 및 건망증 치료제를 개발하기 위하여 연구한 결과, 향청란 추출물이 마우스 건망증 모델 및 조현병 모델에서 정신분열 치료와 동시에 인지기능 개선 효과가 있음을 확인하여 본 발명을 완성하였다.Accordingly, the present inventors completed the present invention by confirming that, as a result of research to develop a new therapeutic agent for schizophrenia and forgetfulness from natural products, the Hyangcheongran extract has an effect of improving cognitive function as well as treating schizophrenia in a mouse model of forgetfulness and schizophrenia. .
본 발명의 목적은 인지기능 장애 또는 정신질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating cognitive dysfunction or mental disease.
본 발명의 다른 목적은 인지기능 장애 또는 정신질환 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for preventing or improving cognitive dysfunction or mental disease.
본 발명의 또 다른 목적은 포스포디에스테라제 타입 10A(PDE10A) 억제용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for inhibiting phosphodiesterase type 10A (PDE10A).
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cognitive dysfunction or mental disease, comprising an extract of Hyangcheongran ( Dracocephalum moldavica ) as an active ingredient.
또한, 본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cognitive dysfunction or mental disease, comprising an extract of hyangcheongran ( Dracocephalum moldavica ) as an active ingredient.
나아가, 본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 포스포디에스테라제 타입 10A(PDE10A) 억제용 조성물을 제공한다.Furthermore, the present invention provides a composition for inhibiting phosphodiesterase type 10A (PDE10A) comprising an extract of Dracocephalum moldavica as an active ingredient.
본 발명의 향청란 추출물을 포함하는 조성물은 PDE10A 억제 및 CREB 인산화 활성화를 통한 스코폴라민 투여 건망증 모델 및 MK-801 투여 조현병 모델에서 인지기능 개선 효과를 나타냄을 확인함에 따라, 알츠하이머병, 조현병, 건망증 또는 헌팅턴병 등 인지기능 장애 또는 정신질환의 예방, 치료 또는 개선용 조성물 및 PDE10A 억제제로 유용할 수 있다.As it was confirmed that the composition containing the Hyangcheongran extract of the present invention exhibits an effect of improving cognitive function in scopolamine-administered forgetfulness model and MK-801-administered schizophrenia model through PDE10A inhibition and CREB phosphorylation activation, Alzheimer's disease, schizophrenia, It may be useful as a composition for preventing, treating or improving cognitive dysfunction or mental disorders, such as forgetfulness or Huntington's disease, and as a PDE10A inhibitor.
도 1은 본 발명의 향청란 추출물의 포스포디에스테라제 타입 10A (phosphodiesterase10A; PDE10A) 활성도(%) 억제능을 나타낸 그래프이다.
도 2는 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 건망증 모델에서 수동회피 시험법으로 머무름 시간을 측정하여 기억력 개선 효능을 확인한 결과를 나타낸 그래프이다(#: p<0.05, ##: p<0.01).
도 3은 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 건망증 모델에서 수중미로 시험법의 훈련기간 동안 플랫폼 도달 시간을 측정하여 기억력 개선 효능을 확인한 결과를 나타낸 그래프이다(#: p<0.05, ##: p<0.01).
도 4는 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 건망증 모델에서 수중미로 시험법의 프로브 시험(probe test)으로 플랫폼이 있던 사분면에 머무름 시간을 측정하여 기억력 개선 효능을 확인한 결과를 나타낸 그래프이다(#: p<0.05).
도 5는 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 해마영역에서의 CERB-ERK 단백질 인산화수준을 나타낸 것이다(#: p<0.05).
도 6은 본 발명의 향청란 추출물 투여 후, 마우스 조현병 모델에서 신사물 인지 시험법을 통해 탐색 시간을 백분율로 계산하여 신사물 인지 개선 효능을 확인한 결과를 나타낸 그래프이다(###: p<0.001).
도 7은 본 발명의 향청란 추출물(실시예) 일주일간 투여 또는 클로자핀(양성대조군) 단회 투여 후, 마우스 조현병 모델에서 열린공간 시험으로 이동거리를 분석하여 과행동(hyperlocomotion) 개선 효능을 확인한 결과를 나타낸 그래프이다(#: p<0.05, ###: p<0.001).1 is a graph showing the phosphodiesterase type 10A (phosphodiesterase10A; PDE10A) activity (%) inhibitory ability of the extract of the present invention.
2 is a graph showing the results of confirming the effect of improving memory by measuring the retention time using the passive avoidance test method in a mouse forgetfulness model after administration of the hyangcheong orchid extract (Example) or donepezil (positive control) of the present invention (#: p <0.05, ##: p<0.01).
3 is a graph showing the results of confirming the memory improvement effect by measuring the platform arrival time during the training period of the water maze test in the mouse forgetfulness model after administration of the hyangcheongran extract (Example) or donepezil (positive control) of the present invention. (#: p<0.05, ##: p<0.01).
Figure 4 is after administration of the Hyangcheongran extract (Example) or donepezil (positive control) of the present invention, memory improvement by measuring the retention time in the quadrant where the platform was as a probe test of the water maze test method in the mouse forgetfulness model; It is a graph showing the results of confirming the efficacy (#: p<0.05).
5 shows the phosphorylation level of CERB-ERK protein in the hippocampal region of mice after administration of the Hyangcheong orchid extract (Example) or donepezil (positive control) of the present invention (#: p<0.05).
FIG. 6 is a graph showing the results of confirming the efficacy of improving cognition of new things by calculating the search time as a percentage through the novel recognition test method in a mouse schizophrenia model after administration of the hyangcheongran extract of the present invention (###: p <0.001) ).
7 shows the results of confirming the effect of improving hyperlocomotion by analyzing the movement distance in an open space test in a mouse schizophrenia model after administration of the hyangcheongran extract (Example) of the present invention for one week or clozapine (positive control) single administration This is the graph shown (#: p<0.05, ###: p<0.001).
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
인지기능 장애 또는 정신질환 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating cognitive dysfunction or mental disease
본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cognitive dysfunction or mental disease, comprising an extract of Hyangcheongran ( Dracocephalum moldavica ) as an active ingredient.
본 발명에서 사용되는 용어 "예방"은 본 발명의 조성물의 투여로 특정 질환 의 증상을 억제하거나 진행을 지연시키는 모든 행위를 의미한다.As used herein, the term “prevention” refers to any action that suppresses the symptoms of a specific disease or delays the progression by administration of the composition of the present invention.
본 발명에서 사용되는 용어 "치료"는 본 발명의 조성물의 투여로 특정 질환의 증상을 호전 또는 이롭게 변경시키는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action that improves or beneficially changes the symptoms of a specific disease by administering the composition of the present invention.
본 발명에 따른 약학적 조성물에 있어서, 상기 인지기능 장애 또는 정신질환은 포스포디에스테라제 타입 10A(PDE10A) 매개 인지기능 장애 또는 정신질환인 것일 수 있고, 바람직하게는 알츠하이머병, 조현병, 건망증 또는 헌팅턴병으로 이루어진 군으로부터 선택되는 1종 이상의 질환인 것일 수 있다.In the pharmaceutical composition according to the present invention, the cognitive dysfunction or mental disease may be phosphodiesterase type 10A (PDE10A) mediated cognitive dysfunction or mental disease, preferably Alzheimer's disease, schizophrenia, forgetfulness Or it may be one or more diseases selected from the group consisting of Huntington's disease.
본 발명에 따른 약학적 조성물에 있어서, 상기 향청란 추출물은 포스포디에스테라제 타입 10A 활성을 억제하여 인지기능 장애 또는 정신질환 예방 또는 치료 효과를 나타내는 것일 수 있다.In the pharmaceutical composition according to the present invention, the Hyangcheongran extract may exhibit the effect of inhibiting phosphodiesterase type 10A activity to prevent or treat cognitive dysfunction or mental disease.
본 발명의 일실시예에서는, 본 발명에 따른 상기 향청란 추출물이 PDE10A 활성도를 억제하며, CREB-ERK 단백질 인산화를 증가시킬 수 있음을 확인하였다(실험예 1 및 3 참조). 또한, 스코폴라민 투여 건망증 모델의 수동회피시험, 수중미로시험 및 MK-801 투여 조현병 모델의 신사물인지시험 및 열린공간 시험에서, 본 발명에 따른 상기 향청란 추출물을 투여한 경우 음성대조군(스코폴라민 또는 MK-801 투여)에 비해 인지 기능 개선능을 보이는 것을 확인하였다(실험예 2, 4 및 5 참조).In one embodiment of the present invention, it was confirmed that the hyangcheongran extract according to the present invention can inhibit PDE10A activity and increase CREB-ERK protein phosphorylation (see Experimental Examples 1 and 3). In addition, in the passive avoidance test of the scopolamine-administered forgetfulness model, the water maze test, and the new substance recognition test and the open space test of the MK-801-administered schizophrenia model, the negative control group (Sco) It was confirmed that the cognitive function improvement ability compared to polamine or MK-801 administration) (see Experimental Examples 2, 4 and 5).
본 발명에 따른 약학적 조성물에 있어서, 상기 향청란 추출물은 과행동을 개선시키는 효과를 나타내는 것일 수 있다.In the pharmaceutical composition according to the present invention, the Hyangcheongran extract may exhibit an effect of improving hyperactivity.
본 발명의 일실시예에서는 MK-801 투여 조현병 모델의 열린공간 시험에서, 본 발명에 따른 상기 향청란 추출물을 투여한 경우 음성대조군(MK-801 투여)에 비해 과행동을 억제시키는 효과가 있음을 확인하였다(실험예 5 참조).In one embodiment of the present invention, in an open space test of a schizophrenia model administered with MK-801, it was found that when the hyangcheong orchid extract according to the present invention was administered, there was an effect of inhibiting hyperactivity compared to the negative control group (administered with MK-801). It was confirmed (see Experimental Example 5).
본 발명에 따른 약학적 조성물에 있어서, 상기 향청란 추출물은 향청란 잎 또는 전초로부터 추출되는 것일 수 있다.In the pharmaceutical composition according to the present invention, the hyangcheongran extract may be extracted from hyangcheongran leaves or whole plants.
본 발명에 따른 약학적 조성물에 있어서, 상기 향청란 추출물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 추출물을 분리 및 수득한 것을 사용할 수 있으며, 본 발명에서 정의된 추출물은 적절한 용매를 이용하여 상기의 방법으로 준비된 유효성분 원료를 그대로 또는 분말 상태로 분쇄하여 추출할 수 있다. 이때 추출물을 수득하기 위해 사용할 수 있는 적절한 용매로는 당업계에서 허용되는 용매라면 어느 것을 사용해도 무방하며, 물, 탄소수 1 내지 탄소수 4의 알코올 또는 이들의 혼합용매로 추출하여 추출물을 제조할 수 있다. 예를 들어, 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있으나, 이에 제한되지는 않는다. 바람직하게는 바람직하게는 물 또는 에탄올로부터 선택되는 1종 이상의 추출용매를 사용하여 추출할 수 있고, 보다 바람직하게는 50-90% 에탄올 수용액을 이용하여 추출할 수 있고, 70% 에탄올 수용액을 이용하는 것이 가장 바람직하다.In the pharmaceutical composition according to the present invention, the hyangcheongran extract may be used to isolate and obtain the extract using a method known in the art for extraction and separation, and the extract defined in the present invention may be prepared using an appropriate solvent. The raw material of the active ingredient prepared by the above method may be extracted as it is or by pulverizing it in a powder state. At this time, as a suitable solvent that can be used to obtain the extract, any solvent acceptable in the art may be used, and the extract can be prepared by extraction with water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. . For example, purified water, methanol (methanol), ethanol (ethanol), propanol (propanol), isopropanol (isopropanol), alcohols having 1 to 4 carbon atoms including butanol (butanol), acetone (acetone), ether (ether) , benzene (benzene), chloroform (chloroform), ethyl acetate (ethyl acetate), methylene chloride (methylene chloride), hexane (hexane) and various solvents such as cyclohexane (cyclohexane) can be used alone or in combination, but Not limited. Preferably, extraction may be performed using at least one extraction solvent selected from water or ethanol, and more preferably extraction may be performed using 50-90% aqueous ethanol solution, and 70% aqueous ethanol solution may be used. Most preferred.
추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있다. 또한, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. 본 발명의 추출물의 제조방법에는 제한이 없으며, 공지되어 있는 어떠한 방법도 이용될 수 있다.As the extraction method, any one of methods such as hot water extraction, cold extraction, reflux cooling extraction, solvent extraction, steam distillation, ultrasonic extraction, elution, and compression may be selected and used. In addition, the desired extract may be further subjected to a conventional fractionation process, and may be purified using a conventional purification method. There is no limitation on the method for preparing the extract of the present invention, and any known method may be used.
예를 들면, 본 발명의 조성물에 포함되는 추출물은 상기한 용매 추출법으로 추출된 1차 추출물을, 원심분리, 여과, 농축후 동결 건조하여 냉장실에 보관하면서 그대로 사용할 수도 있고, 상기 1차 추출물을 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조할 수 있다. 또한, 상기 1차 추출물을 실리카겔 컬럼 크로마토그래피(silica gel column chromatography), 박층 크로마토그래피(thin layer chromatography), 고성능 액체 크로마토그래피(high performance liquid chromatography)등과 같은 다양한 크로마토그래피를 이용하여 추가로 정제된 분획을 얻을 수도 있다. For example, the extract included in the composition of the present invention may be used as it is while storing the primary extract extracted by the solvent extraction method, centrifugation, filtration, concentration, and freeze-drying in a refrigerator, and the primary extract is reduced pressure It may be prepared in a powder state by an additional process such as distillation and freeze drying or spray drying. In addition, the primary extract is further purified using various chromatography methods such as silica gel column chromatography, thin layer chromatography, high performance liquid chromatography, and the like. can also get
따라서 본 발명에 있어서 추출물은 추출, 분획 또는 정제의 각 단계에서 얻어지는 모든 추출액, 분획 및 정제물, 그들의 희석액, 농축액 또는 건조물을 모두 포함하는 개념이다.Therefore, in the present invention, the extract is a concept including all extracts, fractions, and purified products obtained in each step of extraction, fractionation or purification, and dilutions, concentrates or dried products thereof.
상기 약학적 조성물은 약학적으로 허용되는 담체를 추가로 포함할 수 있다. 상기에서 "약학적으로 허용되는"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 약학적으로 허용되는 담체로는, 예를 들면, 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등과 같은 경구투여용 담체 및 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등과 같은 비경구 투여용 담체 등이 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있다. 그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed, Mack Publishing Company, Easton, PA, 1995). The pharmaceutical composition may further include a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. Pharmaceutically acceptable carriers include, for example, carriers for oral administration such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like, water, suitable oils, saline, aqueous glucose and glycols, etc. for parenteral administration. and a carrier, and may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. As other pharmaceutically acceptable carriers, reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed, Mack Publishing Company, Easton, PA, 1995).
본 발명에 따른 약학 조성물은 상술한 바와 같은 약학적으로 허용되는 담체와 함께 당업계에 공지된 방법에 따라 적합한 형태로 제형화 될 수 있다. 즉, 본 발명의 약학 조성물은 공지의 방법에 따라 다양한 비경구 또는 경구 투여용 형태로 제조될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.The pharmaceutical composition according to the present invention may be formulated in a suitable form according to a method known in the art together with a pharmaceutically acceptable carrier as described above. That is, the pharmaceutical composition of the present invention can be prepared in various parenteral or oral administration forms according to known methods. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention and at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. 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. can
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
상기 약학적 조성물은 담체, 부형제 또는 희석제를 더 포함할 수 있다. 담체, 부형제, 또는 희석제는 예를 들어, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 또는 광물유를 포함할 수 있다.The pharmaceutical composition may further include a carrier, excipient or diluent. Carriers, excipients, or diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어, "투여"란 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미하며, 상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한, 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여, 뇌혈관내 투여될 수 있으나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "administration" means introducing a predetermined substance to an individual by an appropriate method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intracerebrovascular administration may be administered, but is not limited thereto.
상기 용어, "개체"란 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 바람직하게는, 인간을 포함한 포유동물일 수 있다.As used herein, the term “individual” refers to all animals including humans, rats, mice, and livestock. Preferably, it may be a mammal including a human.
상기 용어, "약학적으로 유효한 양"이란 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며, 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강 상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다. 일반적으로 약 0.001~100 mg/kg/day이며, 바람직하게는 0.01~35 mg/kg/day이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07~7000 mg/day이며, 바람직하게는 0.7~2500 ㎎/day이며, 투여는 상기 권장 투여량을 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the sex and age of the patient. , body weight, health condition, disease type, severity, drug activity, drug sensitivity, administration method, administration time, route of administration, and rate of excretion, duration of treatment, factors including drugs used in combination or concomitantly, and other medical fields It can be easily determined by a person skilled in the art according to factors well known in the art. Generally, it is about 0.001 to 100 mg/kg/day, and preferably 0.01 to 35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and administration may be administered in the recommended dose once a day, several times It may be administered in divided doses.
본 발명의 조성물은 인지기능 장애 또는 정신질환 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 can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of cognitive dysfunction or mental disease.
인지기능 장애 또는 정신질환 예방 또는 개선용 건강기능식품 조성물Health functional food composition for preventing or improving cognitive dysfunction or mental disease
본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention provides a health functional food composition for preventing or improving cognitive dysfunction or mental disease, comprising an extract of Hyangcheongran ( Dracocephalum moldavica ) as an active ingredient.
본 발명에서 사용되는 용어 "개선"은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action that at least reduces a parameter related to the condition being treated, for example, the severity of symptoms.
본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캡슐제, 환제, 액제, 분말 또는 과립 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 건강기능식품 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품 유래 성분을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 인지기능 장애 또는 정신질환 치료제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The term "health functional food" used in the present invention refers to food manufactured and processed in the form of tablets, capsules, pills, liquids, powders or granules, etc. using raw materials or ingredients having useful functions in the human body. Here, the term 'functionality' refers to obtaining useful effects for health purposes such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be manufactured by a method commonly used in the conventional technical field, and at the time of the production, it can be prepared by adding raw materials and components commonly added in the conventional technical field. In addition, if the formulation of the health functional food is also recognized as a health functional food, it can be prepared without limitation. The health functional food composition of the present invention can be prepared in various types of dosage forms, and unlike general drugs, it uses food-derived ingredients as raw materials and has the advantage of not having side effects that may occur during long-term administration of the drug, and has excellent portability. , The health functional food of the present invention can be ingested as an adjuvant for enhancing the effect of a therapeutic agent for cognitive dysfunction or mental illness.
또한, 본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 인지기능 장애 또는 정신질환 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or improving cognitive dysfunction or mental disease comprising an extract of Hyangcheongran ( Dracocephalum moldavica ) as an active ingredient.
본 발명에 따른 건강기능식품 조성물 또는 건강식품 조성물에 있어서, 상기 인지기능 장애 또는 정신질환은 포스포디에스테라제 타입 10A(PDE10A) 매개 인지기능 장애 또는 정신질환인 것일 수 있고, 바람직하게는 알츠하이머병, 조현병, 건망증 또는 헌팅턴병으로 이루어진 군으로부터 선택되는 1종 이상의 질환인 것일 수 있다.In the health functional food composition or health food composition according to the present invention, the cognitive dysfunction or mental disease may be a phosphodiesterase type 10A (PDE10A) mediated cognitive dysfunction or mental disease, preferably Alzheimer's disease , schizophrenia, forgetfulness, or Huntington's disease may be one or more diseases selected from the group consisting of.
본 발명에 따른 건강기능식품 조성물 또는 건강식품 조성물에 있어서, 상기 향청란 추출물은 포스포디에스테라제 타입 10A 활성을 억제하여 인지기능 장애 또는 정신질환 예방 또는 개선 효과를 나타내는 것일 수 있다.In the health functional food composition or health food composition according to the present invention, the extract of Hyangcheongran may be one that inhibits phosphodiesterase type 10A activity to prevent or improve cognitive dysfunction or mental disease.
본 발명의 일실시예에서는, 본 발명에 따른 상기 향청란 추출물이 PDE10A 활성도를 억제하며, CREB-ERK 단백질 인산화를 증가시킬 수 있음을 확인하였다(실험예 1 및 3 참조). 또한, 스코폴라민 투여 건망증 모델의 수동회피시험, 수중미로시험 및 MK-801 투여 조현병 모델의 신사물인지시험 및 열린공간 시험에서, 본 발명에 따른 상기 향청란 추출물을 투여한 경우 음성대조군(스코폴라민 또는 MK-801 투여)에 비해 인지 기능 개선능을 보이는 것을 확인하였다(실험예 2, 4 및 5 참조).In one embodiment of the present invention, it was confirmed that the hyangcheongran extract according to the present invention can inhibit PDE10A activity and increase CREB-ERK protein phosphorylation (see Experimental Examples 1 and 3). In addition, in the passive avoidance test of the scopolamine-administered forgetfulness model, the water maze test, and the new substance recognition test and the open space test of the MK-801-administered schizophrenia model, the negative control group (Sco) It was confirmed that the cognitive function improvement ability compared to polamine or MK-801 administration) (see Experimental Examples 2, 4 and 5).
한편, 향청란 추출물은 아세틸콜린 에스테라제(AChE) 효소 활성을 억제할 수 있는 것으로 알려진 연구 결과가 있으나, 본 발명자들의 사전 연구 결과, 에스테라제 효소 활성을 억제하는 효과가 없음을 확인하였으며, PDE10A 활성 억제가 인지기능 장애 또는 정신질환 예방 또는 치료 효과를 나타내는 중요한 기전임을 확인하였다.On the other hand, there are research results known to be able to inhibit the acetylcholinesterase (AChE) enzyme activity of the Hyangcheongran extract, but as a result of the prior research of the present inventors, it was confirmed that there was no effect of inhibiting the esterase enzyme activity, PDE10A It was confirmed that inhibition of activity is an important mechanism for preventing or treating cognitive dysfunction or psychiatric disorders.
본 발명에 따른 건강기능식품 조성물 또는 건강식품 조성물에 있어서,상기 향청란 추출물은 과행동을 개선시키는 효과를 나타내는 것일 수 있다.In the health functional food composition or health food composition according to the present invention, the hyangcheong orchid extract may exhibit an effect of improving hyperactivity.
본 발명의 일실시예에서는 MK-801 투여 조현병 모델의 열린공간 시험에서, 본 발명에 따른 상기 향청란 추출물을 투여한 경우 음성대조군(MK-801 투여)에 비해 과행동을 억제시키는 효과가 있음을 확인하였다(실험예 5 참조).In one embodiment of the present invention, in an open space test of a schizophrenia model administered with MK-801, it was found that when the hyangcheong orchid extract according to the present invention was administered, there was an effect of inhibiting hyperactivity compared to the negative control group (administered with MK-801). It was confirmed (see Experimental Example 5).
본 발명에 따른 건강기능식품 조성물 또는 건강식품 조성물에 있어서, 상기 향청란 추출물은 향청란 잎 또는 전초로부터 추출되는 것일 수 있다.In the health functional food composition or health food composition according to the present invention, the hyangcheongran extract may be extracted from hyangcheongran leaves or whole plants.
본 발명에 따른 건강기능식품 조성물 또는 건강식품 조성물에 있어서, 상기 향청란 추출물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 추출물을 분리 및 수득한 것을 사용할 수 있으며, 본 발명에서 정의된 추출물은 적절한 용매를 이용하여 상기의 방법으로 준비된 유효성분 원료를 그대로 또는 분말 상태로 분쇄하여 추출할 수 있다. 이때 추출물을 수득하기 위해 사용할 수 있는 적절한 용매로는 당업계에서 허용되는 용매라면 어느 것을 사용해도 무방하며, 물, 탄소수 1 내지 탄소수 4의 알코올 또는 이들의 혼합용매로 추출하여 추출물을 제조할 수 있다. 예를 들어, 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있으나, 이에 제한되지는 않는다. 바람직하게는 바람직하게는 물 또는 에탄올로부터 선택되는 1종 이상의 추출용매를 사용하여 추출할 수 있고, 보다 바람직하게는 50-90% 에탄올 수용액을 이용하여 추출할 수 있고, 70% 에탄올 수용액을 이용하는 것이 가장 바람직하다.In the health functional food composition or health food composition according to the present invention, the Hyangcheongran extract can be used to isolate and obtain the extract using a method known in the art for extraction and separation, and the extract defined in the present invention is The active ingredient raw material prepared by the above method can be extracted by pulverizing it as it is or in a powder state using an appropriate solvent. At this time, as a suitable solvent that can be used to obtain the extract, any solvent acceptable in the art may be used, and the extract can be prepared by extraction with water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. . For example, purified water, methanol (methanol), ethanol (ethanol), propanol (propanol), isopropanol (isopropanol), alcohols having 1 to 4 carbon atoms including butanol (butanol), acetone (acetone), ether (ether) , benzene (benzene), chloroform (chloroform), ethyl acetate (ethyl acetate), methylene chloride (methylene chloride), hexane (hexane) and various solvents such as cyclohexane (cyclohexane) can be used alone or in combination, but Not limited. Preferably, extraction may be performed using at least one extraction solvent selected from water or ethanol, and more preferably extraction may be performed using 50-90% aqueous ethanol solution, and 70% aqueous ethanol solution may be used. Most preferred.
본 발명에 따른 상기 건강기능식품 조성물 또는 건강식품 조성물은 인지기능 장애 또는 정신질환을 예방 또는 개선시키기 위한 목적으로 상기 향청란 추출물을 식품, 음료 등의 건강기능식품 또는 건강식품에 첨가한 것일 수 있다.The health functional food composition or health food composition according to the present invention may be added to health functional food or health food such as food or beverage for the purpose of preventing or improving cognitive dysfunction or mental disease.
상기 식품의 종류에는 특별한 제한은 없다. 본 발명에 따른 향청란 추출물을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강식품 및 건강기능식품을 모두 포함한다.There is no particular limitation on the type of the food. Examples of foods to which the Hyangcheongnae extract according to the present invention can be added include drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream , various soups, beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and includes both health food and health functional food in the ordinary sense.
본 발명에 따른 건강식품 및 건강기능식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 본 발명에 따른 상기 향청란 추출물의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 및 건강기능식품 중의 상기 향청란 추출물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 유지를 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The health food and health functional food composition according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the hyangcheongran extract according to the present invention may be suitably determined according to the purpose of its use (for prevention or improvement). In general, the amount of the hyangcheongran extract in health food and health functional food may be added in an amount of 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term ingestion for the purpose of maintaining health or for health control, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 건강식품 및 건강기능식품 조성물은 지시된 비율로 필수 성분으로서 본 발명에 따른 향청란 추출물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능성 식품 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health food and health functional food composition of the present invention is not particularly limited in other ingredients other than containing the extract according to the present invention as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates are added as in conventional beverages. It can contain as an ingredient. 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 polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the dietary supplement of the present invention.
상기 외에 본 발명에 따른 향청란 추출물을 함유하는 건강식품 및 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강식품 및 건강기능식품 조성물은 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health food and health functional food composition containing the extract according to the present invention are various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate) etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health food and health functional food composition of the present invention may contain natural fruit juice, fruit juice, and fruit for the production of fruit juice drinks and vegetable drinks.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 유효물질을 함유하는 건강식품 및 건강기능식품 조성물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. The proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.
포스포디에스테라제 타입 10A(PDE10A) 억제용 조성물Composition for inhibiting phosphodiesterase type 10A (PDE10A)
본 발명은 향청란(Dracocephalum moldavica) 추출물을 유효성분으로 포함하는 포스포디에스테라제 타입 10A(PDE10A) 억제용 조성물을 제공한다.The present invention provides a composition for inhibiting phosphodiesterase type 10A (PDE10A) comprising an extract of Dracocephalum moldavica as an active ingredient.
본 발명에 따른 포스포디에스테라제 타입 10A 억제용 조성물에 있어서, 상기 조성물은 포스포디에스테라아제 타입 10A의 억제에 의해 개선될 수 있는 질병 또는 병적 증세의 예방, 치료 또는 개선에 이용되는 것일 수 있다. 상기 질병 또는 병적증세는, 바람직하게는 포스포디에스테라아제 타입 10A에 의해 매개되는 인지기능 장애 또는 정신질환인 것일 수 있고, 보다 바람직하게는, 알츠하이머병, 조현병, 건망증 또는 헌팅턴병으로 이루어진 군으로부터 선택되는 1종 이상의 질환의 예방, 치료 또는 개선에 이용되는 것일 수 있다.In the composition for inhibiting phosphodiesterase type 10A according to the present invention, the composition may be used for preventing, treating, or ameliorating a disease or pathological condition that can be improved by inhibition of phosphodiesterase type 10A. The disease or pathology may be, preferably, a cognitive dysfunction or a mental disorder mediated by phosphodiesterase type 10A, and more preferably, Alzheimer's disease, schizophrenia, forgetfulness or Huntington's disease selected from the group consisting of It may be used for preventing, treating or ameliorating one or more diseases.
본 발명의 일실시예에서는, 본 발명에 따른 상기 향청란 추출물이 PDE10A 활성도를 억제할 수 있음을 확인하였다(실험예 1 참조). 또한, PDE10A 활성 억제를 통해 상기 향청란 추출물이 CREB-ERK 단백질 인산화를 증가시킬 수 있으며, PDE10A 활성 억제를 통해 스코폴라민 투여 건망증 모델의 수동회피시험, 수중미로시험 및 MK-801 투여 조현병 모델의 신사물인지시험 및 열린공간 시험에서, 상기 향청란 추출물을 투여한 경우 음성대조군(스코폴라민 또는 MK-801 투여)에 비해 인지기능 개선 및 과행동 억제가 가능함을 확인하였다(실험예 2 내지 5 참조).In one embodiment of the present invention, it was confirmed that the Hyangcheongran extract according to the present invention can inhibit PDE10A activity (see Experimental Example 1). In addition, through inhibition of PDE10A activity, the Hyangcheongran extract can increase CREB-ERK protein phosphorylation, and through inhibition of PDE10A activity, passive avoidance test of scopolamine administration forgetfulness model, water maze test and MK-801 administration of schizophrenia model In the cognition test and open space test, it was confirmed that when the Hyangcheongran extract was administered, it was possible to improve cognitive function and suppress hyperactivity compared to the negative control group (administered with scopolamine or MK-801) (see Experimental Examples 2 to 5). ).
본 발명에 따른 포스포디에스테라제 타입 10A 억제용 조성물에 있어서, 상기 향청란 추출물은 향청란 잎 또는 전초로부터 추출되는 것일 수 있다.In the composition for inhibiting phosphodiesterase type 10A according to the present invention, the hyangcheongran extract may be extracted from hyangcheongran leaves or whole plants.
본 발명에 따른 포스포디에스테라제 타입 10A 억제용 조성물에 있어서, 상기 향청란 추출물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 추출물을 분리 및 수득한 것을 사용할 수 있으며, 본 발명에서 정의된 추출물은 적절한 용매를 이용하여 상기의 방법으로 준비된 유효성분 원료를 그대로 또는 분말 상태로 분쇄하여 추출할 수 있다. 이때 추출물을 수득하기 위해 사용할 수 있는 적절한 용매로는 당업계에서 허용되는 용매라면 어느 것을 사용해도 무방하며, 물, 탄소수 1 내지 탄소수 4의 알코올 또는 이들의 혼합용매로 추출하여 추출물을 제조할 수 있다. 예를 들어, 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있으나, 이에 제한되지는 않는다. 바람직하게는 바람직하게는 물 또는 에탄올로부터 선택되는 1종 이상의 추출용매를 사용하여 추출할 수 있고, 보다 바람직하게는 50-90% 에탄올 수용액을 이용하여 추출할 수 있고, 70% 에탄올 수용액을 이용하는 것이 가장 바람직하다.In the composition for inhibiting phosphodiesterase type 10A according to the present invention, the Hyangcheongran extract may be used for isolating and obtaining the extract using a method known in the art for extraction and separation, as defined in the present invention. The extract can be extracted by pulverizing the raw material of the active ingredient prepared by the above method as it is or in a powder state using an appropriate solvent. At this time, as a suitable solvent that can be used to obtain the extract, any solvent acceptable in the art may be used, and the extract can be prepared by extraction with water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. . For example, purified water, methanol (methanol), ethanol (ethanol), propanol (propanol), isopropanol (isopropanol), alcohols having 1 to 4 carbon atoms including butanol (butanol), acetone (acetone), ether (ether) , benzene (benzene), chloroform (chloroform), ethyl acetate (ethyl acetate), methylene chloride (methylene chloride), hexane (hexane) and various solvents such as cyclohexane (cyclohexane) can be used alone or in combination, but Not limited. Preferably, extraction may be performed using at least one extraction solvent selected from water or ethanol, and more preferably extraction may be performed using 50-90% aqueous ethanol solution, and 70% aqueous ethanol solution may be used. Most preferred.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited by the following examples.
<실시예 1> 향청란 추출물의 제조<Example 1> Preparation of Hyangcheongran Extract
건조된 향청란(Dracocephalum moldavica)을 구입(내몽고몽약고분유한공사, 중국 내몽고 퉁랴오시)하여 전초를 분쇄기(mixer)를 이용하여 극세말하였다. 상기 극세말한 분말에 70% 에탄올 10배량(v/v)을 가하여 60℃에서 초음파 추출장치(POWERSONIC 410, 화신테크)로 2시간 동안 2회 추출하였다. 추출액을 filter paper (110mmØ, whatman)를 이용하여 감압여과 후, 감압농축기(NE-1001, EYELA)로 감압 농축하고, 동결건조기(FDU-2200, EYELA)로 동결건조하여 향청란 추출물 분말을 얻었다. 동결 건조한 분말을 -70℃ 냉동고에 보관하고, 실험시 0.9% 생리식염수에 녹여 사용하였다. 향청란 추출물의 수득률은 11.98%였다.Dried hyangcheong egg ( Dracocephalum moldavica ) was purchased (Inner Mongolia Mongyak High Powder Co., Ltd., Tongliao City, Inner Mongolia, China), and the outages were finely milled using a mixer. A 10-fold amount (v/v) of 70% ethanol was added to the ultrafine powder, followed by extraction twice for 2 hours at 60° C. using an ultrasonic extraction device (POWERSONIC 410, Hwashin Tech). After filtration under reduced pressure using filter paper (110mmØ, whatman), the extract was concentrated under reduced pressure with a reduced pressure concentrator (NE-1001, EYELA), and freeze-dried with a freeze dryer (FDU-2200, EYELA) to obtain a hyangcheong orchid extract powder. The freeze-dried powder was stored in a -70°C freezer, and was used by dissolving it in 0.9% physiological saline during the experiment. The yield of the Hyangcheongran extract was 11.98%.
<준비예 1> 실험 동물 및 재료 준비<Preparation Example 1> Preparation of experimental animals and materials
1-1. 실험 재료1-1. experimental material
(-)-스코폴라민 하이드로브로마이드, 도네페질 하이드로클로라이드 모노하이드레이트 및 아세틸콜린에스테라제(AChE)는 Sigma Chemical Co.(St. Louis, MO)에서 구매하였다.(-)-scopolamine hydrobromide, donepezil hydrochloride monohydrate and acetylcholinesterase (AChE) were purchased from Sigma Chemical Co. (St. Louis, MO).
항-ERK, 항-인산화된 ERK (p-ERK) 및 항-CREB 항체는 Santa Cruz Biotechnology Inc. (Santa Cruz, CA)에서 구입하고, 항-인산화된 CREB (p-CREB) 항체는 Upstate Lake Placid (Lake Placid, NY)로부터 구입하였다.Anti-ERK, anti-phosphorylated ERK (p-ERK) and anti-CREB antibodies were obtained from Santa Cruz Biotechnology Inc. (Santa Cruz, CA) and anti-phosphorylated CREB (p-CREB) antibody was purchased from Upstate Lake Placid (Lake Placid, NY).
(+)-MK-801 hydrogen maleate, Clozapine은 Sigma Chemical Co.(St. Louis,MO)에서 구입하였다.(+)-MK-801 hydrogen maleate, Clozapine was purchased from Sigma Chemical Co. (St. Louis, MO).
도네페질, 스코폴라민 및 향청란 추출물(실시예 1)은 0.9% 생리 식염수에 용해시켜 사용하였고, MK-801은 0.9% 생리식염수에, Clozapine은 0.9% 생리식염수에 0.1N HCl을 약간 섞어서 녹였다.Donepezil, scopolamine and hyangcheongran extract (Example 1) were dissolved in 0.9% physiological saline, MK-801 was dissolved in 0.9% physiological saline, and Clozapine was dissolved by mixing 0.1N HCl in 0.9% physiological saline slightly.
1-2. 실험 동물1-2. laboratory animal
수컷 CD1-ICR 마우스(6주령, 25-30g)를 Charles River Laboratories(한국 서울)의 Orient Co. Ltd.에서 구입하여, 마우스를 케이지당 5 그룹으로 수용하고, 일정한 온도(23±1℃) 및 상대 습도(60±10%)에서 12시간 명/암주기(07:00~19:00에 점등)를 유지하면서 음식 및 물을 자유롭게 제공하였다. 동물 처리 및 유지 관리는 실험실 동물 관리 원칙(NIH 공보 번호 85-23, 1985년 개정)과 대한민국 경희대학교 동물실험윤리위원회(KHUASP(SE)16-084)에 따라 수행하였다.Male CD1-ICR mice (6 weeks old, 25-30 g) were obtained from Orient Co., Ltd. of Charles River Laboratories (Seoul, Korea). Ltd., housed mice in groups of 5 per cage, lit on a 12 h light/dark cycle (07:00–19:00) at constant temperature (23±1°C) and relative humidity (60±10%). ), food and water were provided ad libitum. Animal handling and maintenance were performed in accordance with the Laboratory Animal Care Principles (NIH Publication No. 85-23, revised in 1985) and the Animal Experimental Ethics Committee (KHUASP(SE)16-084, Kyunghee University, Korea).
<실험예 1> 향청란 추출물의 PDE10A 억제 효과<Experimental Example 1> PDE10A inhibitory effect of Hyangcheongran extract
PDE10A assay를 이용하여 상기 실시예 1의 향청란 추출물 처리 농도(10, 30, 100, 300 및 1000 μg/ml)에 따른 PDE10A 활성도(%)를 측정하여 포스포디에스테라제 타입 10A (phosphodiesterase10A; PDE10A) 억제능을 평가하여 표 1 및 도 1에 나타내었다.PDE10A activity (%) was measured according to the concentration (10, 30, 100, 300 and 1000 μg/ml) of the hyangcheong orchid extract of Example 1 using the PDE10A assay to measure phosphodiesterase type 10A (phosphodiesterase10A; PDE10A) The inhibitory ability was evaluated and shown in Table 1 and FIG. 1 .
도 1은 본 발명의 향청란 추출물의 포스포디에스테라제 타입 10A (phosphodiesterase10A; PDE10A) 억제능을 나타낸 그래프이다.1 is a graph showing the phosphodiesterase type 10A (phosphodiesterase10A; PDE10A) inhibitory ability of Hyangcheongran extract of the present invention.
분석 결과, IC50값이 305.8 mg/ml로 향청란 추출물이 PDE10A 억제능이 있음을 확인하였다.As a result of the analysis, the IC 50 value was 305.8 mg/ml, confirming that the Hyangcheongran extract had the ability to inhibit PDE10A.
<실험예 2> 향청란 추출물의 기억력 개선 효과<Experimental Example 2> Memory improvement effect of Hyangcheongran extract
2-1. 수동 회피 시험2-1. Manual Evasion Test
수동 회피 시험 평가는 50W 전구를 포함하는 동일한 조명 및 비조명 구획(20cm×20cm×20cm)을 사용하여 수행되었다. 비조명 구획의 바닥은 1cm 간격으로 2mm 스테인레스 스틸 막대로 구성되었으며, 두 구획은 길로틴 문(5cm×5cm)으로 분리되었다.The passive avoidance test evaluation was performed using the same illuminated and unilluminated compartments (20 cm x 20 cm x 20 cm) containing a 50 W bulb. The bottom of the non-illuminated compartment was composed of 2 mm stainless steel rods spaced 1 cm apart, and the two compartments were separated by a guillotine door (5 cm × 5 cm).
동물들은 24시간 차이를 두고 2개의 개별 시험(학습 시험 및 평가 시험)을 수행하였다. 학습 시험 1시간 전에, 마우스에 실시예 1의 향청란 추출물(12.5, 25, 50 또는 100mg/kg) 또는 양성 대조군으로서 도네페질(5mg/kg)을 경구 투여(p.o.)하였다. 대조군은 향청란 추출물 또는 도네페질 대신 0.9% 식염수를 투여하였다. 향청란 추출물, 도네페질 또는 식염수 투여 30분 후, 마우스를 스코폴라민(1mg/kg, 복강 내 투여[i.p.])으로 처리하여 건망증을 유발하였다.Animals underwent two separate tests (a learning test and an assessment test) with a difference of 24 hours. One hour before the learning test, mice were orally administered (p.o.) with the Hyangcheong orchid extract of Example 1 (12.5, 25, 50 or 100 mg/kg) or donepezil (5 mg/kg) as a positive control. For the control group, 0.9% saline was administered instead of the Hyangcheong orchid extract or donepezil. Thirty minutes after administration of the Hyangcheongnae extract, donepezil or saline, the mice were treated with scopolamine (1 mg/kg, intraperitoneal administration [i.p.]) to induce forgetfulness.
학습 시험을 위해, 각각의 마우스를 조명 구획에 놓고, 10초 후에, 조명 구획 및 비조명 구획 사이의 문을 열었다. 문을 연 후 마우스가 비조명 구획에 들어가는데 걸리는 시간을 측정하여 머무름 시간(s)으로 정의하였다. 마우스가 비조명 구획에 들어가면 도어가 닫히고 전기 충격(0.5mA, 3초)을 격자 바닥을 통해 전달하여 마우스가 이러한 전기 작용을 기억하게 하였다. 마우스를 조명 구획으로 다시 돌려서 학습 시험 24 시간 후에 평가 시험을 수행 하였다. 학습 시험과 마찬가지로 두 구획 사이의 문을 연 후 마우스가 비조명 구획에 들어가는데 걸리는 시간을 측정하여 머무름 시간(latency time, s)으로 정의하였다. 이때, 각 시험에서의 머무름 시간은 최대 300초 동안 기록하였다.For the learning test, each mouse was placed in an illuminated compartment, and after 10 seconds, the door between the illuminated compartment and the non-illuminated compartment was opened. After opening the door, the time it takes for the mouse to enter the non-illuminated compartment was measured and defined as the retention time (s). When the mouse entered the unilluminated compartment, the door was closed and an electric shock (0.5 mA, 3 s) was delivered through the grid floor, causing the mouse to remember this electrical action. An evaluation test was performed 24 h after the learning test by returning the mice back to the lighting compartment. Like the learning test, the time it takes for the mouse to enter the non-illuminated compartment after opening the door between the two compartments was measured and defined as the latency time (s). At this time, the retention time in each test was recorded for a maximum of 300 seconds.
도 2는 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 건망증 모델에서 수동회피 시험법으로 머무름 시간을 측정하여 기억력 개선 효능을 확인한 결과를 나타낸 그래프이다. 이때, #, ##은 음성대조군에 비해 본 발명에 따른 향청란 추출물을 12.5, 25, 50 또는 100 mg/kg 투여한 군, 양성대조군인 도네페질을 5 mg/kg 투여한 군의 머무름 시간이 통계적으로 유의미하게 증가하였다는 것으로, #은 p<0.05이고, ##은 p<0.01임을 의미한다.2 is a graph showing the results of confirming the effect of improving memory by measuring the retention time by the passive avoidance test method in the mouse forgetfulness model after administration of the hyangcheongran extract (Example) or donepezil (positive control) of the present invention. At this time, # and ## indicate that the retention time of the group administered with 12.5, 25, 50, or 100 mg/kg of the Hyangcheong orchid extract according to the present invention and 5 mg/kg of the positive control, donepezil, was statistically compared to the negative control group. , which means that # is p<0.05 and ## is p<0.01.
도 2에 나타난 바와 같이, 스코폴라민 투여군(대조군)은 정상군 대비 낮은 머무름 시간이 관찰되었으며, 기억력이 감퇴되었음을 확인하였다. 반면에, 스코폴라민과 향청란 추출물을 병용 투여시, 기억력 감퇴가 개선됨을 확인하였다. As shown in FIG. 2 , the scopolamine administration group (control group) had a lower retention time compared to the normal group, and it was confirmed that the memory deteriorated. On the other hand, when scopolamine and Hyangcheongran extract were administered in combination, it was confirmed that the memory loss was improved.
2-2. 모리스 수중 미로 시험2-2. morris water maze test
모리스 수중 미로 장치는 원형 풀(직경 90 cm 및 높이 45 cm)에 검은색 색소를 섞은 물로 30cm 깊이까지 채워서 사용하였고, 탱크는 다양한 시각 신호가 있는 희미한 조명의 방음 시험장에 배치되었다. 풀은 개념적으로 사분면으로 구획을 나누었으며, 검은색 플랫폼(직경 6cm 및 높이 29cm)을 사분면 중 하나에 놓고, 보이지 않도록 수면 아래 1cm에 잠기도록 한 후 모리스 수중미로 시험법의 훈련기간 동안의 마우스의 플랫폼 도달 시간을 측정하여 기억력 개선 효능을 평가하였다.The Morris water maze apparatus was used by filling a circular pool (90 cm in diameter and 45 cm in height) with black-dyed water to a depth of 30 cm, and the tank was placed in a dimly lit soundproofing test site with various visual cues. The pool was conceptually divided into quadrants, with a black platform (6 cm in diameter and 29 cm in height) placed in one of the quadrants, submerged 1 cm below the water surface so as not to be seen, and the mouse during training of the Morris water maze test method. The memory improvement efficacy was evaluated by measuring the platform arrival time.
마우스는 향청란 추출물(50mg/kg, p.o.) 또는 도네페질(5mg/kg, p.o.)은 각 세션의 첫번째 훈련 시험 전에 매일 1시간 동안 투여되었고, 향청란 추출물 또는 도네페질 처리 30분 후에 스코폴라민(1mg/kg, i.p.)에 의해 기억 손상을 유발하였으며, 대조군은 0.9% 식염수만 투여하였다(p.o.).Mice were dosed with chrysanthemum extract (50 mg/kg, p.o.) or donepezil (5 mg/kg, p.o.) daily for 1 hour before the first training trial of each session, and scopolamine (1 mg /kg, i.p.) induced memory impairment, and the control group was administered with only 0.9% saline (p.o.).
시험 첫날은 플랫폼이 없는 상태에서 60초 동안 수영 훈련을 실시하였고, 이후 4일 동안, 플랫폼의 존재하에 하루에 세션당 4번의 훈련 시험을 시행하였다. 마우스가 플랫폼을 찾았을때 10초 동안 그 플랫폼에 머무르도록 허용하였으며, 마우스가 60초 이내에 플랫폼을 찾지 못할 경우, 10초 동안 플랫폼 위에 올려두었다. 각 훈련 시험에 대해, 풀 사분면을 무작위로 선택하여 풀 벽을 향하도록 마우스를 물에 넣었다. 훈련 시험 사이의 시간은 30초였고, 각 시험 후에는 동물을 케이지로 돌려 보내 적외선 램프 하에서 건조시켰다. 각 시험 세션 동안 비디오 카메라 기반 EthoVision 시스템 XT (Noldus Information Technology, Wageningen, Netherlands)를 사용하여 숨겨진 플랫폼을 찾는 데 걸린 시간(대기 시간)을 기록하여, 도 3에 나타내었다.On the first day of the test, swimming training was conducted for 60 seconds in the absence of a platform, and then, for 4 days, 4 training trials per session were conducted in the presence of the platform per day. When the mouse found the platform, it was allowed to stay on the platform for 10 seconds, and if the mouse did not find the platform within 60 seconds, it was placed on the platform for 10 seconds. For each training trial, a pool quadrant was randomly selected and mice were placed in the water facing the pool wall. The time between training trials was 30 seconds, and after each trial the animals were returned to their cages and dried under an infrared lamp. The time taken to find the hidden platform (latency) was recorded during each test session using a video camera-based EthoVision system XT (Noldus Information Technology, Wageningen, Netherlands), and is shown in FIG. 3 .
또한, 마지막 훈련 시험 세션 1일 후, 마우스를 플랫폼을 풀에서 제거하여 프로브 시험(probe test) 세션을 수행하고, 마우스에 60초 동안 검색을 허용하였다. 이전에 플랫폼이 위치했었던 사분면에서 머무른 수영 시간을 측정하여 기록하여, 도 4에 나타내었다.In addition, one day after the last training test session, the mice were removed from the pool to perform a probe test session, and the mice were allowed to search for 60 seconds. The swimming time staying in the quadrant where the platform was previously located was measured and recorded, and is shown in FIG. 4 .
도 3은 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 건망증 모델에서 수중미로 시험법의 훈련기간 동안 플랫폼 도달 시간을 측정하여 기억력 개선 효능을 확인한 결과를 나타낸 그래프이다. 이때, #, ##은 음성대조군에 비해 본 발명에 따른 향청란 추출물을 50 mg/kg 투여한 군, 양성대조군인 도네페질을 5 mg/kg 투여한 군의 도달 시간이 통계적으로 유의미하게 감소하였다는 것으로, #은 p<0.05이고, ##은 p<0.01임을 의미한다.3 is a graph showing the results of confirming the memory improvement effect by measuring the platform arrival time during the training period of the water maze test in the mouse forgetfulness model after administration of the hyangcheongran extract (Example) or donepezil (positive control) of the present invention. . At this time, # and ## indicate that the arrival time of the group administered 50 mg/kg of the Hyangcheongran extract according to the present invention and the group administered with donepezil, a positive control, of 5 mg/kg, was statistically significantly decreased compared to the negative control group. That is, # means p<0.05, and ## means p<0.01.
도 3에 나타난 바와 같이, 수중미로시험을 이용하여 스코폴라민으로 기억력 감퇴를 유도시킨 마우스 건망증 모델에서 향청란 추출물의 기억력 개선 효능을 평가한 결과, 스코폴라민 투여군(대조군)은 정상군 대비 플랫폼을 찾아가는 시간이 줄어들지 않음을 관찰하였으며, 기억력이 감퇴되었음을 확인하였다. 반면에 스코폴라민과 향청란 추출물을 병용 투여시, 기억력 감퇴를 개선시킬 수 있음을 확인하였다.As shown in FIG. 3 , as a result of evaluating the memory improvement efficacy of the Hyangcheong orchid extract in a mouse forgetfulness model induced by scopolamine using the water maze test, the scopolamine administration group (control group) had a platform compared to the normal group. It was observed that the visit time did not decrease, and it was confirmed that the memory was deteriorated. On the other hand, when scopolamine and hyangcheongran extract were administered in combination, it was confirmed that memory loss could be improved.
도 4는 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 건망증 모델에서 수중미로 시험법의 프로브 시험(probe test)으로 플랫폼이 있던 사분면에 머무름 시간을 측정하여 기억력 개선 효능을 확인한 결과를 나타낸 그래프이다. 이때, #은 음성대조군에 비해 본 발명에 따른 향청란 추출물을 50 mg/kg 투여한 군, 양성대조군인 도네페질을 5 mg/kg 투여한 군의 머무름 시간이 통계적으로 유의미하게 감소하였다는 것으로, #은 p<0.05임을 의미한다.Figure 4 is after administration of the Hyangcheongran extract (Example) or donepezil (positive control) of the present invention, memory improvement by measuring the retention time in the quadrant where the platform was as a probe test of the water maze test method in the mouse forgetfulness model; It is a graph showing the results of confirming the efficacy. At this time, # indicates that the retention time of the group administered with 50 mg/kg of the Hyangcheong orchid extract according to the present invention and the group administered with 5 mg/kg of donepezil, a positive control, was statistically significantly reduced compared to the negative control group, # means p<0.05.
플랫폼 제거 후 플랫폼이 있던 사분면에서의 머무름 시간을 측정한 결과, 스코폴라민 투여군(대조군)은 정상군 대비 낮은 머무름 시간이 관찰되어, 기억력이 감퇴되었음을 확인하였고, 스코폴라민과 향청란 추출물을 병용 투여시, 기억력 감퇴를 개선할 수 있음을 확인하였다.As a result of measuring the retention time in the quadrant where the platform was after removal of the platform, the scopolamine-administered group (control group) observed a lower retention time than the normal group, confirming that memory was decreased. It was confirmed that it can improve memory loss.
<실험예 3> 향청란 추출물의 CERB-ERK 단백질 인산화 증가 효과<Experimental Example 3> CERB-ERK protein phosphorylation increase effect of Hyangcheongran extract
도네페질 또는 향청란 추출물과 스코폴라민을 실험예 2와 동일한 방법으로 투여한 후, 마우스를 희생시키고 뇌를 즉시 제거하였다. 단리된 해마 조직을 프로테아제 및 포스파타제 억제제를 함유하는 빙냉 Tris-HCl 완충 용액(20 mM, pH 7.4)에서 균질화시켰다. 조직 용해물을 4℃에서 20분 동안 12,000 rpm에서 원심분리하였다. Pierce BCA 단백질 분석 키트(Thermo Scientific, PA)를 사용하여 브래드 포드(Bradford) 방법을 사용하여 상청액을 정량하고, 환원 조건 하에서 단백질 15μg을 SDS-PAGE(8% 겔)에 가하였다.After donepezil or hyangcheongran extract and scopolamine were administered in the same manner as in Experimental Example 2, mice were sacrificed and the brain was immediately removed. The isolated hippocampal tissue was homogenized in ice-cold Tris-HCl buffer solution (20 mM, pH 7.4) containing protease and phosphatase inhibitors. Tissue lysates were centrifuged at 12,000 rpm for 20 minutes at 4°C. The supernatant was quantified using the Bradford method using the Pierce BCA Protein Assay Kit (Thermo Scientific, PA), and 15 μg of the protein was subjected to SDS-PAGE (8% gel) under reducing conditions.
웨스턴 블롯 분석법을 이용하여 향청란 추출물의 CERB-ERK 단백질 인산화 증가 효과를 평가하였다. 먼저, 단백질을 전달 완충액에서 PVDF막 상으로 옮기고, p-ERK, ERK, CREB 및 p-CREB 수준을 결정하기 위해 4℃에서 2시간 동안 100V에서 추가로 분리하였다. 막을 4℃에서 차단 용액(5% 탈지유)과 함께 2시간 동안 인큐베이션 한 다음, 일차 항체(ERK, 1:3000; p-ERK, 1:1000; CREB, 1:3000; 및 p-CREB, 1:1000)와 함께 overnight으로 인큐베이션 하였다. 이어서, 막을 트윈 20/트리스 완충 식염수(TTBS)로 2회 세척하고, 서양고추냉이 퍼옥시다제가 접합된 2차 항체와 함께 실온에서 2시간 동안 인큐베이션한 다음, TTBS로 3회 세척하고, enhanced chemiluminescence(Amersham Life Science, Arlington Heights, IL)를 사용하여 발색시켰다. 면역 블롯은 LAS-4000 mini imager (Fujifilm Life Science USA, Stamford, CT)를 사용하여 이미지화하고 Multi Gauge version 3.2 (Fujifilm Holdings Corporation, Tokyo, Japan)를 사용하여 분석하였다. 인산화 수준은 동일한 막에서 인산화된 단백질 대 총 단백질의 비율을 계산함으로써 정량화하였다.Western blot analysis was used to evaluate the effect of increasing phosphorylation of CERB-ERK protein of Hyangcheongran extract. First, proteins were transferred onto PVDF membranes in transfer buffer and further separated at 100 V for 2 h at 4° C. to determine p-ERK, ERK, CREB and p-CREB levels. Membranes were incubated for 2 h with blocking solution (5% skim milk) at 4 °C, followed by primary antibodies (ERK, 1:3000; p-ERK, 1:1000; CREB, 1:3000; and p-CREB, 1: 1000) and incubated overnight. Membranes were then washed twice with
도 5는 본 발명의 향청란 추출물(실시예) 또는 도네페질(양성대조군) 투여 후, 마우스 해마영역에서의 CERB-ERK 단백질 인산화수준을 나타낸 것이다(#: p<0.05)5 is a graph showing the phosphorylation level of CERB-ERK protein in the mouse hippocampus after administration of an extract of the present invention (Example) or donepezil (positive control) (#: p<0.05)
스코폴라민으로 유발된 마우스 건망증 모델에서 향청란 추출물을 투여한 경우, CREB 및 ERK 단백질 발현 정도를 유의성 있게 증가시켰다. 이에 따라, CREB-ERK 경로의 활성화를 통해 기억 장애를 약화시킬 수 있음을 확인하였다.In a mouse model of scopolamine-induced forgetfulness, administration of Hyangcheong orchid extract significantly increased the expression levels of CREB and ERK proteins. Accordingly, it was confirmed that memory impairment can be attenuated through activation of the CREB-ERK pathway.
<실험예 4> 향청란 추출물의 신사물 인지 개선 효과<Experimental Example 4> Effect of Hyangcheongran Extract's Recognition Improvement in New Things
향청란 추출물의 신사물 인지 개선을 통한 조현병 치료 효능을 확인하기 위해, 신사물 인지 시험법을 40×40×40 cm의 open field box안에서 실시하였다. 실험동물을 box에 적응시키기 위하여 2일 동안 실험동물을 box에서 10분간 자유로이 머물게 하였다. 실험실시 3일째 되는 날, box에 동일한 물체 두 개를 벽으로부터 5cm 씩 떨어진 곳에 위치해 놓고, 약물(향청란 추출물 또는 클로자핀) 처치 후 MK-801로 조현병을 유발시킨 마우스를 box 중앙에 놓고 5분간 물체에 대해 탐색을 시켰다. 탐색 2시간 후 box 안의 물체 중 한 개를 새로운 물체로 바꾼 뒤, 다시 box 중앙에 실험동물을 놓고 5분간 각 물체에 대하여 탐색하게 하였다. 5분 동안 마우스가 기존에 있던 물체(familiar object)와 새로운 물체(novel object)에 대해서 접촉, 냄새 맡기, 핥기 등의 탐색 행동을 보이는 시간을 측정한 후, 각 물체에 대한 탐색 시간의 비율(% of exploration time)과 전체 탐색시간을 계산하였다. 새로운 물체에 대한 탐색 시간 비율이 높을수록 학습 및 기억 능력이 좋음을 나타낸다.In order to confirm the treatment efficacy of schizophrenia through the improvement of cognition of the Hyangcheongran extract, the cognition test method for synesthesia was carried out in an open field box of 40 × 40 × 40 cm. In order to acclimatize the animals to the box, the animals were allowed to freely stay in the box for 10 minutes for 2 days. On the third day of the laboratory, place two identical objects in a box 5cm apart from the wall, and after treatment with drugs (hyangcheong orchid extract or clozapine), place the mouse that induced schizophrenia with MK-801 in the center of the box and place the object for 5 minutes was explored for After 2 hours of exploration, one of the objects in the box was replaced with a new object, and the experimental animals were placed in the center of the box again and each object was searched for 5 minutes. After measuring the time for which the mouse exhibits search behaviors such as touching, sniffing, and licking for an existing object (familiar object) and a new object (novel object) for 5 minutes, the percentage of the search time for each object (%) of exploration time) and total exploration time were calculated. A higher rate of search time for new objects indicates better learning and memory abilities.
도 6은 본 발명의 향청란 추출물 투여 후, 마우스 조현병 모델에서 신사물 인지 시험법을 통해 탐색 시간을 백분율로 계산하여 신사물 인지 개선 효능을 확인한 결과를 나타낸 그래프이다. ###은 음성대조군 대비 본 발명에 따른 향청란 추출물을 200 또는 400 mg/kg 투여한 군이 기존 물체보다 새로운 물체를 탐색하는 시간(%)이 통계적으로 유의미하게 증가하였다는 것으로, ###은 p < 0.001임을 의미한다.6 is a graph showing the results of confirming the efficacy of improving cognition of new things by calculating the search time as a percentage through the cognition test method for new things in a mouse schizophrenia model after administration of the hyangcheongran extract of the present invention. ### indicates that the time (%) to search for a new object was statistically significantly increased in the group administered 200 or 400 mg/kg of the Hyangcheongran extract according to the present invention compared to the negative control group, and ### It means that p < 0.001.
그 결과, MK-801로 유발된 마우스 조현병 모델에서 향청란 추출물을 투여한 경우, 기존의 적응 물체보다 새로운 물체를 탐색하는 시간이 증가되어, 향청란 추출물이 조현병 모델에서 신사물인지 개선 효과를 나타냄을 확인하였다.As a result, when Hyangcheong orchid extract was administered in the MK-801-induced mouse schizophrenia model, the time to search for a new object was increased compared to the existing adaptive object, indicating that the Hyangcheong orchid extract improved whether the extract was a novelty in the schizophrenia model. was confirmed.
<실험예 5> 향청란 추출물의 과행동 개선 효과<Experimental Example 5> Hyperactivity improvement effect of Hyangcheongran extract
실험동물의 과행동(hyperlocomotion) 활성을 평가하기 위하여 열린공간 시험을 실시하였다. 실험 동물을 open field box(40×40×40 cm의 아크릴 박스) 중앙에 놓고 30분간 Viewer 3.0(Biobserve, germany)을 활용하여 설정시간 동안의 이동거리 등을 측정하였다.An open space test was performed to evaluate the hyperlocomotion activity of experimental animals. The experimental animal was placed in the center of an open field box (40×40×40 cm acrylic box) and the moving distance during the set time was measured using Viewer 3.0 (Biobserve, germany) for 30 minutes.
도 7은 본 발명의 향청란 추출물(실시예) 또는 클로자핀(양성대조군)을 일주일간 투여 후, 마우스 조현병 모델에서 열린공간 시험으로 이동거리를 분석하여 과행동 개선 효능을 확인한 결과를 나타낸 그래프이다. #은 음성대조군 대비 본 발명에 따른 향청란 추출물을 400 mg/kg 투여한 군, 양성대조군인 클로자핀을 1 mg/kg 투여한 군의 총 이동거리가 통계적으로 유의미하게 감소하였다는 것으로, #은 p < 0.05, ###은 p < 0.001 임을 의미한다.7 is a graph showing the results of confirming the hyperactivity improvement effect by analyzing the moving distance in an open space test in a mouse schizophrenia model after administration of the hyangcheongran extract (Example) or clozapine (positive control group) of the present invention for one week. # indicates that the total movement distance of the group administered 400 mg/kg of the Hyangcheongran extract according to the present invention and 1 mg/kg of the positive control, clozapine, was statistically significantly decreased compared to the negative control group, and # is p < 0.05, ### means p < 0.001.
도 7에 나타난 바와 같이, MK-801로 유발된 마우스 조현병 모델에서 향청란 추출물을 투여한 경우, 총 이동거리가 감소하여, 과행동을 개선하는 효과가 있음을 확인하였다.As shown in FIG. 7 , when the Hyangcheongran extract was administered in the MK-801-induced mouse schizophrenia model, it was confirmed that the total movement distance was reduced, thereby improving hyperactivity.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특히 청구범위에 나타나 있으며, 그와 동등한 범위내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated not in the foregoing description, but in particular in the claims, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (11)
상기 조현병은 포스포디에스테라제 타입 10A(PDE10A)에 의해 매개되는 것을 특징으로 하는 약학적 조성물.According to claim 1,
The pharmaceutical composition, characterized in that the schizophrenia is mediated by phosphodiesterase type 10A (PDE10A).
상기 향청란 추출물은 포스포디에스테라제 타입 10A 활성을 억제하여 조현병 예방 또는 치료 효과를 나타내는 것을 특징으로 하는 약학적 조성물.According to claim 1,
The Hyangcheongran extract is a pharmaceutical composition, characterized in that it inhibits the phosphodiesterase type 10A activity to exhibit a preventive or therapeutic effect on schizophrenia.
상기 향청란 추출물은 향청란 잎 또는 전초로부터 추출되는 것을 특징으로 하는 약학적 조성물.According to claim 1,
The hyangcheongran extract is a pharmaceutical composition, characterized in that extracted from hyangcheongran leaves or outpost.
상기 향청란 추출물은 물, 탄소수 1 내지 탄소수 4의 알코올 또는 이들의 혼합용매로 추출하는 것을 특징으로 하는 약학적 조성물.According to claim 1,
The hyangcheongran extract is a pharmaceutical composition, characterized in that extracted with water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof.
상기 건강기능식품은 정제, 캡슐제, 환제, 액제, 분말 또는 과립 형태의 식품인 것을 특징으로 하는 건강기능식품 조성물.9. The method of claim 8,
The health functional food is a health functional food composition, characterized in that the food in the form of tablets, capsules, pills, liquids, powders or granules.
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