KR102649776B1 - Composition for improving memory and preventing, ameliorating or treating cognitive impairment comprising complex of Atractylodes macrocepala and Rumex acetosa extract as effective component - Google Patents
Composition for improving memory and preventing, ameliorating or treating cognitive impairment comprising complex of Atractylodes macrocepala and Rumex acetosa extract as effective component Download PDFInfo
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- KR102649776B1 KR102649776B1 KR1020240006881A KR20240006881A KR102649776B1 KR 102649776 B1 KR102649776 B1 KR 102649776B1 KR 1020240006881 A KR1020240006881 A KR 1020240006881A KR 20240006881 A KR20240006881 A KR 20240006881A KR 102649776 B1 KR102649776 B1 KR 102649776B1
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- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방, 개선 또는 치료용 조성물에 관한 것으로, 상기 백출 및 수영 추출물의 복합물은 해마 신경세포에서 CREB 인산화를 촉진할 뿐만 아니라, 뇌신경세포주에서 세포 보호 효과가 있으며, LTP(Long-term potentiation)가 형성될 때 나타나는 신경세포 말단의 리모델링(synapse remodeling)에 영향을 주어 시냅스 재구성 인자 및 신경 가소성 인자의 단백질 발현량을 증가시키고, 동물모델의 행동 평가에서 단기/장기 기억능력을 향상시키는 것을 확인함으로써, 기억력 증진 및 인지기능장애의 예방, 개선 또는 치료용 건강기능식품, 의약품 또는 사료첨가제료 유용하게 사용될 수 있다.The present invention relates to a composition for improving memory and preventing, improving or treating cognitive dysfunction comprising a complex of Baekchul and Suyeong extracts as an active ingredient, wherein the complex of Baekchul and Suyeong extracts promotes CREB phosphorylation in hippocampal neurons. In addition, it has a cytoprotective effect on brain nerve cell lines and affects synapse remodeling of nerve cell terminals that occurs when long-term potentiation (LTP) is formed, increasing protein expression of synaptic reorganization factors and neuroplasticity factors. By confirming that it improves short-term/long-term memory ability in behavioral evaluations of animal models, it can be usefully used as a health functional food, medicine, or feed additive for memory enhancement and prevention, improvement, or treatment of cognitive dysfunction.
Description
본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for improving memory and preventing, improving or treating cognitive dysfunction, comprising a complex of Baekchul and Suyeong extracts as an active ingredient.
인지기능장애 (Cognitive impairment)는 뇌질환, 뇌상해, 중독, 노령화 등으로 인한 정신적, 행동학적 장애 및 내분비계의 이상과 대사 영양학적 이상, 약물 등에 따른 정신적인 질환을 포괄하는 의미로서, 증상의 정도에 따라 일시적 단기 기억 장애로 판명되는 건망증(Amnesia)뿐만 아니라, 판단력 장애를 유발하는 인지 기능 장애 및 치매(Dementia) 등 신경변성 질환에서도 나타나는 뇌질환의 일종이다. 그 중에서, 경도 인지 장애란 동일한 연령대에 비하여 인지 능력이 저하된 상태를 말한다. 기억력, 언어 능력, 판단력 등의 인지 영역이 저하된 상태이다. 경도 인지 장애는 다양한 원인과 증상을 가지는 증후군이며 노화에 의한 퇴행성, 혈관성 원인에 의한 혈관성, 우울이나 불안 등 정신과적 요인 및 기타 내과적 요인 등의 여러 가지 원인으로 유발되는 것으로 알려져 있다.Cognitive impairment refers to mental and behavioral disorders caused by brain disease, brain injury, addiction, aging, etc., and mental disorders caused by endocrine system abnormalities, metabolic and nutritional abnormalities, drugs, etc. Depending on the severity, it is a type of brain disease that occurs not only in amnesia, which is a temporary short-term memory disorder, but also in neurodegenerative diseases such as cognitive dysfunction and dementia that cause impaired judgment. Among them, mild cognitive impairment refers to a state in which cognitive ability is reduced compared to people of the same age. Cognitive areas such as memory, language ability, and judgment are deteriorated. Mild cognitive impairment is a syndrome with various causes and symptoms, and is known to be caused by various causes such as degeneration due to aging, vascularity due to vascular causes, psychiatric factors such as depression or anxiety, and other medical factors.
한편, 고령화 사회로 이어지면서 노인인구 수가 급격하게 증가하였는데, 이러한 사회 환경에서 노인성 치매 및 파킨슨 질환이 퇴행성 중추신경계 질환으로 인정되고, 그 환자 수가 날로 증가함에 따라 사회적 이슈가 증가되면서 이에 따른 인지기능장애의 예방, 개선 및 치료에 대한 중요성이 점점 더 부각되고 있다. Meanwhile, with the aging society, the number of elderly people has increased rapidly. In this social environment, senile dementia and Parkinson's disease are recognized as degenerative central nervous system diseases, and as the number of patients increases day by day, social issues increase and the resulting cognitive dysfunction increases. The importance of prevention, improvement, and treatment is increasingly highlighted.
알츠하이머성 질환은 콜린성, 아드레날린성, GABA성 및 글루타메이트성 신경 등 거의 모든 신경에 이상이 초래되나, 특히 콜린성 신경의 손상 및 소실이 가장 심각한 것으로 연구되어져 있다. 인지능력이 점진적으로 소실되는 질환인 노인성 치매는 중추신경계의 콜린성 신경세포의 활성과도 관련이 있으며, 이는 뇌에서 아세틸콜린 및 콜린 아세틸트랜스퍼라제(choline acetyltransferase) 활성의 현저한 저하가 주된 원인으로 알려져 있다. 이에 따른 이상적인 콜린성 신경을 회복 또는 개선하고자 하는 방향으로 치료제 개발이 활발하게 이루어지고 있으나, 아직까지는 미비한 실정이다.Alzheimer's disease causes abnormalities in almost all nerves, including cholinergic, adrenergic, GABAergic, and glutamatergic nerves, but damage and loss of cholinergic nerves has been studied to be the most serious. Senile dementia, a disease in which cognitive ability is gradually lost, is also related to the activity of cholinergic neurons in the central nervous system, and is known to be mainly caused by a significant decrease in the activity of acetylcholine and choline acetyltransferase in the brain. . Accordingly, the development of therapeutic agents to restore or improve the ideal cholinergic nerve is actively being developed, but is still insufficient.
한편, 백출(Atractylodes macrocepala)은 삽주 뿌리를 손질하여 말린 것으로, 산개 또는 천개라고도 한다. 매우 쓰며, 약간의 단맛이 있으며, 속이 희며 알이 찬 것이 좋고 특히 가을에 채취한 것이 효능이 좋다고 알려져 있다. Meanwhile, Baekchul ( Atractylodes macrocepala ) is made by trimming and drying the roots of the spatula, and is also called sangae or cheonggae. It is very bitter, has a slightly sweet taste, is white on the inside and has cold eggs, and is known to be especially effective when collected in the fall.
수영(Rumex acetosa)을 포함하는 Rumex 속 식물은 마디풀과(Polygonaceae) 중 가장 큰 속(sp.)으로 전 세계, 주로 북반구 온대지역에 약 200여 종이 분포한다. 그 중 우리나라에는 수영 및 소금쟁이를 포함하여 총 10여 종이 분포되어 있으며, 전국 산야에 자라는 다년초이다. 성체는 30~80cm로 자란다. 줄기에 능이 있고 잎과 더불어 신맛이 난다. 줄기에 달린 잎은 호생하고 장타원형을 밑부분의 것은 짧은 잎자루가 있으나 위로 갈수록 없어진다. 원줄기의 가지 끝에 길이 10~30cm의 원추화서 형태이고 짧은 꽃자루가 있다. 연한 경생엽을 식용으로 하며 민간에서는 뿌리를 옴약(개선충약)으로 사용한다. 수영의 잎은 유럽이나 미국에 존재하는 강한 신맛이 나는 시금치와 비슷하게 생긴 것으로 알려진 식물이다. 수영(R. acetosa) 추출물은 해열, 이뇨, 살충, 항균, 항암 활성 등의 효능이 있다고 알려져 있다. 또한, 수영을 달인 물은 관절염, 위염 또는 위궤양 등의 치료에 민간요법으로 쓰이는 것으로 보고되고 있다. 수영의 성분으로는 잎에 비텍신(vitexin) 및 쿼시트린(quercitrin)이 함유되어 있고, 뿌리에 크리소파놀(chrysophanol)을 비롯한 안트라퀴논(anthraquinone) 및 그 배당체가 함유되어 있으며, 지상부에 오리엔틴(orientin)을 비롯한 플라보노이드류 및 그 배당체가 함유되어 있다고 알려져 있다.The Rumex genus, which includes Rumex acetosa, is the largest genus (sp.) in the Polygonaceae family and has about 200 species distributed around the world, mainly in temperate regions of the Northern Hemisphere. Among them, there are a total of 10 species distributed in Korea, including swimming and water striders, and it is a perennial herb that grows in mountains and fields across the country. Adults grow to 30~80cm. There are ridges on the stem and a sour taste along with the leaves. The leaves on the stem grow alternately and are oblong in shape. The ones at the bottom have short petioles, but they disappear as they go up. It is in the form of a panicle with a length of 10 to 30 cm at the end of the branch of the main stem and has a short peduncle. The tender cauline leaves are edible, and in the private sector, the roots are used as a scabicide. Suyeong's leaves are a plant known to resemble spinach with a strong sour taste found in Europe and the United States. Suyeong (R. acetosa) extract is known to have antipyretic, diuretic, insecticidal, antibacterial, and anticancer activities. In addition, it is reported that swimming water is used as a folk remedy to treat arthritis, gastritis, or stomach ulcers. The ingredients of Suyeong include vitexin and quercitrin in the leaves, anthraquinone and its glycosides including chrysophanol in the roots, and orientin in the aerial part. It is known to contain flavonoids, including orientin, and their glycosides.
인지기능장애 또는 기억력 관련 기술로는 한국공개특허 제2023-0174777호에 육군자탕을 유효성분으로 포함하는 기억력 증진 및 인지기능 장애의 예방, 개선 또는 치료용 조성물이 개시되어 있고, 한국등록특허 제1753057호에 인지기능장애 또는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물이 개시되어 있으나, 아직까지는 본 발명의 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방, 개선 또는 치료용 조성물에 대하여 개시된 바 없다.As a technology related to cognitive dysfunction or memory, Korean Patent Publication No. 2023-0174777 discloses a composition for improving memory and preventing, improving or treating cognitive dysfunction containing Gungunjatang as an active ingredient, and Korean Patent No. 1753057. Although pharmaceutical compositions for the prevention or treatment of cognitive dysfunction or degenerative brain diseases are disclosed, there are still no pharmaceutical compositions for improving memory and preventing, improving or treating cognitive dysfunction containing the complex of Baekchul and Sooyoung extracts of the present invention as an active ingredient. No therapeutic composition has been disclosed.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방, 개선 또는 치료용 조성물을 제공하고, 상기 백출 및 수영 추출물의 복합물은 해마 신경세포에서 CREB 인산화를 촉진할 뿐만 아니라, 뇌신경 세포주에서 세포 보호 효과가 있으며, LTP(Long-term potentiation)가 형성될 때 나타나는 신경세포 말단의 리모델링(synapse remodeling)에 영향을 주어 시냅스 재구성 인자 및 신경 가소성 인자의 단백질 발현량을 증가시키고, 동물모델의 행동 평가에서 단기/장기 기억능력을 향상시키는 것을 확인함으로써, 본 발명을 완성하였다.The present invention was developed in response to the above-mentioned needs, and the present invention provides a composition for improving memory and preventing, improving or treating cognitive dysfunction, comprising a complex of Baekchul and Suyeong extracts as an active ingredient, and providing a composition for preventing, improving or treating cognitive dysfunction. The extract complex not only promotes CREB phosphorylation in hippocampal neurons, but also has a cytoprotective effect in brain nerve cell lines, and affects synapse remodeling of nerve cell terminals that occurs when long-term potentiation (LTP) is formed. The present invention was completed by increasing the protein expression levels of synaptic reorganization factors and neuroplasticity factors and confirming that short-term/long-term memory ability was improved in behavioral evaluations of animal models.
상기 목적을 달성하기 위하여, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 인지기능장애의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cognitive dysfunction containing a complex of Baekchul and Suyeong extract as an active ingredient.
또한, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for improving memory and preventing or improving cognitive dysfunction, comprising a complex of Baekchul and Suyeong extract as an active ingredient.
또한, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 인지기능장애의 예방 또는 치료용 수의학적 조성물을 제공한다.Additionally, the present invention provides a veterinary composition for the prevention or treatment of cognitive dysfunction comprising a complex of Baekchul and Suyeong extract as an active ingredient.
또한, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방 또는 개선용 사료 첨가제를 제공한다.In addition, the present invention provides a feed additive for improving memory and preventing or improving cognitive dysfunction, comprising a complex of Baekchul and Suyeong extracts as an active ingredient.
본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방, 개선 또는 치료용 조성물에 관한 것으로, 상기 백출 및 수영 추출물의 복합물은 해마 신경세포에서 CREB 인산화를 촉진할 뿐만 아니라, 뇌신경 세포주에서 세포 보호 효과가 있으며, LTP(Long-term potentiation)가 형성될 때 나타나는 신경세포 말단의 리모델링(synapse remodeling)에 영향을 주어 시냅스 재구성 인자 및 신경 가소성 인자의 단백질 발현량을 증가시키고, 동물모델의 행동 평가에서 단기/장기 기억능력을 향상시키는 효과가 있다.The present invention relates to a composition for improving memory and preventing, improving or treating cognitive dysfunction comprising a complex of Baekchul and Suyeong extracts as an active ingredient, wherein the complex of Baekchul and Suyeong extracts promotes CREB phosphorylation in hippocampal neurons. In addition, it has a cytoprotective effect in brain nerve cell lines and affects synapse remodeling of nerve cell terminals that occurs when long-term potentiation (LTP) is formed, increasing protein expression of synaptic reorganization factors and neuroplasticity factors. It has the effect of improving short-term and long-term memory ability in behavioral evaluations of animal models.
도 1은 SH-SY5Y 세포에서, 백출 추출물, 수영 추출물 및 백출+수영 복합 추출물의 세포독성을 확인한 결과이다.
도 2는 SH-SY5Y 세포에 스코폴라민(SCO)을 처리하여 유발된 세포사멸에 대한 백출 추출물, 수영 추출물 및 백출+수영 복합 추출물의 세포보호 효과를 확인한 결과이다. ##은 아무것도 처리하지 않은 대조군(Control) 대비 스코폴라민 처리군의 세포보호 효과가 통계적으로 유의미하게 감소하였다는 것으로, p<0.01이고, *, **, ***은 스코폴라민 처리군 대비 백출 추출물, 수영 추출물 및 백출+수영 복합 추출물 처리군의 세포보호 효과가 통계적으로 유의미하게 증가하였다는 것으로, *은 p<0.05이고, **은 p<0.01이며, ***은 p<0.001이다.
도 3은 태아 쥐의 해마(hippocampus)를 1차 배양(primary culture)한 뇌 세포에 백출 추출물, 수영 추출물 및 백출+수영 복합 추출물을 처리한 후, PSD95, AMPA 수용체(subunits: GluA1) 및 NMDA 2A 수용체(NR2A) 단백질 발현량 변화를 확인한 웨스턴 블랏 결과이다.
도 4는 태아 쥐의 해마(hippocampus)를 1차 배양(primary culture)한 뇌 세포에 2:1의 중량비로 혼합한 백출+수영 복합 추출물을 농도별로 처리한 후, PSD95, AMPA 수용체(subunits: GluA1) 및 NMDA 2A 수용체(NR2A) 단백질 발현량 변화를 확인한 웨스턴 블랏 결과이다.
도 5는 SD-랫트에 백출 및 수영 추출물의 복합물을 투여한 후, 모리스 수중 미로 실험(Morris water maze test)으로, 장기(A) 및 단기(B) 기억력에 미치는 효과를 확인한 결과이다. *, ***은 대조군(Control) 대비 본 발명의 백출 및 수영 추출물의 복합물을 투여한 군의 장기 또는 단기 기억력이 통계적으로 유의미하게 증가하였다는 것으로, *은 p<0.05이고, ***은 p<0.001이다.
도 6은 SD-랫트에 백출 및 수영 추출물의 복합물을 투여한 후, 모리스 수중 미로 실험(Morris water maze test)의 단서탐색실험(Probe test)으로, 장기 기억력에 미치는 효과를 확인한 결과이다. **, ***은 대조군(Control) 대비 본 발명의 백출 및 수영 추출물의 복합물을 투여한 군의 도피대가 있었던 분면에서의 수영시간이 통계적으로 유의미하게 증가하였다는 것으로, **은 p<0.01이고, ***은 p<0.001이다.
도 7은 SD-랫트에 백출 및 수영 추출물의 복합물을 투여한 후, 적출한 해마 조직에서, NMDA 수용체(Subunits: NR2A, NR2B), AMPA 수용체(subunits: GluA1) 및 PSD95 단백질의 발현량 변화를 확인한 결과이다. *, **, ***은 대조군 대비 백출 및 수영 추출물의 복합물 투여군의 NMDA 수용체(Subunits: NR2A, NR2B), AMPA 수용체(subunits: GluA1) 및 PSD95 단백질의 발현량이 통계적으로 유의미하게 증가하였다는 것으로, *은 p<0.05이고, **은 p<0.01이며, ***은 p<0.001이다.
도 8은 SD-랫트에 백출 및 수영 추출물의 복합물을 투여한 후, 적출한 해마 조직에서, BDNF 단백질의 발현량 변화(A) 및 ERK, CaMKII 인산화(B)를 확인한 결과이다. **, ***은 대조군 대비 백출 및 수영 추출물의 복합물 투여군의 BDNF 단백질의 발현량 및 ERK, CaMKII 인산화가 통계적으로 유의미하게 증가하였다는 것으로, **은 p<0.01이며, ***은 p<0.001이다.Figure 1 shows the results of confirming the cytotoxicity of Baekchul extract, Suyoung extract, and Baekchul + Suyoung complex extract in SH-SY5Y cells.
Figure 2 shows the results confirming the cytoprotective effects of Baekchul extract, Suyeong extract, and Baekchul + Suyeong complex extract against apoptosis induced by treatment of SH-SY5Y cells with scopolamine (SCO). ## indicates a statistically significant decrease in the cytoprotective effect of the scopolamine-treated group compared to the untreated control group (Control), p < 0.01, and *, **, *** are the scopolamine-treated group. Compared to Baekchul extract, Suyoung extract, and Baekchul + Suyoung combined extract treatment group, the cytoprotective effect was statistically significantly increased. * means p<0.05, ** means p<0.01, and *** means p<0.001. am.
Figure 3 shows the levels of PSD95, AMPA receptor (subunits: GluA1), and NMDA 2A after treating brain cells obtained from primary culture of the hippocampus of fetal rats with Baekchul extract, Suyoung extract, and Baekchul + Suyoung combined extract. This is a Western blot result confirming the change in receptor (NR2A) protein expression level.
Figure 4 shows that after treating brain cells obtained from primary culture of the hippocampus of fetal rats with a Baekchul + Sooyoung complex extract mixed at a weight ratio of 2:1, PSD95, AMPA receptor (subunits: GluA1) ) and Western blot results confirming changes in the protein expression level of NMDA 2A receptor (NR2A).
Figure 5 shows the results of administering a complex of Baekchul and Sooyoung extracts to SD-rats and then confirming the effect on long-term (A) and short-term (B) memory through a Morris water maze test. *, *** indicate a statistically significant increase in long-term or short-term memory in the group administered the complex of Baekchul and Sooyoung extracts of the present invention compared to the control group, * means p < 0.05, and *** means p<0.001.
Figure 6 shows the results of a Morris water maze test cue search test (Probe test) confirming the effect on long-term memory after administering a complex of Baekchul and Suyeong extracts to SD-rats. **, *** indicate a statistically significant increase in swimming time in the quadrant where the escape zone was in the group administered the complex of Baekchul and swimming extracts of the present invention compared to the control group, ** indicates p < 0.01 and *** is p<0.001.
Figure 7 shows changes in the expression levels of NMDA receptors (Subunits: NR2A, NR2B), AMPA receptors (subunits: GluA1), and PSD95 proteins in the extracted hippocampal tissue after administration of a complex of Baekchul and Suyoung extracts to SD-rats. It is a result. *, **, *** indicate a statistically significant increase in the expression levels of NMDA receptors (Subunits: NR2A, NR2B), AMPA receptors (subunits: GluA1), and PSD95 proteins in the group administered the complex of Baekchul and Sooyoung extracts compared to the control group. , * is p<0.05, ** is p<0.01, *** is p<0.001.
Figure 8 shows the results of confirming changes in the expression level of BDNF protein (A) and ERK and CaMKII phosphorylation (B) in hippocampal tissue extracted after administering a complex of Baekchul and Suyoung extracts to SD-rats. **, *** indicate a statistically significant increase in the expression level of BDNF protein and ERK, CaMKII phosphorylation in the group administered the combination of Baekchul and Suyeong extract compared to the control group, ** is p < 0.01, and *** is p It is <0.001.
본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 인지기능장애의 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of cognitive dysfunction comprising a complex of Baekchul and Suyeong extract as an active ingredient.
상기 백출 추출물은 삽주의 뿌리 추출물인 것이 바람직하고, 수영 추출물은 수영 잎 추출물인 것이 바람직하지만 이에 한정하지 않는다.The Baekchul extract is preferably a root extract of Shochu, and the Suyeong extract is preferably a Suyeong leaf extract, but is not limited thereto.
상기 백출 및 수영 추출물의 복합물은 하기의 단계를 포함하는 방법에 의해 제조할 수 있으나, 이에 한정하지 않는다:The complex of the Baekchul and Suyeong extracts can be prepared by a method comprising the following steps, but is not limited to this:
(1) 건조 백출 또는 수영 각각에 대하여, 추출용매를 가하여 추출하는 단계;(1) Extracting by adding an extraction solvent to each of the dried Baekchul or Suyeong;
(2) 상기 단계 (1)의 백출 또는 수영 추출액을 각각 여과하는 단계; (2) filtering the Baekchul or Suyeong extract of step (1), respectively;
(3) 상기 단계 (2)의 여과한 백출 또는 수영 추출액을 건조하여 백출 추출물 및 수영 추출물을 각각 제조하는 단계; 및 (3) drying the filtered Baekchul or Suyeong extract of step (2) to prepare Baekchul extract and Suyeong extract, respectively; and
(4) 상기 단계 (3)에서 제조한 백출 추출물 및 수영 추출물을 혼합하여 백출 및 수영 추출물의 복합물을 획득하는 단계.(4) Mixing the Baekchul extract and Suyeong extract prepared in step (3) to obtain a composite of Baekchul and Suyeong extract.
상기 단계 (1)에서 추출용매는 물, C1~C4의 저급 알코올 또는 이들의 혼합물 중에서 선택하는 것이 바람직하며, 더 바람직하게는 물 또는 에탄올이지만 이에 한정하지 않는다. 상기 제조방법에 있어서, 추출방법은 열수 추출, 침지 추출, 환류 냉각 추출 및 초음파 추출 등의 당 업계에 공지된 모든 통상적인 방법을 이용할 수 있다. 상기 추출용매는 백출 또는 수영 중량의 10~40배 첨가하여 추출하는 것이 바람직하다. 추출온도는 20~110℃인 것이 바람직하나 이에 한정하지 않는다. 또한, 추출시간은 1~5시간인 것이 바람직하며, 2~4시간이 더욱 바람직하지만 이에 한정하지 않는다. 상기 단계 (3)에서, 건조는 감압건조, 진공건조, 비등건조, 분무건조 또는 동결건조하는 것이 바람직하며, 더 바람직하게는 동결건조이나 이에 한정하지 않는다.In step (1), the extraction solvent is preferably selected from water, C 1 -C 4 lower alcohol, or a mixture thereof, more preferably water or ethanol, but is not limited thereto. In the above manufacturing method, all conventional methods known in the art can be used as the extraction method, such as hot water extraction, immersion extraction, reflux cooling extraction, and ultrasonic extraction. It is preferable to extract the extraction solvent by adding 10 to 40 times the weight of Baekchul or Swimming. The extraction temperature is preferably 20 to 110°C, but is not limited thereto. In addition, the extraction time is preferably 1 to 5 hours, and more preferably 2 to 4 hours, but is not limited thereto. In step (3), the drying is preferably reduced pressure drying, vacuum drying, boiling drying, spray drying, or freeze drying, and more preferably freeze drying, but is not limited thereto.
상기 단계 (4)에서 획득한 백출 및 수영 추출물의 복합물은 백출 추출물 및 수영 추출물을 0.5~2.5:1, 더 바람직하게는 1.5~2.5:1의 중량비, 가장 바람직하게는 2:1의 중량비로 혼합한 것이지만 이에 한정하는 것은 아니다.The complex of Baekchul and Suyeong extract obtained in step (4) is mixed with Baekchul extract and Suyeong extract at a weight ratio of 0.5 to 2.5:1, more preferably 1.5 to 2.5:1, and most preferably 2:1. However, it is not limited to this.
상기 인지기능장애는 치매(dementia), 학습장애(learning disorder), 실인증(agnosia), 건망증(amnesia), 실어증(aphasia), 실행증(apraxia) 또는 섬망(delirium), 경도인지장애(mild cognitive impairment) 및 빈스완거 병(Binswangers disease) 중에서 선택된 어느 하나인 것이 바람직하지만 이에 한정하지 않고, 상기 치매는 알츠하이머성 치매, 혈관성 치매, 루이소체 치매, 전두엽 치매, 의미 치매(semantic dementia) 및 다발성 경색성 치매(Multi infarct dementia) 중에서 선택된 어느 하나인 것이 바람직하지만, 이에 한정하지 않는다.The cognitive dysfunction includes dementia, learning disorder, agnosia, amnesia, aphasia, apraxia or delirium, and mild cognitive impairment. ) and Binswanger disease, but is not limited thereto, and the dementia includes Alzheimer's dementia, vascular dementia, Lewy body dementia, frontal lobe dementia, semantic dementia, and multiple infarct dementia. (Multi infarct dementia) is preferably one selected from among, but is not limited to this.
상기 유효성분 이외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 더 포함할 수 있으나, 이에 한정하지 않는다.In addition to the above active ingredients, pharmaceutically acceptable carriers, excipients, or diluents may be further included, but are not limited thereto.
또한, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방 또는 개선용 건강기능식품 조성물에 관한 것이다.Additionally, the present invention relates to a health functional food composition for improving memory and preventing or improving cognitive dysfunction, comprising a complex of Baekchul and Suyeong extracts as an active ingredient.
상기 건강기능식품 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽 및 음료 중에서 선택된 어느 하나의 제형으로 제조되는 것이 바람직하지만 이에 한정하는 것은 아니다. 본 발명의 건강기능식품 조성물은 백출 및 수영 추출물의 복합물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 혼합하여 제조될 수 있고, 통상적인 방법에 따라 적절하게 제조될 수 있다. 상기 백출 및 수영 추출물의 복합물을 첨가할 수 있는 식품의 예로는 캐러멜, 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 수프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 중에서 선택된 어느 하나의 형태일 수 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다. 즉, 상기 식품의 종류에는 특별한 제한은 없다. 상기 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 및 천연 풍미제, 착색제 및 증진제(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. 또한, 천연 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 상기의 성분은 독립적으로 또는 조합하여 사용할 수 있다. The health functional food composition is preferably manufactured in a dosage form selected from powder, granule, pill, tablet, capsule, candy, syrup and beverage, but is not limited thereto. The health functional food composition of the present invention can be prepared by adding the complex of Baekchul and Suyeong extract as is or by mixing it with other foods or food ingredients, and can be prepared appropriately according to conventional methods. Examples of foods to which the complex of Baekchul and Sooyoung extracts can be added include caramel, meat, sausages, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, and various soups. , it may be in any form selected from beverages, teas, drinks, alcoholic beverages, and vitamin complexes, and includes all health functional foods in the conventional sense. That is, there are no particular restrictions on the type of food. The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, and protective colloidal thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Additionally, it may contain pulp for the production of natural fruit juice and vegetable drinks. The above components can be used independently or in combination.
본 발명의 건강기능식품 조성물은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있으며, 상기 천연 탄수화물은 포도당, 과당과 같은 단당류, 말토스, 슈크로스와 같은 이당류, 덱스트린, 사이클로 덱스트린과 같은 다당류, 자일리톨, 소르비톨, 에리트리톨 등의 당 알코올이다. 상기 천연 탄수화물의 비율은 크게 중요하지 않지만, 본 발명의 조성물 100g에 대하여, 0.01~0.04g인 것이 바람직하고, 더욱 바람직하게는 0.02~0.03g을 포함하는 것이지만 이에 한정하지 않는다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.The health functional food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, and the natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, dextrin, and cyclodextrin. Polysaccharides such as xylitol, sorbitol, and erythritol are sugar alcohols. The ratio of the natural carbohydrate is not very important, but is preferably 0.01 to 0.04 g, more preferably 0.02 to 0.03 g, per 100 g of the composition of the present invention, but is not limited thereto. As sweeteners, natural sweeteners such as thaumatin and stevia extract, and synthetic sweeteners such as saccharin and aspartame can be used.
또한, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 인지기능장애의 예방 또는 치료용 수의학적 조성물에 관한 것이다.Additionally, the present invention relates to a veterinary composition for the prevention or treatment of cognitive dysfunction comprising a complex of Baekchul and Suyeong extract as an active ingredient.
본 발명의 수의학적 조성물은 통상의 방법에 따른 적절한 부형제 및 희석제를 더 포함할 수 있다. 본 발명의 수의학적 조성물에 포함될 수 있는 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 세탄올, 스테아릴알콜, 유동파라핀, 솔비탄모노스테아레이트, 폴리소르베이트 60, 메칠파라벤, 프로필파라벤 및 광물유를 들 수 있다. 본 발명에 따른 수의학적 조성물은 충진제, 항응집제, 윤활제, 습윤제, 향신료, 유화제, 방부제 등을 추가로 포함할 수 있는데, 본 발명에 따른 수의학적 조성물은 동물에 투여된 후 유효성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 잘 알려진 방법을 사용하여 제형화될 수 있고, 제형은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 용액, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 좌제, 멸균 주사용액, 멸균 외용제 등의 형태일 수 있다. 본 발명에 따른 수의학적 조성물의 유효한 양은 동물의 개체에 따라 적절하게 선택할 수 있다. 질환 내지 상태의 중증도, 개체의 연령, 체중, 건강상태 또는 성별에 따른 본 발명의 유효성분에 대한 민감도, 투여 경로, 투여 기간, 상기 조성물과 배합 또는 동시 사용되는 다른 조성물을 포함한 요소 및 기타 생리 내지 수의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The veterinary composition of the present invention may further include appropriate excipients and diluents according to conventional methods. Excipients and diluents that may be included in the veterinary composition of the present invention include 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, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, cetanol, stearyl alcohol, liquid paraffin, sorbitan monostearate. , polysorbate 60, methylparaben, propylparaben, and mineral oil. The veterinary composition according to the present invention may further include fillers, anti-aggregants, lubricants, wetting agents, spices, emulsifiers, preservatives, etc. The veterinary composition according to the present invention provides rapid and sustained release of the active ingredient after administration to an animal. or may be formulated using methods well known in the art to provide sustained release, the dosage form being powders, granules, tablets, capsules, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, It may be in the form of a suppository, sterile injectable solution, or sterile topical medication. The effective amount of the veterinary composition according to the present invention can be appropriately selected depending on the individual animal. Severity of the disease or condition, sensitivity to the active ingredient of the present invention depending on the individual's age, weight, health condition or gender, administration route, administration period, factors including other compositions mixed or used simultaneously with the composition, and other physiological or It can be determined based on factors well known in the veterinary field.
또한, 본 발명은 백출 및 수영 추출물의 복합물을 유효성분으로 포함하는 기억력 증진 및 인지기능장애의 예방 또는 개선용 사료 첨가제에 관한 것이다.Additionally, the present invention relates to a feed additive for improving memory and preventing or improving cognitive dysfunction, comprising a complex of Baekchul and Suyeong extracts as an active ingredient.
본 발명의 사료 첨가제는 사료관리법상의 보조사료에 해당한다. 본 발명에서 용어 '사료'는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미할 수 있다. 상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act. In the present invention, the term 'feed' may mean any natural or artificial diet, meal, etc., or a component of the meal, for or suitable for eating, ingestion, and digestion by animals. The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant feeds such as grains, roots and fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, cucurbits or grain by-products; Examples include animal feeds such as proteins, inorganic substances, fats and oils, minerals, oils and fats, single-cell proteins, zooplanktons or foods. These may be used alone or in combination of two or more types.
이하, 실시예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다. Hereinafter, the present invention will be described in more detail using examples. These examples are only for illustrating the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.
실시예Example 1. 백출 및 수영 추출물의 복합물 제조1. Preparation of a complex of Baekchul and Sooyoung extracts
건조된 수영 잎 300g에 9L 증류수를 첨가하여 100℃에서 3시간 동안 가열하여 열수 추출하였다. 상기 추출된 수영 잎 열수 추출물을 감압 농축 및 동결 건조하여 동결건조물 64.45g을 얻었다. 9L distilled water was added to 300g of dried Suyeong leaves and heated at 100°C for 3 hours to perform hot water extraction. The extracted hot water extract of Suyeong leaves was concentrated under reduced pressure and freeze-dried to obtain 64.45 g of lyophilisate.
백출(삽주 뿌리)의 건조 분말을 상기와 동일한 방법으로 추출하였다. 이후, 수영 추출물 및 백출 추출물을 표 1에 개시한 중량비로 혼합하여 효능을 확인하였다. The dried powder of Baekchul (Root root) was extracted in the same manner as above. Afterwards, the efficacy was confirmed by mixing Suyeong extract and Baekchul extract in the weight ratio shown in Table 1.
실시예 2. 태아 쥐의 해마(hippocampus) 신경세포 1차 배양(primary culture)Example 2. Primary culture of fetal rat hippocampus neurons
본 발명의 실시예에서 사용한 모든 세포는 1차 배양한 해마 신경세포(primary cultured Hippocampal neurons)이다. 해마 신경세포는 임신 18일에서 19일의 SD 랫트의 태아로부터 분리하였다. 분리한 해마 신경조직에 0.25% 트립신이 첨가된 HBSS(Hank's Balanced Salt Solution)에 넣어 37℃에서 10분 동안 반응시켰다. HBSS로 수회 세척한 후 1㎖ 피펫을 이용하여 조심스럽게 피펫팅하여 단일세포로 분리하였다. 분리된 세포는 폴리-L-리신(poly-L-lysine, 0.5mg/㎖)으로 미리 코팅해둔 배양 접시에 Neuro basal/B27 배지(0.5mM L-글루타민, 25μM 글루타메이트, 25μM 2-머캅토에탄올, 100U/㎖ 페니실린, 100㎍/㎖ 스트렙토마이신)을 채워 37℃, 5% CO2에서 배양하였다. 세포배양 4일 및 11일째에 배지를 교환하였고, 배양 14일째의 세포를 실험에 사용하였다.All cells used in the examples of the present invention are primary cultured hippocampal neurons. Hippocampal neurons were isolated from SD rat fetuses on days 18 and 19 of pregnancy. The separated hippocampal nerve tissue was placed in HBSS (Hank's Balanced Salt Solution) containing 0.25% trypsin and reacted at 37°C for 10 minutes. After washing several times with HBSS, the cells were separated into single cells by careful pipetting using a 1 ml pipette. The isolated cells were placed in Neuro basal/B27 medium (0.5mM L-glutamine, 25μM glutamate, 25μM 2-mercaptoethanol, 100U/ml penicillin, 100㎍/ml streptomycin) and cultured at 37°C and 5% CO 2 . The medium was changed on the 4th and 11th days of cell culture, and cells on the 14th day of culture were used in the experiment.
실시예Example 3. 태아 쥐의 해마 신경세포에서 CREB 인산화 수준 확인3. Confirmation of CREB phosphorylation level in hippocampal neurons of fetal rats
14일 동안 배양한 1차 배양 해마 신경세포는 시료 처리 1시간 전에 B-27이 없는 배지로 교환하였다. 양성대조군으로는 AMPA 수용체(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor)의 작용제인 AMPA를 100μM 사용하였으며, 백출 추출물, 수영 추출물 및 이들(백출+수영)의 복합 추출물(중량비 1:1)을 농도 1㎍/㎖을 10분 동안 처리한 후 빙-냉(ice-cold) PBS로 세척 후 세포를 용해하였다. 용해된 세포액은 BCA 단백질 정량방법에 따라 정량하여 동일한 양을 인산화-CREB(Ser133) 샌드위치 ELISA 키트(Cell signaling)를 사용하여 제조사의 지시에 따라 측정하였다. Primary cultured hippocampal neurons cultured for 14 days were exchanged for B-27-free medium 1 hour before sample treatment. As a positive control group, 100 μM AMPA, an agonist of the AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), was used, and Baekchul extract, Suyeong extract, and their combined extract (Baekchul + Suyeong) were used. After treatment with a concentration of 1 μg/ml (weight ratio 1:1) for 10 minutes, the cells were washed with ice-cold PBS and lysed. The dissolved cell fluid was quantified according to the BCA protein quantification method, and the same amount was measured using a phosphorylation-CREB (Ser133) sandwich ELISA kit (Cell signaling) according to the manufacturer's instructions.
그 결과, 표 2에 개시한 바와 같이 1㎍/㎖의 백출 추출물 및 수영 추출물 각각의 단독에 대비하여, 본 발명에 따른 백출 및 수영 추출물의 복합물(중량비 1:1)에서 CREB 인산화 수준이 유의미하게 증가하였다. As a result, as shown in Table 2, the level of CREB phosphorylation was significantly higher in the complex of Baekchul and Suyeong extracts according to the present invention (weight ratio 1:1) compared to 1 μg/ml of Baekchul extract and Suyeong extract alone. increased.
*, **, ***은 무처리군 대비 양성대조군, 백출 추출물 처리군 및 본 발명의 백출 및 수영 추출물의 복합물 처리군의 인산화된 CREB의 함량이 유의미하게 증가하였다는 것으로, *는 p<0.05이고, **는 p<0.01이며, ***는 p<0.001이다.*, **, *** indicate a significant increase in the content of phosphorylated CREB in the positive control group, the Baekchul extract treated group, and the group treated with the complex of Baekchul and Suyeong extracts of the present invention compared to the untreated group, * means p< is 0.05, ** is p<0.01, and *** is p<0.001.
추가로 백출 및 수영 추출물의 복합물의 CREB 인산화 증가에 대한 최적 조합 비율을 확인하기 위하여, 상기 표 1에 개시한 바와 같은 다양한 혼합비의 백출 및 수영 추출물의 복합물의 CREB 인산화 증가능에 대한 실험을 실시하였다. In addition, in order to determine the optimal combination ratio for increasing CREB phosphorylation of the complex of Baekchul and Suyeong extracts, an experiment was conducted on the ability of complexes of Baekchul and Suyeong extract at various mixing ratios as shown in Table 1 above to increase CREB phosphorylation. .
그 결과, 아무것도 처리하지 않은 대조군에 대비하여 1:2의 중량비로 혼합한 백출 및 수영 추출물의 복합물을 1㎍/㎖ 농도로 처리한 실험군은 CREB 인산화가 28.81% 증가하였고, 2:1의 중량비로 혼합한 백출 및 수영 추출물의 복합물을 1㎍/㎖ 농도로 처리한 실험군은 CREB 인산화가 39.55% 증가하였다(표 3). As a result, compared to the untreated control group, CREB phosphorylation increased by 28.81% in the experimental group treated with a complex of Baekchul and Suyeong extracts mixed at a weight ratio of 1:2 at a concentration of 1㎍/ml, and at a weight ratio of 2:1. In the experimental group treated with the mixed Baekchul and Suyeong extract complex at a concentration of 1㎍/㎖, CREB phosphorylation increased by 39.55% (Table 3).
(450nm)p-CREB absorbance
(450nm)
**, ***은 무처리군 대비 양성대조군, 본 발명의 백출 및 수영 추출물의 복합물 처리군의 인산화된 CREB의 함량이 유의미하게 증가하였다는 것으로, **는 p<0.01이며, ***는 p<0.001이다.**, *** indicate a significant increase in the content of phosphorylated CREB in the positive control group and the group treated with the complex of Baekchul and Sooyoung extracts of the present invention compared to the untreated group, ** is p < 0.01, *** is p<0.001.
상기 실험 결과로부터, 백출 및 수영 단독 추출물보다 복합 추출물이 CREB 인산화를 증진시키는 시너지 효과가 있으며, 특히 다른 중량비로 혼합한 경우보다 2:1의 중량비로 혼합한 백출 및 수영 추출물의 복합물의 CREB 인산화 효과가 현저하다는 것을 알 수 있었다.From the above experimental results, it can be seen that the composite extract has a synergistic effect in enhancing CREB phosphorylation than the Baekchul and Suyeong extracts alone, and in particular, the CREB phosphorylation effect of the complex of Baekchul and Suyeong extracts mixed at a weight ratio of 2:1 compared to the case of mixing at other weight ratios. was found to be significant.
실시예Example 4. 뇌 신경세포주(SH-SY5Y)에서 스코폴라민으로 유도한 세포사멸에 대한 세포보호 효과 확인4. Confirmation of cytoprotective effect against scopolamine-induced apoptosis in brain nerve cell line (SH-SY5Y)
SH-SY5Y 세포(neuroblastoma, human dopaminergic neuronal cell)를 1% antimycotics/antibiotics와 10% FBS를 함유한 MEM 배지에서 배양하고 96 웰 플레이트에 세포 수가 1×105 세포/㎖가 되도록 분주한 후 24시간 동안 배양하였다. 신경세포에 미치는 세포독성을 확인하기 위하여 50㎍/㎖의 백출 추출물, 수영 추출물 및 백출+수영 복합 추출물을 24시간 동안 처리한 후, MTT 어세이를 이용하여 세포생존율을 확인하였다. SH-SY5Y cells (neuroblastoma, human dopaminergic neuronal cell) were cultured in MEM medium containing 1% antimycotics/antibiotics and 10% FBS and seeded in a 96 well plate at a cell count of 1×10 5 cells/ml for 24 hours. cultured for a while. To confirm cytotoxicity on nerve cells, 50 μg/ml of Baekchul extract, Suyeong extract, and Baekchul + Suyeong complex extract were treated for 24 hours, and then cell viability was confirmed using MTT assay.
그 결과, 백출 추출물, 수영 추출물 및 백출+수영 복합 추출물은 뇌 신경세포주에 대한 세포독성이 나타나지 않았다는 것을 확인하였다(도 1).As a result, it was confirmed that Baekchul extract, Suyeong extract, and Baekchul + Suyeong combined extract did not show cytotoxicity to brain nerve cell lines (Figure 1).
한편, 스코폴라민(Scopolamine, SCO)에 의한 기억력 손상으로 유발되는 세포사멸에 미치는 효과를 확인하기 위하여 SCO를 처리하기 3시간 전에, 30 및 50㎍/㎖의 백출 및 수영 단독 추출물과 이들의 복합 추출물을 처리한 후, 5mM SCO를 처리하고, 24시간이 지난 후 세포 생존율을 측정하였다. Meanwhile, in order to confirm the effect on cell death caused by memory impairment caused by scopolamine (SCO), 30 and 50 μg/ml of Baekchul and Suyeong extracts alone and their combination were administered 3 hours before SCO treatment. After treating the extract, 5mM SCO was treated, and cell viability was measured after 24 hours.
그 결과, 도 2에 나타낸 바와 같이, 1:1 중량비로 혼합된 백출 및 수영 추출물의 복합물의 농도 30 및 50㎍/㎖ 처리군에서, 각각 82.84±0.59% 및 97.47±0.54%의 세포보호 효과가 있었으며, 백출 및 수영 1:2 중량비로 혼합된 복합 추출물에서는 농도 50㎍/㎖에서 98.92±0.57%의 세포보호 효과가 확인되었고, 백출 및 수영의 2:1 중량비로 혼합된 복합 추출물에서는 농도 30 및 50㎍/㎖에서 각각 90.65±0.52% 및 109.38±0.62%으로 가장 우수한 세포보호 효과가 있다는 것을 확인하였다. As a result, as shown in Figure 2, in the groups treated with the concentration of 30 and 50㎍/㎖ of the complex of Baekchul and Suyeong extract mixed at a 1:1 weight ratio, the cytoprotective effect was 82.84 ± 0.59% and 97.47 ± 0.54%, respectively. In the complex extract mixed with Baekchul and Suyoung at a weight ratio of 1:2, a cytoprotective effect of 98.92±0.57% was confirmed at a concentration of 50㎍/㎖, and in the complex extract mixed with Baekchul and Suyoung at a 2:1 weight ratio, the cytoprotective effect was confirmed at a concentration of 30 and It was confirmed that 50㎍/㎖ had the best cytoprotective effect at 90.65±0.52% and 109.38±0.62%, respectively.
실시예 5. 태아 쥐의 해마 신경세포에서 시냅스 재구성(synapse remodeling) 관여 인자 확인Example 5. Identification of factors involved in synapse remodeling in hippocampal neurons of fetal rats
14일 동안 배양한 1차 배양 해마 신경세포에 백출 및 수영 단독 추출물과 이들의 복합 추출물 농도 1㎍/㎖을 1분 동안 처리한 후 ice-cold PBS로 세척 후 Syn-PERTM 시냅스 단백질 추출 시약(Synaptic protein Extraction reagent)을 이용해 세포를 용해하여 웨스턴 블랏을 실시하여 시냅스 재구성 관여 인자인 PSD-95(Post Synaptic Density 95 kDa), AMPA(α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) 수용체 (subunits: GluA1) 및 NMDA(N-methyl-D-aspartate) 2A 수용체의 단백질 발현량을 비교하였다. Primary cultured hippocampal neurons cultured for 14 days were treated with extracts of Baekchul and Swim alone and their combined extracts at a concentration of 1㎍/㎖ for 1 minute, washed with ice-cold PBS, and then washed with Syn-PER TM synaptic protein extraction reagent ( Cells were lysed using Synaptic protein Extraction reagent and Western blot was performed to determine factors involved in synapse reorganization: PSD-95 (Post Synaptic Density 95 kDa) and AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid). ) Protein expression levels of receptor (subunits: GluA1) and NMDA (N-methyl-D-aspartate) 2A receptor were compared.
그 결과, 도 3에 나타낸 바와 같이, 백출 및 수영 단독 추출물 농도 1㎍/㎖을 처리한 경우에 비해 백출 및 수영 추출물의 복합물에서 PSD95, AMPA 수용체 (subunits: GluA1) 및 NMDA 2A 수용체의 단백질 발현이 증가된 것을 확인하였으며, 특히, 2:1 중량비로 혼합된 백출 및 수영 추출물의 복합물에서 단백질 발현량이 가장 증가된 것을 확인하였다.As a result, as shown in Figure 3, the protein expression of PSD95, AMPA receptor (subunits: GluA1), and NMDA 2A receptor in the complex of Baekchul and Suyeong extracts was higher compared to the case of treatment with Baekchul and Suyeong extracts alone at a concentration of 1㎍/㎖. It was confirmed that the protein expression was increased, and in particular, the protein expression amount was confirmed to be most increased in the complex of Baekchul and Suyeong extracts mixed at a weight ratio of 2:1.
또한, 도 4에 나타낸 바와 같이, 가장 높은 활성을 보였던 2:1 중량비로 혼합된 백출 및 수영 추출물의 복합물을 농도별(1, 3 및 10㎍/㎖)로 1분 동안 처리하여 이들의 PSD95, AMPA 수용체(subunits: GluA1) 및 NMDA 2A 수용체의 단백질 발현량 변화를 확인한 결과, 1, 3 및 10㎍/㎖의 농도로 처리한 실험군 모두에서 PSD95, AMPA 수용체 및 NMDA 2A 수용체 단백질 발현량이 현저하게 증가되었다는 것을 확인하였다. In addition, as shown in Figure 4, the complex of Baekchul and Suyeong extracts mixed at a weight ratio of 2:1, which showed the highest activity, was treated at each concentration (1, 3, and 10㎍/㎖) for 1 minute to determine their PSD95, As a result of confirming changes in protein expression levels of AMPA receptor (subunits: GluA1) and NMDA 2A receptor, protein expression levels of PSD95, AMPA receptor, and NMDA 2A receptor were significantly increased in all experimental groups treated at concentrations of 1, 3, and 10㎍/㎖. It was confirmed that it was done.
실시예 6. 모리스 수중 미로 실험 (Morris water maze test) Example 6. Morris water maze test
[실험동물 및 사육][Experimental animals and breeding]
생후 6주령의 수컷 SD-랫트를 ㈜샘타코(SAMTACO, Korea)에서 구입하여 일정한 조건(온도: 22±2℃, 습도: 50±5%, 명암: 12시간 명암 주기)을 유지하는 동물 사육실에서 일주일 동안 적응시킨 후 사용하였다.Six-week-old male SD-rats were purchased from SAMTACO, Korea and kept in an animal breeding room maintaining constant conditions (temperature: 22 ± 2°C, humidity: 50 ± 5%, light/dark: 12-hour light/dark cycle). It was used after acclimatization for a week.
실험동물 행동평가를 위한 수컷 SD-랫트에 본 발명의 백출 및 수영 복합추출물(10, 50 및 100mg/kg)을 21일 동안 1일 1회 경구투여하였으며, 대조군(Control)으로는 시료를 투여하지 않은 무처리군을 사용하였다. 모리스 수중 미로 시험은 원형풀(직경: 180cm, 높이: 75cm)에 물을 25±1cm의 높이까지 채우고, 탈출 플랫폼(24cm)을 수면 1cm 아래에 숨겼다. 위치를 확인할 수 있게, 벽의 4면에 공간단서를 설치하고, 탈지분유를 물에 풀어 도피대를 육안으로 확인할 수 없게 하였다. 실험 하루 전에 모든 실험군을 도피대가 없는 수영장에서 1분 동안 자유롭게 수영하게 하여 수영에 적응시켰다. 본 실험에 들어가 첫 번째 실험일에는 도피대가 놓인 사분면을 제외한 3곳 중 2곳에서 임의의 순서로 동물을 출발시켜 60초 동안 도피대를 찾도록 하였다. 도피대를 찾으면 그로부터 20초 동안 그 위에 머무르게 하고, 45초 안에 도피대를 찾지 못하면 실험자가 손으로 동물을 도피대까지 유도하여 20초 동안 머물도록 하였다. 20초 동안의 위치 학습이 끝나면 바로 임의의 분면에서 동물을 출발시켜 도피대까지 찾아가는 시간과 이동거리를 측정하였다. 도피대를 찾아 올라가면 20초의 시간을 주고 연속적으로 하루에 총 3번, 3일 동안을 시행하였다. 단, 2일, 3일째에서는 전날 습득된 장기기억을 평가하고자 도피대까지 유도하는 초기 학습을 생략하였다. 모든 데이터는 수영장 위에 설치된 카메라로 촬영되어 비디오 추적 장치(Panlab, Barcelona, Spain)로 분석하였다.Baekchul and Sooyoung complex extracts (10, 50, and 100 mg/kg) of the present invention were orally administered to male SD-rats for behavioral evaluation of experimental animals once a day for 21 days, and no samples were administered as a control group. An untreated group was used. In the Morris water maze test, a circular pool (diameter: 180 cm, height: 75 cm) was filled with water to a height of 25 ± 1 cm, and an escape platform (24 cm) was hidden 1 cm below the water surface. To confirm the location, spatial clues were installed on all four sides of the wall, and skim milk powder was dissolved in water so that the escape zone could not be confirmed with the naked eye. One day before the experiment, all experimental groups were allowed to swim freely for 1 minute in a swimming pool without an escape platform to acclimate them to swimming. On the first day of this experiment, animals were started in a random order from two of the three quadrants excluding the quadrant where the escape zone was located and were asked to find the escape zone for 60 seconds. If the animal found an escape platform, it was allowed to stay on it for 20 seconds. If it did not find an escape platform within 45 seconds, the experimenter guided the animal to the escape platform by hand and made it stay there for 20 seconds. After 20 seconds of location learning, the animal was immediately started from a random quadrant and the time and distance traveled to the escape area were measured. After finding an escape platform and climbing up, 20 seconds were given and this was done continuously, a total of 3 times a day, for 3 days. However, on the 2nd and 3rd days, the initial learning leading to the escape zone was omitted in order to evaluate the long-term memory acquired the previous day. All data were captured with a camera installed above the swimming pool and analyzed with a video tracking device (Panlab, Barcelona, Spain).
그 결과, 도 5A에 나타낸 바와 같이, 각 실험일의 첫 번째 시도(First trials)는 장기기억을 나타내는 지표인데, 백출 및 수영 추출물의 복합물 10, 50 및 100mg/kg 투여군의 첫 번째 시도에서 도피대를 탐색하는 시간이 대조군(CTL)의 첫 번째 시도에 비해 유의미하게 감소한 것을 확인할 수 있었다. As a result, as shown in Figure 5A, the first trials of each experimental day are an indicator of long-term memory, and the escape zone was observed in the first trial of the groups administered 10, 50, and 100 mg/kg of the complex of Baekchul and Sooyoung extracts. It was confirmed that the time to explore was significantly reduced compared to the first attempt of the control group (CTL).
또한, 도 5B에 개시한 바, 각 실험일의 마지막 시도(Last trials)는 단기기억을 나타내는 지표인데, 백출 및 수영 복합추출물 10, 50, 및 100mg/kg 투여군의 마지막 시도에서 도피대를 탐색하는 시간이 대조군(CTL)의 마지막 시도에 비해 유의미하게 감소한 것을 확인할 수 있었다. In addition, as shown in Figure 5B, the last trials of each experimental day are an indicator of short-term memory, and the last trial of the Baekchul and Sooyoung complex extract 10, 50, and 100 mg/kg administration groups was used to search for an escape zone. It was confirmed that the time was significantly reduced compared to the last attempt of the control group (CTL).
한편, 3일 동안의 실험이 끝난 24시간 후인 4일째에 프로브 테스트(probe test)를 실시하였다. 도피대 없이 90초 동안 자유수영을 하게 하여 이전 도피대의 위치에 대한 기억(4분면 중, 도피대가 있었던 분면 수영시간)을 보유하고 있는지 에 대한 검사를 실시하였다. Meanwhile, a probe test was conducted on the 4th day, 24 hours after the 3-day experiment ended. The subjects were allowed to swim freely for 90 seconds without an escape platform and were tested to see whether they retained memory of the previous location of the escape platform (swimming time in the quadrant where the escape platform was located).
그 결과, 도 6에 개시한 바와 같이 대조군(CTL)에 대비하여, 백출 및 수영 추출물의 복합물 투여군의 도피대가 있었던 분면에서의 수영시간이 유의미하게 증가하였다. As a result, as shown in Figure 6, compared to the control group (CTL), the swimming time in the quadrant where the escape zone was located in the group administered the combination of Baekchul and swimming extract was significantly increased.
실시예 7. SD-랫트에서 적출한 해마에서 시냅스 재구성 인자 및 신경가소성인자 단백질 발현량 변화 확인Example 7. Confirmation of changes in synaptic reorganization factor and neuroplasticity factor protein expression levels in the hippocampus extracted from SD-rats
모든 행동평가가 끝난 날에 SD-랫트에서 해마를 적출하여 시냅스 재구성 인자인 NMDA(N-methyl-D-aspartate) 수용체(Subunits: NR2A, NR2B), AMPA 수용체(subunits: GluA1) 및 PSD95 단백질 발현량과 신경가소성 인자인 ERK, CaMKII 및 BDNF 단백질 발현량 변화를 웨스턴 블랏으로 확인하였다.On the day when all behavioral evaluations were completed, the hippocampus was removed from SD-rats, and the protein expression levels of synaptic reorganization factors, NMDA (N-methyl-D-aspartate) receptors (Subunits: NR2A, NR2B), AMPA receptors (subunits: GluA1), and PSD95 were measured. Changes in protein expression levels of neuroplasticity factors ERK, CaMKII, and BDNF were confirmed by Western blot.
그 결과, 도 7에 개시한 바와 같이 대조군(Control)에 비해 백출 및 수영 복합추출물(10, 50 및 100mg/kg) 투여군에서 NR2A, NR2B, GluA1 및 PSD95의 단백질 발현량이 증가된 것을 확인할 수 있었다. As a result, as shown in Figure 7, it was confirmed that the protein expression levels of NR2A, NR2B, GluA1, and PSD95 were increased in the group administered Baekchul and Suyeong complex extracts (10, 50, and 100 mg/kg) compared to the control group (Control).
또한, 도 8A에 개시한 바, 대조군(Control)에 비해 백출 및 수영 복합추출물 (10, 50 및 100mg/kg)투여군에서 시냅스 형성에 관여하는 뇌유래신경성장인자 (brain-derived neurotrophic factor, BDNF) 단백질 발현량이 유의미하게 증가되었고, 도 8B에 개시한 바와 같이 백출 및 수영 복합추출물(10, 50 및 100 mg/kg) 투여군에서 시냅스 가소성 조절에 관여하는 신호전달경로 ERK 및 CaMKII 인산화 발현이 유의적으로 증가된 것을 확인하였다. In addition, as shown in Figure 8A, brain-derived neurotrophic factor (BDNF), which is involved in synapse formation, in the group administered Baekchul and Sooyoung complex extracts (10, 50, and 100 mg/kg) compared to the control group (Control) The protein expression level was significantly increased, and as shown in Figure 8B, the expression of ERK and CaMKII phosphorylation, a signaling pathway involved in regulating synaptic plasticity, was significantly increased in the group administered Baekchul and Sooyoung complex extracts (10, 50, and 100 mg/kg). An increase was confirmed.
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