KR20170004912A - Composition for preventing or treating inborn errors of metabolism comprising memantine - Google Patents
Composition for preventing or treating inborn errors of metabolism comprising memantine Download PDFInfo
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- KR20170004912A KR20170004912A KR1020160084378A KR20160084378A KR20170004912A KR 20170004912 A KR20170004912 A KR 20170004912A KR 1020160084378 A KR1020160084378 A KR 1020160084378A KR 20160084378 A KR20160084378 A KR 20160084378A KR 20170004912 A KR20170004912 A KR 20170004912A
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- memantine
- xpnpep1
- preventing
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
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Abstract
Description
본 발명은 메만틴을 유효성분으로 포함하는 선천성 대사 이상증 예방 또는 치료용 약학적 조성물 및 건강기능식품 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition and a health functional food composition for preventing or treating congenital metabolic dysfunction comprising memantine as an active ingredient.
선천성 대사 이상(Inborn errors of metabolism, IEMs)은 생체내 대사경로에 있어 특성과정이 유전적인 결합으로 정상적인 기능을 발휘할 수 없는 경우에 생기는 이상(異常)을 말한다. 유전자변이(gene variation)에 따라 효소이상 또는 생체당백질의 생성이상 등이 발생하며, 그 결과, 효소반응생성물결핍(product deficiency in enzyme reaction), 효소기질과잉축적(enzyme substrate of excess accumulation), 측부로(bypass)에 의한 대사산물의 증가, 생체막이상에 의한 흡수장해(absorption obstruction), 신뇨세관장해(renal tubular obstruction), 세포내전송장해(intracellular transport obstruction), 수용체이상(abnormalities of receptors), 혈액내단백질생성이상(abnormality in the generation of protein intracellular)등이 야기된다. 게다가, 가장 심각한 합병증은 발달 지체, 소두증, 과잉 행동, 주의력 결핍, 간질, 지적 장애와 같은 신경 발달 장애이다[(S. G. Kahler, American journal of medical genetics. Part C, Seminars in medical genetics 117C, 31-41 (2003)), (N. I. Wolf, T. Bast, R. Surtees, Epileptic disorders: international epilepsy journal with videotape 7, 67-81 (2005))]. Inborn errors of metabolism (IEMs) refer to anomalies in the in vivo metabolic pathway when a characterization process can not function normally due to genetic linkage. In addition, enzyme abnormalities or production of white matter in the body may occur due to gene variation, resulting in product deficiency in enzyme reaction, enzyme substrate of excess accumulation, An increase in metabolism by bypass, an absorption obstruction due to biofilm abnormality, renal tubular obstruction, intracellular transport obstruction, abnormalities of receptors, And abnormalities in the production of protein intracellular. In addition, the most serious complications are neurodevelopmental disorders such as developmental delay, microcephaly, hyperactivity, attention deficit, epilepsy, and intellectual disability [(SG Kahler, American journal of medical genetics. Part C, Seminars in medical genetics 117C, 31-41 (2003)), (NI Wolf, T. Bast, R. Surtees, Epileptic disorders: international epilepsy journal with
상기 선천성 대사 이상의 진단은 조기 진단을 위해 신생아 시기에 선별 검사를 시행한다. 이중질량분광분석 기기를 이용하여 43종 이상의 유전성 대사질환, 즉, 유기산, 아미노산, 지방산 대사 이상 질환의 스크리닝 및 진단이 가능하다. 또한, 혈액이나 소변 검사를 통해 전구물질이 증가되고 최종물질이 감소된 것을 확인하여 결함이 있는 대사 경로(탄수화물, 단백질, 유기산 대사 장애 등)를 찾아내기도 하며, 유전자 검사, 효소 검사, 장기 또는 조직의 생검을 시행하기도 한다. 대사산물의 축적 또는 부족으로 발생하는 이차적인 저혈당/고혈당 유무, 암모니아의 상승 여부, 산혈증 여부, 케톤산과 젖산/피루빈산 상승 등을 확인하고 일반 혈액 검사, 간기능 검사, 신장 기능 검사, 요산 등의 검사를 시행한다.The diagnosis of congenital metabolic disorders should be screened at the neonatal period for early diagnosis. Using double mass spectrometry, screening and diagnosis of more than 43 hereditary metabolic diseases such as organic acids, amino acids, and fatty acid metabolism disorders are possible. In addition, blood or urine tests can be used to detect defective metabolic pathways (carbohydrates, proteins, organic acid metabolism disorders, etc.) by confirming that the precursors are increased and the final substances are reduced, and genetic tests, enzyme tests, Biopsy of the tissue may be performed. The presence or absence of secondary metabolites, secondary hypoglycemia / hyperglycemia, elevated ammonia, acidemia, elevated ketone and lactate / pyruvate, and general blood tests, liver function tests, renal function tests, uric acid, etc. .
선천성 대사 이상의 치료는 질환에 따라 대사 경로가 차단되어 쌓인 독성 전구물질을 제거하고 더 이상 전구물질이 만들어지지 않도록 결핍이 있는 효소의 기질을 제한하는 식이요법을 시행한다. 또한, 대사 경로가 차단되어 생성되지 못하므로, 우리 몸에 필요한 최종 물질을 보충하기 위해 직접 조효소나 효소를 투여하기도 한다. 그러나, 선천성 대사 이상은 조기 진단 및 치료가 최선으로 이에 대한 효과적인 치료제 개발의 필요성이 대두되고 있다.The treatment of congenital metabolic disorders is to treat the disease by blocking the metabolic pathway and eliminating accumulated toxic precursors and limiting the substrate of the deficient enzyme so that no more precursors are formed. In addition, since the metabolic pathway is blocked, it can not be produced. Therefore, coenzyme or enzyme may be directly administered to supplement the final substance necessary for the body. However, early diagnosis and treatment of congenital metabolic abnormalities are the best, and it is necessary to develop effective therapeutic agents for them.
본 발명의 목적은 메만틴(memantine)을 유효성분으로 포함하는 선천성 대사 이상증(inborn errors of metabolism) 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of inborn errors of metabolism comprising memantine as an active ingredient.
또한 본 발명의 목적은 메만틴을 유효성분으로 포함하는 선천성 대사 이상증 예방용 건강기능식품 조성물을 제공하는 것이다.It is also an object of the present invention to provide a health functional food composition for preventing congenital metabolic dysfunction comprising memantine as an active ingredient.
상기와 같은 과제를 해결하기 위해, 본 발명은 메만틴(memantine)을 유효성분으로 포함하는 선천성 대사 이상증(inborn errors of metabolism) 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating inborn errors of metabolism comprising memantine as an active ingredient.
또한 본 발명은 메만틴을 유효성분으로 포함하는 선천성 대사 이상증 예방용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing congenital metabolic dysfunction comprising memantine as an active ingredient.
본 발명의 메만틴은 신경 세포의 액포형성 감소, 신경 세포 사멸 억제 및 세포 사멸 신호작용의 감소를 통한 신경 퇴행 완화 효과가 있다. 또한, 주의력 결핍, 간질, 지적 장애, 발달 장애 완화 및 소두증 개선 효과가 있어, 선천성 대사 이상증의 예방 및 치료에 효과적이다. Memantine of the present invention has neurodegenerative mitigation effect through reduction of vacuole formation of nerve cells, suppression of neuronal cell death, and decrease of signaling action of apoptosis. Also, it is effective for the prevention and treatment of congenital metabolic dysfunction because it has the effect of attention deficiency, epilepsy, intellectual disability, alleviation of developmental dysfunction and microcephaly.
도 1은 하루에 두 번씩 39일간 메만틴(10 mg/kg) 또는 식염수를 복강 투여한 시험 과정을 모식화한 도이다.
도 2는 메만틴이 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서, 세포막 전압을 -70 mV로 고정한 상태에서 NMDAR-mEPSCs를 기록한 결과를 나타낸 도이다(좌). 측정을 위해 Mg2+이 제거된 관류액을 사용하였다. 메만틴 또는 식염수(saline)를 처리한 상태에서 NMDA 수용체를 통한 전류의 진폭 및 주파수를 확인한 결과를 나타낸 도이다(우).
도 3은 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 각 마우스의 CA3 영역을 형광 염색한 결과를 나타낸 도이다(좌). 또한, CA3 영역의 신경 밀도를 정량화한 결과를 나타낸 도이다(우).
도 4는 (A)는 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 면역형광을 수행한 결과를 나타낸 도이다(붉은색은 NeuN, 초록색은 MAP2를 나타낸다. 흰색 화살표는 죽은 신경 세포를 나타낸다.). (B)는 HE 염색 후, 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-) 뇌의 해마 CA1, CA2 및 CA3 영역의 액포화를 확인한 결과를 나타낸 도이다..
도 5는 HE 염색 후, 메만틴 또는 식염수가 처리된 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)의 CA3 신경세포에서 액포화를 확인한 결과를 나타낸 도이다.
도 6은 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 세포 사멸 신호 억제를 면역블랏(좌)으로 확인하였다. 또한, 세포 활성과 관련된 p-CamKβ, p-CamKⅡα, Caspase-3(19KDa), Caspase-3(17KDa), Calpain-1(78KDa), Calpain-1(75KDa), LC3B- 및 LC3B- 항체의 반응을 확인한 결과를 정량화(우)한 결과를 나타낸 도이다.
도 7은 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-) 뇌 해마의 CA3 영역의 신경 세포에서, 신경세포 마커 NeuN(붉은색)를 확인하여, 신경 세포의 활성 또는 사멸 정도를 확인하였다. 또한, pCamKII, Caspase-3, Calpain-1, 및 LC3B (초록색)의 면역활성을 확인한 결과를 나타낸 도이다.
도 8은 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)의 이미지(좌) 및 각 마우스의 키(우)를 나타낸 도이다.
도 9는 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 몸무게 변화를 확인한 도이다.
도 10은 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)의 전두의 폭, 길이, 두께를 확인한 도이다.
도 11은 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)의 생존률을 확인하였다.
도 12는 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)의 활동 패턴(좌) 및 1시간 동안 개방형 필드 테스트(우)한 결과를 나타낸 도이다.
도 13은 과잉 행동 및 발달 지연의 관계를 분석한 도이다.
도 14는 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에 대하여 신규한 물체 인지를 테스트한 것으로, 신규한 물체에 대한 선호도(좌) 및 익숙한 물체와 신규한 물체의 총 관찰 시간(오른쪽)에 대한 결과를 나타낸 도이다.
도 15는 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 공간에 대한 공포 조건화를 테스트한 것으로 공포조건화 전(pre-Cs)과 후(CS)에 보이는 활동도의 변화(왼) 및 활동 억제(우) 결과를 나타낸 도이다.
도 16은 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에 메만틴을 처리하였을 때, 생리학적 시그널 변화를 모식화한 도이다. FIG. 1 is a diagram illustrating a test procedure in which abdominal administration of memantine (10 mg / kg) or saline is administered for 39 days twice a day.
FIG. 2 shows NMDAR-mEPSCs recorded with memantine-fixed wild-type and Xpnpep1 knockout mouse (Xpnpep1 - / -) with cell membrane voltage fixed at -70 mV (left). For the measurement, Mg2 + -free perfusion solution was used. (Right), showing the amplitude and frequency of the current through the NMDA receptor under treatment with memantine or saline (right).
FIG. 3 shows fluorescence staining of the CA3 region of each mouse in wild-type and Xpnpep1 knockout mice (Xpnpep1 - / -) treated with memantine or saline (left). It is also shown that the neural density of the CA3 region is quantified (right).
4 (A) is a graph showing the result of immunofluorescence of wild-type and Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine or saline (NeuN in red and MAP2 in green) Arrows represent dead neurons. (B) shows the results of confirming the liquidation of hippocampal CA1, CA2 and CA3 regions of wild-type and Xpnpep1 knockout mouse (Xpnpep1 - / -) brain treated with memantine or saline after HE staining.
FIG. 5 shows the results of confirming liquidation in CA3 neurons of Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine or saline after HE staining.
Figure 6 confirms immunotypic inhibition (left) of apoptotic signal suppression in memantine or saline treated wild type and Xpnpep1 knockout mice (Xpnpep1 - / -). In addition, the response of p-CamKβ, p-CamKIα, Caspase-3 (19KDa), Caspase-3 (17KDa), Calpain-1 (78KDa), Calpain-1 (75KDa), LC3B- and LC3B- (Right) of the results.
FIG. 7 shows the neuronal cell marker NeuN (red color) in neurons of CA3 region of brain hippocampus of wild type and Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine or saline, Respectively. Also, it shows the results of confirming the immunoactivity of pCamKII, Caspase-3, Calpain-1, and LC3B (green).
FIG. 8 is a diagram showing an image (left) and a key (right) of wild type and Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine or saline.
FIG. 9 shows the change in body weight in the wild-type and Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine or saline.
10 is a view showing the width, length and thickness of the forehead of wild type and Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine or saline.
Figure 11 confirms the survival rate of wild-type and Xpnpep1 knockout mice (Xpnpep1 - / -) treated with memantine or saline.
Figure 12 shows activity patterns (left) and 1 hour open field test (right) of wild-type and Xpnpep1 knockout mice (Xpnpep1 - / -) treated with memantine or saline.
13 is an analysis of the relationship between hyperactivity and development delay.
Fig. 14 is a test of the novelty of the wild-type and Xpnpep1 knockout mouse treated with memantine or saline (Xpnpep1 - / -), showing preference for a new object (left) And the total observation time (right).
Figure 15 is a graphical representation of the behavioral activity seen in pre-Cs and post-cortical (CS) conditions by testing panic conditioning in space on wild-type and Xpnpep1 knockout mice treated with memantine or saline (Xpnpep1 - Change (left) and inhibition of activity (right).
16 is a schematic diagram of physiological signal changes when memantine is treated with wild-type and Xpnpep1 knockout mice (Xpnpep1 - / -).
본 발명은 메만틴(memantine)을 유효성분으로 포함하는 선천성 대사 이상증(inborn errors of metabolism) 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating inborn errors of metabolism comprising memantine as an active ingredient.
본 명세서에 있어서, "메만틴(memantine)" 은 2002년 유럽에서 중증 알츠하이머병 치료제로 승인되었다.As used herein, "memantine" was approved in 2002 for treatment of severe Alzheimer's disease in Europe.
본 발명에 있어서, "선천성 대사 이상증"은 우리 몸의 생화학적인 대사 경로를 담당하는 효소나 조효소의 결핍으로 발생하고, 정상적으로 꼭 필요한 최종 물질이 생성되지 못하여 결핍 증상이 나타나고 불필요한 전구물질은 다양한 중요 장기(뇌, 심장, 간, 신장 등)에 축적되어 지능 장애와 같은 과잉 증상을 일으킨다In the present invention, "congenital metabolic disorder" is caused by deficiency of enzymes or coenzymes responsible for the biochemical metabolic pathway of our body, deficiency symptoms occur due to the failure to generate the necessary final substances normally, and unnecessary precursors (Brain, heart, liver, kidney, etc.), causing hyperactivity such as intellectual disability
본 명세서에 있어서, "예방" 은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸리기 쉬운 경향이 있는 동물에서 질환 또는 질병의 발생을 억제하는 것을 의미한다. 본 명세서에서 용어 "치료"는 선천성 대사 이상증 관련 질환 또는 질병의 발전의 억제; 선천성 대사 이상증 관련 질환 또는 질병의 경감; 및 선천성 대사 이상증 관련 질환 또는 질병의 제거를 의미한다.As used herein, "prevention" means inhibiting the development of a disease or disease in an animal that has never been diagnosed as having a disease or disease, but tends to be susceptible to such disease or disease. As used herein, the term "treatment" refers to the inhibition of the development of a disease or disease associated with a congenital metabolic disorder; Alleviation of diseases or diseases associated with congenital metabolic disorders; And the removal of diseases or diseases associated with congenital metabolic dysfunction.
상기 메만틴은 복강 내 투여용이나, 메만틴을 효과적으로 투여하는 투여방법이라면 제한되지 않는다.The memantine is not limited as long as it is intraperitoneally administered or a method of administering memantine effectively.
상기 선천성 대사 이상증은 발달 지체, 소두증, 과잉 행동, 주의력 결핍, 간질, 지적 장애, 페닐케톤뇨증, 단풍당뇨증, 호모시스틴뇨증, 갈락토스혈증, 갑상선기능저하증 및 부신기능항진증으로 이루어진 군에서 선택된 1종 이상이고, 바람직하게는 체내 효소의 결핍이나 기능저하에 의한 발달지체, 소두증, 과잉 행동, 간질 및 지적 장애가 동반되는 질환이나, 이에 제한되지 않는다.The congenital metabolic dysfunction is one or more selected from the group consisting of developmental delay, microcephaly, hyperactivity, attention deficit disorder, epilepsy, intellectual disability, phenylketonuria, diabetic diabetes mellitus, homocystinuria, galactosemia, hypothyroidism, , Preferably a disease accompanied by developmental delay, microcephaly, hyperactivity, epilepsy and intellectual disability due to deficiency or inactivation of an enzyme in the body, but is not limited thereto.
상기 선천성 대사 이상증 동물모델은 뇌 해마(hippocampus)의 CA3 영역 신경세포 밀도가 낮아진 것이고, 상기 뇌 해마의 CA3 영역 신경세포는 비정상적으로 항진된 NMDAR(N-methyl-D-aspartate receptor) 활성이 나타나며, GluN1(Glutamate[NMDA] receptor subunit zeta-1) 및 GluN2A(Glutamate [NMDA] receptor subunit epsilon-1) 단백질 발현이 증가되나, 이에 제한되지 않는다. The animal model of the congenital metabolic dysfunction has a low density of CA3 region neurons in the hippocampus and CA3 region neurons in the brain hippocampus exhibit abnormally enhanced NMDAR (N-methyl-D-aspartate receptor) But not limited to, the expression of GluN1 (Glutamate [NMDA] receptor subunit zeta-1) and GluN2A (Glutamate [NMDA] receptor subunit epsilon-1).
본 발명에 있어서, "해마"는 관자엽의 안쪽에 위치하면서 둘레계통(변연계)에서 한가운데 원호의 일부분을 차지한다. 해마는 학습, 기억 및 새로운 것의 인식 등의 역할을 하며 속후각겉질을 통하여 주된 들섬유를 받아들이고, 뇌활을 통하여 날섬유를 내보낸다.In the present invention, the "hippocampus" occupies a part of the arc in the middle of the circumferential system (limbic system) while being located inside the cotyledon. The hippocampus plays a role of learning, memory and recognition of new things. It accepts the main fibers through the olfactory cortex and sends out the fibers through the skin.
본 발명에 있어서, "해마의 CA3 영역"은 해마를 구성하는 부분 중 하나이다.In the present invention, "CA3 region of hippocampus" is one of the parts constituting hippocampus.
본 발명의 약학적 조성물은 약학적으로 허용되는 담체를 추가적으로 포함할 수 있다. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.
본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc., in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on such factors as formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate, .
한편, 본 발명의 약학적 조성물의 투여량은 바람직하게는 1일 당 0.0001-100 mg/kg(체중)이다.On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.0001-100 mg / kg (body weight) per day.
본 발명의 약학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. 본 발명의 약제학적 조성물은 적용되는 질환의 종류에 따라, 투여 경로가 결정되는 것이 바람직하다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, and the like. In the pharmaceutical composition of the present invention, the route of administration is preferably determined depending on the type of disease to which it is applied.
본 발명의 조성물에 포함되는 유효성분인 증진제 내 해당 유전자 또는 이의 단백질의 발현 억제제의 농도는 치료 목적, 환자의 상태, 필요 기간, 질환의 위중도 등을 고려하여 결정하며 특정 범위의 농도로 한정되지 않는다.The concentration of the gene or the expression inhibitor of the protein of the present invention in the enhancer, which is an active ingredient contained in the composition of the present invention, is determined in consideration of the purpose of treatment, patient's condition, required period, .
본 발명의 약학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated into a unit dosage form by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
또한 본 발명은 메만틴을 유효성분으로 포함하는 선천성 대사 이상증 예방용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing congenital metabolic dysfunction comprising memantine as an active ingredient.
본 발명에 있어서, "개선"은 본 발명의 조성물을 사용하기 전보다 본 발명의 조성물을 사용하고 난 후 증상의 완화 및 경감을 포함하는 넓은 의미로 사용된다.In the present invention, "improvement" is used in a broad sense including mitigating and alleviating symptoms after using the composition of the present invention before using the composition of the present invention.
본 발명에 따른 조성물은 선천성 대사 이상증 예방 또는 개선을 목적으로 하는 건강식품에 포함될 수 있으며, 본 발명의 유효성분을 식품 첨가물로 사용할 경우, 상기 합성 또는 추출물로부터 분리된 것을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 또한 상기 유효 성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적절하게 조절하여 사용 될 수 있다. The composition according to the present invention may be included in a health food for the purpose of preventing or ameliorating congenital metabolic dysfunction. When the active ingredient of the present invention is used as a food additive, Component, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed may be appropriately adjusted depending on the intended use (prevention, health or therapeutic treatment).
상기 식품의 종류에는 특별한 제한이 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함하는 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, drinks, tea, , Alcoholic beverages and vitamin complexes, and includes all health foods in a conventional sense.
본 발명의 식품 보조 첨가제는 여러 가지 향미제 또는 천연 탄수화물 등을 사용할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로 덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에르트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.Various additives such as flavors or natural carbohydrates can be used as the food-aid additive of the present invention. The above-mentioned natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like.
상기 외에 본 발명에 따른 조성물은 여러가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 중점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명에 따른 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.In addition to the above, the composition according to the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid concentrating agents, pH adjusting agents, stabilizers, preservatives, , A carbonating agent used in carbonated drinks, and the like. In addition, the composition according to the present invention may contain flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination.
이하, 실시예를 통해 본 발명을 자세히 설명하도록 한다. 하기 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in detail by way of examples. It is to be understood that the following examples are illustrative only and are not intended to limit the scope of the invention in any way to the scope of the invention as defined by the appended claims. It will be obvious.
실험예 1. 실험 준비 Experimental Example 1. Experimental Preparation
1-1. 동물 준비1-1. Animal preparation
Xpnpep1(X-Prolyl Aminopeptidase 1) 넉아웃 마우스 모델을 제조하기 위하여, Xpnpep1 유전자 트랩이 포함된 마우스 배아 줄기 (ES) 세포 라인(strain 129 Sv/Ev)을 이용하였으며, 이는 프레드 허친슨 암 연구 센터에서 제공받았다. 배아 줄기 세포는 키메라 개체를 생성하기 위해 C57BL / 6J 마우스의 배반포에 주입하였으며, 이를 이형 Xpnpep1 돌연변이 (N1)를 획득하기 위해 C57BL / 6J 암컷과 교배하였다. 생식선 전이 및 마우스 유전자형은 올리고 뉴클레오티드 프라이머를 이용하여 게놈 DNA의 PCR에 의해 모니터 하였다: 5'- CCTTAGACGTGTCCCGAGGT-3' 및 5'-TGCAGCCTAGAGGAAGGACA-3'(야생형) 또는 5'-CCTGGACTACTGCGCCCTAC-3'(β-지역). 마우스를 사용하기 전에 C57BL/6J 및 129S4/SvJae와 8-16 세대 동안 역교배하였다. 모든 분석은 C57BL/6J 및 129S4/SvJae 이형 접합체 부모간의 이종 교배에 의해 생성된 양쪽의 유전자형의 한배 새끼(littermate)에 수행하였다. 마우스는 12 시간 광 주기하에 사료 및 물을 자유롭게 공급하여 기후-제어된 방인 동물 시설에 수용하였다. 동물과 모든 동물 실험의 유지 관리는 서울대학교의 기관 동물 관리 및 사용위원회(IACUC)에서 승인하였다.To prepare the Xpnpep1 (X-Prolyl Aminopeptidase 1) knockout mouse model, a mouse embryonic stem (ES) cell line (strain 129 Sv / Ev) containing the Xpnpep1 gene trap was used and this was provided by the Fred Hutchinson Cancer Research Center received. Embryonic stem cells were injected into blastocysts of C57BL / 6J mice to produce chimeric individuals, which were crossed with C57BL / 6J females to obtain a heterozygous Xpnpep1 mutation (N1). Gonadal metastases and mouse genotypes were monitored by PCR of genomic DNA using oligonucleotide primers: 5'-CCTTAGACGTGTCCCGAGGT-3 'and 5'-TGCAGCCTAGAGGAAGGACA-3' (wild type) or 5'-CCTGGACTACTGCGCCCTAC-3 ' area). Mice were backcrossed with C57BL / 6J and 129S4 / SvJae for 8-16 generations. All analyzes were performed on littermates of both genotypes generated by cross breeding between parental C57BL / 6J and 129S4 / SvJae heterozygotes. The mice were fed free of feed and water under a 12 hour light cycle and housed in a climate-controlled room animal facility. The maintenance of animal and all animal experiments was approved by Seoul National University's Institutional Animal Care and Use Committee (IACUC).
1-2. 형광현미경 분석을 위한 조직 배양 신경 세포의 준비1-2. Preparation of tissue-cultured neurons for fluorescence microscopy analysis
면역조직화학 분석을 위하여, 마우스를 디에틸 에스테르로 깊이 마취시키고, 헤파린이 첨가된 PBS(phosphate-buffered saline)(10 U/ml)로 심장 관류한 후, 4% (w/v) PBS의 파라포름알데히드를 포함하는 고정액을 이용하여 고정하였다. 마우스의 뇌를 제거하고 48시간 동안 4도로 후-고정한 뒤 vibratome (VT1200S, Leica)을 이용하여 60 μm 관상 단면으로 절단하였다. 상기 단면은 상기 동일한 고정액으로 1시간동안 후-고정하였다. 면역세포화학 분석을 위하여, 해리된 해마 신경 세포는 E18 래트로부터 분리하였으며, B27, 글루타맥스 및 페니실린-스트렙토마이신이 첨가된 Neurobasal 배지에 poly-D-lysine으로 코팅한 커버슬립 상에서 배양하였다. 배양된 상기 신경 세포는 mammalian transfection kit (Invitrogen)를 이용하여 형질도입하고, 4% PBS의 파라포름알데히드로 고정하였다. For immunohistochemical analysis, the mice were deeply anesthetized with diethyl ester, perfused with heparin-added PBS (phosphate-buffered saline) (10 U / ml) and then perfused with 4% (w / And fixation was carried out using a fixing solution containing formaldehyde. The brains of mice were removed, post-fixed at 4 degrees for 48 hours, and cut into 60 μm coronal sections using a vibratome (VT1200S, Leica). The section was post-fixed with the same fixative for 1 hour. For immunocytochemical analysis, dissociated hippocampal neurons were isolated from E18 rats and cultured on cover slips coated with poly-D-lysine on Neurobasal medium supplemented with B27, glutamax and penicillin-streptomycin. The cultured neurons were transfected using a mammalian transfection kit (Invitrogen) and fixed with paraformaldehyde in 4% PBS.
1-3. 면역형광염색법1-3. Immunofluorescent staining
상기 단면 또는 신경세포는 PBS 내 0.3 % (v/v) Triton-X로 투과 가능하게 하였으며, 블록킹 버퍼(5 % 정상 염소 혈청, 5 % 말 혈청, 5 % 당나귀 혈청과 및 PBS 내 0.5 % BSA)에 2시간동안 처리하고, 일차 항체로 섭씨 4도에서 밤샘 배양하였다. 그 후, Cy3-, Cy5- 또는 FITC-접합된 이차 항체로 2시간 동안 배양하였다. 각 단계 후, 상기 단면 또는 신경 세포를 PBS로 10분간 3회 세척하였다. 일부 면역조직화학 염색에서, 상기 단편은 블로킹 버퍼에 배양하기 전에 30분 동안 37도 조건으로 트립신 처리를 하였다. 이미지는 냉각 전하 결합 소자 카메라(DP70, Olympus)를 갖춘 공초점 레이저 주사 현미경(LSM510, Zeiss) 또는 형광 현미경(BX51WI, Olympus)을 이용하여 수득하였다.The sections or neurons were permeabilized with 0.3% (v / v) Triton-X in PBS and blocked buffer (5% normal goat serum, 5% horse serum, 5% donkey serum and 0.5% BSA in PBS) For 2 hours, and cultured overnight at 4 ° C with the primary antibody. The cells were then incubated with Cy3-, Cy5- or FITC-conjugated secondary antibodies for 2 hours. After each step, the sections or nerve cells were washed three times with PBS for 10 minutes. In some immunohistochemical stains, the fragments were trypsinized at 37 degrees for 30 minutes before incubation in blocking buffer. Images were obtained using a confocal laser scanning microscope (LSM510, Zeiss) equipped with a cold charge coupled device camera (DP70, Olympus) or a fluorescence microscope (BX51WI, Olympus).
1-4. 헤마톡실린 및 에오신 염색1-4. Hematoxylin and eosin staining
고정된 마우스 뇌는 관상면 방향으로 삽입 모듈(Histocentre 3, Thermo Shandon)을 이용하여 파리핀에 삽입하였다. 파라핀 블록은 rotary microtome (RM2145, Leica)을 이용하여 4 μm 단면으로 절삭하고, 유리 슬라이드에 부착시켰다. 슬라이드는 10분 동안 3회 크실렌을 처리하고, 1분 동안 100% 에탄올에 2회 처리하고, 95% 에탄올을 2회 처리하며, 흐르는 수돗물을 이용하여 탈파라핀화하였다. 탈수 후, 탈파라핀화된 단편은 헤마톡실린(Merck) 및 에오신(Sigma-Aldrich)으로 염색하였다. 상기 염색된 단편은 95% 에탄올, 100% 에탄올 및 크실렌으로 세척하였다. 이미지는 디지털 이미징 시스템(DFC280; Leica)을 포함하는 광학 현미경(BX-51; Olympus)을 사용하여 수득하였다.The fixed mouse brain was inserted into the parin fins using an insertion module (
1-5. 전자현미경 1-5. Electron microscope
마우스를 펜토바비탈나트륨(80 mg/kg, i.p.)으로 깊게 마취시키고 헤파린이 포함된 생리 식염수 10 ml로 심장 내 관류시킨 후, 2.5% 글루타르알데히드 및 1% 파라포름알데히드가 포함된 PBS 50 ml를 이용하여 고정하였다. 해마를 뇌에서 분리 한 후, 상기와 동일한 고정액을 이용하여 2시간 동안 후-고정시키고 4도에서 밤새도록 PBS에 보관하였다. 바이브라톰(Vibratome)을 이용하여 해마를 횡방향으로 60 μm의 절편으로 제작하였다. 상기 단편은 1시간 동안 1% 사산화 오스뮴(osmium tetroxide) (in 0.1 M PB)으로 오스뮴화하였고, 알코올로 탈수시킨 후, Durcupan ACM (Fluka)에 평면 삽입하고 60도에서 48시간 동안 경화시켰다. 해마 CA3 영역을 포함하는 작은 조각은 와이퍼로 절단한 후 시아노아크릴레이트로 플라스틱 블록에 부착시켰다. 초박 단편을 잘라낸 후 포름바(Formvar)-코팅된 단일 슬롯 그리드에 부착시켰다. 단편은 우라닐 아세테이트 및 리드 시트레이트로 염색하고, 80 kV 의 가속 전압에서 전자현미경(Hitachi H-7500; Hitachi)으로 관찰하였다. 디지털 이미지는 CCD camera (SC1000 Orius; Gatan)를 구동하는 GATAN DigitalMicrograph 소프트웨어로 캡처하였고, TIFF 파일로 저장하였다. 이미지의 밝기 및 대비는 Adobe Photoshop 7.0 (Adobe Systems)으로 조절하였다.Mice were deeply anesthetized with sodium pentobarbital (80 mg / kg, ip), perfused intracardially with 10 ml of physiological saline containing heparin, and then 50 ml of PBS containing 2.5% glutaraldehyde and 1% paraformaldehyde . The hippocampus was separated from the brain, post-fixed for 2 hours using the same fixative as described above, and stored in PBS overnight at 4 ° C. Using a Vibratome, the hippocampus was prepared as a 60 μm section in the transverse direction. The fragment was osmized with 1% osmium tetroxide (in 0.1 M PB) for 1 hour, dehydrated with alcohol, flat inserted into Durcupan ACM (Fluka) and cured at 60 degrees for 48 hours. Small pieces containing hippocampal CA3 regions were cut into wipers and then attached to plastic blocks with cyanoacrylate. The ultra-thin fragments were cut and then attached to a Formvar-coated single slot grid. The fragment was stained with uranyl acetate and lead citrate and observed with an electron microscope (Hitachi H-7500; Hitachi) at an acceleration voltage of 80 kV. Digital images were captured with GATAN Digital Micrograph software running on a CCD camera (SC1000 Orius; Gatan) and saved as TIFF files. The brightness and contrast of the image were adjusted with Adobe Photoshop 7.0 (Adobe Systems).
1-6. 항체 및 면역블로팅1-6. Antibodies and Immunoblotting
아미노펩티다아제 P1 항체, GluA1 및 GluA2 항체는 종래 문헌[(S. H. Yoon et al., Biochemical and biophysical research communications 429, 204-209 (2012)), (M. H. Kim et al., the official journal of the Society for Neuroscience 29, 1586-1595 (2009))]을 참고하였다. PSD-95 (Thermo Scientific), 시냅신 I(Chemicon), vGluT1, NMDAR1, NMDAR2A, 및 NMDAR2B(BD Transduction Laboratories), LC3B, Flag, α-튜불린 (sigma), FosB, p-CamKII, 카스파아제-3, 칼페인-1, ERK, CREB, mTOR, 베클린1 (Cell signaling technology) 및 HA(Santa Cruz)는 각 회사에서 구입하였다.Aminopeptidase P1 antibodies, GluA1 and GluA2 antibodies have been described in the prior art (SH Yoon et al., Biochemical and biophysical research communications 429, 204-209 (2012)), (MH Kim et al., The official journal of the Society for Neuroscience 29, 1586-1595 (2009)). PD-CamKII, < / RTI > p-CamKII, < RTI ID = 0.0 > p-CamKII, < / RTI > PSD-95 (Thermo Scientific), Synapsin I (Chemicon), vGluT1, NMDAR1, NMDAR2A and NMDAR2B (BD Transduction Laboratories) 3, Calpain-1, ERK, CREB, mTOR, Cell signaling technology and HA (Santa Cruz) were purchased from each company.
면역블롯팅을 위하여, 마우스 전뇌 또는 해마는 프로테아제 억제 칵테일(Sigma)을 포함하는 균질화 완충액(320 mM 수크로스, 10 mM Tris-HCl, 5 mM EDTA, pH 7.4)으로 균질화하였다. 뇌의 준세포분획(subcelluar fraction)은 종래 기술(Huttner et al, The Journal of cell biology 96, 1374-1388 (1983))에 기술된 바와 같이 수행하였다. 균질 및 준세포 뇌 분획은 SDS-PAGE에서 분리하고, 니트로셀룰로스 막으로 옮겼다. 신호는 강화된 화학 발광(chemiluminescence)(GE Healthcare, UK)으로 검출하였다.For immunoblotting, the mouse whole brain or hippocampus was homogenized with homogenization buffer (320 mM sucrose, 10 mM Tris-HCl, 5 mM EDTA, pH 7.4) containing protease inhibition cocktail (Sigma). The subcellular fraction of the brain was performed as described in the prior art (Huttner et al, The Journal of cell biology 96, 1374-1388 (1983)). Homogeneous and subcellular brain fractions were separated on SDS-PAGE and transferred to a nitrocellulose membrane. Signals were detected with enhanced chemiluminescence (GE Healthcare, UK).
1-7. 슬라이스 전기생리학1-7. Slice electrophysiology
해마 슬라이스로부터 전기생리학적 기록은 종래 문헌[(M. H. Kim et al., the official journal of the Society for Neuroscience 29, 1586-1595 (2009)), (K. Han et al., PLoS biology 7, e1000187 (2009))]의 방법으로 수행하였다.Electrophysiological recordings from hippocampal slices have been reported in the literature (K. Han et al.,
구체적으로, 4-5주령 마우스의 해마 단편(400 μm)에 탄산가스(O2 95%, CO2 5%)를 통해 pH를 적정한 레코딩-aCSF (mM: NaCl 125, NaHCO3 26, KCl 2.5, NaH2PO4 1.25, MgCl2 1.3, CaCl2 2.5, D-글루코스 10)를 지속적으로 관류시켰고, 전체-세포 패치 클램프 레코딩은 MultiClamp 700B 증폭기(Axon instruments)를 이용하였다. AMPAR-mEPSCs는 ACSF에 피크로톡신 (50 μM) 및 TTX(1 μM)의 존재 하에 CsMeSO4 100 mM, TEA-Cl 10 mM, NaCl 8 mM, HEPES 10 mM, QX-314-Cl 5 mM, Mg-ATP 2 mM, Na-GTP 0.3 mM 및 EGTA 10 mM(pH 7.25, 290 mOsm)을 포함하는 용액이 들어있는 피펫(3-4 MΩ)을 이용하여 -70 mV에서 기록하였다. mIPSC 레코딩을 위하여, CsMeSO4 및 피크로톡신은 동일한 농도의 CsCl 및 NBQX(10 M)로 각각 대체되었으며, NMDAR-mEPSCs는 +40 mV 또는 -70 mV의 막전압 고정을 통해 기록하였다. IPSCs, Na-channels, AMPARs 및 mGluRs을 각각 억제하기 위하여 피크로톡신, TTX, NBQX 및 MPEP (10 μM)를 ACSF에 첨가하였다. -70 mV에서 NMDAR-mEPSCs를 기록하기 위하여, MgCl2가 제거된 ACSF를 사용하였다. AMPA/NMDA 비율 실험을 위하여, EPSCs는 ACSF로 채워진 깨진 유리 피펫(0.3~0.5 MΩ)을 이용하여 시냅스 축삭을 자극하여 유발하였다. -70 mV에서 AMPAR-EPSCs 기록 후, NMDAR-EPSCs는 +40 mV 탈분극 및 NBQX를 이용한 AMPAR 억제에 의해 분리되었다. 데이터는 Igor Pro (WaveMetrics)로 작성된 사용자 지정 매크로를 사용하여 분석하였다.More specifically, hippocampus fragments of 4-5-week-old mice of carbon dioxide in (400 μm) (O 2 95 %,
1-8. 행동 분석1-8. Behavior analysis
모든 행동 실험은 수컷 한배 새끼(littermates)에 수행하였다. 데이터는 Noldus (Ethovision XT) 유래의 videotracking 소프트웨어를 이용하여 분석하였다. 개방 필드 활동(open field activity)은 조명이 어두운 공간에서 흰색 플라스틱 챔버(40 x 40 x 40 cm)에 1시간 동안 두어 측정하였다. All behavioral experiments were performed on male littermates. Data were analyzed using videotracking software from Noldus (Ethovision XT). Open field activity was measured by placing it in a white plastic chamber (40 x 40 x 40 cm) for 1 hour in a darkened room with light.
신규한 물체 인식 테스트는 종래 문헌(M. H. Kim et al., the official journal of the Society for Neuroscience 29, 1586-1595 (2009))에 기술한 바와 같이 수행하였다. 구체적으로, 마우스를 개별적으로 각각 트레이닝 세션 전에 오픈 필드 챔버(40 x 40 x 40 cm)에 1시간 동안 적응시켜 놓았다. 2개의 신규한 물체는 트레이닝 세션 동안에 챔버 안에 배치하였으며, 회상 세션 동안 물체 중 하나를 새로운 것으로 교체하였다. 각 세션에는, 마우스가 10분 동안 물체를 탐색하도록 하였다. 트레이닝 및 회상 세션간의 간격은 24시간이었다. 선호 지수(preference index)는 새 물체 탐색에 걸린 시간을 새것 및 친숙한 물체를 탐색하는데 걸린 총 시간으로 나눈 값으로 계산하였다. New object recognition tests were performed as described in the prior art (M. H. Kim et al., The Journal of the Society for Neuroscience 29, 1586-1595 (2009)). Specifically, the mice were individually adapted to an open field chamber (40 x 40 x 40 cm) for one hour before each training session. Two new objects were placed in the chamber during the training session and one of the objects was replaced with a new one during the recall session. In each session, the mouse was allowed to search for objects for 10 minutes. The interval between training and recall sessions was 24 hours. The preference index was calculated by dividing the time spent searching for new objects by the total time spent searching for new and familiar objects.
공포 조건화는 챔버(Coulbourn instruments)에서 300초의 탐사 기간(exploration) 이후 18초의 소리(tone)와 2초의 발쇼크(foot shock, 0.7 mA)를 통해 공간(contextual) 및 소리신호(auditory cued)에 대한 공포 조건화 트레이닝 세션을 수행하였다. 그 후, 각 마우스를 홈 케이지에 돌려 보내기 전에 60초 동안 챔버에 두었다. 공간에 대한 공포 조건화 테스트는 트레이닝 전 5분동안 마우스 행동을 모니터링하고 24시간 후에 동일한 챔버(CS, contextual)에서 수행하였다. 소리신호에 의한 공포 조건화를 위하여, 마우스를 상이한 방의 별개 챔버에 배치하고, 소리신호가 제시되기 전 (pre-CS) 마우스의 행동을 180초 동안 모니터링 하고, 소리신호가 제시되는 동안 (180초, CS) 마우스의 행동을 모니터하였다. 활성의 억제 정도는 다음과 같이 나타낼 수 있다: (pre-CS 동안의 이동 거리 - CS 동안의 이동 거리)/(pre-CS 동안의 이동 거리)Fear conditioning is performed on the Coulbourn instruments with a sound of 18 seconds after a 300 second exploration and 2 seconds of foot shock (0.7 mA) for contextual and auditory cued A fear conditioning training session was conducted. Each mouse was then placed in the chamber for 60 seconds before being returned to the home cage. The fear conditioning test for space was performed in the same chamber (CS, contextual) after 24 hours monitoring mouse behavior for 5 minutes before training. For fear conditioning by sound signals, the mice were placed in separate chambers of different rooms, and the behavior of the mouse (pre-CS) was monitored for 180 seconds before the sound signal was presented (180 seconds, CS) mice. The degree of inhibition of activity can be expressed as: (travel distance during pre-CS-travel distance during CS) / (travel distance during pre-CS)
실시예Example 1. One. 메만틴Memantine (( memantinememantine ) 처리에 의한 ) Treatment Xpnpep1Xpnpep1 -/- 마우스 해마에서 액포 형성 감소, 신경 세포 사멸 억제를 통한 신경 퇴행 완화 효과 확인- / - Confirmation of neurodegenerative mitigation effect by suppression of vacuole formation and inhibition of neuronal cell death in mouse hippocampus
Xpnpep1-/- 마우스는 뇌의 해마 영역인 CA1, CA2 및 CA3 영역 중에서 CA3 영역의 신경세포 밀도가 유의적으로 감소된 특징이 있다. 또한, Xpnpep1-/- 마우스 뇌의 해마 CA3 영역은 비정상적으로 항진된 NMDAR(N-methyl-D-aspartate receptor) 신호가 나타나고, 상기 NMDAR는 GluN1(Glutamate[NMDA] receptor subunit zeta-1) 및 GluN2A(Glutamate [NMDA] receptor subunit epsilon-1) 단백질 발현이 증가되는 특징이 있다.The Xpnpep1 - / - mice are characterized in that the neuronal density of the CA3 region is significantly reduced in the hippocampal regions CA1, CA2 and CA3 of the brain. In addition, the hippocampal CA3 region of the Xpnpep1 - / - mouse brain exhibits abnormally enhanced N-methyl-D-aspartate receptor (NMDAR) signals, and the NMDAR includes GluN1 (Glutamate [NMDA] receptor subunit zeta-1) and GluN2A Glutamate [NMDA] receptor subunit epsilon-1) protein expression is increased.
이에 따라, 메만틴이 처리된 Xpnpep1-/- 마우스에서 비정상적으로 항진된 NMDAR 신호의 정상회복 및 상기 마우스의 뇌의 해마 CA3 영역에서 액포 감소, 신경 세포 사멸 및 관련 신호작용의 감소를 확인하여, 최종적으로 메만틴 처리가 신경 퇴행 완화 효과를 나타냄을 확인하였다. As a result, normal recovery of abnormally enhanced NMDAR signal in memantine-treated Xpnpep1 - / - mice and reduction of vacuolization, neuronal cell death and related signaling in the hippocampal CA3 region of the mouse brain were confirmed, And memantine treatment showed neurodegenerative effects.
보다 구체적으로, 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 제작한 해마 절편을 메만틴(2 μM) 또는 대조군으로서 식염수(saline)를 처리한 상태에서, NMDAR-mEPSCs 레코딩하고, 진폭 및 주파수를 확인하였다. 또한, 각 마우스에 도 1과 같이, 하루에 두번씩 39일간 메만틴 또는 식염수(10 mg/kg)를 복강 투여하고, 각 마우스 해마의 CA3 신경 밀도, HE 염색, 면역블랏, 면역반응의 정량화 등을 통하여 확인하였다. 그 결과를 도 2 내지 도 7에 나타내었다.More specifically, NMDAR-mEPSCs were recorded in the hippocampal slices prepared in the wild-type and Xpnpep1 knockout mice (Xpnpep1 - / -) with treatment with memantine (2 [mu] M) or saline as a control, Respectively. In addition, each mouse was intraperitoneally administered memantine or saline (10 mg / kg) twice a day for 39 days twice as shown in Fig. 1, and CA3 neuron density, HE staining, immunoblot, quantification of immune response Respectively. The results are shown in FIG. 2 to FIG.
도 2에 나타낸 바와 같이, 메만틴이 처리된 Xpnpep1-/- 마우스 해마 CA3영역의 신경세포에서는 비정상적으로 항진된 NMDAR 활성이 억제됨을 확인하였다. As shown in Fig. 2, it was confirmed that abnormally enhanced NMDAR activity was suppressed in nerve cells of CA3 region of hippocampal Xpnpep1 - / - mouse treated with memantine.
또한, 도 3에 나타낸 바와 같이, 메만틴이 처리된 Xpnpep1-/- 마우스의 신경 세포의 밀도가 식염수를 처리한 Xpnpep1-/- 마우스 보다 유의적으로 높음을 확인하였다. Furthermore, as shown in Fig. 3, it was confirmed that the density of neurons in Xpnpep1 - / - mice treated with memantine was significantly higher than that of Xpnpep1 - / - mice treated with saline.
도 4 및 도 5에 나타낸 바와 같이, 메만틴 또는 식염수가 처리된 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 면역 형광 기법과 HE 염색을 통해 액포생성 정도를 확인한 결과, 메만틴을 처리한 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 액포화가 현저히 감소함을 확인하였다. 또한, 상기 메만틴을 처리한 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서, 구체적으로, 뇌의 해마 CA3 영역에서 액포화 감소 효과가 나타남을 확인하였다. As shown in Figs. 4 and 5, the degree of vacuole formation was examined by immunofluorescence and HE staining in memantine or saline treated wild-type and Xpnpep1 knockout mouse (Xpnpep1 - / -). As a result, It was confirmed that the liquidation was significantly reduced in the Xpnpep1 knockout mouse (Xpnpep1 - / -). In addition, it was confirmed that the effect of decreasing liquid saturation was observed in the hippocampal CA3 region of the brain in Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine.
또한, 도 6에 나타낸 바와 같이, 세포 사멸과 관련된 p-CamKβ, p-CamKⅡα, Caspase-3(19KDa), Caspase-3(17KDa), Calpain-1(78KDa), Calpain-1(75KDa), LC3B- 및 LC3B-의 발현 수준을 확인한 결과, 메만틴을 처리한 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에서 식염수를 처리한 마우스보다 유의적으로 상기 인자들의 발현 수준이 감소함을 확인하였다. 따라서, 메만틴 처리는 신경 세포의 사멸과 관련된 신호작용을 억제함을 확인하였다. 도 7에 나타낸 바와 같이, 메만틴을 처리한 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)의 해마 CA3에서 식염수를 처리한 마우스보다 신경세포 사멸과 관련된 분자의 발현 수준이 현저히 감소함을 면역조직화학기법을 통하여 확인하였다. 6, caspase-3 (17KDa), Calpain-1 (78KDa), Calpain-1 (75KDa), and LC3B - and LC3B-, the level of expression of these factors was significantly decreased in Xpnpep1 knockout mice treated with memantine (Xpnpep1 - / -) than in mice treated with saline solution. Thus, it has been confirmed that memantine treatment inhibits signaling associated with neuronal death. As shown in FIG. 7, the expression levels of molecules related to neuronal cell death were significantly decreased in mice treated with saline in hippocampal CA3 of Xpnpep1 knockout mouse (Xpnpep1 - / -) treated with memantine, Respectively.
따라서, 상기와 같은 결과를 통하여 메만틴을 처리 시, Xpnpep1-/- 마우스에서 액포화가 감소되고, 신경 세포 사멸이 억제되며, 세포 사멸과 관련된 분자의 신호작용이 억제됨을 확인하였다.Thus, it was confirmed from the above results that when memantine was treated, liquidation was reduced in Xpnpep1 - / - mice, neuronal cell death was suppressed, and signaling of molecules involved in cell death was inhibited.
실시예Example 2. 2. 메만틴Memantine (( memantinememantine ) 처리에 의한 ) Treatment Xpnpep1Xpnpep1 -/- 마우스의 발달 장애 개선 확인- / - Confirm improvement of mouse developmental disorder
메만틴 처리에 의한 Xpnpep1-/- 마우스의 발달 장애 개선 또는 치료 정도를 확인하였다.And the improvement or treatment of Xpnpep1 - / - mice by memantine treatment was confirmed.
구체적으로, 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에 메만틴(10 mg/kg) 또는 식염수(saline)를 매일 2회씩 복강주입을 통해 처리하고, 키, 몸무게 및 전두 사이즈 및 각 어린 마우스의 생존률을 확인하였다. 그 결과를 도 8 내지 도 11에 나타내었다.Specifically, memantine (10 mg / kg) or saline was treated twice daily with intraperitoneal injection in wild type and Xpnpep1 knockout mice (Xpnpep1 - / -), and the height, weight, Of the survival rate. The results are shown in Fig. 8 to Fig.
도 8에 나타낸 바와 같이, 메만틴이 처리된 Xpnpep1-/- 마우스가 식염수가 처리된 Xpnpep1-/- 마우스보다 유의적으로 키가 더 큼을 확인하였다. 도 9에 나타낸 바와 같이, Xpnpep1-/- 마우스에 메만틴을 처리하는 경우, 식염수를 처리한 대조군과 비교하여 몸무게가 유의적으로 증가함을 확인하였다. As shown in Fig. 8, it was confirmed that Xpnpep1 - / - mice treated with memantine were significantly taller than Xpnpep1 - / - mice treated with saline. As shown in Fig. 9, when Xpnpep1 - / - mice were treated with memantine, the body weight was significantly increased as compared with the control group treated with saline.
또한, 도 10에 나타낸 바와 같이, 메만틴이 처리된 Xpnpep1-/- 마우스가 식염수가 처리된 Xpnpep1-/- 마우스보다 유의적으로 전두의 길이가 더 길고 두께가 더 두꺼움을 확인하여 소두증을 개선할 수 있음을 확인하였다.In addition, as shown in Fig. 10, it was confirmed that memantine-treated Xpnpep1 - / - mice significantly longer in frontal length and thicker than Xpnpep1 - / - mice treated with saline to improve microcephaly Respectively.
또한, 도 11에 나타낸 바와 같이, 식염수가 처리된 Xpnpep1-/- 마우스는 생존률이 시간에 지남에 따라 떨어지나, 메만틴이 처리된 Xpnpep1-/- 마우스는 야생형과 유사한 생존률을 보임을 확인하였다.In addition, as shown in Fig. 11, it was confirmed that the survival rate of Xpnpep1 - / - mice treated with saline decreased with time, but the survival rate of Xpnpep1 - / - mice treated with memantine was similar to that of wild type.
따라서, 상기와 같은 결과를 통하여 Xpnpep1-/- 마우스에 메만틴을 처리 시, 미처리 대조군과 비교하여 키가 더 크고, 몸무게가 증가하며, 소두증을 개선하고 생존률이 야생형과 유사하게 높음을 확인하여 메만틴이 발달 장애 개선에 효과적임을 확인하였다.Thus, the results showed that when Xpnpep1 - / - mice were treated with memantine, the mice were larger in height, increased in body weight, improved in microcephaly and higher in survival rate than wild type mice Tin was effective in improving developmental disability.
실시예 3. 메만틴 처리에 의한 Xpnpep1-/- 마우스의 행동 이상 개선 확인Example 3 Confirmation of behavioral improvement of Xpnpep1 - / - mice by memantine treatment
메만틴 처리에 의한 Xpnpep1-/- 마우스의 행동 장애(과잉 행동, 인지기능 및 학습과 기억 기능 저하) 개선 효과를 확인하였다.(Hyperactivity, cognitive function and learning and memory impairment) of Xpnpep1 - / - mice by memantine treatment.
구체적으로, 상기 실험예 1-8에 기재된 바와 같이, 야생형 및 Xpnpep1 넉아웃 마우스(Xpnpep1-/-)에 메만틴(10 mg/kg) 또는 식염수(saline)를 매일 2회씩 39일 동안 처리하고, 개방형 필드 테스트, 신규한 물체 인지 테스트, 공간에 대한 공포 조건화 테스트를 수행하였다. 그 결과를 도 12 내지 도 15에 나타내었다.Specifically, memantine (10 mg / kg) or saline was treated twice a day for 39 days in wild-type and Xpnpep1 knockout mice (Xpnpep1 - / -) as described in Experimental Example 1-8, Open field tests, novel object recognition tests, and fear conditioning tests on space. The results are shown in Figs. 12 to 15. Fig.
도 12에 나타낸 바와 같이, 개방형 필드 테스트에서, 메만틴이 처리된 Xpnpep1-/- 마우스가 식염수가 처리된 Xpnpep1-/- 마우스보다 유의적으로 이동 거리(m)가 짧아짐을 확인하였다. As shown in Fig. 12, in the open field test, it was confirmed that the movement distance (m) of Xpnpep1 - / - mice treated with memantine was significantly shorter than that of the Xpnpep1 - / - mice treated with saline.
또한, 도 13에 나타낸 바와 같이, 이동 거리 및 마우스의 몸무게간의 관계를 분석한 결과, 이는 과잉행동 및 발달 지연과 강한 상관관계가 있음을 확인하였다 (R = -0.852). As shown in FIG. 13, the relationship between the movement distance and the weight of the mouse was analyzed. As a result, it was confirmed that there was a strong correlation with hyperactivity and developmental delay (R = -0.852).
또한, 도 14에 나타낸 바와 같이, 신규한 물체 인지 테스트에서, 메만틴이 처리된 Xpnpep1-/- 마우스가 식염수가 처리된 Xpnpep1-/- 마우스보다 유의적으로 신규한 물체에 대한 선호 비율이 높음을 확인하고, 야생형 마우스와 유사한 수준의 선호 수준을 나타냄을 확인하였다.In addition, as shown in Fig. 14, in a novel object or test, the preference ratio of memantine-treated Xpnpep1 - / - mice to a novel object significantly higher than that of saline-treated Xpnpep1 - / - mice , And it was confirmed that they showed similar level of preference to that of wild type mice.
또한, 도 15에 나타낸 바와 같이, 공간에 대한 공포 조건화 테스트에서, 메만틴이 처리된 Xpnpep1-/- 마우스가 식염수가 처리된 Xpnpep1-/- 마우스보다 자극전(Pre-CS(conditioned stimulus)) 또는 자극(CS) 후 반응에 있어서, 유의한 차이가 있음을 확인하였다. 보다 구체적으로, 행동 억제는 메만틴이 처리된 Xpnpep1-/- 마우스가 식염수가 처리된 Xpnpep1-/- 마우스보다 유의적으로 높음을 확인하였다. 또한, 메만틴 처리군에서는 조건화 자극(CS) 후 유의적으로 이동거리가 감소하였으며, 대조군과 비교하여 활동도가 현저히 감소함을 확인하였다. In addition, as shown in Fig. 15, in a fear conditioning test for space, Xpnpep1 - / - mice treated with memantine were pre-CS (conditioned stimulus) or After the stimulation (CS), there was a significant difference in the responses. More specifically, behavioral inhibition was found to be significantly higher for memantine-treated Xpnpep1 - / - mice than for saline-treated Xpnpep1 - / - mice. In the memantine treated group, the movement distance was significantly decreased after the conditioning stimulus (CS), and the activity was significantly decreased compared with the control group.
상기의 일련의 실험 결과를 통하여, Xpnpep1-/- 마우스 뇌의 해마 CA3 영역에는 비정상적으로 항진된 NMDAR(N-methyl-D-aspartate receptor) 활성이 나타나고, 이로 인해 유도되는 신경적, 행동적 장애들이 메만틴 처리에 의해 유의적으로 치료 개선될 수 있음을 확인하였다. 이러한 결과는 뉴런에서의 대사성 장애가 NMDAR의 항상성을 교란시키고, 이에 따라 시냅스의 기능 장애를 유발한다는 것을 나타낸다. 도 16은 본 발명의 메만틴의 작용 효과를 도식화한 결과이다. 따라서, 메만틴의 처리는 비정상적으로 항진된 NMDAR의 기능을 정상적인 수준으로 회복시키고 다양한 선천성 대사 이상 장애 및 이에 의해 유발되는 신경적, 정신의학적 장애를 개선할 수 있다. The results of the above series of experiments show that NMDAR (N-methyl-D-aspartate receptor) activity is abnormally enhanced in the hippocampal CA3 region of Xpnpep1 - / - mouse brain and neural and behavioral disorders It was confirmed that the treatment can be significantly improved by memantine treatment. These results indicate that metabolic disturbances in neurons disturb the homeostasis of NMDAR, thereby causing dysfunction of the synapses. Fig. 16 shows the result of illustrating the action and effect of memantine of the present invention. Thus, treatment with memantine may restore abnormal functioning of NMDAR to normal levels and ameliorate various congenital metabolic disorders and the neurological and psychiatric disorders caused thereby.
특히, 본 발명의 메만틴은 Xpnpep1 유전자 넉아웃을 통해 유발되는 선천성 대사 이상으로 인하여 나타나는 발달 지체, 소두증, 과잉 행동, 주의력 결핍, 간질, 지적 장애 등과 같은 증상을 모두 개선시킬 수 있으므로, 선천성 대사 이상을 포괄적으로 치료 및 개선할 수 있다. In particular, memantine of the present invention can ameliorate symptoms such as developmental delay caused by congenital metabolic abnormalities induced by Xpnpep1 gene knockout, microcephaly, hyperactivity, attention deficit, epilepsy and intellectual disability, Can be treated and improved in a comprehensive manner.
Claims (7)
상기 선천성 대사 이상증은 발달 지체, 소두증, 과잉 행동, 주의력 결핍, 간질, 지적 장애, 페닐케톤뇨증, 단풍당뇨증, 호모시스틴뇨증, 갈락토스혈증, 갑상선기능저하증 및 부신기능항진증으로 이루어진 군에서 선택된 1종 이상인 것을 특징으로 하는, 선천성 대사 이상증 예방 또는 치료용 약학적 조성물.The method according to claim 1,
The congenital metabolic dysfunction is one or more selected from the group consisting of developmental delay, microcephaly, hyperactivity, attention deficit disorder, epilepsy, intellectual disability, phenylketonuria, colorectal diabetes mellitus, homocystinuria, galactosemia, hypothyroidism, ≪ / RTI > or a pharmaceutically acceptable salt thereof.
상기 메만틴은 복강 내 투여용인 것을 특징으로 하는, 선천성 대사 이상증 예방 또는 치료용 약학적 조성물.The method according to claim 1,
The pharmaceutical composition for preventing or treating congenital metabolic dysfunction, wherein the memantine is for intraperitoneal administration.
상기 선천성 대사 이상증은 뇌 해마의 CA3(Region of hippocampus proper) 영역 신경세포 밀도가 낮아진 것을 특징으로 하는, 선천성 대사 이상증 예방 또는 치료용 약학적 조성물.The method according to claim 1,
The pharmaceutical composition for preventing or treating congenital metabolic dysfunction, wherein the congenital metabolic dysfunction is characterized in that the concentration of neurons in the region of hippocampus proper (CA3) of the brain hippocampus is lowered.
상기 뇌 해마의 CA3 영역 신경세포는 비정상적으로 항진된 NMDAR(N-methyl-D-aspartate receptor) 활성이 나타나는 것을 특징으로 하는, 선천성 대사 이상증 예방 또는 치료용 약학적 조성물.5. The method of claim 4,
Wherein the CA3 domain neuron of the brain hippocampus exhibits abnormally enhanced NMDAR (N-methyl-D-aspartate receptor) activity.
상기 뇌 해마의 CA3 영역 신경세포는 GluN1(Glutamate[NMDA] receptor subunit zeta-1) 및 GluN2A(Glutamate [NMDA] receptor subunit epsilon-1) 단백질 발현이 증가되는 것을 특징으로 하는, 선천성 대사 이상증 예방 또는 치료용 약학적 조성물.5. The method of claim 4,
The CA3 region neurons of the brain hippocampus are characterized by increased expression of GluN1 (Glutamate [NMDA] receptor subunit zeta-1) and GluN2A (Glutamate [NMDA] receptor subunit epsilon-1) A pharmaceutical composition.
A health functional food composition for preventing congenital metabolic dysfunction comprising memantine as an active ingredient.
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