KR20190134130A - Novel composition useful for prevention or treatment of dementia by inhibiting synthesis of β-amyloid - Google Patents
Novel composition useful for prevention or treatment of dementia by inhibiting synthesis of β-amyloid Download PDFInfo
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- KR20190134130A KR20190134130A KR1020180059373A KR20180059373A KR20190134130A KR 20190134130 A KR20190134130 A KR 20190134130A KR 1020180059373 A KR1020180059373 A KR 1020180059373A KR 20180059373 A KR20180059373 A KR 20180059373A KR 20190134130 A KR20190134130 A KR 20190134130A
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- dementia
- amyloid
- present
- beta
- synthesis
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Abstract
Description
본 발명은 베타-아밀로이드(Aβ) 합성 억제를 통한 치매증상 개선을 위한 새로운 치료용 조성물에 관한 것으로, 더욱 구체적으로는 독성 베타-아밀로이드(Aβ)의 합성을 저해하는 효과를 가지는 린코마이신(lincomycin), 아자세린(azaserine) 또는 벨라돈나(belladonna) 추출물을 유효성분으로 함유하는 치매 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a novel therapeutic composition for improving dementia symptoms by inhibiting beta-amyloid (Aβ) synthesis. More specifically, lincomycin having an effect of inhibiting the synthesis of toxic beta-amyloid (Aβ). , Azaserrine or It relates to a composition for preventing or treating dementia, which contains belladonna extract as an active ingredient.
치매(dementia)는 인구의 급속한 고령화와 함께 심각한 사회문제로 대두되고 있는 대표적인 노년기 질환으로서, 정상적으로 생활해오던 사람이 후천적으로 다양한 원인에 의해 뇌기능이 손상되면서 지적능력을 상실하고 인지장애, 행동 및 성격의 점진적 황폐화에 의해 이전에 비해 인지 기능이 지속적이고 전반적으로 저하되어 일상생활에 상당한 지장을 초래하는 퇴행성 질환이다. 여기서 인지 기능이란 기억력, 언어 능력, 시공간 파악 능력, 판단력, 학습능력, 저장능력 및 추상적 사고력 등 다양한 지적 능력을 가리키는 것으로 각 인지기능은 특정 뇌 부위와 밀접한 관련이 있다. Dementia is a representative old age disease that has emerged as a serious social problem with the rapid aging of the population. The dementia suffers from intellectual impairment, cognitive impairment, behavior and It is a degenerative disease that causes cognitive function to be continuously and deteriorated by the progressive gradual deterioration of personality, which causes significant obstacles in daily life. Here, cognitive function refers to various intellectual abilities such as memory, language ability, space-time grasping ability, judgment ability, learning ability, storage ability, and abstract thinking ability.
특히, 알츠하이머병(Alzheimer's disease, AD)은 특징적인 병변인 신경반(neuritic plaque)과 신경섬유다발(neurofibrillary tangle) 등이 관찰되고, 육안 관찰 시에는 신경세포 소실로 인해 전반적 뇌 위축 소견을 보이는 것으로 알려져 있다. 이러한 뇌 병리 소견은 질병 초기에는 주로 기억력을 담당하는 주요 뇌 부위인 해마와 내후각뇌피질 부위에 국한되어 나타나지만 점차 두정엽, 전두엽 등을 거쳐 뇌 전체로 퍼져나간다. 베타 아밀로이드(β-amyloid, Aβ)는 노인반(senile plaque)의 주요 구성성분으로 알츠하이머병이 발생하는 중요한 원인으로 추정되고, 활성 산소종(reactive oxygen species, ROS)을 발생시켜 산화적 스트레스(oxidative stress)로 인한 뇌신경세포의 괴사 및 세포사멸을 유발하는 것으로 알려져 있다. 일부 노화로 인한 신경퇴행성으로 발병하여 진행과정이 느린 경우를 노인성 치매(senile dementia)라고 하며 알츠하이머병은 진행성으로 노인성 치매보다 증상의 진행속도가 빠르다. In particular, Alzheimer's disease (AD) is characterized by characteristic lesions such as neuritic plaque and neurofibrillary tangle, and when visually observed, they show general brain atrophy due to neuronal loss. Known. These pathological findings are limited to the hippocampus and the olfactory olfactory cortex, which are the major brain areas that are primarily responsible for memory, but gradually spread throughout the brain through the parietal lobe and frontal lobe. Beta amyloid (β-amyloid, Aβ) is a major component of the senile plaque and is considered to be an important cause of Alzheimer's disease, and oxidative stress due to the generation of reactive oxygen species (ROS). Is known to cause necrosis and apoptosis of neuronal cells. Some cases of neurodegenerative disease caused by aging and slow progression are called senile dementia. Alzheimer's disease is progressive and progresses faster than senile dementia.
현재까지 알려진 항치매 약물은 치매 환자의 인지 기능 저하를 예방하고 개선시키는 것으로서, 콜린에스테라제(cholinesterase) 차단제, 혈관 확장제, 도내피질(donepezil), 리바스티그민(revastigmine), 갈란타민(galantamine), 뇌영양제(nootropics) 등의 약물요법이 있고, 행동 심리증상 치료를 위한 항우울제, 진정제 등의 향정신성 약물요법과 심리, 인지, 행동, 작업, 재활치료의 비약물요법이 활용되고 있다.Anti-dementia drugs known to date are used to prevent and improve cognitive decline in dementia patients, including cholinesterase blockers, vasodilators, donepezil, revastigmine, and galantamine. There are also pharmacotherapy such as nootropics, and psychotropic drug therapy such as antidepressants and sedatives for the treatment of behavioral psychological symptoms, and non-pharmaceutical therapy of psychology, cognition, behavior, work, and rehabilitation.
이러한 치매 예방 및 개선효과를 나타내는 조성물로서 대한민국 등록특허 제10-1807953호에서는 고수 추출물을 이용하여 치매의 원인물질인 Aβ42의 독성을 감소시키고, 신경세포의 사멸을 억제하며 운동능력을 개선하는 효능을 개시하고 있다. 또한, 대한민국 등록특허 제10-1801478호에서는 비오카닌 A를 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 조성물로 BACE1(beta-secretase 1)의 활성을 억제하여 베타-아밀로이드 플라크의 생성을 억제하여 퇴행성 뇌질환을 예방 또는 치료하는 방법을 개시하고 있다.As a composition exhibiting the effect of preventing and improving dementia, the Republic of Korea Patent No. 10-1807953 uses the coriander extract to reduce the toxicity of Aβ42, a causative agent of dementia, inhibit the death of nerve cells and improve the exercise ability. It is starting. In addition, the Republic of Korea Patent No. 10-1801478 is a composition for the prevention or treatment of degenerative brain disease, including biocanine A as an active ingredient inhibits the activity of BACE1 (beta-secretase 1) to produce beta-amyloid plaques Disclosed is a method for preventing or treating degenerative brain disease.
상기에서 기재한 바와 같이, 치매에 효과적인 생약 추출물 개발이 주요한 관심의 대상이 되고 있으며, 이에 대한 연구가 이루어지고 있으나, 아직 미비한 실정이다.As described above, the development of an effective herbal extract for dementia has been of major interest, and research on this has been made, but it is still inadequate.
이에 본 발명자는 치매 치료의 작용기전을 규명하고 이를 치매 치료에 활용하고자 노력한 결과, 상기와 같은 문제점을 해소함과 동시에 치매 치료에 효율적으로 적용할 수 있는 치매 예방 또는 치료용 조성물을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors have tried to identify the mechanism of action of dementia treatment and use it in the treatment of dementia, as well as to solve the above problems and to identify a composition for preventing or treating dementia that can be effectively applied to the treatment of dementia and the present invention Completed.
따라서, 본 발명에서 해결하고자 하는 기술적 과제는 치매 치료 작용기전을 활용한 치매 치료효과가 우수한 치매 예방 또는 치료용 조성물을 제공하기 위한 것이다. Therefore, the technical problem to be solved in the present invention is to provide a composition for preventing or treating dementia excellent in dementia treatment effect utilizing the dementia treatment mechanism.
또한, 본 발명의 또 다른 목적은 독성 베타-아밀로이드(Aβ)의 합성을 저해하는 효과를 가지는 린코마이신(lincomycin), 아자세린(azaserine) 또는 벨라돈나(belladonna) 추출물을 유효성분으로 함유하는 치매 예방 또는 치료용 조성물을 제공하는 것이다.In addition, another object of the present invention is lincomycin (azaserine) or azaserine (lincomycin) having the effect of inhibiting the synthesis of toxic beta-amyloid (Aβ) or It is to provide a composition for preventing or treating dementia containing belladonna extract (belladonna) as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
상기한 기술적 과제를 해결하기 위하여, 본 발명에서는 베타-아밀로이드(Aβ) 합성을 억제하는 것을 특징으로 하는 린코마이신(lincomycin)을 유효성분으로 함유하는 치매 예방 또는 치료용 조성물을 제공한다.In order to solve the above technical problem, the present invention provides a composition for preventing or treating dementia containing lincomycin as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
또한, 본 발명에서는 베타-아밀로이드(Aβ) 합성을 억제하는 것을 특징으로 하는 아자세린(azaserine)을 유효성분으로 함유하는 치매 예방 또는 치료용 조성물을 제공한다.The present invention also provides a composition for preventing or treating dementia, which contains azaserrine as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
또한, 본 발명에서는 베타-아밀로이드(Aβ) 합성을 억제하는 것을 특징으로 하는 벨라돈나(belladonna) 추출물을 유효성분으로 함유하는 치매 예방 또는 치료용 조성물을 제공한다.In another aspect, the present invention provides a composition for preventing or treating dementia, containing a belladonna extract (belladonna) as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
본 발명에서, 고령자의 뇌에 특징적인 노인반(senile plaque)의 주성분은 독성 물질인 베타-아밀로이드 단백질(β-amyloid protein, 일명 Aβ)이다. 즉, 아밀로이드 전구 단백질(amyloid precursor protein-APP) 유전자는 염색체 21번에 위치하며 대부분의 조직에서 발현되어 있고 주로 3개의 가분자종이 있는데 이들은 아미노산 수에 따라 APP695, APP751, APP770이고 APP는 I형 막단백질이다.In the present invention, the main component of the senile plaque characteristic of the brain of the elderly is beta-amyloid protein (aka Aβ) which is a toxic substance. In other words, amyloid precursor protein (APP) gene is located on chromosome 21 and is expressed in most tissues, and there are mainly three polymolecular species. These are APP695, APP751, and APP770 depending on the number of amino acids. Protein.
여기서, 염색체 14번에 위치하는 프리세닐린 1(PS 1) 유전자와 염색체 1번에 위치하는 프리세닐린 2(PS 2) 유전자는 분비단백질로서 세포막을 통과하는 기구(감각수용체+ 신호펩티드)의 막관통단백질로서의 기능을 가지고 있다.Herein, the presenilin 1 (PS 1) gene located on chromosome 14 and the presenilin 2 (PS 2) gene located on chromosome 1 are secreted proteins that are used to pass the cell membranes (sensor receptors + signal peptides). It has a function as a transmembrane protein.
이때, 이 유전자들의 펩티드 합성은 리보솜 23SrRNA가 아마노산실에 프리세닐린 1(카르복실기말단 펩티딜tRNA로서 존재)과 프리세닐린 2의 합성에 의하여 생성된다. 그리고 이들 유전자들은 베타-세크리타제(β-secretase) 작용 후, 감마-세크리타제(γ-secretase) 작용에 의해서 모두 독성 물질인 베타-아밀로이드 단백질(Aβ)을 과다 생성시켜 대뇌 혈관벽에 침착되어 노인반(senile plaque)이 된다.At this time, peptide synthesis of these genes is generated by the synthesis of ribosome 23SrRNA into pre-sanelin 1 (present as carboxyl terminal peptidyl tRNA) and presenilin 2 in the amanosanyl acid chamber. And these genes, after beta-secretase (β-secretase) action, by gamma-secretase action (γ-secretase) all over-producing beta-amyloid protein (Aβ) to be deposited on the cerebral blood vessel wall is deposited in the senile plaque ( senile plaque).
본 발명에서, 노인성 치매(senile dementia)는 아밀로이드 전구 단백질이 베타-아밀로이드 단백질(Aβ)로 변화됨으로써 신경전달물질과 신호펩티드가 결합되는 정상적인 신진대사를 할 수 없는 상태를 말한다. 즉, 신경전달물질과 신호펩티드로서 기능을 유지해야 하는데 독성 물질인 베타-아밀로이드 단백질(Aβ)로 과다 생성되어 본래의 기능인 신경전달물질과 결합되어 이온채널투과로 막을 통과하지 못해 온몸에 신경전달물질의 불균형 신진대사로 인하여 정상인으로서의 인지능이 결여되어 노인성치매가 된다. In the present invention, senile dementia refers to a condition in which normal metabolism of neurotransmitters and signal peptides is unable to bind due to changes in amyloid precursor protein to beta-amyloid protein (Aβ). In other words, it must maintain its function as a neurotransmitter and a signal peptide. It is excessively produced by the toxic beta-amyloid protein (Aβ) and combined with the neurotransmitter, which is an original function, and cannot pass through the membrane through ion channel permeation. Due to the imbalance of metabolism, senile dementia is lacking as a normal person, resulting in senile dementia.
여기서, 신호펩티드(signal peptide)는 전구체 폴리펩티드로 합성하는 특정 종류의 분비단백질인데, 세포막단백질로서 N말단 측에 포함되는 막을 통과할 때 신호가 되는 아미노산 순서 15~25개 정도의 아미노산으로 구성되고, N말단 근처에 염기성 아미노산을 갖는 것 외에는 주로 소수성 아미노산을 포함한다. 특히 그 중앙부에서는 하전을 띠는 아미노산을 발견할 수 없다. 이 배열로 인해 합성 도중에 전구체폴리펩티드가 소포체막에 결합한다. 이어 막결합형 폴리솜이 형성되고, 폴리펩티드사슬은 합성되면서 막을 통과한다. 막 통과와 동시에 막에 있는 신호펩티드 가수분해효소가 신호펩티드를 절단, 제거한다. 동물세포의 분비단백질이 세포막을 통과하는 기구를 설명하기 위한 시그널설(signal hypothesis)이 제기된바 있다. 그 후 막단백질의 전구체에서도 발견되고 진핵세포, 원핵세포에도 존재한다는 사실이 밝혀져서 단백질의 국재화에 널리 관여하는 것으로 추정하고 있다.Here, the signal peptide is A specific type of secretory protein synthesized from a precursor polypeptide, which is a cell membrane protein composed of 15 to 25 amino acids in amino acid sequence that is signaled when passing through a membrane included on the N-terminal side and having a basic amino acid near the N-terminal. Other mainly hydrophobic amino acids. In particular, no charged amino acids can be found in the center. This arrangement causes the precursor polypeptide to bind to the endoplasmic reticulum membrane during synthesis. Then, membrane-bound polysomes are formed, and the polypeptide chains pass through the membrane as they are synthesized. Simultaneously through the membrane, the signal peptide hydrolase in the membrane cleaves and removes the signal peptide. Signal hypothesis has been suggested to explain the mechanism by which secretory proteins of animal cells cross the cell membrane. Later, it was found that it is found in the precursors of membrane proteins and also in eukaryotic and prokaryotic cells, presumably involved in the localization of proteins.
여기서, 펩티드기전달효소(peptidyl transferase)는 폴리펩티드사슬 연쇄반응에서의 펩티드결합 형성을 촉매하는 효소로서. 리보솜의 대단위 및 소단위에 내재한다. 펩티드결합은 리보솜 P부위에 위치하는 연장도 상의 펩티드사슬(펩티딜tRNA로서 존재)의 카르복실 말단이 리보솜 A부위에 새로 들어오는 아미노아실tRNA의 아미노기에 전이됨으로써 형성된다. 세균의 경우 50S소단위 내에 존재하고 활성에는 리보솜 단백질의 L6, L11, L16 등이 관여하는 것으로 알려져 있지만 촉매활성의 본체는 23SrRNA가 나타내는 리보자임 활성으로 보고 있다.Here, the peptide transferase (peptidyl transferase) As an enzyme catalyzing the formation of peptide bonds in a polypeptide chain reaction. Inherent in major and minor units of ribosomes. Peptide bonds are formed by the transfer of the carboxyl terminus of the peptide chain (present as a peptidyl tRNA) on the extension of the ribosome P site to the amino group of the aminoacyl tRNA newly entering the ribosome A site. Bacteria exist within 50S subunits and are known to be involved in the activity of L6, L11, L16 of ribosomal proteins, but the main body of catalytic activity is reported to be ribozyme activity represented by 23SrRNA.
여기서, 펩티딜전달효소는 단백질생합성의 종결에도 관여하는 리보솜 P부위에 존재하는 펩티딜tRNA의 펩티드사슬과 tRNA간의 에스테르결합을 가수분해하는 반응을 촉매하여 신호펩티드와 결합하여 독성 베타-아밀로이드 단백질(Aβ)을 생성하려 한다. 이때 세균의 펩티딜전달효소 활성은 클로람페니콜, 린코마이신, 카보마이신 등을 투입시켜, 진핵세포의 것은 시클로헥시미드에 의해 저해되어, 즉, 다시말해 23SrRNA가 신호펩티드와 결합하지 못해 독성 베타-아밀로이드 단백질(Aβ)로 되는 것을 막고 본래기능인 신호펩티드로서 신경전달물질과 결합하여 막을 통과하는 정상적이고 균형있는 신진대사가 이루어지도록 한다.Here, the peptidyl transferase catalyzes the reaction of hydrolysis of the ester bond between the peptide chain of the peptidyl tRNA and the tRNA present in the ribosome P region, which is also involved in the termination of protein biosynthesis, and binds to the signal peptide to produce toxic beta-amyloid protein Try to produce Aβ). At this time, bacterial peptidyl transferase activity was injected with chloramphenicol, lincomycin, carbomycin, etc., and eukaryotic cells were inhibited by cycloheximide, that is, 23SrRNA could not bind to signal peptide and thus toxic beta-amyloid. It prevents it from becoming a protein (Aβ) and combines it with a neurotransmitter to ensure normal and balanced metabolism through the membrane.
본 발명에서, 치매 치료에 적용되는 린코마이신(lincomycin, C18H34N2O6S)은 저해제로서, 이의 작용기전은 유전자23SrRNA가 나타내는 리보자임 활성에 의하여 카르복실 말단이 아미노아실tRNA의 아미노기에 전이됨으로써 펩티드결합이 형성되는 과정 자체가 일어나지 못하도록 억제함으로써 치매 치료 또는 개선에 효과를 나타낼 수 있다.In the present invention, lincomycin (C 18 H 34 N 2 O 6 S) applied to the treatment of dementia is an inhibitor, its mechanism of action is the amino group of aminoacyltRNA at the carboxyl terminus by ribozyme activity represented by gene 23SrRNA. It can be effective in treating or improving dementia by inhibiting the process of forming a peptide bond itself by transferring to.
이때, 상기 린코마이신(lincomycin)은 Strep-tomyces lincolnensis가 생산하는 항생물질로서 작용기구는 단백질합성 저해로, 세균리보솜의 50S 소단위에 결합하여 펩티드전이반응을 저해하며, 혐기성 균에 대해서는 좀더 강력한 항균력을 갖는다.At this time, the lincomycin is an antibiotic produced by Strep-tomyces lincolnensis, the mechanism of action is the inhibition of protein synthesis, binds to the 50S subunit of bacterial ribosomes, inhibits the peptide transfer reaction, and has a stronger antimicrobial activity against anaerobic bacteria. Have
또한, 본 발명에서, 아자세린(azaserine) 조성물은 γ-글루타밀트랜스펩티다아제(γ-glutamyltranspeptidase)의 활성을 저해하여 베타-아밀로이드 단백질(Aβ) 합성을 억제함으로써 치매 치료 또는 개선에 효과를 나타낼 수 있다.In addition, in the present invention, the azaserrine composition may be effective in treating or improving dementia by inhibiting the beta-amyloid protein (Aβ) synthesis by inhibiting the activity of γ-glutamyltranspeptidase. .
[구조식 1] 아자세린(azaserine)Structural Formula 1 Azaserine
본 발명에서, 유전자23SrRNA가 막 통과와 동시에 막에 있는 신호펩티드가수분해효소에 의해서 신호펩티드를 절단하고 동시에 신호펩티드와 에스테르결합하고 γ-secretas의 작용에 의해서 독성 베타-아밀로이드 단백질(Aβ)로 된다. 이때, 해독대사에 중요한 역할을 하는 것은 글루타티온(glutathione)이며, 감마-세크리타제(γ-secretase)에 작용하는 γ-글루타밀트랜스펩티다아제(γ-glutamyltranspeptidase, γ-GTPase)는 글루타티온에서 감마-글루타밀(γ-glutamyl)기를 떼내어 아미노산과 결합하는 반응을 촉매하는 효소로서, 아자세린(azaserine)에 의해 저해되어 독성 베타-아밀로이드 단백질(Aβ)로 되는 것을 막을 수 있다.In the present invention, the gene 23SrRNA cleaves the signal peptide by the signal peptide hydrolase on the membrane at the same time as it passes through the membrane, simultaneously ester-links the signal peptide and becomes a toxic beta-amyloid protein (Aβ) by the action of γ-secretas. . At this time, an important role in the detox metabolism is glutathione, and γ-glutamyltranspeptidase (γ-GTPase), which acts on gamma-secretase, is gamma-glutamyl in glutathione. It is an enzyme that catalyzes the reaction of the ( γ- glutamyl) group to bind amino acids. It can be inhibited by azaserrine and prevented from becoming toxic beta-amyloid protein (Aβ).
본 발명에서, 벨라돈나(Belladonna) 추출물은 가지과에 속하는 식물인 베라돈나에 들어 있는 트로파산과 트로핀의 에스테르화합물로서 무수카린아세틸콜린 수용체와 결합하여 아세틸콜린의 무스카린유사작용을 억제한다. In the present invention, Belladonna extract is an ester compound of Tropaic acid and Tropin contained in Veradonna, a plant belonging to the branch family, and binds to the anhydrous carline acetylcholine receptor to inhibit the muscarinic action of acetylcholine.
이때, 아세틸콜린 수용체는 신경전달물질인 아세틸콜린을 받는 창구역할을 하는 당단백질의 일종으로 시냅스후막에 매몰 형태로 존재하며 이온채널을 내포하고 있어 아세틸콜린이 결합되면 막의 이온투과성을 변화시켜 신경세포의 흥분을 다음 세포로 전달함으로써 아세틸콜린이 무스카린성 아세틸콜린수용체에 결합하는 것으로서 일어나며, 수용체 저해제인 아트로핀에 의해 차단된다. 아세틸콜린은 부교감신경말단의 전달물질이므로 아트로핀은 부교감계 지배가 많은 기관과 조직에 작용한다.At this time, acetylcholine receptor is a type of glycoprotein that acts as a nasal passage to receive acetylcholine, a neurotransmitter. It exists in the form of burying in the synaptic membrane and contains ion channels. When acetylcholine is combined, nerve cell is changed by changing the ion permeability of membrane. Acetylcholine is caused by binding to the muscarinic acetylcholine receptor by delivering the excitability of to the next cell, and is blocked by the receptor inhibitor atropine. Acetylcholine is a carrier of parasympathetic nerve endings, so atropine acts on many parasympathetic organs and tissues.
본 발명의 조성물은 약학 조성물 및 식품(건강기능성 식품) 조성물로 제조될 수 있다.The composition of the present invention may be prepared as a pharmaceutical composition and a food (health functional food) composition.
본 발명의 조성물이 약학 조성물로 제조되는 경우, 본 발명의 약학 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약학 조성물에 포함되는 약제학적으로 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 약학 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the preparation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, silicic acid Calcium, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils, and the like. It is not. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약학 조성물은 경구 또는 비경구 투여 방식으로 적용될 수 있으며, 본 발명의 약학 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 pharmaceutical compositions of the present invention may be applied orally or parenterally, and suitable dosages of the pharmaceutical compositions of the present invention may be formulated, methods of administration, age, weight, sex, morbidity, food, time of administration, administration of the patient. Various prescriptions can be made by factors such as pathway, excretion rate and response sensitivity.
본 발명의 약학 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient, according to methods which can be easily carried out by those skilled in the art. Or by incorporating into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or may be in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.
본 발명의 조성물이 식품 조성물 또는 건강기능성 식품 조성물로 제조되는 경우, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제(타우마틴, 스테비아 추출물, 예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is made of a food composition or a nutraceutical composition, it includes ingredients that are commonly added during food preparation, and include, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. . Examples of the above carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As flavoring agents, natural flavoring agents (tauumatin, stevia extract, for example rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙 등을 추가로 포함시킬 수 있다. For example, when the food composition of the present invention is prepared with a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and the like may be further included.
본 발명에 따른 조성물은 치매의 원인물질인 베타-아밀로이드 단백질(Aβ) 합성을 억제시키고, 신경전달을 원활히 하며 운동능력 개선 효능을 나타내는바, 노인성 치매, 알츠하이머병 또는 혈관성 치매 등의 예방, 개선 또는 치료에 유용하게 사용될 수 있다.The composition according to the present invention inhibits the synthesis of beta-amyloid protein (Aβ), which is a causative agent of dementia, facilitates neurotransmission and improves motor performance, and prevents, improves, or improves dementia, Alzheimer's disease, or vascular dementia. It can be usefully used for treatment.
이하, 실시 예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시 예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시 예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to the following examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
실험예Experimental Example 1. 치매 치료용 린코마이신(lincomycin)의 활성1. Activity of lincomycin for the treatment of dementia
(1) 치매 치료의 작용기전(1) Mechanism of action of dementia treatment
유전자 자리 14번 염색체에 있는 프리세닐린(PS 1) 유전자와 1번 염색체에 있는 PS 2 유전자들은 아미노산실 tRNA세린아미노산과 합성하여 신호펩티드로 시냅스막 주변에 대기하고 있다가 신경전달물질과 결합하여 생체막을 통과하는 기능을 한다(막 이온채널 투과성 도구). 프리세닐린/신호펩티드는 동족체인데 막결합형 폴리솜이 형성되고, 폴리펩티드사슬은 합성되면서 막을 통과한다.The presenilin (PS 1) gene on the chromosome 14 and the PS 2 gene on the chromosome 1 are synthesized with the amino acid tRNA serine amino acid, which is waiting around the synaptic membrane as a signal peptide, and then binds to a neurotransmitter. It functions to pass through biological membranes (membrane ion channel permeability tool). Presenilin / signal peptides are homologues in which membrane-bound polysomes are formed, and the polypeptide chains pass through the membrane as they are synthesized.
세포의 분비단백질이 세포막을 통과하는 기구로서 막 통과와 동시에 막에 있는 신호펩티드가수분해효소가 프리세닐린 1 (PS1)과 프리세닐린 2 (PS2)로 신호펩티드를 절단, 제거한다. 이와 같이 순리적인 신진대사를 해야하는데 리보솜에 있던 23SrRNA(카르복실기말단 펩티딜tRNA로서 존재)와 병적인 폴리펩티드결합이 생성된다.As the secretory protein of the cell passes through the cell membrane, the signal peptide hydrolase on the membrane cleaves and removes the signal peptide with presenilin 1 (PS1) and presenilin 2 (PS2). In this way, metabolic metabolism is required, resulting in pathological polypeptide binding to 23SrRNA (present as a carboxyl terminal peptidyl tRNA) in ribosomes.
즉, 신호 전달펩티드들이 병적인 유전자와 결합되어 신경전달물질과 결합해서 막투과성 기능을 못하고, 베타-세크리타제(β-secretase)와 작용 후 감마-세크리타제(γ-secretase)의 작용에 의해서 독성 물질인 독성 베타-아밀로이드(Aβ)로 되어 대뇌 혈관벽에 침착되어 노인반이 된다.That is, signal transduction peptides are combined with pathological genes to bind to neurotransmitters and thus do not have a membrane-permeable function, and are toxic by beta-secretase and β-secretase. It becomes a substance called toxic beta-amyloid (Aβ) and is deposited on the cerebral blood vessel walls to become senile plaques.
아밀로이드 전구체 단백질(APP)는 I형 막단백질인데, 베타-세크리타제(β-secretase)와 감마-세크리타제(γ-secretase)로 절단하면 38~43아미노산잔기의 베타-아밀로이드(Aβ)를 생산하여 세포 외에 분비한다. 정상적인 아밀로이드 전구체 단백질(APP)이 독성 베타-아밀로이드로(Aβ)로 생성되는 것은 베타-세크리타제(β-secretase)와 감마-세크리타제(γ-secretase)의 작용 때문인데, 프리세닐린 1 (PS1)과 프리세닐린 2 (PS2)는 바로 감마-세크리타제(γ-secretase)와 같은 기질이다 . Amyloid precursor protein (APP) is a type I membrane protein. When it is cleaved with beta-secretase and gamma-secretase, it produces 38-43 amino acid residues of beta-amyloid (Aβ). Secrete extracellularly. The production of normal amyloid precursor protein (APP) into toxic beta-amyloid (Aβ) is due to the action of beta-secretase and gamma-secretase, presenilin 1 (PS1). ) And presenilin 2 (PS2) are substrates such as gamma-secretase.
이 절단된 유전자에 병적인 변이가 있으면 아밀로이드 전구체 단백질(APP)과 프리세닐린 1 (PS1)과 프리세닐린 2 (PS2)가 베타-세크리타제(β-secretase)와 감마-세크리타제(γ-secretase)의 작용에 의해서 독성 베타-아밀로이드로(Aβ)로 되어 베타-아밀로이드로(Aβ)가 혈관벽에 침착된다. 병적인 유전자들과 주로 신호전달펩티드(APP, PS1, PS2)들과 결합되어 독성 베타-아밀로이드로(Aβ)가 되어 뇌혈관벽에 침착이 되어 노인반이 된다.Pathological mutations in these truncated genes result in amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) as beta-secretase and gamma-secretase (γ-). Under the action of secretase, it becomes toxic beta-amyloidro (Aβ) and beta-amyloidro (Aβ) is deposited on the blood vessel wall. It is combined with pathological genes and mainly signaling peptides (APP, PS1, PS2) to become toxic beta-amyloid (Aβ), which is deposited on the cerebrovascular wall to become senile plaques.
실험예 2. 치매 치료용 아자세린(azaserine)의 활성Experimental Example 2 Activity of Azaserine for Dementia Treatment
(1) 치매 치료의 작용기전(1) Mechanism of action of dementia treatment
유전자23SrRNA가 막 통과와 동시에 막에 있는 신호펩티드가수분해효소에 의해서 신호펩티드를 절단하고 동시에 신호펩티드와 에스테르결합 하고 감마-세크리타제(γ-secretase)의 작용에 의해서 독성 베타-아밀로이드로(Aβ)로 된다.As the 23SrRNA gene passes through the membrane, it cleaves the signal peptide by the signal peptide hydrolase on the membrane, simultaneously ester-links the signal peptide, and acts as a toxic beta-amyloid by the action of gamma-secretase. It becomes
이것은 γ-글루타밀트랜스펩티다아제(γ-glutamyltranspeptidase, γ-GTPase)가 해독대사에 중요한 역할을 하는 글루타티온(glutathione)으로 이 글루타티온에서 감마-글루타밀(γ-glutamyl)기를 떼어내어 아미노산과 결합하는 반응을 촉매하는 효소 γ-GTPase이며. 아자세린(azaserine)에 의해 저해되어 독성 베타-아밀로이드로(Aβ)로 되는 것을 막는다. 그리하여 신호펩티드로서 본래기능인 신경전달물질들과 결합하여 막 이온 투과 도구로서 할 일을 해냄으로 정상인으로 균형적인 신진대사 진행을 한다.This γ- glutamyl trans-peptidase (γ-glutamyltranspeptidase, γ-GTPase ) the gamma in the glutathione as glutathione (glutathione) which play an important role in the detoxification metabolism - the reaction were removed to an glutamyl (γ -glutamyl) in combination with amino acids Is the catalytic enzyme γ- GTPase. It is inhibited by azaserine, preventing it from becoming toxic beta-amyloid (Aβ). Thus, by combining with neurotransmitters, which are inherently functional as signal peptides, they perform a job as a membrane ion permeation tool, thereby promoting balanced metabolism to the normal person.
[실시예 1] 치매 치료용 벨라돈나 추출물Example 1 Belladonna Extract for Treatment of Dementia
(1) 치매 치료의 작용기전(1) Mechanism of action of dementia treatment
아세틸콜린 수용체는 신경전달물질인 아세틸콜린을 받는 창구역할을 하는 당단백질의 일종으로 시냅스후막에 매몰 형태로 존재하며 이온채널을 내포하고 있어 아세틸콜린이 결합되면 막의 이온투과성을 변화시켜 신경세포의 흥분을 다음 세포로 전달하여, 아세틸콜린이 무스카린성 아세틸콜린수용체에 결합하는 것으로서 일어나며, 수용체 저해제인 아트로핀에 의해 차단된다.Acetylcholine receptor is a glycoprotein that acts as a nasal passage to receive acetylcholine, a neurotransmitter. It exists in the form of burying in the synaptic membrane and contains ion channels. When acetylcholine is combined, it changes the ion permeability of the membrane to excite nerve cells. Is delivered to the next cell, whereby acetylcholine binds to the muscarinic acetylcholine receptor and is blocked by the receptor inhibitor atropine.
가지과에 속하는 식물인 벨라돈나에 들어 있는 트로파산과 트로핀의 에스테르화합물로서 무수카린아세틸콜린수용체와 결합하여 아세틸콜린의 무스카린유사작용을 억제한다. 아세틸콜린은 부교감신경말단의 전달물질이므로 아트로핀은 부교감계 지배가 많은 기관과 조직에 작용한다.It is an ester compound of Tropaic acid and Tropin in Belladonna, a plant belonging to the branch family. Acetylcholine is a carrier of parasympathetic nerve endings, so atropine acts on many parasympathetic organs and tissues.
(2) 복용방법(2) How to take
벨라돈나 추출물은 Root powder 형태로, 1일 최대 복용량은 300㎎이며, 벨라돈나 추출물의 평균 1회 복용량은 10㎎이다. 이때, 1회 최대 복용량은 50㎎, 1일 최대 복용량은 150㎎이다.Belladonna Extract In the form of root powder, the maximum daily dose is 300 mg and the average single dose of belladonna extract is 10 mg. At this time, the maximum daily dose is 50 mg, and the maximum daily dose is 150 mg.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.
Claims (3)
A composition for preventing or treating dementia comprising lincomycin as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
A composition for preventing or treating dementia comprising azaserrine as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
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KR101807953B1 (en) | 2015-06-30 | 2017-12-12 | 동국대학교 경주캠퍼스 산학협력단 | The pharmaceutical composition for the prevention or treatment of the symptoms in the dementia comprising the extracts from Coriandrum sativum |
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KR101801478B1 (en) | 2016-07-29 | 2017-11-27 | 동아대학교 산학협력단 | Composition for preventing or treating neurodegenerative disease comprising biochanin A as active ingredient |
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