KR102404658B1 - Compositions for Preventing, Improving or Treating Cognitive Disorder and Depression - Google Patents
Compositions for Preventing, Improving or Treating Cognitive Disorder and Depression Download PDFInfo
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- KR102404658B1 KR102404658B1 KR1020200123017A KR20200123017A KR102404658B1 KR 102404658 B1 KR102404658 B1 KR 102404658B1 KR 1020200123017 A KR1020200123017 A KR 1020200123017A KR 20200123017 A KR20200123017 A KR 20200123017A KR 102404658 B1 KR102404658 B1 KR 102404658B1
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- dementia
- lactobacillus casei
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- preventing
- depression
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Abstract
본 발명은 인지기능장애 및 우울증 예방, 개선 또는 치료용 조성물에 관한 것으로, 본 발명의 조성물에 유효성분으로 포함되는 락토바실러스 카제이 HY2782 균주는 뇌신경세포 증식 효과 및 스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과를 나타내므로, 인지기능장애 및 우울즐의 예방, 개선 또는 치료에 유용하게 활용될 수 있다.The present invention relates to a composition for preventing, improving, or treating cognitive dysfunction and depression, and the Lactobacillus casei HY2782 strain included as an active ingredient in the composition of the present invention has a brain nerve cell proliferation effect and an inhibitory effect on brain nerve cell death by stress hormone. Therefore, it can be usefully utilized for the prevention, improvement or treatment of cognitive dysfunction and depression.
Description
본 발명은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 인지기능장애 및 우울증 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating cognitive dysfunction and depression, comprising the Lactobacillus casei HY2782 strain as an active ingredient.
고령화 사회로 빠르게 진행되고 있는 현대 사회에서 노화 과정을 지연시키는 것은 중요한 보건 과제 중 하나이다. 우리나라의 경우 2010년에 65세 이상의 인구가 11.3%를 차지하였으며, 2050년에는 37.3%로 급증할 것으로 예상되고 있다. 이와 같은 고령화 사회에서는 질병 이환율의 상승 및 막대한 의료비 지출이 예상되며 치매 등의 노인성 질환의 급증이 사회적으로 문제가 될 것으로 예상된다. 노화가 진행되는 과정은 유전, 환경, 그리고 생활 방식의 복합적인 작용에 의해 영향을 받으며, 다양한 형태적, 생화학적 변화가 수반되는데, 특히, 산화스트레스의 증가와 염증 반응의 증가는 노화 촉진에 관여하는 주요 원인으로 여겨지고 있다. Delaying the aging process is one of the important health challenges in modern society, which is rapidly progressing toward an aging society. In the case of Korea, the population aged 65 years or older accounted for 11.3% in 2010, and is expected to rapidly increase to 37.3% by 2050. In such an aging society, an increase in disease morbidity and huge medical expenses are expected, and a surge in geriatric diseases such as dementia is expected to become a social problem. The aging process is affected by the complex action of genetics, environment, and lifestyle, and various morphological and biochemical changes are involved. is considered to be the main cause of
감정적 또는 물리적 위협이나 위험 등 외부의 압력과 같은 스트레스 요인에 의해서 긴장, 흥분, 각성 또는 불안과 같은 생리적 반응이 일어나게 되는데 이러한 반응으로부터 원상태로 돌아가려는 반작용을 스트레스라고 한다. 스트레스 반응 초기에는 교감신경계와 부신수질로부터 에피네프린과 노르에피네프린이 분비 증가가 일어난다. 이후, 시상하부 뇌하수체 부신수질 축 시스템으로 뇌의 시상하부에서 부신피질호르몬 유리 호르몬이 분비되고, 뇌하수체를 자극하면 뇌하수체에서 부신피질 자극 호르몬이 분비되며, 부신피질 자극 호르몬이 부신에서 에피네프린과 코르티코이드의 분비를 유도한다.Physiological reactions such as tension, excitement, arousal, or anxiety are caused by stress factors such as emotional or physical threats or risks, such as external pressure. The reaction to return to the original state is called stress. In the early stage of the stress response, the secretion of epinephrine and norepinephrine from the sympathetic nervous system and adrenal medulla is increased. After that, the hypothalamus secretes adrenocorticotropin-free hormone from the hypothalamus into the hypothalamic-pituitary adrenal-medullary axis system, and when the pituitary is stimulated, the adrenocorticotropic hormone is secreted from the pituitary gland, and the adrenocorticotropic hormone secretes epinephrine and corticoids from the adrenal glands. induce
면역세포에서 분비되는 펩타이드이며 면역세포 간의 정보를 매개하는 역할을 하는 사이토카인은 단핵 혹은 대식세포와 림프구에서 주로 분비되며, 신경원 내피세포 성상세포 혹은 소교세포등의 뇌세포에서도 분비된다. 사이토카인에 대한 수용체들은 면역계뿐만 아니라 말초신경계와 중추신경계를 포함한 다양한 조직에 위치하고 있는데, 사이토카인은 부신피질자극호르몬을 자극하여 시상하부 뇌하수체 부신수질축을 활성화시켜 코르티솔 분비를 촉진하여 우울증을 유발한다. 또한, 염증성 사이토카인은 신경영양성 인자와 모노아민 신경전달인자를 감소시켜 신경세포 자멸사와 신경교 손상을 유발한다.Cytokines, which are peptides secreted from immune cells and play a role in mediating information between immune cells, are mainly secreted from monocytes or macrophages and lymphocytes, and are also secreted from brain cells such as neuronal endothelial cells, astrocytes or microglia. Receptors for cytokines are located in various tissues including the peripheral nervous system and central nervous system as well as the immune system. Cytokines stimulate adrenocorticotropic hormone to activate the hypothalamic-pituitary adrenal medulla to promote cortisol secretion and induce depression. In addition, inflammatory cytokines reduce neurotrophic factors and monoamine neurotransmitters, causing neuronal apoptosis and glial damage.
치매에는 알츠하이머형 치매(Alzheimer's disease), 혈관성 치매, 및 기타 혼합형이 있으며, 우리나라 65세 이상의 노인 치매 환자중 50~60%가 알츠하이머형 치매이고 15~30%가 혈관성 치매이며 나머지 10~15%가 이 두 가지 질환의 혼합형이다. 뇌속 노폐물인 베타아밀로이드(Aß)가 알츠하이머형 치매의 주요 발병 원인으로 알려져 있으며, 알츠하이머형 치매의 치료를 위해 많은 약물들이 치료제로 시도되었으나 아직까지 뚜렷한 효과가 입증된 약물은 알려져 있지 않다. 알츠하이머형 치매 환자들에게 부족한 뇌속 중요 신경전달물질 중 하나인 아세틸콜린(acetylcholine)에 작용하는 아세틸콜린에스테라아제(acetylcholinesterease) 제해제가 치료제로서 유일하게 사용되고 있으나, 이 약물은 부분적으로 인지기능의 호전은 보이지만 알츠하이머병의 진행에는 전혀 작용을 하지 못하는 것으로 알려져 있으며, 효과적인 치매 예방 또는 치료제의 개발이 요구되고 있다.Dementia includes Alzheimer's disease, vascular dementia, and other mixed types. In Korea, 50-60% of elderly dementia patients over the age of 65 are Alzheimer's type dementia, 15-30% vascular dementia, and the remaining 10-15% It is a mixture of these two diseases. Beta-amyloid (Aß), a waste product in the brain, is known to be the main cause of Alzheimer's type dementia. An acetylcholinesterease inhibitor, which acts on acetylcholine, one of the important neurotransmitters in the brain, which is lacking in Alzheimer-type dementia patients, is the only treatment used, but this drug partially improves cognitive function. It is known that it does not act at all in the progression of Alzheimer's disease, and the development of an effective dementia prevention or treatment agent is required.
알츠하이머병은 전뇌의 콜린성 뉴런이 퇴화하여 신경 전달 물질인 아세틸콜린의 방출이 감소함으로써 인식 능력의 저하를 일으킨다(Murer MG et al., 2001). 파킨슨병은 흑질 도파민성(substantia nigral dopaminergic) 신경세포의 수가 감소되게 되고 이는 선조체의 도파민(striatal dopamine)의 고갈을 초래하여 운동 기능 장애와 같은 징후를 초래하게 된다. 스트레스는 신경 쇠약과 해마를 포함한 다양한 뇌 지역의 부피를 감소시킬 뿐만 아니라(Duman, R.S. and Monteggia, L.M.2006) 해마의 BDNF mRNA 발현을 감소시켜 우울증을 유발하는 것으로 알려져 있으며(Duman, R.S. and Monteggia, L.M. 2006 Smith, M.A. et al., 1995), 스트레스에 의하여 해마나 전전뇌 피질의 감소된 BDNF의 발현을 다시 증가시킴으로써 신경쇠약과 세포수 감소를 회복시킴으로 우울증과 같은 정신질환의 치료가 가능한 것으로 보고되었다(Duman, R.S. and Monteggia, L.M. 2006).In Alzheimer's disease, cholinergic neurons in the forebrain degenerate and the release of acetylcholine, a neurotransmitter, decreases, leading to a decrease in cognitive ability (Murer MG et al., 2001). In Parkinson's disease, the number of substantia nigral dopaminergic neurons decreases, which leads to depletion of striatal dopamine, resulting in symptoms such as motor dysfunction. Stress is known to induce depression by reducing BDNF mRNA expression in the hippocampus, as well as neurasthenia and decreased volume of various brain regions including the hippocampus (Duman, R.S. and Monteggia, L.M.2006). L.M. 2006 Smith, M.A. et al., 1995), reported that it is possible to treat mental disorders such as depression by re-increasing the expression of BDNF decreased in the hippocampus or forebrain cortex due to stress, thereby restoring neurasthenia and cell number reduction. (Duman, R.S. and Monteggia, L.M. 2006).
신경영양성 인자(Neurotrophic factor)는 발생 과정 동안 신경 세포의 생존과 분화를 조절하며(Davies, 1994), 개체의 일생 동안 신경 구조의 유지 및 이온 채널의 활성, 신경 전달 물질 방출, 그리고 액손 경로 탐색 (axon path-finding) 등의 기능에 영향을 끼친다(Schnell et al., 1994; Song and Poo, 1999; Schinder and Poo, 2000). 신경 영양성 인자 중 BDNF는 중추신경계(Central Nervous System, CNS)에서 학습 및 기억, 고등 사고 능력을 담당하는 해마, 피질 그리고 전뇌 기저부에 많이 발현되고 있다. 시냅스 전달 및 시냅스 가소성의 중요한 조절자인 BDNF는 퇴행성 뇌질환인 알츠하이머 병(Alzheimer's disease, AD), 파킨슨병 (Parkinson's disease, PD), 스트레스에 의한 우울증(Depression), 뇌졸중, 헌팅톤무도병, 대뇌허혈성질환, 신경퇴화질환 또는 당뇨병성 신경병증 등 다양한 질병과 관련되어 있는 것으로 알려져 있다. 다만, BDNF 그 자체는 14kDa의 거대분자 단백질로써 혈뇌장벽(Blood-brain barrier, BBB)을 통과하지 못할 뿐만 아니라, 직접적인 투여가 어렵다는 문제점이 있다. Neurotrophic factors regulate the survival and differentiation of nerve cells during development (Davies, 1994), and throughout the life of an individual, the maintenance of nerve structures and activation of ion channels, neurotransmitter release, and axon pathway exploration ( axon path-finding) and other functions (Schnell et al., 1994; Song and Poo, 1999; Schinder and Poo, 2000). Among neurotrophic factors, BDNF is widely expressed in the hippocampus, cortex, and forebrain, which are responsible for learning, memory, and higher thinking abilities in the central nervous system (CNS). BDNF, an important regulator of synaptic transmission and synaptic plasticity, is a degenerative brain disease Alzheimer's disease (AD), Parkinson's disease (PD), stress-induced depression, stroke, Huntington's chorea, cerebral ischemic disease , is known to be associated with various diseases such as neurodegenerative disease or diabetic neuropathy. However, BDNF itself, as a 14kDa macromolecular protein, does not pass through the blood-brain barrier (BBB) and has problems in that direct administration is difficult.
이에, 본 발명자들은 스트레스 및 우울증, 인지장애 및 치매에 유익한 효과를 갖는 유산균을 발굴하기 위한 연구를 수행하여 본 발명을 완성하였다.Accordingly, the present inventors completed the present invention by conducting a study to discover lactic acid bacteria having a beneficial effect on stress and depression, cognitive impairment and dementia.
본 발명의 하나의 목적은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 인지기능장애 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for preventing or treating cognitive dysfunction comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 다른 목적은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 우울증 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating depression comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 또 다른 목적은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 인지기능장애 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving cognitive dysfunction comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 또 다른 목적은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 우울증 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving depression comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 일 양상은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 인지기능장애 예방 또는 치료용 약학적 조성물을 제공한다.One aspect of the present invention provides a pharmaceutical composition for preventing or treating cognitive dysfunction comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 다른 양상은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 우울증 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating depression comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 약학적 조성물은 약학적으로 허용되는 담체를 포함할 수 있다. 본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 약제의 제조에 통상적으로 이용되는 것으로써, 락토오스, 덱스트로스, 수크로오스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산칼슘, 알기네이트, 젤라틴, 규산칼슘, 미세결정성 셀룰로오스, 폴리비닐피롤리돈, 셀룰로오스, 물, 시럽, 메틸 셀룰로오스, 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: the science and practice of pharmacy 22nd edition (2013)에 상세히 기재되어 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in the manufacture of pharmaceuticals, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin. , calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, etc. It is not limited. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington: the science and practice of pharmacy 22nd edition (2013).
본 발명의 일 구체예에 따른 약학적 조성물은 하나 이상의 인지기능장애 및/또는 우울증의 치료에 활성을 나타내는 물질과 함께 투여될 수 있다.The pharmaceutical composition according to one embodiment of the present invention may be administered together with a substance that is active in the treatment of one or more cognitive dysfunction and/or depression.
또한, 본 발명의 일 구체예에 따른 약학적 조성물은 인지기능장애 및/또는 우울증의 치료를 위하여 단독으로, 또는 시술, 호르몬 치료, 약물치료 및/또는 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용될 수 있다.In addition, the pharmaceutical composition according to one embodiment of the present invention is used alone or in combination with methods using procedures, hormone therapy, drug therapy and/or biological response modifiers for the treatment of cognitive dysfunction and/or depression. can be used
본 발명의 약학적 조성물은 그 제형의 제제화에 필요하고 적절한 각종 기제 및/또는 첨가물을 포함할 수 있으며, 그 효과를 떨어트리지 않는 범위 내에서 비이온 계면활성제, 실리콘 폴리머, 체질안료, 향료, 산화 안정화제, 유기 용매, 이온성 또는 비이온성 증점제, 유연화제, 산화방지제, 자유 라디칼 파괴제, 불투명화제, 안정화제, 에몰리언트(emollient), 실리콘, α-히드록시산, 소포제, 보습제, 비타민, 곤충 기피제, 향료, 보존제, 계면활성제, 소염제, 물질 P 길항제, 충전제, 중합체, 추진제, 염기성화 또는 산성화제, 또는 착색제 등 공지의 화합물을 더 포함하여 제조될 수 있다.The pharmaceutical composition of the present invention may contain various bases and/or additives necessary and appropriate for the formulation of the formulation, and within the range that does not reduce the effect, nonionic surfactants, silicone polymers, extenders, fragrances, oxidizing agents Stabilizers, organic solvents, ionic or nonionic thickeners, emollients, antioxidants, free radical scavengers, opacifiers, stabilizers, emollients, silicones, α-hydroxy acids, defoamers, humectants, vitamins, insects It may be prepared by further comprising known compounds such as repellents, fragrances, preservatives, surfactants, anti-inflammatory agents, substance P antagonists, fillers, polymers, propellants, basifying or acidifying agents, or coloring agents.
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. 본 발명의 약학적 조성물의 투여량은 성인 기준으로 0.001~1000㎎/kg일 수 있다.A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient. can be The dosage of the pharmaceutical composition of the present invention may be 0.001 to 1000 mg/kg based on an adult.
본 발명의 약학적 조성물은 경구 투여할 수 있다.The pharmaceutical composition of the present invention may be administered orally.
본 발명의 약학적 조성물은 경구 투여 시 다양한 제형으로 투여될 수 있는데, 환제, 분말제, 과립제, 정제 또는 캡슐제 등의 고형제제 형태로 투여될 수 있으며, 여러 가지 부형제, 예를 들어, 습윤제, 감미제, 방향제, 보존제 등을 더 포함할 수 있다. 구체적으로, 본 발명의 조성물을 분말, 과립, 정제 또는 캅셀 형태로 제형화할 경우, 이의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 예를 들어, 락토오스, 덱스트로스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 인산칼슘, 규산칼슘, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및/또는 광물유가 사용될 수 있으나 이에 한정되지 않는다. 또한, 제제화에 일반적으로 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함하여 조제될 수 있으며, 상기 부형제 이외에 마그네슘 스테아레이트 또는 탈크 같은 윤활제를 더 포함할 수 있다.The pharmaceutical composition of the present invention may be administered in various dosage forms upon oral administration, and may be administered in the form of solid preparations such as pills, powders, granules, tablets or capsules, and various excipients, for example, wetting agents, It may further include a sweetening agent, a flavoring agent, a preservative, and the like. Specifically, when the composition of the present invention is formulated in powder, granule, tablet or capsule form, it may further include appropriate carriers, excipients and diluents commonly used in the preparation thereof. The carrier, excipient and diluent include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and/or mineral oil may be used, but are not limited thereto. In addition, it may be prepared by including diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. generally used for formulation, and may further include a lubricant such as magnesium stearate or talc in addition to the excipients. .
본 발명의 일 구체예에 따르면, 상기 인지기능장애는 노인성 치매, 알츠하이머병, 혈관성 치매, 루이체 치매, 전측두엽 치매, 파킨슨병 치매, 헌팅턴병 치매, 정상압 뇌수두증에 의한 치매, 두부 외상으로 인한 치매, 및 물질로 유발된 치매로 이루어진 군으로부터 선택되는 질환일 수 있다.According to one embodiment of the present invention, the cognitive dysfunction is senile dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease dementia, Huntington's disease dementia, dementia due to normal pressure hydrocephalus, dementia due to head trauma, And it may be a disease selected from the group consisting of substance-induced dementia.
우울증 및 치매 등 인지기능장애 환자에서는 BDNF의 발현의 감소에 따른 신경세포의 감소가 나타난다. 본 발명의 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 조성물은 뇌신경세포 활성 유전자인 BDNF 및 세포 생존관련 유전자인 RELA의 발현을 증가시키고, 세포 사멸 유전자인 CASPASE3 발현을 감소시켜 뇌신경세포 증식 효과 및 스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과를 나타내므로, 우울증 및 치매 등 인지기능장애의 개선에 유용하게 활용될 수 있다.In patients with cognitive dysfunction such as depression and dementia, a decrease in neuronal cells appears due to a decrease in the expression of BDNF. The composition comprising the Lactobacillus casei HY2782 strain of the present invention as an active ingredient increases the expression of BDNF, a brain neuron activity gene, and RELA, a cell survival-related gene, and reduces the expression of CASPASE3, an apoptosis gene. Since it exhibits an inhibitory effect on brain nerve cell death caused by stress hormone, it can be usefully used to improve cognitive dysfunction such as depression and dementia.
본 발명의 일 구체예에 따르면, 상기 락토바실러스 카제이 HY2782 균주는 락토바실러스 카제이 HY2782 생균체, 락토바실러스 카제이 HY2782 사균체, 이의 파쇄물, 이의 배양액, 상기 균주의 추출물, 상기 균주의 추출물, 상기 파쇄물의 추출물 또는 상기 배양액의 추출물일 수 있다.According to one embodiment of the present invention, the Lactobacillus casei HY2782 strain is Lactobacillus casei HY2782 live cells, Lactobacillus casei HY2782 dead cells, a lysate thereof, a culture solution thereof, an extract of the strain, an extract of the strain, and the It may be an extract of the lysate or an extract of the culture solution.
본 발명의 또 다른 양상은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 인지기능장애 예방 또는 개선용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for preventing or improving cognitive dysfunction comprising the Lactobacillus casei HY2782 strain as an active ingredient.
본 발명의 또 다른 양상은 락토바실러스 카제이 HY2782 균주를 유효성분으로 포함하는 우울증 예방 또는 개선용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for preventing or improving depression comprising the Lactobacillus casei HY2782 strain as an active ingredient.
전술한 내용과 중복되는 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다. In order to avoid undue complexity of the present specification, descriptions of contents overlapping with the above are omitted.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로써 락토바실러스 카제이 HY2782 균주 외에, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함할 수 있다. 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 당알콜일 수 있다. 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 prepared as a food composition, as an active ingredient, in addition to the Lactobacillus casei HY2782 strain, ingredients commonly added during food production may be included, for example, proteins, carbohydrates, fats, nutrients, seasoning and flavoring agents may be included. Examples of carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, natural flavoring agents [taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)] and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
또한, 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. In addition, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있으며, 이러한 첨가제의 비율은 본 발명의 식품 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택될 수 있으나, 이에 한정되는 것은 아니다.These components may be used independently or in combination, and the ratio of these additives may be selected from 0 to about 20 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 식품 조성물은 식품, 식품첨가제, 음료, 음료첨가제, 발효유, 건강기능식품 등으로 사용될 수 있다. 식품, 식품첨가제, 음료, 음료첨가제, 또는 건강기능식품으로 사용되는 경우, 각종 식품류, 발효유, 육류, 음료수, 초콜렛, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 알코올 음료, 비타민 복합제, 주류 또는 그 밖의 건강기능식품 제형으로 제공될 수 있으나, 이에 한정되는 것은 아니다.The food composition of the present invention can be used as food, food additive, beverage, beverage additive, fermented milk, health functional food, and the like. When used as food, food additive, beverage, beverage additive, or health functional food, various foods, fermented milk, meat, beverage, chocolate, snack, confectionery, pizza, ramen, other noodles, gum, ice cream, alcoholic beverage, vitamin It may be provided as a combination drug, alcoholic beverage or other health functional food formulation, but is not limited thereto.
본 발명의 일 구체예에 따르면, 상기 인지기능장애는 노인성 치매, 알츠하이머병, 혈관성 치매, 루이체 치매, 전측두엽 치매, 파킨슨병 치매, 헌팅턴병 치매, 정상압 뇌수두증에 의한 치매, 두부 외상으로 인한 치매, 및 물질로 유발된 치매로 이루어진 군으로부터 선택되는 질환일 수 있다.According to one embodiment of the present invention, the cognitive dysfunction is senile dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease dementia, Huntington's disease dementia, dementia due to normal pressure hydrocephalus, dementia due to head trauma, And it may be a disease selected from the group consisting of substance-induced dementia.
본 발명의 일 구체예에 따르면, 상기 락토바실러스 카제이 HY2782 균주는 락토바실러스 카제이 HY2782 생균체, 락토바실러스 카제이 HY2782 사균체, 이의 파쇄물, 이의 배양액, 상기 균주의 추출물, 상기 균주의 추출물, 상기 파쇄물의 추출물 또는 상기 배양액의 추출물일 수 있다.According to one embodiment of the present invention, the Lactobacillus casei HY2782 strain is Lactobacillus casei HY2782 live cells, Lactobacillus casei HY2782 dead cells, a lysate thereof, a culture solution thereof, an extract of the strain, an extract of the strain, and the It may be an extract of the lysate or an extract of the culture solution.
인지기능장애 및 우울증 예방, 개선 또는 치료용 조성물에 따르면, 본 발명의 조성물에 유효성분으로 포함되는 락토바실러스 카제이 HY2782 균주는 뇌신경세포 증식 효과 및 스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과를 나타내므로, 인지기능장애 및 우울즐의 예방, 개선 또는 치료에 유용하게 활용될 수 있다.According to the composition for preventing, improving, or treating cognitive dysfunction and depression, the Lactobacillus casei HY2782 strain included as an active ingredient in the composition of the present invention exhibits a brain nerve cell proliferation effect and an inhibitory effect on brain nerve cell death by stress hormone, It can be usefully used for the prevention, improvement or treatment of cognitive dysfunction and depression.
도 1은 신경세포에서 락토바실러스 카제이 HY2782 균주에 의한 신경세포의 증식율을 나타낸 그래프이다.
도 2는 스트레스호르몬인 부신피질호르몬(corticosterone) 및/또는 락토바실러스 카제이 HY2782 균주에 의한 신경세포의 생존율을 나타낸 그래프이다.
도 3는 스트레스호르몬인 부신피질호르몬 및/또는 락토바실러스 카제이 HY2782 균주에 의한 신경세포의 세포사멸관련 유전자인 BDNF의 발현량 변화를 나타낸 그래프이다.
도 4은 스트레스호르몬인 부신피질호르몬 및/또는 락토바실러스 카제이 HY2782 균주에 의한 신경세포의 세포사멸관련 유전자인 RELA의 발현량 변화를 나타낸 그래프이다.
도 5은 스트레스호르몬인 부신피질호르몬 및/또는 락토바실러스 카제이 HY2782 균주에 의한 신경세포의 세포사멸관련 유전자인 Caspase3의 발현량 변화를 나타낸 그래프이다.
도 6은 비 유발군 (sham), 유발군 (scopolamine), 유발군에 락토바실러스 카제이 HY2782 균주를 처리한 군 (HY2782) 및 유발군에 donepezil을 처리한 군 (donepezil, 양성대조군)의 신규물체 인식 시험 결과를 나타내는 그래프이다.
도 7은 비 유발군 (sham), 유발군 (scopolamine), 유발군에 락토바실러스 카제이 HY2782 균주를 처리한 군 (HY2782) 및 유발군에 donepezil을 처리한 군 (donepezil, 양성대조군)의 수동회피 시험 결과를 나타내는 그래프이다.
도 8은 비 유발군 (sham), 유발군 (scopolamine), 유발군에 락토바실러스 카제이 HY2782 균주를 처리한 군 (HY2782) 및 유발군에 donepezil을 처리한 군 (donepezil, 양성대조군)의 β-amyloid 42 측정 결과를 나타내는 그래프이다.
도 9는 비 유발군 (sham), 유발군 (scopolamine), 유발군에 락토바실러스 카제이 HY2782 균주를 처리한 군 (HY2782) 및 유발군에 donepezil을 처리한 군 (donepezil, 양성대조군)의 BDNF 측정 결과를 나타내는 그래프이다. 1 is a graph showing the proliferation rate of neurons by Lactobacillus casei HY2782 strain in neurons.
2 is a graph showing the survival rate of nerve cells by the stress hormone, corticosterone and / or Lactobacillus casei HY2782 strain.
Figure 3 is a graph showing the change in the expression level of BDNF, a gene related to apoptosis of nerve cells by the stress hormone, adrenocortical hormone and / or Lactobacillus casei HY2782 strain.
4 is a graph showing the change in the expression level of RELA, a gene related to apoptosis of nerve cells by the stress hormone, adrenocortical hormone and/or Lactobacillus casei HY2782 strain.
5 is a graph showing the change in the expression level of Caspase3, a gene related to apoptosis of nerve cells by the stress hormone, adrenocortical hormone and/or Lactobacillus casei HY2782 strain.
6 is a new object of the non-induced group (sham), the induced group (scopolamine), the group treated with the Lactobacillus casei HY2782 strain in the induced group (HY2782), and the group treated with donepezil (donepezil, positive control) It is a graph showing the recognition test result.
7 shows passive avoidance of the non-induced group (sham), the induced group (scopolamine), the group treated with the Lactobacillus casei HY2782 strain in the induced group (HY2782) and the group treated with donepezil (donepezil, positive control) in the induced group It is a graph showing the test result.
8 is a β- of the non-induced group (sham), the induced group (scopolamine), the group treated with the Lactobacillus casei HY2782 strain in the induced group (HY2782) and the group treated with donepezil in the induced group (donepezil, positive control) It is a graph showing the measurement result of amyloid 42.
9 is a non-induced group (sham), a induced group (scopolamine), a group treated with the Lactobacillus casei HY2782 strain in the induced group (HY2782), and the induced group treated with donepezil (donepezil, positive control) BDNF measurement It is a graph showing the result.
이하 본 발명을 하나 이상의 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through one or more embodiments. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1. 락토바실러스 카제이 HY2782 균주의 분리 및 동정Example 1. Isolation and identification of Lactobacillus casei HY2782 strain
1-1.1-1. 락토바실러스 카제이 HY2782 균주의 분리Isolation of Lactobacillus casei HY2782 strain
락토바실러스 카제이(Lactobacillus casei) YIT9018을 MRT 액체배지(문헌: 1969. Nippon Nogei Kagaku Kaishi. 43(5). p.311)에서 대수기 초기까지 배양하여 세척하고, 돌연변이 유발물질을 처리하여 37℃에서 30분간 배양하였다. 이를 원심분리하여 인산염용액(pH 7.0)으로 세척하여 새로운 MRT 액체배지로 현탁한 다음, 로고사(Rogosa) 한천평판배지(문헌: 1962. J.Infect. Dis. 110, p.258)에 도말하여 30℃에서 48시간 동안 배양하였다. 배양된 균체들 중에서 레프리카-플레이팅방법(relpica-plating method, 문헌: 1982, Molecular cloning, a laboratory manual. Cold spring harbor laboratory)에 의해 37℃에서 성장이 가능하고 42℃에서는 성장이 억제되는 균체들을 온도감수성 변이주로 분리하였다. 분리된 570개의 온도감수성 변이주들을 42℃에서 30분간 열처리하여 30℃에서 24시간 동안 배양하여 소프트-아가 레이어방법(soft-agar layer method, 문헌: 1959. Interscience publisher Inc. New York)으로 잠재성 파아지의 수를 측정하여 잠재성 파아지의 수가 열처리 후 현격히 증가하는 것을 열유발성 변이주(thermoinducible mutants)로 분리하였다. 분리된 열유발성 변이주를 잠재성 파아지가 불활성화 될 수 있는 항혈청이 포함된 새로운 MRT 액체 배지에 접종하여 대수기 초기까지 배양한 다음 42℃에서 30분간 열처리한 후, 즉시 로고사 한천평판배지에 도말하고 37℃에서 배양하여 콜로니(colony)를 형성하는 240균주를 분리하였다. 분리된 균주들을 지시균으로 사용하여 소프트-아가 레이어 방법으로 락토바실러스 카제이(Lactobacillus casei) YIT9018 배양액의 상층을 얹어 배양한 후, 플라크 형성유무를 조사하여 플라크가 형성되는 것을 분리하였다. 그리고, 프로파아지가 제거된 락토바실러스 카제이(Lactobacillus casei) YIT9029(일본미생물공업연구소 균주기탁 제5852호)를 지시균으로하여 소프트-아가 레이어 방법으로 분리된 균주들이 배양액 상층을 얹어 배양한 후, 플라크 형성유무를 조사하여 플라크가 형성되지 않은 균주를 분리하였다. 또한 분리된 균주를 37℃에서 대수기 초기까지 배양한 후 42℃에서 30분간 열처리한 다음, 소프트-아가레이어 방법으로 플라크의 생성유무를 확인하여 플라크가 생성되지 않는 것을 프로파아지 커어드 스트레인(prophage cured strain)으로 최종 분리하였다. 이렇게 하여 분리된 균주의 수는 32균주였다. 이 균주들이 균학적 특성을 조사하여 모균주인 락토바실러스 카제이(Lactobacillus casei) YIT9018과균학적 특성이 거의 동일한 본 발명의 락토바실러스 카제이(Lactobacillus casei) HY2782를 분리였다. Lactobacillus casei (Lactobacillus casei) YIT9018 was cultured in MRT liquid medium (Document: 1969. Nippon Nogei Kagaku Kaishi. 43(5). p.311) until the early log phase, washed, treated with a mutagen, and treated at 37 ° C. incubated for 30 min. It was centrifuged, washed with a phosphate solution (pH 7.0), suspended in fresh MRT liquid medium, and plated on Rogosa agar plate medium (Document: 1962. J. Infect. Dis. 110, p. 258). Incubated at 30 °C for 48 hours. Among the cultured cells, cells capable of growth at 37 ° C and inhibited growth at 42 ° C by the repica-plating method (Reference: 1982, Molecular cloning, a laboratory manual. Cold spring harbor laboratory) were selected. Temperature-sensitive mutants were isolated. The isolated 570 temperature-sensitive mutants were heat-treated at 42°C for 30 minutes, incubated at 30°C for 24 hours, and then latent phage was performed using the soft-agar layer method (Reference: 1959. Interscience publisher Inc. New York). The number of latent phages increased significantly after heat treatment by measuring the number of heat-induced mutants (thermoinducible mutants). The isolated heat-induced mutant was inoculated into a new MRT liquid medium containing antisera that can inactivate latent phages, incubated until the beginning of the log phase, and then heat-treated at 42°C for 30 minutes, and immediately placed on logosa agar plate medium. 240 strains forming colonies were isolated by plating and culturing at 37°C. Using the isolated strains as indicator bacteria, the soft-agar layer method was used to place the upper layer of the Lactobacillus casei YIT9018 culture solution on top of the culture solution, and then, by examining the presence or absence of plaque formation, the plaque formation was isolated. Then, the strains separated by the soft-agar layer method using Lactobacillus casei YIT9029 (Japanese Microorganism Industry Research Institute strain deposit No. 5852) as an indicator bacteria were cultured by placing the upper layer of the culture medium on top of the culture solution, By examining the presence or absence of plaque formation, strains without plaque formation were isolated. In addition, after culturing the isolated strain at 37°C until the early log phase, heat treatment at 42°C for 30 minutes, and then confirming the presence or absence of plaque formation using the soft-agar layer method. cured strain) was finally isolated. The number of strains isolated in this way was 32 strains. By examining the mycological characteristics of these strains, the parent strain Lactobacillus casei YIT9018 and Lactobacillus casei HY2782 of the present invention having almost the same mycological properties were isolated.
락토바실러스 카제이 HY2782 균주의 특성 확인Characterization of Lactobacillus casei HY2782 strain
락토바실러스 카제이 HP2782의 균학적 특성은 표 1과 같다.Table 1 shows the mycological characteristics of Lactobacillus casei HP2782.
최적온도: 33~37℃Growth possible Growth temperature: 13~43℃
Optimum temperature: 33~37℃
최적 pH: 5.0~5.5Growable Growth pH: 4.5~7.5
Optimum pH: 5.0-5.5
1-2.1-2. 락토바실러스 카제이 HP2782 균주의 동정Identification of Lactobacillus casei HP2782 strain
락토바실러스 카제이 HP2782 균주의 동정을 위하여, 16S rDNA 유전자 분석과 Biomerieux 사의 API 50 CHL kit 동정을 수행하였다.For identification of Lactobacillus casei HP2782 strain, 16S rDNA gene analysis and Biomerieux's
16S rDNA 분석을 통한 분자유전학적인 방법을 실시하여 본 발명의 균주를 동정하였다. 16S rDNA 염기 서열 분석 결과를 표 2에 나타내었다( <http://www.ncbi.nlm.nih.gov/blast>). The strain of the present invention was identified by performing a molecular genetic method through 16S rDNA analysis. 16S rDNA sequencing results are shown in Table 2 (<http://www.ncbi.nlm.nih.gov/blast>).
identMax
ident
상기의 표 2에서 확인할 수 있는 바와 같이, 본 발명의 락토바실러스 카제이(Lactobacillus casei) HY2782의 16S rRNA 유전자는 락토바실러스 카제이(Lactobacillus casei)의 16S rRNA 유전자와 99% 일치하는 것으로 확인되었다.As can be seen in Table 2 above, the 16S rRNA gene of Lactobacillus casei HY2782 of the present invention was confirmed to be 99% identical to the 16S rRNA gene of Lactobacillus casei.
상기 16S rRNA 서열 및 균학적 특성에 의해 본 발명의 균주를 락토바실러스 카제이(Lactobacillus casei) HY2782로 명명하였으며, 2017년 12월 19일자로 한국생명공학연구원(KCTC)에 기탁하였다(수탁번호: KCTC 13438BP).According to the 16S rRNA sequence and mycological characteristics, the strain of the present invention was named Lactobacillus casei HY2782, and was deposited at the Korea Research Institute of Bioscience and Biotechnology (KCTC) on December 19, 2017 (Accession No.: KCTC) 13438BP).
실시예 2. 락토바실러스 카제이 HY2782 균주의 뇌신경세포 증식 효과 및 스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과 확인Example 2. Confirmation of brain nerve cell proliferation effect of Lactobacillus casei HY2782 strain and inhibitory effect on brain nerve cell death by stress hormone
2-1. 세포 배양 및 유산균 처리2-1. Cell culture and lactic acid bacteria treatment
사람의 신경모세포종 SK-N-SH를 10% 비활성화 우태아 혈청(fetal bovine serum)과 1% 페니실린-스트렙토마이신용액(penicillin/streptomycin)을 넣은 EMEM 배양액으로 5% CO2가 공급되는 배양기에서 37℃ 조건으로 배양하였다. 충분한 세포를 얻기 위해 배양용 플라스크(T75cm2)에서 세포를 배양하고, 2 내지 3일에 한 번씩 배지를 80% 교체하여 배양하였다. 세포가 충분히 자랐을 때 trypsin-EDTA(ethylene diamine tetraacetic acid) 용액(1x)을 사용하여 부착된 세포를 떼어낸 후, 우태아 혈청과 항생제를 첨가하지 않은 성장배지에 2×104 cells/well 내지 3×104 cells/well로 조정하여 96-웰 플레이트에 접종하였다. 그 후, 실시예 1에서 분리한 락토바실러스 카제이 HY2782 균주 및 비교 균주로써, 락토바실러스 플란타룸(Lactobacillus plantarum) HY12, 락토바실러스 플란타룸 HY14, 락토바실러스 플란타룸 KY32, 락토바실러스 카제이(Lactobacillus casei) HY7207 및 락토바실러스 커바투스(Lactobacillus curvatus) HY76을 각각 5, 10, 50 또는 100㎍/㎖ 농도로 처리하고, 24시간 동안 배양하여 MTT assay와 세포 내 유전자 발현량를 검출하기 위하여 사용하였다.Human neuroblastoma SK-N-SH is an EMEM culture medium containing 10% inactivated fetal bovine serum and 1% penicillin/streptomycin solution (penicillin/streptomycin) in an incubator supplied with 5% CO 2 at 37°C. cultured under conditions. In order to obtain sufficient cells, the cells were cultured in a culture flask (T75cm 2 ), and the culture medium was replaced by 80% once every 2-3 days. When the cells are sufficiently grown, the adherent cells are detached using a trypsin-EDTA (ethylene diamine tetraacetic acid) solution (1x), and then 2×10 4 cells/well to 3 It was adjusted to ×10 4 cells/well and inoculated into a 96-well plate. Then, as Lactobacillus casei HY2782 strains and comparative strains isolated in Example 1, Lactobacillus plantarum HY12, Lactobacillus plantarum HY14, Lactobacillus plantarum KY32, Lactobacillus casei ( Lactobacillus casei ) HY7207 and Lactobacillus curvatus HY76 were treated at a concentration of 5, 10, 50 or 100 μg/ml, respectively, and cultured for 24 hours to detect MTT assay and intracellular gene expression level.
2-2. 세포 증식율 또는 생존율 측정2-2. Measurement of cell proliferation or viability
유산균의 뇌신경세포의 증식효과를 확인하기 위하여, 세포 증식율 또는 생존율을 측정하였다.In order to confirm the proliferative effect of lactic acid bacteria on brain neurons, the cell proliferation rate or survival rate was measured.
구체적으로, 실시예 2-1에서 균주가 처리된 SK-N-SH 세포의 증식율 또는 생존율은 Chung 등이 사용한 MTT[3-(4,5-dimethythiazol-2-yl)-2,5-dipheylterazolium bromid]환원 방법을 이용하여 측정하였다. 각 웰에 MTT 용액(5㎎/㎖)을 성장배지의 1/10 부피비로 첨가하고, 37℃에서 4시간 배양한 다음, MTT를 환원시켜 생성된 formazon이 배지에 따라 나가지 않도록 배지를 조심스럽게 제거하였다. 남아있는 배지를 완전히 제거하기 위해 실온에서 30분간 방치한 후, DMSO를 이용하여 용해시킨 시료를 570nm에서 흡광도를 측정하였다. 흡광도 측정시 대조군은 DMSO로 하였고, 세포의 증식율 또는 생존율은 하기의 식을 사용하여 계산하였다.Specifically, the proliferation or survival rate of SK-N-SH cells treated with the strain in Example 2-1 was MTT[3-(4,5-dimethythiazol-2-yl)-2,5-dipheylterazolium bromid used by Chung et al. ]Measured using the reduction method. MTT solution (5 mg/ml) was added to each well in a volume ratio of 1/10 of the growth medium, incubated at 37° C. for 4 hours, and then the medium was carefully removed so that the formazon produced by reducing MTT does not flow out depending on the medium. did. After standing at room temperature for 30 minutes to completely remove the remaining medium, the absorbance of the sample dissolved using DMSO was measured at 570 nm. When the absorbance was measured, DMSO was used as a control, and the cell proliferation or viability was calculated using the following formula.
세포 증식율 또는 생존율(%)=[시료 처리군의 흡광도/대조군의 흡광도]×100Cell proliferation rate or viability (%) = [absorbance in the sample treatment group / absorbance in the control group] × 100
그 결과, 50 또는 100㎍/㎖ 농도의 락토바실러스 카제이 HY2782 균주를 단독 처리하였을 때, 유의적으로 세포 증식 효과가 나타난 것으로 확인되었으며, 각각의 평균 증식율은 표 3과 같다(도 1).As a result, when the Lactobacillus casei HY2782 strain at a concentration of 50 or 100 μg/ml was treated alone, it was confirmed that a significant cell proliferation effect was exhibited, and the average growth rate of each is shown in Table 3 (FIG. 1).
또한, 락토바실러스 카제이 HY2782 균주를 250μM 스트레스호르몬(corticosterone)과 같이 처리한 결과, 250μM 스트레스호르몬(corticosterone) 단독처리인 양성 대조군과 비교하여 뇌신경세포 SK-N-SH는 생존율이 15 내지 21% 증가한 것으로 확인되었으며, 각각의 평균 생존율은 표 4과 같다(도 2).In addition, as a result of treating the Lactobacillus casei HY2782 strain with 250 μM stress hormone (corticosterone), the survival rate of brain neurons SK-N-SH was increased by 15 to 21% compared to the positive control group treated with 250 μM stress hormone (corticosterone) alone. was confirmed, and the average survival rate of each is shown in Table 4 (FIG. 2).
2-3. 유전자 발현 분석2-3. gene expression analysis
스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과를 평가하기 위하여 유전자 발현 분석을 수행하였다. In order to evaluate the inhibitory effect of stress hormone on brain apoptosis, gene expression analysis was performed.
구체적으로, 실시예 2-2에서 균주가 처리된 SK-N-SH 세포에서 유전자 발현을 분석하기 위하여, Total RNA Extraction Kit(IntronBio)를 이용하여 RNA를 추출하였다. Total RNA 정량 후, 분리한 RNA로부터 Quantitect reverse transcription kit(Qiagen, Valencia, CA)를 사용하여 cDNA를 합성하였다. 유전자의 발현량은 Taqman probe 및 Real-time PCR(applied biosystems, QuantStudio™ 6 real time PCR)을 이용하여 수행하였다. Real-time PCR을 통해 얻어진 결과는 glyceraldehyde 3-phosphate dehydrogenase(GAPDH)의 발현수준과 비교하여 보정하였고, comparative cycle threshold method를 이용하여 분석하였다. 또한, 각각의 PCR reaction의 melting curve를 통해 증폭된 유전자의 순도를 확인하였다. Cycle threshold 상대적인 정량 값으로 표현하였다.Specifically, to analyze gene expression in the SK-N-SH cells treated with the strain in Example 2-2, RNA was extracted using the Total RNA Extraction Kit (IntronBio). After total RNA quantification, cDNA was synthesized from the isolated RNA using the Quantitect reverse transcription kit (Qiagen, Valencia, CA). The expression level of the gene was performed using Taqman probe and Real-time PCR (applied biosystems, QuantStudio™ 6 real time PCR). Results obtained through real-time PCR were corrected by comparing with the expression level of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and analyzed using the comparative cycle threshold method. In addition, the purity of the amplified gene was confirmed through the melting curve of each PCR reaction. It was expressed as a quantitative value relative to the cycle threshold.
그 결과, 락토바실러스 카제이 HY2782 균주 10㎍/㎖을 250μM 스트레스호르몬(corticosterone)과 같이 처리한 결과, 250μM 스트레스호르몬 단독처리한 양성 대조군과 비교하여 뇌신경세포 활성 유전자인 BDNF 발현율은 약 7% 증가하였고(도 3), 세포 생존관련 유전자인 RELA 발현율은 약 5% 증가하였다(도 4). 또한, 락토바실러스 카제이 HY2782 균주 5㎍/㎖ 또는 10㎍/㎖을 250μM 스트레스호르몬(corticosterone)과 같이 처리한 결과, 250μM 스트레스호르몬 단독처리한 양성 대조군과 비교하여 세포 사멸 유전자인 CASPASE3 발현율은 각각 20% 및 17% 감소된 것으로 확인되었다(도 5).As a result, when 10 μg/ml of Lactobacillus casei HY2782 strain was treated with 250 μM stress hormone (corticosterone), the expression rate of BDNF, a brain nerve cell activation gene, was increased by about 7% compared to the positive control group treated with 250 μM stress hormone alone. (FIG. 3), the expression rate of RELA, a gene related to cell survival, increased by about 5% (FIG. 4). In addition, as a result of treatment with Lactobacillus
이와 같은 결과를 통하여, 락토바실러스 카제이 HY2782 균주는 뇌신경세포 증식 효과 및 스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과를 나타냈다는 점에서, 인지기능장애 및/또는 우울증의 예방, 개선 또는 치료에 락토바실러스 카제이 HY2782 균주가 효과적으로 활용될 수 있음을 확인하였다.Through these results, the Lactobacillus casei HY2782 strain showed an effect on brain nerve cell proliferation and suppression of brain nerve cell death caused by stress hormone, and Lactobacillus cartilage for the prevention, improvement or treatment of cognitive dysfunction and/or depression It was confirmed that the strain J. HY2782 can be effectively utilized.
실시예 3. 동물모델에서의 유효성 평가Example 3. Efficacy evaluation in animal models
3-1. 투여물질의 준비3-1. Preparation of dosing material
음성 대조물질 (vehicle)로 PBS를 사용하였고, 양성 대조물질 (Positive control)로 Donepezil을 사용하였고, 최종 용량 5 ㎎/10 ㎖/kg에 맞게 칭량하여 조제하여 사용하였다. 급성 인지능 저하를 유도하는 물질로서 scopolamine을 사용하였다. PBS was used as a negative control material (vehicle), Donepezil was used as a positive control material (positive control), and it was weighed and prepared according to the final dose of 5 mg/10 ㎖/kg. As a substance inducing acute cognitive decline, scopolamine was used.
3-2. 실험동물의 준비 및 투여물질의 투여3-2. Preparation of experimental animals and administration of administration materials
6주령 수컷 ICR mouse를 준비하였고, 비 유발군 (sham), 유발군 (scopolamine), 유발군에 락토바실러스 카제이 HY2782 균주를 처리한 군 (HY2782) 및 유발군에 donepezil을 처리한 군 (donepezil, 양성대조군)으로 구별하여 실험하였다. A 6-week-old male ICR mouse was prepared, and the non-induced group (sham), the induced group (scopolamine), the induced group treated with the Lactobacillus casei HY2782 strain (HY2782) and the induced group treated with donepezil (donepezil, positive control) and tested.
3-3. 신규물체 인식 시험3-3. New object recognition test
본 발명의 균주를 통해 기억력 개선 효과를 확인하기 위해 신규물체 시험을 수행하였다. A novel object test was performed to confirm the effect of improving memory through the strain of the present invention.
시험 방법은 구체적으로, 40 cm x 40 cm의 아크릴 케이지에 상이한 2개의 물체를 이용하여 기억력을 평가하였다. 아크릴 케이지 내를 익숙하게 한 후, 2개의 물체를 일정한 위치에 위치하여 자유롭게 인지하게 한 후, 각 물체를 탐색한 시간을 측정하였다. 24시간의 지연시간을 개체별로 주고 다시 동일한 위치에 한 가지 물체만 다른 물체로 변경하였다. 이 때 변경한 물체를 신규물체로 인식하여 탐색 시간이 길수록 기억력이 좋은 것으로 판단할 수 있다. 24시간 전의 물체를 기억하지 못한다면 신규 물체와 기존 물체를 구분하지 못하고 양쪽 물체 모두 균일하게 탐색할 가능성이 있다. 총 10분간 자유롭게 탐색하도록 하며, 결과는 preference index (PI, 신규물체 탐색 시간/총 탐색 시간)로 나타내었다. 낮은 PI 값은 새로운 물체를 인식하는 능력이 손상되었음을 의미한다. 분석은 SMART VIDEO TRACKING Software (Panlab, USA)을 이용하여 실시하였다. The test method specifically evaluated memory using two different objects in an acrylic cage of 40 cm x 40 cm. After familiarizing themselves with the inside of the acrylic cage, two objects were freely recognized by positioning them at certain positions, and then the time spent searching for each object was measured. A delay time of 24 hours was given to each individual, and only one object was changed to another object at the same location. At this time, the changed object is recognized as a new object, and it can be judged that the longer the search time, the better the memory. If the object cannot be remembered 24 hours ago, there is a possibility that the new object and the old object cannot be distinguished, and both objects are searched uniformly. A total of 10 minutes were allowed to freely search, and the results were expressed as preference index (PI, new object search time/total search time). A low PI value means that the ability to recognize new objects is impaired. Analysis was performed using SMART VIDEO TRACKING Software (Panlab, USA).
신규 물체의 탐색에 선호도를 보임을 비교함으로 인지능과 관련한 유효성을 검증하였다. 이 실험은 기본적으로 마우스의 단기 기억력을 확인하는 시험이기 때문에 정상적인 탐색 기능을 가지지 않은 개체는 결과 해석에 배제하였다. 그 기준은 총 탐색 시간이 15초 이하인 개체는 결과에서 제외하였다. Cognitive intelligence-related validity was verified by comparing the preference for the search for new objects. Since this experiment is basically a test to check the mouse's short-term memory, subjects without normal search function were excluded from the interpretation of the results. The criterion was that subjects with a total search time of 15 seconds or less were excluded from the results.
Sham(미유발군)은 신규물체에 대한 preference index (PI) 값이 0.60 ± 0.11을 나타내었고, Scopolamin(유발군)과 비교하여 유의적인 차이를 보여주었다. 락토바실러스 카제이 HY2782 균주(실험군)는 0.56 ± 0.22의 PI 값을 보여주었다. Donepezil(양성대조군)은 0.59 ± 0.13의 PI로 Scopolamin(유발군)과 비교하여 차이를 보여주었다 (도 6). Sham (uninduced group) showed a preference index (PI) value of 0.60 ± 0.11 for new objects, and showed a significant difference compared with Scopolamin (induced group). Lactobacillus casei HY2782 strain (experimental group) showed a PI value of 0.56 ± 0.22. Donepezil (positive control group) showed a difference compared to Scopolamin (induced group) with a PI of 0.59 ± 0.13 (FIG. 6).
3-4. 수동회피 시험3-4. passive evasion test
본 발명의 균주를 통해 기억력 개선 효과를 확인하기 위해 수동회피 시험을 수행하였다. A passive avoidance test was performed to confirm the effect of improving memory through the strain of the present invention.
시험 방법은 구체적으로, 수동회피 실험은 어두운 곳을 선호하는 설치류의 습성을 이용한 행동실험으로, 동일한 크기의 2개의 케이지(검은색 아크릴과 화이트 아크릴)를 맞대어 제작되었다. 어두운 cage에는 foot shock이 발생하는 철망구조로 되어 밝은 곳에서 어두운 곳으로 개체가 진입하였을 때, 0.5 mA의 전류를 3초동안 주어 전기 자극을 주어 강제 기억을 유발하였다. 24시간 후 다시 밝은 곳에 개체를 두어 어두운 방으로 들어가는 시간을 측정하여 기억력 능력을 평가하였다. 결과치는 300초를 최대값으로 하며 Step through latency (sec)로 나타내었다. Acquisition time이 200초 이상 나오는 개체는 정상적 탐색 능력을 보인 개체가 아니라고 판단하여 최종 결과에서 제외하였다.The test method is specifically, the passive avoidance experiment is a behavioral experiment using the rodents' habit of preferring dark places, and was produced by putting two cages of the same size (black acrylic and white acrylic) together. The dark cage has a wire mesh structure where foot shock occurs, and when an object enters from a bright place to a dark place, a current of 0.5 mA is applied for 3 seconds to induce an electrical stimulus to induce forced memory. After 24 hours, the subject was placed in a bright place again and the time to enter a dark room was measured to evaluate memory ability. The result is expressed as Step through latency (sec) with 300 seconds as the maximum value. An entity with an acquisition time of 200 seconds or more was excluded from the final result as it was judged not to be an entity with normal search ability.
전기 자극에 대한 기억으로 인해 어두운 곳으로 가려는 습성을 억제하는 정도를 관찰하여 기억력에 대한 시험군 간의 비교로 유효성을 검증하는 시험방법으로 알려져 있다. 어두운 방에 들어가지 않는 시간을 비교함으로써 인지능과 관련한 유효성을 검증하였다. 이 실험은 기본적으로 마우스의 단기 기억력을 확인하는 시험이기 때문에 어두운 방을 잘 찾아가지 않는 개체, 기억을 통해 어두운 방을 들어가지 않는 것이 아니라 Freezing에 의해 아예 움직임이 없는 개체는 결과 해석 시 배제하였다. 이번 시험계에서 해당하는 개체는 없는 것으로 판단하였다.It is known as a test method to verify the effectiveness by comparing the test groups on memory by observing the degree to which the habit of going to a dark place is suppressed due to the memory of the electrical stimulus. Cognitive intelligence-related validity was verified by comparing the time not to enter a dark room. Since this experiment is basically a test to check the mouse's short-term memory, subjects who do not visit dark rooms well, subjects that do not enter dark rooms through memory, but do not move at all due to freezing were excluded from the interpretation of the results. In this test system, it was judged that there was no corresponding object.
Sham(미유발군)은 어두운 방으로 이동하는 평균 시간(sec)이 171.13 ± 113.78을 나타내었고, Scopolamin(유발군)과 비교하여 차이를 보여주었다. 락토바실러스 카제이 HY2782 균주(실험군)는 103.00 ± 74.26 의 어두운 방으로 이동하는 평균 시간을 나타내었다 (도 7). Sham (uninduced group) showed an average time (sec) of moving to a dark room of 171.13 ± 113.78, and showed a difference compared to Scopolamin (induced group). Lactobacillus casei HY2782 strain (experimental group) exhibited an average time to move to a dark room of 103.00 ± 74.26 (FIG. 7).
3-5. β-amyloid 42 측정3-5. Measurement of β-amyloid 42
본 발명의 균주를 통한 인지능 개선 효과를 확인하기 위해 β-amyloid 42 측정하였다. β-amyloid 42 was measured to confirm the cognitive improvement effect through the strain of the present invention.
구체적으로, β-amyloid 42, 40측정은 마우스 혈액에서 Elisa kit(Abcam, USA)를 이용하여 측정하였다.Specifically, β-
그 결과, Sham(미유발군)은 β-amyloid 42 혈액농도(pg/ml)가 52.55 ± 3.75을 나타내었고, Scopolamin(유발군) 66.06 ± 2.74와 비교하여 차이를 보여주었다. 락토바실러스 카제이 HY2782 균주(실험군)는 50.75 ± 1.23 농도를 나타내었다 (도 8). As a result, Sham (uninduced group) had a β-amyloid 42 blood concentration (pg/ml) of 52.55 ± 3.75, which was different from that of Scopolamin (induced group) 66.06 ± 2.74. Lactobacillus casei HY2782 strain (experimental group) showed a concentration of 50.75 ± 1.23 (FIG. 8).
3-6. BDNF 측정3-6. BDNF measurement
본 발명의 균주를 통한 인지능 개선 효과를 확인하기 위해 BDNF 측정하였다. BDNF was measured to confirm the effect of improving cognitive ability through the strain of the present invention.
그 결과, Sham(미유발군)은 BDNF 혈액농도(pg/ml)가 2.74 ± 0.31을 나타내었고, Scopolamin(유발군) 1.58 ± 0.17에서 Sham(미유발군)과 비교하여 감소하는 차이를 보여주었다. 락토바실러스 카제이 HY2782 균주(실험군)는 2.37 ± 0.16 농도를 나타내었다 (도 8).As a result, Sham (uninduced group) showed a BDNF blood concentration (pg/ml) of 2.74 ± 0.31, and Scopolamin (induced group) showed a decreasing difference compared to Sham (uninduced group) at 1.58 ± 0.17. Lactobacillus casei HY2782 strain (experimental group) showed a concentration of 2.37 ± 0.16 (FIG. 8).
상기한 동물모델 실험 결과 본 발명의 락토바실러스 카제이 HY2782 균주는 인지능 개선의 효과를 가짐을 알 수 있다. As a result of the above animal model experiment, it can be seen that the Lactobacillus casei HY2782 strain of the present invention has an effect of improving cognitive ability.
이와 같은 결과를 통하여, 락토바실러스 카제이 HY2782 균주는 뇌신경세포 증식 효과 및 스트레스호르몬에 의한 뇌신경세포 사멸 억제 효과를 나타냈다는 점에서, 인지기능장애 및/또는 우울증의 예방, 개선 또는 치료에 락토바실러스 카제이 HY2782 균주가 효과적으로 활용될 수 있음을 확인하였다.Through these results, the Lactobacillus casei HY2782 strain showed an effect on brain nerve cell proliferation and suppression of brain nerve cell death caused by stress hormone, and Lactobacillus cartilage for the prevention, improvement or treatment of cognitive dysfunction and/or depression It was confirmed that the strain J. HY2782 can be effectively utilized.
이제까지 본 발명에 대하여 그 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been looked at focusing on the embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (10)
상기 락토바실러스 카제이 HY2782 균주는 락토바실러스 카제이 HY2782 생균체 또는 락토바실러스 카제이 HY2782 사균체인 치매 예방 또는 치료용 약학적 조성물.
As a pharmaceutical composition for preventing or treating dementia comprising the Lactobacillus casei HY2782 strain as an active ingredient;
The Lactobacillus casei HY2782 strain is a Lactobacillus casei HY2782 live cell or a Lactobacillus casei HY2782 dead cell, a pharmaceutical composition for preventing or treating dementia.
The method of claim 1, wherein the dementia is senile dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease dementia, Huntington's disease dementia, normal pressure hydrocephalus dementia, dementia due to head trauma, and substance induced A pharmaceutical composition for preventing or treating dementia which is a disease selected from the group consisting of dementia.
상기 락토바실러스 카제이 HY2782 균주는 락토바실러스 카제이 HY2782 생균체 또는 락토바실러스 카제이 HY2782 사균체인 우울증 예방 또는 치료용 약학적 조성물.
As a pharmaceutical composition for preventing or treating depression comprising the Lactobacillus casei HY2782 strain as an active ingredient;
The Lactobacillus casei HY2782 strain is a Lactobacillus casei HY2782 live cell or a Lactobacillus casei HY2782 dead cell, a pharmaceutical composition for preventing or treating depression.
상기 락토바실러스 카제이 HY2782 균주는 락토바실러스 카제이 HY2782 생균체 또는 락토바실러스 카제이 HY2782 사균체인 치매 예방 또는 개선용 식품 조성물.
As a food composition for preventing or improving dementia comprising the Lactobacillus casei HY2782 strain as an active ingredient;
The Lactobacillus casei HY2782 strain is Lactobacillus casei HY2782 live cells or Lactobacillus casei HY2782 dead cells, a food composition for preventing or improving dementia.
7. The method of claim 6, wherein the dementia is senile dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease dementia, Huntington's disease dementia, dementia due to normal pressure hydrocephalus, dementia due to head trauma, and substance induced A food composition for preventing or improving dementia which is a disease selected from the group consisting of dementia.
상기 락토바실러스 카제이 HY2782 균주는 락토바실러스 카제이 HY2782 생균체 또는 락토바실러스 카제이 HY2782 사균체인 우울증 예방 또는 개선용 식품 조성물.
As a food composition for preventing or improving depression comprising the Lactobacillus casei HY2782 strain as an active ingredient;
The Lactobacillus casei HY2782 strain is a Lactobacillus casei HY2782 live cell or a Lactobacillus casei HY2782 dead cell, a food composition for preventing or improving depression.
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