WO2022235023A1 - Pharmaceutical composition for prevention or treatment of ischemic brain disease - Google Patents
Pharmaceutical composition for prevention or treatment of ischemic brain disease Download PDFInfo
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- WO2022235023A1 WO2022235023A1 PCT/KR2022/006197 KR2022006197W WO2022235023A1 WO 2022235023 A1 WO2022235023 A1 WO 2022235023A1 KR 2022006197 W KR2022006197 W KR 2022006197W WO 2022235023 A1 WO2022235023 A1 WO 2022235023A1
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- pharmaceutical composition
- preventing
- present
- brain disease
- ischemic brain
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/13—Nucleic acids or derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disease comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
- PDRN polydeoxyribonucleotide
- Ischemic encephalopathy is a generic term for diseases that cause pathological abnormalities in blood vessels supplying blood to the brain mainly due to thrombus and embolism, and includes hypoxic ischemic encephalopathy, ischemic stroke, vascular dementia, Alzheimer's disease, Huntington's disease, Parkinson's disease can
- hypoxic-ischemic encephalopathy is brain damage caused by decreased oxygen delivery to brain cells due to various causes.
- the causes of hypoxic damage include abnormal oxygen delivery from the lungs, decreased intra-arterial oxygen, anemic hypoxia caused by lack of hemoglobin, etc., and failure of intracellular oxygen delivery due to poisoning with toxic substances.
- hypoxic ischemic encephalopathy induces very rapid cell death, and as platelet aggregation and thrombotic hemostasis rapidly progress, cells inherent in the nervous system, migration of inflammatory and immune cells, death of parenchymal cells, and cell debris It leads to various complications such as formation.
- hypoxic ischemic encephalopathy may further exacerbate the condition by causing secondary damage such as metabolic acidosis, cell destruction, and reperfusion damage, in addition to damage caused by hypoxia itself.
- the brain has different sensitivity and resistance to hypoxia depending on each tissue included in the brain, irregular damage may occur.
- areas of the brain susceptible to hypoxic ischemic injury include the hippocampus, Cerebellar Purkinje cells, and Neocortical neurons in layers 3, 5, 6, and hypoxic As the condition progresses, damage to the entire cerebrum, the Perirolandic cortex, the cerebellum, and even deep gray matter structures can be induced.
- hypoxic ischemic encephalopathy can cause damage to various parts of the brain, as described above, various types of clinical symptoms such as reduced arousal, cognitive decline, epilepsy, autonomic nervous system failure, and movement disorders, such as vegetative humans and complications.
- the method used as a treatment for ischemic brain disease is non-existent except for thrombolysis that has been successful in clinical trials, and antioxidants or immunosuppressants can be used in prophylactic treatment methods, but these questions are limited due to toxicity. can only be used as
- PDRN polydeoxyribonucleotide
- PDRN is a piece of DNA extracted from the semen of fish and is being used in various fields in the medical world as its effects such as cell growth promotion, wound healing, and cell therapy are known. More specifically, PDRN is a DNA polymer, and since it is a biocomponent, there is no allergic reaction or rejection reaction in synthetic materials, etc., and it is a material with hydrophilic properties because the main component is DNA having a negative charge. Very easy. Furthermore, PDRN has been confirmed to have effects of recovery of severe wounds, angiogenesis, and rapid skin regeneration in several clinical trials, but there is no effect on the central nervous system.
- the inventors of the present invention tried to apply PDRN to ischemic brain disease, and eventually found that PDRN can protect or regenerate damaged nerve cells and vascular cells due to ischemia.
- the inventors of the present invention have found that when a specific concentration of PDRN is treated, factors related to inducing inflammation and factors inducing apoptosis in various cells including neurons and vascular cells are reduced.
- the inventors of the present invention have found that when a specific concentration of PDRN is treated, factors capable of promoting differentiation, production and regeneration in neurons and vascular cells are increased.
- ischemic brain disease caused by hypoxia and hyponutrient can be overcome through treatment with a specific concentration of PDRN.
- an object of the present invention is to provide a pharmaceutical composition capable of preventing or treating ischemic brain disease and a health functional food for improvement by including polydeoxyribonucleotide (PDRN) as an active ingredient.
- PDRN polydeoxyribonucleotide
- a pharmaceutical composition for preventing or treating ischemic brain disease comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
- PDRN polydeoxyribonucleotide
- the ischemic brain disease includes hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, and transient ischemic attack. ), cerebral infarction (lacune), head trauma, cerebral circulatory metabolic disorder, brain functional coma, traumatic brain injury, vascular dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease. It may include all ischemic diseases caused by reperfusion after hypoxic and hyponutrient conditions.
- HIE hypoxic-ischemic encephalopathy
- composition of the present invention may further include at least one of the group consisting of a pharmaceutically acceptable carrier, diluent and adjuvant, but is not limited thereto.
- the composition may be characterized in that it is administered through at least one route of administration from the group consisting of oral, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous and nasal. It is not limited.
- the composition may be formulated as a tablet, ointment or injection, but is not limited thereto, and does not modify the PDRN contained in the composition of the present invention, and may include various It can be formulated in any form.
- PDRN may be included in a concentration of 30 to 150 ⁇ g/ml, but is not limited thereto.
- PDRN by decreasing the expression of at least one of Bax, mTOR, and DKK-1, may exhibit an effect on neuroprotection and nerve regeneration.
- PDRN by increasing the expression of at least one of BCL-2, VEGF, BDNF, WNT-3 ⁇ and ⁇ , may exhibit an effect on nerve protection and nerve regeneration.
- PDRN by reducing the expression of at least one of TNF ⁇ , iNOS, IL-1 ⁇ , CSF1, STAT1 and IL-6, it can exhibit an effect on anti-inflammatory.
- a health functional food for preventing or improving ischemic brain disease comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
- PDRN polydeoxyribonucleotide
- PDRN may be included in a concentration of 30 to 150 ⁇ g/ml, but is not limited thereto.
- the present invention can provide a therapeutic and/or prophylactic effect on ischemic brain disease.
- the present invention reduces inflammatory and apoptotic responses caused by various stresses such as hypoxia and nutritional deficiency, protects nerve cells and blood vessels, and promotes their differentiation, generation and regeneration, so that the above-mentioned stress It is possible to prevent and treat brain diseases caused by various stresses such as hypoxia and nutritional deficiency, protects nerve cells and blood vessels, and promotes their differentiation, generation and regeneration, so that the above-mentioned stress It is possible to prevent and treat brain diseases caused by various stresses such as hypoxia and nutritional deficiency, protects nerve cells and blood vessels, and promotes their differentiation, generation and regeneration, so that the above-mentioned stress It is possible to prevent and treat brain diseases caused by various stresses such as hypoxia and nutritional deficiency, protects nerve cells and blood vessels, and promotes their differentiation, generation and regeneration, so that the above-mentioned stress It is possible to prevent and treat brain diseases caused by various stresses such as hypoxia and nutritional deficiency, protects nerve cells and blood vessels, and promotes their differentiation, generation and regeneration
- the present invention can differentiate, develop and grow various cells as well as nerve cells and blood vessels, it is possible to prevent and treat various ischemic diseases caused by hypoxia and/or hyponutrition. Accordingly, the present invention relates to hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, transient ischemic attack, cerebral infarction (lacune),
- HIE hypoxic-ischemic encephalopathy
- stroke cerebral infarction
- cerebral ischemia cerebral ischemia
- thrombosis embolism
- transient ischemic attack cerebral infarction (lacune)
- ischemic stroke including at least one of head trauma, cerebral circulatory metabolic disorder, brain functional coma, traumatic brain injury, vascular dementia, Alzheimer's disease, Huntington's disease and Parkinson's disease, preventive and/or therapeutic effect can have
- the present invention can effectively inhibit nerve cell damage due to ischemic reperfusion by preventing hyperexcitation of nerve cells occurring during reperfusion after hypoxia and nutritional deficiency, thereby preventing ischemic brain disease including ischemic stroke , can be usefully used for improvement and treatment.
- the effect according to the present invention is not limited by the contents exemplified above, and more various effects are included in the present specification.
- FIG. 1 illustrates a procedure of a method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention.
- Figure 2 shows the hypoxic ischemic encephalopathy model construction and processing of the composition of the present invention for confirming the effect of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention.
- Figure 3a shows the cell viability results according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- Figure 3b shows the results of the inflammatory response factors according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- Figure 3c shows the results of angiogenesis according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- Figure 3d shows the results of neuroprotection according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- Figure 3e shows the results of nerve regeneration according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- Figure 3f shows the results of cell death according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- 4a to 4d show the results of gene expression related to the anti-inflammatory effect according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
- prevention may refer to any action that inhibits or delays the onset of brain disease by administration of the composition.
- treatment refers to any action in which the symptoms of brain disease already induced by the administration of the composition of the present invention are improved or beneficial.
- the term "subject” may mean a subject that can have an effect on the regeneration, protection, and production of nerve cells and/or vascular cells and an effect on anti-inflammatory through the composition of the present invention, , may be used interchangeably with terms such as “host”, “subject” and “patient”.
- the method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention includes the step of including polydeoxyribonucleotide (PDRN) as an active ingredient (S110).
- PDRN polydeoxyribonucleotide
- PDRN may refer to a fragment of DNA extracted from semen of fish, and any material commercially extracted from wolves and semen of fish may be used in the art.
- the molecular weight of PDRN may be 50 to 1500 kDa. That is, the PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may be a natural material, not a synthetic material.
- the concentration of PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease may be 30 to 150 ⁇ g/ml, but is not limited thereto. At this time, when the concentration of PDRN is less than 30 ⁇ g/ml, its effect may be insignificant, and when it is 150 ⁇ g/ml or more, the increase in the effect according to the increase is very weak, and stability in the formulation may not be ensured. , a preferred concentration of PDRN may be 30 to 150 ⁇ g/ml.
- the PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease reduces the expression of at least one of Bax, mTOR, and DKK-1, thereby exhibiting effects on nerve protection and nerve regeneration.
- PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease increases the expression of at least one of BCL-2, VEGF, BDNF, WNT-3 ⁇ and ⁇ , thereby protecting and It may have an effect on nerve regeneration.
- PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease reduces the expression of at least one of TNF ⁇ , iNOS, IL-1 ⁇ , CSF1, STAT1 and IL-6, It may have an effect on inflammation.
- the ischemic brain disease that can have a preventive or therapeutic effect through the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention is hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction. , cerebral ischemia, thrombosis, embolism, transient ischemic attack, cerebral infarction (lacune), head trauma, cerebral circulatory metabolic disorder, cerebral coma, traumatic brain injury, vascular It may include at least one of dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease, but is not limited thereto, and may include all of various ischemic diseases induced by reperfusion after hypoxia and hyponutrition.
- HIE hypoxic-ischemic encephalopathy
- stroke cerebral infarction.
- cerebral ischemia cerebral ischemia, thrombosis, embolism, transient ischemic attack, cerebral infarction (lacune)
- head trauma cerebral circulatory metabolic disorder
- cerebral coma traumatic brain injury
- vascular It may include
- the method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may further include the step of including at least one of the group consisting of a pharmaceutically acceptable carrier, diluent and adjuvant.
- the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may be prepared in the form of a pharmaceutical formulation suitable for oral or parenteral administration.
- pharmaceutically acceptable carriers, diluents and adjuvants include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- fillers, anti-aggregants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like, which are commonly used in the preparation of the formulation may be further included.
- the compositions of the present invention may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
- the method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease may further include the step of including a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is toxic to the human body. It should not adversely affect the biological activity and physicochemical properties of the parent compound.
- a pharmaceutically acceptable salt may be prepared by a method conventional in the art, and specifically, a base addition salt produced by adding a base may be included.
- the base is an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide), alkali metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate), alkali metal carbonate (eg, sodium carbonate, potassium carbonate, calcium carbonate)
- alkali metal hydroxide eg, sodium hydroxide, potassium hydroxide
- alkali metal bicarbonate eg, sodium bicarbonate, potassium bicarbonate
- alkali metal carbonate eg, sodium carbonate, potassium carbonate, calcium carbonate
- Inorganic bases such as, etc., or organic bases such as primary and secondary tertiary amine amino acids
- hydrates or solvates may be included in addition to the pharmaceutically acceptable salts described above.
- hydrates and solvates can be prepared by dissolving the parent compound in a solvent, adding a free acid or a free base, and then crystallizing or recrystallizing the composition.
- solvates particularly hydrates
- a pharmaceutical formulation can be prepared according to a conventional method using the composition of the present invention.
- the active ingredient may be mixed with a carrier, diluted with a carrier, or enclosed in a carrier in the form of a capsule, sachet or other container.
- the dosage form is a tablet, pill, powder, capsule, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft or hard gelatin capsule, solution or suspension for injection, ointment, cream, gel or lotion. It may be in the form of
- the route of administration of the composition of the present invention is not limited thereto, but for example, oral, nasal, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, Enteral, sublingual or topical administration is possible.
- the dosage of the pharmaceutical composition for preventing or treating ischemic brain disease varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but is appropriately determined by those skilled in the art. can be selected.
- a pharmaceutical composition capable of effectively preventing or treating ischemic brain disease can be prepared.
- a health functional food for preventing or improving ischemic brain disease can be manufactured.
- examples of food include drinks, meat, sausage, bread, biscuits, rice cakes, sun food, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, alcohol There are beverages and vitamin complexes, dairy products and processed dairy products, and in addition, all health functional foods in the ordinary sense are included.
- hypoxic ischemic encephalopathy model construction and the composition processing process of the present invention for confirming the effect of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are illustrated.
- Neuro2A cells are differentiated into neurons (Neuron cells), which are then oxygen-induced glucose deprivation (OGD) and damaged (hypoxic ischemic) neurons
- OGD oxygen-induced glucose deprivation
- the model was built, and thus it was performed by treating a pharmaceutical composition for preventing or treating ischemic brain disease (PDRN) and a control group (PBS) according to various embodiments of the present invention.
- PDRN ischemic brain disease
- PBS control group
- Neuro2A cells were cultured in DMEM medium containing 10% FBS at 37 ° C., 5% CO 2 environment for 1 day ( D0 to D1), and cultured in DMEM medium containing 20 ⁇ M retionic acid (RA) and 2% FBS for 4 days (D1 to D4) to differentiate into neurons.
- DMEM medium containing 10% FBS at 37 ° C., 5% CO 2 environment for 1 day ( D0 to D1)
- DMEM medium containing 20 ⁇ M retionic acid (RA) and 2% FBS for 4 days (D1 to D4 to differentiate into neurons.
- HIE hypoxic-ischemic encephalopathy
- the OGD-induced neuronal model is treated with PDRN or PBS, respectively. 37 °C, 5% CO 2 After culturing for 18 hours or more in an environment, the effect on reperfusion and treatment with the composition of the present invention was confirmed.
- the cell viability results according to the treatment of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention are shown.
- the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention was treated by 50 ⁇ g/ml or 100 ⁇ g/ml in the OGD-induced neuronal model, that is, the HIE model, respectively.
- Cell Counting Kit8 was used for cell counting.
- the OGD group (OGD+PDRN 50 ⁇ g/ml and OGD+PDRN 100 ⁇ g/ml) treated with the pharmaceutical composition for preventing or treating ischemic brain disease is a control group, that is, only PBS It appeared that the cell viability was significantly higher than that of the treated OGD group (OGD) (P ⁇ 0.05).
- the group treated with the composition of the present invention at 100 ⁇ g/ml was significantly higher than the group treated with the composition of the present invention at 50 ⁇ g/ml (OGD+PDRN 50 ⁇ g/ml).
- the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention can effectively improve the survival rate of nerve cells, and proportionally according to the amount of treatment for the composition of the present invention, the cell viability is increased.
- FIG. 3B the results of the inflammatory response factors according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown.
- Examples of the present invention show that the expression of iNOS, TNF- ⁇ and IL-1 ⁇ , which are factors related to the inflammatory response, is significantly lower than those of Comparative Examples 1 and 2 (P ⁇ 0.05).
- the expression level of iNOS for Examples of the present invention is shown to be 0.4 and 0.1 times lower than those of Comparative Examples 1 and 2, respectively, and the expression level of TNF- ⁇ for Examples of the present invention is higher than that of Comparative Examples 1 and 2, respectively. 0.3 and 0.09 times lower, and the expression level of IL-1 ⁇ for Examples of the present invention is 0.4 and 0.1 times lower than those of Comparative Examples 1 and 2, respectively.
- the inflammatory cytokines TNF- ⁇ (tumor necrosis factor- ⁇ ) and IL-1 ⁇ (interleukin-1beta) and the inflammatory protein iNOS (inducible nitrous oxide) act as catalysts and mediators of inflammatory responses in the body. factors, and their increase promotes the catabolism of muscles, thereby reducing muscle mass and accumulating fat in the body, thereby causing immune aging.
- composition of the present invention can alleviate the inflammatory response induced by oxygen-glucose deficiency, and thus can even prevent the immune aging phenomenon that may appear in a chain.
- FIG. 3C the results of angiogenesis according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown.
- Examples of the present invention show that the expression of VEGF, an angiogenic factor, is significantly higher than those of Comparative Examples 1 and 2 (P ⁇ 0.05). Furthermore, the expression levels of VEGF for Examples of the present invention are 2.5 and 13.4 times higher than those of Comparative Examples 1 and 2, respectively.
- vascular endothelial growth factor is an intrinsic factor that promotes angiogenesis, as well as angiogenesis, as well as vasculogenesis in embryogenesis, lymphogenesis and maintenance of homeostasis. also participate in That is, VEGF, like many growth factor receptors, may also be involved in cell migration, survival, and proliferation, and may have a function of transmitting a signal capable of forming a three-dimensional blood vessel or adjusting vascular permeability.
- the composition of the present invention can promote the generation of blood vessels by improving the expression of VEGF, and furthermore, it can be improved by activating the migration, survival and proliferation of various cells including nerve and vascular cells.
- FIG. 3D the results of neuroprotection according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown.
- Examples of the present invention show that the expression of mTOR is significantly lower than Comparative Examples 1 and 2 (P ⁇ 0.05).
- the Example of the present invention shows that the expression of BDNF is significantly higher than Comparative Examples 1 and 2 (P ⁇ 0.05).
- the expression level of mTOR for Examples of the present invention is 0.3 times and 0.09 times lower than those of Comparative Examples 1 and 2, respectively, and the expression level of BDNF for Examples of the present invention is 2.7 than Comparative Examples 1 and 2, respectively. , 6.5 times higher.
- mTOR mimmalian target of rapamycin
- kinase serine / threonine protein kinase
- PIKK PI3K-related kinase
- mTOR not only has a close relationship with autophagy, but also affects the inflammatory response that significantly affects apoptosis and the expression of related chemokines. and expression may be increased.
- the signal of mTOR increases due to abnormal function in neurons, it may lead to a decrease in memory storage ability due to the death of neurons.
- mTOR is a central mechanism in anabolic and catabolism of lipid metabolism, its excessive activity may lead to metabolic effects such as obesity and insulin resistance. Accordingly, when mTOR is inhibited, it induces enhancement of autophagy, activation of lifespan-related genes, potential suppression, and reduction of reactive oxygen species production, leading to aging and death of various cells including nerve cells. can reduce
- composition of the present invention by reducing the expression of mTOR, can reduce aging and death for neurons.
- BDNF Brain-Derived Neurotrophic Factor
- composition of the present invention by increasing the expression of BDNF, can actively improve the signal transduction between neurons, can promote the differentiation, development and growth of neurons, and furthermore, the survival of neurons can be improved
- the composition of the present invention reduces the expression of mTOR and increases the expression of BDNF, thereby protecting neurons from various stresses, and allowing the neurons to stably differentiate, develop and grow.
- FIG. 3E the results of nerve regeneration according to the treatment of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention are shown.
- Examples of the present invention show significantly higher expression of WNT-3 ⁇ and ⁇ than Comparative Examples 1 and 2 (P ⁇ 0.05).
- the Example of the present invention shows that the expression of DKK-1 is significantly lower than Comparative Examples 1 and 2 (P ⁇ 0.05).
- the expression level of WNT-3 ⁇ for Examples of the present invention is 3.5 and 11.7 times higher than those of Comparative Examples 1 and 2, respectively, and the expression level of ⁇ -Catenin for Examples of the present invention is Comparative Examples 1 and 2 3.7 and 20.5 times higher, respectively.
- the expression level of DKK-1 for Examples of the present invention is shown to be 0.2 and 0.04 times lower than Comparative Examples 1 and 2, respectively.
- WNT-3 ⁇ is a protein that induces nervous system growth and can regenerate damaged nerves. Furthermore, the pathway according to WNT-3 ⁇ and ⁇ can protect neurons by reducing the toxicity of neurons by amyloid beta.
- composition of the present invention by increasing the expression of WNT-3 ⁇ and ⁇ , it is possible to improve not only the protection of nerve cells, but also the regeneration ability.
- DKK-1 (Dikkopf1) is an inhibitor of the aforementioned WNT-3 ⁇ / ⁇ -Catenin signal, as its expression is reduced, the neuronal protection and regenerative ability by the aforementioned WNT-3 ⁇ and ⁇ become more active. It can be activated, and its effect can be improved.
- Examples of the present invention show that the expression of Bax is significantly lower than Comparative Examples 1 and 2 (P ⁇ 0.05).
- the Example of the present invention shows that the expression of Bcl-2 is significantly lower than Comparative Examples 1 and 2 (P ⁇ 0.05).
- the expression level of Bax for Examples of the present invention is shown to be 0.5 and 0.1 times lower than those of Comparative Examples 1 and 2, respectively, and the expression level of Bcl-2 for Examples of the present invention is higher than that of Comparative Examples 1 and 2, respectively. 3.5 and 10.8 times higher.
- Bax is a factor capable of inducing apoptosis by damaging cells.
- composition of the present invention by reducing the expression of Bax, it is possible to reduce the death of various cells as well as neurons.
- Bcl-2 can inhibit apoptosis by binding to the above-mentioned Bax and inducing its structural change.
- composition of the present invention by increasing the expression of Bcl-2, it is possible to prevent and block the death of various cells including neurons by Bax.
- the pharmaceutical composition for the prevention or treatment of ischemic brain disease reduces inflammation and apoptosis caused by various stresses such as hypoxia and nutritional deficiency, nerve cells and vascular cells It is possible to prevent and treat brain diseases caused by the above-described stress by protecting and promoting its differentiation, generation and regeneration.
- the pharmaceutical composition for preventing or treating ischemic brain disease can differentiate, develop and grow various cells as well as nerve cells and blood vessels, hypoxia and/or hyponutrient Thereafter, various ischemic diseases caused by reperfusion can also be prevented and treated.
- the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention is hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism ), transient ischemic attack, lacune, head trauma, cerebral circulatory metabolic disorder, cerebral coma, traumatic brain injury, vascular dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease.
- HIE hypoxic-ischemic encephalopathy
- ischemic encephalopathy including, it may have a preventive and / or therapeutic effect.
- the pharmaceutical composition for preventing or treating ischemic brain disease may be more effective for anti-inflammatory.
- RNA sequencing transcriptome array analysis confirmed the differentially expressed genes (DEGs) by selecting only genes with fold change of 1.7 or more and -1.7 or less, p-value ⁇ 0.05, and RTPCR based on SYBRgreen for their expression. It was confirmed through the method.
- DEGs differentially expressed genes
- OGD oxygen-by glucose deprivation
- up-regulated genes up-regulated genes
- down-regulated genes down-regulated genes 838 appears to be a species.
- up-regulated genes are shown to be 102 kinds, and the down-regulated genes are genes) appear to be 210 species.
- FIG. 4B a list of genes differentially expressed in FIG. 4A described above is shown.
- the genes differentially expressed by induction of OGD and treatment with the composition of the present invention are Csf1, Il6, Stat1, Cxcl14, Hspa8, Ccl4, Cd14, Ptpn6, Ccl3, Lpl, C1qc, Rac2, C1qb and Ctsk. Expression appears to have an opposing pattern by treatment with OGD and compositions of the present invention.
- Csf1, Il6 and Stat1 are expressed to be increased due to OGD, and Csf1, Il6 and Stat1 are inflammation-related factors secreted by inflammatory cells or cancer cells. That is, due to oxygen-glucose deprivation, inflammatory response factors may be increased.
- the pharmaceutical composition for preventing or treating ischemic brain disease can reduce the expression of a factor capable of promoting an inflammatory response caused by hypoxia and nutritional deficiency or reperfusion after the aforementioned condition. and, accordingly, may have an anti-inflammatory effect.
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Abstract
The present description provides a pharmaceutical composition containing polydeoxyribonucleotide (PDRN) as an active ingredient for prevention or treatment of ischemic brain diseases.
Description
본 발명은 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disease comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
허혈성 뇌질환은 주로 혈전 및 색전 등에 의해 뇌에 혈류를 공급하는 혈관에 병리학적 이상이 생기는 질환의 총칭이며, 저산소성 허혈성 뇌병증, 허혈성 뇌졸중, 혈관성 치매, 알츠하이머성 치매, 헌팅턴병, 파킨슨병 등이 포함될 수 있다.Ischemic encephalopathy is a generic term for diseases that cause pathological abnormalities in blood vessels supplying blood to the brain mainly due to thrombus and embolism, and includes hypoxic ischemic encephalopathy, ischemic stroke, vascular dementia, Alzheimer's disease, Huntington's disease, Parkinson's disease can
이 중, 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE)은 다양한 원인으로 뇌세포에 산소 전달이 감소하게 되어 발생하는 뇌의 손상이다. 예를 들어, 저산소성 손상의 원인으로는 폐에서부터의 산소 전달 이상, 동맥내 산소의 저하, 혈색소 부족 등에 의한 빈혈성 저산소증, 독성 물질에 의한 중독으로 세포 내 산소 전달의 부전 등이 있다. Among them, hypoxic-ischemic encephalopathy (HIE) is brain damage caused by decreased oxygen delivery to brain cells due to various causes. For example, the causes of hypoxic damage include abnormal oxygen delivery from the lungs, decreased intra-arterial oxygen, anemic hypoxia caused by lack of hemoglobin, etc., and failure of intracellular oxygen delivery due to poisoning with toxic substances.
저산소성 허혈성 뇌병증은 아주 빠른 세포의 사멸을 유도하여, 혈소판 응집 및 혈전성 지혈이 급격하게 진행됨에 따라, 신경계 고유의 세포, 염증 및 면역 세포의 이동, 간세포(parenchymal cells)의 사멸 및 세포 파편의 형성 등의 다양한 합병증을 초래한다.Hypoxic ischemic encephalopathy induces very rapid cell death, and as platelet aggregation and thrombotic hemostasis rapidly progress, cells inherent in the nervous system, migration of inflammatory and immune cells, death of parenchymal cells, and cell debris It leads to various complications such as formation.
즉, 저산소성 허혈성 뇌병증은 저산소증 자체에 의한 손상 외에도, 이차적인 손상인 대사성산증, 세포 파괴, 재관류 손상을 초래하여 병증을 더욱 악화시킬 수 있다.That is, hypoxic ischemic encephalopathy may further exacerbate the condition by causing secondary damage such as metabolic acidosis, cell destruction, and reperfusion damage, in addition to damage caused by hypoxia itself.
보다 구체적으로, 뇌는 저산소증에 대한 예민도 및 저항성이 뇌에 포함되어 있는 각각의 조직에 따라 상이하여 불규칙한 손상이 나타날 수 있다. 예를 들어, 저산소성 허혈성 손상에 취약한 뇌의 부위로는 해마체, 소뇌의 퍼킨제 세포(Cerebellar Purkinje cells) 및 신피질세포증 3, 5, 6(Neocortical neuronsin layers 3, 5, 6)이 있으며, 저산소성 상태가 보다 경과될 경우, 대뇌 전체, 롤란드피질 주변부(Perirolandic cortex), 소뇌 및 심부회색질(Deep grey matter structures)까지도 손상이 유발될 수 있다.More specifically, since the brain has different sensitivity and resistance to hypoxia depending on each tissue included in the brain, irregular damage may occur. For example, areas of the brain susceptible to hypoxic ischemic injury include the hippocampus, Cerebellar Purkinje cells, and Neocortical neurons in layers 3, 5, 6, and hypoxic As the condition progresses, damage to the entire cerebrum, the Perirolandic cortex, the cerebellum, and even deep gray matter structures can be induced.
저산소성 허혈성 뇌병증은 전술한 바와 같이 뇌의 다양한 부위에 손상을 초래할 수 있음에 따라, 식물 인간과 같은 각성 상태의 저하, 인지 저하, 뇌전증, 자율신경계 부전, 운동 장애 등의 다양한 형태의 임상 증상 및 합병증을 유발할 수 있다.As hypoxic ischemic encephalopathy can cause damage to various parts of the brain, as described above, various types of clinical symptoms such as reduced arousal, cognitive decline, epilepsy, autonomic nervous system failure, and movement disorders, such as vegetative humans and complications.
한편, 이러한 허혈성 뇌질환의 치료법으로 사용되고 있는 방법은 임상 실험에서 성공한 혈전 용해술을 제외하면, 전무한 실정이며, 예방적 치료 방법에서 있어서도 항산화제 또는 면역억제제가 사용될 수 있으나, 이러한 문질들은 독성으로 인하여 제한적으로 사용될 수밖에 없다.On the other hand, the method used as a treatment for ischemic brain disease is non-existent except for thrombolysis that has been successful in clinical trials, and antioxidants or immunosuppressants can be used in prophylactic treatment methods, but these questions are limited due to toxicity. can only be used as
이에, 저산소증에 의하여 손상된 신경세포의 사멸을 감소시키며, 혈류를 회복시킬 수 있는, 새로운 허혈성 뇌질환에 대한 치료제의 개발이 필요한 실정이다.Accordingly, there is a need to develop a new therapeutic agent for ischemic brain disease that can reduce the death of nerve cells damaged by hypoxia and restore blood flow.
발명의 배경이 되는 기술은 본 발명에 대한 이해를 보다 용이하게 하기 위해 작성되었다. 발명의 배경이 되는 기술에 기재된 사항들이 선행기술로 존재한다고 인정하는 것으로 이해되어서는 안 된다. The description underlying the invention has been prepared to facilitate understanding of the invention. It should not be construed as an admission that the matters described in the background technology of the invention exist as prior art.
한편, 본 발명의 발명자들은, 허혈성 뇌질환 치료제로서, 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 주목하였다. PDRN은 어류의 정액에서 추출한 DNA의 조각으로 세포성장 촉진, 상처 치료, 세포치료등의 효과가 알려지면서, 의학계에서 다방면으로 사용되고 있다. 보다 구체적으로, PDRN은 DNA 중합체로 생체 구성성분이기 때문에 합성물질 등에서 나타나는 알러지 반응이나 체내 거부반응이 없고, 주성분이 음전하를 가지는 DNA로 이루어져 친수성의 특성을 지닌 물질로 이러한 특성들로 인해 산업적 적용이 매우 용이하다. 나아가, PDRN은 여러 임상에서 중증 상처의 회복, 혈관 신생, 빠른 피부재생의 효과가 확인되었으나, 중추신경계에 대한 효과는 전무한 실정이다. Meanwhile, the inventors of the present invention paid attention to polydeoxyribonucleotide (PDRN) as a therapeutic agent for ischemic brain disease. PDRN is a piece of DNA extracted from the semen of fish and is being used in various fields in the medical world as its effects such as cell growth promotion, wound healing, and cell therapy are known. More specifically, PDRN is a DNA polymer, and since it is a biocomponent, there is no allergic reaction or rejection reaction in synthetic materials, etc., and it is a material with hydrophilic properties because the main component is DNA having a negative charge. Very easy. Furthermore, PDRN has been confirmed to have effects of recovery of severe wounds, angiogenesis, and rapid skin regeneration in several clinical trials, but there is no effect on the central nervous system.
이에, 본 발명의 발명자들은 PDRN를 허혈성 뇌질환에 적용하고자 하였으며, 결국, PDRN가 허혈로 인한 손상된 신경세포 및 혈관세포를 보호 또는 재생시킬 수 있다는 것 발견하였다. Accordingly, the inventors of the present invention tried to apply PDRN to ischemic brain disease, and eventually found that PDRN can protect or regenerate damaged nerve cells and vascular cells due to ischemia.
보다 구체적으로, 본 발명의 발명자들은 특정 농도의 PDRN를 처리할 경우, 신경세포 및 혈관세포를 포함하는 다양한 세포에서 염증을 유발과 관련된 인자 및 세포 사멸을 유도하는 인자가 감소된다는 것을 발견하였다.More specifically, the inventors of the present invention have found that when a specific concentration of PDRN is treated, factors related to inducing inflammation and factors inducing apoptosis in various cells including neurons and vascular cells are reduced.
더욱이, 본 발명의 발명자들은 특정 농도의 PDRN를 처리할 경우, 신경세포 및 혈관세포에서 분화, 생성 및 재생을 촉진할 수 있는 인자가 증가된다는 것을 발견하였다.Moreover, the inventors of the present invention have found that when a specific concentration of PDRN is treated, factors capable of promoting differentiation, production and regeneration in neurons and vascular cells are increased.
이에, 본 발명의 발명자들은 저산소 및 저영양으로 인하여 초래된 허혈성 뇌질환을 특정 농도의 PDRN를 처리를 통하여 극복할 수 있다는 것을 인지하였다.Accordingly, the inventors of the present invention have recognized that ischemic brain disease caused by hypoxia and hyponutrient can be overcome through treatment with a specific concentration of PDRN.
따라서, 본 발명이 해결하고 하는 과제는, 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함함으로써, 허혈성 뇌질환을 예방 또는 치료할 수 있는 약학적 조성물 및 개선용 건강 기능성 식품을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition capable of preventing or treating ischemic brain disease and a health functional food for improvement by including polydeoxyribonucleotide (PDRN) as an active ingredient. .
본 발명의 과제들은 이상에서 언급한 과제들로 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다. The problems of the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
전술한 바와 같은 과제를 해결하기 위해, 본 발명의 일 실시예에 따르면, 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물이 제공된다.In order to solve the above problems, according to an embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating ischemic brain disease, comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
본 발명의 특징에 따르면, 허혈성 뇌질환은, 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE), 뇌졸중, 뇌경색, 뇌허혈, 혈전증(thrombosis), 색전증(em-bolism), 일과성 허혈 발작(transient ischemic attack), 뇌경색(lacune), 두부손상(head trauma), 뇌순환대사장애, 뇌 기능혼수, 외상성 뇌손상, 혈관성 치매, 알츠하이머성 치매, 헌팅턴병 및 파킨슨 병 중 적어도 하나를 포함할 수 있으나, 이에 제한되는 것은 아니며, 저산소 및 저영양 상태 이후 재관류로 인하여 발생하는 허혈성 질환을 모두 포함할 수 있다. 그러나, 본 발명의 일 실시예에 따른 폴리데옥시리보뉴클레오타이드 (polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE)에 가장 효과적일 수 있다.According to a feature of the present invention, the ischemic brain disease includes hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, and transient ischemic attack. ), cerebral infarction (lacune), head trauma, cerebral circulatory metabolic disorder, brain functional coma, traumatic brain injury, vascular dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease. It may include all ischemic diseases caused by reperfusion after hypoxic and hyponutrient conditions. However, the pharmaceutical composition for preventing or treating ischemic encephalopathy comprising polydeoxyribonucleotide (PDRN) as an active ingredient according to an embodiment of the present invention is hypoxic-ischemic encephalopathy (HIE) may be most effective for
본 발명의 다른 특징에 따르면, 본 발명의 조성물은, 약제학적으로 허용가능한 담체, 희석제 및 어주번트로 이루어진 그룹 중 적어도 하나를 더 포함할 수 있으나, 이에 제한되는 것은 아니다.According to another feature of the present invention, the composition of the present invention may further include at least one of the group consisting of a pharmaceutically acceptable carrier, diluent and adjuvant, but is not limited thereto.
본 발명의 또 다른 특징에 따르면, 조성물은, 경구, 경피, 근육내, 복막내, 정맥내, 피하 내 및 비강으로 이루어진 그룹 중 적어도 하나의 투여경로를 통해 투여되는 것을 특징으로 할 수 있으나, 이에 제한되는 것은 아니다.According to another feature of the present invention, the composition may be characterized in that it is administered through at least one route of administration from the group consisting of oral, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous and nasal. It is not limited.
본 발명의 또 다른 특징에 따르면, 조성물은, 정제, 연고제 또는 주사제로 제형화될 수 있으나, 이에 제한되는 것은 아니며, 본 발명의 조성물에 포함되어 있는 PDRN을 변형시키지 않으며, 이를 포함할 수 있는 다양한 형태로 모두 제형화될 수 있다.According to another feature of the present invention, the composition may be formulated as a tablet, ointment or injection, but is not limited thereto, and does not modify the PDRN contained in the composition of the present invention, and may include various It can be formulated in any form.
본 발명의 또 다른 특징에 따르면, PDRN은, 30 내지 150 μg/ml의 농도로 포함될 수 있으나, 이에 제한되는 것은 아니다.According to another feature of the present invention, PDRN may be included in a concentration of 30 to 150 μg/ml, but is not limited thereto.
본 발명의 또 다른 특징에 따르면, PDRN은, Bax, mTOR 및 DKK-1 중 적어도 하나의 발현을 감소시킴으로써, 신경 보호 및 신경 재생에 대한 효과를 나타낼 수 있다.According to another feature of the present invention, PDRN, by decreasing the expression of at least one of Bax, mTOR, and DKK-1, may exhibit an effect on neuroprotection and nerve regeneration.
본 발명의 또 다른 특징에 따르면, PDRN은, BCL-2, VEGF, BDNF, WNT-3α 및 β중 적어도 하나의 발현을 증가시킴으로써, 신경 보호 및 신경 재생에 대한 효과를 나타낼 수 있다.According to another feature of the present invention, PDRN, by increasing the expression of at least one of BCL-2, VEGF, BDNF, WNT-3α and β, may exhibit an effect on nerve protection and nerve regeneration.
본 발명의 또 다른 특징에 따르면, PDRN은, TNFα, iNOS, IL-1β, CSF1, STAT1 및 IL-6 중 적어도 하나의 발현을 감소시킴으로써, 항염증에 대한 효과를 나타낼 수 있다.According to another feature of the present invention, PDRN, by reducing the expression of at least one of TNFα, iNOS, IL-1β, CSF1, STAT1 and IL-6, it can exhibit an effect on anti-inflammatory.
전술한 바와 같은 과제를 해결하기 위해, 본 발명의 일 실시예에 따르면, 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는, 허혈성 뇌질환 예방 또는 개선용 건강기능성 식품이 제공된다.In order to solve the above problems, according to an embodiment of the present invention, there is provided a health functional food for preventing or improving ischemic brain disease, comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
본 발명의 또 다른 특징에 따르면, PDRN은, 30 내지 150 μg/ml의 농도로 포함될 수 있으나, 이에 제한되는 것은 아니다.According to another feature of the present invention, PDRN may be included in a concentration of 30 to 150 μg/ml, but is not limited thereto.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명한다. 다만, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것에 불과하므로 본 발명의 범위가 이들 실시예에 의해 한정되는 것으로 해석되어서는 아니된다. Hereinafter, the present invention will be described in more detail through examples. However, since these examples are only for illustrative purposes of the present invention, the scope of the present invention should not be construed as being limited by these examples.
본 발명은 허혈성 뇌질환에 대한 치료 및 또는 예방 효과를 제공할 수 있다.The present invention can provide a therapeutic and/or prophylactic effect on ischemic brain disease.
보다 구체적으로, 본 발명은 저산소 및 영양 결핍 등의 다양한 스트레스에 의하여 초래된 염증 및 세포사멸 반응을 감소시켜, 신경세포 및 혈관세포를 보호하고, 이의 분화, 생성 및 재생을 촉진시켜, 전술한 스트레스에 의하여 초래된 뇌질환을 예방 및 치료할 수 있다. More specifically, the present invention reduces inflammatory and apoptotic responses caused by various stresses such as hypoxia and nutritional deficiency, protects nerve cells and blood vessels, and promotes their differentiation, generation and regeneration, so that the above-mentioned stress It is possible to prevent and treat brain diseases caused by
나아가, 본 발명은 신경세포 및 혈관세포뿐만 아니라, 다양한 세포를 분화, 발달 및 성장을 시킬 수 있음에 따라, 저산소 및/또는 저영양으로 인하여 초래된 다양한 허혈성 질환에 대해서도 예방 및 치료할 수 있다. 이에, 본 발명은 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE), 뇌졸중, 뇌경색, 뇌허혈, 혈전증(thrombosis), 색전증(em-bolism), 일과성 허혈 발작(transient ischemic attack), 뇌경색(lacune), 두부손상(head trauma), 뇌순환대사장애, 뇌 기능혼수, 외상성 뇌손상, 혈관성 치매, 알츠하이머성 치매, 헌팅턴병 및 파킨슨 병 중 적어도 하나를 포함하는 허혈성 뇌질한에 대하여, 예방 및/또는 치료 효과를 가질 수 있다.Furthermore, since the present invention can differentiate, develop and grow various cells as well as nerve cells and blood vessels, it is possible to prevent and treat various ischemic diseases caused by hypoxia and/or hyponutrition. Accordingly, the present invention relates to hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, transient ischemic attack, cerebral infarction (lacune), For ischemic stroke, including at least one of head trauma, cerebral circulatory metabolic disorder, brain functional coma, traumatic brain injury, vascular dementia, Alzheimer's disease, Huntington's disease and Parkinson's disease, preventive and/or therapeutic effect can have
즉, 본 발명은 저산소 및 영양 결핍 이후 나타나는 재관류 시 발생하는 신경세포의 과흥분을 방지함으로서, 허혈성 재관류로 인한 신경세포의 손상을 효과적으로 억제할 수 있음에 따라, 허혈성 뇌졸중을 비롯한 허혈성 뇌질환의 예방, 개선 및 치료에 유용하게 이용될 수 있다.That is, the present invention can effectively inhibit nerve cell damage due to ischemic reperfusion by preventing hyperexcitation of nerve cells occurring during reperfusion after hypoxia and nutritional deficiency, thereby preventing ischemic brain disease including ischemic stroke , can be usefully used for improvement and treatment.
본 발명에 따른 효과는 이상에서 예시된 내용에 의해 제한되지 않으며, 더욱 다양한 효과들이 본 명세서 내에 포함되어 있다. The effect according to the present invention is not limited by the contents exemplified above, and more various effects are included in the present specification.
도 1은 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 제조 방법의 절차를 도시한 것이다. 1 illustrates a procedure of a method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention.
도 2는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 효과 확인을 위한 저산소성 허혈성 뇌병증 모델 구축 및 본 발명의 조성물 처리 과정을 도시한 것이다.Figure 2 shows the hypoxic ischemic encephalopathy model construction and processing of the composition of the present invention for confirming the effect of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention.
도 3a는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 세포 생존율 결과를 도시한 것이다.Figure 3a shows the cell viability results according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
도 3b는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 염증 반응 인자에 대한 결과를 도시한 것이다. Figure 3b shows the results of the inflammatory response factors according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
도 3c는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 혈관 생성에 대한 결과를 도시한 것이다Figure 3c shows the results of angiogenesis according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
도 3d는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 신경 보호에 대한 결과를 도시한 것이다.Figure 3d shows the results of neuroprotection according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
도 3e는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 신경 재생에 대한 결과를 도시한 것이다.Figure 3e shows the results of nerve regeneration according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
도 3f는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 세포 사멸에 대한 결과를 도시한 것이다.Figure 3f shows the results of cell death according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
도 4a 내지 4d는 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 항염증 효과 관련 유전자 발현 결과를 도시한 것이다.4a to 4d show the results of gene expression related to the anti-inflammatory effect according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention.
본 발명의 이점 및 특징, 그리고 그것들을 달성하는 방법은 첨부되는 도면과 함께 상세하게 후술되어 있는 실시예들을 참조하면 명확해질 것이다. 그러나, 본 발명은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 것이며, 단지 본 실시예들은 본 발명의 개시가 완전하도록 하며, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다. Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described below in detail in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but will be embodied in various different forms, and only these embodiments allow the disclosure of the present invention to be complete, and common knowledge in the art to which the present invention pertains It is provided to fully inform those who have the scope of the invention, and the present invention is only defined by the scope of the claims.
본 명세서에서 사용되는 용어, "예방"은, 조성물의 투여로 뇌질환의 발병을 억제 또는 지연시키는 모든 행위를 의미할 수 있다.As used herein, the term "prevention" may refer to any action that inhibits or delays the onset of brain disease by administration of the composition.
본 명세서에서 사용되는 용어, "치료"는, 본 발명의 조성물의 투여로 인해 이미 유발된 뇌질환의 증세가 호전되거나 이롭게 되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which the symptoms of brain disease already induced by the administration of the composition of the present invention are improved or beneficial.
본 명세서에서 사용되는 용어, "개체"는, 본 발명의 조성물을 통하여 신경세포 및/또는 혈관세포의 재생, 보호, 생성에 대한 효과 및 항염증에 대한 효과를 가질 수 있는 대상체를 의미할 수 있으며, "숙주", "대상체" 및 "환자"와 같은 용어와 혼용되어 사용될 수 있 다As used herein, the term "subject" may mean a subject that can have an effect on the regeneration, protection, and production of nerve cells and/or vascular cells and an effect on anti-inflammatory through the composition of the present invention, , may be used interchangeably with terms such as “host”, “subject” and “patient”.
허혈성 뇌질환 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating ischemic brain disease
이하에서는 도 1을 참조하여 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 대하여 설명하도록 한다.Hereinafter, a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention will be described with reference to FIG. 1 .
도 1을 참조하면, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 제조 방법의 절차가 도시된다. 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 제조 방법은 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는 단계(S110)를 포함한다.Referring to FIG. 1 , a procedure of a method for preparing a pharmaceutical composition for preventing or treating ischemic encephalopathy according to an embodiment of the present invention is illustrated. The method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention includes the step of including polydeoxyribonucleotide (PDRN) as an active ingredient (S110).
이때, PDRN은 어류의 정액에서 추출한 DNA의 조각을 의미할 수 있으며, 당업계에서 상업적으로 어류의 이리 및 정액에서 추출된 모든 물질이 사용될 수 있다. 이때, 바람직한, PDRN의 분자량은 50 내지 1500 kDa일 수 있다. 즉, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 사용된 PDRN는 합성된 물질이 아닌 천연 물질일 수 있다.In this case, PDRN may refer to a fragment of DNA extracted from semen of fish, and any material commercially extracted from wolves and semen of fish may be used in the art. In this case, preferably, the molecular weight of PDRN may be 50 to 1500 kDa. That is, the PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may be a natural material, not a synthetic material.
나아가, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 사용된 PDRN의 농도는 30 내지 150 μg/ml일 수 있으나, 이에 제한되는 것은 아니다. 이때, PDRN의 농도가 30 μg/ml 미만일 경우, 이의 효과가 미미할 수 있으며, 150 μg/ml 이상일 경우, 증가에 따른 효과의 증가가 매우 미약하고, 제형상의 안정성이 확보되지 않을 수 있음에 따라, 바람직한 PDRN의 농도는 30 내지 150 μg/ml일 수 있다.Furthermore, the concentration of PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may be 30 to 150 μg/ml, but is not limited thereto. At this time, when the concentration of PDRN is less than 30 μg/ml, its effect may be insignificant, and when it is 150 μg/ml or more, the increase in the effect according to the increase is very weak, and stability in the formulation may not be ensured. , a preferred concentration of PDRN may be 30 to 150 μg/ml.
이러한, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 사용된 PDRN는 Bax, mTOR 및 DKK-1 중 적어도 하나의 발현을 감소시킴으로써, 신경 보호 및 신경 재생에 대한 효과를 나타낼 수 있다.The PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention reduces the expression of at least one of Bax, mTOR, and DKK-1, thereby exhibiting effects on nerve protection and nerve regeneration. can indicate
더욱이, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 사용된 PDRN는 BCL-2, VEGF, BDNF, WNT-3α 및 β중 적어도 하나의 발현을 증가시킴으로써, 신경 보호 및 신경 재생에 대한 효과를 나타낼 수 있다.Moreover, PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention increases the expression of at least one of BCL-2, VEGF, BDNF, WNT-3α and β, thereby protecting and It may have an effect on nerve regeneration.
더욱이, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 사용된 PDRN는 TNFα, iNOS, IL-1β, CSF1, STAT1 및 IL-6 중 적어도 하나의 발현을 감소시킴으로써, 항염증에 대한 효과를 나타낼 수 있다.Moreover, PDRN used in the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention reduces the expression of at least one of TNFα, iNOS, IL-1β, CSF1, STAT1 and IL-6, It may have an effect on inflammation.
이때, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 통하여 예방 또는 치료 효과를 가질 수 있는 허혈성 뇌질환은 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE), 뇌졸중, 뇌경색, 뇌허혈, 혈전증(thrombosis), 색전증(em-bolism), 일과성 허혈 발작(transient ischemic attack), 뇌경색(lacune), 두부손상(head trauma), 뇌순환대사장애, 뇌 기능혼수, 외상성 뇌손상, 혈관성 치매, 알츠하이머성 치매, 헌팅턴병 및 파킨슨 병 중 적어도 하나를 포함할 수 있으나, 이에 제한되는 것은 아니며, 저산소 및 저영양상태 이후 재관류로 인하여 유발된 다양한 허혈성 질환을 모두 포함할 수 있다. In this case, the ischemic brain disease that can have a preventive or therapeutic effect through the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention is hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction. , cerebral ischemia, thrombosis, embolism, transient ischemic attack, cerebral infarction (lacune), head trauma, cerebral circulatory metabolic disorder, cerebral coma, traumatic brain injury, vascular It may include at least one of dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease, but is not limited thereto, and may include all of various ischemic diseases induced by reperfusion after hypoxia and hyponutrition.
한편, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 제조 방법은 약제학적으로 허용가능한 담체, 희석제 및 어주번트로 이루어진 그룹 중 적어도 하나를 포함하는 단계를 더 포함할 수 있다. 이에, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물 경구 또는 비경구 투여에 적합한 의약품 제제의 형태로 제조가 가능할 수 있다. 예를 들어, 약제학적으로 허용가능한 담체, 희석제 및 어주번트는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 제형 제조시에 통상적으로 사용되고 있는 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다. 본 발명의 조성물은 포유동물에 투여된 후 활성성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당 업계에 잘 알려진 방법을 사용하여 제형화 될 수 있다.Meanwhile, the method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may further include the step of including at least one of the group consisting of a pharmaceutically acceptable carrier, diluent and adjuvant. have. Accordingly, the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may be prepared in the form of a pharmaceutical formulation suitable for oral or parenteral administration. For example, pharmaceutically acceptable carriers, diluents and adjuvants include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, fillers, anti-aggregants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like, which are commonly used in the preparation of the formulation may be further included. The compositions of the present invention may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 제조 방법은 약제학적으로 허용가능한 염을 포함하는 단계를 더 포함할 수 있으며, 약제학적으로 허용 가능한 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 이러한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있으며, 구체적으로 염기가 부가되어 생성된 염기부가염이 포함될 수 있다. 이때, 염기는 알칼리금속 수산화물 (예를 들면, 수산화나트륨, 수산화칼륨), 알칼리금속 중탄산염 (예를 들면, 중탄산나트륨, 중탄산칼륨), 알칼리금속 탄산염 (예를 들면, 탄산나트륨, 탄산칼륨, 탄산칼슘) 등과 같은 무기염기, 또는 1차, 2차 3차 아민 아미노산과 같은 유기염기가 포함될 수 있다. 또한, 전술한 약제학적으로 허용 가능한 염 이외에도 수화물 또는 용매화물도 포함될 수 있다. 본 발명의 조성물로서 수화물 및 용매화물은 모화합물을 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화 또는 재결정화하여 제조될 수 있다. 또는 본 발명의 조성물을 분리하는 동안 또는 조성물의 흡습성으로 인해 시간이 경과함에 따라 용매화물 (특히 수화물)이 형성될 수도 있다.The method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention may further include the step of including a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is toxic to the human body. It should not adversely affect the biological activity and physicochemical properties of the parent compound. Such a salt may be prepared by a method conventional in the art, and specifically, a base addition salt produced by adding a base may be included. In this case, the base is an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide), alkali metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate), alkali metal carbonate (eg, sodium carbonate, potassium carbonate, calcium carbonate) Inorganic bases such as, etc., or organic bases such as primary and secondary tertiary amine amino acids may be included. In addition, hydrates or solvates may be included in addition to the pharmaceutically acceptable salts described above. As the composition of the present invention, hydrates and solvates can be prepared by dissolving the parent compound in a solvent, adding a free acid or a free base, and then crystallizing or recrystallizing the composition. Alternatively, solvates (particularly hydrates) may form during isolation of the composition of the present invention or over time due to the hygroscopicity of the composition.
또한, 본 발명의 조성물을 사용하여 통상적인 방법에 따라 약학 제형을 제조할 수 있다. 제형의 제조에 있어, 활성성분을 담체와 함께 혼합하거나, 담체로 희석하거나, 캅셀, 새세이 또는 기타 용기 형태의 담체 내에 봉입시킬 수 있다. 따라서 제형은 정제, 환제, 분제, 캡슐, 새세이, 엘릭씨르, 현탁제, 에멀젼, 액제, 시럽제, 에어로졸, 연질 또는 경질 젤라틴 캅셀제, 주사용 용액 또는 현탁액, 연고제, 크림제, 겔제 또는 로숀제 등의 형태일 수 있다.In addition, a pharmaceutical formulation can be prepared according to a conventional method using the composition of the present invention. In preparing the formulation, the active ingredient may be mixed with a carrier, diluted with a carrier, or enclosed in a carrier in the form of a capsule, sachet or other container. Accordingly, the dosage form is a tablet, pill, powder, capsule, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft or hard gelatin capsule, solution or suspension for injection, ointment, cream, gel or lotion. It may be in the form of
이에, 본 발명의 조성물의 투여경로는 이들로 한정되는 것은 아니지만, 예를 들면, 경구, 비강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 장관, 설하 또는 국소 투여가 가능하다.Accordingly, the route of administration of the composition of the present invention is not limited thereto, but for example, oral, nasal, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, Enteral, sublingual or topical administration is possible.
나아가, 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.Furthermore, the dosage of the pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but is appropriately determined by those skilled in the art. can be selected.
이상의 본 발명의 일 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 제조 방법에 따라, 허혈성 뇌질환을 효과적으로 예방 또는 치료할 수 있는 약학적 조성물이 제조될 수 있다.According to the method for preparing a pharmaceutical composition for preventing or treating ischemic brain disease according to an embodiment of the present invention, a pharmaceutical composition capable of effectively preventing or treating ischemic brain disease can be prepared.
나아가, 동일한 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는 단계(S110)를 포함함에 따라, 허혈성 뇌질환 예방 또는 개선용 건강기능성 식품이 제조될 수 있다. 이때, 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 선식, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 그 밖에도 통상적인 의미에서의 건강기능식품을 모두 포함한다.Furthermore, by including the step (S110) of including the same polydeoxyribonucleotide (PDRN) as an active ingredient, a health functional food for preventing or improving ischemic brain disease can be manufactured. At this time, examples of food include drinks, meat, sausage, bread, biscuits, rice cakes, sun food, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, alcohol There are beverages and vitamin complexes, dairy products and processed dairy products, and in addition, all health functional foods in the ordinary sense are included.
본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 효과 확인Confirmation of the effect of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention
이하에서는 도 2 내지 4d를 참조하여, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 효과에 대하여 설명하도록 한다.Hereinafter, with reference to FIGS. 2 to 4D, the effect of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention will be described.
먼저, 도 2를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 효과 확인을 위한 저산소성 허혈성 뇌병증 모델 구축 및 본 발명의 조성물 처리 과정이 도시된다. First, referring to FIG. 2 , the hypoxic ischemic encephalopathy model construction and the composition processing process of the present invention for confirming the effect of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are illustrated.
본 발명의 조성물의 효과 확인은 Neuro2A 세포 (neuroblastoma cell line)를 신경세포(Neuron cell)로 분화시킨 뒤, 이를 산소-포도당 결핍(Oxygen Glucose Deprivation, OGD)을 유도하여 손상된 (저산소성 허혈성) 신경세포 모델을 구축하였으며, 이에 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물(PDRN) 및 대조군(PBS)를 처리하여 수행되었다.To confirm the effect of the composition of the present invention, Neuro2A cells (neuroblastoma cell line) are differentiated into neurons (Neuron cells), which are then oxygen-induced glucose deprivation (OGD) and damaged (hypoxic ischemic) neurons The model was built, and thus it was performed by treating a pharmaceutical composition for preventing or treating ischemic brain disease (PDRN) and a control group (PBS) according to various embodiments of the present invention.
이때, Neuro2A 세포 (neuroblastoma cell line)를 신경세포(Neuron cell)로 분화시키는 과정에서는 Neuro2A 세포를 10% FBS가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2 환경에서 1일간 배양한 뒤(D0 내지 D1), 20 μM의 retionic acid(RA) 및 2% FBS가 함유된 DMEM 배지에서 4일간 배양하여(D1 내지 D4) 신경세포로 분화시켰다.At this time, in the process of differentiating Neuro2A cells (neuroblastoma cell line) into neurons (Neuron cells), Neuro2A cells were cultured in DMEM medium containing 10% FBS at 37 ° C., 5% CO 2 environment for 1 day ( D0 to D1), and cultured in DMEM medium containing 20 μM retionic acid (RA) and 2% FBS for 4 days (D1 to D4) to differentiate into neurons.
그 다음, 산소-포도당 결핍(Oxygen Glucose Deprivation, OGD)을 유도하여 손상된 (저산소성 허혈성) 신경세포 모델을 구축하는 과정에서는, 분화된 신경세포를 glucose free DMEM 배지를 사용하여 1% O2 tension의 혐기성 챔버에서 3시간 동안 배양하였다. 이에, 혐기적 조건에서 3시간 동안 배양된 신경세포는 전술한 배양조건이 아닌 일반적인 배양 조건 즉, FBS가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2 환경에서 배양될 경우, 저산소증 및 재관류 손상(Hypoxia and reperfusion injury)이 유발되어, 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE) 모델로 사용될 수 있다.Next, in the process of constructing a (hypoxic ischemic) neuronal model damaged by inducing oxygen-glucose deprivation (OGD), differentiated neurons were treated with 1% O 2 tension using glucose-free DMEM medium. Incubated in an anaerobic chamber for 3 hours. Therefore, neurons cultured for 3 hours in anaerobic conditions are hypoxia and reperfusion when cultured in a normal culture condition other than the above-described culture conditions, that is, in a DMEM medium containing FBS at 37° C. and 5% CO 2 environment. Injury (Hypoxia and reperfusion injury) is induced, it can be used as a model of hypoxic-ischemic encephalopathy (HIE).
그 다음, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물(PDRN) 및 대조군(PBS)를 처리하는 과정에서는, OGD가 유도된 신경세포 모델에 PDRN 또는 PBS를 각각 처리하여 37℃, 5% CO2 환경에서 18시간 이상 배양한 뒤, 재관류 및 본 발명의 조성물 처리에 대한 효과를 확인하였다.Then, in the process of treating the pharmaceutical composition (PDRN) and the control (PBS) for preventing or treating ischemic brain disease according to various embodiments of the present invention, the OGD-induced neuronal model is treated with PDRN or PBS, respectively. 37 ℃, 5% CO 2 After culturing for 18 hours or more in an environment, the effect on reperfusion and treatment with the composition of the present invention was confirmed.
이에, 도 3a을 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 세포 생존율 결과가 도시된다. 이때, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 OGD가 유도된 신경세포 모델 즉, HIE 모델에 각각 50 μg/ml 또는 100 μg/ml씩 처리되었다. 나아가, 세포 계수를 위하여, Cell Counting Kit8가 사용되었다.Accordingly, referring to FIG. 3A , the cell viability results according to the treatment of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention are shown. At this time, the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention was treated by 50 μg/ml or 100 μg/ml in the OGD-induced neuronal model, that is, the HIE model, respectively. Furthermore, for cell counting, Cell Counting Kit8 was used.
보다 구체적으로, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물이 처리된 OGD 그룹(OGD+PDRN 50 μg/ml 및 OGD+PDRN 100 μg/ml)은 대조군 즉, PBS만 처리된 OGD 그룹(OGD)보다 유의하게 세포 생존율(cell viability)이 높은 것으로 나타난다(P<0.05).More specifically, the OGD group (OGD+PDRN 50 μg/ml and OGD+PDRN 100 μg/ml) treated with the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention is a control group, that is, only PBS It appeared that the cell viability was significantly higher than that of the treated OGD group (OGD) (P<0.05).
나아가, 100 μg/ml의 본 발명의 조성물이 처리된 그룹(OGD+PDRN 100 μg/ml)은 50 μg/ml의 본 발명의 조성물이 처리된 그룹(OGD+PDRN 50 μg/ml)보다 유의하게 세포 생존율이 높은 것으로 나타난다(P<0.05).Furthermore, the group treated with the composition of the present invention at 100 μg/ml (OGD+PDRN 100 μg/ml) was significantly higher than the group treated with the composition of the present invention at 50 μg/ml (OGD+PDRN 50 μg/ml). Cell viability appears to be high (P<0.05).
즉, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 신경세포의 생존율을 효과적으로 향상시킬 수 있으며, 본 발명의 조성물에 대한 처리량에 따라 비례적으로, 세포 생존율이 증가될 수 있다.That is, the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention can effectively improve the survival rate of nerve cells, and proportionally according to the amount of treatment for the composition of the present invention, the cell viability is increased. can
이하에서는 본 발명의 조성물의 처리에 따른 염증, 혈관생성능, 신경보호능, 신경재생능 및 세포사멸의 효과와 관련된 RNA 수준의 유전자 발현을 확인하기 위하여, 실시예로서, 100 μg/ml의 본 발명의 조성물을 처리한 뒤, SYBRgreen에 기초한 rtPCR 방법을 수행하였다. 나아가, 대조군으로서, OGD가 유도되지 않은 정상 신경세포(NON-OGD)를 비교예 1 및 PBS가 처리되고 OGD가 유도된 저산소성 허혈성 뇌병증 신경세포 모델(NON-OGD)를 비교예 2로 설정한 뒤, 본 발명의 실시예와 비교하였다.Hereinafter, in order to confirm the gene expression of RNA levels related to the effects of inflammation, angiogenesis, neuroprotection, nerve regeneration and apoptosis according to the treatment of the composition of the present invention, as an example, 100 μg/ml of the present invention After treating the composition of the SYBRgreen based rtPCR method was performed. Furthermore, as a control, normal neurons (NON-OGD) not induced with OGD were treated with Comparative Example 1 and PBS-treated and OGD-induced hypoxic ischemic encephalopathy neuronal model (NON-OGD) was set as Comparative Example 2. Then, it was compared with the Example of the present invention.
도 3b를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 염증 반응 인자에 대한 결과가 도시된다. Referring to FIG. 3B , the results of the inflammatory response factors according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown.
본 발명의 실시예는 비교예 1 및 2보다 염증 반응 관련 인자인 iNOS, TNF-α 및 IL-1β의 발현이 유의하게 낮은 것으로 나타난다(P<0.05).Examples of the present invention show that the expression of iNOS, TNF-α and IL-1β, which are factors related to the inflammatory response, is significantly lower than those of Comparative Examples 1 and 2 (P<0.05).
나아가, 본 발명의 실시예에 대한 iNOS의 발현량은 비교예 1 및 2보다 각각 0.4, 0.1배 낮은 것으로 나타나며, 본 발명의 실시예에 대한 TNF-α의 발현량은 비교예 1 및 2보다 각각 0.3, 0.09 배 낮은 것으로 나타나며, 본 발명의 실시예에 대한 IL-1β의 발현량은 비교예 1 및 2보다 각각 0.4, 0.1배 낮은 것으로 나타난다.Furthermore, the expression level of iNOS for Examples of the present invention is shown to be 0.4 and 0.1 times lower than those of Comparative Examples 1 and 2, respectively, and the expression level of TNF-α for Examples of the present invention is higher than that of Comparative Examples 1 and 2, respectively. 0.3 and 0.09 times lower, and the expression level of IL-1β for Examples of the present invention is 0.4 and 0.1 times lower than those of Comparative Examples 1 and 2, respectively.
보다 구체적으로, 염증성 사이토카인인 TNF-α(tumor necrosis factor-α), IL-1β(interleukin-1beta)과 염증 유발 단백질인 iNOS(inducible nitrous oxide)는 체내에서 염증 반응의 촉매 및 매개제로 작용하는 인자이며, 이들의 증가는 근육의 이화작용을 촉진시켜 근육량의 감소 및 체내의 지방을 축적시켜 면역 노화 현상까지 유발시킬 수 있다.More specifically, the inflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1beta) and the inflammatory protein iNOS (inducible nitrous oxide) act as catalysts and mediators of inflammatory responses in the body. factors, and their increase promotes the catabolism of muscles, thereby reducing muscle mass and accumulating fat in the body, thereby causing immune aging.
따라서, 본 발명의 조성물은, 산소-포도당 결핍으로 유도된 염증 반응을 완화시킬 수 있으며, 이에 따라 연쇄적으로 나타날 수 있는 면역 노화 현상까지도 예방할 수 있다.Therefore, the composition of the present invention can alleviate the inflammatory response induced by oxygen-glucose deficiency, and thus can even prevent the immune aging phenomenon that may appear in a chain.
도 3c를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 혈관 생성에 대한 결과가 도시된다. Referring to FIG. 3C , the results of angiogenesis according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown.
본 발명의 실시예는 비교예 1 및 2보다 혈관 생성 인자인 VEGF의 발현이 유의하게 높은 것으로 나타난다(P<0.05). 나아가, 본 발명의 실시예에 대한 VEGF의 발현량은 비교예 1 및 2보다 각각 2.5, 13.4배 높은 것으로 나타난다.Examples of the present invention show that the expression of VEGF, an angiogenic factor, is significantly higher than those of Comparative Examples 1 and 2 (P<0.05). Furthermore, the expression levels of VEGF for Examples of the present invention are 2.5 and 13.4 times higher than those of Comparative Examples 1 and 2, respectively.
이때, 혈관 내피 세포 성장 인자(vascular endothelial growth factor, VEGF)는 혈관 신생을 촉진하는 내재적인 인자로서, 혈관 생성(angiogenesis)뿐만 아니라, 배아발생에서의 혈관발달(vasculogenesis), 림프의 발생 및 항상성 유지에도 관여한다. 즉, VEGF는 많은 성장인자 수용체와 마찬가지로 세포 이동, 생존 및 증식에도 관여할 수 있으며, 삼차원의 혈관을 형성할 수 있는 신호를 전달하거나 혈관 투과성을 조정하는 기능을 가질 수 있다.At this time, vascular endothelial growth factor (VEGF) is an intrinsic factor that promotes angiogenesis, as well as angiogenesis, as well as vasculogenesis in embryogenesis, lymphogenesis and maintenance of homeostasis. also participate in That is, VEGF, like many growth factor receptors, may also be involved in cell migration, survival, and proliferation, and may have a function of transmitting a signal capable of forming a three-dimensional blood vessel or adjusting vascular permeability.
따라서, 본 발명의 조성물은, VEGF의 발현을 향상시켜 혈관의 생성을 촉진시킬 수 있으며, 나아가, 신경 및 혈관 세포를 포함하는 다양한 세포의 이동, 생존 및 증식을 활성화시켜 향상시킬 수 있다.Therefore, the composition of the present invention can promote the generation of blood vessels by improving the expression of VEGF, and furthermore, it can be improved by activating the migration, survival and proliferation of various cells including nerve and vascular cells.
도 3d를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 신경 보호에 대한 결과가 도시된다.Referring to FIG. 3D , the results of neuroprotection according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown.
본 발명의 실시예는 비교예 1 및 2보다 mTOR의 발현이 유의하게 낮은 것으로 나타난다(P<0.05). 또한, 본 발명의 실시예는 비교예 1 및 2보다 BDNF의 발현이 유의하게 높은 것으로 나타난다(P<0.05).Examples of the present invention show that the expression of mTOR is significantly lower than Comparative Examples 1 and 2 (P<0.05). In addition, the Example of the present invention shows that the expression of BDNF is significantly higher than Comparative Examples 1 and 2 (P<0.05).
나아가, 본 발명의 실시예에 대한 mTOR의 발현량은 비교예 1 및 2 보다 각각 0.3배, 0.09배 낮은 것으로 나타나며, 본 발명의 실시예에 대한 BDNF의 발현량은 비교예 1 및 2보다 각각 2.7, 6.5배 높은 것으로 나타난다.Furthermore, the expression level of mTOR for Examples of the present invention is 0.3 times and 0.09 times lower than those of Comparative Examples 1 and 2, respectively, and the expression level of BDNF for Examples of the present invention is 2.7 than Comparative Examples 1 and 2, respectively. , 6.5 times higher.
이때, mTOR(mammalian target of rapamycin)는 PIKK (PI3K-related kinase) 그룹에 속하는 세린(serine)/트레오닌(threonine) 단백질 인산화효소(kinase)로서, 성장인자, 영양, 스트레스 자극에 의한 세포의 성장, 증식, 자가포식(autophagy), 단백질 합성에 관여할 수 있다. 보다 구체적으로, mTOR은 자가포식과도 밀접한 연관성을 가지고 있을 뿐만 아니라, 세포 사멸에 상당한 영향을 미치는 염증반응 및 이와 관련된 chemokine의 발현에도 영향을 미치며, 노화, 영양 결핍 및 스트레스에 의하여, mTOR의 활성 및 발현이 증가될 수 있다. 나아가, 신경세포(neuron)에서 기능 이상으로 mTOR의 신호가 증가하면, 신경세포 사멸에 따른 기억 저장 능력의 저하를 가져올 수 있다. 또한, mTOR은 지질대사의 동화작용 및 이화작용에 중심 기전임에 따라, 이의 과도한 활성은 비만, 인슐린 저항성 등의 대사 작용을 초래할 수 있다. 이에, mTOR가 억제될 경우, 자가포식력의 증진, 수명과 관련된 유전자의 활성화, 전위억제, 활성 산소종(reactive oxygen species) 생산의 감소를 유발하여, 신경세포를 포함하는 다양한 세포의 노화 및 사멸을 감소시킬 수 있다.At this time, mTOR (mammalian target of rapamycin) is a serine / threonine protein kinase (kinase) belonging to the PIKK (PI3K-related kinase) group. It may be involved in proliferation, autophagy, and protein synthesis. More specifically, mTOR not only has a close relationship with autophagy, but also affects the inflammatory response that significantly affects apoptosis and the expression of related chemokines. and expression may be increased. Furthermore, when the signal of mTOR increases due to abnormal function in neurons, it may lead to a decrease in memory storage ability due to the death of neurons. In addition, as mTOR is a central mechanism in anabolic and catabolism of lipid metabolism, its excessive activity may lead to metabolic effects such as obesity and insulin resistance. Accordingly, when mTOR is inhibited, it induces enhancement of autophagy, activation of lifespan-related genes, potential suppression, and reduction of reactive oxygen species production, leading to aging and death of various cells including nerve cells. can reduce
따라서, 본 발명의 조성물은, mTOR의 발현을 감소시킴에 따라, 신경세포에 대한 노화 및 사멸을 감소시킬 수 있다.Therefore, the composition of the present invention, by reducing the expression of mTOR, can reduce aging and death for neurons.
나아가, BDNF(Brain-Derived Neurotrophic Factor)는 신경영양인자(neurotrophins)로서, 신경세포의 생존 및 분화를 촉진시킬 수 있으며, 시냅스전달(synaptic transmission)과 시냅스 가소성(synapse plasticity)의 분자기전 즉, 신경세포 간 신호전달 경로를 활성시킬 수 있다.Furthermore, BDNF (Brain-Derived Neurotrophic Factor) is a neurotrophins that can promote the survival and differentiation of neurons, and the molecular mechanisms of synaptic transmission and synapse plasticity, that is, neurons It can activate hepatic signaling pathways.
따라서, 본 발명의 조성물은, BDNF의 발현을 증가시킴에 따라, 신경세포 간 신호전달을 활발하게 향상시켜, 신경세포에 대한 분화, 발달 및 성장을 촉진시킬 수 있으며, 나아가, 신경세포의 생존을 향상시킬 수 있다.Therefore, the composition of the present invention, by increasing the expression of BDNF, can actively improve the signal transduction between neurons, can promote the differentiation, development and growth of neurons, and furthermore, the survival of neurons can be improved
결국, 본 발명의 조성물은, mTOR의 발현을 감소시키고, BDNF의 발현을 증가시킴에 따라, 신경세포를 다양한 스트레스로부터 보호하며, 신경세포가 안정적으로 분화, 발달 및 성장시킬 수 있다.As a result, the composition of the present invention reduces the expression of mTOR and increases the expression of BDNF, thereby protecting neurons from various stresses, and allowing the neurons to stably differentiate, develop and grow.
도 3e를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 신경 재생에 대한 결과가 도시된다.Referring to FIG. 3E , the results of nerve regeneration according to the treatment of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention are shown.
본 발명의 실시예는 비교예 1 및 2보다 WNT-3α 및 β의 발현이 유의하게 높은 것으로 나타난다(P<0.05). 또한, 본 발명의 실시예는 비교예 1 및 2보다 DKK-1의 발현이 유의하게 낮은 것으로 나타난다(P<0.05).Examples of the present invention show significantly higher expression of WNT-3α and β than Comparative Examples 1 and 2 (P<0.05). In addition, the Example of the present invention shows that the expression of DKK-1 is significantly lower than Comparative Examples 1 and 2 (P<0.05).
나아가, 본 발명의 실시예에 대한 WNT-3α의 발현량은 비교예 1 및 2보다 각각 3.5, 11.7 배 높은 것으로 나타나며, 본 발명의 실시예에 대한 β-Catenin의 발현량은 비교예 1 및 2보다 각각 3.7, 20.5 배 높은 것으로 나타난다. 또한, 본 발명의 실시예에 대한 DKK-1의 발현량은 비교예 1 및 2보다 각각 0.2, 0.04 배 낮은 것으로 나타난다.Furthermore, the expression level of WNT-3α for Examples of the present invention is 3.5 and 11.7 times higher than those of Comparative Examples 1 and 2, respectively, and the expression level of β-Catenin for Examples of the present invention is Comparative Examples 1 and 2 3.7 and 20.5 times higher, respectively. In addition, the expression level of DKK-1 for Examples of the present invention is shown to be 0.2 and 0.04 times lower than Comparative Examples 1 and 2, respectively.
이때, WNT-3α는 신경계 성장을 유도하는 단백질로, 손상된 신경 재생을 재생시킬 수 있다. 나아가, WNT-3α 및 β에 따른 기전(pathway)는 아밀로이드 베타에 의한 신경세포의 독성을 감소시켜, 신경세포를 보호할 수 있다. At this time, WNT-3α is a protein that induces nervous system growth and can regenerate damaged nerves. Furthermore, the pathway according to WNT-3α and β can protect neurons by reducing the toxicity of neurons by amyloid beta.
따라서, 본 발명의 조성물은, WNT-3α 및 β의 발현을 증가시킴에 따라, 신경세포의 보호뿐만 아니라 재생능까지 향상시킬 수 있다.Therefore, the composition of the present invention, by increasing the expression of WNT-3α and β, it is possible to improve not only the protection of nerve cells, but also the regeneration ability.
나아가, DKK-1(Dikkopf1)은 전술한 WNT-3α/β-Catenin 신호의 억제제임에 따라, 이의 발현이 감소됨에 따라, 전술한 WNT-3α 및 β에 의한 신경세포 보호 및 재생능이 보다 활발하게 활성화되어, 이의 효과가 향상될 수 있다.Furthermore, as DKK-1 (Dikkopf1) is an inhibitor of the aforementioned WNT-3α/β-Catenin signal, as its expression is reduced, the neuronal protection and regenerative ability by the aforementioned WNT-3α and β become more active. It can be activated, and its effect can be improved.
도 3f를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 세포 사멸에 대한 결과가 도시된다.Referring to Figure 3f, the results of cell death according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention is shown.
본 발명의 실시예는 비교예 1 및 2보다 Bax의 발현이 유의하게 낮은 것으로 나타난다(P<0.05). 또한, 본 발명의 실시예는 비교예 1 및 2보다 Bcl-2의 발현이 유의하게 낮은 것으로 나타난다(P<0.05).Examples of the present invention show that the expression of Bax is significantly lower than Comparative Examples 1 and 2 (P<0.05). In addition, the Example of the present invention shows that the expression of Bcl-2 is significantly lower than Comparative Examples 1 and 2 (P<0.05).
나아가, 본 발명의 실시예에 대한 Bax의 발현량은 비교예 1 및 2보다 각각 0.5, 0.1 배 낮은 것으로 나타나며, 본 발명의 실시예에 대한 Bcl-2의 발현량은 비교예 1 및 2보다 각각 3.5, 10.8배 높은 것으로 나타난다.Furthermore, the expression level of Bax for Examples of the present invention is shown to be 0.5 and 0.1 times lower than those of Comparative Examples 1 and 2, respectively, and the expression level of Bcl-2 for Examples of the present invention is higher than that of Comparative Examples 1 and 2, respectively. 3.5 and 10.8 times higher.
이때, Bax는 세포에 손상을 입혀 세포사멸(apoptosis)을 유도할 수 있는 인자이다. In this case, Bax is a factor capable of inducing apoptosis by damaging cells.
따라서, 본 발명의 조성물은, Bax의 발현을 감소시킴에 따라, 신경세포뿐만 아니라 다양한 세포의 사멸을 감소시킬 수 있다.Therefore, the composition of the present invention, by reducing the expression of Bax, it is possible to reduce the death of various cells as well as neurons.
나아가, Bcl-2는 전술한 Bax에 결합하여, 이의 구조변화를 유도하여 세포사멸을 억제시킬 수 있다. Furthermore, Bcl-2 can inhibit apoptosis by binding to the above-mentioned Bax and inducing its structural change.
따라서, 본 발명의 조성물은, Bcl-2의 발현을 증가시킴에 따라, Bax에 의한 신경세포를 포함하는 다양한 세포의 사멸을 예방 및 차단할 수 있다.Therefore, the composition of the present invention, by increasing the expression of Bcl-2, it is possible to prevent and block the death of various cells including neurons by Bax.
이상의 결과에 따라, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 저산소 및 영양 결핍 등의 다양한 스트레스에 의하여 초래된 염증 및 세포사멸 반응을 감소시켜, 신경세포 및 혈관세포를 보호하고, 이의 분화, 생성 및 재생을 촉진시켜, 전술한 스트레스에 의하여 초래된 뇌질환을 예방 및 치료할 수 있다. According to the above results, the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention reduces inflammation and apoptosis caused by various stresses such as hypoxia and nutritional deficiency, nerve cells and vascular cells It is possible to prevent and treat brain diseases caused by the above-described stress by protecting and promoting its differentiation, generation and regeneration.
나아가, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 신경세포 및 혈관세포뿐만 아니라, 다양한 세포를 분화, 발달 및 성장을 시킬 수 있음에 따라, 저산소 및/또는 저영양 이후 재관류로 인하여 초래된 다양한 허혈성 질환에 대해서도 예방 및 치료할 수 있다. 이에, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE), 뇌졸중, 뇌경색, 뇌허혈, 혈전증(thrombosis), 색전증(em-bolism), 일과성 허혈 발작(transient ischemic attack), 뇌경색(lacune), 두부손상(head trauma), 뇌순환대사장애, 뇌 기능혼수, 외상성 뇌손상, 혈관성 치매, 알츠하이머성 치매, 헌팅턴병 및 파킨슨 병 중 적어도 하나를 포함하는 허혈성 뇌질한에 대하여, 예방 및/또는 치료 효과를 가질 수 있다.Furthermore, as the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention can differentiate, develop and grow various cells as well as nerve cells and blood vessels, hypoxia and/or hyponutrient Thereafter, various ischemic diseases caused by reperfusion can also be prevented and treated. Accordingly, the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention is hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism ), transient ischemic attack, lacune, head trauma, cerebral circulatory metabolic disorder, cerebral coma, traumatic brain injury, vascular dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease. For ischemic encephalopathy, including, it may have a preventive and / or therapeutic effect.
한편, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 항염증에 보다 효과적일 수 있다.On the other hand, the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention may be more effective for anti-inflammatory.
보다 구체적으로, 도 4a 내지 4d를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 항염증 효과 관련 유전자 발현 결과가 도시된다.More specifically, referring to Figures 4a to 4d, the anti-inflammatory effect-related gene expression results according to the treatment of the pharmaceutical composition for the prevention or treatment of ischemic brain disease according to various embodiments of the present invention is shown.
도 4a를 참조하면, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 따른 전사체(transcriptome) 프로파일링 분석 결과가 도시된다. 이때, RNA sequencing transcriptome array 분석은 Fold change가 1.7 이상 및 -1.7 이하이고, p-value <0.05으로 명명된 유전자만은 선별하여 differentially expressed genes (DEGs)를 확인하였으며, 이들의 발현을 SYBRgreen에 기초한 rtPCR 방법을 통하여 확인하였다.Referring to FIG. 4A , the results of transcriptome profiling analysis according to the treatment of the pharmaceutical composition for preventing or treating ischemic encephalopathy according to various embodiments of the present invention are shown. At this time, RNA sequencing transcriptome array analysis confirmed the differentially expressed genes (DEGs) by selecting only genes with fold change of 1.7 or more and -1.7 or less, p-value <0.05, and RTPCR based on SYBRgreen for their expression. It was confirmed through the method.
먼저, 도 4a의 (a)를 참조하면, 2,736종의 유전자가 큰 발현 변화(log2(fold change) 1.7이상, -1.7이하)를 보인 것으로 나타나며, 이의 패턴은 비교예 1, 비교예 2 및 실시예에 따라 서로 상이한 것으로 나타난다. First, referring to (a) of Figure 4a, it is shown that 2,736 genes showed a large expression change (log2 (fold change) 1.7 or more, -1.7 or less), and the pattern thereof is Comparative Example 1, Comparative Example 2 and Example They appear to be different depending on the example.
나아가, 도 4a의 (b)를 참조하면, OGD 즉, 산소-포도당 결핍에 의하여, 상향 조절된 유전자는(up-regulated genes) 809종인 것으로 나타나며, 하향 조절된 유전자는(down-regulated genes) 838종인 것으로 나타난다. Furthermore, referring to (b) of Figure 4a, OGD, that is, oxygen-by glucose deprivation, up-regulated genes (up-regulated genes) appear to be 809 kinds, down-regulated genes (down-regulated genes) 838 appears to be a species.
또한, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물의 처리에 의하여, 상향 조절된 유전자는(up-regulated genes) 102종인 것으로 나타나며, 하향 조절된 유전자는(down-regulated genes) 210종인 것으로 나타난다. In addition, by the treatment of the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention, up-regulated genes are shown to be 102 kinds, and the down-regulated genes are genes) appear to be 210 species.
보다 구체적으로, 도 4b를 참조하면, 전술한 도 4a에서 차등적으로 발현된 유전자에 대한 리스트가 도시된다. OGD의 유도 및 본 발명의 조성물 처리에 의하여 차별적으로 발현된 유전자는 Csf1, Il6, Stat1, Cxcl14, Hspa8, Ccl4, Cd14, Ptpn6, Ccl3, Lpl, C1qc, Rac2, C1qb 및 Ctsk인 것으로 나타나며, 이들의 발현은 OGD 및 본 발명의 조성물 처리에 의하여 상반되는 패턴은 갖는 것으로 나타난다. More specifically, referring to FIG. 4B , a list of genes differentially expressed in FIG. 4A described above is shown. The genes differentially expressed by induction of OGD and treatment with the composition of the present invention are Csf1, Il6, Stat1, Cxcl14, Hspa8, Ccl4, Cd14, Ptpn6, Ccl3, Lpl, C1qc, Rac2, C1qb and Ctsk. Expression appears to have an opposing pattern by treatment with OGD and compositions of the present invention.
이때, 도 4c를 참조하면, Csf1, Il6 및 Stat1는 OGD로 인하여 발현이 증가되는 것으로 나타나며, Csf1, Il6 및 Stat1는 염증세포 또는 암세포에 의하여 분비되는 염증 관련 인자이다. 즉, 산소-포도당 결핍로 인하여, 염증 반응 인자가 증가될 수 있다.At this time, referring to FIG. 4C , Csf1, Il6 and Stat1 are expressed to be increased due to OGD, and Csf1, Il6 and Stat1 are inflammation-related factors secreted by inflammatory cells or cancer cells. That is, due to oxygen-glucose deprivation, inflammatory response factors may be increased.
반면에, 도 4d를 참조하면, 전술한 Csf1, Il6 및 Stat1의 발현은 본 발명의 조성물 처리로 인하여, 감소되는 것으로 나타난다. On the other hand, referring to FIG. 4D , the above-described expression of Csf1, Il6 and Stat1 appears to be decreased due to treatment with the composition of the present invention.
즉, 본 발명의 다양한 실시예에 따른 허혈성 뇌질환 예방 또는 치료용 약학적 조성물은 저산소 및 영양결핍 또는 전술한 상태 이후의 재관류에 의하여 초래된 염증 반응을 촉진시킬 수 있는 인자의 발현을 감소시킬 수 있으며, 이에 따라, 항염증 효과를 가질 수 있다.That is, the pharmaceutical composition for preventing or treating ischemic brain disease according to various embodiments of the present invention can reduce the expression of a factor capable of promoting an inflammatory response caused by hypoxia and nutritional deficiency or reperfusion after the aforementioned condition. and, accordingly, may have an anti-inflammatory effect.
이상 첨부된 도면을 참조하여 본 발명의 실시 예들을 더욱 상세하게 설명하였으나, 본 발명은 반드시 이러한 실시 예로 국한되는 것은 아니고, 본 발명의 기술사상을 벗어나지 않는 범위 내에서 다양하게 변형 실시될 수 있다. 따라서, 본 발명에 개시된 실시 예들은 본 발명의 기술 사상을 한정하기 위한 것이 아니라 설명하기 위한 것이고, 이러한 실시 예에 의하여 본 발명의 기술 사상의 범위가 한정되는 것은 아니다. 그러므로, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 본 발명의 보호 범위는 아래의 청구범위에 의하여 해석되어야 하며, 그와 동등한 범위 내에 있는 모든 기술 사상은 본 발명의 권리범위에 포함되는 것으로 해석되어야 할 것이다.Although the embodiments of the present invention have been described in more detail with reference to the accompanying drawings, the present invention is not necessarily limited to these embodiments, and various modifications may be made within the scope without departing from the technical spirit of the present invention. Therefore, the embodiments disclosed in the present invention are not intended to limit the technical spirit of the present invention, but to explain, and the scope of the technical spirit of the present invention is not limited by these embodiments. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The protection scope of the present invention should be construed by the following claims, and all technical ideas within the equivalent range should be construed as being included in the scope of the present invention.
Claims (12)
- 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating ischemic brain disease, comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
- 제 1항에 있어서,The method of claim 1,상기 허혈성 뇌질환은, The ischemic brain disease is저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE), 뇌졸중, 뇌경색, 뇌허혈, 혈전증(thrombosis), 색전증(em-bolism), 일과성 허혈 발작(transient ischemic attack), 뇌경색(lacune), 두부손상(head trauma), 뇌순환대사장애, 뇌 기능혼수, 외상성 뇌손상, 혈관성 치매, 알츠하이머성 치매, 헌팅턴병 및 파킨슨 병 중 적어도 하나를 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물.Hypoxic-ischemic encephalopathy (HIE), stroke, cerebral infarction, cerebral ischemia, thrombosis, em-bolism, transient ischemic attack, lacune, head trauma ), cerebral circulation metabolic disorder, brain functional coma, traumatic brain injury, vascular dementia, Alzheimer's disease, including at least one of Huntington's disease and Parkinson's disease, ischemic brain disease prevention or treatment pharmaceutical composition.
- 제 2항에 있어서,3. The method of claim 2,상기 허혈성 뇌질환은, The ischemic brain disease is저산소성 허혈성 뇌병증(Hypoxic-ischemic encephalopathy, HIE)인, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating ischemic encephalopathy, which is hypoxic-ischemic encephalopathy (HIE).
- 제 1항에 있어서,The method of claim 1,상기 조성물은,The composition is약제학적으로 허용가능한 담체, 희석제 및 어주번트로 이루어진 그룹 중 적어도 하나를 더 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating ischemic brain disease, further comprising at least one of the group consisting of a pharmaceutically acceptable carrier, diluent and adjuvant.
- 제 1항에 있어서,The method of claim 1,상기 조성물은,The composition is경구, 경피, 근육내, 복막내, 정맥내, 피하 내 및 비강으로 이루어진 그룹 중 적어도 하나의 투여경로를 통해 투여되는 것을 특징으로 하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating ischemic brain disease, characterized in that it is administered through at least one route of administration from the group consisting of oral, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous and nasal.
- 제 1항에 있어서,The method of claim 1,상기 조성물은,The composition is정제, 연고제 또는 주사제로 제형화된, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating ischemic brain disease, formulated as a tablet, ointment or injection.
- 제 1항에 있어서,The method of claim 1,상기 PDRN은,The PDRN is30 내지 150 μg/ml인, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. 30 to 150 μg/ml, a pharmaceutical composition for preventing or treating ischemic brain disease.
- 제 1항에 있어서,The method of claim 1,상기 PDRN은,The PDRN isBax, mTOR 및 DKK-1 중 적어도 하나의 발현을 감소시킴으로써, By reducing the expression of at least one of Bax, mTOR and DKK-1,신경 보호 및 신경 재생에 대한 효과를 나타내는, 허혈성 외질환 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating a non-ischemic disease, showing an effect on nerve protection and nerve regeneration.
- 제 1항에 있어서,The method of claim 1,상기 PDRN은,The PDRN isBCL-2, VEGF, BDNF, WNT-3α 및 β중 적어도 하나의 발현을 증가시킴으로써, By increasing the expression of at least one of BCL-2, VEGF, BDNF, WNT-3α and β,상기 신경 보호 및 신경 재생에 대한 효과를 나타내는, 허혈성 외질환 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating extraischemic disease, which exhibits the effect on the nerve protection and nerve regeneration.
- 제 1항에 있어서,The method of claim 1,상기 PDRN은,The PDRN isTNFα, iNOS, IL-1β, CSF1, STAT1 및 IL-6 중 적어도 하나의 발현을 감소시킴으로써,By reducing the expression of at least one of TNFα, iNOS, IL-1β, CSF1, STAT1 and IL-6,항염증에 대한 효과를 나타내는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating ischemic brain disease, which exhibits an anti-inflammatory effect.
- 폴리데옥시리보뉴클레오타이드(polydeoxyribonucleotide, PDRN)를 유효성분으로 포함하는, 허혈성 뇌질환 예방 또는 개선용 건강기능성 식품. A health functional food for preventing or improving ischemic brain disease, comprising polydeoxyribonucleotide (PDRN) as an active ingredient.
- 제 11항에 있어서,12. The method of claim 11,상기 PDRN은,The PDRN is30 내지 150 μg/ml인, 허혈성 뇌질환 예방 또는 개선용 건강기능성 식품. 30 to 150 μg/ml, a functional health food for preventing or improving ischemic brain disease.
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| KR1020210058632A KR20220151414A (en) | 2021-05-06 | 2021-05-06 | Pharmaceutical composition for prevention of treatment of ischemic brain disease |
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| KR930012808A (en) * | 1992-12-08 | 1993-07-21 | ||
| WO1994015953A1 (en) * | 1993-01-04 | 1994-07-21 | The Regents Of The University Of California | Platelet-specific therapeutic compound and method of treating platelet-mobilizing diseases |
| CN111132663A (en) * | 2017-08-03 | 2020-05-08 | 爵士制药爱尔兰有限公司 | Formulations comprising high concentrations of nucleic acids |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR930012808A (en) * | 1992-12-08 | 1993-07-21 | ||
| WO1994015953A1 (en) * | 1993-01-04 | 1994-07-21 | The Regents Of The University Of California | Platelet-specific therapeutic compound and method of treating platelet-mobilizing diseases |
| CN111132663A (en) * | 2017-08-03 | 2020-05-08 | 爵士制药爱尔兰有限公司 | Formulations comprising high concentrations of nucleic acids |
Non-Patent Citations (2)
| Title |
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| KO IL-GYU, JIN JUN-JANG, HWANG LAKKYONG, KIM SANG-HOON, KIM CHANG-JU, JEON JUNG WON, CHUNG JUN-YOUNG, HAN JIN HEE: "Adenosine A2A receptor agonist polydeoxyribonucleotide ameliorates short-term memory impairment by suppressing cerebral ischemia-induced inflammation via MAPK pathway", PLOS ONE, vol. 16, no. 3, pages e0248689, XP093001667, DOI: 10.1371/journal.pone.0248689 * |
| PARK JEE YOON, BYEON JUNG HYE, PARK SUNG-WON, EUN SO-HEE, CHAE KYU YOUNG, EUN BAIK-LIN: "Neuroprotective effect of human placental extract on hypoxic–ischemic brain injury in neonatal rats", BRAIN & DEVELOPMENT, AMSTERDAM, NL, vol. 35, no. 1, 1 January 2013 (2013-01-01), NL , pages 68 - 74, XP093001668, ISSN: 0387-7604, DOI: 10.1016/j.braindev.2012.01.009 * |
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