WO2022235023A1 - Composition pharmaceutique pour la prévention ou le traitement d'une maladie ischémique cérébrale - Google Patents

Composition pharmaceutique pour la prévention ou le traitement d'une maladie ischémique cérébrale Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
preventing
present
brain disease
ischemic brain
Prior art date
Application number
PCT/KR2022/006197
Other languages
English (en)
Korean (ko)
Inventor
조성래
김성훈
백아름
조성문
Original Assignee
연세대학교 산학협력단
연세대학교 원주산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 연세대학교 산학협력단, 연세대학교 원주산학협력단 filed Critical 연세대학교 산학협력단
Publication of WO2022235023A1 publication Critical patent/WO2022235023A1/fr

Links

Images

Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Polymers & Plastics (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Food Science & Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente description concerne une composition pharmaceutique contenant du polydésoxyribonucléotide (PDRN) en tant que principe actif pour la prévention ou le traitement de maladies cérébrales ischémiques.
PCT/KR2022/006197 2021-05-06 2022-04-29 Composition pharmaceutique pour la prévention ou le traitement d'une maladie ischémique cérébrale WO2022235023A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2021-0058632 2021-05-06
KR1020210058632A KR20220151414A (ko) 2021-05-06 2021-05-06 허혈성 뇌질환 예방 또는 치료용 약학적 조성물

Publications (1)

Publication Number Publication Date
WO2022235023A1 true WO2022235023A1 (fr) 2022-11-10

Family

ID=83932786

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2022/006197 WO2022235023A1 (fr) 2021-05-06 2022-04-29 Composition pharmaceutique pour la prévention ou le traitement d'une maladie ischémique cérébrale

Country Status (2)

Country Link
KR (1) KR20220151414A (fr)
WO (1) WO2022235023A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR930012808A (fr) * 1992-12-08 1993-07-21
WO1994015953A1 (fr) * 1993-01-04 1994-07-21 The Regents Of The University Of California Compose therapeutique specifique aux plaquettes et methode de traitement des maladies mobilisant les plaquettes
CN111132663A (zh) * 2017-08-03 2020-05-08 爵士制药爱尔兰有限公司 包含高浓度核酸的制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR930012808A (fr) * 1992-12-08 1993-07-21
WO1994015953A1 (fr) * 1993-01-04 1994-07-21 The Regents Of The University Of California Compose therapeutique specifique aux plaquettes et methode de traitement des maladies mobilisant les plaquettes
CN111132663A (zh) * 2017-08-03 2020-05-08 爵士制药爱尔兰有限公司 包含高浓度核酸的制剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
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 *

Also Published As

Publication number Publication date
KR20220151414A (ko) 2022-11-15

Similar Documents

Publication Publication Date Title
WO2018004143A1 (fr) Composition favorisant l'angiogenèse contenant une nanovésicule mimétique d'exosome dérivé de cellules souches adultes
WO2018117659A1 (fr) Composition pharmaceutique comprenant un extrait de levis pulverata indigo ou une fraction de celui-ci comme principe actif pour prévenir ou traiter une maladie intestinale inflammatoire
WO2020113759A1 (fr) Méthodes de traitement de la dégénérescence maculaire liée à l'âge
CZ287892A3 (en) Pharmaceutical preparations
WO2017048072A1 (fr) Composition de promotion de différenciation de myocytes contenant des acides aminés
WO2024191081A1 (fr) Composition pour la prévention ou le traitement de l'infarctus cérébral
WO2020196953A1 (fr) Composition pharmaceutique, pour la prévention ou le traitement de maladies inflammatoires, comprenant de l'ostéocalcine
WO2024191080A1 (fr) Composition pour la prévention ou le traitement de l'infarctus cérébral
Xiong et al. Effect of sutellarin on neurogenesis in neonatal hypoxia–ischemia rat model: potential mechanisms of action
WO2022235023A1 (fr) Composition pharmaceutique pour la prévention ou le traitement d'une maladie ischémique cérébrale
WO2024106716A1 (fr) Composition pour atténuer ou traiter la démence, contenant du 2'-fucosyllactose
WO2014042325A1 (fr) Composition pour la prévention et le traitement de maladies inflammatoires et de maladies immunitaires, contenant apo-9'-fucoxanthinone en tant que principe actif
WO2015178653A1 (fr) Composition utilisable en vue du traitement ou de la prévention d'une maladie métabolique et contenant, en tant qu'ingrédient actif, des vésicules extracellulaires provenant de bactéries de l'espèce akkermansia muciniphila
WO2021246610A1 (fr) Composition pour la prévention ou le traitement de maladies inflammatoires, comprenant une souche de lactobacillus sakei cvl-001
CN118021854A (zh) 副干酪乳杆菌Lp.R3在制备预防和/或缓解神经系统疾病药物的应用
TW202404616A (zh) 鼠李糖在製備用於治療或預防神經退行性疾病的藥物中的用途、藥物組合物及其應用
KR100855389B1 (ko) 치매증 치료용 숙신산 유도체 에스테르의 용도
JPWO2008056452A1 (ja) 希少糖の筋萎縮性側索硬化症と関連した運動障害の発症または進行の遅延への利用
JP2599151B2 (ja) 豚の溶連菌感染症の予防及び治療剤
WO2021112615A1 (fr) Composition contenant un peptide ou un composé peptidique utilisé comme principe actif, et son utilisation médicale
WO2021132897A1 (fr) Composition pour la prévention, l'amélioration ou le traitement de la cachéxie cancéreuse contenant de la pipérine
WO2016064009A1 (fr) Composition destinée à prévenir ou à traiter les maladies neurodégénératives, contenant de la ramaline
CN112168812A (zh) 棕榈油酸用于制备预防或治疗炎症性疾病的组合物的用途
EP2369926A1 (fr) Compositions pharmaceutiques et procédés de traitement de la dégénérescence maculaire liée à l âge avec des analogues de la mélatonine
WO2022240165A1 (fr) Composition pharmaceutique pour la prévention ou le traitement de la dégénérescence maculaire liée à l'âge

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22799066

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22799066

Country of ref document: EP

Kind code of ref document: A1