WO2025009945A1 - Composition pharmaceutique pour la prévention ou le traitement de maladies cérébrales dégénératives comprenant du sélexipag - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de maladies cérébrales dégénératives comprenant du sélexipag Download PDF

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WO2025009945A1
WO2025009945A1 PCT/KR2024/009678 KR2024009678W WO2025009945A1 WO 2025009945 A1 WO2025009945 A1 WO 2025009945A1 KR 2024009678 W KR2024009678 W KR 2024009678W WO 2025009945 A1 WO2025009945 A1 WO 2025009945A1
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selexipag
disease
expression
acceptable salt
degenerative brain
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Korean (ko)
Inventor
허향숙
황정우
정유주
박진희
장지영
김정하
조아란
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Daegu Gyeongbuk Institute of Science and Technology
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Daegu Gyeongbuk Institute of Science and Technology
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Degenerative brain diseases are diseases that cause various symptoms such as motor and sensory function impairment, memory, learning, and higher-order causal functions such as computational reasoning due to degenerative changes in the nerve cells of the central nervous system.
  • Types of degenerative brain diseases include Alzheimer's disease (AD), Parkinson's disease, and memory impairment.
  • Degenerative brain diseases are characterized by the death of nerve cells due to rapid or slow progression of necrosis or apoptosis.
  • Inflammation in the central nervous system causes degenerative brain diseases and is mediated by the release of cytokines and chemokines by glial cells in the CNS.
  • Glial cells are divided into two types, microglia and astrocytes, and they play an important role in maintaining neurons and detecting and defending against pathogens.
  • microglia are immune cells that reside in the central nervous system and are known to be activated by external stimuli to induce immune and inflammatory responses.
  • Microglia are cells that perform primary immune functions in the central nervous system, and maintain the shape of thin, long branches and a thin cell body, but when toxins introduced from the outside or generated internally are present, they change into an activated shape with thick, short branches and a fat cell body to protect nerve cells from these toxins.
  • microglia when microglia are activated by substances such as bacterial endotoxins, lipopolysaccharide (LPS), interferon- ⁇ , beta-amyloid, or ganglioside, unlike normal microglia, they actively perform phagocytosis, proliferate, and express genes such as cytokines such as TNF- ⁇ , IL-1 ⁇ , and IL-6, chemokines, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) to produce inflammatory mediators.
  • cytokines such as TNF- ⁇ , IL-1 ⁇ , and IL-6
  • chemokines inducible nitric oxide synthase (iNOS)
  • COX-2 cyclooxygenase-2
  • microglia activation has the effect of removing damaged cells and protecting neurons from invading bacteria or viruses, but nitric oxide (NO) produced by iNOS, prostaglandins produced by COX-2, TNF- ⁇ , etc. are also toxic to neurons, so microglia activation ends up worsening the damage to neurons. Therefore, suppressing appropriate activation of microglia may be another way to treat degenerative brain diseases.
  • NO nitric oxide
  • degenerative brain diseases are known to occur when specific brain cells die or degenerate temporarily or over a long period of time, and because dead brain cells cannot be regenerated, they eventually lead to fatal loss of brain function.
  • brain dysfunction accompanied by progressive decline in cognitive, sensory, motor, and systemic functions eventually leads to changes in personality and behavior, and patients reach a point where they cannot take care of themselves.
  • the main pathways of this brain cell death include oxidative toxicity due to oxidative stress, excitatory toxicity, and apoptosis, and each induces cell death through a unique signaling process.
  • oxidative damage to proteins, nucleic acids, and lipids following the accumulation of reactive oxygen species has been suggested as the main cause of brain cell death in patients with stroke, brain injury, Alzheimer's disease, and Parkinson's disease.
  • oxidative stress caused by free radicals has been reported to be the main cause of cell death in each tissue in the body, and has also been suggested as one of the cycles of cell death in neurological diseases (Schapira, A.H., Curr. Opin. Neurol., 9(4):260-264, 1996).
  • astrocytes play an important role in maintaining normal brain activity as well as in the development process of the brain. It has been revealed that astrocytes in the brain assist in the activity of nerve cells by appropriately removing neurotransmitters secreted by nerve cells or regulating the concentration of ions in the brain. In addition, it has been revealed that they play a crucial role in helping neural stem cells differentiate into nerve cells.
  • astrocytes when injured in the brain, they proliferate actively, swell, and become activated as reactive astrocytes such as astrogliosis. These reactive astrocytes are observed in AIDS-related dementia, brain damage, ischemic brain disease, Alzheimer's disease, etc. Therefore, continuous activation of astrocytes eventually leads to the death of nerve cells. Therefore, appropriate inhibition of astrocyte activation can also be another way to treat degenerative brain diseases.
  • drugs are generally used to supplement dopamine that has been deficient in the brain, correct the imbalance of neurotransmitters caused by dopamine deficiency, prevent or delay the destruction of nerve cells, and control other symptoms such as depression.
  • selexipag is a drug for treating pulmonary arterial hypertension (PAH) currently marketed under the name Uptravi.
  • PH pulmonary arterial hypertension
  • Selexipag and its active metabolite ACT-333679 are known to be prostacyclin receptor agonists that induce vasodilation in the pulmonary circulation (see Patent Document 0001).
  • selexipag previously known as a pulmonary arterial hypertension treatment agent, inhibits the expression and production of pro-inflammatory or inflammatory cytokines in brain tissue induced by LPS, inhibits the activity of microglia or astrocytes, and inhibits NLRP3 inflammasome activity and CDK6 expression, and thus the use of selexipag for the prevention or treatment of degenerative brain diseases was proposed.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a reagent composition for inhibiting activation of microglia or astrocytes, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a reagent composition for inhibiting tau phosphorylation, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a health functional food for preventing or improving neuroinflammation or degenerative brain disease, comprising Selexipak or a food-wise acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a health functional food for improving cognitive function, learning ability or memory, comprising Selexipak or a food scientifically acceptable salt thereof as an effective ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising selexipak or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Selexipag is a compound with the following structural formula, its chemical name is 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]-N-methylsulfonylacetamide, and it is a prostacyclin receptor agonist.
  • the pharmaceutical composition of the present invention may use not only Selexipag as an active ingredient, but also a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt should have low toxicity to humans and should not have any negative effects on the biological activity and physicochemical properties of the parent compound.
  • the pharmaceutically acceptable salt may be an acid addition salt formed by a pharmaceutically acceptable free acid.
  • the acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid
  • non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoate, dinitrobenzoate, hydroxybenzoates, methoxybenzoates, phthalates, terephthalate, benzenesulfonate, tol
  • Selectipak may have one or more of the following activities:
  • selixipag may have anti-inflammatory activity, and specifically, may inhibit or alleviate an inflammatory response in brain tissue.
  • selexipag can inhibit the expression and production of pro-inflammatory cytokines or inflammatory cytokines in brain tissue.
  • selexipag can decrease inflammatory factors induced by LPS (e.g., COX-2, IL-6, IL-1 ⁇ , or TNF- ⁇ ) or increase anti-inflammatory cytokines (e.g., TGF- ⁇ , or IL-10).
  • LPS which is one of the endotoxins, promotes the secretion of proinflammatory cytokines, which causes the secretion of inflammatory mediators such as nitric oxide and prostaglandin, and various inflammatory diseases are caused by excessive inflammatory responses.
  • selexipag may inhibit LPS-induced proinflammatory responses, thereby preventing, improving, or treating degenerative brain diseases that may be caused by excessive inflammatory responses in brain tissue.
  • Selexipag can inhibit the formation of inflammasomes or the level of cyclin-dependent kinase (CDK) in brain tissue. Specifically, Selexipag can act as an inhibitor of CDK4/6 by reducing or inhibiting the expression of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein-3) produced by inflammatory responses induced by LPS, etc., thereby inhibiting the NLRP3 inflammasome pathway, or by reducing or inhibiting the expression of CDK6.
  • NLRP3 nucleotide-binding domain and leucine-rich repeat protein-3
  • Inflammasome is a protein complex consisting of several proteins including NLRP3, NLRC4, AIM2, and NLRP6, which directly activates caspase-1 in response to bacterial infection, stress, and damage signals, thereby inducing the secretion of potent proinflammatory cytokines (e.g., IL-1 ⁇ or IL-18) and causing pyroptosis, an inflammatory cell death.
  • cytokines e.g., IL-1 ⁇ or IL-18
  • CDK4/6 is a cell cycle regulatory protein that can regulate DNA synthesis and division of cells in relation to the cell cycle, but overactivity of CDK4/6 affects the survival and cell cycle control of neurons, affects amyloid beta accumulation, and induces neuronal degeneration. Therefore, CDK4/6 inhibitors are reported to have therapeutic effects on inflammatory diseases, neurological and neurodegenerative diseases, and Alzheimer's disease.
  • selexipag can prevent, improve or treat degenerative brain diseases that can be caused by excessive inflammatory response in brain tissue by inhibiting the expression or level of NLRP3 and CDK6 induced by LPS in brain tissue.
  • Selexipag can inhibit the activity of microglia or astrocytes. Specifically, it can inhibit the damage that activated microglia or activated astrocytes cause to neurons.
  • Microglia which act as macrophages in the brain, are important effector cells that regulate immune responses in the central nervous system (CNS). Their activation plays an important role in maintaining homeostasis of the CNS by removing foreign substances caused by drugs or toxins and secreting nerve growth factors. However, when exposed to harmful stresses such as signals from damaged neurons, accumulation of abnormally shaped proteins altered by external stimuli, and invasion of pathogens, the activity of microglia may increase excessively, causing damage to nerve cells and causing degenerative neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral infarction.
  • CNS central nervous system
  • microglia unlike normal microglia, actively perform phagocytosis, undergo cell proliferation, and express genes such as cytokines such as TNF- ⁇ , IL-1 ⁇ , and IL-6, chemokines, and COX-2 to produce inflammatory mediators.
  • cytokines such as TNF- ⁇ , IL-1 ⁇ , and IL-6
  • chemokines such as IL-1 ⁇ , and IL-6
  • COX-2 chemokines
  • astrocytes are also known to play an important role in maintaining normal brain activity, and in particular, they are known to play a role in the formation of synapses in neurons, regulation of the number of synapses, synaptic function, and differentiation of neural stem cells into neurons.
  • these astrocytes become excessively reactive, that is, when they remain in an excessively activated state, they cause the death of neurons and induce the death of neighboring neurons, acting as a cause of degenerative brain diseases.
  • Substances that cause excessive activation of microglia and astrocytes include bacterial endotoxins, LPS, interferon- ⁇ , beta-amyloid, and gangliosides, which can induce inflammatory responses.
  • selexipag can suppress excessive activation of microglia and/or astrocytes in brain tissue, and therefore selexipag can be useful for preventing, improving, or treating degenerative brain diseases that can be caused by excessive inflammatory response in brain tissue.
  • selexipag and pharmaceutically acceptable salts thereof have excellent effects of inhibiting the aggregation of amyloid-beta and/or decomposing aggregates, inhibiting the aggregation of tau protein and/or decomposing aggregates, and inhibiting the phosphorylation of tau protein, selexipag or a pharmaceutical composition comprising it can be usefully used for the prevention or treatment of diseases related to the inhibition of amyloid-beta aggregation and/or decomposition of aggregates, the inhibition of tau protein aggregation and/or decomposition of aggregates, and/or the inhibition of phosphorylation of tau protein, such as degenerative brain diseases.
  • a pharmaceutical composition according to the present invention comprises:
  • selexipag reduces the accumulation of amyloid beta by regulating the expression of insulin degrading enzyme (IDE), an amyloid beta degrading enzyme, in an amyloid overexpressing Alzheimer's disease animal model.
  • IDE insulin degrading enzyme
  • selexipag inhibits tau hyperphosphorylation by inhibiting the expression and activity of DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) and p-CDK5, which are tau phosphorylation enzymes, in a tau overexpressing animal model, which is another Alzheimer's disease animal model.
  • prevention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering a compound or pharmaceutical composition according to the present invention
  • treatment means any act of improving or beneficially changing the symptoms of the disease by administering a compound or pharmaceutical composition according to the present invention.
  • abnormal in this specification may refer to an individual of the same species as the subject to which the pharmaceutical composition is applied, who does not have the "degenerative brain disease” defined above, or brain tissue or brain cells (brain nerve cells) isolated and/or cultured from the individual.
  • the term “inhibition” means inhibition of any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-protein binding, protein activation, or signal transduction through the same.
  • composition may refer to a molecule or compound that, when administered to a subject, imparts some beneficial effect.
  • beneficial effects may include enabling a diagnostic determination; improving a disease, symptom, disorder or condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or condition.
  • degenerative brain disease is used to comprehensively describe all diseases related to degenerative changes in the brain, especially all diseases (brain diseases) that can be caused by factors such as aggregation of amyloid-beta in the brain and/or brain neurons.
  • the degenerative brain disease may be selected from the group consisting of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, senile dementia, multiple sclerosis, multiple neurotrophy, epilepsy, encephalophathy, and frontotemporal dementia, but is not limited thereto, and any disease caused by aggregation of amyloid-beta, aggregation of tau protein, and/or phosphorylation of tau protein may be the target.
  • the term "cognition” herein may be a mental activity or process of acquiring knowledge and understanding through thinking, experiencing, and feeling. This may include processes such as knowledge, attention, memory and working memory, judgment and evaluation, reasoning and calculation, problem solving and decision making, and understanding and production of language.
  • the cognitive impairment is a category of mental health disorders that primarily affect learning, memory, perception, and problem solving, and may include amnesia, dementia, and delirium.
  • the above memory improvement may mean improving the storage, retention and retrieval of memories as a result of damage to neuroanatomical structures. It may also mean improving memory impairments that may be progressive (including Alzheimer's disease).
  • memory improvement and “cognitive ability improvement” refer to the effect of maintaining cognitive ability by controlling harmful substances that damage brain cells or improving reduced cognitive ability by controlling neurotransmitters in the brain when the brain atrophies and brain nerve cells are destroyed due to physical fatigue, lack of sleep, excessive alcohol consumption, dementia, etc., memory decline, memory impairment, or cognitive ability decline.
  • the memory is the ability to accept necessary information, store it in the brain, and retrieve and use it when needed, and cognitive ability refers to the ability to recognize and discern objects.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier in addition to an active ingredient.
  • the pharmaceutically acceptable carrier is one commonly used in the preparation of a formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition in addition to the effective ingredient, may further contain one or more auxiliary agents selected from the group consisting of pharmaceutically acceptable carriers, excipients, diluents, fillers, bulking agents, wetting agents, disintegrating agents, emulsifiers (surfactants), lubricants, sweeteners, flavoring agents, suspending agents, preservatives, etc.
  • auxiliary agents may be appropriately adjusted depending on the formulation to which the pharmaceutical composition is applied, and one or more auxiliary agents commonly used in the pharmaceutical field may be selected and used.
  • the pharmaceutically acceptable carrier is one commonly used in the formulation of drugs, and other common additives such as antioxidants, buffers, and bacteriostatic agents may be added as needed.
  • compositions can be additionally added to formulate the composition into injectable formulations such as aqueous solutions, suspensions and emulsions, pills, capsules, granules or tablets, and target organ-specific antibodies or other ligands can be combined with the carrier to specifically act on the target organ.
  • injectable formulations such as aqueous solutions, suspensions and emulsions, pills, capsules, granules or tablets, and target organ-specific antibodies or other ligands can be combined with the carrier to specifically act on the target organ.
  • target organ-specific antibodies or other ligands can be combined with the carrier to specifically act on the target organ.
  • the composition can be preferably formulated according to each disease or ingredient using an appropriate method in the art or a method disclosed in Remington's literature (Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA).
  • the effective amount of the above-mentioned effective ingredient or the pharmaceutical composition can be administered orally or parenterally during clinical administration and can be used in the form of a general pharmaceutical preparation.
  • Parenteral administration can mean administration via an administration route other than oral, such as rectal, intravenous, peritoneal, muscular, arterial, transdermal, nasal, inhalation, ocular or subcutaneous, and can be administered by local administration to a lesioned area, etc.
  • the pharmaceutical composition can be formulated as a formulation that coats the active ingredient to prevent the active ingredient from being decomposed in the stomach or protects it from decomposition in the stomach.
  • the pharmaceutical composition of the present invention when used as a pharmaceutical, it can additionally contain one or more effective ingredients exhibiting the same or similar function.
  • active ingredient in this specification may mean a physiologically active substance used for achieving the pharmacological activity (e.g., treatment of degenerative brain disease) mentioned in this specification, and this is distinguished from administering the substance alone, in combination with another substance, or additionally to treat the disease mentioned in this specification. That is, the selexipag may be administered as a sole active ingredient for the direct treatment effect of degenerative brain disease, or may be administered in combination with another drug.
  • the pharmaceutical composition above may be formulated in the form of a solution, suspension, syrup or emulsion in an aqueous or oily medium, or in the form of a powder, granule, tablet or capsule, and may additionally contain a dispersant or stabilizer for formulation.
  • a dispersant or stabilizer for formulation.
  • it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants that are commonly used.
  • Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • Non-aqueous solvents and suspensions may include vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable esters such as ethyl oleate.
  • the suppository bases that can be used include Witepsol, Macrogol, Tween 61, cocoa butter, liurin butter, and glycerogelatin.
  • the above pharmaceutical composition may be used by mixing with various carriers acceptable as pharmaceuticals, such as saline solution or organic solvents, and carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins or other stabilizers may be used as pharmaceuticals to increase stability or absorbability.
  • carriers acceptable as pharmaceuticals such as saline solution or organic solvents
  • carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins or other stabilizers may be used as pharmaceuticals to increase stability or absorbability.
  • the pharmaceutical composition described above can be administered in a pharmaceutically effective amount.
  • the dosage can vary depending on the degree of absorption in the body, body weight, patient's age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.
  • the pharmaceutical composition of the present invention is manufactured in consideration of the effective dosage range, and the unit dosage form preparation formulated in this way can be administered several times at regular time intervals using a specialized dosage method according to the judgment of a specialist who monitors or observes the administration of the drug and the individual's needs, as needed.
  • the dosage of the pharmaceutical composition can be 1 ug/kg/day to 1,000 mg/kg/day, but is not limited thereto.
  • the daily or one-time dosage can be formulated as a single preparation in the form of a unit dosage, formulated in an appropriate amount, or manufactured by placing it in a multi-dose container.
  • the subject may be a mammal, such as a human, cow, horse, pig, dog, sheep, goat, or cat.
  • the subject may be an individual in need of treatment for a degenerative brain disease.
  • the present invention provides a use of selexipag or a pharmaceutically acceptable salt thereof for preventing or treating degenerative brain diseases.
  • the present invention provides a use of selexipag or a pharmaceutically acceptable salt thereof for preventing or treating cognitive impairment, learning disability or memory impairment.
  • the present invention provides a use of selexipag or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of degenerative brain diseases.
  • the present invention provides a use of selexipag or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating cognitive impairment, learning disability or memory impairment.
  • the present invention provides a method for preventing or treating a degenerative brain disease, comprising administering selexipag or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention provides a method for preventing or treating cognitive impairment, learning disability or memory impairment, comprising administering selexipag or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention can provide a composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • selexipag can suppress excessive inflammatory response in nerve cells or brain tissue, thereby suppressing damage to nerve cells caused by inflammatory response.
  • the present invention provides a use of selexipag or a pharmaceutically acceptable salt thereof for inhibiting damage to nerve cells caused by an inflammatory response.
  • the present invention provides a method for inhibiting damage to nerve cells caused by an inflammatory reaction, comprising administering selexipag or a pharmaceutically acceptable salt thereof to a subject in need of inhibition of damage to nerve cells caused by an inflammatory reaction.
  • the present invention provides a reagent composition for inhibiting activation of microglia or astrocytes, comprising selexipag or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food for preventing or improving neuroinflammation or degenerative brain disease, comprising Selexipak or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food for improving cognitive function, learning ability or memory, comprising Selexipak or a food scientifically acceptable salt thereof as an effective ingredient.
  • the present invention provides a health functional food for inhibiting tau protein aggregation, decomposing tau protein aggregates, and/or inhibiting tau protein phosphorylation, comprising selexipak or a food scientifically acceptable salt thereof as an active ingredient.
  • the above health functional food refers to a food manufactured using nutrients that are easily deficient in daily meals or raw materials or ingredients (hereinafter, “functional raw materials”) that have functions useful to the human body, and all foods that help maintain health or prevent and/or improve certain diseases or symptoms, and there are no special restrictions on the final product form.
  • functional raw materials include nutrients that are easily deficient in daily meals or raw materials or ingredients (hereinafter, “functional raw materials”) that have functions useful to the human body, and all foods that help maintain health or prevent and/or improve certain diseases or symptoms, and there are no special restrictions on the final product form.
  • the above health functional food may be selected from the group consisting of various foods, beverage compositions, food additives, etc., but is not limited thereto.
  • the content of the effective ingredient contained in the above health functional food is not particularly limited, depending on the form of the food, the desired use, etc.
  • the above health functional food can be used alone or in combination with other foods or food ingredients, and can be used appropriately according to a conventional method.
  • the content of the effective ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
  • the composition of the present specification can be added in an amount of 15 parts by weight or less relative to the raw material.
  • the above health functional food may additionally contain at least one selected from the group consisting of various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents or natural flavoring agents, coloring agents, thickening agents (cheese, chocolate, etc.), pectic acid or its salt, alginic acid or its salt, organic acid, protective colloid thickener, pH regulator, stabilizer, preservative, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
  • the proportion of such additives is generally selected in the range of 0.001 to about 20 parts by weight per 100 parts by weight of the total health functional food, but is not limited thereto.
  • Selexipag inhibited the expression and production of pro-inflammatory or inflammatory cytokines in brain tissue induced by LPS, inhibited the activity of microglia or astrocytes, and inhibited NLRP3 inflammasome activity and CDK6 expression.
  • Selexipag reduced the accumulation of amyloid beta by regulating the expression of IDE, an amyloid beta degrading enzyme, in an amyloid overexpressing Alzheimer's disease animal model administered, and at the same time inhibited the activity of microglia and astrocytes in the Alzheimer's disease animal model.
  • DYRK1A and p-CDK5 which are tau kinases, thereby inhibiting tau hyperphosphorylation.
  • Selexipag may be useful for the prevention or treatment of degenerative brain diseases, cognitive impairment, learning disabilities, or memory impairment.
  • Figure 1 is a graph analyzing the cytotoxicity of microglial BV2 cells according to the treatment concentration of Selexipag using an MTT assay.
  • Figures 2a and 2b are graphs showing the expression levels of proinflammatory cytokines in BV2 microglia induced by LPS following selexipag treatment ((a) 1 ⁇ M and (b) 5 ⁇ M) using real-time PCR.
  • Figures 3a and 3b are images and graphs analyzing the activation level of microglia induced by inflammation by LPS following selexipag treatment through immunofluorescence staining (anti-Iba-1 antibody) (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 4a and 4b are images and graphs analyzing the activation level of astrocytes induced by inflammation by LPS following selexipag treatment through immunofluorescence staining (anti-GFAP antibody) (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 5a and 5b are images and graphs analyzing the level of inhibition of COX-2 expression induced by LPS according to selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 6a and 6b are images and graphs analyzing the level of inhibition of IL-6 expression induced by LPS according to selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 7a and 7b are images and graphs analyzing the level of inhibition of IL-1 ⁇ expression induced by LPS according to selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 8a and 8b are images and graphs analyzing the level of inhibition of TNF- ⁇ expression induced by LPS according to selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 9a and 9b are images and graphs analyzing the level of inhibition of NLRP3 expression induced by LPS according to selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 10a and 10b are images and graphs analyzing the level of inhibition of CDK6 expression induced by LPS according to selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 11a, 11b, and 11c are images and graphs analyzing the level of amyloid plaques (CA1: Cornu Ammonis 1) in an amyloid-overexpressing dementia animal model (5xFAD) treated with selexipag by immunofluorescence staining.
  • CA1 Cornu Ammonis 1
  • Figures 12a, 12b, and 12c are images and graphs analyzing the expression level of IDE in amyloid-overexpressing dementia animals (5xFAD) treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 13a and 13b are images and graphs analyzing the activity level of microglial cells through immunofluorescence staining (anti-Iba-1 antibody) in amyloid-overexpressing dementia animals (5xFAD) treated with Selexipag (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 14a and 14b are images and graphs analyzing the expression level of GFAP through immunofluorescence staining in amyloid-overexpressing dementia animals (5xFAD) treated with selexipag (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 15a and 15b are images and graphs analyzing the expression level of IL-1 ⁇ in amyloid-overexpressing dementia animals (5xFAD) treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 16a and 16b are images and graphs analyzing the level of NLRP3 expression inhibition in amyloid-overexpressing dementia animals (5xFAD) treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 17a and 17b are images and graphs analyzing the degree of tau hyperphosphorylation in tau overexpressing dementia animals (PS19) treated with selexipag through immunofluorescence staining using AT8 antibody (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 18a and 18b are images and graphs analyzing the degree of tau hyperphosphorylation in tau overexpressing dementia animals (PS19) treated with selexipag through immunofluorescence staining using AT180 antibody (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 19a and 19b are images and graphs analyzing the level of expression of tau kinase DYRK1A in tau overexpressing dementia animals (PS19) treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 20a and 20b are images and graphs analyzing the level of p-CDK5 expression of tau kinase in an Alzheimer's disease animal model (PS19) treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • LPS (Sigma, Cat no: L2630, Escherichia coli) reagent was dissolved in PBS and used for in vivo experiments. To induce central nervous system immune responses including neuroinflammation in in vivo experiments, 10 mg/kg of LPS was treated at 8-hour intervals.
  • selexipag (Invivochem, Cat no: V8461, Libertyville, IL, USA) was dissolved in DMSO (dimethyl sulfoxide) and used for in vitro experiments, and was dissolved in vehicle (saline solution containing 1% DMSO) and used for in vivo experiments.
  • BV2 microglial cells obtained from Dr. Kyung-Ho Suk were cultured in high-glucose DMEM (Invitrogen, Carlsbad, CA, USA) medium containing 5% fetal bovine serum (FBS, Invitrogen), 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin. Cultures were performed in an incubator maintained at 5% CO 2 and 37°C.
  • Wild-type C57BL6 mice male, 8 weeks old were housed in a pathogen-free condition at 22 ⁇ 2°C, 50 ⁇ 5% humidity, and a 12-h light/dark cycle with free access to food and water.
  • the mice were randomly assigned to three experimental groups: control (Veh), LPS treatment (LPS), and 1 mg/kg selexipag plus LPS treatment (Sel+LPS).
  • Selexipag (1 mg/kg) or vehicle (1% DMSO in saline) was administered intraperitoneally (i.p.) daily for 7 days. On day 7, 30 min after the final administration, 10 mg/kg LPS or PBS was administered intraperitoneally, and 8 h later, the mice were perfused and fixed with PBS and 4% paraformaldehyde, respectively.
  • mice which are animal models of Alzheimer's disease, with amyloid overexpression
  • PS19 mice which are tau overexpression, with dementia
  • the mice were housed under pathogen-free conditions of 22 ⁇ 2°C, 50 ⁇ 5% humidity, and a 12-h light/dark cycle with free access to food and water.
  • the mice were randomly assigned to two experimental groups: control (Veh) and 1 mg/kg selexipag.
  • the mice in each experimental group were intraperitoneally (i.p.) administered selexipag (1 mg/kg) or vehicle (1% DMSO in saline) daily for 14 days. On the 14th day, 2 hours after the final administration, the mice were perfused and fixed with PBS and 4% paraformaldehyde, respectively.
  • brain tissues stored in 4% paraformaldehyde for 24 h at 4°C were immersed in PBS containing 30% sucrose for 72 h and then sectioned to 30 ⁇ m thickness using a cryostat (Leica CM1850, Wetzlar, Germany). Brain sections were blocked with 10% normal goat serum (Vector Laboratories, Burlingame, CA, USA) for 2 h at room temperature and then immunostained with primary antibodies overnight at 4°C. Brain sections were then washed with PBST buffer and reacted with Alexa 594- or Alexa 488-conjugated secondary antibodies for 2 h at room temperature.
  • BV2 microglial cells were treated with vehicle or selexipag at various concentrations (1, 5, 10, 25, or 50 ⁇ M) for 24 h, and the cell viability of selexipag at various concentrations was analyzed.
  • BV2 microglial cells were first cultured in FBS-free medium in 96-well plates (2 ⁇ 10 5 cells/well) for 1 h, and then treated with selexipag at various concentrations (1, 5, 10, 25, and 50 ⁇ M) for 24 h, or a group treated with 1% DMSO (vehicle) was used as a control. The cells were then cultured with MTT solution for 2 h, and then treated with DMSO to dissolve the formazan product. After 20 min, the absorbance was measured at 570 nm (reference wavelength 660 nm) using a SPECTROstar Nano microplate reader (BMG Labtech, Germany). The results are shown in Figure 1.
  • Figure 1 is a graph analyzing the cytotoxicity of microglial BV2 cells according to the treatment concentration of Selexipag using an MTT assay.
  • Example 2 Reduced levels of LPS-induced proinflammatory cytokines by selexipag in BV2 microglia
  • LPS Lipopolysaccharid
  • BV2 microglial cells were treated with selexipag (1 ⁇ M, 5 ⁇ M) or 1% DMSO (vehicle) for 30 min and then treated with 200 ng/mL LPS or PBS for 5.5 h, and then the expression levels of proinflammatory cytokines COX-2, IL-1 ⁇ , IL-6, and TNF- ⁇ were analyzed by real-time PCR.
  • cDNA synthesized with Superscript cDNA Premix Kit II was analyzed by real-time PCR at 40 cycles using Fast SYBR Green Master Mix (Thermo Fisher Scientific, CA, USA) and QuantStudio 5 system (Thermo Fisher Scientific). The values were normalized to the cycle threshold (Ct) value of GAPDH (housekeeping gene). The fold change in the LPS-only treatment group and the LPS and selexipag co-treatment group was calculated based on the control group (vehicle treatment). The results are shown in Figures 2a and 2b.
  • Figures 2a and 2b are graphs showing the expression levels of proinflammatory cytokines in BV2 microglia induced by LPS following selexipag treatment ((a) 1 ⁇ M and (b) 5 ⁇ M) using real-time PCR.
  • mice 8-week-old wild-type mice were intraperitoneally administered selexipag (1 mg/kg) or vehicle daily for 7 days, and on day 7, LPS (10 mg/kg) or PBS was intraperitoneally administered 30 minutes after the intraperitoneal administration of selexipag or vehicle. Then, 8 hours after the LPS injection, brain sections obtained from the mice were subjected to immunofluorescence staining with anti-Iba-1 (Wako, 019-19741, 1:500, rabbit) or anti-GFAP antibody (Invitrogen, 13-0300, 1:500, rat) according to the method described in the experimental methods above. The results are shown in Figures 3a and 3b and Figures 4a and 4b, respectively.
  • Figures 3a and 3b are images and graphs analyzing the activation level of microglia induced by inflammation by LPS following selexipag treatment through immunofluorescence staining (Iba-1 antibody) (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 4a and 4b are images and graphs analyzing the activation level of astrocytes induced by inflammation by LPS following selexipag treatment through immunofluorescence staining (GFAP antibody) (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • mice 8-week-old wild-type mice were intraperitoneally administered selexipag (1 mg/kg) or vehicle daily for 7 days, and on day 7, LPS (10 mg/kg) or PBS was intraperitoneally administered 30 minutes after the intraperitoneal administration of selexipag or vehicle. Then, 8 hours after LPS injection, immunofluorescence staining of the isolated brain sections from the mice was performed with anti-COX-2 (Abcam, ab15191, 1:200, rabbit) or anti-IL-6 antibody (Santa Cruz, SC57315, 1:50, mouse). The results are shown in Figs. 5a and 5b and 6a and 6b.
  • Figures 5a and 5b are images and graphs analyzing the level of inhibition of COX-2 expression induced by LPS according to selexipag treatment by immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 6a and 6b are images and graphs analyzing the level of inhibition of IL-6 expression induced by LPS according to selexipag treatment by immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • mice 8-week-old wild-type mice were intraperitoneally administered selexipag (1 mg/kg) or vehicle daily for 7 days, and on day 7, LPS (10 mg/kg) or PBS was intraperitoneally administered 30 minutes after the intraperitoneal administration of selexipag or vehicle. Then, 8 hours after LPS injection, immunofluorescence staining of the isolated brain sections from the mice was performed with anti-IL-1 ⁇ (Abcam, ab9722, 1:200, rabbit) or anti-TNF- ⁇ antibody (Novus, NBP-19532, 1:200, rabbit). The results are shown in Figures 7a and 7b and Figures 8a and 8b , respectively.
  • Figures 7a and 7b are images and graphs analyzing the level of inhibition of IL-1 ⁇ expression induced by LPS according to selexipag treatment using immunofluorescence staining.
  • Figures 8a and 8b are images and graphs analyzing the level of inhibition of TNF- ⁇ expression induced by LPS according to Selexipak treatment using immunofluorescence staining.
  • mice 8-week-old wild-type mice were intraperitoneally administered selexipag (1 mg/kg) or vehicle daily for 7 days, and on day 7, LPS (10 mg/kg) or PBS was intraperitoneally administered 30 minutes after the intraperitoneal administration of selexipag or vehicle. Then, 8 hours after LPS injection, brain tissue sections isolated from the mice were immunofluorescently stained with anti-NLRP3 antibody (Novus, NBP-12446, 1:500, rabbit) or anti-CDK6 antibody (Invitrogen, PA5-27978, 1:200, rabbit). The results are shown in Figs. 9a and 9b and 10a and 10b.
  • Figures 9a and 9b are images and graphs analyzing the level of inhibition of NLRP3 expression induced by LPS according to selexipag treatment using immunofluorescence staining.
  • Figures 10a and 10b are images and graphs analyzing the level of inhibition of CDK6 expression induced by LPS according to selexipag treatment using immunofluorescence staining.
  • Example 7 Reduction of amyloid plaques by selexipag in amyloid-overexpressing dementia animals
  • selexipag 3-4 month old Alzheimer's disease animal model mice (5xFAD) were intraperitoneally administered selexipag (1 mg/kg) or vehicle daily for 14 days, and selexipag was administered on the 14th day. After 2 hours, immunofluorescence staining was performed using anti-6E10 antibody (Biolegend, 803002, 1:500, mouse), and the results are shown in Figs. 11a, 11b, and 11c.
  • Figures 11a, 11b, and 11c are images and graphs analyzing the level of amyloid plaques (6E10) in amyloid-overexpressing animals treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1).
  • Example 8 Increased expression of amyloid beta-degrading enzyme IDE by selexipag in amyloid-overexpressing animals
  • selexipag (1 mg/kg) or vehicle was administered intraperitoneally daily for 14 days to 3-4 month-old amyloid-overexpressing animals (5xFAD), and on the 14th day, 2 hours after selexipag administration, brain sections obtained from the mice were subjected to immunofluorescence staining using IDE antibody (Abcam, ab32216, 1:200, rabbit). The results are shown in Figures 12a, 12b, and 12c.
  • Figures 12a, 12b, and 12c are images and graphs analyzing the expression level of IDE in amyloid-overexpressing animals treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • selexipag may reduce amyloid plaques by increasing the expression of IDE, an amyloid beta-degrading enzyme, in amyloid-overexpressing animals.
  • selexipag (1 mg/kg) or vehicle was administered intraperitoneally daily for 14 days to 3-4 month-old amyloid-overexpressing animals (5xFAD), and on the 14th day, 2 hours after selexipag administration, brain sections obtained from the mice were subjected to immunofluorescence staining using Iba-1 (Wako, 019-19741, 1:500, rabbit) or GFAP antibody (Invitrogen, 13-0300, 1:500, rat). The results are shown in Figures 13a and 13b and Figures 14a and 14b, respectively.
  • Figures 13a and 13b are images and graphs analyzing the activity level of microglial cells in amyloid-overexpressing animals treated with selexipag through immunofluorescence staining (Iba-1 antibody) (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 14a and 14b are images and graphs analyzing the activity level of astrocytes in amyloid-overexpressing animals treated with selexipag through immunofluorescence staining (GFAP antibody) (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Selexipag could regulate the activation of microglia and astrocytes in amyloid-overexpressing animals, and in particular, it could improve and alleviate microgliosis and astrogliosis by inhibiting microglia and astrocyte activation in amyloid-overexpressing animals.
  • Example 10 Reduction of IL-1 ⁇ and NLRP3 expression levels by selexipag in amyloid-overexpressing animals
  • selexipag (1 mg/kg) or vehicle was administered intraperitoneally daily for 14 days to 3-4 month-old amyloid-overexpressing animals (5xFAD), and on the 14th day, 2 hours after selexipag administration, brain sections obtained from the mice were subjected to immunofluorescence staining using IL-1 ⁇ (Abcam, ab9722, 1:200, rabbit) and NLRP3 (Adipogen, AG-20B-0014-100c, 1:200, mouse) antibodies. The results are shown in Figs. 15a and 15b and Figs. 16a and 16b.
  • IL-1 ⁇ Abcam, ab9722, 1:200, rabbit
  • NLRP3 Adipogen, AG-20B-0014-100c, 1:200, mouse
  • Figures 15a and 15b are images and graphs analyzing the expression level of IL-1 ⁇ , a proinflammatory cytokine, in animals overexpressing amyloid following treatment with selexipag by immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 16a and 16b are images and graphs analyzing the expression level of NLRP3 inflammasome in animals overexpressing amyloid following selexipag treatment through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Example 11 Reduction of expression levels of AT8 and AT180, indicators of tau hyperphosphorylation, by selexipag in tau overexpressing animals
  • selexipag (1 mg/kg) or vehicle was administered intraperitoneally daily for 14 days to 3-4 month-old tau-overexpressing animals (PS19), and on the 14th day, 2 hours after selexipag administration, brain sections obtained from the mice were subjected to immunofluorescence staining with anti-AT8 (Invitrogen, mn1020, 1:200, mouse) and anti-AT180 (Invitrogen, mn1040, 1:200, mouse) according to the method described in the experimental method. The results are shown in Figs. 17a and 17b and Figs. 18a and 18b.
  • Figures 17a and 17b are images and graphs analyzing the expression level of AT8, an indicator of tau hyperphosphorylation, through immunofluorescence staining in tau overexpressing animals treated with selexipag (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 18a and 18b are images and graphs analyzing the expression level of AT180, an indicator of tau hyperphosphorylation, in tau overexpressing animals treated with selexipag through immunofluorescence staining (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Example 12 Reduction in the expression levels of DYRK1A and p-CDK5, tau kinases, by selexipag in tau overexpressing animals
  • selexipag (1 mg/kg) or vehicle was administered intraperitoneally daily for 14 days to 3-4 month-old tau-overexpressing animals (PS19), and on the 14th day, 2 hours after selexipag administration, brain sections obtained from the mice were subjected to immunofluorescence staining with anti-DYRK1A (Abcam, ab180910, 1:200, rabbit) and anti-p-CDK5 (LSbio, LS-c354604-100, 1:200, rabbit) according to the method described in the experimental method. The results are shown in Figs. 19a and 19b and Figs. 20a and 20b.
  • Figures 19a and 19b are images and graphs analyzing the expression level of DYRK1A, a tau kinase, through immunofluorescence staining in tau overexpressing animals treated with selexipag (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Figures 20a and 20b are images and graphs analyzing the expression level of p-CDK5, a tau kinase, through immunofluorescence staining in a tau overexpression animal model following selexipag treatment (CA1: Cornu Ammonis 1, DG: Dentate Gyrus).
  • Selexipag inhibits the expression and production of proinflammatory or inflammatory cytokines in brain tissue induced by LPS, inhibits the activity of microglia or astrocytes, and inhibits NLRP3 inflammasome activity and CDK6 expression.
  • glutamate-overexpressing animals 5xFAD
  • it inhibits amyloid plaques and increases the expression of amyloid beta-degrading enzyme IDE
  • IDE amyloid beta-degrading enzyme
  • it inhibits the expression and production of proinflammatory cytokines, and inhibits the activity of microglia or astrocytes.
  • tau hyperphosphorylation and the expression of tau kinase in tau-overexpressing animals (PS19) administered Selexipag may be useful as a new therapeutic agent for the prevention or treatment of degenerative brain diseases.

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement de maladies cérébrales dégénératives, comprenant du sélexipag ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif. La sélexipag inhibe l'expression et la production de cytokines pro-inflammatoires ou inflammatoires dans le tissu cérébral, inhibe l'activité de la microglie ou des astrocytes, inhibe l'activité de l'inflammasome NLRP3 et l'expression de CDK6, réduit les plaques amyloïdes, augmente l'expression de l'enzyme IDE de dégradation de bêta-amyloïde, et inhibe l'hyperphosphorylation de la protéine tau et l'expression de la tau kinase, et peut ainsi être efficacement utilisée en tant que nouvel agent thérapeutique pour la prévention ou le traitement de maladies cérébrales dégénératives, de troubles cognitifs, de handicaps d'apprentissage ou de troubles de la mémoire.
PCT/KR2024/009678 2023-07-06 2024-07-08 Composition pharmaceutique pour la prévention ou le traitement de maladies cérébrales dégénératives comprenant du sélexipag Ceased WO2025009945A1 (fr)

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