WO2022114691A1 - Composition pour la prévention ou le traitement de l'épilepsie comprenant de la gintonine en tant que principe actif - Google Patents

Composition pour la prévention ou le traitement de l'épilepsie comprenant de la gintonine en tant que principe actif Download PDF

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WO2022114691A1
WO2022114691A1 PCT/KR2021/017130 KR2021017130W WO2022114691A1 WO 2022114691 A1 WO2022114691 A1 WO 2022114691A1 KR 2021017130 W KR2021017130 W KR 2021017130W WO 2022114691 A1 WO2022114691 A1 WO 2022114691A1
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gintonin
epilepsy
preventing
pharmaceutical composition
active ingredient
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PCT/KR2021/017130
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English (en)
Korean (ko)
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조익현
최종희
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경희대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/185—Vegetable proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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 composition for preventing, improving or treating epilepsy comprising gintonin as an active ingredient.
  • epilepsy epilepsy
  • epilepsy a very common neurological disease
  • antiepileptic drugs levetiracetam, etc.
  • Temporal lobe epilepsy is the most common type of epilepsy in adults. Sclerosis of the medial temporal lobe, especially the hippocampus (hippocampal sclerosis, the most common cause), and tumors of the medial temporal lobe (cancer) , stroke, vascular malformations, cortical dysplasia, infection, etc. can be the cause. Symptoms include complex partial seizures (the most common), epigastric aura, and automatism. However, it is known that the therapeutic effect of antiepileptic drugs is poor compared to other focal epilepsy, and there is no innovative preventive or therapeutic agent yet.
  • temporal lobe epilepsy is induced in animals with pilocarpine, kainic acid, and kindling.
  • kainic acid cainic acid, KA
  • KA-induced epileptic seizures histopathologically similar to the characteristics of human temporal lobe epilepsy, hippocampal neuronal destruction and astrocyte activation appear.
  • Ginseng has been generally used as a tonic for longevity/life extension, or as an adaptogen (adaptogenic agent) to fight various stresses, fatigue, diseases, cancer, and diabetes.
  • improve Ginseng has been used as a tonic or adaptogen for over a thousand years not only in Korea but also in China and Japan.
  • ginseng is one of the most famous medicinal herbs consumed in the world.
  • ginseng saponins a component of ginseng
  • ginseng saponins a component of ginseng
  • Gintonin is a novel glycolipoproteins composed of sugar, fat and protein among the components of ginseng (Korea Patent No. 10-0973202), and the previously known ginseng saponin (ginseno Side), it has been found that its activity appears through the membrane signal transducton pathway through interaction with a cell membrane protein that has not yet been identified/identified.
  • treatment with gintonin in mouse EAT (Ehrlich Ascites Tumor) cells is similar to the signaling pathway that occurs when G protein coupled receptors (GPCRs or 7TM receptors) are activated, phospholipase C, PLC), it temporarily induces an increase in intracytoplasmic free Ca 2+ (Free Ca 2+ ), and when treated with Xenopus oocytes, it is not sensitive to pertussis toxin (PTX).
  • GPCRs or 7TM receptors G protein coupled receptors
  • PLC phospholipase C
  • Non-G protein ⁇ PLC phospholipase C
  • IP3 inositol 1,4,5-triphosphate
  • Ca 2+ activated calcium-dependent chlorine ion channel
  • ER endoplasmic reticulum
  • CaCC calcium reservoir Chloride Channel
  • the present inventors found that gintonin significantly reduces the degree of epilepsy in an animal model of temporal lobe epilepsy induced by kainic acid (KA), and in the hippocampus (CA3) region. It was confirmed that there was an effect of remarkably reducing the neuronal cell death, the activation level of microglia and astrocytes, and the expression level of COX-2 and iNOS. The present invention was completed by confirming that it can be used as a new preventive or therapeutic agent.
  • KA kainic acid
  • CA3 hippocampus
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating epilepsy.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving epilepsy.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating damage and death of nerve cells caused by kainic acid.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving nerve cell damage and death caused by caic acid.
  • the present invention provides a pharmaceutical composition for preventing or treating epilepsy comprising gintonin as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving epilepsy comprising gintonin as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating damage and death of nerve cells caused by kainic acid containing gintonin as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving nerve cell damage and death caused by caic acid containing gintonin as an active ingredient.
  • the gintonin of the present invention reduces seizure behavior in an animal model of temporal lobe epilepsy in which excitatory neuronal cell death is induced by kainic acid, hippocampal neuronal cell death, and activation of microglia and astrocytes. And since it has an effect of significantly inhibiting the expression of COX-2 and iNOS, which are representative inflammatory mediators, the composition comprising gintonin of the present invention may be useful as a composition for preventing, treating or improving epilepsy.
  • FIG. 1 shows the inhibitory effect of gintonin (GT) on seizure behavior in an animal model of epilepsy caused by kainic acid (KA).
  • Figure 1A shows the oral administration of gintonin (GT, 50 and 100 mg/kg) 2 hours before the administration of caic acid (KA, 55 mg/kg, ip), and the time flow for 2 hours after KA administration It is a graph showing the results of measuring the severity of seizures;
  • 1B is a graph showing the sum of seizure grades between 5-120 minutes after KA administration for each group;
  • 1C shows that Ki16425 (30 mg/kg) was intraperitoneally administered 2.5 hours before KA (55 mg/kg, ip), and gintonin (100 mg/kg) was orally administered 2 hours before, KA administration It is a graph showing the results of measuring the seizure severity over time for 2 hours;
  • 1D is a graph showing the sum of seizure grades between 5-120 minutes after KA administration for each group (ANOVA test; * P ⁇
  • Figure 2 shows the protective effect of gintonin against hippocampal neuronal cell death in an animal model of epilepsy caused by KA.
  • FIG. 3 is a graph showing the inhibitory effect of gintonin on immune cell activity and immune mediators in an animal model of epilepsy caused by KA.
  • FIG. 3A shows that gintonin (100 mg/kg) was orally administered 2 hours before KA (0.2 ⁇ g/4 ⁇ l) was directly injected into the brain, and Iba-1 as a frozen section of the hippocampus 72 hours after KA administration.
  • 3B is a graph showing the results of Western blot analysis on the expression of the Iba-1 and GFAP proteins
  • 3C is a graph showing the quantified value of the degree of immune response of Iba-1 (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group)
  • 3D is a graph showing the quantified value of the degree of immune response of the GFAP (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group).
  • FIG. 4 shows the inhibitory effect of gintonin on the expression of inflammatory mediators in an animal model of epilepsy caused by KA.
  • FIG. 4A shows that gintonin (100 mg/kg) was orally administered 2 hours before KA (0.2 ⁇ g/4 ⁇ l) was directly injected into the brain, and the hippocampus tissue was taken 72 hours after KA administration to COX-2 and western blot analysis of iNOS protein expression (ANOVA test; # P ⁇ 0.05 vs Sham group; * P ⁇ 0.05 vs KA group);
  • Figure 4B is a graph showing the quantified value of the expression level of the iNOS protein; 4C is a graph showing the quantified value of the expression level of the iNOS protein (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group).
  • the present invention provides a pharmaceutical composition for preventing or treating epilepsy comprising gintonin as an active ingredient.
  • the gintonin may be a glycolipoprotein extracted and isolated from ginseng (Patent Registration No. 10-0973202) provided and used.
  • the epilepsy may be temporal lobe epilepsy, and the temporal lobe epilepsy may be caused by excitatory neuronal cell death.
  • the gintonin may inhibit convulsive seizures caused by epilepsy.
  • seizure behavior was increased in an animal model of temporal lobe epilepsy in which excitatory neuronal cell death was induced by kainic acid, and these seizure behaviors were suppressed and improved upon treatment with gintonin. It was confirmed that there is an effect (see Experimental Example 1).
  • the gintonin exhibits an epilepsy preventing or therapeutic effect by inhibiting any one or more symptoms selected from the group consisting of hippocampal neuronal cell death, immune cell activity increase, sclerosis, and inflammation.
  • the hippocampus may be one or more of the CA1 region and the CA3 region
  • the immune cells may be one or more of the microglia and astrocytes.
  • the gintonin of the present invention prevents epilepsy by inhibiting any one or more symptoms selected from the group consisting of neuronal cell death, microglia activity increase, astrocyte activity increase, sclerosis, and inflammation of the CA3 region of the hippocampus. Or it may be to show a therapeutic effect.
  • gintonin has a protective effect on apoptosis of hippocampal neurons in an animal model of caic acid-induced temporal lobe epilepsy, an effect of reducing immune cell activity such as microglia and astrocytes, and an inflammatory mediator It was confirmed that there is an effect of suppressing the expression of (see Experimental Examples 2 to 4).
  • the gintonin prevents or treats epilepsy by inhibiting the production or increase in expression of any one or more selected from the group consisting of Iba-1, GFAP, COX-2 and iNOS in the hippocampus.
  • the hippocampus may be at least one of a CA1 region and a CA3 region.
  • it may be to show an effect of preventing or treating epilepsy.
  • gintonin reduces immune cell activity through inhibition of Iba-1 (ionized calcium binding adapter molecule 1) and glial fibrillary acidic protein (GFAP) expression, and COX-2 (cyclooxygenase-2) and It was confirmed that by suppressing iNOS (inducible nitric oxide) expression, it was possible to alleviate epilepsy-related symptoms such as neuronal cell death, microglia activity increase, astrocyte activity increase, sclerosis, and inflammation (see Experimental Examples 3 to 4). .
  • Iba-1 ionized calcium binding adapter molecule 1
  • GFAP glial fibrillary acidic protein
  • COX-2 cyclooxygenase-2
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not normally cause allergic reactions or similar reactions such as gastrointestinal disorders, dizziness, etc., when administered to humans.
  • Pharmaceutically acceptable carriers include, for example, carriers for oral administration such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like, and water, suitable oils, saline, aqueous glucose and glycols for parenteral administration. and a carrier, and may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • the pharmaceutical composition according to the present invention may be formulated in a suitable form according to a method known in the art together with a pharmaceutically acceptable carrier as described above. That is, the pharmaceutical composition of the present invention can be prepared in various parenteral or oral administration forms according to known methods. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention and at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
  • the pharmaceutical composition may further include a carrier, excipient or diluent.
  • Carriers, excipients, or diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • administration means introducing a predetermined substance to an individual by an appropriate method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue.
  • Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration may be administered intrarectally, but is not limited thereto.
  • the term “individual” refers to all animals including humans, rats, mice, and livestock. Preferably, it may be a mammal including a human.
  • the term "pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's gender and age. , body weight, health condition, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other medical fields It can be easily determined by a person skilled in the art according to factors well known in Generally, it is about 0.001 to 100 mg/kg/day, and preferably 0.01 to 35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and the recommended dosage may be administered once a day, or several times. It may be administered in divided doses.
  • composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of epilepsy.
  • the present invention provides a pharmaceutical composition for preventing or treating epilepsy, comprising gintonin as an active ingredient, and for reducing convulsive seizures in patients with epilepsy induced by excitatory neuronal cell death.
  • the present invention provides a pharmaceutical composition for preventing or treating epilepsy, comprising gintonin as an active ingredient, and for reducing excitatory neuronal cell death in the hippocampus.
  • the present invention contains gintonin as an active ingredient, and for reducing the activity of microglia and astrocytes in patients with increased activity of microglia and astrocytes in the hippocampus, for preventing or treating epilepsy Provides an enemy composition.
  • the present invention includes gintonin as an active ingredient, and the production of Iba-1, GFAP, COX-2 and iNOS in patients with increased production or expression of Iba-1, GFAP, COX-2 and iNOS in the hippocampus Or for reducing the expression, it provides a pharmaceutical composition for preventing or treating epilepsy.
  • the patient may be a human or an animal.
  • epilepsy Health functional food composition for prevention or improvement
  • the present invention provides a health functional food composition for preventing or improving epilepsy comprising gintonin as an active ingredient.
  • health functional food used in the present invention refers to food manufactured and processed in the form of tablets, capsules, pills, liquids, powders and granules, etc. using raw materials or ingredients useful for the human body.
  • 'functionality' refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body.
  • the health functional food of the present invention can be manufactured by a method commonly used in the ordinary technical field, and at the time of the preparation, it can be prepared by adding raw materials and components commonly added in the conventional technical field.
  • the dosage form of the health functional food may also be manufactured without limitation as long as it is a dosage form recognized as a health functional food.
  • the health functional food composition of the present invention can be prepared in various types of dosage forms, and unlike general drugs, it uses food-derived ingredients as raw materials and has the advantage of not having side effects that may occur during long-term administration of the drug, and has excellent portability.
  • the health functional food of the present invention can be ingested as an adjuvant to enhance the effect of the epilepsy therapeutic agent.
  • the present invention provides a health food composition for preventing or improving epilepsy comprising gintonin as an active ingredient.
  • the epilepsy may be temporal lobe epilepsy, and the temporal lobe epilepsy may be caused by excitatory neuronal cell death.
  • the gintonin may inhibit convulsive seizures caused by epilepsy.
  • seizure behavior was increased in an animal model of temporal lobe epilepsy in which excitatory neuronal cell death was induced by kainic acid, and these seizure behaviors were suppressed and improved upon treatment with gintonin. It was confirmed that there is an effect (see Experimental Example 1).
  • the gintonin prevents epilepsy or It may indicate an improvement effect.
  • the hippocampus may be one or more of the CA1 region and the CA3 region
  • the immune cells may be one or more of the microglia and astrocytes.
  • the gintonin of the present invention prevents epilepsy by inhibiting any one or more symptoms selected from the group consisting of neuronal cell death, microglia activity increase, astrocyte activity increase, sclerosis, and inflammation of the CA3 region of the hippocampus. Or it may show an improvement effect.
  • gintonin has a protective effect on apoptosis of hippocampal neurons in an animal model of caic acid-induced temporal lobe epilepsy, an effect of reducing immune cell activity such as microglia and astrocytes, and an inflammatory mediator It was confirmed that there is an effect of suppressing the expression of (see Experimental Examples 2 to 4).
  • the gintonin is selected from the group consisting of Iba-1, GFAP, COX-2 and iNOS of the hippocampus by inhibiting the production or increase in expression of any one or more It may be to show a preventive or ameliorating effect.
  • the hippocampus may be at least one of a CA1 region and a CA3 region.
  • it may be to exhibit an effect of preventing or improving epilepsy.
  • gintonin reduces immune cell activity through inhibition of Iba-1 (ionized calcium binding adapter molecule 1) and glial fibrillary acidic protein (GFAP) expression, and COX-2 (cyclooxygenase-2) and It was confirmed that by suppressing iNOS (inducible nitric oxide) expression, it was possible to alleviate epilepsy-related symptoms such as neuronal cell death, microglia activity increase, astrocyte activity increase, sclerosis, and inflammation (see Experimental Examples 3 to 4). .
  • Iba-1 ionized calcium binding adapter molecule 1
  • GFAP glial fibrillary acidic protein
  • COX-2 cyclooxygenase-2
  • the health functional food composition or health food composition according to the present invention can be added to health functional food or health food such as food and beverage for the purpose of preventing or improving related diseases through the prevention or improvement effect of epilepsy.
  • Examples of foods to which gintonin according to the present invention can be added include drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream , various soups, beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and includes both health food and health functional food in the ordinary sense.
  • the health food and health functional food composition according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the gintonin according to the present invention may be suitably determined according to the purpose of its use (for prevention or improvement).
  • the amount of gintonin in health food and health functional food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food.
  • the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.
  • the health food and health functional food composition of the present invention is not particularly limited in other ingredients except for containing the gintonin according to the present invention as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates are added like a conventional beverage. It can contain as an ingredient.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the dietary supplement of the present invention.
  • health food and health functional food composition containing gintonin are various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate) etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the health food and health functional food composition of the present invention may contain natural fruit juice, fruit juice, and fruit for the production of a vegetable drink.
  • These components may be used independently or in combination.
  • the proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.
  • the present invention provides a health functional food composition for preventing or improving epilepsy, comprising gintonin as an active ingredient, and for reducing convulsive seizures in epilepsy patients induced by excitatory neuronal cell death.
  • the present invention provides a health functional food composition for preventing or improving epilepsy, comprising gintonin as an active ingredient, and for reducing excitatory neuronal cell death in the hippocampus.
  • the present invention includes gintonin as an active ingredient, and for reducing the activity of microglia and astrocytes in patients with increased activity of microglia and astrocytes in the hippocampus, for preventing or improving epilepsy health
  • gintonin as an active ingredient, and for reducing the activity of microglia and astrocytes in patients with increased activity of microglia and astrocytes in the hippocampus, for preventing or improving epilepsy health
  • gintonin as an active ingredient
  • the present invention includes gintonin as an active ingredient, and the production of Iba-1, GFAP, COX-2 and iNOS in patients with increased production or expression of Iba-1, GFAP, COX-2 and iNOS in the hippocampus Or for reducing the expression, it provides a health functional food composition for preventing or improving epilepsy.
  • the present invention provides a pharmaceutical composition for preventing or treating damage and death of nerve cells caused by kainic acid containing gintonin as an active ingredient.
  • the damage and death of the nerve cells may be excitatory nerve cell death of the hippocampus induced by caic acid.
  • the pharmaceutical composition may be to prevent or treat a disease caused by damage and death of nerve cells caused by caic acid.
  • the disease may be epilepsy, preferably temporal lobe epilepsy.
  • the gintonin may have an effect of inhibiting convulsive seizures caused by epilepsy induced by caic acid.
  • the gintonin may have an effect of inhibiting any one or more symptoms selected from the group consisting of cainic acid-induced hippocampal neuronal cell death, immune cell activity increase, sclerosis, and inflammation.
  • the gintonin may have an effect of inhibiting the production or increase in expression of any one or more selected from the group consisting of Iba-1, GFAP, COX-2 and iNOS in the hippocampus.
  • seizure behavior is increased in an animal model of temporal lobe epilepsy in which excitatory neuronal cell death is induced by caic acid, and gintonin treatment has the effect of suppressing and improving the seizure behavior was confirmed (see Experimental Example 1).
  • gintonin exhibits a protective effect against apoptosis of hippocampal neurons in an animal model of caic acid-induced temporal lobe epilepsy (see Experimental Example 2).
  • gintonin inhibits the expression of ionized calcium binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) induced by caic acid, and cyclooxygenase-2 (COX-2) and It was confirmed that by suppressing iNOS (inducible nitric oxide) expression, it was possible to alleviate epilepsy-related symptoms such as neuronal cell death, increased activity of immune cells, microglia and astrocytes, sclerosis, and inflammation (Experimental Examples 3 to 4) Reference).
  • Iba-1 ionized calcium binding adapter molecule 1
  • GFAP glial fibrillary acidic protein
  • COX-2 cyclooxygenase-2
  • the present invention provides a health functional food composition for preventing or improving nerve cell damage and death caused by caic acid containing gintonin as an active ingredient.
  • the damage and death of the nerve cells may be excitatory nerve cell death of the hippocampus induced by caic acid.
  • the health functional food composition may be to prevent or improve diseases caused by damage and death of nerve cells caused by caic acid.
  • the disease may be epilepsy, preferably temporal lobe epilepsy.
  • the gintonin may have an effect of inhibiting convulsive seizures caused by epilepsy induced by caic acid.
  • the gintonin may have an effect of inhibiting any one or more symptoms selected from the group consisting of cainic acid-induced hippocampal neuronal cell death, immune cell activity increase, sclerosis, and inflammation.
  • the gintonin may have an effect of inhibiting the production or increase in expression of any one or more selected from the group consisting of Iba-1, GFAP, COX-2 and iNOS in the hippocampus.
  • seizure behavior is increased in an animal model of temporal lobe epilepsy in which excitatory neuronal cell death is induced by caic acid, and gintonin treatment has the effect of suppressing and improving the seizure behavior was confirmed (see Experimental Example 1).
  • gintonin exhibits a protective effect against apoptosis of hippocampal neurons in an animal model of caic acid-induced temporal lobe epilepsy (see Experimental Example 2).
  • gintonin inhibits the expression of ionized calcium binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) induced by caic acid, and cyclooxygenase-2 (COX-2) and It was confirmed that by suppressing iNOS (inducible nitric oxide) expression, it was possible to alleviate epilepsy-related symptoms such as neuronal cell death, increased activity of immune cells, microglia and astrocytes, sclerosis, and inflammation (Experimental Examples 3 to 4) Reference).
  • Iba-1 ionized calcium binding adapter molecule 1
  • GFAP glial fibrillary acidic protein
  • COX-2 cyclooxygenase-2
  • the present invention provides a method for preventing or treating epilepsy, comprising administering to a patient the pharmaceutical composition for preventing or treating epilepsy according to the present invention.
  • the treatment method of the present invention comprises administering the pharmaceutical composition to a subject in a therapeutically effective amount.
  • a specific therapeutically effective amount for a particular subject will depend on the type and extent of the response to be achieved, the specific composition, including whether other agents are used, if necessary, the subject's age, weight, general health, sex and diet, time of administration; It is preferable to apply differently depending on various factors including the route of administration and secretion rate of the composition, the duration of treatment, the drug used together with or concurrently with the specific composition, and similar factors well known in the pharmaceutical field. Therefore, it is preferable to determine the effective amount of the composition suitable for the purpose of the present invention in consideration of the foregoing.
  • the patient is applicable to any mammal, and the mammal includes not only humans and primates, but also domestic animals such as cattle, pigs, sheep, horses, dogs and cats.
  • the method for preventing or treating epilepsy of the present invention includes reducing convulsive seizures in patients with epilepsy induced by excitatory neuronal cell death; decrease excitatory neuronal apoptosis in hippocampus; reducing the activity of microglia and astrocytes in patients with increased activity of microglia and astrocytes in the hippocampus; Or by reducing the production or expression of Iba-1, GFAP, COX-2 and iNOS in patients with increased production or expression of Iba-1, GFAP, COX-2 and iNOS in the hippocampus; through epilepsy, preferably It may be a method for preventing or treating temporal lobe epilepsy.
  • Gintonin was prepared according to the method of Choi et al. (Front. Pharmacol. 6;245, 2015). Briefly, 1 kg of 4-year-old ginseng (Korea Ginseng Corporation, Daejeon, Korea) was ground into small pieces (> 3 mm) and refluxed 8 times with 70% fermented ethanol at 80° C. for 8 hours to obtain an extract. The extract was concentrated, and the concentrate (340 g) was dissolved in distilled cold water at a ratio of 1:10, and water precipitation was performed while stored at 4° C. for 24-96 hours.
  • the supernatant and precipitate fractions obtained by the water fractionation (water precipitation method) of the ethanol extract of ginseng were separated through centrifugation (3000 rpm, 20 minutes), and the precipitate was freeze-dried to obtain gintonin.
  • Gintonin was composed of carbohydrates, lipids and ginseng protein, and the proportions of total carbohydrates, lipids and proteins in gintonin were about 30%, 20.2% and 30.3%, respectively, including other minor components.
  • the lipid composition of gintonin based on LC-MS/MS analysis was as follows: fatty acids (7.53% linoleic acid, 2.82% palmitic acid and 1.46% oleic acid); lysophospholipids and phospholipids (0.60%); and phosphoric acid (1.75%).
  • the total lipid content of gintonin is about 14.2%.
  • Qualitative analysis showed that gintonin also contains diacylglycerol and triacylglycerol.
  • mice of C57BL/6 strain were used. The mice were allowed to freely consume water and feed, and were used after being acclimatized to the breeding environment for a week.
  • the temperature of the breeding room was 23 ⁇ 2°C, and the humidity was maintained at 55-60%, and the lights were turned on and off in a 12-hour cycle (07:00 ⁇ 19:00). .
  • the experimental animals were divided into 5-7 animals per group, and gintonin was dissolved in 0.9% saline and administered orally at doses of 50 and 100 mg/kg.
  • Gintonin (GT, 50 and 100 mg/kg) was orally administered (p.o.) 2 hours prior to intraperitoneal injection (i.p.) of caic acid (KA, 55 mg/kg) for inducing excitatory neuronal death in mice (p.o.) did Intraperitoneal injection of KA in mice results in behavior similar to epileptic seizures.
  • the seizure behavior of the mice was measured for about 2 hours, and the scores were scored on a scale of 0 to 6 according to the symptoms as shown in FIG. 1 .
  • FIG. 1A shows seizures over time for 2 hours after administration of caic acid (KA, 55 mg/kg, i.p.) and gintonin (GT, 50 and 100 mg/kg) orally administered 2 hours before administration of caic acid (KA, 55 mg/kg, i.p.) It is a graph showing the result of measuring the degree of
  • gintonin is a ligand of lysophosphatidic acid receptors (LPARs), its antagonist may weaken or disappear the antiepileptic effect of gintonin.
  • Ki16425 an antagonist of LPA; 30 mg/kg
  • gintonin 100 mg/kg was orally administered 2 hours before, the same method as above. was measured for 2 hours after KA administration (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group).
  • 1C shows that Ki16425 (30 mg/kg) was intraperitoneally administered 2.5 hours before KA (55 mg/kg, i.p.) administration, gintonin (100 mg/kg) was orally administered 2 hours before, and KA administration It is a graph showing the results of measuring the seizure severity over time for 2 hours afterward.
  • Figure 1D shows that Ki16425 (30 mg/kg) was administered intraperitoneally 2.5 hours before administration of KA (55 mg/kg, ip), and gintonin (100 mg/kg) was orally administered 2 hours before, each group.
  • KA 55 mg/kg, ip
  • gintonin 100 mg/kg
  • gintonin has a protective effect on hippocampal neuronal apoptosis by KA
  • 2 hours before direct injection of KA into the brain Pre-2h
  • 12 hours after induction of the animal model Post- 12h
  • 36 hours after induction of the animal model Post-36h
  • 60 hours after induction of the animal model Post-60h
  • gintonin 100 mg/kg was orally administered.
  • KA was administered in the lateral ventricle at a concentration of 0.2 ⁇ g/4 ⁇ l (i.c.v.; AP: -2.9, ML: 2.0, DV: -3.8 ) was done.
  • KA i.c.v.
  • each mouse was anesthetized 72 hours later, and samples (brain) samples were collected for histological analysis. Specifically, the mouse was anesthetized, and 4% paraformaldehyde (PFA, paraformaldehyde) was perfused into the heart to fix it, and the brain was extracted. The extracted brain was immersed in 4% PFA and fixed at 4°C for one more day, then changed to 30% sucrose and stored at 4°C for 3 days or more to prevent freeze damage. The hippocampus was cut into 30 ⁇ m thick using a cryosection and stored in PBS.
  • PFA paraformaldehyde
  • a frozen brain section containing the hippocampus cut to a thickness of 30 ⁇ m is placed on a coated slide, dried, and then immersed in 0.5% cresyl violet (pH 3.9) solution for 10-15 minutes for Nissl stain; cresyl violet stain. was implemented.
  • the color was adjusted by immersion in 70% ethanol and 80% ethanol, and when dehydrated in 95% or 100% ethanol, immersed in xylene and then a cover glass was covered.
  • neurons were scored on a scale of 0 - 6 according to the extent of damage or death (0, no damage or death observed; +1, ⁇ 10% damage or death observed; +2, 11-25% damage or death observed; +3, 26-50% damage or death observed; +4, 51-75% damage or death observed; +5, 76-90% damage or death observed; +6, ⁇ 91% cell damage or death observed).
  • Figure 2B shows KA (0.2 ⁇ g/4 ⁇ l) directly into the brain 2 hours before injection (Pre-2h), 12 hours after induction of the animal model (Post-12h), and 36 hours after induction of the animal model. (Post-36h) and 60 hours after induction of the animal model (Post-60h), gintonin (100 mg/kg) was orally administered, and needle staining was performed with frozen sections of the hippocampus 72 hours after KA administration. This is a graph showing the quantified value of the result (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group).
  • the Pre-2h group exhibited a significant inhibitory effect on neuronal cell death in the CA3 region of the hippocampus.
  • KA administration of Sham group (Nor), KA group, Pre-2 h group (KA+GT) and GT group in the same manner as in Experimental Example 2 After 72 hours, frozen sections of hippocampal tissue were subjected to immunohistochemistry and Western blot for Iba-1 and GFAP.
  • the tissue sections were treated in 3% H 2 O 2 for 30 minutes to block endogenous peroxidase. Wash with PBS 3 times for 10 minutes each, and add in a blocking solution (5% normal goat serum, 2% bovine serum albumin, 2% fetal bovine serum and 0.1% triton X-100 in PBS) to reduce non-specific reactions that may occur during immunostaining. The reaction was carried out for 1 hour. After that, each tissue was treated with primary antibody rabbit anti-ionized calcium binding adapter molecule 1 (Iba-1; 1:2,000; WAKO, Japan) or rabbit anti-glial fibrillary acidic protein (GFAP; 1:2,000; DACO, USA). The reaction was carried out for at least 18 hours.
  • Iba-1 primary antibody rabbit anti-ionized calcium binding adapter molecule 1
  • GFAP rabbit anti-glial fibrillary acidic protein
  • the tissue was washed 3 times for 10 minutes with PBS, and then reacted with secondary antibodies such as goat anti-rabbit IgG (Vector, CA, USA) and ABC complex (Vector, CA, USA) for 1 hour each at room temperature. made it After the antigen-antibody reaction has been completed, check color development in a Tris buffer (pH 7.4) solution containing DAB for 3 to 5 minutes, then place the brain tissue on a slide and dry it. After dehydration and clearing, the mounting solution was dropped, the cover glass was sealed, and each immunoreactivity was observed under a microscope.
  • secondary antibodies such as goat anti-rabbit IgG (Vector, CA, USA) and ABC complex (Vector, CA, USA) for 1 hour each at room temperature. made it After the antigen-antibody reaction has been completed, check color development in a Tris buffer (pH 7.4) solution containing DAB for 3 to 5 minutes, then place the brain tissue on a slide and dry it. After dehydration and clearing, the mounting solution was dropped, the
  • the protein of each individual was quantified using the Bradford (Bio-rad, USA) method using the isolated tissue section protein (BSA, bovine serum albumin, sigma, USA). 25 ⁇ g was separated by 10% SDS-PAGE (Sodium Dodecyl Sulfate-polyacrylamide gel electrophoresis) and transferred to a PVDF (polyvinylidene difluoride) membrane (membrane, Gendepot, UK). PVDF membranes were blocked in 5% skimmed milk (BD, USA) for 1 hour. After washing with TBST, the same antibody was diluted 1:1,000 in 3% skim milk, reacted at 4° C.
  • 3B is a graph showing the results of Western blot analysis on the expression of the Iba-1 and GFAP proteins.
  • 3C and 3D are graphs showing quantified values of the immune response levels of Iba-1 and GFAP, respectively (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group).
  • the isolated protein was quantified using the Bradford (Bio-rad, USA) method using bovine serum albumin (BSA, sigma, USA), and 25 ⁇ g of the protein was subjected to 10% SDS-PAGE ( It was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a PVDF (polyvinylidene difluoride) membrane (membrane, Gendepot, UK). PVDF membranes were blocked in 5% skimmed milk (BD, USA) for 1 hour.
  • BSA bovine serum albumin
  • FIG. 4 shows the inhibitory effect of gintonin on the expression of inflammatory mediators in an animal model of epilepsy caused by KA.
  • FIG. 4A shows that gintonin (100 mg/kg) was orally administered 2 hours before KA (0.2 ⁇ g/4 ⁇ l) was directly injected into the brain, and the hippocampus tissue was taken 72 hours after KA administration to COX-2 and western blot analysis for iNOS protein expression (ANOVA test; # P ⁇ 0.05 vs Sham group (Nor); * P ⁇ 0.05 vs KA group);
  • Figure 4B is a graph showing the quantified value of the expression level of the iNOS protein; 4C is a graph showing the quantified value of the expression level of the iNOS protein (ANOVA test; * P ⁇ 0.05, ** P ⁇ 0.01 vs KA group).

Abstract

La présente invention concerne une composition de prévention ou de traitement de l'épilepsie, la composition comprenant de la gintonine comme principe actif. La gintonine selon la présente invention a pour effet: la réduction de comportement convulsif dans un modèle animal d'épilepsie du lobe temporal dans lequel l'apoptose de neurones excitateurs est induite par l'acide kaïnique; et l'inhibition significative de l'apoptose des neurones de l'hippocampe, de l'activité des cellules microgliales et des astrocytes, et l'expression de COX-2 et d'oxyde nitrique synthase inductible (iNOS) qui sont des médiateurs représentatifs de l'inflammation. Par conséquent, la composition comprenant de la gintonine selon la présente invention peut être utile en tant que composition pour la prévention, le traitement ou l'amélioration de l'épilepsie.
PCT/KR2021/017130 2020-11-24 2021-11-22 Composition pour la prévention ou le traitement de l'épilepsie comprenant de la gintonine en tant que principe actif WO2022114691A1 (fr)

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