WO2021054637A1 - Composition pour la prévention, l'amélioration ou le traitement d'une maladie dégénérative du cerveau, comprenant un extrait de periostracum cicadae - Google Patents

Composition pour la prévention, l'amélioration ou le traitement d'une maladie dégénérative du cerveau, comprenant un extrait de periostracum cicadae Download PDF

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WO2021054637A1
WO2021054637A1 PCT/KR2020/011454 KR2020011454W WO2021054637A1 WO 2021054637 A1 WO2021054637 A1 WO 2021054637A1 KR 2020011454 W KR2020011454 W KR 2020011454W WO 2021054637 A1 WO2021054637 A1 WO 2021054637A1
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disease
extract
composition
degenerative brain
extraction
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PCT/KR2020/011454
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English (en)
Korean (ko)
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박건혁
임혜선
김중선
문병철
최고야
이준
류승목
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한국한의학연구원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • 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
    • 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
    • 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
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/204—Animal extracts

Definitions

  • the present invention relates to a pharmaceutical composition for use in the prevention or treatment of degenerative brain diseases including adenoid extract or a composition for use in neuronal protection.
  • the present invention also relates to a method for preventing or treating a degenerative brain disease comprising administering a sedentary extract to a patient with a degenerative brain disease.
  • Parkinson's disease is an idiopathic brain degenerative disease whose cause is unknown. This disease affects 1-2% of the world's population over the age of 65. As a representative degenerative motor disorder brain disease that rapidly enters an aging society, the number of patients is rapidly increasing. Representative symptoms include tremor, rigidity, and bradykinesis. Pathological findings include dopaminergic neurons (substantia nigra pars compacta, SNpc) or striatum (ST). Dopaminergic neuron) is lost, resulting in symptoms of dopamine deficiency in which the concentration of dopamine is reduced by more than 80%, resulting in behavioral abnormalities due to abnormal motor circuit regulation.
  • Nuclear receptor related 1 protein plays an important role in the development, maintenance, or survival of the brain's dopaminergic system.
  • Nurr1 plays a fundamental role in maintaining dopamine homeostasis by regulating the transcription of genes that control dopamine synthesis, storage and reuptake. It also regulates the survival of dopaminergic neurons by stimulating the transcription of genes encoding neurotrophic factors, anti-inflammatory responses and oxidative stress, and the management of mitochondrial dysfunction, and by inhibiting the transcription and expression of pro-inflammatory genes. Mutations in this gene are known to be associated with dopaminergic dysfunction, including PD, schizophrenia or manic depression.
  • Seontoe (Cicadidae Periostracum) refers to the breakdown of cicadas or horse cicadas, and is also called'seontae'. Seontoe is a bent oval shape similar to a cicada, about 3.5cm long, about 2cm in diameter, and its outer surface is yellowish white to yellowish brown, translucent and glossy, almost no smell, and tasteless. In oriental medicine, it has been used as an antipyretic and pain reliever since ancient times, and it is sometimes used for epilepsy by crushing 5 senates with wings and legs removed and eating after meals 3 times a day. It is also used in the treatment of fever due to cold, chronic relief asthma, sore throat, tetanus, itching, eye problems, swelling or hives.
  • Korean Patent Application No. 10-2005-0056188 relates to a composition for the prevention and treatment of cardiac circulatory disorders comprising an adenoid extract or an acetyl-dopamine-based compound isolated therefrom, and a novel acetyl-dopamine-based adenoid extract or a novel acetyl-dopamine-based isolated therefrom Since the compound has excellent antioxidant activity against low-density lipoproteins, it is disclosed that it is effective in preventing and treating cardiac circulatory diseases such as hyperlipidemia or arteriosclerosis caused by oxidation of low-density lipoproteins.
  • the present inventors have made diligent efforts to provide a composition that is effective against degenerative brain diseases such as Parkinson's disease while using resources derived from natural natural products, and as a result, adenoid extract increases the activity of the Nurr1 protein, ultimately resulting from degenerative brain disease. It was confirmed that there is an effect of improving behavioral disorders, and the present invention was completed.
  • Another object of the present invention is to provide a method for preventing or treating degenerative brain disease, comprising administering a sedentary extract to a patient with degenerative brain disease.
  • the present invention provides a composition for use in the prevention, improvement or treatment of degenerative brain diseases, including the extract of Cicadidae Periostracum, or a composition for use in neuronal protection.
  • the lineage extract may be extracted using one or more selected from the group consisting of water, an organic solvent, and an inorganic solvent as a solvent.
  • the extract is extracted by any one or more extraction methods selected from the group consisting of decompression high temperature extraction, hot water extraction, reflux extraction, hot water extraction, cold needle extraction, room temperature extraction, ultrasonic extraction, and steam extraction method. It may have been.
  • the degenerative brain disease may be a disease caused by a dysfunction of the Nurr1 protein.
  • diseases caused by dysfunction of the Nurr1 protein are Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, Huntington's disease, frontotemporal dementia, cortical-basal ganglia degeneration, progressive supranuclear palsy, decreased concentration, and ADHD.
  • Schizophrenia depression, and may be any one or more selected from the group consisting of manic depression.
  • the neurons are brain neurons, astrocytes, microglia, oligodendroglia, ependymal cells, and Schwann cells. It may be any one or more selected from the group consisting of (Schwann's cell) and ganglion cell (capsular cell).
  • the composition may have an effect of inhibiting neuronal cell death or neuroinflammation.
  • the composition may be a food composition, a pharmaceutical composition, or a quasi-drug composition.
  • the present invention provides a method for preventing or treating degenerative brain diseases comprising administering an extract of Cicadidae Periostracum to a patient with degenerative brain disease.
  • the degenerative brain disease may be a disease caused by a dysfunction of the Nurr1 protein.
  • diseases caused by dysfunction of the Nurr1 protein are Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, Huntington's disease, frontotemporal dementia, cortical-basal ganglia degeneration, progressive supranuclear palsy, decreased concentration, and ADHD.
  • Schizophrenia depression, and may be any one or more selected from the group consisting of manic depression.
  • the adenoid extract (CP) of the present invention amplifies neurotrophic factors or dopamine by increasing the activity of the Nurr1 protein, and has a neuroprotective effect by inhibiting neuronal cell death or neuroinflammation, resulting from degenerative brain diseases such as Parkinson's disease. Behavioral disorders can be improved, and further, it can be expected to improve concentration, ADHD, schizophrenia, depression or manic depression due to a decrease in dopamine (FIG. 1).
  • Example 3 When the CP of the present invention was administered to a mouse model that caused degenerative brain disease with MPTP, the exercise capacity of the mouse, which had been reduced, was improved (Example 3).
  • CP was directly treated with the brain tissue of the mouse models or the mouse-derived PC12 cell line or microglia BV2 cell line, dopaminergic neurons or dopamine were increased (Example 5, Example ⁇ 8-2>), The level of Nurr1 and its regulatory proteins, neurotrophic factors, was increased (Example 7).
  • the present invention can provide a pharmaceutical composition for use in the prevention or treatment of degenerative brain diseases, including the extract of Seontaek (Cicadidae Periostracum).
  • the sedentary extract of the present invention is an extract of sedentary cicada, which is a deterioration of cicada, and the solvent that can be used during extraction may be extracted using one or more selected from the group consisting of water, an organic solvent, and an inorganic solvent. It is preferably water or a C1 to C4 lower alcohol, more preferably water, methanol, ethanol or propanol, and most preferably water as a solvent.
  • the sedentary extract of the present invention may be extracted by any one or more extraction methods selected from the group consisting of decompression high temperature extraction, hot water extraction, reflux extraction, hot water extraction, cold needle extraction, room temperature extraction, ultrasonic extraction, and steam extraction method, Preferably, it is preferably extracted by any one or more extraction methods selected from the group consisting of decompression high temperature extraction, hot water extraction, reflux extraction, and hot water extraction, and most preferably extraction by reflux extraction method.
  • the degenerative brain disease of the present invention may be a disease caused by a dysfunction of the Nurr1 protein, and the diseases caused by a dysfunction of the Nurr1 protein include Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, Huntington's disease, frontotemporal dementia, Cortical-basal ganglia degeneration, progressive supranuclear palsy, decreased concentration, ADHD, schizophrenia, depression, and manic depression, preferably any one or more selected from the group consisting of, more preferably Parkinson's disease, Alzheimer's disease, decreased concentration, ADHD, mental It is preferably any one or more selected from the group consisting of schizophrenia, depression, and manic depression, and most preferably Parkinson's disease.
  • the pharmaceutical composition of the present invention may be in an oral or parenteral formulation.
  • buffers e.g., saline or PBS
  • antioxidants e.g., bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, bulking agents, binders, adjuvants (e.g., Aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrants or surfactants, diluents or excipients.
  • bacteriostatic agents e.g., EDTA or glutathione
  • chelating agents e.g., EDTA or glutathione
  • fillers e.g., bulking agents, binders, adjuvants (e.g., Aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrants or surfactants, diluents or excipients.
  • adjuvants e.g., Aluminum hydroxide
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato Starch), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin.
  • starch corn starch, wheat starch, rice starch, potato Starch
  • calcium carbonate sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions or syrups, and various excipients, such as wetting agents, sweeteners, fragrances or preservatives, are included in addition to water and liquid paraffin, which are commonly used simple diluents.
  • excipients such as wetting agents, sweeteners, fragrances or preservatives
  • water and liquid paraffin which are commonly used simple diluents.
  • cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and an anti-aggregating agent, a lubricant, a wetting agent, a fragrance, an emulsifying agent and a preservative, etc. may be additionally included. .
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations or suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
  • injectable ester such as ethyl oleate
  • a base for suppositories witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like may be used.
  • composition of the present invention may be administered orally or parenterally, and for parenteral administration, the composition may be used externally to the skin; Intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerebrovascular injection; Transdermal administration; Alternatively, it may be formulated in the form of a nasal inhalant according to a method known in the art.
  • suitable carriers for injections include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof, and/or solvents or dispersion media containing vegetable oils.
  • suitable carriers include isotonic solutions such as Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanol amine or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used.
  • the injection may further contain an isotonic agent such as sugar or sodium chloride in most cases.
  • transdermal administration means that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.
  • the compounds used according to the invention can be used in a pressurized pack or with a suitable propellant, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered from a nebulizer in the form of an aerosol spray.
  • the dosage unit can be determined by providing a valve that delivers a metered amount.
  • gelatin capsules and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • a pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of disease, severity, drug activity, drug sensitivity, administration time of the patient. , Route of administration and rate of excretion, duration of treatment, factors including concurrent drugs and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple.
  • the total effective amount of the composition of the present invention may be administered to a patient in a single dose, and may be administered by a fractionated treatment protocol that is administered for a long period in multiple doses. . It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity.
  • the adenum extract is preferably administered in an amount of 0.01 to 50 mg, more preferably 0.1 to 30 mg per 1 kg of body weight per day, and oral administration of the present invention. It may be administered in divided doses from 1 to several times so as to be administered in an amount of preferably 0.01 to 100 mg, more preferably 0.01 to 10 mg per 1 kg of body weight per day based on the adenoid extract.
  • the dosage amount does not limit the scope of the present invention in any way.
  • composition of the present invention may be used alone or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response modifiers.
  • the pharmaceutical composition of the present invention may also be provided in the form of an external preparation comprising a sedum extract as an active ingredient.
  • an external preparation comprising a sedum extract as an active ingredient.
  • the pharmaceutical composition for use in the prevention and treatment of degenerative brain diseases of the present invention is used as an external application for skin, additionally fatty substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, stabilizers , Foaming agent, fragrance, surfactant, water, ionic emulsifier, nonionic emulsifier, filler, sequestering agent, chelating agent, preservative, vitamin, blocker, wetting agent, essential oil, dye, pigment, hydrophilicity It may contain an adjuvant commonly used in the field of dermatology such as an active agent, a lipophilic active agent, or any other component commonly used in skin external preparations such as lipid vesicles.
  • the above ingredients may be introduced in an amount generally used in
  • the pharmaceutical composition for use in the prevention or treatment of degenerative brain diseases of the present invention is provided as an external preparation for skin, it is not limited thereto, but may be a formulation such as an ointment, patch, gel, cream, or spray.
  • the present invention can provide a health functional food composition for preventing or improving degenerative brain diseases, including the extract of Seontaek (Cicadidae Periostracum).
  • Seondae extract is the same as that contained in the pharmaceutical composition, the description is replaced with the above description.
  • the health functional food composition according to the present invention can be prepared in various forms according to conventional methods known in the art.
  • General foods include, but are not limited to, beverages (including alcoholic beverages), fruits and processed foods thereof (e.g., canned fruit, canned food, jam, marmalade, etc.), fish, meat and processed foods thereof (e.g. ham, sausage) Corn beef), bread and noodles (e.g. udon, buckwheat noodles, ramen, spagate, macaroni, etc.), fruit juice, various drinks, cookies, sweets, dairy products (e.g.
  • the sesame extract of the present invention can be prepared by adding the sesame extract of the present invention.
  • a nutritional supplement it is not limited thereto, but may be prepared by adding the Seontoe extract of the present invention to capsules, tablets, pills, and the like.
  • the health functional food is not limited thereto, but for example, the Seontoe extract of the present invention itself is liquefied, granulated, encapsulated, and powdered so that it can be drinkable (healthy beverage) by manufacturing it in the form of tea, juice, and drinks. Can be consumed.
  • the sesame extract of the present invention in the form of a food additive, it may be prepared and used in the form of a powder or a concentrate. In addition, it may be prepared in the form of a composition by mixing the adenum extract of the present invention with a known active ingredient known to have an effect of preventing or improving degenerative brain diseases.
  • the health drink composition may contain various flavoring agents or natural carbohydrates as an additional component, like a normal drink.
  • the natural carbohydrates described above include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Polysaccharides such as dextrin and cyclodextrin; It may be a sugar alcohol such as xylitol, sorbitol, and erythritol.
  • Sweeteners include natural sweeteners such as taumatin and stevia extract; Synthetic sweeteners such as saccharin and aspartame can be used.
  • the ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
  • the sedentary extract of the present invention may be contained as an active ingredient of a health functional food composition for preventing or improving degenerative brain diseases, the amount of which is not particularly limited to an amount effective to achieve the effect of preventing or improving degenerative brain diseases, It is preferably 0.01 to 100% by weight based on the total weight of the total composition.
  • the health functional food composition of the present invention may be prepared by mixing together with the extract of Seondeae and other active ingredients known to be effective in degenerative brain diseases.
  • the health functional food of the present invention includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives. , Glycerin, alcohol, or a carbonation agent.
  • the health functional food of the present invention may contain flesh for the manufacture of natural fruit juice, fruit juice beverage, or vegetable beverage. These ingredients may be used independently or in combination. Although the proportion of these additives is not very important, it is generally selected from 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
  • the present invention can provide a composition for use in the protection of nerve cells containing adenum extract.
  • the neurons of the present invention are brain neurons, astrocytes, microglia, oligodendroglia, ependymal cells, Schwann's cells, and ganglions. It may be any one or more selected from the group consisting of glial cells (capsular cells), preferably any one or more selected from the group consisting of brain neurons (neuron), astrocytes (astrocyte) and microglia cells (microglia) desirable.
  • the composition of the present invention may have an effect of suppressing or alleviating damage or reduction of nerve cells. More preferably, the composition may have an effect of inhibiting neuronal cell death or neuroinflammation.
  • composition of the present invention may be a food composition, a pharmaceutical composition, or a quasi-drug composition.
  • the present invention can provide a method for preventing or treating degenerative brain diseases comprising administering an extract of Cicadidae Periostracum to a patient with degenerative brain disease.
  • Seondae extract is the same as that contained in the pharmaceutical composition, the description is replaced with the above description.
  • the adenoid extract of the present invention amplifies neurotrophic factors or dopamine by increasing the activity of Nurr1 protein, and has a neuroprotective effect by inhibiting neuronal cell death or neuroinflammation, thereby preventing behavioral disorders caused by degenerative brain diseases such as Parkinson's disease.
  • it can be expected to improve concentration, ADHD, schizophrenia, depression or manic depression due to dopamine decrease.
  • Figure 1 schematically shows the efficacy of the extract of the present invention.
  • the adenoid extract of the present invention increases the amount of neurotrophic factors including GDNF by increasing the activity of the Nurr1 protein, can suppress neuronal cell death and neuroinflammation, and increases the amount of dopamine, resulting in Parkinson's disease. It can improve behavioral disorders of back degenerative brain diseases.
  • FIG. 2 shows the design of an animal experiment for confirming the effect of adenoid extract (CP) on an animal model of degenerative brain disease.
  • adenoid extract (CP) on an animal model of MPTP degenerative brain disease. It was confirmed that adenoid extract improved behavioral disorders in an animal model of degenerative brain disease induced by MPTP.
  • FIGS. 4A and 4B show the effect of adenoid extract (CP) on MPTP-induced dopamine neuronal cell death.
  • A shows the number of TH-immune positive dopaminergic neurons in SNpc
  • B shows the optical density of ST (TH-positive dopaminergic fiber density).
  • C shows the level of dopamine in ST
  • D shows the rate of MAO-B inhibition in the cell-free system.
  • E shows micrographs of SNpc and ST. Values are expressed as mean ⁇ S.E.M. *P ⁇ 0.05, **p ⁇ 0.01 and ***p ⁇ 0.001 compared to the control group and #p ⁇ 0.05, ##p ⁇ 0.01 and ###p ⁇ 0.001 compared to the MPTP-treated group or the control group.
  • FIG. 5 shows the design of a cell experiment for confirming the effect of adenoid extract (CP) on nerve cells.
  • CP adenoid extract
  • FIGS. 7A and 7B show Western neurotrophic factors, which are differentiated PC12 cells (C), mouse SNpc (D), and differentiated PC12 cells pretreated with adenoid extract (CP) and ERK inhibitor (SCH772984), and their regulatory proteins. The results measured by blotting are shown.
  • the bar graph shows the relative expression of Nurr1 (F), TH (G), DDC (H), DAT (I) and VMAT2 (J) for (C-E). Values are expressed as mean ⁇ S.E.M. *p ⁇ 0.05, **p ⁇ 0.01 and ***p ⁇ 0.001 were compared with the control group, and #p ⁇ 0.05 and ##p ⁇ 0.01 were compared with the CP treatment group.
  • CP adenoid extract
  • FIGS. 9A and 9B show that the expression of Nurr1, TH, DDC, DAT and VMAT2 was detected by Western blotting using specific antibodies in SNpc (D).
  • the bar graph shows the relative expression of Nurr1 (A), TH (E), DDC (F), DAT (G) and VMAT2 (H) versus (D). It shows the results of real-time RT-PCR to see the effect of the adenoid extract (CP) on the mRNA expression of Nurr1 (I), TH (J), DAT (K) and VMAT2 (L). Moreover, it shows the effect of Nurr1 upregulating neuromodulatory factors (TH, DAT and VMAT2) in Nurr1 siRNA-transfected differentiated PC12 cells (M).
  • the displayed values represent the mean ⁇ S.E.M. *p ⁇ 0.05 and ***p ⁇ 0.001 were compared with the control group, and #p ⁇ 0.05, ##p ⁇ 0.01 and ###p ⁇ 0.001 were compared with the MPTP treatment group.
  • FIG. 10 shows the effect of adenoid extract (CP) on MPTP-induced mitochondrial-mediated apoptosis.
  • A shows the results of measuring mitochondrial-induced apoptosis factors Bcl-2, Bax, Cyt-c, cleaved caspase-3, cleaved caspase-9, and PARP1 by Western blotting.
  • the differentiated PC12 cells were treated with CP and exposed to MPP + for 48 hours, and then the red, green (B) and ratio (C) of the fluorescence of the mitochondrial membrane potential were expressed as a percentage of the control group.
  • FIG. 11 shows the effect of adenoid extract (CP) on the GDNF signaling factor related to MPTP-induced survival.
  • CP adenoid extract
  • GFNF and Ret were measured by Western blotting (D) and ELISA kit (E). Values are expressed as mean ⁇ S.E.M. ***P ⁇ 0.001 compared to the control and #p ⁇ 0.05 or ### p ⁇ 0.001 compared to the MPP+ or MPTP-treated group.
  • FIGS. 12A and 12B show the effect of adenoid extract (CP) on the MPTP-induced neuroinflammation signal transduction factor.
  • CP adenoid extract
  • Neuroglial activation proteins GFAP and Iba-1
  • iNOS and Cox-2 neuroinflammation signaling factors
  • the level of neuroinflammation signaling factor was normalized to ⁇ -actin (C-F).
  • G shows a representative micrograph of SNpc.
  • (I) to (M) show the density ratio of the array, and show differences in cytokine markers (ICAM-1, KC, IL-6, MCP-5, and RANTES).
  • (N) shows the results of measuring neuronal culture activation markers (GFAP and Iba-1) and neuroinflammation signaling factors (iNOS and Cox-2) using Western blotting (N).
  • the bar graph shows the relative expression of GFAP, Iba-1, iNOS and Cox-2 (O) versus (N).
  • the displayed values represent the mean ⁇ S.E.M. *p ⁇ 0.05 and ***p ⁇ 0.001 were compared with the control group, and #p ⁇ 0.05, ##p ⁇ 0.01 and ###p ⁇ 0.001 were compared with the MPTP treatment group.
  • Seontoe (Cicadidae Periostracum, CP; Gwangmyeongdang, Ulsan, Korea) was selected and the voucher sample (3-18-0038) was deposited at the Korean Oriental Medicine Research Institute's Oriental Medicine Resource Research Center after being discriminated by Dr. Choi Choi, the Oriental Medicine Resource Research Center, Korea Institute of Oriental Medicine. . Briefly, distilled water was added to the toe, followed by reflux extraction at 100 ⁇ 2° C. for about 3 hours, and then filtered. The filtrate of the sesame extract was evaporated in a rotary vacuum evaporator and lyophilized (yield: 6.30%), and the sample was stored at 4°C until use.
  • mice Male C57BL/6 mice (8 weeks, 23-24g) were purchased (Dooyeol Biotech, Seoul) and stored under temperature and light control conditions (20-23°C, 12 hours light/12 hours dark cycle). All animals were acclimated for 7 days prior to drug administration.
  • the experimental protocol was approved by the Institutional Animal Care Committee (KIOM-18-056) of the Korea Institute of Oriental Medicine (KIOM) and was carried out according to the guidelines of the Animal Care and Use Committee of KIOM.
  • LPS lipopolysaccharides
  • CP dissolved in physiological saline was continuously orally administered for 5 days.
  • the control group and the MPTP group were orally administered 0.25 ml of normal physiological saline for the same period.
  • MPTP or LPS was acutely administered as previously described.
  • MPTP (20 mg/kg, dissolved in saline) was injected intraperitoneally 4 times at 2 hour intervals.
  • LPS was dissolved in saline and injected intraperitoneally at a dose of 5 mg/kg.
  • the Rotarod test was used to measure behavioral disorders such as hypokinesia in a Parkinson's disease (PD) mouse model induced through MPTP administration.
  • PD Parkinson's disease
  • mice were evaluated for sensorimotor coordination with rotarod on the first day after the last injection of MPTP.
  • the rotarod device Ugo Basile, Comerio Varese, Italy
  • the rotarod device consisted of a rotating spindle with a diameter of 3 cm and 5 individual compartments capable of simultaneously testing 5 mice.
  • the first day was trained at 4 rpm and the second day was trained at a rotational speed of 20 rpm, and then the experiment was conducted at 25 rpm on the third day. At this time, the fall time was measured.
  • the practice was performed twice at 5 minute intervals with a 300 second limit time per session, and this experiment was performed 3 times at 5 minute intervals, and the average value was used.
  • the Pole test was used to measure behavioral disorders such as bradykinesia in a PD mouse model induced through MPTP administration.
  • the T-turn or T-LA time significantly decreased when the adenoid extract (CP) was administered to a mouse model induced PD with MPTP. I did.
  • CP adenoid extract
  • the drop time was similar to that of the control group, and the T-turn or T-LA time decreased more effectively than the positive control, lopinirol administration group. It was confirmed that the effect appeared.
  • mice were immediately anesthetized on the 1st and 7th days after MPTP treatment, or 3 hours after LPS treatment (Example 2) and transcardiac perfusion with 0.05M phosphate buffered saline (PBS; Sigma-Aldrich, St. Louis, MO, USA). After (transcardially) cold 4% paraformaldehyde (paraformaldehyde, PFA; Sigma-Aldrich, St. Louis, MO, USA) was dissolved in 0.1M phosphate buffer. Brains were removed in 0.1M phosphate buffer containing 4% PFA (Sigma-Aldrich, St.
  • brain melanoma (SNpc) and striatum (ST) were rapidly dissected, homogenized, and centrifuged by a skilled technique. The final supernatant was stored at -70 °C until all supernatant.
  • the present inventors tried to confirm the effect of adenoid extract (CP) on dopamine neuronal cell death, dopamine levels, and MAO-B through immunohistochemistry (Immunohistochemistry, IHC) using mouse brain melanoma or striatum.
  • CP adenoid extract
  • IHC immunohistochemistry
  • the brain tissue prepared in ⁇ Example 4> was simply washed with PBS and treated with 1% hydrogen peroxide (Sigma-Aldrich, St. Louis, MO, USA) for 15 minutes. Sections were 4 in the presence of 0.3% Triton X-100 (Vector Laboratories, Burlingame, CA, USA) and normal goat serum (Vector Laboratories, Burlingame, CA, USA) or normal horse serum (Vector Laboratories, Burlingame, CA, USA). Incubated with rabbit anti-tyrosine hydroxylase (TH; 1:1000) for 24 hours at °C.
  • Triton X-100 Vector Laboratories, Burlingame, CA, USA
  • normal goat serum Vector Laboratories, Burlingame, CA, USA
  • normal horse serum Vector Laboratories, Burlingame, CA, USA
  • MPTP treatment significantly reduced the level of striatal dopamine to 8.47 ⁇ 0.25 nmol/ml compared to the control
  • MPTP-induced striatal treatment with 1-25 mg/kg of CP or ropinirol Dopamine was increased to 12.84 ⁇ 1.36 to 15.20 ⁇ 1.18 nmol/ml and 16.94 ⁇ 0.93 nmol/ml.
  • only when treated with 5-25 mg/kg CP increased striatal dopamine from 16.86 ⁇ 0.21 to 17.65 ⁇ 0.29 nmol/ml compared to the control.
  • PC12 cell line (Korea Cell Line Bank, # 21721) derived from the adrenal medulla of rats is 10% heat-inactivated fetal serum (Gibco, MD, USA) and 1% penicillin/streptomycin (Gibco) at 37°C. , MD, USA) in RPMI medium (Roswell Park Memorial Institute; Gibco, MD, USA) supplemented with 95% air and 5% CO 2 .
  • PC12 cells were inoculated on a 96-well plate or a 6-well plate at a density of 1 or 2 ⁇ 10 5 cells/ml, and the adenoid extract (CP) prepared in Example 1 was diluted in PBS for 24 hours.
  • CP adenoid extract
  • differentiated PC12 It was treated with 0 ⁇ 1000 ⁇ g/ml.
  • the medium was newly replaced every 2 to 3 days.
  • Differentiated PC12 cells were treated with nerve growth factor (NGF; Sigma-Aldrich, St. Louis, MO, USA) for 7 days, and fresh medium and reagents were supplied every 24 hours.
  • Differentiated PC12 cells were treated with CP (1 ⁇ 200 ⁇ g/ml) for 1 hour. Thereafter, stimulation was performed using MPP + (100 ⁇ M) for an additional 23 hours (Fig. 5).
  • NGF nerve growth factor
  • Mouse microglial BV2 cell line is Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal bovine serum and 1% penicillin/streptomycin in an atmosphere of 95% air and 5% CO 2 at 37 °C (Gibco, MD). , USA).
  • BV2 cells were inoculated into a 24-well plate at a density of 1.5 ⁇ 10 5 cells/ml and treated with CP (0 ⁇ 1000 ⁇ g/ml) for 24 hours (FIG. 5).
  • Cytotoxicity was evaluated using a Cell Counting Kit (CCK-8; Dojindo, Kumamoto, Japan) according to the manufacturer's protocol.
  • the PC12 cells of Example ⁇ 6-1> were plated on a 96-well plate and treated with the sediment extract (0, 0.1, 1, 10, 50, 100 or 200 ⁇ g/ml) prepared in Example 1 I did.
  • CCK-8 reagent was added to each well and the mixture was incubated for 4 hours.
  • Absorbance was read at 450 nm using a SpectraMax i3 multimode detection platform (Molecular Devices, Sunnyvale, CA, USA). Cell viability was calculated using the following equation.
  • % Of cells remaining after treatment with adenoid extract (average absorbance in treated cells / average absorbance in untreated control) ⁇ 100
  • adenoid extract CP
  • the levels of Nurr1, TH, DDC, DAT and VMAT2 were measured in differentiated PC12 cells or mouse SNpc.
  • ERK activation contributed to the increase of Nurr1 expression by CP.
  • ⁇ -actin protein was used as an internal control.
  • the differentiated PC12 cells were treated with CP by Nurr1: 95.42 ⁇ 8.31% to 226.96 ⁇ 22.30%; TH: 272.45 ⁇ 29.81% at 152.26 ⁇ 14.77%; DDC: 128.03 ⁇ 2.89% to 173.43 ⁇ 22.66%; DAT: 118.17 ⁇ 6.47% to 278.32 ⁇ 29.55%; VMAT2: increased from 147.26 ⁇ 3.32% to 203.69 ⁇ 31.21%.
  • SNpc cells were treated with CP by Nurr1:201.02 ⁇ 32.55%; TH: 197.50 ⁇ 33.64%; DDC: 161.74 ⁇ 27.33%; DAT: 140.97 ⁇ 14.67%; And VMAT2: increased to 142.77 ⁇ 22.56%.
  • differentiated PC12 cells treated with ERK inhibitor were treated with CP, Nurr1: 196.24 ⁇ 30.19% and 94.31 ⁇ 11.10%; TH: 258.87 ⁇ 33.33% and 111.47 ⁇ 19.10%; DDC: 166.88 ⁇ 23.84% and 68.21 ⁇ 7.94%; DAT: 350.47 ⁇ 56.53% and 187.24 ⁇ 16.89%; And VMAT2: 224.09 ⁇ 36.33% and 89.09 ⁇ 10.16%.
  • CP adenoid extract
  • Nurr1 specific immunofluorescence analysis brain sections were simply washed with PBS and treated with 0.5% BSA (Sigma-Aldrich, St. Louis, MO, USA) for 30 minutes. Sections were transferred to mouse anti-TH (1:100) or rabbit anti-glass fibrous acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), Nurr1 or cyclooxygenase-2 (Cox-2; 1: 200) was incubated at 4° C. for 24 hours in the presence of 0.3% Triton X-100 and normal goat serum. Then, it was incubated with Alexa Fluor-conjugated secondary antibody (1:500) for 1 hour.
  • BSA Sigma-Aldrich, St. Louis, MO, USA
  • the levels of Nurr1, TH, DDC, DAT and VMAT2 in mouse SNpc were confirmed by Real Time RT-PCR or Western blotting. Homogenization of SNpc tissue was performed using TRIzol reagent (Invitrogen, Carlsbad, CA, USA). After homogenization, 0.2 ml of chloroform was added to each sample. The tube was shaken vigorously by hand for 15 seconds and then incubated for 3 minutes at room temperature. Subsequently, the mixture was centrifuged at 14,000 rpm at 4° C. for 15 minutes, and then 400 ⁇ l of the supernatant was transferred to a new tube to which 0.5 ml of 2-propanol was added. After incubation at 4° C.
  • RNA pellet was dried, and the purified RNA was dissolved in diethyl pyrocarbonate (DEPC)-distilled water.
  • DEPC diethyl pyrocarbonate
  • PCR real-time PCR was performed on selected genes using CFX96 real-time PCR system (Bio-Rad) and SYBR green fluorescence quantification system (Bio-Rad). PCR conditions were 95°C (30s), 50 cycles of 58°C (30s) and a standard denaturation curve. The primer sequence is as shown in Table 1 below, and the annealing temperature of each gene is 59°C. PCR conditions for each target were optimized according to the primer concentration, the absence of primer dimer formation, and the amplification efficiency of the target gene and amplification gene. Housekeeping control genes.
  • the PCR reaction mixture contained 1 ⁇ l of cDNA and 9.5 ⁇ l of PCR Master Mix, which contained 2 ⁇ SYBR Green, 10 pmol each of the forward and reverse primers, and 4.5 ⁇ l of DEPC-distilled water in a final volume of 15 ⁇ l.
  • CT comparative threshold
  • adenoid extract affects mitochondrial dysfunction and mitochondrial mediated apoptosis
  • ⁇ m is tetraethylbenzimidazolylcarbocyanine iodide (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine), a lipophilic cationic probe provided with the ⁇ m detection kit.
  • iodide, JC-1) reagent was used to monitor according to the manufacturer's instructions.
  • Differentiated PC12 cells were seeded on a cover slip of a 96-well plate and treated simultaneously with CP with 1, 10, or 50 ⁇ g/ml and 100 ⁇ M MPP+ for 24 hours.
  • the cells were rinsed with PBS and incubated with the lipophilic cationic probe JC-1 diluted at 37° C. For 30 minutes, the cells were washed and transferred to a 96-well plate. The ratio of red (585/590 nm) and green (510/527 nm) fluorescence was determined using a fluorescent plate reader.
  • adenoid extract CP
  • the levels of GDNF and Ret in mouse SNpc were evaluated.
  • the dopamine content in a section of the mouse brain was confirmed using a commercially available fluorescence assay or ELISA (enzyme-linked immunosorbent assay) kit according to the protocol provided by the manufacturer (Rocky Mountain Diagnostics).
  • adenoid extract CP
  • glial/microglia activation and neuroinflammation factor levels of microglia BV2 cells and mouse SNpc were evaluated.
  • microglia BV2 cells were treated with CP for 2 hours and LPS for an additional 22 hours. After 24 hours of incubation, GFAP, Iba-1, iNOS and GFAP, Iba-1, iNOS and released upon inflammation stimulation by Western blotting using a cytokine membrane array kit according to the manufacturer's instructions (R&D Systems, Minneapolis, MN, USA) in the culture The expression level of Cox-2 was measured. Images were taken by immunofluorescence staining with anti-Cox-2, GFAP and Iba-1 antibodies in SNpc.
  • the levels of GFAP, Iba-1, iNOS, and Cox-2 in the SNpc of the MPTP-treated group were 482.97 ⁇ 28.90% and 384.06, respectively. Increased by ⁇ 65.22%, 264.07 ⁇ 77.82% and 179.78 ⁇ 11.50%.
  • CP decreased these GFAP, Iba-1, iNOS, and Cox-2 levels (381.29 ⁇ 19.15% to 52.02 ⁇ 24.48%, 407.13 ⁇ 85.73% to 124.79 ⁇ 19.71%, 164.17 ⁇ 23.04% to 63.20 ⁇ 24.39%, and) 92.02 ⁇ 2.36% at 109.09 ⁇ 23.71%).
  • MTT analysis result of Example ⁇ 6-2> Microglia BV2 cells were not affected by 1-62.5 ⁇ g/ml CP. However, 125-1000 ⁇ g/ml CP increased cytotoxicity (data not shown). Therefore, all further experiments were performed with CP at 1-62.5 ⁇ g/ml.
  • the cytokine array kit has the levels of ICAM-1, IL-6, KC, MCP-5, and RANTES in LPS-treated microglia BV2 cells, respectively, 205.03. It showed a significant increase of ⁇ 4.24%, 3468.59 ⁇ 51.63%, 687.96 ⁇ 6.04%, 336.64 ⁇ 0.07% and 192.58 ⁇ 1.65%.
  • CP increased ICAM-1, IL-6, KC, MCP-5 and RANTES by LPS treatment by 62.45 ⁇ 12.28%, 2185.72 ⁇ 11.60%, 102.53 ⁇ 2.19%, 168.26 ⁇ 3.22% and 104.78 ⁇ 0.46%, respectively It was suppressed by %.
  • the levels of iNOS and Cox-2 in SNpc of the LPS-treated group were also significantly increased to 235.75 ⁇ 18.69% and 555.89 ⁇ 55.49%, respectively.
  • CP treatment suppressed these increases in iNOS and Cox-2 to 118.92 ⁇ 10.06% and 301.61 ⁇ 58.46% (N-O in FIG. 13B).
  • the extended citation index database of the Web of Science core collection was searched as the source database.
  • a search tool for interacting gene search (STRING) software was used to construct a network model showing protein interactions based on known and predicted protein-protein interactions.
  • protein ontology and functional relationships were obtained from the Kyoto Encyclopedia and Genomic Database (KEGG).
  • the main research method was based on Scientometrics, and the analysis software included a similarity visualization viewer (VISviewer, developed by van Eck and Waltman of Leiden University, Netherlands) (version 1.6.9, www.vosviewer.com) and text files.
  • VOSviewer can analyze complex networks using clustering analysis according to the connection strength between projects.
  • Knowledge domain display mapping especially clustering; Analyzing large data sets; It has a strong advantage when building a complex network.
  • the adenoid extract of the present invention amplifies neurotrophic factors or dopamine by increasing the activity of Nurr1 protein, and has a neuroprotective effect by inhibiting neuronal cell death or neuroinflammation, thereby preventing behavioral disorders caused by degenerative brain diseases such as Parkinson's disease.
  • it can be expected to improve concentration, ADHD, schizophrenia, depression or manic depression due to dopamine decrease.
  • the adenum extract of the present invention can be used in pharmaceutical compositions for degenerative brain diseases, health functional food compositions, compositions for use in neuronal protection, or in preventive or therapeutic methods, and thus has industrial applicability.
  • SEQ ID NO: 1 is a forward primer sequence for the Nurr1 gene, consisting of a total of 22 nucleotide sequences.
  • SEQ ID NO: 2 is a reverse primer sequence for the Nurr1 gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 3 is a forward primer sequence for the TH gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 4 is a reverse primer sequence for the TH gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 5 is a forward primer sequence for the DAT gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 6 is a reverse primer sequence for the DAT gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 7 is a forward primer sequence for the VMAT2 gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 8 is a reverse primer sequence for the VMAT2 gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 9 is a forward primer sequence for the GAPDH gene, consisting of a total of 20 nucleotide sequences.
  • SEQ ID NO: 10 is a reverse primer sequence for the GAPDH gene, consisting of a total of 20 nucleotide sequences.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à être utilisée dans la prévention ou le traitement d'une maladie dégénérative du cerveau ou une composition destinée à être utilisée dans la neuroprotection, comprenant un extrait de Periostracum Cicadae. En outre, la présente invention concerne un procédé de prévention ou de traitement d'une maladie dégénérative du cerveau, comprenant l'étape d'administration d'un extrait de Periostracum Cicadae à un patient atteint de la maladie dégénérative du cerveau. L'extrait de Periostracum Cicadae de la présente invention amplifie les facteurs neurotrophiques ou la dopamine en augmentant l'activité du protéome de Nurr1, et a un effet de neuroprotection en inhibant la mort des cellules neuronales ou l'inflammation nerveuse, ce qui permet d'améliorer les troubles du comportement provoqués par une maladie dégénérative du cerveau telle que la maladie de Parkinson, et on peut en outre s'attendre à rencontrer un effet d'amélioration de la baisse de la concentration, du TDAH, de la schizophrénie, de la dépression ou de la dépression maniaque résultant d'une diminution de la dopamine.
PCT/KR2020/011454 2019-09-18 2020-08-27 Composition pour la prévention, l'amélioration ou le traitement d'une maladie dégénérative du cerveau, comprenant un extrait de periostracum cicadae WO2021054637A1 (fr)

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Citations (3)

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KR20100134323A (ko) * 2009-06-15 2010-12-23 우석대학교 산학협력단 피지 억제 및 여드름 개선용 화장료 조성물
KR20160081870A (ko) * 2016-03-31 2016-07-08 대전대학교 산학협력단 항산화 및 항염증에 효능이 있는 가미청기산 조성물
KR20190102926A (ko) * 2018-02-27 2019-09-04 청연의학연구소(주) 아토피 피부염에 대한 예방 및 치료용 약학 조성물 및 그 제조방법

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KR20100134323A (ko) * 2009-06-15 2010-12-23 우석대학교 산학협력단 피지 억제 및 여드름 개선용 화장료 조성물
KR20160081870A (ko) * 2016-03-31 2016-07-08 대전대학교 산학협력단 항산화 및 항염증에 효능이 있는 가미청기산 조성물
KR20190102926A (ko) * 2018-02-27 2019-09-04 청연의학연구소(주) 아토피 피부염에 대한 예방 및 치료용 약학 조성물 및 그 제조방법

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