WO2024057782A1 - Agent d'amélioration des fonctions cérébrales, et composition pour amélioration des fonctions cérébrales - Google Patents

Agent d'amélioration des fonctions cérébrales, et composition pour amélioration des fonctions cérébrales Download PDF

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WO2024057782A1
WO2024057782A1 PCT/JP2023/028953 JP2023028953W WO2024057782A1 WO 2024057782 A1 WO2024057782 A1 WO 2024057782A1 JP 2023028953 W JP2023028953 W JP 2023028953W WO 2024057782 A1 WO2024057782 A1 WO 2024057782A1
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brain function
microglia
improving
mass
composition
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PCT/JP2023/028953
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Japanese (ja)
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里佳 阿波
弘恭 岩橋
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丸善製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • the present invention relates to a brain function improving agent and a composition for improving brain function.
  • Methods to improve brain function that have been studied include improving the supply of nutrients and oxygen to nerve cells in the brain (e.g., raising intracerebral glucose, improving blood flow, etc.); Improved transmission (supply of neurotransmitter precursors, increased release of neurotransmitters, activation of receptors, inhibition of conversion of released neurotransmitters, etc.).
  • neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease
  • protein waste products such as amyloid- ⁇ and alpha-synuclein are not removed from the brain and accumulate, and the accumulation of such waste products contributes to the neurodegenerative diseases mentioned above. It is believed that there are.
  • the lymphatic system contributes to the removal of protein wastes, but since the lymph system does not exist in the brain, it was thought that protein wastes were broken down and removed in the brain.
  • protein waste products such as amyloid ⁇ and ⁇ -synuclein can be efficiently removed from the brain, which can be used to treat Alzheimer's disease, Parkinson's disease, Lewy body dementia, and other diseases. It is expected that this will lead to the prevention, treatment, or improvement of neurodegenerative diseases such as system atrophy.
  • Astrocytes have also been shown to play an important role in repairing damaged brain tissue. Around the injured area, astrocytes proliferate and increase in number, minimizing the spread of inflammation by surrounding damaged nerve cells, astrocytes themselves, and inflammatory cells that have entered the injured area. It has been reported that On the other hand, it has been pointed out that the proliferative ability of astrocytes after injury decreases with age. It is also becoming clear that astrocyte dysfunction and a decrease in the number of astrocytes are involved in the onset of neurodegenerative diseases such as Alzheimer's disease and depression symptoms.
  • glial cell line-derived neurotrophic factor is a type of protein called neurotrophic factor, and plays a role in regulating the growth, functional maintenance, repair, etc. of nerve cells. Therefore, if the expression of GDNF can be promoted, it is thought that brain function can be improved through growth, function maintenance, repair, etc. of nerve cells.
  • astrocytes, microglia, etc. are associated with various brain function disorders.
  • microglia become activated, leading to increased production of inflammatory cytokines such as interleukin-1 ⁇ (IL-1 ⁇ ) and inflammation-related factors such as nitric oxide (NO). and cause neurological damage.
  • IL-1 ⁇ interleukin-1 ⁇
  • NO nitric oxide
  • the enhancement or chronicity of neurological disorders is associated with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as cognitive impairment, depression, etc. (see, for example, Non-Patent Document 3). Therefore, if neurological disorders can be suppressed, cognitive functions (memory ability, learning ability, etc.) that have deteriorated due to neurological disorders due to aging etc.
  • Non-Patent Document 4 a neurodegenerative diseases such as Parkinson's disease and Parkinson's disease.
  • An object of the present invention is to solve the problems in the conventional art and achieve the following objects. That is, an object of the present invention is to provide a brain function improving agent and a brain function improving composition that have an excellent brain function improving effect and are highly safe.
  • ⁇ 1> A brain function improving agent characterized by containing at least one of the compounds represented by any of the following structural formulas (1) to (3).
  • ⁇ 2> Promoting astrocyte proliferation, promoting glial cell line-derived neurotrophic factor (GDNF) mRNA expression in astrocytes, promoting aquaporin 4 (AQP4) mRNA expression in astrocytes, suppressing nitric oxide (NO) production in microglia
  • GDNF glial cell line-derived neurotrophic factor
  • AQP4 aquaporin 4
  • NO nitric oxide
  • TNF- ⁇ tumor necrosis factor- ⁇
  • ⁇ 3> A composition for improving brain function, comprising the brain function improving agent according to any one of ⁇ 1
  • the brain function improving agent and brain function improving composition of the present invention it is possible to solve the above-mentioned problems in the past, achieve the above-mentioned objectives, have an excellent brain function-improving effect, and be safe.
  • the brain function improving agent of the present invention contains at least one of the compounds represented by any of the following structural formulas (1) to (3) as an active ingredient, and further contains other ingredients as necessary.
  • improving brain function does not only mean improving the function of a brain whose function has decreased, but also includes preventing a decrease in brain function and enhancing brain function. It will be done.
  • the brain function-improving effects of the compounds represented by structural formulas (1) to (3) include, for example, astrocyte proliferation-promoting action and glial cell line-derived neurotrophic factor (GDNF) mRNA expression promoting action in astrocytes. , promoting aquaporin 4 (AQP4) mRNA expression in astrocytes, suppressing nitric oxide (NO) production in microglia, suppressing tumor necrosis factor- ⁇ (TNF- ⁇ ) production in microglia, and inflammation-related gene mRNA expression in microglia. It is preferable that the effect is exerted based on one or more types of effects selected from the group consisting of suppressive effects.
  • the brain function-improving effects of the compounds represented by structural formulas (1) to (3) are not limited to the brain function-improving effects exerted based on the above-mentioned effects.
  • Inflammation-related genes in microglia include, for example, tumor necrosis factor- ⁇ (TNF- ⁇ ), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and interleukin-1 ⁇ (IL- 1 ⁇ ), interleukin-12 (IL-12), and chemokine (CXC motif) ligand 2 (CXCL2).
  • TNF- ⁇ tumor necrosis factor- ⁇
  • iNOS inducible nitric oxide synthase
  • IL-6 interleukin-6
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-12 interleukin-12
  • CXC motif chemokine ligand 2
  • the name of the compound represented by the following structural formula (2) is 3-(4-hydroxyphenyl)propionic acid (English name: 3-(4-Hydroxyphenyl)propionic acid).
  • the name of the compound represented by the following structural formula (3) is 3-phenylpropionic acid (English name: 3-Phenylpropionic acid).
  • the compounds represented by any of the structural formulas (1) to (3) above are all known compounds, and commercially available products may be used, or those extracted from plants etc. may be used.
  • the compounds represented by any of the structural formulas (1) to (3) may be used alone or in combination of two or more.
  • the brain function improving agent may consist of at least one compound represented by any one of the structural formulas (1) to (3), or may include only one compound represented by any one of the structural formulas (1) to (3). ) may be a formulation of at least one compound represented by any of the following.
  • the compound represented by any of the structural formulas (1) to (3) can be prepared into powder or granules using a conventional method using a pharmaceutically acceptable carrier such as dextrin or cyclodextrin or any other auxiliary agent. It can be formulated into any desired dosage form, such as solid or liquid.
  • a pharmaceutically acceptable carrier such as dextrin or cyclodextrin or any other auxiliary agent. It can be formulated into any desired dosage form, such as solid or liquid.
  • auxiliary agent for example, an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a flavoring agent, etc. can be used.
  • the brain function improving agent can be used in combination with other compositions (for example, compositions for improving brain function described below), and can also be used in tablets, powders, capsules, granules, extracts, It can also be used as oral preparations such as syrup; parenteral preparations such as injections, drops, and suppositories; ointments, eye drops, external solutions, and patches.
  • compositions for improving brain function described below can also be used in tablets, powders, capsules, granules, extracts, It can also be used as oral preparations such as syrup; parenteral preparations such as injections, drops, and suppositories; ointments, eye drops, external solutions, and patches.
  • the total content of the compounds represented by any of the structural formulas (1) to (3) in the formulated brain function improving agent is not particularly limited and can be appropriately selected depending on the purpose.
  • the other ingredients are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected depending on the usage form of the brain function improving agent, such as excipients, moisture proofing agents, and preservatives.
  • agent strengthener, thickener, emulsifier, antioxidant, sweetener, acidulant, seasoning, colorant, fragrance, whitening agent, humectant, oily component, ultraviolet absorber, surfactant, thickener
  • examples include alcohols, powder components, colorants, aqueous components, water, and skin nutrients. These may be used alone or in combination of two or more.
  • the content of the other components in the brain function improving agent is not particularly limited and can be appropriately selected depending on the purpose.
  • the usage of the brain function improving agent is not particularly limited and can be appropriately selected depending on the purpose, and examples include oral, parenteral, and external usage.
  • the dosage form of the brain function improving agent is not particularly limited, and known dosage forms can be appropriately selected depending on the purpose.
  • the method for producing the brain function improving agent in any dosage form is not particularly limited, and any known method can be selected as appropriate.
  • the administration method, dosage, administration site, administration period, administration interval, etc. of the brain function improving agent are not particularly limited and can be appropriately selected depending on the purpose.
  • the brain function improving agent increases the efficiency of removal and excretion of protein wastes in the brain by the glymphatic system through the brain function improving effect of the compound represented by any of the structural formulas (1) to (3). It also suppresses neurological disorders and further supports, regulates, or protects nerve cells, and through these actions, improves memory and learning abilities; prevents, treats, or improves amnesia and senile cognitive dysfunction; Alzheimer's disease. It can be used for the prevention, treatment, or amelioration of neurodegenerative diseases such as Parkinson's disease, and for the prevention, treatment, or amelioration of mood disorders such as depression.
  • the brain function-improving agent of the present invention can be used in all other uses in which it is meaningful to exhibit a brain function-improving effect in addition to these uses.
  • the brain function improving agent has an excellent brain function improving effect and is highly safe, so it can be used in a wide range of applications such as medicines, quasi-drugs, food and drinks, etc. It can be suitably used as an active ingredient of a composition for functional improvement.
  • at least one compound represented by any one of the above structural formulas (1) to (3) may be blended as is, or a compound represented by any one of the above structural formulas (1) to (3) may be blended as is.
  • a formulation of at least one of the compounds listed above may be blended.
  • the above-mentioned brain function improving agent can be prepared by blending other ingredients having a brain function-improving effect with the compound represented by any of the structural formulas (1) to (3) above, as necessary. It can also be used as
  • the brain function improving agent of the present invention is suitably applied to humans, but as long as its effects are achieved, it can also be applied to animals other than humans (e.g. mice, rats, hamsters, dogs, cats, etc.). It can also be applied to cows, pigs, monkeys, etc.).
  • the brain function improving agent of the present invention can also be used as a reagent for research on the mechanism of action of improving brain function.
  • composition for improving brain function of the present invention contains the brain function improving agent of the present invention, and further contains other components as necessary.
  • the brain function improving agent is the brain function improving agent of the present invention described above.
  • the content of the brain function improving agent in the brain function improving composition is not particularly limited and can be adjusted as appropriate depending on the form of the brain function improving composition.
  • the amount is preferably 0.0001% by mass to 30% by mass, more preferably 0.0001% by mass to 10% by mass, in terms of the total amount of the compounds represented by any of 1) to (3).
  • the brain function improving composition may consist only of the brain function improving agent.
  • composition for improving brain function are not particularly limited and can be appropriately selected depending on the usage form of the composition for improving brain function, such as the above-mentioned brain function improving agent.
  • Other ingredients similar to those listed in the section above may be mentioned. These may be used alone or in combination of two or more.
  • the content of the other components in the composition for improving brain function is not particularly limited and can be appropriately selected depending on the purpose.
  • composition for improving brain function is not particularly limited and can be appropriately selected depending on the purpose, and includes, for example, pharmaceuticals, quasi-drugs, food and drink products, and the like.
  • the composition for improving brain function of the present invention can be used on a daily basis and improves brain function by the action of the active ingredient, a compound represented by any one of the structural formulas (1) to (3). It can extremely effectively exhibit various physiologically active effects, including the function-improving effect of .
  • composition for improving brain function of the present invention is suitably applied to humans, but it can also be applied to animals other than humans (e.g. mice, rats, hamsters, dogs) as long as the respective effects are achieved. , cats, cows, pigs, monkeys, etc.).
  • composition for improving brain function of the present invention is not particularly limited and can be appropriately selected depending on the purpose, and examples include oral, parenteral, and external methods, but oral is preferred. .
  • Examples of the oral composition include oral preparations and food and drink products.
  • food and beverages refer to foods that have little risk of harming human health and are ingested orally or through gastrointestinal administration in normal social life, and are administratively classified foods, drugs, and quasi-drugs. It is not limited to such categories. Therefore, the above-mentioned foods and drinks include general foods that are orally ingested, health foods (functional foods and drinks), foods with health claims (foods for specified health uses, foods with nutritional function claims, foods with functional claims), quasi-drugs, and pharmaceuticals. This term refers to a wide range of food and beverages that make up food and beverages.
  • the type of the oral composition is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include beverages such as tea beverages, soft drinks, carbonated beverages, nutritional beverages, fruit beverages, lactic acid beverages, alcoholic beverages, coffee beverages, and coffee-containing soft drinks (including concentrated liquids and powders for adjusting these beverages); cold desserts such as ice cream, ice sorbet, and shaved ice; noodles such as soba, udon, harusame, gyoza wrappers, shumai wrappers, Chinese noodles, and instant noodles; sweets such as candy, candy, gum, chocolate, tablet candy, snacks, biscuits, jellies, jams, creams, baked goods, and bread; seafood such as crab, salmon, clams, tuna, sardines, shrimp, bonito, mackerel, whales, oysters, pacific saury, squid, ark shells, scallops, abalone, sea urchins, salmon roe, and tokobushi; kamaboko
  • processed seafood and livestock foods such as sausages and sausages
  • dairy products such as processed milk and fermented milk
  • oils and fats and oil-based processed foods such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressings
  • seasonings such as sauces and sauces
  • retort pouch foods such as curry, stew, oyakodon, porridge, porridge, Chinese rice bowl, katsudon, tendon, unadon, hayashi rice, oden, mapo tofu, beef bowl, meat sauce, egg soup, omelet rice, gyoza, shumai, hamburger steak, and meatballs
  • side dishes such as salads and pickles
  • health, beauty, and nutritional supplements in various forms
  • medicines and quasi-drugs such as tablets, powders, capsules, granules, extracts, syrups, drinks, lozenges, and mouthwash
  • oral fresheners and toothpastes used in the oral cavity such as mouth fresheners and breath fresheners.
  • the method for producing the composition for improving brain function is not particularly limited, and can be appropriately selected depending on the usage form of the composition for improving brain function.
  • the amount, period of use, interval of use, etc. of the composition for improving brain function are not particularly limited and can be appropriately selected depending on the purpose.
  • the present invention also relates to a method for improving brain function, which comprises administering to an individual at least one selected from the group consisting of the brain function improving agent and the composition for improving brain function. .
  • the compounds represented by any of the structural formulas (1) to (3) have an effect of promoting astrocyte proliferation, an effect of promoting GDNF mRNA expression in astrocytes, an effect of promoting AQP4 mRNA expression in astrocytes, and an effect of promoting NO in microglia.
  • Astrocyte proliferation promoter, GDNF mRNA expression promoter in astrocytes, and AQP4 mRNA expression promoter in astrocytes by utilizing production suppressing effect, TNF- ⁇ production suppressing effect in microglia, or inflammation-related gene mRNA expression suppressing effect in microglia. It may be used as an active ingredient of an agent, an agent for suppressing NO production in microglia, an agent for suppressing TNF- ⁇ production in microglia, or an agent for suppressing inflammation-related gene mRNA expression in microglia.
  • the present invention also provides a method for promoting proliferation of astrocytes, which comprises administering to an individual at least one of the compounds represented by any one of the structural formulas (1) to (3).
  • a method of promoting the expression of GDNF mRNA in astrocytes a method of promoting the expression of AQP4 mRNA in astrocytes, a method of suppressing NO production in microglia, a method of suppressing TNF- ⁇ production in microglia, or an inflammation-related method in microglia.
  • the present invention also relates to a method of suppressing gene mRNA expression.
  • test examples and formulation examples of the present invention will be explained, but the present invention is not limited to these test examples and formulation examples.
  • Test sample In each test example described below, the following compounds were used as test samples. - Compound represented by the above structural formula (1) (manufactured by SIGMA) - Compound represented by the above structural formula (2) (manufactured by SIGMA) - Compound represented by the above structural formula (3) (manufactured by Tokyo Chemical Industry Co., Ltd.)
  • a mouse-derived astrocyte culture strain (C8-S) was cultured using DMEM containing 10% by mass of FBS, and then the cells were collected by trypsin treatment. The collected cells were diluted with DMEM containing 10 mass% FBS to a concentration of 2.5 x 10 4 cells/mL, then seeded at 100 ⁇ L per well in a 96-well plate, and incubated at 37°C under 5% CO 2 The cells were cultured for 6 hours.
  • test sample dissolved in DMEM containing 10% by mass FBS (see Table 1 below for final sample concentration) was added to each well and cultured for 4 days.
  • DMEM containing 10% by mass FBS 100 ⁇ L of DMEM containing 10% by mass FBS without addition of the test sample was added and cultured in the same manner.
  • a mouse-derived astrocyte culture strain (C8-S) was cultured using DMEM containing 10% by mass of FBS, and then the cells were collected by trypsin treatment. The collected cells were diluted with DMEM containing 10% by mass FBS to a concentration of 5.0 x 10 4 cells/mL, then seeded at 2 mL per well in a 6-well plate, and incubated at 37°C under 5% CO 2 The cells were cultured until confluent.
  • RNA After culturing, remove the culture medium, extract total RNA using RNeasy (registered trademark) mini kit (manufactured by Qiagen), calculate the amount of RNA from the absorbance at a wavelength of 260 nm, and adjust the total RNA to 100 ng/ ⁇ L. did.
  • RNeasy registered trademark
  • mini kit manufactured by Qiagen
  • GDNF and GAPDH mRNA which was an internal standard, were measured. Detection of mRNA was performed using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (manufactured by TaKaRa) using PrimeScript TM RT Master Mix (Perfect Real Time) and TB Gr een (registered trademark) Fast qPCR Mix (manufactured by TaKaRa) ) was carried out using a two-step real-time RT-PCR reaction. The expression level of GDNF mRNA was calculated by correcting the expression level of GAPDH mRNA.
  • the promotion rate (%) of GDNF mRNA expression was calculated using the following formula.
  • GDNF mRNA expression promotion rate (%) C/D x 100 C to D in the above formula each represent the following.
  • a mouse-derived astrocyte culture strain (C8-S) was cultured using DMEM containing 10% by mass of FBS, and then the cells were collected by trypsin treatment. The collected cells were diluted with DMEM containing 10 mass% FBS to a concentration of 5.0 x 10 4 cells/mL, then seeded in 2 mL per well in a 6-well plate, and incubated at 37°C under 5% CO 2 The cells were cultured until confluent.
  • test sample (see Table 3 below for final sample concentration) dissolved in DMEM containing 10 mass% FBS containing a final concentration of 0.5% DMSO was added to each well. Cultured for hours. As a control, 2 mL of DMEM containing 10 mass % FBS containing 0.5% DMSO and no test sample was added and cultured in the same manner.
  • RNA After culturing, remove the culture medium, extract total RNA using RNeasy (registered trademark) mini kit (manufactured by Qiagen), calculate the amount of RNA from the absorbance at a wavelength of 260 nm, and adjust the total RNA to 100 ng/ ⁇ L. did.
  • RNeasy registered trademark
  • mini kit manufactured by Qiagen
  • RNA was analyzed for the expression levels of AQP4 and GAPDH mRNA, which was an internal standard. Detection of mRNA was performed using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (manufactured by TaKaRa) using PrimeScript TM RT Master Mix (Perfect Real Time) and TB Gr een (registered trademark) Fast qPCR Mix (manufactured by TaKaRa) ) was carried out using a two-step real-time RT-PCR reaction. The expression level of AQP4 mRNA was calculated by correcting the expression level of GAPDH mRNA.
  • Thermal Cycler Dice registered trademark
  • Real Time System III manufactured by TaKaRa
  • PrimeScript TM RT Master Mix Perfect Real Time
  • TB Gr een registered trademark
  • Fast qPCR Mix manufactured by TaKaRa
  • the AQP4 mRNA expression promotion rate (%) was calculated using the following formula.
  • AQP4 mRNA expression promotion rate (%) E/F x 100
  • E to F in the above formula each represent the following.
  • a mouse-derived microglia culture strain (C8-B4) was cultured using DMEM containing 10% by mass of FBS, and then the cells were collected by trypsin treatment. The collected cells were diluted with DMEM containing 10 mass% FBS to a concentration of 1.0 x 10 5 cells/mL, then seeded at 100 ⁇ L per well in a 96-well plate, and incubated at 37°C under 5% CO 2 The cells were cultured until confluent.
  • LPS Lipopolysaccharide
  • IFN- ⁇ interferon-gamma
  • the amount of nitric oxide (NO) produced was measured using the amount of nitrite ion (NO 2 ⁇ ) as an index. Specifically, after the completion of the culture, the same amount of Griss reagent (5% by mass phosphoric acid solution containing 1% by mass sulfanilamide and 0.1% by mass N-1-naphthyl ethylenediamine dihydrochloride) was added to 100 ⁇ L of the culture solution in each well. was added and reacted for 10 minutes at room temperature. After the reaction, absorbance at a wavelength of 540 nm was measured. A calibration curve was created using NO 2 - as an indicator, and the amount of NO produced in the culture supernatant was determined.
  • Griss reagent 5% by mass phosphoric acid solution containing 1% by mass sulfanilamide and 0.1% by mass N-1-naphthyl ethylenediamine dihydrochloride
  • TNF- ⁇ Tumor necrosis factor- ⁇ (TNF- ⁇ ) production inhibition test in microglia
  • a mouse-derived microglia culture strain (C8-B4) was cultured using DMEM containing 10% by mass of FBS, and then the cells were collected by trypsin treatment. The collected cells were diluted with DMEM containing 10 mass% FBS to a concentration of 1.0 x 10 5 cells/mL, then seeded at 100 ⁇ L per well in a 96-well plate, and incubated at 37°C under 5% CO 2 The cells were cultured until confluent.
  • LPS Lipopolysaccharide
  • TNF- ⁇ production inhibition rate (%) ⁇ (J-I)/J ⁇ 100 I to J in the above formula each represent the following. I: TNF- ⁇ amount when test sample is added J: TNF- ⁇ amount when test sample is not added
  • a mouse-derived microglia culture strain (C8-B4) was cultured using DMEM containing 10% by mass of FBS, and then the cells were collected by trypsin treatment. The collected cells were diluted with DMEM containing 10 mass% FBS to a concentration of 1.0 x 10 5 cells/mL, then seeded in 2 mL per well in a 6-well plate, and incubated at 37°C under 5% CO 2 The cells were cultured until confluent.
  • LPS Lipopolysaccharide
  • FBS interferon-gamma
  • TNF- ⁇ tumor necrosis factor- ⁇
  • iNOS inducible nitric oxide synthase
  • IL-6 interleukin-6
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-12 interleukin-12
  • CXC motif chemokine ligand 2
  • Detection of mRNA was performed using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (manufactured by TaKaRa) using PrimeScript TM RT Master Mix (Perfect Real Time) and TB Gr een (registered trademark) Fast qPCR Mix (manufactured by TaKaRa) ) was carried out using a two-step real-time RT-PCR reaction.
  • TNF- ⁇ , iNOS, IL-6, IL-1 ⁇ , IL12, and CXCL2 are known to be inflammation-inducing factors, and when stimulated with LPS and IFN- ⁇ , they are The expression of these mRNAs was increased compared to .
  • mRNA expression rate (%) of each gene K/L x 100 K to L in the above formula each represent the following. K: Correction value when test sample is added, LPS and IFN- ⁇ stimulation L: Correction value when test sample is not added, LPS and IFN- ⁇ stimulation
  • Combination example 1 Tablets having the following composition were manufactured by a conventional method.
  • - Compound represented by the above structural formula (1) 5.0 mg ⁇ Dolomite 83.4mg (Contains 20% calcium and 10% magnesium) ⁇ Casein phosphopeptide 16.7mg ⁇ Vitamin C 33.4mg ⁇ Maltitol 136.8mg ⁇ Collagen 12.7mg ⁇ Sucrose fatty acid ester 12.0mg
  • Combination example 2 An oral liquid preparation having the following composition was produced by a conventional method. ⁇ Composition in 1 ampoule (100 mL per bottle)> - Compound represented by the above structural formula (2) 0.3% by mass ⁇ Sorvit 12.0% by mass ⁇ Sodium benzoate 0.1% by mass ⁇ Fragrance 1.0% by mass ⁇ Calcium sulfate 0.5% by mass ⁇ Remaining purified water
  • Combination example 4 Capsules having the following composition were manufactured by a conventional method. Note that a No. 1 hard gelatin capsule was used as the capsule. ⁇ Composition in 1 capsule (1 tablet 200mg)> - Compound represented by the above structural formula (1) 30.0 mg ⁇ Corn starch 70.0mg ⁇ Lactose 80.0mg ⁇ Calcium lactate 10.0mg ⁇ Hydroxypropylcellulose (HPC-L) 10.0mg

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Abstract

L'invention concerne un agent d'amélioration des fonctions cérébrales contenant au moins un composé représenté par une des formules de structure (1) à (3).
PCT/JP2023/028953 2022-09-16 2023-08-08 Agent d'amélioration des fonctions cérébrales, et composition pour amélioration des fonctions cérébrales WO2024057782A1 (fr)

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JP2022-147644 2022-09-16

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WO2024057782A1 true WO2024057782A1 (fr) 2024-03-21

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