JP2023076373A - AMYLOID β AGGREGATION INHIBITOR AND PHARMACEUTICAL COMPOSITION AND BEVERAGE PRODUCT CONTAINING THE SAME, NEPRILYSIN PRODUCTION PROMOTER AND γ-SECRETASE PRODUCTION INHIBITOR - Google Patents

Abstract

Kind Code: A1 An amyloid β aggregation inhibitor capable of suppressing amyloid β (Aβ) aggregation, and a pharmaceutical composition, food and drink, etc. for treating and/or preventing diseases caused by amyloid aggregation (especially Alzheimer's dementia). to provide The present invention provides an amyloid β-aggregation inhibitor containing an Aspergillus oryzae-derived composition. [Selection drawing] Fig. 1

Description

TECHNICAL FIELD The present invention relates to an amyloid β-aggregation inhibitor, a pharmaceutical composition and food and drink containing the same, a neprilysin production promoter and a γ-secretase production inhibitor.

In Japan, where the elderly population is increasing and the birth rate is declining, it is expected that by 2025, one in three people will be 65 years old or older, and one in five people will be 75 years old or older. It is said to become human. Furthermore, it is predicted that one in four Japanese elderly people will become dementia patients by 2060, and dementia prevention measures are urgently needed. Above all, Alzheimer's dementia (AD) occupies a high proportion of about 60% of the number of dementia patients.

One of the underlying causes of Alzheimer's disease (AD) is believed to be an increase in senile plaques produced by amyloid β (Aβ). Aβ is a small protein with a molecular weight of about 4 kDa, consisting of 38 to 43 amino acids, and produced by being cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase. As major molecular species of Aβ, there are Aβ40 and Aβ42 due to differences in the number of amino acids. Among these, Aβ42 is known to have stronger pathogenicity due to its high aggregation property.

In addition, Aβ is believed to accumulate in the brain through two stages of "Aβ generation" and "Aβ aggregation". As a composition having the activity of inhibiting Aβ aggregation, for example, a composition containing perilla extract as an active ingredient has been proposed (Patent Document 1). In addition, as a composition having an activity to inhibit γ-secretase, which is one of the protein processing enzymes involved in Aβ generation, a γ-secretase inhibitory composition containing a plant extract derived from Hishka etc. as an active ingredient has been proposed ( Patent document 2).

Japanese Patent Application Laid-Open No. 2016-124865 Japanese Patent Application Laid-Open No. 2013-53076

However, none of the conventionally proposed compositions for treating Alzheimer's disease dementia has a certain effect on the increase in senile plaques for reasons such as insufficient permeability of the blood-brain barrier. , No definitive treatment for Alzheimer's dementia has been established.

The present invention has been made in view of the above circumstances, and an amyloid β aggregation inhibitor capable of suppressing aggregation of amyloid β (Aβ) and a disease caused by amyloid β aggregation (especially Alzheimer's disease) ) to provide pharmaceutical compositions, foods and beverages for the treatment and/or prevention of

In order to solve the above problems, the amyloid β-aggregation inhibitor of the present invention is characterized by containing an Aspergillus oryzae-derived composition.

The pharmaceutical composition of the present invention is characterized by containing the amyloid β aggregation inhibitor.

The food or drink of the present invention is characterized by containing the amyloid β aggregation inhibitor.

The neprilysin production promoter of the present invention is characterized by containing an Aspergillus oryzae-derived composition. Furthermore, the γ-secretase production inhibitor of the present invention is characterized by containing an Aspergillus oryzae-derived composition.

The amyloid β aggregation inhibitor of the present invention can reliably suppress amyloid β aggregation. In addition, according to the pharmaceutical composition and food and drink of the present invention, Alzheimer's dementia can be treated or prevented in particular.

Fig. 2 is a diagram confirming Aβ42 aggregation in aged mice and young mice to which the rice koji extract was administered. [ Fig. 10] Fig. 10 is a diagram showing the results of measuring the expression level of Aβ production and accumulation-related gene mRNA by real-time PCR in aged mice to which the rice koji extract was administered. [ Fig. 10] Fig. 10 is a diagram showing the results of measuring the expression level of Aβ production and accumulation-related gene mRNA by real-time PCR in young mice to which the rice koji extract was administered. FIG. 2 is a diagram showing the results of blood biochemical tests performed on aged mice and young mice that orally ingested a rice koji extract.

Hereinafter, one embodiment of the amyloid β-aggregation inhibitor, pharmaceutical composition, and food and drink of the present invention will be described.

(Amyloid β Aggregation Inhibitor)
The amyloid β aggregation inhibitor of the present invention contains an Aspergillus oryzae-derived composition.

In the present invention, "Aspergillus" refers to the fungus itself obtained by culturing an Aspergillus strain, and "Aspergillus" refers to, for example, grains such as rice, wheat, soybeans, etc., which are grown by adhering Aspergillus oryzae. Say.

As the koji mold, koji mold (imperfect fungus belonging to the genus Aspergillus) that has been used in the production of foods such as miso, sake, shochu, awamori, and soy sauce can be used. These Aspergillus oryzae are microorganisms indispensable for the production of fermented foods, and are excellent in terms of safety to humans.

The type of koji mold is not particularly limited, but examples include Aspergillus oryzae, Aspergillus kawachii, Aspergillus awamori, Aspergillus sojae, and Aspergillus glaucus. , Aspergillus tamari, Aspergillus luchuensis, Aspergillus nigar, and the like. There may be. In addition, commercially available koji molds can be used. Among them, the koji mold is preferably Aspergillus oryzae.

The method for culturing the koji mold is not particularly limited, and known methods such as a solid culture method in which koji mold is attached to grains such as rice, wheat, and soybeans and propagated, and a culture method using an agar medium or a liquid medium. can be adopted as appropriate. In addition, there are various methods such as preservation culture suitable for long-term preservation of koji mold, subculture suitable for subculture preservation of koji mold, seed koji culture suitable for obtaining a large amount of conidia of koji mold, isolation of koji mold and characterization of koji mold. It may be in the form of a monoculture isolate suitable for study. The method of culturing koji mold also includes brewing and fermentation using koji mold. The conditions for culturing the koji mold are not particularly limited, either. For example, the koji mold can be cultured at a predetermined temperature (eg, 10° C. to 40° C.) in a temperature-controlled place such as a constant temperature bath.

In the present invention, the term "composition derived from Aspergillus oryzae" means a composition containing a compound produced by Aspergillus oryzae. is a composition comprising a compound that is Therefore, the "composition derived from koji mold" may be a composition contained in koji, processed products of koji, fermented products such as koji miso, etc., and also includes koji, processed products of koji, koji miso, etc. itself. Morphology is also included.

Here, the processed product of koji may be various processed products obtained by physically, chemically or biologically treating koji.

Specifically, physical and chemical processed products include, for example, sun-dried, air-dried, freeze-dried and freeze-dried products, blenders, homogenizers, pulverized products such as ball mills, and the like. can do. In addition, as the biological treatment method, a fermentation state control treatment and the like can be exemplified.

In addition, processed products of koji include extracts obtained from koji by various extraction methods as long as they contain active ingredients. Examples of extraction methods include various solvent extractions and supercritical fluid extractions. The extract is subjected to various solid-liquid separation methods such as sedimentation separation, cake filtration, clarification filtration, centrifugal filtration, centrifugal sedimentation, compression separation, and filter press, various concentration methods, various drying methods, and formulation methods such as granulation or powderization. , various purification methods, and the like.

In one embodiment of the present invention, the koji mold-derived composition is preferably a composition contained in rice koji or a processed product of rice koji. Also included are forms that are Processed products of rice malt include fermented foods made from rice malt, such as rice malt miso.

The amyloid β aggregation inhibitor of the present invention can contain, for example, a pharmaceutically acceptable salt in addition to the Aspergillus oryzae-derived composition. Such salts include, for example, sodium salts, potassium salts, lithium salts, hydrochlorides, bromates, sulfates, hydrogen sulfates, dihydrogen phosphates, methanesulfonates, methyl sulfates, acetates, Examples include maleate, fumarate, 2-naphthalenesulfonate, benzenesulfonate, glycolate, gluconate, citrate, isethionate, and para-toluenesulfonate.

The amyloid β aggregation inhibitor of the present invention can suppress the production of senile plaques due to Aβ aggregation, and can treat or prevent Alzheimer's dementia. In addition, the amyloid β-aggregation inhibitor of the present invention is highly safe because it contains the Aspergillus oryzae-derived composition as an active ingredient.

(Pharmaceutical composition and food and drink)
The Aβ aggregation inhibitor of the present invention described above can be used in combination with additives or the like commonly used in pharmaceutical compositions or foods and beverages to prepare pharmaceutical compositions and foods and beverages for the prevention or treatment of Alzheimer's disease, amyloidosis, and the like. It can be used in the form of

In the present invention, in the case of pharmaceutical compositions and foods and beverages for Alzheimer's disease, the target of intake means animals suffering from or capable of suffering from Alzheimer's disease, such as mammals including humans.

One embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition for treatment and/or prevention of Alzheimer's dementia, containing the amyloid β aggregation inhibitor of the present invention described above.

The pharmaceutical composition may be in a dosage form for oral use or may be in a dosage form for parenteral use. Dosage forms for oral use include, for example, powders, granules, tablets, capsules, elixirs, microcapsules and the like. Dosage forms for parenteral use include, for example, injections, inhalants, suppositories, patches and the like.

A pharmaceutical composition can include a pharmaceutically acceptable carrier. Examples of such carriers include known excipients, disintegrants, binders, lubricants, surfactants, buffers, solubilizers, stabilizers, tonicity agents, suspending agents, and emulsifying agents. , solvents, thickeners, mucolytic agents, wetting agents, preservatives and the like.

The pharmaceutical composition may further contain additives. Additives include lubricating agents such as magnesium stearate; sweeteners such as sucrose, lactose and saccharin; flavoring agents such as peppermint and red leaf oil; stabilizers such as benzyl alcohol and phenol; buffers such as phosphate and sodium acetate. agents; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives and the like.

A pharmaceutical composition can be formulated by appropriately combining the above-mentioned carriers, additives, and the like, and admixing them in a unit dose form generally required for pharmaceutical practice. The form of the pharmaceutical composition is not particularly limited, and may be oral or parenteral. Oral preparations include granules, powders, tablets, capsules, syrups and the like. Parenteral agents include injections, drops, ointments, nasal drops, suppositories and the like.

The dose of the pharmaceutical composition varies depending on the body weight and age of the patient, the symptoms of the patient, the administration method, etc., but a person skilled in the art can appropriately select the appropriate dose. For example, the daily intake of Aspergillus oryzae for an adult can be in the range of 1 mg to 1000 mg, preferably 10 mg to 100 mg.

The food and drink (food and drink) of the present invention contain the above-described amyloid β aggregation inhibitor of the present invention.

Examples of food and drink include health food and drink (supplements, nutritional supplements, health supplements, nutritional adjustment food, etc.), soft drinks, tea drinks, jelly drinks, sports drinks, coffee drinks, carbonated drinks, vegetable drinks, fruit juice drinks, fermented vegetable drinks, fermented fruit juice drinks, fermented milk drinks (yogurt, etc.), lactic acid drinks, milk drinks, Powdered beverages, cocoa beverages, alcoholic beverages, sweets (e.g., biscuits, cookies, chocolate, candies, chewing gums, tablets), jelly, and the like can be exemplified. may contain components commonly used in the field of Specifically, for example, various fats and oils (e.g., vegetable oils such as soybean oil, corn oil, safflower oil, and olive oil, animal fats and oils such as beef tallow and sardine oil), crude drugs (e.g., royal jelly, carrots, etc.), amino acids (e.g., glutamine, cysteine, leucine, arginine, etc.), polyhydric alcohols (e.g., ethylene glycol, polyethylene glycol, propylene glycol, glycerin, sugar alcohols, e.g., sorbitol, erythritol, xylitol, maltitol, mannitol, etc.), natural polymers (e.g., arabic gum, agar, water-soluble corn fiber, gelatin, xanthan gum, casein, gluten or gluten hydrolysate, lecithin, starch, dextrin, etc.), vitamins (e.g. vitamin C, vitamin B group, etc.), minerals (e.g. calcium, magnesium, zinc) , iron, etc.), dietary fiber (e.g., mannan, pectin, hemicellulose, etc.), surfactant (e.g., glycerin fatty acid ester, sorbitan fatty acid ester, etc.), purified water, diluent, stabilizer, tonicity agent, pH adjuster , buffering agents, wetting agents, solubilizing agents, suspending agents, coloring agents, flavoring agents, flavoring agents, flavoring agents, antioxidants, sweeteners, taste components, acidulants, and the like.

The intake of food and drink varies depending on the patient's body weight and age, patient's symptoms, administration method, etc., but a person skilled in the art can appropriately select an appropriate dosage. For example, the daily intake of Aspergillus oryzae for an adult can be in the range of 1 mg to 1000 mg, preferably 10 mg to 100 mg.

In addition, the neprilysin production promoter of the present invention contains an Aspergillus oryzae-derived composition. Furthermore, the γ-secretase production inhibitor of the present invention contains an Aspergillus oryzae-derived composition. The neprilysin production-enhancing agent and the γ-secretase production inhibitor of the present invention can contain other compounds as long as the effect is not inhibited, similarly to the above-described amyloid β-aggregation inhibitor.

The amyloid β-aggregation inhibitor, the pharmaceutical composition and food and drink containing the same, the neprilysin production promoter, and the γ-secretase production inhibitor of the present invention are not limited to the above embodiments.

Hereinafter, the present invention will be described in more detail with examples. The present invention is by no means limited by the following examples.

<Example 1> Investigation of cerebral amyloid aggregation inhibitory effect by oral intake of rice koji extract 1% rice koji was added to sterilized phosphate-buffered saline (PBS), glass beads were added, and the mixture was homogenized. , 3,000 rpm, 5 min, and the obtained supernatant was adjusted with sterilized PBS to obtain a rice koji extract (1×10 ⁶ cfu/mL).
Aged mice (48-week-old healthy ICR strain inbred mice) and young mice (4-week-old) were treated with the above rice koji extract (1×10 ⁶ cfu/mL) by the sonde method. 100 μL of the solution was orally ingested once a day for 4 weeks. Then, under anesthesia, blood was collected from aged and young mice, and brain tissue was collected. Aβ42 aggregation in the brain was confirmed by fluorescence staining, and the mRNA expression level of genes related to Aβ production and accumulation was measured by real-time PCR. bottom.

The results are shown in FIGS. 1-3. FIG. 1 is a diagram showing aggregation of Aβ42 in the cerebral cortex and medulla of brain tissue confirmed by fluorescent immunostaining in aged mice and young mice to which the rice koji extract was administered. Fig. 2 shows the results of measuring the mRNA expression levels of genes related to Aβ production and accumulation by real-time PCR in aged mice to which the rice malt extract was administered. FIG. 10 is a diagram showing the results of measuring the mRNA expression level of genes associated with Aβ production and accumulation in aged mice by real-time PCR.

As shown in FIG. 1, it was confirmed that Aβ42 aggregation was suppressed in aged mice and young mice to which the rice koji extract was administered. In addition, as shown in FIG. 2, it was confirmed that the neprilysin gene (NEP) mRNA expression level was increased in aged mice to which the rice koji extract was administered. Neprilysin is known to degrade senile plaques.
On the other hand, as shown in FIG. 3, it was confirmed that the expression level of γ-secretase gene mRNA decreased in young mice to which the rice koji extract was administered. γ-Secretase is known to be involved in the production of Aβ42.
From these facts, the rice koji extract (koji mold-derived composition) has a neprilysin production promoting action or a γ-secretase production inhibitory action, and oral intake of the rice koji extract can suppress the aggregation of Aβ42 in the brain. was confirmed. It is conceivable that the low-molecular-weight compounds contained in the rice koji extract pass through the brain barrier and act.

Therefore, it can be considered that the rice koji extract functions as an active ingredient of an Aβ42 aggregation inhibitor, and that pharmaceutical compositions and food and drink products containing it have therapeutic and preventive effects particularly on Alzheimer's dementia. .

<Example 2> Blood Biochemistry Test Blood biochemistry tests were performed on the aged mice and young mice that orally ingested the rice koji extract by the enzymatic reaction colorimetric method.

The results are shown in FIG.

As shown in FIG. 4, it was confirmed from a physicochemical point of view that oral intake of the rice koji extract poses no health problems.

Claims (9)

An amyloid β aggregation inhibitor comprising a composition derived from Aspergillus oryzae. 2. The amyloid β-aggregation inhibitor according to claim 1, wherein the koji mold-derived composition is a composition contained in rice koji or processed rice koji. 2. The amyloid β aggregation inhibitor according to claim 1, wherein the koji mold contains Aspergillus oryzae. A pharmaceutical composition comprising the amyloid β-aggregation inhibitor according to any one of claims 1 to 3. 5. The pharmaceutical composition according to claim 4, which is used for treatment and/or prevention of Alzheimer's dementia. A food or drink containing the amyloid β-aggregation inhibitor according to any one of claims 1 to 3. 7. The food or drink according to claim 6, which is for treatment and/or prevention of Alzheimer's dementia. A neprilysin production promoter comprising a composition derived from Aspergillus oryzae. A γ-secretase production inhibitor comprising a composition derived from Aspergillus oryzae.

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