Composition for preventing noise-related hearing impairment and composition for inhibiting expression of γ-aminobutyric acid a receptor

Abstract

To provide a composition containing a naturally sourced component that is confirmed to be safe and capable of preventing noise-related hearing impairment as an active ingredient, and to provide a composition containing a component that acts on a neurotransmitter or its receptor as an active ingredient.SOLUTION: The above problem is solved by a composition for preventing noise-related hearing impairment, containing bee larvae as an active ingredient; and a composition for inhibiting expression of γ-aminobutyric acid A receptor, containing bee larvae as an active ingredient.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a composition for preventing noise-induced hearing loss and a composition for suppressing the expression of γ-aminobutyric acid A receptor.

Background Art

[0002] Hearing impairment refers to a state where sound cannot be heard at all (total deafness) or is difficult to hear (hearing loss) due to a disorder in any part of the site for sending sound information to the brain.

[0003] Hearing loss is roughly classified into conductive hearing loss occurring from the external ear to the middle ear, sensorineural hearing loss occurring from the inner ear or auditory nerve, and mixed hearing loss in which these are combined. Sensorineural hearing loss is caused by damage to the inner ear due to aging, noise, etc., and often becomes permanent hearing loss.

[0004] Sensorineural hearing loss is further subdivided into age-related hearing loss, noise-induced hearing loss, sudden deafness, congenital deafness, etc. Age-related hearing loss is caused by internal factors such as a decrease in blood flow in the cochlea in the inner ear and the induction of cell death in cells localized in auditory tissues by reactive oxygen species generated from mitochondria.

[0005] Bee larvae are known as an active ingredient for improving age-related hearing loss (for example, Non-Patent Document 1). Non-Patent Document 1 describes that when elderly people aged 60 or above suffering from age-related hearing loss ingested freeze-dried powder of enzymatically decomposed bee larvae for 12 weeks, the ability to hear voices in a noisy environment was improved, but no improvement in hearing level was brought about in either a quiet environment or a noisy environment. In addition, Non-Patent Document 1 suggests that the effect of such freeze-dried powder of enzymatically decomposed bee larvae is related to a decrease in the amount of cortisol in the blood. Further, Non-Patent Document 2 describes that the dried powder of enzymatically decomposed bee larvae can relieve the depressive state associated with tinnitus in elderly people aged 60 or above who have developed tinnitus.

[0006] Among sensorineural hearing loss, noise-induced hearing loss is caused by excessive acoustic stimulation, which affects the hair cells in the inner ear, synapses, and the auditory nerve transmission mechanism. When the damage is mild, it remains a temporary nerve transmission disorder and hearing ability recovers. When the damage is severe or repeated, it leads to damage such as the death of hair cells and auditory nerve cells, resulting in permanent hearing loss.

[0007] Some neurological disorders are improved by changes in signal transmission by the receptor of the neurotransmitter γ-aminobutyric acid (GABA). Among GABA receptors, the GABA A receptor is a pentameric transmembrane receptor containing various combinations of 19 different subunit polypeptides, and there are at least 15 GABA A receptor subtypes.

[0008] GABA A When the GABA receptor is activated, the secretion of neurotransmitters is suppressed. Thus, GABA receptor agonists such as benzodiazepines are used as sleep-inducing agents. Conversely, when the activity of the GABA A receptor is inhibited, the excitability of nerves is moderately enhanced. As a result, for example, it is known that maze learning in mice is promoted, and plastic modifications around glutamate receptors are promoted in the hippocampus. There is also a report that a decrease in the expression of the GABA A receptor after brain injury affects the functional recovery of the brain. Thus, when the activity of the GABA A receptor decreases due to a decrease in expression or the like, the improvement of nervous system excitability can bring about the promotion of memory, learning, and brain functional recovery. A

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0010] Non-Patent Document 1 states that even after ingesting bee larvae for 12 weeks, the hearing levels of elderly people aged 60 and above suffering from presbycusis did not improve. Therefore, even after ingesting bee larvae for 12 weeks, the difficulty in hearing due to presbycusis is not improved. What is described in Non-Patent Document 2 is that bee larvae can relieve the depressive state associated with tinnitus, and there is no description related to the difficulty in hearing due to presbycusis.

[0011] On the other hand, noise-induced hearing loss caused by acoustic disorders may be caused by components that can affect neurotransmitters such as GABA or receptors of neurotransmitters such as GABA receptors, which play a role in the information transmission mechanism of the nervous system, and there is a possibility of recovery before permanent hearing loss occurs. A Moreover, hearing impairment caused by noise such as noise-induced hearing loss can be caused by sudden noise. Therefore, a component that improves noise-induced hearing impairment is expected to be ingested daily and continuously, and further ingested for the purpose of preventing noise-induced hearing impairment. For example, it is desirable that the component is of natural origin and has recognized safety.

[0012] However, there has been little knowledge so far about components that are of natural origin, have recognized safety, and can prevent noise-induced hearing impairment.

[0013]

[0014] ​Therefore, the present invention aims to provide a composition containing as an active ingredient a component that is naturally derived, recognized as safe, and capable of preventing noise-induced hearing impairment. Furthermore, in view of the fact that noise-induced hearing impairment is caused by damage to hair cells and auditory nerve cells and their neurotransmission, the present invention aims to provide a composition containing as an active ingredient a component that acts on a neurotransmitter or its receptor. [Means for solving the problem]

[0015] The present inventors have conducted extensive research to solve the above problem, and have conducted trial and error to obtain an active ingredient that can prevent noise-induced hearing impairment by using numerous components alone or in appropriate combination.

[0016] And, after repeated investigations, the inventors finally found that by ingesting natural and edible bee larvae in advance, it is possible to alleviate temporary damage to hearing caused by noise and prevent permanent hearing loss. This was obtained as a result of trying a different approach to hearing loss prevention, based on the fact that bee larvae do not improve the decline in hearing level caused by age-related hearing loss, as described in Non-Patent Document 1.

[0017] More surprisingly, the inventors found that ingesting bee larvae reduces the expression level of GABA A receptors in the inner ear after noise exposure. This fact suggests that the decreased expression of GABA A receptors may have enhanced the excitability of the nervous system around the inner ear, thereby alleviating neurotransmission disorders and thus preventing permanent hearing loss.

[0018] Based on such findings, the inventors of the present invention have successfully created a composition containing, as an active ingredient, a component that is naturally derived, has recognized safety, and can prevent noise-induced hearing impairment, and a composition containing, as an active ingredient, a component that acts on the receptor of neurotransmitters in the auditory nervous system. The present invention is an invention completed based on such findings first discovered by the inventors and such successful examples first achieved.

[0019] Therefore, from each aspect of the present invention, the following aspects are provided: [1] A composition for preventing noise-induced hearing impairment, containing bee larvae as an active ingredient. [2] A composition for suppressing the expression of γ-aminobutyric acid type A receptor, containing bee larvae as an active ingredient. [3] The composition according to [1] or [2], wherein the bee larvae are enzymatically decomposed bee larvae powder. [4] The composition according to [1] or [2], wherein the composition is for ingestion by a subject for 1 to 10 weeks. [5] The composition according to [1] or [2], which is a food, a cosmetic, a quasi-drug, or a pharmaceutical.

Effects of the Invention

[0020] According to the present invention, noise-induced hearing impairment can be prevented by alleviating the damage to the auditory system caused by noise and suppressing the permanent decrease in hearing level. According to the present invention, the expression of γ-aminobutyric acid type A receptor, that is, GABA A receptor can be suppressed. Further, the composition for preventing noise-induced hearing impairment and the composition for suppressing the expression of GABA A receptor according to one aspect of the present invention have high safety because the active ingredient is naturally derived and is bee larvae with food experience. Therefore, the composition for preventing noise-induced hearing impairment and the composition for suppressing the expression of GABA A receptor according to one aspect of the present invention can be used to prevent noise-induced hearing impairment in various forms such as food and drink products, cosmetics, pharmaceuticals, and quasi-drugs.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0022] Hereinafter, the details of each aspect of the present invention will be described. However, the present invention is not limited only by the matters in this section, and can take various aspects as long as the object of the present invention is achieved.

[0023] Each term in this specification is used in the meaning usually used by those skilled in the fields of food, cosmetics, pharmaceuticals, and quasi-drugs, unless otherwise specified, and should not be construed as having an unduly restrictive meaning. Also, the assumptions and theories made in this specification are based on the inventors' knowledge and experience so far, and the present invention is not restricted only by such assumptions and theories.

[0024] "Composition" is not particularly limited as having the commonly used meaning, and examples thereof include a substance formed by combining two or more components. "Component" means a substance used (added) in manufacturing a composition, and is synonymous with a substance and a (raw) material. A component may exist in a composition in a state where it is maintained or changed qualitatively and / or quantitatively as compared with before use. "Content" is synonymous with concentration and addition amount (usage amount), and means the ratio of the amount of a component to the total amount of a composition. However, the total amount of the content of a component does not exceed 100%. When using a commercially available product, the content of the component is preferably the amount of the component contained in the commercially available product, but may also be the amount of the commercially available product itself. "Comprise", "contain", and "include" mean that elements other than those explicitly stated as being included can be added (synonymous with "at least comprise"), and include "consist of" and "essentially consist of". That is, "comprise" can mean including the explicitly stated elements and any one or two or more elements, consisting of the explicitly stated elements, or essentially consisting of the explicitly stated elements. Examples of elements include limitations such as components, steps, conditions, and parameters. "And / or" means any one of the multiple related items listed, or any combination or all combinations of two or more. The "~" in a numerical range represents a range that includes the numerical values before and after it, and also includes a range excluding one of the included limit values. For example, "0%~100%" can be 0% or more, 100% or less, or any value between 0% and 100%. "About" means an amount within ±10% of the quantity following the term. For example, "about 100" means 100 ± 10%, that is, 90 to 110.

[0025] The "receptor expression inhibitory action" refers to at least one action selected from the group consisting of reducing the expression level of the receptor gene (i.e., the amount of mRNA), reducing the translation amount of the receptor (protein) (i.e., the amount of protein), and inhibiting the production of the receptor.

[0026] [Summary of the Invention] One aspect of the present invention is a composition for preventing noise-induced hearing loss, which is used for preventing noise-induced hearing loss. Another aspect of the present invention is a composition for suppressing the expression of the gamma-aminobutyric acid A receptor (hereinafter also referred to as the GABA A receptor), which is used for suppressing the expression of the GABA A receptor.

[0027] By ingesting the composition for preventing noise-induced hearing loss according to one aspect of the present invention, damage to hearing caused by noise can be reduced, and the degree of symptoms of hearing loss can be alleviated. Specifically, by ingesting the composition for preventing noise-induced hearing loss according to one aspect of the present invention, a decrease in hearing level due to noise after ingestion can be reduced.

[0028] By ingesting the composition for suppressing the expression of the GABA A receptor according to one aspect of the present invention, the expression level of the GABA A receptor in the inner ear can be suppressed. It is known that a decrease in the expression of the GABA A receptor can improve the excitability of the nervous system and promote the functional recovery of the brain after brain injury. From these facts, a decrease in the expression of the GABA A receptor can change the excitability of the auditory nervous system and alleviate the degree of symptoms of hearing loss and reduce a permanent decrease in hearing level due to noise, for example, by reducing or blunting the damage to the auditory system caused by noise.

[0029] [Active ingredient] The composition for preventing noise-induced hearing loss according to one aspect of the present invention and the composition for suppressing the expression of the GABA A receptor contain bee pupae as an active ingredient.

[0030] Bee pupae are a general term for bee larvae and nymphs. The type of bee is not particularly limited. For example, bees such as Japanese honeybees, Western honeybees, Africanized honeybees, wasps (including black wasps), giant hornets, and bumblebees can be mentioned. Since they are beekept and easily available, honeybees are preferred, and Western honeybees are more preferred. Note that the sex of the bee is not limited, and it may be a male bee or a female bee, but a male bee is preferred.

[0031] The larvae and nymphs are not particularly limited as long as they are hatched from eggs. For example, preferably, they are bee larvae and nymphs after 16 to 23 days have passed since hatching, and more preferably, they are bee larvae and nymphs after 18 to 21 days have passed since hatching.

[0032] Bee larvae accumulate nutrients in their bodies. For example, male honeybees have long been used as a material in traditional Chinese medicine. They contain various amino acids, including essential amino acids, in a well-balanced manner, and also contain abundant proteins, lipids, saccharides, vitamins such as vitamin B group, folic acid, nicotinic acid, pantothenic acid, and minerals such as zinc and selenium (selenium).

[0033] The bee larvae are preferably raw bee larvae or processed products of raw bee larvae. Examples of the processed products of bee larvae include crushed products of bee larvae, dried products of bee larvae, heat-treated products of bee larvae, extracts of bee larvae obtained using solvents such as water and hydrous ethanol, etc. The processing may be a combination of these, for example, it may be a dried powder of bee larvae obtained by subjecting bee larvae to drying treatment and crushing treatment. When using a plurality of processing treatments, the order of the processing treatments is not particularly limited. From the viewpoints of the amount of nutrients contained and storage stability, the bee larvae are preferably dried powder of bee larvae prepared by drying (raw) bee larvae and then crushing them.

[0034] The drying treatment is not particularly limited, and examples include known drying treatments employed in general food processing such as natural drying like ventilation drying and sun drying, forced drying by heating with electricity etc. to dry, freeze drying etc. Since the damage to bee larvae is small, freeze drying is preferably used. The drying conditions are not particularly limited, and for example, in the case of natural drying such as ventilation and sun drying, it may be about 3 days, and in the case of forced drying by heating with electricity etc., it may be about 1 to 3 days at about 50 °C. The degree of drying is not particularly limited, and for example, it is the degree that the moisture content becomes below a predetermined amount, preferably below 10% by mass, more preferably below 5% by mass.

[0035] The crushing treatment (powdering treatment) is not particularly limited, and for example, it can be carried out using known treatments such as a treatment of crushing using a crusher (mill) and a treatment of grinding using a mortar.

[0036] The heat treatment is not particularly limited, and examples include treatments carried out at a high temperature of 70°C or higher, preferably a heat treatment at 70°C to 120°C. For simplicity, it may be a heat treatment of putting the bee larvae into boiling water, but in order to avoid elution of useful components such as various vitamins and amino acids as much as possible, it is preferable to perform a heat treatment of steaming the bee larvae with steam.

[0037] The extraction treatment is not particularly limited. For example, an extraction treatment in which an extraction solvent such as water or hydrous ethanol is added to the bee larvae, the obtained extraction product after stirring is centrifuged to obtain an extract as a supernatant, and an extraction treatment in which the extraction product is filtered using a filter medium to obtain an extract as a filtrate, etc. may be mentioned.

[0038] By treating the bee larvae with a proteolytic enzyme, the proteins contained in the bee larvae can be reduced in molecular weight, and the allergic reaction caused by the proteins can be suppressed. That is, by subjecting the bee larvae to an enzymatic treatment, a hypoallergenic enzymatic treatment product of the bee larvae can be obtained.

[0039] The proteolytic enzyme used for the enzymatic treatment is not particularly limited as long as it is an enzyme having an activity of decomposing proteins. Examples include peptidase and protease. Since the allergen can be further reduced in molecular weight, peptidase is preferable. The peptidase only needs to have at least one of the activities of endopeptidase activity and exopeptidase activity.

[0040] The peptidase has an EC number (enzyme number) in the 3.4 group, and is not particularly limited as to its origin as long as it acts on the bee larvae to obtain a hypoallergenic enzymatic treatment product. Peptidases derived from animals, plants, and microorganisms (bacteria, viruses, fungi (molds, yeasts, mushrooms, etc.), algae, etc.) can be widely used. However, since there is a track record in food processing, peptidases derived from bacteria or fungi are preferable.

[0041] Peptidases having endopeptidase activity are not particularly limited, and examples thereof include endopeptidases derived from animals (e.g., trypsin, chymotrypsin, etc.), plants (e.g., papain, etc.), and microorganisms (e.g., lactic acid bacteria, yeast, mold, Bacillus subtilis, actinomycetes, etc.). Preferably, they are peptidases produced by Bacillus subtilis, Bacillus licheniformis, Bacillus stearothermophilus, Bacillus amyloliquefaciens, and Bacillus spp.

[0042] Peptidases having exopeptidase activity include carboxypeptidase, aminopeptidase, and exopeptidases derived from microorganisms (e.g., lactic acid bacteria, Aspergillus spp., Rhizopus spp., etc.). Furthermore, pancreatin, pepsin, etc., which also have endopeptidase activity, are included. Preferably, they are peptidases produced by Aspergillus oryzae, Aspergillus sojae, Aspergillus spp., and Rhizopus oryzae.

[0043] The peptidase preferably has both exopeptidase activity and endopeptidase activity. Examples thereof include peptidases produced by Streptomyces griseus, Aspergillus oryzae, Aspergillus melleus, etc. Preferably, it is a peptidase produced by Aspergillus oryzae.

[0044] Peptidases may be classified as acidic, neutral, or alkaline according to their optimal pH, and may be described, for example, as acidic exopeptidases, neutral aminopeptidases, or alkaline endopeptidases.

[0045] Peptidases may be commercially available products, such as, for example, "Sumitomo LP-G" (manufactured by Shin Nippon Chemical Industry Co., Ltd.), "Protease M 'Amano' SD", "Protease P 'Amano' 3SD", "Proteax" (manufactured by Amano Enzyme Inc.), "Flavourzyme" (manufactured by Novozymes Japan K.K.), etc., but are not limited thereto.

[0046] Enzymatic treatment for reducing the allergy of royal jelly can be carried out with reference to, for example, the descriptions in Japanese Patent No. 7260203 and JP-A-2009-159997. In the enzymatic treatment, both a peptidase having endopeptidase activity and a peptidase having exopeptidase activity may be used, or one of them may be used first and then the other. If a peptidase having both endopeptidase activity and exopeptidase activity is used, it is possible to reduce the molecular weight of proteins in a one-step enzymatic treatment.

[0047] For example, a diluted royal jelly solution obtained by dispersing royal jelly in water is adjusted to a pH of 7 to 10, and then an aqueous solution of "Proteax" (manufactured by Amano Enzyme Inc.) having both endopeptidase activity and exopeptidase activity and water are added to the obtained pH-adjusted diluted royal jelly solution. Then, the obtained mixture is subjected to a hydrolysis reaction by stirring at 40°C to 70°C for 1 hour to 5 hours, and then to an enzyme inactivation reaction by stirring at about 80°C for 10 minutes to 20 minutes, whereby a low-allergen enzymatic-treated product of royal jelly is obtained.

[0048] [Composition for Preventing Noise-Induced Hearing Loss] The composition for preventing noise-induced hearing loss according to one aspect of the present invention contains an active ingredient, and can prophylactically reduce the degree of hearing loss caused by noise. By ingesting the composition for preventing noise-induced hearing loss according to one aspect of the present invention, it has an effect of reducing the degree of damage to hearing caused by noise generated after ingestion, preferably an effect of suppressing the decrease in hearing ability caused by noise generated after ingestion, which is called the preventive effect of noise-induced hearing loss.

[0049] The content of the active ingredient in the composition for preventing noise-induced hearing loss according to one aspect of the present invention is not particularly limited as long as the composition for preventing noise-induced hearing loss according to one aspect of the present invention has a preventive effect on noise-induced hearing loss. For example, it is preferably 0.01% by mass to 100% by mass, more preferably 1% by mass to 80% by mass, and even more preferably 5% by mass to 70% by mass based on the total amount of the composition.

[0050] The application target of the composition for preventing noise-induced hearing loss according to one aspect of the present invention is not particularly limited. For example, animals, especially mammals, can be mentioned. Examples of mammals include humans, dogs, cats, cows, horses, pigs, sheep, rabbits, etc. Among these, humans are preferably used. The application target may be a healthy subject, but it is preferably a subject currently exposed to noise or a subject at risk of being exposed to noise.

[0051] Noise-induced hearing loss may be any disorder in which hearing ability is reduced by noise. Since the composition for preventing noise-induced hearing loss according to one aspect of the present invention can prophylactically relieve the state in which it is difficult to hear sounds due to noise, noise-induced hearing loss is preferably noise-induced hearing impairment. The magnitude and duration of the noise are not particularly limited as long as they cause hearing impairment. For example, it is preferably 50 dB or more, 60 dB or more, or 70 dB or more, and more preferably 80 dB or more, 90 dB or more, or 100 dB; it is preferably 1 minute or more, 2 minutes or more, 3 minutes or more, or 4 minutes or more, and more preferably 5 minutes or more or 10 minutes or more.

[0052] However, the composition for preventing noise-induced hearing loss according to one aspect of the present invention is not used for treating presbycusis. Therefore, the composition for preventing noise-induced hearing loss according to one aspect of the present invention is preferably ingested by a subject not suffering from presbycusis or a human under 50 years old, and more preferably ingested by a human under 50 years old not suffering from presbycusis. Regarding the prevalence of hearing loss, for the age group of 40 to 44 years old, there is little change in the age group of 50 to 55 years old, but it is known to increase in the age group of 55 to 59 years old and subsequent age groups (see, for example, Japanese Geriatrics Society Journal, Vol. 49, No. 2, pp. 222-227 (2012)).

[0053] The administration route of the composition for preventing noise-induced hearing loss according to one aspect of the present invention is not particularly limited, and may be oral administration or parenteral administration. Oral administration includes enteral administration, and parenteral administration includes local administration, for example, transdermal administration.

[0054] When the composition for preventing noise-induced hearing loss according to one aspect of the present invention is orally administered, the dosage can be appropriately set depending on factors such as the amount of the active ingredient, the form of the composition, and the application method, and is not particularly limited. For example, for an adult weighing 60 kg, the amount of the active ingredient in terms of dry solid content is preferably 100 mg to 10,000 mg per day, more preferably 300 mg to 4,000 mg, 500 mg to 2,000 mg, and 600 mg to 1,000 mg. The dosage can be appropriately increased or decreased according to factors such as the health status of the administration subject, the administration method, and the combination with other agents.

[0055] The composition for preventing noise-induced hearing loss according to one aspect of the present invention may be administered once a day or divided into multiple doses, such as twice a day or three times a day, as long as the effective daily dosage is within the above range. The composition for preventing noise-induced hearing loss according to one aspect of the present invention is preferably administered continuously. For example, continuous administration for 1 week or more is preferred, continuous administration for 1 month or more, 6 months or more, or 1 year or more is more preferred, and continuous administration for 1 week to 10 weeks is even more preferred.

[0056] Since the composition for preventing noise-induced hearing loss according to one aspect of the present invention is used for preventive measures, it is preferably administered continuously starting from at least one week before the possible occurrence of noise, more preferably starting from at least two weeks before, at least three weeks before, at least four weeks before, or at least one month before the possible occurrence of noise.

[0057] When the composition for preventing noise-induced hearing loss according to one aspect of the present invention is administered parenterally, the dosage can be appropriately set depending on factors such as the amount of the active ingredient, the site of application, and the scope of application, and is not particularly limited. For example, the dosage applied to the skin is preferably 0.001 mg to 50 mg as the amount of the active ingredient in terms of dry solid content, more preferably 0.02 mg to 40 mg, and even more preferably 0.01 mg to 35 mg or 0.02 mg to 30 mg.

[0058] The composition for preventing noise-induced hearing loss according to one aspect of the present invention contains other components in addition to the active ingredient. The other components are not particularly limited as long as they do not hinder the solution of the problems of the present invention. For example, powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbon oils, higher fatty acids, higher alcohols, ester oils, silicone oils, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, humectants, water-soluble polymers, thickeners, film-forming agents, ultraviolet absorbers, sequestering agents, lower alcohols, polyhydric alcohols, sugars, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant aids, fragrances, water, preservatives (such as ethyl paraben, butyl paraben, etc.), anti-inflammatory agents (such as glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.), whitening agents (such as placenta extract, snowdrop extract, arbutin), various extracts (such as eucommia, turmeric, shikon, peony, ginseng, birch, sage, loquat, carrot, aloe, Japanese butterbur, iris, grape, yomogi, loofah, lily, saffron, cnidium, ginger, forget-me-not, ononis, garlic, pepper, chinpi, toki, seaweed, etc.), activators (such as photosensitins, cholesterol derivatives, etc.), blood circulation promoters (such as wrenyllamide nonylate, benzyl nicotinate, β-butoxyethyl nicotinate, capsaicin, gingerol, cantharidin, ichthyol, tannic acid, α-borneol, tocopherol nicotinate, inositol hexanicotinate, cyclandelate, cinnarizine, tazoline, acetylcholine, verapamil, cephalanthin, γ-oryzanol, etc.), anti-seborrheic agents (such as sulfur, thiantol), anti-inflammatory agents (such as tranexamic acid, thiotaurine, hypotaurine), beekeeping products other than bee larvae (such as royal jelly, propolis, honey, beeswax, pollen load, bee venom, etc.), and the like.

[0059] The composition for preventing noise-induced hearing loss according to one aspect of the present invention can be produced by a conventional method by mixing an active ingredient and one or more other ingredients to obtain a desired form. The form of the composition for preventing noise-induced hearing loss according to one aspect of the present invention is not particularly limited as long as the preventive effect of noise-induced hearing loss by the active ingredient is exhibited. For example, solid, liquid, gel, suspension, cream, sheet, stick, powder, granule, granule, tablet, rod, plate, block, paste, capsule, caplet, aerosol, foam, etc. can be mentioned.

[0060] The composition for preventing noise-induced hearing loss according to one aspect of the present invention may be a container-packed composition filled in a sealable airtight container or a sealed container. The container is not particularly limited as long as it is an airtight container or a sealed container. For example, a single-layer or laminated (laminated) film bag, retort pouch, vacuum pack, molded container, bottle, can, etc. made of a metal such as aluminum or steel, paper, plastic such as PET, glass, etc. can be mentioned. The container-packed composition can be independently distributed and commercially available by itself. Note that a container with a lid used for the purpose of storing food at home is a sealed container, and is strictly distinguished from an airtight container and a sealed container, especially a sealed container.

[0061] The preventive effect of noise-induced hearing loss possessed by the composition for preventing noise-induced hearing loss according to one aspect of the present invention may be such that the decrease in hearing ability immediately after exposure to noise is reduced compared to those (controls) not containing the active ingredient under the same conditions. In particular, the composition for preventing noise-induced hearing loss according to one aspect of the present invention can exhibit an excellent preventive effect on noise-induced hearing loss for subjects intermittently exposed to a large sound volume, which is noise, a plurality of times.

[0062] The preventive effect against noise-induced hearing loss can be confirmed by the method described in the examples below. For example, it can be confirmed by measuring the hearing ability immediately after exposure to noise in a subject who has ingested the composition for preventing noise-induced hearing loss according to one embodiment of the present invention. The composition for preventing noise-induced hearing loss according to one embodiment of the present invention preferably has a preventive effect against noise-induced hearing loss such that the hearing threshold (dB) immediately after exposure to noise is 95% or less, more preferably 90% or less, and even more preferably 87% or less, when compared with a composition containing no active ingredient (control) under the same conditions, for a subject who has ingested it for one week. Here, the "preventive effect against noise-induced hearing loss such that the hearing threshold (dB) immediately after exposure to noise is 95% or less" means, for example, when the hearing threshold (dB) of the control is 100 dB, the composition for preventing noise-induced hearing loss according to one embodiment of the present invention has a preventive effect against noise-induced hearing loss such that the hearing threshold (dB) becomes 95 dB or less.

[0063] [Composition for suppressing the expression of GABA A receptor] The composition for suppressing the expression of GABA A receptor according to one embodiment of the present invention can suppress the expression of GABA A receptor in the inner ear tissue by containing an active ingredient. The composition for suppressing the expression of GABA A receptor according to one embodiment of the present invention can regulate the excitability of the nervous system and prevent or treat disorders related to neurotransmission, such as noise-induced hearing loss, through the effect of suppressing the expression of GABA A receptor, and further, preservation and recovery of hearing function can be expected.

[0064] GABA A receptor is a pentameric transmembrane receptor containing various combinations of 19 different subunit polypeptides, and there are at least 15 types of GABA A receptor subtypes. The composition for suppressing the expression of GABA A receptor according to one embodiment of the present invention suppresses the expression of one or more types of GABA AIt is only necessary that it suppresses the expression of the receptor subunit. For example, it is preferable that it can suppress the expression of any one, two, three, or all four of subunit α1, subunit γ2, subunit β2, and subunit α6.

[0065] GABA of one aspect of the present invention A Regarding the composition for suppressing the expression of the GABA receptor of one aspect of the present invention, for the type and amount of the active ingredient, the method and amount of administration, the contained components, the shape, the manufacturing method, etc., refer to the items of the above [composition for preventing noise-induced hearing loss].

[0066] GABA of one aspect of the present invention A The GABA that the composition for suppressing the expression of the receptor of one aspect of the present invention has A The inhibitory effect on the expression of the receptor may be the degree to which the expression of the GABA receptor in the inner ear is suppressed as compared with that of a control (without the active ingredient) under the same conditions. A

[0067] GABA A The inhibitory effect on the expression of the receptor can be confirmed by the method described in the examples below. For example, the composition for suppressing the expression of the GABA receptor of one aspect of the present invention, by the method described in the examples below, compared with a control (without the active ingredient) under the same conditions, after noise exposure, the expression level of subunit α1 is reduced, and / or the expression level of subunit γ2 is reduced, and / or the expression level of subunit β2 is reduced, and / or the expression level of subunit α6 is reduced, GABA A receptor expression inhibitory action is preferably such that. A It is preferable that it has an inhibitory effect on the expression of the receptor.

[0068] [Foods and drinks, cosmetics, quasi-drugs, and pharmaceuticals] The composition for preventing noise-induced hearing loss and GABA of one aspect of the present invention A ​The composition for suppressing the expression of the receptor can be used as foods, such as foods for the purpose of health care, health maintenance, promotion, etc. (for example, health foods, functional foods, nutritional compositions, dietary supplements, supplements, health foods, foods for specified health use, foods with nutritional functions, or foods with functional claims), cosmetics, quasi-drugs, and pharmaceuticals. Further, the composition for preventing noise-induced hearing loss according to one aspect of the present invention can also be used as an additive for imparting a preventive effect on noise-induced hearing loss.

[0069] The content of the active ingredient in the foods, cosmetics, quasi-drugs, and pharmaceuticals according to one aspect of the present invention is not particularly limited, and is an effective amount that can achieve the dosage of the composition for preventing noise-induced hearing loss and GABA A as long as it is an effective amount that can achieve the dosage of oral administration or parenteral administration of the composition for suppressing the expression of the receptor.

[0070] For example, the dosage of the food or pharmaceutical can be appropriately set according to various conditions such as the weight, age, gender, symptoms, etc. of the recipient, and is not particularly limited. However, for example, as the amount of bee larvae per day, it is preferably 0.5 g or more, more preferably 0.7 g or more, and even more preferably 1 g or more.

[0071] The foods, cosmetics, quasi-drugs, and pharmaceuticals according to one aspect of the present invention contain the composition for preventing noise-induced hearing loss or GABA A as one component of the composition for suppressing the expression of the receptor. For example, in the intermediate products in the manufacturing process of these products, the composition for preventing noise-induced hearing loss or GABA A can be produced by adding the composition for suppressing the expression of the receptor.

[0072] The food according to one aspect of the present invention contains, in addition to the active ingredient, components usually used in foods, such as excipients, glazing agents, minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, coloring agents, fragrances, stabilizers, preservatives, sustained-release regulators, surfactants, solubilizers, wetting agents, etc.

[0073] The type of food is not particularly limited. For example, dairy products; fermented foods (such as yogurt); beverages (soft drinks such as coffee, juice, tea beverages, milk beverages, lactic acid bacteria beverages, beverages containing lactic acid bacteria, yogurt beverages, carbonated beverages, Japanese sake, Western liquor, fruit wine, etc.); spreads (such as custard cream); pastes (such as fruit paste); Western confectionery (such as chocolate, donuts, pies, cream puffs, gums, gummies, jelly, candies, cookies, cakes, puddings, etc.); Japanese confectionery (such as mochi, rice cakes, steamed buns, castella, anmitsu, agar jelly, etc.); frozen confections (such as ice cream, ice candy, sherbet, etc.); foods (such as curry, beef bowl, miso soup, soup, meat sauce, pasta, pickles, jam, etc.); seasonings (such as dressing, furikake, umami seasoning, soup stock, etc.) and the like can be mentioned.

[0074] A specific example of the food is a supplement. The dosage unit form when used as a supplement is not particularly limited and can be appropriately selected. For example, tablets such as chewables and troches, capsules, granules, liquids, powders, pellets, syrups, pastes, drinks, gummies, etc. can be mentioned.

[0075] The cosmetics of one aspect of the present invention contain, in addition to the active ingredient, ingredients usually used in cosmetics. For example, bactericides, preservatives, surfactants, alcohols, aqueous components, water, colorants, pH adjusters, solubilizers, abrasives, foaming agents, enzymes, flavoring agents, chelating agents, excipients, thickeners, bases, emulsifiers, solvents, stabilizers, oils, cleaners (lactic acid bacteria), whitening agents, moisturizing agents, antioxidants, ultraviolet absorbers, powder components, coloring materials, various skin nutrients, etc. can be appropriately contained as needed.

[0076] The cosmetics may be those applied to the skin, mucous membranes, body hair, hair, scalp, nails, teeth, facial skin, lips, etc. of animals (including humans) and are not particularly limited.

[0077] The dosage forms of cosmetics can take a wide range of dosage forms, such as aqueous solution systems, solubilized systems, emulsion systems, powder systems, oil solution systems, gel systems, ointment systems, aerosol systems, water-oil two-layer systems, water-oil-powder three-layer systems, etc., and are not particularly limited.

[0078] The uses of cosmetics are not particularly limited. For example, in the case of basic cosmetics, there are facial cleansers, lotions, milks, creams, gels, essences, beauty serums, packs, masks, etc.; in the case of makeup cosmetics, there are foundations, lipsticks, blushes, eyeshadows, eyeliners, mascaras, etc.; in the case of nail cosmetics, there are manicures, base coats, top coats, cuticle removers, etc.; in addition, there are facial cleansers, (paste or liquid) toothpastes, mouthwashes, massage agents, cleansing agents, aftershave lotions, pre-shave lotions, shaving creams, body soaps, soaps, shampoos, conditioners, hair treatments, hair styling products, hair tonics, hair growth stimulants, hair tonics, antiperspirants, bath salts, etc.

[0079] The pharmaceutical of one aspect of the present invention can be referred to as a preparation of bee larvae. In addition to the active ingredient, the pharmaceutical contains ingredients usually used in pharmaceuticals, and can be used in admixture with other pharmaceutical ingredients described in the Japanese Pharmacopoeia, such as vitamins and crude drugs.

[0080] The pharmaceutical can prepare the active ingredient together with ingredients acceptable in pharmaceuticals into forms such as tablets (including plain tablets, sugar-coated tablets, effervescent tablets, film-coated tablets, chewable tablets, troches, etc.), capsules, pills, powders (powders), fine granules, granules, liquids, suspensions, emulsions, syrups, pastes, injections (including the case of preparing as a liquid by mixing with an infusion such as distilled water or amino acid infusion or electrolyte infusion at the time of use), etc., to make a pharmaceutical preparation.

[0081] The administration of the pharmaceutical may be local or systemic. The administration method is not particularly limited and is administered orally or parenterally. Examples of parenteral administration routes include subcutaneous, intradermal, intramuscular, intraperitoneal, intravenous or intraarterial administration, transdermal administration, etc.

[0082] In addition to the active ingredient, the pharmaceutical product can be appropriately formulated with pharmaceutically acceptable ingredients usually used in pharmaceutical products, such as excipients, binders, disintegrants, lubricants, colorants, suspending agents, thickeners, antioxidants, absorption promoters, pH adjusters, preservatives, antiseptics, stabilizers, surfactants, sweeteners, flavoring agents, fragrances, etc.

[0083] The cosmetics and pharmaceutical products of one aspect of the present invention include quasi-drugs.

[0084] The composition for preventing noise-induced hearing loss and the composition for suppressing the expression of GABA A receptor of one aspect of the present invention are applied to mammals including humans (preferably humans) so as to be applied to foods, cosmetics, pharmaceutical products and quasi-drugs. Thus, the composition for preventing noise-induced hearing loss and the composition for suppressing the expression of GABA A receptor of one aspect of the present invention uses bee larvae, which have been conventionally used as a food material, as an active ingredient, and thus has high safety.

[0085] [Another aspect of the present invention] Another aspect of the present invention is a method for preventing noise-induced hearing loss, which includes administering an active ingredient to a subject to prevent noise-induced hearing loss in the subject. Another aspect of the present invention is to administer an active ingredient to a subject to suppress the expression of GABA A receptor in the subject, which includes a method for suppressing the expression of GABA A receptor. Another aspect of the present invention is a method of using an active ingredient for producing the composition for preventing noise-induced hearing loss and the composition for suppressing the expression of GABA A receptor of one aspect of the present invention.

[0086] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples, and the present invention can take various aspects as long as the problems of the present invention can be solved.

Examples

[0087] [Example 1. Evaluation of suppression of hearing impairment due to noise exposure (1)] Experimental animals fed a test diet containing bee larvae were exposed to noise, and it was evaluated whether ingestion of the test diet reduces auditory damage caused by loud noise.

[0088] The test diet was prepared by mixing bee larva powder into the standard diet "AIN-93M" (manufactured by Oriental Yeast Co., Ltd.) so that the final concentration was 6.4% by mass. The bee larva powder was prepared by subjecting male bee larvae and pupae to enzymatic treatment using the peptidase "Proteax" (manufactured by Amano Enzyme Inc.) according to the description in the specification of Patent No. 7260203, and then pulverizing it by freeze-drying.

[0089] Fifteen-week-old C57BL / 6J female mice were fed the test diet (N = 12) or the standard diet (control) (N = 12) for 1 week, and then the 16-week-old mice were exposed to noise (white noise, 110 dB, 5 minutes). Immediately before and after the noise exposure, the hearing ability was measured by the following auditory brainstem response test (ABR).

[0090] Needle electrodes were inserted into the skin of the top of the head, cheek, and back of mice intraperitoneally administered with a three-component mixed anesthesia (medetomidine hydrochloride 0.3 mg / kg, midazolam 4 mg / kg, butorphanol tartrate 5 mg / kg), and the auditory brainstem response (evoked brain wave) to sound stimuli was measured using an ABR measuring device ("System3", manufactured by TDT). Pure tones (24 kHz) below 100 dB were used as sound stimuli, and the threshold was determined in 5 dB steps. After the measurement, atipamezole hydrochloride (0.3 mg / kg) was intraperitoneally administered to wake the mice from anesthesia. During the measurement as well, the mice were placed on a warming mat during anesthesia to keep their body temperature from dropping.

[0091] A comparison between the two groups (t-test) was performed at each of immediately before and after the noise exposure based on the obtained thresholds.

[0092] The results of the hearing tests are shown in Fig. 1. As shown in Fig. 1, there were almost no differences between the test diet group and the control group immediately before noise exposure. However, immediately after noise exposure, the test diet group had a significantly lower threshold compared to the control group. Thus, it was found that royal jelly powder has the effect of suppressing transient auditory transmission disorders immediately after noise exposure.

[0093] [Example 2. Evaluation of the suppression of hearing impairment due to noise exposure (2)] Five-week-old C57BL / 6J male mice (N = 24) were purchased from a breeder. After one week of acclimation, their hearing was measured at 6 weeks of age (the first series). To avoid group differences, the mice were divided into three groups: a test diet group, a control group, and a non-noise-exposed control group. From 8 weeks of age, the test diet group was fed the test diet, and the control group and the non-noise-exposed control group were fed a standard diet. One week after ingestion, at 9 weeks of age, two groups of mice in the test diet group and the control group were exposed to noise (white noise, 110 dB, for 10 minutes). At 10 weeks of age, one week after the exposure, the hearing of the three groups, including the non-noise-exposed control group, was measured by an auditory brainstem response test (ABR) (the second series). Similarly, at 10 weeks of age (two weeks after ingestion), 11 weeks of age (three weeks after ingestion), and 13 weeks of age (five weeks after ingestion), the hearing of the mice in the test diet group and the control group was measured, and then they were exposed to noise. For the non-noise-exposed control group, only hearing measurements were performed without noise exposure (the third series to the fifth series). At 14 weeks of age (six weeks after ingestion), only the hearing of each group of mice was measured, and one week later, the hearing was measured again (the sixth series).

[0094] The results of the hearing measurements for each group in the first series to the sixth series are shown in Fig. 2. As shown in Fig. 2, in the control group, the hearing continued to decline as the number of noise exposures increased. Also, the hearing did not recover even after the noise exposure was stopped (the sixth series), indicating that it had developed into permanent hearing loss. However, the test diet group that ingested royal jelly powder stably suppressed the hearing impairment due to noise exposure over a long period. Thus, it was found that royal jelly powder has the effect of stably suppressing permanent hearing loss due to noise exposure over a long period.

[0095] [Example 3. GABA A Evaluation of suppression of receptor expression] Eight-week-old male C57BL / 6J mice (N = 24) were divided into three groups: a test diet group, a control group, and a non-noise-exposed control group. The test diet group was fed the test diet, and the control group and the non-noise-exposed control group were fed a standard diet. One week after ingestion, the mice in the test diet group and the control group were exposed to noise (white noise, 110 dB, for 10 minutes). Four days after noise exposure, the inner ear tissues of each group were collected. Total RNA was extracted from the inner ear tissues. After quantifying the extracted total RNA, for each group, a sample was prepared by pooling the same amount of RNA from each mouse, and microarray analysis was performed according to a conventional method.

[0096] Table 1 shows a list of genes whose expression levels in the test diet group were higher or lower than those in the control group and the non-noise-exposed control group. In Table 1, "Bee" represents the test diet group, "Ctrl" represents the control group, and "None" represents the non-noise-exposed control group.

[0097] As shown in Table 1, the test diet group was found to suppress the expression of GABA receptor genes such as Gabra1, Gabrg2, Gabrb2, and Gabra6 compared to the control group and the non-noise-exposed control group. Thus, it was found that royal jelly powder has an effect of suppressing the expression level of the GABA receptor. A receptor. A

[0098] [Table 1]

Industrial Applicability

[0099] The composition for preventing noise-induced hearing loss and the composition for suppressing the expression of the GABA receptor according to one aspect of the present invention are derived from nature and have an active ingredient with recognized safety, and have a preventive effect on noise-induced hearing loss and A receptor. A ​Suppression of receptor expression acts in concert to prevent noise-induced hearing loss and can be used in various forms such as foods, cosmetics, pharmaceuticals, quasi-drugs, etc.

Claims

1. A composition for preventing noise-induced hearing loss, comprising bee larvae as an active ingredient.

2. A composition for inhibiting the expression of γ-aminobutyric acid A receptors, comprising bee larvae as an active ingredient.

3. The composition according to claim 1 or 2, wherein the bee larvae is an enzymatically decomposed bee larvae powder.

4. The composition according to claim 1 or 2, wherein the composition is intended to be ingested by a subject for a period of between 1 week and 10 weeks.

5. The composition according to claim 1 or 2, which is a food product, a cosmetic product, a quasi-drug product or a pharmaceutical product.

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