KR102062597B1 - Composition for preventing or treating sarcopenia and muscle loss comprising resveratrol analogue - Google Patents

Abstract

The present invention relates to a composition for preventing or treating muscle loss, which includes a resveratrol derivative as an active ingredient. The resveratrol derivative HS-1793 is a mitochondria against oxidative stress caused by tBHP, which is a representative oxidative stress-inducing drug in mouse muscle cell line (C2C12). Since it has been shown to function and inhibit cell death, HS-1793 can be usefully used as a drug for preventing, improving or treating muscle loss.

Description

Composition for preventing or treating sarcopenia and muscle loss comprising resveratrol analogue comprising resveratrol derivative as an active ingredient

The present invention relates to a composition for preventing or treating muscle loss, which includes a resveratrol derivative as an active ingredient. The resveratrol derivative HS-1793 is a mitochondria against oxidative stress caused by tBHP, which is a representative oxidative stress-inducing drug in mouse muscle cell line (C2C12). It protects function and inhibits cell death.

One of the antioxidants, resveratrol is a plant-derived antibiotic that can be found in various plant species and is also an edible substance. These plant antibiotics resveratrol has a variety of physiological activity and many reports have been reported on its mechanism. However, the activity is lower than other physiological drugs and has the disadvantage that it is easily oxidized. In order to overcome this drawback, resveratrol derivatives have been synthesized and the physiological mechanisms thereof have been studied. Resveratrol is known to have the effect of preventing damage caused by ischemic reperfusion and preventing heart failure and hypertension caused by diabetes.

Oxidative stress caused by side effects of aging, anticancer drugs and drugs promotes cell death along with mitochondrial dysfunction, and muscle loss caused by these oxidative stress in muscle cells is a serious disease (sarcopenia or muscle atrophy). Inhibition of muscle loss through inhibition of mitochondrial oxidative stress (sacopenia) is a well-known therapeutic target, but various treatments have been developed. However, there have been no reports on the effects of resveratrol derivatives on muscle loss.

Korea Patent Registration No. 10-1771680 (Registered Aug. 21, 2017)

It is an object of the present invention to provide a composition for preventing, improving or treating muscle loss, which comprises resveratrol derivative HS-1793 as an active ingredient.

The present invention provides a pharmaceutical composition for preventing or treating muscle loss, comprising HS-1793, a resveratrol derivative as an active ingredient.

The present invention also provides a health functional food composition for preventing or improving muscle loss, comprising HS-1793, which is a resveratrol derivative as an active ingredient.

The present invention relates to a composition for preventing or treating muscle loss, which includes a resveratrol derivative as an active ingredient. The resveratrol derivative HS-1793 is a mitochondria against oxidative stress caused by tBHP, which is a representative oxidative stress-inducing drug in mouse muscle cell line (C2C12). Since it has been shown to function and inhibit cell death, HS-1793 can be usefully used as a drug for preventing, improving or treating muscle loss.

1 shows the structure of HS-1793.
Figure 2 shows the cytotoxicity test results of HS-1793.
Figure 3 shows the results of the mitochondrial function enhancement by HS-1793 and the prevention of mitochondrial damage by oxidative stress-induced drug (tBHP). # p <0.05 non-control versus treatment group. * P <0.05 between treatment groups. tBHP: tert-Butyl hydroperoxide, a representative oxidative stress-inducing drug.
4 shows the cytotoxicity reduction results by tBHP (50 μM) of HS-1793.
Figure 5 shows the results of mitochondrial quantitative increase and related biosynthesis related gene increase by HS-1793 drug.
6 shows the results of activation of the AKT / mTOR signal transduction pathway in HS-1793 treatment.
7 shows the muscle mitochondrial protection and cell protection mechanisms of HS-1793.

Therefore, the present inventors confirmed that the HS-1793 compound, which is a resveratrol derivative, exhibits mitochondrial function protection and cell death suppression effect on oxidative stress by tBHP, a representative oxidative stress-inducing drug in mouse muscle cell line (C2C12). Completed.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating muscle loss, comprising a resveratrol derivative represented by the following formula (1) as an active ingredient.

[Formula 1]

Preferably, the resveratrol derivative may be 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol (hereinafter, abbreviated as HS-1793).

Preferably, the resveratrol derivative may induce increased ATP production of mitochondria in muscle cells, inhibition of production of free radicals (ROS), and inhibition of loss of mitochondrial membrane voltage (ΔΨm).

Preferably, the resveratrol derivative may activate the AKT / mTOR signal transduction pathway in muscle cells.

"AKT" is a protein closely related to cell survival and is a serine / threonine-specific protein kinase, also known as protein kinase B (PKB).

The "mamtorian target of rapamycin" (mTOR) is an important regulator of cell growth and proliferation and is known as a factor involved in tumor formation. mTOR has been shown to be involved in the PI3K-Akt signaling pathway in general and is also regulated by AMP-activated protein kinase (AMPK), which acts as an energy sensor within cells and induces apoptosis, particularly in cancer cells.

Preferably, the resveratrol derivative may increase the expression of PGC-1α, a mitochondrial biosynthesis regulatory gene.

Preferably, the muscular dystrophy may exhibit muscle atrophy, work force, muscular dystrophy, muscle rigidity, muscle dysfunction, muscle weakness, muscle regression axis, muscular dystrophy, or severe work force symptoms, but is not limited thereto.

In addition, the present invention provides a health functional food composition for preventing or improving muscle loss, comprising a resveratrol derivative represented by the following formula (1) as an active ingredient.

[Formula 1]

Preferably, the resveratrol derivative may be 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol (hereinafter, abbreviated as HS-1793).

The pharmaceutical composition may further include a suitable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition.

Carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.

The pharmaceutical compositions according to the present invention may be used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods. Can be.

When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed and prepared.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The resveratrol derivative of the present invention may be included in an amount of 0.01 to 30.0 parts by weight based on 100 parts by weight of the pharmaceutical composition. When the content is less than 0.01% by weight, the effect on muscle loss is insignificant, and when the content exceeds 30.0% by weight may cause a problem that the effect of the amount used is insignificant.

The amount of the resveratrol derivative which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, weight, and disease of the patient, but is preferably 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg per day. It may be administered several times to several times.

In addition, the dosage of the resveratrol derivative of the present invention may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.

The pharmaceutical composition may be administered to various mammals such as mice, mice, livestock, humans, and the like. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine dural or intracerebroventricular injection.

The health functional food composition may be provided in the form of a health functional food or a health beverage, it is preferable to use in the form of a soft or hard capsule filled with functional powders, pills, tablets or dry powdered ingredients.

For example, the health functional food includes various foods, candy, chocolate, beverages, gums, teas, vitamin complexes, various health supplements, and the like, and may be used in the form of powders, granules, tablets, pills, capsules, or beverages.

The health functional food may further include a food acceptable carrier. As an example, when the health food of the present invention is a beverage, there are no special limitations on the liquid components except for containing naphthyl-1,3-benzenediol derivatives as essential ingredients in the indicated ratios. Eggplant flavor or natural carbohydrate and the like may be included as additional ingredients. At this time, examples of natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as conventional sugars such as dextrin, cyclodextrin and the like and sugar alcohols such as xylitol, sorbitol, erythritol and the like. In addition, as the flavoring agent, natural flavoring agents, for example, taumartin, stevia extract, hebadioside A, glycyrrhizin and synthetic flavoring agents such as saccharin, aspartame, and the like can be used.

In addition to the beverage, the health functional food of the present invention is a flavor, colorant, enhancer, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloids such as various nutrients, vitamins, minerals, synthetic flavors and natural flavors. Thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.

 The terms, techniques, and the like described in the present invention are used in the meanings generally used in the technical field to which the present invention belongs unless there is no particular limitation. In addition, all the documents mentioned in this specification are included in this specification as the documents for demonstrating this invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

< Example >

Cell safety was confirmed for the HS-1793 drug (FIG. 2). Concentration of HS-1793 in the C2C12 cell line, a mouse muscle cell line, showed no cytotoxicity at concentrations of 0-10 μM.

In addition, mitochondrial function enhancement by HS-1793 and mitochondrial damage by oxidative stress-inducing drug (tBHP) was confirmed. As a result, HS-1793 improved mitochondrial function of C2C12 cells at doses up to 10 μM. ATP analysis showed that HS-1793 increased cellular and mitochondrial ATP and improved ATP levels in tBHP treated cells (FIG. 3A). ATP was recovered upon treatment of HS-1793 at doses below 10 μM. Mitochondrial membrane potential was reduced in tBHP treated cells and recovered upon HS-1793 treatment (FIG. 3B). ROS measurements increased in tBHP-treated cells but ROS levels decreased upon HS-1793 treatment (FIG. 3C). In other words, the treatment of tBHP causes inhibition of mitochondrial ATP production, increased free radical (ROS) production, and loss of mitochondrial membrane voltage (ΔΨm), but co-treatment with HS-1793 enhances production of ATP and production of reactive oxygen (ROS). It showed the effect of suppression and prevention of membrane voltage loss.

As a result of confirming the effect of HS-1793 on the cytotoxicity reduction by tBHP (50 μM), the cell death occurred at 12 and 24 hours when 50 μM of tBHP treatment, and the toxicity was proportional to the concentration of HS-1793 treatment. This was confirmed to be reduced (FIG. 4).

The effect of HS-1793 on the amount of mitochondria and related biosynthesis related genes were confirmed. As shown in FIG. 5A, treatment of HS-1793 increases the mitochondrial content. Confocal microscopy images of C2C12 stained with NAO, a mitochondrial specific staining agent, showed that higher mitochondrial signals were increased in 5 μM, 10 μM treated cells. 5B shows a quantitative comparison graph of mitochondrial signals, and FIG. 5C shows the results of expression changes of representative mitochondrial biosynthesis regulatory genes. HS-1793 significantly increased the expression of PGC-1α, an important mitochondrial biosynthesis regulatory gene, at 5 μM and 10 μM.

The effect on activation of the AKT / mTOR signaling pathway was confirmed in HS-1793 treatment. AKT / mTOR signaling is an important signaling system for muscle proliferation and growth. It was confirmed that this signal was improved in proportion to the concentration of HS-1793, and HS-1793 was found to increase and activate phosphorylation of mTOR and Akt protein (FIG. 6A). Figure 6B shows the relative quantification of mTOR phosphorylation, and Figure 6C shows the relative quantification of Akt protein phosphorylation.

Based on the above results, the muscle mitochondrial protection and cell protection mechanism of HS-1793 is as shown in Figure 7, HS-1793 can be usefully used to prevent or treat muscle loss caused by oxidative stress.

Having described the specific part of the present invention in detail, it is obvious to those skilled in the art that such a specific description is only a preferred embodiment, thereby not limiting the scope of the present invention. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A pharmaceutical composition for preventing or treating muscle loss, comprising the resveratrol derivative represented by the following Formula 1 as an active ingredient.
[Formula 1]

The pharmaceutical composition for preventing or treating muscle loss, according to claim 1, wherein the resveratrol derivative is 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol. The pharmaceutical composition for preventing or treating muscle loss, according to claim 1, wherein the resveratrol derivative induces increased ATP production of mitochondria in muscle cells, inhibition of production of free radicals (ROS), and inhibition of mitochondrial membrane voltage (ΔΨm). . The pharmaceutical composition of claim 1, wherein the resveratrol derivative activates the AKT / mTOR signal transduction pathway in muscle cells. The pharmaceutical composition of claim 1, wherein the resveratrol derivative increases the expression of PGC-1α, a mitochondrial biosynthesis regulatory gene. The muscle loss syndrome according to any one of claims 1 to 5, the muscular dystrophy, muscular dystrophy, muscular dystrophy, muscular rigidity, muscular dystonia, muscle weakness, muscle retraction axis, muscular dystrophy or severe workforce symptoms A pharmaceutical composition for preventing or treating muscle loss, characterized in that it represents. A health functional food composition for preventing or improving muscle loss comprising the resveratrol derivative represented by the following Formula 1 as an active ingredient.
[Formula 1]

According to claim 7, wherein the resveratrol derivative is 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol, functional health food composition for preventing or improving muscle loss, characterized in that.

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