KR101830543B1 - Composition for prevention or treatment of neurodegenerative disease comprising astragalin - Google Patents

Abstract

The present invention relates to a composition for preventing or treating brain diseases containing astragalin as an active ingredient. The astragalin suppresses apoptosis and DNA damage in neural cells, reduces oxidative stress in cells, and improves memory, thereby being useful as the active ingredient in compositions for preventing and treating brain diseases.

Description

TECHNICAL FIELD [0001] The present invention relates to a composition for preventing or treating cerebrospinal fluid comprising astragalin as an active ingredient. BACKGROUND OF THE INVENTION 1. Field of the Invention [0001]

The present invention relates to a composition for preventing or treating brain diseases comprising astragalin as an active ingredient.

According to the ratio of the elderly population in Korea, the proportion of the population aged 65 and over in the total population was 7.2% in 2000 and entered the aging society in 2000. In 2019, this proportion will reach 14% . Chronic degenerative diseases are becoming a more serious problem than acute communicable diseases that have been the main cause of death for the past 50 years due to the increase in the aging population.

Alzheimer, a typical disease of degenerative brain disease, is the most common form of senile dementia, causing neurons in the brain to degenerate and the brain to contract, resulting in progressive mental disorders. Tacrine (Cognex, 1994) and donepezil (Aricept, 1996) have been approved by the US FDA as a representative dementia remedy known so far. The mechanism of action of these drugs is to prevent the dementia by increasing the concentration of acetylcholine, a neurotransmitter, by inhibiting the activity of acetylcholinesterase (AChE), the enzyme of acetylcholine, which plays a central role in the central nervous system (Patent Document 1). However, the tacrine is more expensive than the efficacy and has a serious problem of hepatotoxicity. Although the donepezil is not toxic to the liver, it stimulates the parasympathetic nerve and causes various side effects such as vomiting, nausea and diarrhea.

Accordingly, there is a demand for the development of a therapeutic agent for degenerative brain diseases derived from natural substances that can inhibit or prevent damage to nerve cells, protect nerve cells, and exhibit no side effects.

1. Korean Patent No. 10-1404566

One aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of brain diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and a food composition for preventing or ameliorating brain diseases It is to:

An aspect of the present invention provides a pharmaceutical composition for preventing or treating brain diseases comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

According to one embodiment of the present invention, the brain disease is one or more selected from the group consisting of stroke, memory loss, dementia, Parkinson's disease, and Alzheimer's disease But is not limited thereto.

As used herein, the term "brain disease" refers to a disease in which degenerative changes in nerve cells develop due to damage or aging of nerve cells and various symptoms are expressed.

According to one embodiment, the compound of Chemical Formula 1 may inhibit apoptosis of neuronal cells and may protect nerve cells by inhibiting DNA damage.

In addition, the compound of formula (1) can protect nerve cells because it inhibits the generation of active oxygen in nerve cells and reduces oxidative stress.

The composition of the present invention may further comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans. Pharmaceutically acceptable carriers include, for example, carriers for oral administration such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like, water for parenteral administration such as water, suitable oils, saline, aqueous glucose and glycols And may further contain stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995). The pharmaceutical composition according to the present invention may be formulated into a suitable form according to a method known in the art together with a pharmaceutically acceptable carrier as described above. That is, the pharmaceutical composition of the present invention can be prepared in various parenteral or oral administration forms according to known methods. Representative examples of formulations for parenteral administration include isotonic aqueous solutions or suspensions in the form of injection. The injectable formulations may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, each component may be formulated for injection by dissolving in saline or buffer. In addition, formulations for oral administration include, but are not limited to, powders, granules, tablets, pills, and capsules.

The pharmaceutical composition formulated as described above may be administered in an effective amount through various routes including oral, transdermal, subcutaneous, intravenous, or muscular. The term " effective amount " as used herein refers to an amount that shows a preventive or therapeutic effect when administered to a patient. The dosage of the pharmaceutical composition according to the present invention can be appropriately selected depending on the route of administration, subject to be administered, age, gender, individual difference, and disease state. Preferably, the pharmaceutical composition of the present invention may be administered in an effective amount of 1 to 100 mg / kg / day in the form of parenteral administration, depending on the severity of the disease.

Another aspect of the present invention provides a food composition for preventing or ameliorating brain diseases, which comprises the compound represented by Formula 1 as an active ingredient.

The food composition according to the present invention may be formulated in the same manner as the above pharmaceutical composition and used as a functional food or may be added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meats, chocolates, foods, confectionery, pizza, ramen noodles, gums, ice cream, alcoholic beverages, vitamin complexes, .

The compound of formula (I) according to the present invention may be added directly to the food composition or may be used together with other food or food ingredients, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound of formula (I) in the health supplement may be 0.01 to 15% by weight of the total food, and the health beverage composition may be added in an amount of 0.02 to 5 g, preferably 0.3 to 1 g, . However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

The food composition of the present invention can contain, in addition to the compound of formula (1), a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese and chocolate, Salts of alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. These ingredients may be used independently or in combination, and the proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the compound of the present invention.

According to one embodiment of the present invention, the compound of formula (1) is useful as a food composition for preventing or ameliorating brain diseases because it has an effect of protecting nerve cells.

The astragalin of the present invention is effective for inhibiting DNA damage and apoptosis in neurons, reducing oxidative stress in cells, and improving memory, and therefore is useful as a composition for preventing or treating brain diseases, It can be usefully used as an active ingredient of the composition.

FIG. 1A is a graph showing the results of measurement of cell survival rate in astragalin-treated neurons. FIG.
FIG. 1B is a graph showing the results of measurement of LDH activity and intracellular active oxygen levels in neurons exposed to hydrogen peroxide after pretreatment with astragalin. FIG.
FIG. 2A is a graph showing the results of analysis of nerve cells exposed to hydrogen peroxide by pretreatment with astragalin using a flow cytometer. FIG.
FIG. 2B is a fluorescence image showing the result of staining neurons exposed to hydrogen peroxide with pretreatment of astragalin with PI and FITC-dUTP.
FIG. 3 is a graph showing a result of measurement of a maze exit time of a mouse in an underwater maze test.
FIG. 4 is a graph showing the results of measurement of the room escape time of a mouse in the passive avoidance experiment. FIG.
5 is a graph showing the results of measurement of acetylcholine concentration and acetylcholinesterase activity in brain tissue of astragalin-treated mice.
6 is a graph showing the results of measurement of the expression level of p-CREB (Ser133) protein in brain tissue of astragalin-treated mice.
FIG. 7 is a graph showing the results of measurement of phosphorylated p21, phosphorylated p38, and phosphorylated JNK levels in brain tissue of astragalin-treated mice.

Hereinafter, one or more embodiments will be described in more detail by way of examples. However, these embodiments are intended to illustrate one or more embodiments, and the scope of the present invention is not limited to these embodiments.

Experimental Method

1. Cell viability, lactate dehydrogenase activity (lactate dehydrogenase , LDH ) And Intracellular Oxidative  Measure stress level

1-1: Measurement of cell viability

SK-N-SH cells, a human neuroblastoma cell line, were purchased from the American Type Culture Collection (ATCC) and cultured in 10% (v / v) heat-inactivated fetal serum (FBS) The cells were cultured in an EMEM medium containing 1% (v / v) penicillin / streptomycin in a thermostat maintained at 37 and 5% humidity.

The MTT (3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide), hydrogen peroxide (H ₂ O ₂ ) and DCF- DA (2,7- dichlorofluorescein diacetate) Were purchased from Aldrich (Sigma-Aldrich Co., USA).

Cell viability was determined by measuring mitochondrial dehydrogenase activity. Specifically, SK-N-SH cells were treated with astragalin (kaempferol-3-O-glucoside; Sigma-Aldrich Co., 68437) at a concentration of 5 and 10 μg / ml, respectively, and cultured for 24 hours. The medium was removed. MTT (3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide) solution (5 mg / ml) was then added to each well in ten times the volume of the culture medium. After standing for 4 hours, the MTT solution was removed and the cells were allowed to dry for 30 minutes. Then, DMSO was added to the cells, and the cells were lysed by shaking for 30 minutes. Then, the optical density was measured at 570 nm using a microplate reader (Molecular Devices co., USA). Cell viability was calculated as the ratio of viable cells in the experimental group compared to the number of cells in the control group without hydrogen peroxide.

1-2: LDH  Active and Intracellular Oxidative  Stress measurement

LDH activity was measured in supernants of cells using the LDH Cytotoxity Detection Kit (Takara Bio Inc., Japan) according to the manufacturer's instructions.

The intracellular oxidative stress was measured by using DCF-DA (2,7-dichlorofluorescein diacetate) to determine the generation of free radicals. Specifically, the cells were treated with DCF-DA for 45 minutes, then the DCF-DA solution was removed, and the cells were washed twice with phosphate buffered saline. The fluorescence intensity of DCF-DA was measured at 485 nm excitation and 538 nm emission using a fluorescence spectrophotometer (Synergy MX, BioTek, Winooski, USA).

2. Cell death ( apoptosis ) Measure

2-1: Flow cell  analysis

The degree of apoptosis was measured using the Apoptosis Detection Kit (Biovision, USA) according to the manufacturer's instructions. Specifically, SK-N-SH cells were plated at a concentration of 2 × 10 ⁵ cells / well in 6-well plates and treated with astragalin (5 μg / ml) for 24 hours. After 24 hours, the cells were treated with 500 쨉 m of hydrogen peroxide (H ₂ O ₂ ) for 30 minutes, and the cells were washed with ice-cold PBS and centrifuged to collect the cell pellet. Next, the cell pellet was suspended in binding buffer containing Annexin V-FITC and propidium iodide (PI). Cells were suspended in cows at room temperature for 5 minutes. Cells were immediately analyzed using a FACSCalibur flow cytometer (Beckman Coulter, Korea). The results were analyzed using CXP software (Beckman Coulter, Seoul, Korea).

2-2: Tunnel Assay ( TUNEL  assay)

The tunnel assay was performed using the ApoDIRECT In Situ DNA Fragmentation Assay Kit (Biovision Research Products, USA) according to the manufacturer's instructions. Specifically, SK-N-SH cells were divided into 6-well plates (2x10 ⁵ cells / well), treated with astragalin (5 μg / ml), cultured for 24 hours, treated with 500 μM hydrogen peroxide for 30 minutes Respectively. Next, the cells were fixed with 1% paraformaldehyde at 4 ° C for 15 minutes, and the cells were washed with wash buffer solution. The cells were then stained with the staining solution at 37 캜 for 60 minutes, and the cells were washed with rinse buffer solution. After incubation at room temperature with PI / RNase A solution for 30 min, apoptotic cells were observed using a fluorescence microscope (Leica, Germany).

3. Behavioral Experiment and Organizational Analysis

The 5-week-old male ICR mouse (ICR-mouse) used in the experiment was purchased from Samtaco BIOKOREA (Osan, Gyeonggi-do, Korea) and quarantined for one week at the Animal Research Institute of Animal Research Institute (No. 412, After the purification and breeding, they were used. The mice were fed at a temperature of 22 ± 3 ° C, 50 ± 10% relative humidity and 12 hours of illumination time. Feeds were fed with solid feed (Samtaco BIOKOREA, Korea) and free drinking water. 24 hours prior to dissection, only water was supplied and fasted. At this time, the experimental animals were treated within a certain time (10: 00-12: 00 am) in consideration of the fluctuation of enzyme activity in the daytime.

The mice were divided into 5 groups of 10 mice per group and the mice were divided into five groups: normal (N, saline), control (C, demented group, oral saline), positive control , Tacrin 2 ㎎ / ㎏), experimental group 1 (oral 0.5 mg / kg astragalin) and experimental group 2 (2 mg / kg astragalin administered orally). In the control group to the test group 2, scopolamine was further administered at a dose of 5 mg / kg per day to induce dementia.

This study was conducted in accordance with the policies and regulations of SEMI (SEMI 15-07), the Institute of Animal Care and Use of Southeast Asia.

3-1: Underwater maze  And passive avoidance experiment

The underwater labyrinth measuring device is a device for measuring the Haitian dependent spatial learning ability and memory ability. The water level was adjusted so that the circular platform was located 1.5 cm below the water surface, and the water temperature was maintained at 21 to 32 ° C.

Training trials were conducted by setting the time to reach the platform by placing the mouse in a water tank for 90 seconds. If the mouse could not find the platform within 90 seconds, it was taken out and left on the platform for 15 seconds. After 30 seconds, the mouse was put back into the tank to record the time to reach the platform. One learning experiment was performed over 5 days, and when the mouse reached the platform within 90 seconds, the learning test was considered completed. After performing the learning test, scofuran was administered to perform a test test.

Test trials were conducted by measuring the escape time, which is the time for the mouse to arrive at the platform in the tank for each group of mice for which the learning test was completed. The test was conducted for 3 days in the same manner as the test method, and the maximum measurement time was 90 seconds.

The passive avoidance test was performed to measure the working memory ability of the rodents. The experiment was conducted in a dark room with a noise level of 60 dB or less. The measuring instrument was a shuttle box (50x15x40 cm, electric grid floor, Ugo, Italy) and the box was divided into half with a connecting guillotine door (10-10 cm) to form a room of 25x15 cm, Can be illuminated with a 20 W bulb. I put a mouse in one room (room A) of two divided cubicles and opened a cubicle with lighting of 1500 Lux. When the mouse went around the room and went into the room (room B) without lighting, The partition was closed.

 The learning test was repeated five times. When the mouse was moved to the room B, a current of 3 mA was flown through a stainless steel grid under the room for 3 seconds while the light was off, and a foot-shock was applied. I noticed the relationship between a dark room and a foot-shock.

3-2: Measurement of enzymatic activity of brain tissue

After the breeding period was completed, the animals were fasted for 12 hours, then the brain was anesthetized with CO2, and the animals were washed with physiological saline, and then water was removed from the feces. Homogenization buffer (12.5 mM sodium phosphate buffer, pH 7.0, 400 mM sodium chloride) was added to the extracted brain tissue to homogenize and centrifuged at 1,000 × g for 10 minutes. A portion of the supernatant was used as an enzyme source .

The activity of acetylcholinesterase in brain tissue was analyzed by using acetylcholine iodide as a substrate. Specifically, 2.6 ml of 0.1 M phosphate buffer (pH 8.0), 100 μl of 10 mM Ellman's solution (10 mM 5,5'-dithio-bis-2-nitrobenzoic acid and 15 mM sodium bicarbonate) The absorbance at 410 nm was measured and the absorbance change at 405 nm was measured by adding 20 μl of 75 mM acetylcholine iodide (Sigma-Aldrich Co.) to the wells. The absorbance of the control group in which the same amount of buffer solution was added instead of the enzyme source and the absorbance of the experimental group containing the enzyme source were measured. After 3 repeated experiments, enzyme activity was calculated.

The acetylcholine content of brain tissue was measured based on the reaction of σ-acyl derivatives with alkaline hydroxylamine. Specifically, 50 μl of 1% hydroxylamine was added to 50 μl of brain homogenate, mixed with 500 μl of FeCl ₃ (10% in 0.1N HCl), and the absorbance at 490 nm was measured to determine the acetylcholine content Respectively.

3-3: Brain tissue Western Blot

For protein analysis, 200 μl of cell lysis buffer was added to 20 mg of brain tissue, the tissue was disrupted using a homogenizer, and centrifuged at 800 rpm for 10 seconds to collect only supernatant. The collected supernatant was left on ice for 24 hours, centrifuged at 4 and 14,000 rpm for 20 minutes, and the supernatant was collected again to quantify the proteins according to the Bradford method.

Proteins were separated by size using SDS-PAGE (Polyacrylamide Gel Electrophoresis) and proteins were transferred to a nitrocellulose membrane (NC membrane) using a semi-dry transfer system (Bio-Rad, USA) . Then, the NC membrane was treated with blocking buffer (0.5% skim milk and 1X PBST buffer) containing 5% skim milk for 1 hour and washed 3 times with 1X PBST buffer for 10 minutes. After washing, the primary antibodies p-CREB (Ser133), total-CREB, JNK, p-JNK, p21, p-p21, p38 and p-p38 (Santa Cruz Biotechnology, USA) Lt; / RTI > The next day, the NC membrane was washed three times for 10 minutes with 1X PBST buffer, and reacted with the NC membrane using Western blot detection kit (Abfrontier, WEST SAVE GOLD). The degree of expression was observed using Chemi-Doc (AMERSHARM 600) , And GAPDH, respectively.

4. Statistical Analysis

Experimental results were expressed as mean ± standard deviation, and the values repeated three to eight times in each experiment were averaged. Each experiment was performed at least 3 times. The results were analyzed using SPSS package (Version 10.0, SPSS, SPSS Inc., USA) and one-way analysis of variance (ANOVA). Duncan's multiple range test was used to compare the results of each experimental group, and P <0.05 was considered statistically significant.

Animal test results were statistically analyzed and the mean and standard deviation were calculated. Statistical analysis was performed using statistical software Anova t-test.

Experiment result

1. Cell survival rate, lactate dehydrogenase activity and Intracellular  Active oxygen level measurement results

1-1: Results of cell viability measurement

SK-N-SH cells were treated with astragalin (Ast) at a concentration of 5 and 10 μg / ml, respectively. After 24 hours, the survival rate of the SK-N-SH cells was examined and the survival rate of astrocytes was not changed Respectively. When Astragalin pretreated cells were exposed to 500 ㎛ H ₂ O ₂ for 30 min, Astragalin pretreatment (Ast 5 and 10) compared with control (Con) treated with H ₂ O ₂ alone, It was found that cell death was suppressed by about 10 to 20% (FIG. 1A).

1-2: LDH  And Intracellular Oxidative  Stress measurement result

As a result of measuring a cellular LDH activity that can determine the damage in the test group by the LDH activity increased by H ₂ O ₂ treatment process the Astra ground it it was confirmed that the inhibition by H ₂ O ₂ treatment the previous level. In addition, intracellular reactive oxygen species levels were measured, and it was found that the pretreatment group of astragalin was reduced by about 36.3% compared with the control group (Con) (FIG. 1B).

2. Results of cell death measurement

Cells pretreated with astragalin (5 and 10 μg / ml) were exposed to 500 μM H ₂ O ₂ for 30 minutes and the degree of apoptosis was confirmed.

First, double-stained with annexin V-FITC and PI, and confirmed by flow cytometry, cell death was observed in about 36% of cells by exposure to H ₂ O ₂ . On the other hand, in astragalin-pretreated experimental groups, apoptotic cells were 7.6% and 7.3%, respectively, indicating that cell death was reduced even when exposed to H ₂ O ₂ (FIG.

In addition, DNA fragmentation was confirmed using the TUNEL assay. As a result, it was confirmed that FITC-dUTP stained remarkably in the control group treated with only H ₂ O ₂ , resulting in DNA fragmentation. However, it was confirmed that the degree of DNA fragmentation decreased in the pretreatment group of astragalin (Fig. 2B).

These results indicate that astragalin inhibits DNA damage and thus protects neurons from apoptosis.

3. Results of animal experiments

3-1: Underwater maze  And passive avoidance test results

As a result of the underwater maze test evaluating the hippocampal dependent spatial learning ability, the escape time of the control group (C) which induced the dementia by administration of scofuran decreased to 27.75 seconds and the escape time decreased during this experiment period And it was significantly different from the 18.20 seconds of the normal group (N). On the other hand, in the positive control group (P) consumed with tacrine, the escape time was decreased in comparison with the control group, and in astragalin-treated group 1 and 2, 29.83 sec and 10.50 sec, respectively, (Fig. 3).

In addition, we observed the effect of astragalin on memory impairment through passive avoidance experiment. As a result, despite the electrical shock of 3 ㎃, the control group (P) showed 38.67 seconds staying in the dark room, and the escape time was about 3 times longer than the normal group (N) of 12.42 seconds. The mice in the control group did not remember the electric shock in the learning test. On the other hand, in the positive control group (P), the escape time was significantly reduced compared to the control group at 17.75 sec, and the experimental group 1 and the experimental group 2 also showed a significant decrease in the escape time compared with the control group. (Fig. 4).

3-2: Results of enzyme activity measurement of brain tissue

Acetylcholine is a neurotransmitter found in neurons and is associated with the cholinergic system of the central nervous system, and the collapse of the cholinergic system is known to be a major cause of early Alzheimer 's disease. The acetylcholinesterase decomposes acetylcholine into acetate and choline.

The acetylcholine concentration was 26.12 ± 1.76 ㎛ / ㎎ protein in the control group (C), which was about 20% lower than that of the normal group (N) 32.65 ± 3.67 ㎛ / ㎎ protein. On the other hand, acetylcholine content in the experimental group 1 and the experimental group 2 was significantly higher than that of the control group (p <0.05) (FIG. 5).

The activity of acetylcholinesterase was measured to be 10.39 ± 0.07 unit / mg protein / min in the scopolamine-treated control group (P) compared to 6.27 ± 2.60 unit / mg protein / min in the normal group Acetylcholinesterase activity was significantly increased (p < 0.05). On the other hand, in the experimental group 1 and the experimental group 2, in which astragalin was administered for 4 weeks, the activity of acetylcholinesterase was decreased compared with that of the control group, and it was confirmed that the acetylcholinesterase activity was similar to or lower than that of the normal group (FIG.

Since it is known that acetylcholine content decreases in geriatric dementia and acetylcholinesterase activity increases, the administration of astragalin for 4 weeks affects the acetylcholine content and acetylcholinesterase activity, It is expected to help prevent dementia.

3-3: Brain tissue Western Blot  result

Since CREB (cAMP response element-binding transcription factor) is known to be a factor involved in long-term memory formation, the expression level of the CREB protein was confirmed.

The expression of p-CREB (ser133) was decreased by about 4-fold in the control (C) group compared to the normal group, which was significant at p <0.05 level. On the other hand, the expression of p-CREB (ser133) protein in the experimental group 1 and the experimental group 2 tended to be higher than that of the control group, especially in the experimental group 1 (p <0.05).

In addition, expression of p38, p21, and JNK associated with the inflammatory response was confirmed. As a result, it was found that the degree of phosphorylation of p21, which was increased by administration of scopramin, was significantly (p <0.05) decreased by administration of astragalin. The phosphorylation of p38 was also significantly decreased (p <0.001) in the experimental group 1 and the experimental group 2 compared with the control group, and the degree of phosphorylation of JNK was decreased in the experimental group 1 (Fig. 7)

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (6)

1. A pharmaceutical composition for preventing or treating brain diseases comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof,
These compounds inhibit the death of nerve cells, damage of DNA and oxidative stress of nerve cells,
The brain disease is any one selected from the group consisting of stroke, memory impairment, dementia, Parkinson's disease, and Alzheimer's disease,
Wherein the pharmaceutical composition is orally administered at a total dose of 0.5 mg / kg to 2.0 mg / kg per day.
[Chemical Formula 1]

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