KR20060000048A - Compositions for preventing or treating an acute or chronic neurodegenerative diseases comprising flavonoide derivatives - Google Patents

Abstract

The present invention provides a 4 ', 7-dihydroxyflavone; 3 ', 4', 7-trihydroxyflavones; 3,3'-di- O -methylquaacetin; Camperide; Galangin; Maline; Amentoflavones; Hinokiflavones; Oak flavones; Orcnaflavone 4'- 0 -methyl ether; Camphorol 3- O- (6 ''-coumaroylglucosyl) (1 → 2) rhamnoside; Quacetin 3- O- (6 ''-coumaroylglucosyl) (1 → 2) rhamside; Camphorol 3- O -glucosyl (1 → 2) rhamnoside; Camphorol 3- O- 2 ″, 6 ″ -diramnosylglucoside; Quacetin 3- O -2``, 6 ''-diramnosylglucoside; And it provides a composition for the prevention or treatment of acute or chronic degenerative brain disease, comprising a flavonoid derivative selected from the group consisting of camphorol 3 -O -Lutinoside as an active ingredient, a pharmaceutically acceptable carrier.

Flavonoid derivatives, degenerative brain diseases, dementia, stroke

Description

Compositions for the prevention or treatment of acute or chronic degenerative brain diseases, including flavonoid derivatives {compositions for preventing or treating an acute or chronic neurodegenerative diseases comprising flavonoide derivatives}

1 shows the results of morphological analysis of neuronal cell death inhibitory effects of flavonoid derivatives (camphoride and moline),

2A and 2B are diagrams showing the brain damage inhibitory effect of flavonoid derivatives (amentoflavones), respectively.

The present invention relates to a composition for the prevention or treatment of acute or chronic degenerative brain diseases, including a flavonoid derivative as an active ingredient.

In addition to degenerative brain diseases such as dementia and ischemic stroke, acute degenerative brain disease is a disease in which brain nerve cells are gradually destroyed and lose brain function. Memory impairment, speech impairment, spatiotemporal cognitive impairment, judgment ability It presents a variety of symptoms, including disability, personality and emotional control disorders, and can cause permanent loss of brain function.

In Korea, degenerative brain disease accounts for 10% of the elderly aged 65 or older, and about 1% of Parkinson's disease. In addition, ischemic stroke is one of the second leading causes of death after cancer, and according to statistics from 2001, 74 deaths per year per 100,000 population occur. These brain diseases are mainly adult diseases with a sharp increase in the frequency of elderly people over 50 years old, and are not only a serious social and economic burden, but also a major disease causing quality deterioration in the elderly. In addition, the recent trend shows that the number of degenerative brain diseases is increasing due to the increase of the old age population due to the extension of the average life expectancy, and the development of the prevention and treatment of the degenerative brain diseases is urgently needed.

Drug therapy for the treatment of brain damage caused by stroke is currently clinically attempted to reduce brain damage by decomposing antiplatelet agents (pTA) in the aggregation of platelets in the cerebrovascular vessels, but the therapeutic efficacy is not high. However, hemorrhagic stroke has limited clinical use because it can worsen brain damage when used. Current trends in the development of global stroke treatments include NMDA antagonists and platelet anticoagulants, which are in clinical trials but are often discontinued in phase 2 or 3 due to their poor efficacy or side effects.

As a representative treatment for dementia, a representative disease of degenerative brain disease, cholinegic drugs such as tacrine and donepezil are currently on the market. There are disadvantages. Recently, drugs that selectively act on the muscarinic cholinergic nervous system, including xanomeline, are under clinical trials for the treatment of dementia. Gamma secretase inhibitors, glycogen synthase kinase (GSK3β) inhibitors, cyclin-dependent kinase-5 (cdk5) inhibitors, and nonsteroidal agents to prevent and treat dementia by inhibiting accumulation and neurotoxicity of beta amyloid (Aβ) Anti-inflammatory drugs are in the preclinical and clinical trial phase.

Acute and chronic degenerative brain diseases are caused by different pathogens and mechanisms, but ultimately lead to the loss of nerve cells, leading to decreased brain function. In this regard, the development of therapeutic agents that directly block neuronal cell death processes has been attempted. The preclinical testing phase includes MAP kinase inhibitors, caspase inhibitors, calpine inhibitors, and anti-inflammatory drugs. For example.

The production of reactive oxygen species (ROS) in normal cells is regulated by biological antioxidants or antioxidant enzymes. Under pathophysiological conditions, the production of oxidants beyond the antioxidant capacity of cells may cause oxidative damage to proteins, lipids and DNA. As shown in various studies, ROS is involved in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as in ischemic or hemorrhagic stroke. ROS plays an important role in the development of neurodegenerative diseases caused by excitotoxicity, beta amyloid, ischemia or recovery of nerve growth factors. Recently, antioxidant therapy has been used to treat acute or chronic neurodegenerative diseases.

Flavonoids are naturally occurring polyhydric phenol compounds contained in fruits, vegetables, seeds, and the like, and various flavonoid derivatives classified into flavonol, flavone, and isoflavone structures are known, and biological and pharmacological studies are being conducted on them.

On the other hand, the present inventors while studying the effects on the degenerative brain disease in a variety of flavonoid derivatives, surprisingly found that certain flavonoid derivatives have an excellent preventive or therapeutic effect of degenerative brain disease, to complete the present invention.

Accordingly, an object of the present invention is to provide a composition for the prevention or treatment of acute or chronic degenerative brain disease, which comprises a flavonoid derivative as an active ingredient.

The present invention is 4 ', 7-dihydroxyflavone (4', 7-dihydroxyflavone); 3 ', 4', 7-trihydroxyflavone; 3,3'-di - O - methyl exigua paroxetine (3,3'-di- O -methylquercetin); Kaempferide; Galangin; Morin; Amentoflavones; Hinokiflavones; Ochnaflavone; Oak or flavone 4'- O - methyl ether (ochnaflavone 4'- O -methyl ether); Camperol 3- O- (6 ''-coumaroylglucosyl) (1 → 2) kaempferol 3- O- (6 ''-coumaroylglucosyl) (1 → 2) rhamnoside; Exigua paroxetine 3- O - (6 '' - Kumar In one glucosyl) (1 → 2) ramno seed (quercetin 3- O - (6 ' ' - coumaroylglucosyl) (1 → 2) rhamnoside); Camp Ferrol 3- O - glucosyl (1 → 2) ramno seed (kaempferol 3- O -glucosyl (1 → 2) rhamnoside); Camp Ferrol 3- O -2 '', 6 ' ' - Dirham nosil glucoside (kaempferol 3- O -2 '', 6 '' - dirhamnosylglucoside); Exigua paroxetine 3- O -2 '', 6 ' ' - Dirham nosil glucoside (quercetin 3- O -2 '', 6 '' - dirhamnosylglucoside); And camp Ferrol 3 -O - Rutino seed (kaempferol 3 -O - rutinoside) including a flavonoid derivative selected from the group consisting of as active ingredients, and the prevention of an acute or chronic degenerative brain disease comprising a pharmaceutically acceptable carrier or A therapeutic composition is provided.

The structure of the flavonoid derivative included in the composition of the present invention is as follows.

(1) 4 ', 7-dihydroxyflavone:

R = R ₁ = R ₂ = R ₃ = R ₅ = H, R ₄ = OH

(2) 3 ', 4', 7-trihydroxyflavone:

R = R ₁ = R ₂ = R ₅ = H, R ₃ = R ₄ = OH

(3) 3,3'-di- O -methylquacetin (3,3'-di- O- methylquercetin):

R ₁ = R ₄ = OH, R ₂ = R ₅ = H, R = R ₃ = OCH ₃

(4) kaempferide:

R = R ₁ = OH, R ₂ = R ₃ = R ₅ = H, R ₄ = OCH ₃

(5) galangin:

R = R ₁ = OH, R ₂ = R ₃ = R ₄ = R ₅ = H

(6) morin:

R = R ₁ = R ₂ = R ₄ = OH, R ₃ = R ₅ = H

(7) amentoflavones

(8) hinokiflavone

(9) ochnaflavone:

R = H

10, Oak or flavone 4'- O - methyl ether (ochnaflavone 4'- O -methyl ether):

R = CH ₃

11 Camp Ferrol 3- O - (6 '' - glucosyl days Kumar) (1 → 2) ramno seed (kaempferol 3- O - (6 ' ' - coumaroylglucosyl) (1 → 2) rhamnoside):

R = H, R '=

12 exigua paroxetine 3- O - (6 '' - glucosyl days Kumar) (1 → 2) ramno seed (quercetin 3- O - (6 ' ' - coumaroylglucosyl) (1 → 2) rhamnoside):

R = OH, R '=

13 Camp Ferrol 3- O - glucosyl (1 → 2) ramno seed (kaempferol 3- O -glucosyl (1 → 2) rhamnoside):

R = R '= H

14 Camp Ferrol 3- O -2 '', 6 ' ' - Dirham nosil glucoside (kaempferol 3- O -2 '', 6 '' - dirhamnosylglucoside):

R = H, R ₁ =

15 exigua paroxetine 3- O -2 '', 6 ' ' - Dirham nosil glucoside (quercetin 3- O -2 '', 6 '' - dirhamnosylglucoside):

R = OH, R ₁ =

(16) Ferrol Camp 3 -O - Rutino seed (kaempferol 3 -O -rutinoside):

R = R ₁ = H

The composition of the present invention comprises a pharmaceutically acceptable carrier and can be administered orally or parenterally to humans or animals for the prevention or treatment of acute or chronic degenerative brain diseases including dementia or stroke.

The composition for oral administration may be in various forms such as tablets, capsules, powders, granules, solutions, suspensions, gels, and the like, and may include conventional additives such as excipients, disintegrants, lubricants, and the like. The additives include conventional excipients such as syrup, gum arabic, gelatin, sorbitol, lactose, sugar, corn-starch, calcium phosphate, glycine, magnesium stearate, talc, polyethylene glycol, silica, potato starch, or sodium lauryl sulfate. Flavoring or coloring agents. In addition, compositions for parenteral administration (eg, injections) of the compositions according to the invention may be isotonic solutions, may also be sterilized and / or may contain conventional additives such as preservatives, stabilizers and the like.

The pharmaceutical composition of the present invention may be administered to an average adult patient (about 70 kg) at a dose of about 100 mg / day to 1 g / day for the purpose of preventing or treating acute or chronic degenerative brain disease, but the dose is a disease It can be changed according to the type and state of the. Thus, for a typical adult patient, each unit dosage form may comprise from about 100 mg to 1 g of a compound according to the invention together with a suitable pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrating the present invention, and the present invention is not limited to these examples.

Example 1 Inhibitory Effect on Neuronal Cell Death by Increased Activation Oxygen

After inducing neuronal cell death by ischemia, the neuronal cell death inhibition effect of flavonoid derivatives was measured. As a neuronal cell line, SH-SY5Y cells (Korea Cell Line Bank No. 22266) were used. The neurons were dispensed in 48-well cell culture plates at 5 × 10 ⁴ cells / well concentration and contained DMEM medium containing 5% fetal bovine serum and 10% horse serum. The cells were added and cultured at 37 ° C.

In order to induce neuronal cell death by ischemic stimulation, the cell culture medium was replaced with DMEM medium without serum, and 0.5 mM hydrogen peroxide solution was added and cell culture was continued for 24 hours. To measure apoptosis, MTT (methylthiazoletetrazolium) was added to the cell medium, incubated for 3 hours, the medium was removed, 100 ul dimethylsulfoxide (dimethylsulfoxide, DMSO) was added, and the absorbance was measured at 595 nm.

The flavonoid derivatives were dissolved in DMSO and added to the cells so that the final concentration of the compound was 0.4, 2, 10, 50 uM, and then treated with hydrogen peroxide solution for 1 hour to induce cell death. At this time, the final concentration of DMSO was not more than 0.5% and at this concentration DMSO did not affect apoptosis. Cell survival in serum-containing condition was 100%, and the relative cell survival rate, that is, the degree of inhibition of cell death (%) was determined. All experiments were performed three times. The degree of inhibiting apoptosis of each flavonoid derivative is shown in Table 1.

Flavonoid Derivatives * Concentration (μM) 0.4 2 10 50 (One) -0.3 ± 1.4 10.4 ± 0.6 55.4 ± 2.7 (2) 24.5 ± 1.9 61.9 ± 1.5 61.4 ± 0.6 (3) 14.6 ± 2.0 37.2 ± 2.0 122.4 ± 0.1 (4) 34.0 ± 3.0 47.6 ± 0.4 65.0 ± 4.0 (5) 9.0 ± 3.1 42.4 ± 3.2 15.5 ± 3.4 (6) 3.5 ± 0.1 20.0 ± 1.2 48.6 ± 2.6 (7) 34.7 ± 1.9 73.6 ± 2.8 34.7 ± 1.9 (8) 5.3 ± 1.0 34.0 ± 1.7 43.7 ± 1.3 (9) 12.0 ± 4.2 -4.1 ± 1.7 43.7 ± 1.3 10 10.4 ± 1.7 14.7 ± 4.4 21.9 ± 1.1 (11) 12.0 ± 1.3 24.9 ± 3.2 55.1 ± 0.9 (12) -1.0 ± 2.1 58.4 ± 1.6 86.0 ± 7.9 (13) 25.6 ± 1.6 32.2 ± 1.6 26.8 ± 5.1 (14) 17.2 ± 2.3 12.8 ± 1.1 13.7 ± 2.0 (15) 29.2 ± 0.7 41.7 ± 7.1 17.3 ± 1.1 (16) 3.6 ± 1.9 12.4 ± 2.0 16.2 ± 0.7

* Each flavonoid derivative is as follows.

(1) 4 ', 7-dihydroxyflavones

(2) 3 ', 4', 7-trihydroxyflavones

(3) 3,3'-di- O -methylquacetin

(4) camperide

(5) Galangin

(6) Maureen

(7) amentoflavones

(8) Hinoki Flavones

(9) oak flavones

(10) oxaflavones 4'- 0 -methyl ether

(11) Camperol 3- O- (6 ''-coumaroylglucosyl) (1 → 2) rhamnoside

(12) Quacetin 3- O- (6 ''-coumaroylglucosyl) (1 → 2) rhamnoside

(13) Camperol 3- O -glucosyl (1 → 2) rhamnoside

(14) Camperol 3- O- 2 '', 6 ''-diramnosylglucoside

(15) Quercetin 3- O- 2 '', 6 ''-diramnosylglucoside

(16) Camperol 3- O -Lutinoside

As can be seen in Table 1, the flavonoid derivatives exhibit neuronal cell death inhibitory activity at concentrations of 0.4-50 uM against neuronal cell death induced by activated oxygen.

To morphologically analyze neuronal cell death inhibition, neuronal cell lines were incubated in serum and treated with camphoride (10 uM) and morine (10 uM) for 1 hour, followed by adding 0.5 mM hydrogen peroxide. Eight hours after induction of death, cells were stained with propidium iodide (10 uM) for 10 minutes, and then cell death was analyzed by phase contrast microscope and fluorescence microscope.

As can be seen in Figure 1, about 30% of dead cells stained with propidium iodide were observed in neurons treated with hydrogen peroxide, but the death of neurons treated with camphoride or morine was significantly reduced. .

As described above, the flavonoid derivatives exhibit excellent pharmacological activity of inhibiting neuronal cell death caused by activated oxygen, and thus can be used as an effective therapeutic agent for preventing and treating nerve damage caused by ischemia such as stroke.

Example 2: Inhibitory effect on neuronal cell death by mitochondrial damage

Stress stimulation on cells (eg, removal of growth hormone, ischemia, hypoxia) has been reported to stimulate neuronal death by stimulating apoptosis signaling from mitochondria. Inhibition of cell death via mitochondria with staurosporine and inhibition of apoptosis of flavonoid compounds was measured.

SH-SY5Y cells were aliquoted into 48-well cell culture plates and cultured in serum-containing medium. In order to induce neuronal cell death, cell culture medium was replaced with medium without serum, and then 100 nM starrosporin was added and cell culture was continued for 24 hours. In order to measure apoptosis, MTT was added to the cell medium and incubated for 3 hours, after which the medium was removed and mixed with 100 ul DMSO, and the absorbance was measured at 595 nm.

The flavonoid derivatives were dissolved in DMSO and added to the cells to a final concentration of 0.4, 2, 10, 50 uM, and then treated with hydrogen peroxide solution for 1 hour to induce cell death. At this time, the final concentration of DMSO was not more than 0.5% and at this concentration DMSO did not affect apoptosis. Apoptosis was obtained by 100% cell survival in the presence of serum, and the relative cell survival rate, that is, the degree of inhibition of cell death (%) was determined. All experiments were performed three times. The degree of inhibiting apoptosis of each flavonoid derivative is shown in Table 2.

Flavonoid Derivatives * Concentration (μM) 0.4 2 10 50 (One) -15.1 ± 1.9 -10.6 ± 3.1 -16.5 ± 4.2 (2) -2.7 ± 0.5 -1.2 ± 0.5 3.7 ± 1.4 (3) -9.7 ± 2.3 -1.7 ± 4.3 57.9 ± 9.6 (4) -8.9 ± 0.3 58.4 ± 0.3 37.3 ± 1.7 (5) 0.7 ± 5.8 7.3 ± 7.2 83.4 ± 0.7 (6) 0.7 ± 2.2 15.4 ± 3.2 64.4 ± 0.7 (7) 20.9 ± 2.3 39.8 ± 3.3 85.2 ± 2.1 101.8 ± 0.8 (8) 8.1 ± 0.3 54.2 ± 0.8 50.3 ± 1.1 (9) 4.0 ± 1.0 -7.0 ± 0.7 -26.8 ± 0.7 30.6 ± 1.7 10 3.7 ± 1.7 16.3 ± 1.5 34.3 ± 0.9 23.9 ± 0.7 (11) -9.6 ± 1.0 1.1 ± 0.2 23.6 ± 0.4 (12) 0.6 ± 1.3 25.6 ± 2.6 37.0 ± 2.3 (13) -1.9 ± 1.0 4.6 ± 0.6 38.0 ± 0.3 (14) -5.7 ± 0.7 -15.4 ± 0.3 -9.3 ± 0.8 (15) -6.8 ± 0.3 -5.7 ± 1.7 -16.7 ± 0.9 (16) -10.8 ± 0.5 -8.8 ± 0.7 -9.6 ± 1.0

* Each flavonoid derivative is as defined in Table 1.

As can be seen in Table 2, it can be seen that the flavonoid derivatives effectively inhibit neuronal cell death induced by starrosporin. Therefore, the flavonoid compounds can inhibit neuronal cell death via mitochondria induced by stress stimulation.

Example 3: Inhibitory Effect on Neuronal Cell Death by Beta Amyloid

In patients with dementia, neuronal damage has been reported to cause neuronal loss, primarily by the accumulation of beta amyloid (Aβ), or by inflammatory reactions caused by the activation of microglia cells. . The beta amyloid (Aβ _25-35 ) peptide was used to induce neuronal cell death and the neuronal cell death inhibition of flavonoid derivatives was measured.

Cell lines (PC12 cells, Korea Cell Line Bank No. 21721) having similar characteristics to neurons were measured for neuronal cell death induced by Aβ _25-35 . PC12 cells were aliquoted into 48-well cell culture plates at ⁵ × 10 ⁴ cells / well concentration and cell cultured at 37 ° C. with DMEM medium containing 10% fetal bovine serum.

To induce cell death, cells were treated with Aβ _{25-35 in} which cell culture medium was replaced with DMEM medium without serum, and cell culture was continued for 24 hours. In order to measure apoptosis, MTT was added to the cell medium and incubated for 3 hours, the medium was removed, mixed with 100 ul DMSO, and the absorbance was measured at 595 nm.

The flavonoid derivatives were dissolved in DMSO and added to the cells so that their final concentrations were 2, 10 and 50 uM, and then treated with Aβ _25-35 for 1 hour to induce apoptosis. At this time, the final concentration of DMSO was not more than 0.5% and at this concentration DMSO did not affect apoptosis. Cell survival in serum-containing condition was 100%, and the relative cell survival rate, that is, the degree of inhibition of cell death (%) was determined. All experiments were performed three times. The degree of inhibiting apoptosis of each flavonoid derivative is shown in Table 3.

Flavonoid Derivatives * Concentration (μM) 2 10 50 (One) 5.7 ± 1.1 39.3 ± 0.9 53.9 ± 0.8 (2) 7.1 ± 1.1 21.9 ± 2.1 40.5 ± 1.4 (3) 11.3 ± 0.1 74.3 ± 1.0 126.3 ± 0.3 (4) 35.7 ± 2.3 79.5 ± 1.4 97.0 ± 1.8 (5) 33.1 ± 3.2 74.1 ± 6.7 42.7 ± 0.5 (6) 21.6 ± 1.2 10.6 ± 5.9 33.4 ± 0.8 (7) 13.8 ± 0.9 23.1 ± 0.3 15.0 ± 0.7 (8) 0.5 ± 1.1 24.4 ± 0.7 -12.6 ± 1.9 (9) -15.5 ± 1.6 -4.9 ± 0.6 17.1 ± 2.2 10 3.2 ± 1.4 -14.1 ± 2.6 -14.0 ± 1.1 (11) 16.3 ± 1.5 16.0 ± 1.2 11.5 ± 2.2 (12) 18.8 ± 0.8 54.3 ± 2.1 88.9 ± 2.9 (13) 2.6 ± 0.3 9.1 ± 0.1 7.6 ± 2.5 (14) 24.0 ± 4.7 9.2 ± 1.2 7.7 ± 1.4 (15) 1.6 ± 1.3 -4.5 ± 0.3 5.7 ± 1.0 (16) 4.9 ± 0.6 11.1 ± 2.3 2.0 ± 1.1

* Each flavonoid derivative is as defined in Table 1.

As can be seen in Table 3, the flavonoid derivatives have the effect of inhibiting neuronal cell death induced by beta amyloid.

Example 4: anti-inflammatory effect on microglia

In patients with dementia, beta amyloid (Aβ) forms insoluble plaques in the brain and activates peripheral microglia, causing an inflammatory response. Even in ischemic stroke, necrotic necrosis causes inflammatory plaques and secondary neuronal damage caused by the inflammatory response, which has been reported to be effective in treating stroke. Therefore, the compound that exhibits anti-inflammatory action against microglia is expected to be used as a therapeutic agent for degenerative brain disease.

Brain microglial cell culture line (BV-2, Ewha Womans University College of Medicine Pharmacology) cells were dispensed in 48-well cell culture plates at 5X10 ⁴ cells / well concentration and 10% fetal bovine serum. DMEM medium containing serum) was added and the cells were cultured at 37 ° C.

Cell lines were treated with 100 ng / ml lipopolysaccharide (LPS) and cell culture was continued for 24 hours to induce inflammation. Nitrous oxide (NO), a substance that mediates the inflammatory response, was measured by the concentration of the cell culture medium. A calibration curve was prepared using sodium nitrite as a standard solution.

Flavonoid derivatives were dissolved in DMSO and added to the cells to a final concentration of 0.4, 2, 10 uM, and then treated with lipopolysaccharide for 1 hour to cause inflammation. At this time, the final concentration of DMSO was not more than 0.5%. At this concentration, DMSO did not affect nitrous oxide production. All experiments were repeated three or more times, and the effect (%) of inhibiting NO production was measured for the control group. The results are shown in Table 4.

Flavonoid Derivatives * Concentration (μM) 0.4 2 10 (One) 17.2 ± 1.8 18.0 ± 0.2 43.8 ± 1.0 (2) 19.8 ± 0.5 12.2 ± 0.8 55.1 ± 0.3 (3) 24.7 ± 0.7 48.0 ± 0.6 91.3 ± 1.4 (4) 2.4 ± 1.0 9.1 ± 2.4 65.5 ± 0.4 (5) 4.9 ± 0.4 5.5 ± 0.9 30.8 ± 0.9 (6) -0.9 ± 1.0 1.5 ± 1.4 18.9 ± 1.2 (7) 3.3 ± 0.6 5.7 ± 0.6 25.4 ± 0.3 (8) 9.6 ± 0.7 62.8 ± 0.3 97.2 ± 0.4 (9) -7.6 ± 1.4 32.2 ± 0.1 88.7 ± 0.8 10 17.5 ± 0.8 25.1 ± 0.5 38.2 ± 0.6 (11) 17.1 ± 0.8 20.5 ± 1.0 17.8 ± 1.6 (12) 18.8 ± 1.2 16.6 ± 1.0 13.9 ± 0.8 (13) 8.3 ± 0.4 6.7 ± 0.7 16.9 ± 0.7 (14) 29.8 ± 1.4 31.5 ± 1.5 25.9 ± 1.8 (15) 12.2 ± 1.1 13.9 ± 1.1 10.3 ± 0.8 (16) 33.7 ± 1.5 38.4 ± 1.5 22.7 ± 0.1

* Each flavonoid derivative is as defined in Table 1.

As can be seen in Table 4, it can be seen that the flavonoid derivatives effectively inhibit the production of nitrous oxide activated by lipopolysaccharide. Therefore, the flavonoid derivatives may exhibit an effect of treating brain injury by inhibiting an inflammatory response occurring in dementia and stroke.

Example 5: Inhibitory Effect on Neuronal Cell Death in an Ischemic Stroke Animal Model

To induce hypoxic-ischemic brain injury, 7-day-old Sprague-Dawley rats were ligated to the left carotid artery under isofluorene anesthesia, and the surgical site was sutured to recover from anesthesia. The rats were exposed to 8% oxygen-92% nitrogen gas for 2.5 hours to cause brain damage. Amentoflavones were administered intraperitoneally at a 30 mg / kg dose. One week after the induction of brain damage, the brains were extracted, the brains were fixed in paraformaldehyde, the brains were sectioned and stained with cresyl violet, and the area of brain tissue damage was obtained. The results are shown in Figures 2a and 2b.

As shown in Figures 2a and 2b, it can be seen that amentoflavones significantly inhibited brain injury, so the flavonoid derivatives may have a therapeutic effect on brain injury due to ischemic stroke or hypoxic-ischemia.

The composition comprising the flavonoid derivatives according to the present invention can be used to effectively prevent or treat acute or chronic degenerative brain diseases such as dementia or stroke.

Claims (2)

4 ', 7-dihydroxyflavone; 3 ', 4', 7-trihydroxyflavone; 3,3'-di - O - methyl exigua paroxetine (3,3'-di- O -methylquercetin); Kaempferide; Galangin; Morin; Amentoflavones; Hinokiflavones; Ochnaflavone; Oak or flavone 4'- O - methyl ether (ochnaflavone 4'- O -methyl ether); Camperol 3- O- (6 ''-coumaroylglucosyl) (1 → 2) kaempferol 3- O- (6 ''-coumaroylglucosyl) (1 → 2) rhamnoside; Exigua paroxetine 3- O - (6 '' - Kumar In one glucosyl) (1 → 2) ramno seed (quercetin 3- O - (6 ' ' - coumaroylglucosyl) (1 → 2) rhamnoside); Camp Ferrol 3- O - glucosyl (1 → 2) ramno seed (kaempferol 3- O -glucosyl (1 → 2) rhamnoside); Camp Ferrol 3- O -2 '', 6 ' ' - Dirham nosil glucoside (kaempferol 3- O -2 '', 6 '' - dirhamnosylglucoside); Exigua paroxetine 3- O -2 '', 6 ' ' - Dirham nosil glucoside (quercetin 3- O -2 '', 6 '' - dirhamnosylglucoside); And Camp Ferrol 3 -O - Rutino seed (kaempferol 3 -O -rutinoside) A composition for preventing or treating acute or chronic degenerative brain disease, comprising a flavonoid derivative selected from the group consisting of an active ingredient, and comprising a pharmaceutically acceptable carrier. The composition of claim 1, wherein the acute or chronic degenerative brain disease is stroke or dementia.

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