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WO2006001665A1 - Composition destinee a prevenir ou traiter des maladies cerebrales degeneratives aigues ou chroniques et contenant des derives de flavonoides - Google Patents

Composition destinee a prevenir ou traiter des maladies cerebrales degeneratives aigues ou chroniques et contenant des derives de flavonoides Download PDF

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Publication number
WO2006001665A1
WO2006001665A1 PCT/KR2005/001986 KR2005001986W WO2006001665A1 WO 2006001665 A1 WO2006001665 A1 WO 2006001665A1 KR 2005001986 W KR2005001986 W KR 2005001986W WO 2006001665 A1 WO2006001665 A1 WO 2006001665A1
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WO
WIPO (PCT)
Prior art keywords
kaempferol
composition
degenerative brain
cell death
rhamnoside
Prior art date
Application number
PCT/KR2005/001986
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English (en)
Inventor
Byung-Hee Han
Sam-Sik Kang
Kun-Ho Son
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Seoul National University Industry Foundation
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Filing date
Publication date
Application filed by Seoul National University Industry Foundation filed Critical Seoul National University Industry Foundation
Publication of WO2006001665A1 publication Critical patent/WO2006001665A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a composition for preventing or treating acute or chronic degenerative brain diseases including a flavonoid derivative as an effective ingredient.
  • Acute degenerative brain diseases such as ischemic stroke, together with chronic degenerative brain diseases such as dementia, are disorders causing loss of brain function due to continuous destruction of cerebral nerve cells.
  • Degenerative brain diseases exhibit various symptoms such as memory disorder, language disorder, space- time perception disability, judgment disability, personality and emotional disorder according to the degree of brain damage and an affected site, and cause permanent loss of brain function.
  • In Korea about 10% and 1% of people with the age of 65 or more suffer from senile dementia and Parkinson's disease, respectively.
  • Ischemic stroke is the second leading cause of death after cancer. According to the 2001 data from the National Bureau of Statistics, stroke causes 74 deaths per 100,000 population per a year. These degenerative brain diseases are adult diseases that the frequency of occurrence rapidly increases in aged persons with 50 or more of age. These degenerative brain diseases are major diseases that represent a serious social and economical burden and lower the life quality of aged persons. Furthermore, a recent trend is toward elevation of de ⁇ generative brain disease patients due to an increase in aged population with increasing average lifespan. Thus, the development of preventive and therapeutic strategies for degenerative brain diseases is strongly required. [4] As a medication for the treatment of cerebral damage due to stroke, there has been a clinical trial to reduce cerebral damage by removing platelet clots in brain blood vessels using an antiplatelet drug (pTA).
  • pTA antiplatelet drug
  • Cholinergic drugs selectively acting on the muscarinic cholinergic nerve system are currently in clinical trials to dementia patients.
  • dementia preventive or treatment drugs based on inhibition of betaamyloid (A ⁇ ) accumulation and neurotoxicity, such as gamma- secretase inhibitors, glycogen synthase kinase (GSK3 ⁇ ) inhibitors, cyclin-dependent kinase-5 (cdk5) inhibitors, and nonsteroidal anti-inflammatory drugs, are currently in pre-clinical trials or clinical trials.
  • Acute and chronic degenerative brain diseases are different in causes and mechanism but lead to nerve cell loss, resulting in cerebral dysfunction. In this respect, attempts to develop agents directly blocking nerve cell death have been made.
  • ROSs reactive oxygen species
  • Flavonoids are naturally occurring multivalent phenol compounds present in fruits, vegetables, seeds, etc.
  • flavonols, flavones, and isoflavones are known, and their biological and pharmacological activities have been studied.
  • the present invention provides a composition for the prevention or treatment of acute or chronic degenerative brain diseases including a flavonoid derivative as an effective ingredient.
  • a composition for preventing or treating an acute or chronic degenerative brain disease including as an effective ingredient a flavonoid derivative selected from the group consisting of 4',7-dihydroxyflavone; 3',4',7-trihydroxyflavone; 3,3'-di-0 - methylquercetin; kaempferide; galangin; morin; amentoflavone; hinokiflavone; ochnaflavone; ochnaflavone 4'-0-methyl ether; kaempferol 3-0 - (6"-coumaroylglucosyl)(l ⁇ 2)rhamnoside; quercetin 3-O-(6"-coumaroylglucosyl)(l ⁇ 2)rhamnoside; kaempferol 3-O-glucosyl(l ⁇ 2)rhamnoside; kaempferol 3-0 - 2",6"-dir
  • composition of the present invention includes a pharmaceutically acceptable carrier, and may be administered orally or parenterally to human beings or animals for the prevention or treatment of acute or chronic degenerative brain diseases including dementia and stroke.
  • a composition for oral administration according to the present invention may be in any form including tablets, capsules, powders, granules, liquids, suspensions, gels, etc., and may include a conventional excipient such as a diluent, a disintegrating agent, a lubricant, etc.
  • the excipient includes a conventional diluent such as syrup, Arabic gum, gelatin, sorbitol, lactose, sugar, corn-starch, calcium phosphate, glycine, magnesium stearate, talc, polyethyleneglycol, silica, potato starch, or sodium lauryl sulfate, and a conventional flavorant or colorant.
  • a composition for parenteral admin ⁇ istration according to the present invention may be an isotonic solution or a sterile isotonic solution, and/or may include a conventional excipient such as a preservative or a stabilizer.
  • a pharmaceutical composition of the present invention can be administered in the form of a daily dosage of 100 mg-lg for average 70 kg adult for the prevention or treatment of acute or chronic degenerative brain diseases. However, an adequate dosage is determined depending on the type of disease and the degree of disease severity. In this regard, for typical adult patients, a unit dosage form includes about 100 mg to 1 g of the extract according to the present invention in combination with a pharmaceutically acceptable carrier.
  • FIG. 1 shows the morphological analysis results for the inhibitory effects of flavonoid derivatives (kaempferide and morin) against nerve cell death; and [49] FIGS. 2A and 2B show the inhibitory effect of a flavonoid derivative (amentoflavone) against cerebral damage.
  • Example 1 Evaluation of inhibitory activity of flavonoid derivatives against nerve cell death caused by increased reactive oxygen species
  • SH-SY5Y cells Kerean Cell Line Bank (KCLB), No. 22266) were used as nerve cell lines. The nerve cells were deposited in a volume of 5X10 cells/well in a 48-well plate. Then, DMEM media containing 5% fetal bovine serum and 10% horse serum were added thereto and the cell cultures were incubated at 37 0 C
  • the mixed solution was added to the cells until the final concentration of the used compound was 0.4, 2, 10, and 50 uM, and treated with a hydrogen peroxide water solution at one hour after the addition of the mixed solution to induce cell death.
  • the final concentration of DMSO was adjusted to up to 0.5% to eliminate an influence of DMSO on cell death. Assuming that cell viability in serum-containing conditions was 100%, relative cell viability (%), i.e., degree of inhibition of cell death (%) was calculated. All ex ⁇ periments were repeated three times. The degree of inhibition of cell death at each con ⁇ centration of each flavonoid derivative is presented in Table 1 below. [55] Table 1
  • Flavonoid Cell viability (%) at each concentration derivative 0.4 uM 2 uM 10 uM 5O uM
  • the nerve cell lines were cultured in serum-containing conditions and pretreated with kaempferide (10 uM) and morin (10 uM) for one hour, and then 0.5 mM of a hydrogen peroxide water solution was added thereto to induce cell death.
  • the cells were stained with propidium iodide (10 uM) for 10 minutes and phase-contrast and fluorescence mi ⁇ croscopic analyses for the cells were performed. The analysis results are shown in FIG. 1.
  • FIG. 1 As shown in FIG.
  • Example 2 Evaluation of inhibitory activity of flavonoid derivatives against nerve cell death induced by mitochondria damage
  • stress stimuli to cells e.g., growth hormone removal, ischemia, low oxygen state
  • mitochondria-mediated cell death was induced by staurosporine and the inhibitory activities of flavonoid derivatives against the cell death were measured.
  • SH-SY5Y cells were deposited in a 48-well plate and then cultured in serum- containing media. To induce nerve cell death, the cell culture media were replaced with serum-free media.
  • Flavonoid Cell viability (%) at each concentration derivative* 0.4 uM 2 uM 10 uM 5O uM
  • Each flavonoid derivative is as defined in Table 1. [78] As shown in Table 2, the flavonoid derivatives effectively prevented nerve cell death induced by staurosporine. Thus, it can be seen that flavonoid derivatives can prevent mitochondria-mediated nerve cell death induced by stress stimuli.
  • Example 3 Evaluation of inhibitory activity of flavonoid derivatives against nerve cell death induced by betaamyloid
  • a ⁇ betaamyloid
  • nerve cell damage in dementia patients is mainly caused by direct neu ⁇ rological toxicity due to betaamyloid (A ⁇ ) accumulation or inflammation due to activation of microglial cells.
  • nerve cell death was induced by be ⁇ taamyloid (A ⁇ ) peptides, and the inhibitory effect of flavonoid derivatives against the nerve cell death was evaluated.
  • the degree of nerve cell death induced by A ⁇ was measured using cell lines (PC12 cells, KCLB No. 21721) having similar characteristics to nerve cells.
  • the PC12 cells are deposited in a volume of 5X10 cells/well in a 48-well plate. Then, DMEM media containing 10% fetal bovine serum were added thereto and the cell cultures were incubated at 37 0 C . [82] To induce nerve cell death, the cell culture media were replaced with serum-free DMEM media. Then, A ⁇ was added thereto and the cell cultures were incubated 1 25-35 for 24 hours. To measure the degree of cell death, MTT was added to the cell culture media and incubated for 3 hours. The culture media were removed, 100 D DMSO was added and mixed, and absorbance was measured at 595 nm. [83] Each flavonoid derivative was dissolved in DMSO.
  • Each flavonoid derivative is as defined in Table 1. [86] As shown in Table 3, the flavonoid derivatives exhibited inhibitory activity against nerve cell death induced by betaamyloid. [87] Example 4: Evaluation of anti-inflammatory effect of flavonoid derivatives in microglial cells [88] In dementia patients, betaamyloid (A ⁇ ) activates neighboring microglial cells by insoluble plague formation in the brain, thereby leading to inflammation. In ischemic stroke patients, nerve cell necrosis causes inflammation, thereby leading to secondary nerve cell damage. In this respect, there was reported that nonsteroidal anti ⁇ inflammatory drugs are effective for the treatment of stroke. Thus, it is anticipated that anti-inflammatory compounds for microglial cells can be used as treatment agents for degenerative brain diseases.
  • Microglial cells (BV-2 cell line, Pharmacology Room of the College of Medicine of Ehwa Women's Univ.) were deposited in a volume of 5X10 cells/well in a 48-well plate. Then, DMEM media containing 10% fetal bovine serum were added thereto and the cell cultures were incubated at 37 0 C . [90] To induce inflammation, the microglial cells were treated with 100 ng/ml of lipopolysaccharide (LPS) and cultured for 24 hours. The concentration of an in ⁇ flammation mediator, nitric oxide (NO) released into the cell cultures was measured. A calibration curve was prepared using a sodium nitrite solution as a standard solution.
  • LPS lipopolysaccharide
  • Flavonoid NO production inhibition (%) at each concentration derivative* 0.4 uM 2 uM 10 uM
  • each flavonoid derivative is as defined in Table 1. [94] As shown in Table 4, the flavonoid derivatives effectively inhibited NO production activated by LPS. Therefore, it can be seen that flavonoid derivatives can effectively treat cerebral damage by preventing inflammation that occurs in dementia or stroke.
  • Example 5 Evaluation of therapeutic effect of flavonoid derivatives against cerebral nerve cell death in ischemic stroke animal models
  • Sprague-Dawley rats (7 days after birth) were subjected to left carotid artery ligation followed by suture under anes ⁇ thetization with isoflurane and then allowed to recover from anesthesia. The rats were exposed to a mixed gas of 8% oxygen and 92% nitrogen for 2.5 hours to induce cerebral damage. 30 mg/kg of amentoflavone was administered intraperitoneally to the Sprague-Dawley rats.
  • the flavonoid derivative-containing composition according to the present invention can be effectively used for the prevention or treatment of acute or chronic degenerative brain diseases such as dementia or stroke.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
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  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition destinée à prévenir ou traiter une maladie cérébrale dégénérative aiguë ou chronique, cette composition contenant, comme ingrédient efficace, un dérivé de flavonoïde choisi dans le groupe constitué par la 4',7-dihydroxyflavone, la 3',4',7-trihydroxyflavone, la 3,3'-di-O-méthylquercétine, le kaempféride, la galangine, la morine, l'amentoflavone, l'hinokiflavone, l'ochnaflavone, l'ochnaflavone-4'-O-méthyléther, le kaempférol-3-O-(6''-coumaroylglucoxyl)(1 → 2)rhamnoside, le kaempférol-3-O-glucosyl(1 → 2)rhamnoside, le kaempférol-3-O-2'',6''-dirhamnosylglucoside, le quercétin-3-O-2'',6''-dirhamnosylglucoside et le kaempférol-3-O-rutinoside, ainsi qu'un support pharmaceutiquement acceptable.
PCT/KR2005/001986 2004-06-28 2005-06-24 Composition destinee a prevenir ou traiter des maladies cerebrales degeneratives aigues ou chroniques et contenant des derives de flavonoides WO2006001665A1 (fr)

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KR1020040048899A KR100610562B1 (ko) 2004-06-28 2004-06-28 플라보노이드 유도체를 포함하는 급성 또는 만성 퇴행성뇌질환의 예방 또는 치료용 조성물
KR10-2004-0048899 2004-06-28

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007077279A1 (fr) * 2005-12-30 2007-07-12 Universidad Del País Vasco Composes a proprietes neuroprotectrices
WO2008154900A1 (fr) * 2007-06-21 2008-12-24 Analyticon Discovery Gmbh Composition pharmaceutique avec un dérivé de trihydroxychromenone
EP2117306A4 (fr) * 2007-02-14 2010-02-10 Mars Inc Composés neurogéniques
WO2011156479A2 (fr) 2010-06-09 2011-12-15 Emory University Agonistes trkb et leurs procédés d'utilisation
EP2317994A4 (fr) * 2008-07-23 2012-09-12 Massachusetts Inst Technology L'activation de l'histone désacétylase 1 (hdac1) protège contre des lésions de l'adn et augmente la survie neuronale
US9115053B2 (en) 2011-07-22 2015-08-25 Massachusetts Institute Of Technology Activators of class I histone deacetlyases (HDACS) and uses thereof
US20150306122A1 (en) * 2012-03-19 2015-10-29 Buck Institute For Research On Aging APP SPECIFIC BACE INHIBITORS (ASBIs) AND USES THEREOF
CN106474101A (zh) * 2015-06-17 2017-03-08 海南医学院 高良姜素在治疗糖尿病脑病药物中的应用
US9593125B2 (en) 2012-07-27 2017-03-14 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
CN108524530A (zh) * 2017-03-01 2018-09-14 中国药科大学 香豆酰基黄酮苷在神经保护方面的应用
CN109453162A (zh) * 2019-01-07 2019-03-12 海南热带海洋学院 穗花杉双黄酮在制备保护和/或修复神经细胞药物中的应用、药物组合物及应用
CN115475159A (zh) * 2021-05-31 2022-12-16 中国医学科学院药物研究所 山奈酚在制备抑制小脑炎症反应药物中的用途
CN115867255A (zh) * 2021-04-23 2023-03-28 一丸自然美健有限公司 胶原蛋白产生促进剂及包含其的皮肤外用剂

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US6221357B1 (en) * 1999-09-02 2001-04-24 Korea Research Institute Of Bioscience And Biotechnology Flavonoids derived from citrus peels as collagen-induced platelet aggregation inhibitor
US20030055103A1 (en) * 2001-07-04 2003-03-20 Horacio Heinzen Utilization of achyrocline satureoides ("Marcela") extracts and liposomal preparations of natural and semi-synthetic flavonoids for the prevention and treatment of the consequences of stroke and neurodegenerative diseases
US20030158237A1 (en) * 2001-09-04 2003-08-21 Colba R & D Inc. Combination of antioxidant substances for the treatment of alzheimer's disease
US20030232763A1 (en) * 2002-04-30 2003-12-18 Unigen Pharmaceuticals, Inc. Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent

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US5756538A (en) * 1993-08-17 1998-05-26 University Of Strathclyde Flavonoid and biflavonoid derivatives, their pharmaceutical compositions, their anxiolytic activity
US6221357B1 (en) * 1999-09-02 2001-04-24 Korea Research Institute Of Bioscience And Biotechnology Flavonoids derived from citrus peels as collagen-induced platelet aggregation inhibitor
US20030055103A1 (en) * 2001-07-04 2003-03-20 Horacio Heinzen Utilization of achyrocline satureoides ("Marcela") extracts and liposomal preparations of natural and semi-synthetic flavonoids for the prevention and treatment of the consequences of stroke and neurodegenerative diseases
US20030158237A1 (en) * 2001-09-04 2003-08-21 Colba R & D Inc. Combination of antioxidant substances for the treatment of alzheimer's disease
US20030232763A1 (en) * 2002-04-30 2003-12-18 Unigen Pharmaceuticals, Inc. Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481500B2 (en) 2005-12-30 2013-07-09 Universidad Del Pais Vasco Compounds having neuroprotective properties
WO2007077279A1 (fr) * 2005-12-30 2007-07-12 Universidad Del País Vasco Composes a proprietes neuroprotectrices
EP2478901A3 (fr) * 2007-02-14 2012-11-14 Mars Incorporated Composés neurogènes
JP2010518164A (ja) * 2007-02-14 2010-05-27 マース インコーポレーテッド 神経性化合物
EP2117306A4 (fr) * 2007-02-14 2010-02-10 Mars Inc Composés neurogéniques
WO2008154900A1 (fr) * 2007-06-21 2008-12-24 Analyticon Discovery Gmbh Composition pharmaceutique avec un dérivé de trihydroxychromenone
EP2317994A4 (fr) * 2008-07-23 2012-09-12 Massachusetts Inst Technology L'activation de l'histone désacétylase 1 (hdac1) protège contre des lésions de l'adn et augmente la survie neuronale
WO2011156479A2 (fr) 2010-06-09 2011-12-15 Emory University Agonistes trkb et leurs procédés d'utilisation
EP2579870A4 (fr) * 2010-06-09 2013-11-27 Univ Emory Agonistes trkb et leurs procédés d'utilisation
US9029561B2 (en) 2010-06-09 2015-05-12 Emory University TRKB agonists and methods of use
AU2011264917B2 (en) * 2010-06-09 2015-08-06 Emory University TrkB agonists and methods of use
US9504674B2 (en) 2010-06-09 2016-11-29 Emory University TrkB agonists and methods of use
US10167277B2 (en) 2011-07-22 2019-01-01 Massachusetts Institute Of Technology Activators of class I histone deacetlyases (HDACs) and uses thereof
US9115053B2 (en) 2011-07-22 2015-08-25 Massachusetts Institute Of Technology Activators of class I histone deacetlyases (HDACS) and uses thereof
US11084803B2 (en) 2011-07-22 2021-08-10 Massachusetts Institute Of Technology Activators of class I histone deacetylases (HDACs) and uses thereof
US10357508B2 (en) * 2012-03-19 2019-07-23 Buck Institute For Research On Aging APP specific BACE inhibitors (ASBIs) and uses thereof
CN106902108B (zh) * 2012-03-19 2020-07-21 巴克老龄化研究所 App特异性bace抑制剂(asbi)及其用途
USRE49873E1 (en) 2012-03-19 2024-03-19 Buck Institute For Research On Aging APP specific bace inhibitors (ASBIs) and uses thereof
US20150306122A1 (en) * 2012-03-19 2015-10-29 Buck Institute For Research On Aging APP SPECIFIC BACE INHIBITORS (ASBIs) AND USES THEREOF
CN106902108A (zh) * 2012-03-19 2017-06-30 巴克老龄化研究所 App特异性bace抑制剂(asbi)及其用途
US10835546B2 (en) 2012-03-19 2020-11-17 Buck Institute For Research On Aging App specific BACE inhibitors (ASBIs) and uses thereof
US9593125B2 (en) 2012-07-27 2017-03-14 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
US10596145B2 (en) 2012-07-27 2020-03-24 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
US10010526B2 (en) 2012-07-27 2018-07-03 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
CN106474101A (zh) * 2015-06-17 2017-03-08 海南医学院 高良姜素在治疗糖尿病脑病药物中的应用
CN108524530A (zh) * 2017-03-01 2018-09-14 中国药科大学 香豆酰基黄酮苷在神经保护方面的应用
CN109453162A (zh) * 2019-01-07 2019-03-12 海南热带海洋学院 穗花杉双黄酮在制备保护和/或修复神经细胞药物中的应用、药物组合物及应用
CN115867255A (zh) * 2021-04-23 2023-03-28 一丸自然美健有限公司 胶原蛋白产生促进剂及包含其的皮肤外用剂
CN115475159A (zh) * 2021-05-31 2022-12-16 中国医学科学院药物研究所 山奈酚在制备抑制小脑炎症反应药物中的用途

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KR100610562B1 (ko) 2006-08-08

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