WO2009154197A1 - 認知障害改善剤 - Google Patents
認知障害改善剤 Download PDFInfo
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- WO2009154197A1 WO2009154197A1 PCT/JP2009/060937 JP2009060937W WO2009154197A1 WO 2009154197 A1 WO2009154197 A1 WO 2009154197A1 JP 2009060937 W JP2009060937 W JP 2009060937W WO 2009154197 A1 WO2009154197 A1 WO 2009154197A1
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- nobiletin
- royal jelly
- hydroxy
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- benzyloxy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/63—Arthropods
- A61K35/64—Insects, e.g. bees, wasps or fleas
- A61K35/644—Beeswax; Propolis; Royal jelly; Honey
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/63—Arthropods
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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
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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
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/41—Crassulaceae (Stonecrop family)
-
- 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
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a cognitive impairment improving agent comprising nobiletin or its analog or citrus extract, and royal jelly as active ingredients.
- Japan which is becoming an aging society, the prevention and treatment of cognitive disorders such as concentration, memory, organization, planning, and problem-solving ability caused by aging, especially Alzheimer's disease, which is a typical disease, is a serious problem. It has become to.
- Nobiletin one of the polymethoxyflavonoids contained in many citrus fruits, has been reported to have an effect of promoting information transmission that governs memory and to suppress the increase in learning impairment. It is a cognitive impairment improving agent such as Alzheimer's disease. It is known that it is useful as (patent documents 1 and 2).
- Royal jelly is a secretion from the pharyngeal gland of young bees in bees and is fed as food for the queen larvae and adult queen bees. It is the only energy source in the life of a queen bee that lives 40 times longer than a worker bee. In addition, it contains many vitamins, minerals and amino acids that are incomparable to honey, and is known to contain various nutrients with high protein. However, the effect of royal jelly on cognitive impairment is not yet known.
- An object of the present invention is to provide a cognitive impairment improving agent useful for the prevention or treatment of cognitive impairment, particularly preferably Alzheimer's disease.
- a cognitive impairment improving agent comprising royal jelly as an active ingredient
- a cognitive impairment improving agent comprising nobiletin or an analog thereof or citrus extract, and royal jelly as active ingredients
- 2- (4-Benzyloxy-3-methoxyphenyl)-by reacting 2′-hydroxy-3 ′, 4 ′, 5 ′, 6′-tetramethoxyacetophenone with 4-benzyloxy-3-methoxybenzaldehyde Obtaining 1- (2-hydroxy-3,4,5,6-tetramethoxyphenyl) -propenone; The obtained 3- (4-benzyloxy-3-methoxyphenyl) -1- (2-hydroxy-3,4,5,6-tetramethoxyphenyl) -propenone was reacted in the presence of
- the vertical axis represents the relative value of phosphorylated ERK with respect to total ERK.
- FIG. 2 shows the enhancing effect of nobiletin on royal jelly-induced stimulation of ERK phosphorylation in PC12D cells. Representative results from at least 3 independent trials are shown (top).
- the numerical value on the vertical axis is a concentration measurement value for ERK phosphorylation in PC12D cells, and is shown as a relative value to the numerical value of the subject group (0.1% DMSO).
- ## is p ⁇ 0.01 with respect to 30 ⁇ M nobiletin, and ### is p ⁇ 0.005.
- FIG. 5 shows the effect of nobiletin concentration on CRE-dependent transcription in cultured rat hippocampal neurons.
- FIG. 6 shows the concentration-dependent effect of 4-demethylnobiletin on CRE-dependent transcription in cultured rat hippocampal neurons. Cells were seeded at a density of 8 ⁇ 10 4/48-well plate, and maintained the plates 10-14 days.
- Nobiletin that can be used in the present invention includes 5,6,7,8,3 ′, 4′-hexamethoxyflavone, pharmaceutically acceptable salts, hydrates or solvates thereof. .
- the nobiletin of the present invention can be chemically synthesized using methods well known to those skilled in the art. It can also be extracted from citrus plants. In the present invention, an extract of a citrus family plant containing nobiletin can also be used. For example, 4'-hydroxy-5,6,7,8,3'-pentamethoxyflavone (4-demethylated nobiletin), a pharmaceutically acceptable salt thereof, and a hydrate thereof, which are analogs of nobiletin Or a solvate is included.
- Citrus Lemon (Citrus depressa), Satsuma mandarin (Citrus unshiu), Giant Citrus (Citrus tangerina), Cobb mandarin (Citrus erythrosa), Daidai (Citrus aurantium), Mediterranean mandarin (Citrus deliciosa), Zabong (Citrus deliciosa)
- Examples include Cyrus kinokuni, Ponkan (Citrus reticulata), Tachibana (Citrus tachibana), and Sankitsu (Citrus sunki).
- the extract of the citrus plant used in the present invention may be extracted from either a raw state after collection or a dried state.
- Examples of the site include mature or immature fruit, pericarp, seed, leaf, petiole, branch, root, flower and the like. Preferable are fruits and pericarps.
- the royal jelly that can be used in the present invention is not particularly limited, and commercially available royal jelly can be used.
- the product of Japan Royal Jelly can be mentioned.
- royal jelly freeze-dried powder FD powder is used unless otherwise specified.
- the content of nobiletin is 0.0025 wt% to 2.00 wt%, preferably 0.005 wt% to 1.50 wt%, more preferably 0.01 wt% to 1.00 wt%. %.
- an extract containing 10% nobiletin when used, it is 0.025 wt% to 20.0 wt%, preferably 0.05 wt% to 15.0 wt%, more preferably 0.1 wt% to 10 wt%. 0.0% by weight.
- the content of the royal jelly is 3 wt% to 60 wt%, preferably 5 wt% to 45 wt%, more preferably 10 wt% to 30 wt% as the royal jelly FD powder.
- the ratio of the nobiletin content to the royal jelly content is 2: 3 to 1: 24000, preferably 3:10 to 1: 9000, more preferably 1:10 to 1: 600.
- the ratio is 20: 3 to 1: 2400, preferably 3: 1 to 1: 900, more preferably 1: 1 to 1:60.
- the cognitive impairment-improving agent of the present invention can be added to pharmaceuticals, quasi drugs or foods.
- the neurite outgrowth agent of the present invention can be used for either oral administration or parenteral administration.
- Pharmaceutical forms include tablets, capsules, granules, syrups and the like. These pharmaceuticals can be produced using additives in normal pharmaceutical production.
- the dose of the cognitive impairment improving agent of the present invention is not particularly limited.
- it is 10 to 60 mg / kg body weight per day, preferably 20 mg / kg body weight per day. In some cases, it is 2 to 6 mg / kg body weight per day, preferably 2 to 3 mg / kg body weight.
- the above dose can be administered once a day or divided into 2 to 3 times a day, and can be appropriately increased or decreased depending on the age, disease state, and symptoms.
- the additive examples include lactose, dextrin, sucrose, mannitol, corn starch, sorbitol, crystalline cellulose, polyvinylpyrrolidone and the like, and these can be used alone or in appropriate combination.
- These pharmaceuticals can be produced by a method suitable for each pharmaceutical form according to the description of the Japanese Pharmacopoeia.
- a flavoring agent, a coloring agent, a sweetener, etc. can also be used suitably.
- the content of these additives can be appropriately selected by those skilled in the art.
- quasi drugs examples include tablets, capsules, granules, jellies, and drinks. These quasi-drugs can be manufactured using the additives in normal quasi-drug manufacture. Furthermore, these quasi drugs may contain other active ingredients such as vitamins. In addition, additives such as sweeteners, flavoring agents, coloring agents, and antioxidants may be used alone or in appropriate combination. These quasi drugs can be produced by methods well known to those skilled in the art.
- Food forms include noodles, pasta, granules, tablets, jelly, liquid (beverage), and the like. These foods can be produced by appropriately using various food materials. Specific examples of food materials are rice, wheat, corn, potato, sweet potato, soy flour, seaweed flour, starch syrup, lactose, glucose, fructose, sucrose, mannitol, etc., which can be used alone or in appropriate combination. it can. If necessary, the desired shape can be obtained by using water or the like. Furthermore, flavoring agents, coloring agents, sweetening agents, edible oils, vitamins and the like can be added as appropriate.
- CAMP / PKA / ERK / CREB-dependent signal transduction pathways have been shown to be closely related to the memory and learning ability of the brain.
- AD amyloid ⁇ protein
- synaptic plasticity disorder without neuronal cell death due to soluble A ⁇ is a cause of memory impairment in Alzheimer's disease (AD). It has come to be understood as one.
- LTP neurotransmission
- a ⁇ is known to inhibit PKA / CREB signaling and suppress the generation of this LTP. That is, a food containing a physiologically active substance that improves or suppresses signal transduction inhibition by A ⁇ is considered to be useful for improving / preventing AD.
- PC12D cells (Aichi Prefectural Colony Research Laboratories) were inactivated (56 ° C, 30 minutes) with 5% horse serum (HS: Gibco), 10% fetal calf serum (FCS: CELLect), penicillin (Subcultured using Dulbecco's modified Eagle medium (DMEM) supplemented with 50 units / mL) and streptomycin (50 ⁇ g / mL). The cells were cultured in an incubator containing 95% air-5% CO 2 kept at 37 ° C. In this experiment, a medium adjusted to 2% HS and 1% FCS was used for drug dilution.
- HS horse serum
- FCS CELLect
- penicillin Subcultured using Dulbecco's modified Eagle medium (DMEM) supplemented with 50 units / mL) and streptomycin (50 ⁇ g / mL).
- DMEM Dulbecco's modified Eagle medium
- streptomycin 50 ⁇ g /
- the membrane was washed with TBST, incubated with an HRP-labeled IgG antibody diluted with a blocking buffer for 2 hours at room temperature, and washed again with TBST.
- the ECL method was used for band detection.
- the antibody was removed using a stripping buffer (62.5 mM Tris-HCl, 2% SDS, 100 mM ⁇ -mercaptoethanol; pH 7.4), and then the internal standard protein was detected.
- PC12D cells were seeded at a cell density of 1 ⁇ 10 6 cells / 3.5 cm dish, cultured overnight, and treated with low serum medium containing various drugs for 15 minutes Then, the cells were lysed with a cell lysate to obtain a cell extract. The expression level of p-ERK and total ERK in this cell extract was analyzed using Western blotting. The royal jelly solution was prepared in a 25% solution and then diluted with a low serum medium for use in the experiment.
- the pellet was dispersed in a dispersion liquid (SUMILON), and then a removal liquid (SUMILON) was added to the well dispersed cells by pipetting, followed by centrifugation at 800 rpm for 5 minutes, and then the supernatant was removed.
- the pellet was suspended in Neurobasal medium (Phenol red-free Neurobasal medium 500 ml, 50 ⁇ B-27 Supplement 10 ml, 0.5 mM L-glutamine, 0.005% penicillin-streptomycin) and added to a polylysine-coated 48-well plate.
- the cells were seeded at 8 ⁇ 10 4 cells / well, and after one day of culture, the cells were washed with PBS and then replaced with a new medium.
- PC12D cells were seeded in a 48-well plate at 8 ⁇ 10 4 cells / well, cultured for 24 hours in growth medium, and then pCRE reporter gene plasmid (Firefly luciferase) was used at 0.1 ⁇ g / well for internal standard.
- PRG-TK plasmid Umi Shiitakel Schifferase
- Lipofectamine TM 2000 reagent invitrogen
- hippocampal neurons prepared by the above method were cultured in Neurobasal medium for 10-14 days, and then a reporter plasmid (0.1 ⁇ g / well) and a Renilla pRG-TK plasmid (0.01 ⁇ g / well) were transfected by lipofection. The drug was treated for a certain period of time. Transcriptional activity was measured using Promega's Dual-Luciferase (registered trademark) Reporter Assay System.
- nobiletin promoted CRE-dependent transcription in a hippocampal neuron in a concentration-dependent manner.
- nobiletin As shown in FIG. 5, the effect of nobiletin on CRE-dependent transcription was examined using a reporter gene assay. As a result, nobiletin promoted CRE-dependent transcription in hippocampal neurons in a concentration-dependent manner. In addition, as shown in FIG. 6, 4-demethylnobiletin also promoted CRE-dependent transcription in a concentration-dependent manner, like nobiletin.
- the reaction solution was filtered through Celite, The solvent was distilled off under reduced pressure.
- the organic layer obtained by extracting the residue with Et 2 O was washed with brine and dried over MgSO 4 , and the solvent was distilled off under reduced pressure.
- the residue was subjected to silica gel chromatography, and 1,2,3,4,5-pentamethoxybenzene (42 mg, 0.18 mmol, 34%) was obtained as a colorless solid from the fraction eluted with AcOEt / hexane (5: 7 v / v). It was.
- the oxidative cyclization reaction (flavone skeleton synthesis) from 2′-hydroxychalcone to flavone using I 2 / DMSO (synthesis of flavone skeleton) is performed by AMS Silva, DCGA Pinto, JAS Cavaleiro, Tetrahedron Lett, 1994, 35, 5899.
- AMS Silva, DCGA Pinto, JAS Cavaleiro, Tetrahedron Lett, 1994, 35, 5899 For conversion of compound 1 to 2 (oxidation of aromatic aldehyde to phenol) in -5902, M. Matsumoto, H. Kobayashi, Y. Hotta, J. Org. Chem. 1984, 49, 4740
- compound 3 was synthesized separately in D.
- the recommended amount of ingredients to be blended when the product of the present invention is used as a health food is shown below.
- health food is not limited because it is a part of food.
- Royal jelly and nobiletin are essential, but may contain DHA (docosahexaenoic acid), red ginseng extract powder, phosphatidylserine, ferulic acid and the like.
- DHA docosahexaenoic acid
- red ginseng extract powder phosphatidylserine
- ferulic acid a sugar-coated tablet is shown below.
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Abstract
Description
[1]ローヤルゼリーを有効成分として含む、認知障害改善剤、
[2]ノビレチン若しくはその類縁体又は柑橘類エキス、及びローヤルゼリーを有効成分として含む、認知障害改善剤、
[3]ノビレチン若しくはその類縁体及びローヤルゼリー、さらに、紅景天エキス、イチョウ葉エキス及びフェルラ酸を有効成分として含む認知障害改善剤、
[4]2’-ヒドロキシ-3’,4’,5’,6’-テトラメトキシアセトフェノンを4-ベンジルオキシ-3-メトキシベンズアルデヒドと反応させ3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンを得る工程、
得られた3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンをヨウ素の存在下で反応させ3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンを得る工程、及び
得られた3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンを水素及びパラジウム炭素の存在下で反応させ2-(4-ヒドロキシ-3-メトキシフェニル)-5,6,7,8-テトラメトキシクロメン-4-オンを得る工程を含む、4-脱メチル化ノビレチンを製造する方法
に関する。
PC12D細胞の培養
PC12D細胞(愛知県コロニー研究所)は、非働化(56℃、30分)した5%ウマ血清(HS:Gibco)、10%ウシ胎児血清(FCS:CELLect)、ペニシリン(50単位/mL)およびストレプトマイシン(50μg/mL)を添加したダルベッコ改変イーグル培地(DMEM)を用い、継代培養した。細胞は37℃に保温した95%air-5%CO2を含むインキュベーター中で培養した。なお、本実験では、HSが2%、FCSが1%になるように調整した培地を薬物の希釈に使用した。
滅菌したスパーテルを用いて、滅菌済の2mlチューブに0.25gの「ローヤルゼリーFD末」(ジャパンローヤルゼリー株式会社)を秤量した。その後、クリーンベンチ内で、滅菌済PBS(-)を加えて、容量を1mlとした。攪拌後、冷蔵庫に移し、1時間毎に攪拌を繰り返し、一晩冷蔵庫内で静置した。翌日、攪拌した後、12000×g、4℃で、10分間遠心した。その上清をフィルター滅菌し、分注後-20℃で凍結保存した。
35mmディッシュに、PC12D細胞を1×106細胞/ディッシュで播種し、CO2インキュベーター内で24時間培養後、薬物で処理した。薬物処理した細胞を90μlの細胞可溶化液(1mMEDTA、1%SDS、10mMNaF、10nMカリクリン、320nMオカダ酸、1mMオルトバナジン酸ナトリウム、1mMp-APMSF、10μg/mlペプスタチン、10μg/mlアンチペイン、10μg/mlロイペプチン、10μg/mlキモスタチン、10μg/mlホスフォラミドン、10mMHEPES(pH7.5))で可溶化した後に、1.5mlチューブに回収し、95℃で5分間加熱した。さらに、氷水中で5分間超音波処理した後に、14,000rpmで20分間遠心し、上清を回収し、タンパク質を定量した。その後、SDS-PAGEサンプルバッファーを加えた。SDS-PAGE後、ウエスタンブロット法によりPVDFメンブレンにタンパク質を転写し、ブロッキングバッファー(10mMTris-HCl、100mMNaCl、0.05%Tween20、5%スキムミルク;pH7.4)を用いて2時間ブロッキングした。その後、メンブレンをTBSTで洗浄し、ブロッキングバッファーで希釈した一次抗体と4℃で一晩インキュベートした。さらに、メンブレンをTBSTで洗浄し、ブロッキングバッファーで希釈したHRP標識IgG抗体と室温で2時間インキュベートし、再度TBSTで洗浄した。バンドの検出にはECL法を用いた。リプロービングは、ストリッピングバッファー(62.5mMTris-HCl、2%SDS、100mMβ-メルカプトエタノール;pH7.4)を用いて抗体を除去し、その後内部標準タンパク質を検出した。
実験値を平均値±標準誤差で表示した。統計処理はスチューデントのt検定、分散分析およびダネット検定を用い、危険率5%未満の場合を有意差ありと判定した。
PC12D細胞におけるERKリン酸化に対するローヤルゼリーおよびノビレチンの効果
PC12D細胞を1×106細胞/3.5cmディッシュの細胞密度で播種し、一晩培養し、種々の薬物を含む低血清培地で15分間処理して、細胞可溶化液で細胞を溶解させて、細胞抽出液を得た。ウエスタンブロット法を用いて、この細胞抽出液中のp-ERKおよび全ERKの発現量を分析した。なお、ローヤルゼリー溶液は、25%溶液を調製後、低血清培地で希釈して実験に供した。
さらに、非常に興味深い結果が得られた。すなわち、単独ではERKのリン酸化の弱い促進作用しか示さなかった30μMノビレチンは、ローヤルゼリーの顕著なERKのリン酸化促進活性をさらに増強することが判明した。このことは、ローヤルゼリーとノビレチンの併用が記憶・学習と密接に関連するcAMP/PKA/ERK/CREB依存的シグナル伝達を顕著に促進する可能性を強く示すものである(図2)。
ラット海馬神経細胞初代培養
妊娠SDラット(E18)をエーテル麻酔した後、頚椎脱臼させた。その後、腹部を70%EtOHで消毒後、腹部正中切開により胎児を摘出した。さらに、ラット胎仔から脳を摘出し、実態顕微鏡下で海馬を分離した。海馬神経細胞の培養は、住友ベークライト社製のSUMITOMO Nerve-Cell Culture Systemを用いて行った。パパイン酵素を含む分散液(SUMILON)で海馬組織を分散させ、1,000rpmで4分間遠心した後、上清を除去した。ペレットを分散液(SUMILON)中で分散させ、さらにピペッティングにより十分に分散した細胞に除去液(SUMILON)を加え、800rpmで5分間遠心した後、上清を除去した。ペレットをNeurobasal 培地(フェノールレッド不含Neurobasal 培地 500 ml、50×B-27 Supplement 10m1、 0.5mM L-グルタミン、0.005%ペニシリン-ストレプトマイシン)を用いて懸濁し、ポリリジンコーティングした48ウェルプレートに8×104細胞/ウェルで播種し、培養1日後に、PBSで洗浄した後に新しい培地に交換し、その後は2-3日おきに培地半量交換により10μMAraC含有培地にて培養した。
PC12D細胞を48ウェルプレートに8×104細胞/ウェルで播種し、増殖培地で24時間培養後、pCREのレポータージーンプラスミド(ホタル・ルシフエラーゼ)を0.1μg/ウェル、内標準用のpRG-TKプラスミド(ウミ・シイタケルシフエラーゼ)を0.01μg/ウェルの濃度でリポフェクタミン(商標)2000試薬(invitrogen)を用いてコトランスフェクションした。トランスフェクション16時間後に種々の薬物を添加した培地に交換した。種々の濃度の薬物を含む培地で5時間処理した後、培地を吸引し、Passive Lysis Buffer(Dual-Luciferase Reportor Assay System Cat.# E1960 (Promega))を細胞に加えて溶解して回収した。なお、ホタル及びウミシイタケルシフエラーゼの活性はDual-Ruciferase Reporter Assay System (Promega)を用いてルミノメーター(Mini Lumat LB9506(BERTHOLD))で測定した。
他方、上記の方法で調製した海馬神経細胞をNeurobasal培地で10-14日間培養後、レポータープラスミド(0.1μg/ウェル)、ウミシイタケpRG-TKプラスミド(0.01μg/ウェル)をリポフェクション法にてトランスフェクトし、一定時間薬物処置した。転写活性の測定はPromega社製のDual-Luciferase(登録商標) Reporter Assay Systemを用いて行った。
レポータージーンアッセイで得られた結果をone-way ANOVA (Tukey)を用いて評価した。有意水準を両側5%として検定し、p<0.05を有意とした。
3,4,5-トリメトキシベンズアルデヒド(2.0g,10.2mmol)のMeOH(20.4ml,0.5M)溶液に、氷冷下濃硫酸(0.54ml,10.2mmol)を加えた後、30%過酸化水素水溶液(3.5ml,30.6mmol)をゆっくりと加えた。室温にて15分攪拌後、氷冷下10%水酸化ナトリウム水溶液と亜硫酸ナトリウムを加え、反応を停止した。AcOEtにて抽出した有機層をブラインで洗浄後、MgSO4で乾燥し、減圧下溶媒を留去した。残渣をシリカゲルクロマトグラフィーに付し、AcOEt/ヘキサン(5:6v/v)溶出部より3,4,5-トリメトキシフェノール(1.08g,7.0mmol,58%)を無色固体として得た。
3,4,5-トリメトキシフェノール(0.10g,0.54mmol)のDMF(3.6ml,0.15M)溶液に、室温下2-ヨードキシ安息香酸(IBX)(160mg,5.7mmol)を加え、30分攪拌した。10%Pd/C(10mg)を加えた後、系内を水素雰囲気に置換し1日間攪拌した。系内をアルゴン雰囲気に戻した後、炭酸カリウム(220mg,1.6mmol)と硫酸ジメチル(0.13ml,1.4mmol)を加え、さらに3時間室温にて攪拌後、反応溶液をセライトろ過し、減圧下溶媒を留去した。残渣をEt2Oにて抽出した有機層をブラインで洗浄後、MgSO4で乾燥し、減圧下溶媒を留去した。残渣をシリカゲルクロマトグラフィーに付し、AcOEt/ヘキサン(5:7v/v)溶出部より1,2,3,4,5-ペンタメトキシベンゼン(42mg,0.18mmol,34%)を無色固体として得た。
2,6-ジメトキシ[1,4]ベンゾキノン(10g,58.8mmol)をラネーNi(3.5g)のMeOH(100ml,0.59M)溶液に加え、室温、水素雰囲気下で6時間攪拌した。反応溶液をセライトろ過し、減圧下溶媒を留去することで粗2,6-ジメトキシベンゼン-1,4-ジオールを得た。
粗2,6-ジメトキシベンゼン-1,4-ジオール(<58.8mmol)のアセトン(100ml,<0.59M)溶液に、炭酸カリウム(41g,297mmol)と硫酸ジメチル(14ml,147mmol)を加え、さらに3時間加熱還流にて攪拌した。AcOEtにて抽出した有機層をブラインで洗浄後、MgSO4で乾燥し、減圧下溶媒を留去した。残渣をシリカゲルクロマトグラフィーに付し、AcOEt/ヘキサン(1:2v/v)溶出部より1,2,3,5-テトラメトキシベンゼン(11.5g,158.1mmol,99%)を無色油状として得た。
1,2,3,5-テトラメトキシベンゼン(11.5g,58.1mmol)のEt2O(200ml,0.29M)溶液に、AlCl3(26g,192mmol)を氷冷下にて加えた。その後、AcCl(5.4ml,75.5mmol)をゆっくりと加え、室温にて2時間攪拌した。氷冷下水をアルミニウムが溶解するまで加えることで反応を停止させた。Et2Oにて抽出した有機層をブラインで洗浄後、MgSO4で乾燥し、減圧下溶媒を留去した。残渣をシリカゲルクロマトグラフィーに付し、AcOEt/ヘキサン(1:1v/v)溶出部より2’-ヒドロキシ-3’,4’,6’-トリメトキシアセトフェノン(11.1g,49.1mmol,85%)を黄色固体として得た。
2’-ヒドロキシ-3’,4’,6’-トリメトキシアセトフェノン(10.8g,47.7mmol)のMeOH(130ml,0.37M)溶液に、氷冷下10%水酸化ナトリウム水溶液(40ml,48mmol)を加えた後、6%過酸化水素水溶液(82ml,143mmol)をゆっくりと加えた。室温にて30分攪拌後、氷冷下10%塩酸と亜硫酸ナトリウムを加え、反応を停止した。AcOEtにて抽出した有機層をブラインで洗浄後、MgSO4で乾燥し、減圧下溶媒を留去することで粗3,4,6-トリメトキシベンゼン-1,2-ジオールを無色固体として得た。
4-ベンジルオキシ-3-メトキシベンズアルデヒド(340mg,1.41mmol)と2’-ヒドロキシ-3’,4’,5’,6’-テトラメトキシアセトフェノン(240mg,0.94mmol)のEtOH(5.0ml,0.19M)溶液に、室温下50%水酸化カリウム水溶液(0.37ml,3.3mmol)を滴下した。24時間攪拌後、氷冷下10%塩酸を加えることで反応を停止させ、AcOEtにて抽出した。有機層をブラインで洗浄後、MgSO4で乾燥し、減圧下溶媒を留去した。残渣をシリカゲルクロマトグラフィーに付し、AcOEt/ヘキサン(1:2v/v)溶出部より3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノン(0.32g,0.66mmol,71%)を黄色固体として得た。
2-(4-ベンジルオキシ-3-メトキシフェニル)-5,6,7,8-テトラメトキシクロメン-4-オン(79mg,0.17mmol)をPd/C(8mg)のEtOH(2ml,0.08M)溶液に加え、室温、水素雰囲気下で2時間攪拌した。反応溶液をセライトろ過し、減圧下溶媒を留去した。残渣をシリカゲルクロマトグラフィーに付し、AcOEt溶出部よりG010(64mg,0.17mmol,99%)を黄色固体として得た。
Claims (4)
- ローヤルゼリーを有効成分として含む、認知障害改善剤。
- ノビレチン若しくはその類縁体又は柑橘類エキス、及びローヤルゼリーを有効成分として含む、認知障害改善剤。
- ノビレチン若しくはその類縁体及びローヤルゼリー、さらに、紅景天エキス、イチョウ葉エキス及びフェルラ酸を有効成分として含む認知障害改善剤。
- 2’-ヒドロキシ-3’,4’,5’,6’-テトラメトキシアセトフェノンを4-ベンジルオキシ-3-メトキシベンズアルデヒドと反応させ3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンを得る工程、
得られた3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンをヨウ素の存在下で反応させ3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンを得る工程、及び
得られた3-(4-ベンジルオキシ-3-メトキシフェニル)-1-(2-ヒドロキシ-3,4,5,6-テトラメトキシフェニル)-プロペノンを水素及びパラジウム炭素の存在下で反応させ2-(4-ヒドロキシ-3-メトキシフェニル)-5,6,7,8-テトラメトキシクロメン-4-オンを得る工程を含む、4-脱メチル化ノビレチンを製造する方法。
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US12/672,768 US20110287106A1 (en) | 2008-06-17 | 2009-06-16 | Cognitive impairment ameliorant |
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JP2017514874A (ja) * | 2014-05-08 | 2017-06-08 | ディーエスエム アイピー アセッツ ビー.ブイ. | 10−ヒドロキシ−2−デセン酸を含む方法及び組成物 |
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WO2015184509A1 (en) | 2014-06-06 | 2015-12-10 | Deakin University | Methods of treating neurodevelopmental diseases and disorders |
JP6238089B1 (ja) * | 2016-06-01 | 2017-11-29 | 株式会社三協ホールディングス | 医薬組成物および食品 |
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CN102260728A (zh) * | 2011-07-05 | 2011-11-30 | 北京师范大学 | 一种蜂王浆多肽及其用途 |
CN102260728B (zh) * | 2011-07-05 | 2014-08-06 | 北京师范大学 | 一种蜂王浆多肽及其用途 |
JP2017514874A (ja) * | 2014-05-08 | 2017-06-08 | ディーエスエム アイピー アセッツ ビー.ブイ. | 10−ヒドロキシ−2−デセン酸を含む方法及び組成物 |
JP6117453B1 (ja) * | 2015-10-16 | 2017-04-19 | 国立大学法人東北大学 | ローヤルゼリー分画の製造方法 |
WO2017065314A1 (ja) * | 2015-10-16 | 2017-04-20 | 国立大学法人東北大学 | ローヤルゼリー分画の製造方法 |
WO2017078175A1 (ja) * | 2015-11-05 | 2017-05-11 | ジャパンローヤルゼリー株式会社 | ローヤルゼリーの抗認知症活性の増強剤 |
JP6201086B1 (ja) * | 2015-11-05 | 2017-09-20 | ジャパンローヤルゼリー株式会社 | ローヤルゼリーの抗認知症活性の増強剤 |
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KR20110036040A (ko) | 2011-04-06 |
KR101627001B1 (ko) | 2016-06-03 |
US20130129832A1 (en) | 2013-05-23 |
EP2311472A4 (en) | 2012-02-01 |
JPWO2009154197A1 (ja) | 2011-12-01 |
CN101801398A (zh) | 2010-08-11 |
EP2311472B1 (en) | 2014-03-05 |
EP2311472A1 (en) | 2011-04-20 |
JP5676881B2 (ja) | 2015-02-25 |
US20110287106A1 (en) | 2011-11-24 |
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