JPH06256179A - Learning ability improver - Google Patents
Learning ability improverInfo
- Publication number
- JPH06256179A JPH06256179A JP5048176A JP4817693A JPH06256179A JP H06256179 A JPH06256179 A JP H06256179A JP 5048176 A JP5048176 A JP 5048176A JP 4817693 A JP4817693 A JP 4817693A JP H06256179 A JPH06256179 A JP H06256179A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- group
- learning ability
- active ingredient
- glycerol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は学習能を向上させること
が可能な学習能向上剤に関する。TECHNICAL FIELD The present invention relates to a learning ability improving agent capable of improving learning ability.
【０００２】[0002]
【従来の技術】近年、学習能力や記憶力等の脳の機能を
高める物質の探索が多方面にわたって検討されている。
その結果、脳の機能を高める物質は脳の血行を良くし脳
細胞への酸素や栄養の供給を高める脳循環改善剤、また
は脳細胞の働きを活性化する脳代謝改善剤に分類され、
これらの物質は医薬品を目的として化学合成されてい
る。しかし脳の機能を高める物質の機能発現には一般的
に長期間の摂取が必要であるにも拘らず、化学合成され
た多くのこれらの物質は副作用が極めて強く、長期の摂
取、投与は困難である。2. Description of the Related Art In recent years, the search for substances that enhance brain functions such as learning ability and memory ability has been studied in various fields.
As a result, substances that enhance brain function are classified into cerebral circulation improving agents that improve blood circulation in the brain and increase the supply of oxygen and nutrients to brain cells, or cerebral metabolism improving agents that activate the function of brain cells,
These substances are chemically synthesized for the purpose of pharmaceutical products. However, despite the fact that long-term intake is generally required for the expression of functions that enhance brain function, many of these chemically synthesized substances have extremely strong side effects, making long-term intake and administration difficult. Is.
【０００３】一方、学習能を向上させる天然の食品成分
としてα−リノレン酸（生化学、５９、１２３５、１９
８７）や、ドコサヘキサエン酸（以下、ＤＨＡと略す場
合がある）またはその塩、アミド、エステル、リン脂
質、トリグリセリド等の誘導体（特開平１−２７９８２
７号公報）が公知であり、α−リノレン酸はラットの明
度弁別学習実験で、またＤＨＡまたはその誘導体はラッ
トのＹ路迷路明暗弁別餌取実験で正反応率を向上させる
ことが知られている。On the other hand, α-linolenic acid (Biochemistry, 59 , 1235, 19) is used as a natural food ingredient for improving learning ability.
87), or docosahexaenoic acid (hereinafter sometimes abbreviated as DHA) or its salt, amide, ester, phospholipid, triglyceride derivative (JP-A-1-27982).
No. 7) is known, and α-linolenic acid is known to improve the positive reaction rate in a rat lightness discrimination learning experiment, and DHA or a derivative thereof in a rat Y-maze light-dark discrimination food feeding experiment. .
【０００４】しかし、特開平１−２７９８２７号公報に
記載されているドコサヘキサエン酸や、そのエステル、
トリグリセリド、リン脂質等の誘導体が学習効果を発揮
するには長期間にわたって多量に摂取する必要がある。
またリン脂質についてはグリセロリン脂質なのか、また
はスフィンゴリン脂質なのかも記載されておらず、誘導
体の構造も明らかにされていない。However, docosahexaenoic acid and its ester described in JP-A-1-279827,
Derivatives such as triglycerides and phospholipids need to be ingested in large amounts over a long period of time to exert learning effects.
In addition, regarding phospholipids, it is not described whether they are glycerophospholipids or sphingophospholipids, and the structures of derivatives have not been clarified.
【０００５】ＤＨＡの配坐と充填特性のコンピューター
によるモデル化の研究（ジャーナル・オブ・リピッド・
リサーチ，２７，６５８，１９８６）において、グリセ
ロールのｓｎ−１位にアシル連鎖を有し、ｓｎ−２位に
ＤＨＡを組み込むと、ｓｎ−１位のアシル連鎖とｓｎ−
２位の山形鉄状の連鎖構造をとるＤＨＡのＶ字溝にｓｎ
−１位のアシル連鎖が充填され、ＤＨＡの２つの平面と
アシル連鎖との分子間相互作用により非常に特異的な立
体構造を示すことが示唆されており、このような化合物
の立体構造は重要である。Computer modeling study of conformation and packing characteristics of DHA (Journal of Lipids
Research, 27 , 658, 1986), glycerol has an acyl chain at the sn-1 position and incorporates DHA at the sn-2 position.
Sn in the V-shaped groove of DHA, which has a second iron-like chain structure
It has been suggested that the acyl chain at the -1 position is filled, and that a very specific three-dimensional structure is exhibited by the intermolecular interaction between the two planes of DHA and the acyl chain, and the three-dimensional structure of such a compound is important. Is.
【０００６】一方、特開昭６４−２５８９号公報、特開
昭６４−５１０９１号公報、特開平１−１６０９８９号
公報には、ｓｎ−１位に飽和またはモノエン脂肪酸残
基、ｓｎ−２位に高度不飽和脂肪酸残基がエステル結合
した１，２−ジアシル−ｓｎ−グリセロール誘導体が記
載されている。しかし、これらはグリセロール誘導体の
製造方法に関するものであり、１，２−ジアシル−ｓｎ
−グリセロール誘導体の具体的な生理活性については何
ら開示されていない。On the other hand, in JP-A-64-2589, JP-A-64-51091 and JP-A-1-160989, saturated or monoene fatty acid residue at the sn-1 position and sn-2 position are disclosed. A 1,2-diacyl-sn-glycerol derivative in which a polyunsaturated fatty acid residue is ester-bonded is described. However, these relate to a method for producing a glycerol derivative, which is 1,2-diacyl-sn
-No specific physiological activity of the glycerol derivative is disclosed.
【０００７】また、特開平２−４５４２４号公報には、
ｓｎ−１位にオレオイル基、ｓｎ−２位にドコサヘキサ
エノイル基またはエイコサペンタエノイル基がエステル
結合した１，２−ジアシル−ｓｎ−グリセロール誘導体
を有効成分とする抗アレルギー剤が記載されている。し
かしこの公報においても、上記グリセロール誘導体に学
習能向上作用があることは明らかにされていない。Further, Japanese Patent Laid-Open No. 2-45424 discloses that
Described is an anti-allergic agent containing a 1,2-diacyl-sn-glycerol derivative having an oleoyl group at the sn-1 position and a docosahexaenoyl group or an eicosapentaenoyl group at the sn-2 position as an active ingredient. Has been done. However, even in this publication, it has not been clarified that the glycerol derivative has a learning ability improving action.
【０００８】[0008]
【発明が解決しようとする課題】本発明の目的は、短期
間でしかも少量の投与量で優れた学習能向上効果が得ら
れ、かつ毒性が低くて安全な学習能向上剤を提供するこ
とである。SUMMARY OF THE INVENTION An object of the present invention is to provide a safe learning ability-improving agent which has an excellent effect of improving learning ability in a short period of time and with a small dose and has low toxicity. is there.
【０００９】[0009]
【課題を解決するための手段】本発明は、一般式The present invention has the general formula
【化２】 （式中、Ｒ1は炭素数１４〜２４の飽和またはモノエン
脂肪酸残基、Ｒ2はアラキドン酸、エイコサペンタエン
酸またはドコサヘキサエン酸残基、Ｒ3は水素、ホスホ
リルコリン基、ホスホリルエタノールアミン基、ホスホ
リルセリン基、ホスホリルイノシトール基またはリン酸
基を表わす。）で示される１，２−ジアシル−ｓｎ−グ
リセロール誘導体を有効成分として含有することを特徴
とする学習能向上剤である。[Chemical 2] (In the formula, R 1 is a saturated or monoene fatty acid residue having 14 to 24 carbon atoms, R 2 is an arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid residue, R 3 is hydrogen, a phosphorylcholine group, a phosphorylethanolamine group, a phosphorylserine group. Group, a phosphorylinositol group or a phosphoric acid group) is contained as an active ingredient in the learning ability improving agent.
【００１０】一般式〔１〕のＲ1としては、ミリスチン
酸、パルミチン酸、ステアリン酸、アラキン酸、ベヘン
酸、リグノセリン酸等の炭素数１４〜２４の飽和脂肪酸
残基；オレイン酸（ｃｉｓ−９−オクタデセン酸）、パ
ルミトレイン酸（ｃｉｓ−９−ヘキサデセン酸）、ミリ
ストレイン酸（ｃｉｓ−９−テトラデセン酸）、バクセ
ン酸（ｔｒａｎｓ−１１−オクタデセン酸）、ｃｉｓ−
バクセン酸、エライジン酸（ｔｒａｎｓ−９−オクタデ
セン酸）、ペトロセリン酸（ｃｉｓ−６−オクタデセン
酸）、ペトロセライジン酸（ｔｒａｎｓ−６−オクタデ
セン酸）、ガドレイン酸（ｃｉｓ−９−エイコセン
酸）、ｃｉｓ−１１−エイコセン酸、ゴンドイン酸（１
１−エイコセン酸）、セトレイン酸（１１−ドコセン
酸）、エルカ酸（ｃｉｓ−１３−ドコセン酸）、ブラシ
ジン酸（ｔｒａｎｓ−１３−ドコセン酸）、ネルボン酸
（ｃｉｓ−１５−テトラコン酸）等の炭素数１４〜２４
のモノエン脂肪酸残基などがあげられる。Ｒ1としては
オレイン酸残基（オレオイル基）が好ましい。As R 1 in the general formula [1], saturated fatty acid residues having 14 to 24 carbon atoms such as myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid; oleic acid (cis-9) -Octadecenoic acid), palmitoleic acid (cis-9-hexadecenoic acid), myristoleic acid (cis-9-tetradecenoic acid), vaccenic acid (trans-11-octadecenoic acid), cis-
Vaccenoic acid, elaidic acid (trans-9-octadecenoic acid), petroselinic acid (cis-6-octadecenoic acid), petroselinic acid (trans-6-octadecenoic acid), gadoleic acid (cis-9-eicosenoic acid), cis -11-Eicosenoic acid, Gondoinic acid (1
Carbon such as 1-eicosenoic acid), cetoleic acid (11-docosenoic acid), erucic acid (cis-13-docosenoic acid), brassic acid (trans-13-docosenoic acid), nervonic acid (cis-15-tetraconic acid) Number 14 to 24
The monoene fatty acid residue of R 1 is preferably an oleic acid residue (oleoyl group).
【００１１】Ｒ2はアラキドン酸、エイコサペンタエン
酸またはドコサヘキサエン酸のアシル残基である。これ
らの中ではドコサヘキサエン酸のアシル残基が好まし
い。R 2 is an acyl residue of arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. Of these, the acyl residue of docosahexaenoic acid is preferred.
【００１２】Ｒ3は水素、あるいはR 3 is hydrogen or
【化３】 で示されるホスホリルコリン基、ホスホリルエタノール
アミン基、ホスホリルセリン基、ホスホリルイノシトー
ル基またはリン酸基である。これらの中では水素、ホス
ホリルコリン基が好ましい。[Chemical 3] Is a phosphorylcholine group, a phosphorylethanolamine group, a phosphorylserine group, a phosphorylinositol group or a phosphoric acid group. Of these, hydrogen and phosphorylcholine groups are preferable.
【００１３】本発明で用いる１，２−ジアシル−ｓｎ−
グリセロール誘導体は、そのｓｎ−１位に前記Ｒ1のア
シル基がエステル結合し、ｓｎ−２位に前記Ｒ2のアシ
ル基が結合した立体特異性を有するものである。一般式
〔１〕で示される１，２−ジアシル−ｓｎ−グリセロー
ル誘導体の具体的なものとして、次に示すものが例示さ
れる。1,2-diacyl-sn-used in the present invention
The glycerol derivative has stereospecificity in which the acyl group of R 1 is ester-bonded to the sn-1 position and the acyl group of R 2 is bonded to the sn-2 position. Specific examples of the 1,2-diacyl-sn-glycerol derivative represented by the general formula [1] include the following.
【００１４】１−オレオイル−２−ドコサヘキサエノイ
ル−ｓｎ−グリセロ−３−ホスホリルコリン（以下、Ｏ
ＤＰＣと略す場合がある） １−オレオイル−２−ドコサヘキサエノイル−ｓｎ−グ
リセロール（以下、ＯＤＤＧと略す場合がある） １−オレオイル−２−エイコサペンタエノイル−ｓｎ−
グリセロ−３−ホスホリルエタノールアミン １−パルミトレイル−２−ドコサヘキサエノイル−ｓｎ
−グリセロ−３−ホスホリルセリン １−ステアロイル−２−ドコサヘキサエノイル−ｓｎ−
グリセロ−３−リン酸 １−ミリストイル−２−アラキドノイル−ｓｎ−グリセ
ロ−３−ホスホリルイノシトール1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphorylcholine (hereinafter O
1-oleoyl-2-docosahexaenoyl-sn-glycerol (hereinafter sometimes abbreviated as ODDG) 1-oleoyl-2-eicosapentaenoyl-sn-
Glycero-3-phosphorylethanolamine 1-palmitrail-2-docosahexaenoyl-sn
-Glycero-3-phosphorylserine 1-stearoyl-2-docosahexaenoyl-sn-
Glycero-3-phosphate 1-myristoyl-2-arachidonoyl-sn-glycero-3-phosphorylinositol
【００１５】これらの中ではＯＤＰＣ、ＯＤＤＧが好ま
しい。なお、ＯＤＰＣは生体内の生体膜を構成する主要
構成リン脂質であるホスファチジルコリン中に存在し、
また魚卵や卵黄のリン脂質の主成分であり、グリセロー
ルのｓｎ−１位にオレオイル基、ｓｎ−２位にドコサヘ
キサエノイル基、ｓｎ−３位にホスホリルコリン基がエ
ステル結合した淡黄色の脂溶性の油状物質である。ＯＤ
ＤＧも生体を構成する脂質であるジグリセリド中に存在
し、ＯＤＰＣのｓｎ−３位が遊離水酸基となった淡黄色
の脂溶性の油状物質である。Of these, ODPC and ODDG are preferable. ODPC is present in phosphatidylcholine, which is the main constituent phospholipid that constitutes the biological membrane in vivo,
In addition, it is the main component of phospholipids of fish eggs and egg yolk, and is a pale yellow color in which oleoyl group at the sn-1 position of glycerol, docosahexaenoyl group at the sn-2 position, and phosphorylcholine group at the sn-3 position are ester-bonded. It is a fat-soluble oily substance. OD
DG is also present in diglyceride, which is a lipid constituting a living body, and is a pale yellow oil-soluble oily substance in which the sn-3 position of ODPC is a free hydroxyl group.
【００１６】一般式〔１〕で示されるグリセロール誘導
体は、短期間でしかも少量の投与で優れた学習能を示
す。例えば、ドコサヘキサエン酸の学習能に関する従来
の報告では、ラット１日当り約０．７ｇのドコサヘキサ
エン酸を約１０週間摂取させているのに対し、本発明で
使用するグリセロール誘導体は、１１〜１２週令の雄Ｆ
３４４種ラット（この時点のラットの体重２５０〜３０
０ｇ）の腹腔へ１回１．３〜１．７ｍｇを投与すること
により、学習能の向上効果が認められる。The glycerol derivative represented by the general formula [1] exhibits excellent learning ability in a short period of time and in a small dose. For example, in a conventional report on the learning ability of docosahexaenoic acid, about 0.7 g of docosahexaenoic acid per day of a rat was ingested for about 10 weeks, whereas the glycerol derivative used in the present invention was 11-12 weeks old. Male F
344 rats (rat weight at this point of 250-30
The effect of improving the learning ability is recognized by administering 1.3 to 1.7 mg once to the abdominal cavity of 0 g).
【００１７】前記グリセロール誘導体は自然界の食物の
組成成分の脂質やグリセロリン脂質の構成成分として存
在している天然由来のものであり、経口投与または非経
口投与による毒性が低く、生理学的に安全である。例え
ばＯＤＰＣ、ＯＤＤＧの場合、生体内において生合成さ
れるＯＤＰＣやＯＤＤＧと自然食物の脂質成分として存
在するこれらの立体構造は同一であり、生体内に摂取さ
れると通常の脂質と同様に代謝され何等の副作用もな
い。ＯＤＰＣは毒性の面からも安全であり、マウスに対
する経口投与のＬＤ50は１３，０００ｍｇ／ｋｇ以上で
あり、経静脈投与のＬＤ50は６５０ｍｇ／ｋｇ以上であ
る。The glycerol derivative is of natural origin and exists as a constituent of lipids and glycerophospholipids that are constituents of foods in nature, has low toxicity by oral or parenteral administration, and is physiologically safe. . For example, in the case of ODPC and ODDG, the three-dimensional structure of ODPC and ODDG biosynthesized in the living body and those existing as lipid components of natural foods are the same, and when ingested in the living body, they are metabolized in the same manner as normal lipids. There are no side effects. ODPC is safe from the viewpoint of toxicity, and the LD 50 for oral administration to mice is 13,000 mg / kg or more, and the LD 50 for intravenous administration is 650 mg / kg or more.
【００１８】本発明で使用するグリセロール誘導体は、
例えば魚卵や卵黄のリン脂質のカラム分離による方法、
１−オレオイル−ｓｎ−３−グリセロホスホコリンをド
コサヘキサエン酸無水物でエステル化する化学合成法、
魚卵や卵黄のリン脂質のカラム分離の後、得られたホス
ファチジルコリンやホスファチジルエタノールアミンを
ホスホリパーゼＣで処理する方法、化学合成したホスフ
ァチジルコリンやホスファチジルエタノールアミンをホ
スホリパーゼＣで処理する方法など、公知の方法により
得ることができる。これらの方法の詳細は、特開昭６４
−２５８９号公報、特開昭６４−５１０９１号公報、特
開平１−１６０９８９号公報などに記載されている。The glycerol derivative used in the present invention is
For example, a method by column separation of phospholipids of fish eggs and yolk,
A chemical synthesis method for esterifying 1-oleoyl-sn-3-glycerophosphocholine with docosahexaenoic anhydride,
After column separation of phospholipids of fish eggs and egg yolk, the obtained phosphatidylcholine or phosphatidylethanolamine is treated with phospholipase C, or the chemically synthesized phosphatidylcholine or phosphatidylethanolamine is treated with phospholipase C. Obtainable. For details of these methods, see JP-A-64
No. 2589, Japanese Patent Application Laid-Open No. 64-51091, Japanese Patent Application Laid-Open No. 1-160989.
【００１９】なお、本発明で使用するグリセロール誘導
体としては、純粋品の他に、上記方法により得られるグ
リセロール誘導体を高濃度に含有する画分や、グリセロ
ール誘導体を含有する天然原料も使用することができ
る。As the glycerol derivative used in the present invention, in addition to a pure product, a fraction containing a high concentration of the glycerol derivative obtained by the above method and a natural raw material containing the glycerol derivative may be used. it can.
【００２０】本発明の学習能向上剤は一般式〔１〕で示
されるグリセロール誘導体を有効成分として含有するも
のであり、学習能向上機能性食品や学習能向上用医薬と
して利用できる。グリセロール誘導体はそのまま学習能
向上剤とすることもできるが、有効成分を摂取しやすく
するため、または食品素材などに均一に分散させるた
め、水溶液または粉体などの形態として学習能向上剤と
することもできる。The learning ability-improving agent of the present invention contains the glycerol derivative represented by the general formula [1] as an active ingredient and can be used as a learning ability-improving functional food or a learning ability-improving medicine. The glycerol derivative can be used as a learning ability improver as it is, but in order to make it easier to ingest the active ingredient or to evenly disperse it in food materials, etc., it should be used as a learning ability improver in the form of an aqueous solution or powder. You can also
【００２１】水溶液とするには、ホモミキサー、ジュー
スミキサー、超音波乳化機などによって水分散液とする
ことができる。このような分散方法によって１０重量％
分散液を得ることもできる。また粉末にするには、上記
水溶液に澱粉、デキストリン、乳糖等の炭水化物；カゼ
イン、アルブミン等のタンパク質などを２５〜７０重量
％添加し、噴霧乾燥する方法などにより行うことができ
る。The aqueous solution can be made into an aqueous dispersion using a homomixer, a juice mixer, an ultrasonic emulsifier or the like. 10% by weight by such a dispersion method
It is also possible to obtain a dispersion. Further, powdering can be performed by adding 25 to 70% by weight of a carbohydrate such as starch, dextrin, lactose, protein such as casein and albumin to the above aqueous solution, and spray drying.
【００２２】本発明の学習能向上剤は、有効成分である
グリセロール誘導体として５０ｍｇ〜１０ｇ／体重６０
ｋｇ／日を経口投与することができる。The learning ability improving agent of the present invention is 50 mg to 10 g / 60 body weight as a glycerol derivative as an active ingredient.
kg / day can be administered orally.
【００２３】本発明の学習能向上剤は、通常の脂質と同
様に取り扱うことができる。このため、脂肪輸液タイプ
の食品や各種の食品などに添加することができ、これに
より被添加物に学習能向上効果を付与することができ
る。またこの有効成分によって学習能が向上し、記憶力
も改善されることから老人性痴呆症の治療のための医薬
品としても利用できる。The learning ability-improving agent of the present invention can be treated in the same manner as ordinary lipids. Therefore, it can be added to fat infusion type foods, various foods, and the like, and thereby, the learning ability improving effect can be imparted to the additive. Further, since the active ingredient improves learning ability and memory ability, it can be used as a medicine for treating senile dementia.
【００２４】例えば、水溶液状の学習能向上剤は、濃縮
ジュース、スープ、酒類、果汁等の飲料やソース等の各
種食品に添加して学習能向上機能性食品として用いられ
る。また水溶液状の学習能向上剤に酢酸、乳酸、コハク
酸、クエン酸、リンゴ酸等の食用有機酸；練乳、エバミ
ルク、乳糖、発酵乳等の乳製品などを添加して各種食品
の加工に用いたり、飲料として用いられる。粉末状の学
習能向上剤は流動性が良く水分散性であるので、上記の
水溶液として用いる他に、製菓製パン用素材としてピ
ザ、パン、クッキー、パイ等に加工することができ、ま
たスキムミルク等と混合してインスタント食品に加工す
ることもできる。また学習能向上剤に、さらにアミノ
酸、ビタミン類、ミネラル類を補給して総合栄養強化食
品とすることもできる。For example, the learning ability improving agent in the form of an aqueous solution is used as a learning ability improving functional food by adding it to various foods such as concentrated juice, soup, alcoholic beverages, fruit juice and other beverages and sauces. In addition, edible organic acids such as acetic acid, lactic acid, succinic acid, citric acid, and malic acid; dairy products such as condensed milk, evaporated milk, lactose, and fermented milk are added to the learning ability improver in the form of an aqueous solution and used for processing various foods. Or used as a beverage. Since the powdery learning ability improver has good fluidity and water dispersibility, it can be processed into pizza, bread, cookies, pies, etc. as a material for confectionery bread, in addition to being used as the above aqueous solution, and skim milk. It can also be mixed with the like and processed into an instant food. Further, the learning ability improver may be supplemented with amino acids, vitamins and minerals to prepare a comprehensive nutrition-enhancing food.
【００２５】[0025]
【作用】本発明の学習能向上剤は、摂取により学習能が
向上する。後述の比較例から明らかなように、オレイン
酸分子、ドコサヘキサエン酸分子、グリセロホスホコリ
ン分子、またはグリセロールの３個の水酸基に全てＤＨ
Ａを結合させたトリＤＨＡには、学習能向上効果が認め
られない。また神経伝達物質のアセチルコリンの前駆物
質のコリンを含む塩化コリンでも学習能向上効果が認め
られないことから、グリセロホスホコリンのコリン分子
が学習能向上に直接作用していないことも明らかであ
る。従って、一般式〔１〕で示されるグリセロール誘導
体の学習能向上効果は、ドコサヘキサエン酸等の高度不
飽和酸分子に由来するものではなく、飽和またはモノエ
ン脂肪酸残基と、高度不飽和酸残基とが、グリセロール
と立体特異な結合により生じた分子構造に基づいている
と推定される。The learning ability-improving agent of the present invention improves learning ability when ingested. As is clear from the comparative examples described below, all three hydroxyl groups of oleic acid molecule, docosahexaenoic acid molecule, glycerophosphocholine molecule, or glycerol have DH.
Avian DHA to which A is bound has no learning ability improving effect. Further, since the learning ability improving effect is not recognized even with choline chloride containing choline which is a precursor of acetylcholine which is a neurotransmitter, it is clear that the choline molecule of glycerophosphocholine does not directly act on the learning ability improving. Therefore, the learning ability improving effect of the glycerol derivative represented by the general formula [1] is not derived from a highly unsaturated acid molecule such as docosahexaenoic acid, and a saturated or monoene fatty acid residue and a highly unsaturated acid residue are obtained. Is presumed to be based on the molecular structure generated by stereospecific binding with glycerol.
【００２６】本発明の１，２−ジアシル−ｓｎ−グリセ
ロールはそのままの分子構造で、また１，２−ジアシル
−ｓｎ−グリセロール誘導体は生体内で１，２−ジアシ
ル−ｓｎ−グリセロールに代謝されるから、中枢の神経
細胞のプロテインキナーゼＣを活性化することにより、
細胞内セカンドメッセンジャー系を賦活していることが
推定される。さらに、学習を司る神経機構であると考え
られている海馬の神経細胞に対して、長期増強作用を引
き起こすことにより学習能を向上させていると考えられ
る。実施例のスコアの増大には、ここで用いた化合物の
立体構造が重要であることが示されている。The 1,2-diacyl-sn-glycerol of the present invention has a molecular structure as it is, and the 1,2-diacyl-sn-glycerol derivative is metabolized in vivo to 1,2-diacyl-sn-glycerol. Therefore, by activating protein kinase C in central nerve cells,
It is presumed that it activates the intracellular second messenger system. Furthermore, it is considered that learning ability is improved by inducing a long-term potentiation effect on hippocampal nerve cells, which are considered to be the neural mechanism that controls learning. It has been shown that the three-dimensional structure of the compound used here is important for increasing the scores of the examples.
【００２７】[0027]
【発明の効果】以上の通り、本発明によれば、グリセロ
ールのｓｎ−１位に飽和またはモノ脂肪酸残基、ｓｎ−
２位に特定の高度不飽和脂肪酸残基がエステル結合した
１，２−ジアシル−ｓｎ−グリセロール誘導体を有効成
分として用いるようにしたので、短期間でしかも少量の
投与量で優れた学習能向上効果が得られ、かつ毒性が低
くて安全な学習能向上剤が得られる。INDUSTRIAL APPLICABILITY As described above, according to the present invention, saturated or mono-fatty acid residue, sn-, is present at the sn-1 position of glycerol.
Since a 1,2-diacyl-sn-glycerol derivative in which a specific highly unsaturated fatty acid residue is ester-bonded at the 2-position is used as an active ingredient, it has an excellent learning ability improving effect in a short period of time and with a small dose. And a safe learning ability improving agent with low toxicity is obtained.
【００２８】[0028]
【実施例】次に実施例により本発明をさらに詳細に説明
する。 実施例 ＯＤＰＣとＯＤＤＧをそれぞれエタノールに２８μｍｏ
ｌ／ｍｌとなるように溶解した。溶液は小型の褐色瓶に
入れ、窒素で充填した後４℃で保存した。ラット腹腔内
投与は、それらの内の１種類を２μｍｏｌ／ラットとな
るように行った。実験にはＦ３４４／ＮＳ１ｃ種の雄ラ
ット（１１−１２週令）を用いた。ラットの飼育は、実
験開始前から実験中を通じ、気温を２４±１℃、湿度を
５０±１０％、１２時間の暗闇−１２時間の照明のサイ
クル、さらに餌および水は自由摂取との条件で行った。EXAMPLES The present invention will be described in more detail with reference to examples. Example 28 μmo of ODPC and ODDG in ethanol respectively
It melt | dissolved so that it might become 1 / ml. The solution was placed in a small amber bottle, filled with nitrogen, and stored at 4 ° C. Rats were intraperitoneally administered so that one of them was 2 μmol / rat. F344 / NS1c male rats (11-12 weeks old) were used for the experiment. Rats were bred under the condition that the temperature was 24 ± 1 ° C., the humidity was 50 ± 10%, the darkness was 12 hours and the lighting was 12 hours, and the food and water were freely ingested before the start of the experiment. went.
【００２９】実験開始日に、ラットを飼育用ケージから
実験用ケージに移した。実験用ケージには棒状の器具レ
バー（ステンレス製、５×４０ｍｍ）が底から３ｃｍの
高さで壁面から飛び出して取り付けられている。底は、
１ｃｍおきに取り付けたステンレス棒（直径５ｍｍ）で
できている。床は、全面にわたって直流電源からの供給
により、隣合った２本の棒の間に電気を流すことができ
る。実験は、時計の読みで０８：００から１５：００ま
での間に行った。On the day of the start of the experiment, the rats were transferred from the breeding cage to the experimental cage. A rod-shaped instrument lever (made of stainless steel, 5 × 40 mm) is attached to the experimental cage by protruding from the wall surface at a height of 3 cm from the bottom. The bottom is
It is made of stainless steel rods (diameter 5 mm) attached every 1 cm. The floor can be supplied with electricity from a DC power supply over its entire surface so that electricity can flow between two adjacent bars. The experiment was carried out between 08:00 and 15:00 on the clock reading.
【００３０】ラットは、パソコン（ＭＢＣ−２００、商
標、三洋電気（社）製）で操作する連続および繰り返し
（１秒間５回）のブザーにより、識別による回避の学習
に訓化した。ラットには、１回の試行ごとに、電撃（７
０ボルト、３秒、直流）に続いて５秒間、連続したブザ
ー音か、繰り返しのブザー音かのどちらかを聞かせた。
５秒間の連続したブザー音の後、５秒以内にレバーを押
し下げれば、ラットは床からの電撃を受けずにすむ。し
かし、繰り返しのブザー音の５秒以内にレバーを押し下
げたのであれば、ラットは５秒後に床からの電撃を受け
ることになる。そうなると、ラットは電撃を受けないで
すむよう、２種類のブザー音を識別し、さらにレバーを
押し下げた方がいいのかそうでないのかを選択する必要
に迫られる。Rats were trained to learn to avoid by discrimination by continuous and repeated (5 times per second) buzzers operated by a personal computer (MBC-200, trademark, manufactured by Sanyo Denki Co., Ltd.). Rats received an electric shock (7
After 0 volt, 3 seconds, direct current), for 5 seconds, he heard either a continuous or repeated buzzer sound.
After 5 seconds of continuous buzzing sound, pressing the lever down within 5 seconds will prevent the rat from being hit by electric shock from the floor. However, if the lever is pushed down within 5 seconds of repeated buzzing sounds, the rat will receive a shock from the floor after 5 seconds. In that case, the rat will have to distinguish between the two buzzer sounds and choose whether or not the lever should be pushed down so that it is not hit by electric shock.
【００３１】連続したブザー音と繰り返しのブザー音の
それぞれを１試行とし、不規則に聞かせた。１回の試行
から次の回までの間には、１３秒間をおいた。連続して
行った１００回の試行を１回分とし、１回分の内での連
続したブザー音の回数は繰り返しのブザー音の回数と同
じにした。１匹のラットに対しては１日の試行回数は１
回分を限度とし、次の１回分の試行までは前回から４８
時間をおいた。Each of the continuous buzzer sound and the repeated buzzer sound was set as one trial, and the sounds were heard randomly. There was 13 seconds between each trial. One hundred consecutive trials were defined as one trial, and the number of continuous buzzer sounds within one trial was the same as the number of repeated buzzer sounds. The number of trials per day for one rat is 1
The number of batches is limited, and until the next one trial is 48 from the last time.
I had time.
【００３２】ラットが電撃からの回避に成功した回数は
１回分ごとに記録し、１回分の全部の試行回数に対する
成功回数の合計から回避率を算出した。最初の１回分で
回避率が６６％を上回ったラットは、実験対照から外し
た。１回分を通じてのレバーを押し下げた回数を総計
し、電撃と全くまたは殆ど関係なくレバーを押し下げた
ラットについては、電撃回避とは関係なくレバーを押し
下げても５０％の確率では回避に成功するため、データ
を除外した。The number of times the rat succeeded in avoiding the electric shock was recorded for each time, and the avoidance rate was calculated from the total number of times of success for all the number of trials for one time. Rats whose avoidance rate exceeded 66% in the first dose were excluded from experimental controls. The total number of times the lever was pushed down through one dose, and for rats that pushed the lever down irrespective of or almost nothing to electric shock, even if the lever was pushed down regardless of the electric shock avoidance, there is a 50% chance of successful avoidance. Data excluded.
【００３３】第２回で行う１回分の実験の開始５分前
に、それぞれのラットに、２種類の薬剤のいずれかを第
１回と同一量投与した。得られたデータはｔ−テストに
より解析し、統計的に有意差があるかどうかを調べた。
結果を表１に示す。Five minutes before the start of the single dose experiment conducted in the second round, each rat was administered with one of the two drugs in the same dose as in the first round. The data obtained was analyzed by t-test to see if there was a statistically significant difference.
The results are shown in Table 1.
【００３４】比較例 ドコサヘキサエン酸（ＤＨＡ）、オレイン酸、ＤＨＡエ
ステルをそれぞれエタノールに２８μｍｏｌ／ｍｌとな
るように溶解した。グリセロホスホコリン（ＧＰＣ）、
塩化コリンは滅菌生理食塩水に２μｍｏｌ／ｍｌとなる
ようにそれぞれ溶解した。またトリＤＨＡはそのまま用
いた。溶液は小型の褐色瓶に入れ、窒素で充填した後４
℃で保存した。腹腔内投与は、それらの内の１種類を２
μｍｏｌ／ｒａｔとなるように行った。コントロールは
エタノールのみと滅菌食塩水のみを投与した。以下は実
施例と同様に実施した。Comparative Example Docosahexaenoic acid (DHA), oleic acid, and DHA ester were dissolved in ethanol at 28 μmol / ml. Glycerophosphocholine (GPC),
Choline chloride was dissolved in sterile physiological saline at a concentration of 2 μmol / ml. The avian DHA was used as it was. Place the solution in a small amber bottle and fill with nitrogen, then
Stored at ° C. For intraperitoneal administration, one of them is 2
It was carried out so that it became μmol / rat. As a control, only ethanol and sterile saline were administered. The following was carried out in the same manner as in the examples.
【００３５】第２回に行う１回分の実験の開始５分前
に、それぞれのラットに、６種類の薬剤のいずれかを第
１回と同一量投与した。得られたデータはｔ−テストに
より解析し、統計的に有意差があるかどうかを調べた。
結果を表１に示す。Five minutes before the start of the second experiment, each rat was dosed with one of the six drugs in the same dose as the first dose. The data obtained was analyzed by t-test to see if there was a statistically significant difference.
The results are shown in Table 1.
【００３６】[0036]
【表１】 ＯＤＰＣ：１−オレオイル−２−ドコサヘキサエノイル
−ｓｎ−グリセロ−３−ホスホリルコリン ＯＤＤＧ：１−オレオイル−２−ドコサヘキサエノイル
−ｓｎ−グリセロール ＤＨＡ：ドコサヘキサエン酸 トリＤＨＡ：トリドコサエノイルグリセロール ＧＰＣ：グリセロホスホコリン ＊：ｔ−テストによる検定の結果、対照群の第２回学習
に対しＰ＜０．００１で統計的に有意である ＊＊：ｔ−テストによる検定の結果、対照群の第２回学
習に対しＰ＜０．０５で統計的に有意である[Table 1] ODPC: 1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphorylcholine ODDG: 1-oleoyl-2-docosahexaenoyl-sn-glycerol DHA: docosahexaenoic acid tri DHA: tridocosaenoyl glycerol GPC: glycerophosphocholine *: As a result of the test by the t-test, P <0.001 is statistically significant for the second learning of the control group **: As a result of the test by the t-test, the result of the control group P <0.05 for the 2nd learning is statistically significant
【００３７】表１の結果から、次のことがわかる。ＯＤ
ＰＣ、ＯＤＤＧ投与群とも、第１回学習はコントロール
との間に回避率で有意差は認められなかった。第２回学
習は両試料投与群ともコントロールとの間に有意に大き
な値を示した。比較例の試料の場合、第１回学習ではコ
ントロールと各試料投与群との間に回避率での有意差は
認められなかった。第２回学習も各試料投与群ともコン
トロールとの間に回避率での有意差は認められなかっ
た。ＧＰＣ投与群は、２回目の回避率が１回目よりも有
意に大きな値を示したが、コントロールとの間に有意差
は認められなかった。From the results shown in Table 1, the following can be understood. OD
In both the PC and ODDG administration groups, the avoidance rate was not significantly different from the control in the first learning. The second learning showed a significantly large value between the control group and the control in both sample administration groups. In the case of the sample of Comparative Example, no significant difference in the avoidance rate was observed between the control and each sample administration group in the first learning. In the second learning and each sample administration group, no significant difference in the avoidance rate was observed between the control group and the control group. In the GPC administration group, the avoidance rate at the second time was significantly higher than that at the first time, but no significant difference was observed with the control.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 橋本 真明 山梨県中巨摩郡玉穂町成島1559−１−Ｂ 404 (72)発明者 伊崎 義憲 山梨県甲府市大里町4346 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinmei Hashimoto 1559-1-B 404 Narishima, Tamago-cho, Nakakoma-gun, Yamanashi Prefecture (72) Yoshinori Izaki 4346 Osato-cho, Kofu-shi, Yamanashi Prefecture
Claims (1)
脂肪酸残基、Ｒ2はアラキドン酸、エイコサペンタエン
酸またはドコサヘキサエン酸残基、Ｒ3は水素、ホスホ
リルコリン基、ホスホリルエタノールアミン基、ホスホ
リルセリン基、ホスホリルイノシトール基またはリン酸
基を表わす。）で示される１，２−ジアシル−ｓｎ−グ
リセロール誘導体を有効成分として含有することを特徴
とする学習能向上剤。1. A general formula: (In the formula, R 1 is a saturated or monoene fatty acid residue having 14 to 24 carbon atoms, R 2 is an arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid residue, R 3 is hydrogen, a phosphorylcholine group, a phosphorylethanolamine group, a phosphorylserine group. Group, a phosphorylinositol group or a phosphoric acid group), is included as an active ingredient, and a learning ability improving agent characterized by containing a 1,2-diacyl-sn-glycerol derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04817693A JP3467794B2 (en) | 1993-03-09 | 1993-03-09 | Learning ability improver |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04817693A JP3467794B2 (en) | 1993-03-09 | 1993-03-09 | Learning ability improver |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06256179A true JPH06256179A (en) | 1994-09-13 |
| JP3467794B2 JP3467794B2 (en) | 2003-11-17 |
Family
ID=12796083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04817693A Expired - Lifetime JP3467794B2 (en) | 1993-03-09 | 1993-03-09 | Learning ability improver |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3467794B2 (en) |
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| KR102079747B1 (en) | 2015-02-11 | 2020-02-20 | 에이커 바이오마린 앤탁틱 에이에스 | Lipid composition |
-
1993
- 1993-03-09 JP JP04817693A patent/JP3467794B2/en not_active Expired - Lifetime
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