JP6864899B2 - 損傷治療剤 - Google Patents
損傷治療剤 Download PDFInfo
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- JP6864899B2 JP6864899B2 JP2016221422A JP2016221422A JP6864899B2 JP 6864899 B2 JP6864899 B2 JP 6864899B2 JP 2016221422 A JP2016221422 A JP 2016221422A JP 2016221422 A JP2016221422 A JP 2016221422A JP 6864899 B2 JP6864899 B2 JP 6864899B2
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- phosphatidic acid
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Description
好ましくは、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸は、式(1)で示される化合物である。
好ましくは、損傷が外傷性損傷である。
好ましくは、損傷が、外傷性脳損傷である。
好ましくは、本発明の損傷治療剤は、止血作用を有する止血剤として使用される。
本発明によればさらに、損傷の治療において使用するための、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩が提供される。
本発明は、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩を有効成分として含有する、損傷治療剤に関する。本発明の損傷治療剤は、損傷を治療するために使用することができ、環状ホスファチジン酸カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸、あるいはその塩を有効成分として含む。環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸としては本発明の効果を示すものであれば特に限定されないが、好ましくは、下記式(I)で示される環状ホスファチジン酸を使用することができる。
ル基、フェネチル基、p−ペンチルフェニルオクチル基などが挙げられる。
(1)Xが−O−であり、Yが−O−である。
(2)Xが−CH2−であり、Yが−O−である(2カルバcPA(2ccPAとも略記))。またはXが−S−であり、Yが−O−である。
(3)Xが−O−であり、Yが−CH2−である(3カルバcPA(3ccPAとも略記))。またはXが−O−であり、Yが−S−である。
上記の中でも、Xが−CH2−でありYが−O−である(2カルバcPA)が特に好ましい。
得られたアルコールを、トルエン中で過剰のp-トルエンスルホン酸のピリジニウム塩を用いて80℃で反応させることにより、環化体(3)を得る。この環化体を、水素雰囲気下で20% Pd(OH)2-Cを用いて加水素分解し、脱ベンジル化を行う(4)。縮合剤として1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩を用いて、脂肪酸と反応させてカップリング体(5)を得る。次に、求核剤としてブロモトリメチルシランを用いて、メチル基だけを位置選択的に除去し、環状ホスホン酸(6)を得る。これをエーテルを用いて分液ロートに移しこみ、少量の0.02Nの水酸化ナトリウム水溶液を滴下して、分液操作を行い、ナトリウム塩(7)として目的化合物を抽出、精製する。
本発明の損傷治療剤の投与量は患者の年齢、性別、体重、症状、及び投与経路などの条件に応じて適宜増減されるべきであるが、一般的には、成人一日あたりの有効成分の量として1μg/kgから1,000mg/kg程度の範囲であり、好ましくは10μg/kgから100mg/kg程度の範囲である。上記投与量の損傷治療剤は一日一回に投与してもよいし、数回(例えば、2〜4回程度)に分けて投与してもよい。
(1)被験化合物
実験で用いたカルバcPAは2ccPA (18:1)である。2ccPA (18:1)の構造は以下の通りである。ここで−C17H33は、−(CH2)7CH=CH(CH2)7CH3(シス体)を示す。2ccPA (18:1)は、特開2004−010582号公報に記載の方法により合成した。
6週齢雌性ICRマウス(チャールスリバー)を、プラスチック製ケージを用いて動物飼育室内で飼育した。飼育環境は温度を22℃で一定とし、明暗は12時間周期とした。実験は、文部科学省およびお茶の水女子大学動物実験委員会によって承認を受け、これらのガイドラインに従って行った。
穿刺傷害は、6週齢雌マウスに対して行った。マウスに三種混合麻酔薬(0.75 mg/kg ドミトール(日本全薬工業), 4.0 mg/kg ミダゾラム(サンド), 5.0 mg/kg ベトルファール(Meiji Seika ファルマ))を腹腔投与し麻酔をかけた後、後頭部頭蓋骨を露出させ、注射針(テルモ注射針19G×1 1/2", テルモ)を用いて後頭部の右脳側の頭蓋骨に穴を開けた。次に、注射針(テルモ注射針27G×3/4", テルモ)を用いて頭蓋骨の穴から大脳皮質に水平に刺傷した。刺傷後、麻酔に対する拮抗薬アンチセダン(0.75 mg/kg)(日本全薬工業)を腹腔投与した。左脳を対照実験として扱った。損傷直後から24時間おきに、500 μg/ml 2ccPAを1.8 mg/kg/day量腹腔投与した。またControl群として、リン酸緩衝液(PBS; 0.135M NaCl, 8.1mM Na2HPO4, 2.685mM KCl, 1.47mM KH2PO4)を同量腹腔投与したものを作製した。
穿刺傷害1、3、5、7日後にそれぞれCO2を用いてマウスを安楽死させ、PBSを50ml、固定液(4%パラホルムアルデヒド, 80mM Na2HPO4, 20mM NaH2PO4) 50mlの順に左心室に注入し、灌流固定を行った。全脳を摘出した後、固定液に入れ室温で一晩振盪させた。固定液を15%スクロースに置換し4℃で一晩振盪し、さらにその後30% スクロースに置き換え4℃で一晩振盪を行った。
包埋剤(O.C.T Compound)(サクラファインテック)を、全脳を入れたクリオモルド(TED PELLA, Inc.)に入れ、4℃で30分振盪させ、ドライアイスとイソペンタンを入れた発砲スチロール箱内で全脳を凍結させ、-80℃で保管した。凍結組織切片作製装置クライオスタット(CM1850, ライカ)を用いて凍結組織切片を作製し、スライドグラス(Superfrost Plus, Fisher Scientific)に貼り付けた。切片は、厚さ20μmの冠状断切片とした。
損傷修復の指標として、損傷部から脳組織への血液の漏出を観察した。穿刺傷害1、3、5、7日後のマウス脳の冠状断凍結切片において抗マウスIgG抗体を用いた酵素抗体染色を行い、IgGを発色させることで血液の漏出を可視化させた。さらに発色強度から2ccPA投与群及びControl群での血液漏出量を解析した。酵素抗体染色の方法を以下に示す。まず、冠状断凍結切片を37℃で1時間乾燥させた。後の操作は全て室温で行った。固定液で30分間固定し、PBSで5分×2回、トリス緩衝液(TBS;25mM Tris, 137mM NaCl, 2.68mM KCl, pH 7.4)で5分×2回洗浄を行った。10%メタノール、3% H2O2を含むTBS混合液を添加し、10分反応させることで内在性ペルオキシダーゼを不活性化させた後、TBSで5分×3回洗浄した。その後、ブロッキング溶液(10% 仔ウシ血清, 3% ウシ血清アルブミン,133mM グリシン, 0.4% トリトンX-100:in TBS)を用いてブロッキングを1時間行った。次にビオチン標識抗マウスIgG抗体(AP124B, メルクミリポア)をブロッキング溶液で希釈し、1時間反応させた。さらにVECTASTAIN Elite ABC Standard Kit試薬(ベクターラボラトリーズ)を1時間反応させることでアビジン−ビオチン標識酵素複合体を形成させた後、0.1M Tris-HCl(pH 8.0)を用いて5分×3回洗浄した。発色は0.05% ジアミノベンジジン, 0.003% H2O2, 0.1M Tris-HCl(pH 8.0)混合液で一晩反応させることで行った。翌日、蒸留水で洗浄後、70% エタノール, 95% エタノール, 100% エタノール, キシレンの順に置換していき、最後にカナダバルサムで封入した。
2ccPA投与群及びControl群の穿刺傷害1、3、5、7日後における酵素抗体染色画像は、倒立顕微鏡(FSX-100, オリンパス)を用いて明視野で観察、撮影を行った。結果を図1に示す。
IgGの発色強度はImageJを用いて以下のように定量化した。まず、各切片において撮影した画像を8ビットに変換し、グレースケール画像にした。さらに白黒を反転させた。その後、右脳損傷領域周辺の5つの領域(8×8 μm2)をランダムに選択し、各領域内のMean Gray Valueを計測した。また、損傷していない左脳の大脳皮質領域からも5つの領域を選択し、Mean Gray Valueを計測した。染色のバックグラウンドを取り除くために右脳側から左脳側のMean Gray Valueを引き、その値をIgGの発色強度とした。上記の操作は、各個体から摘出した全脳の損傷部位を含む切片(1個体あたり8から10枚)に対して行った。各切片から得られたIgGの発色強度の平均値をその個体の数値とし、それぞれ3個体の数値を平均した結果を図2に示している。
穿刺傷害後に2ccPAを腹腔投与することにより、血液漏出量はControl群と比較して1日目 28%、3日目 34%、5日目 42%、7日目 60% 有意に減少していた。このことから2ccPAは血液漏出を抑制し、修復を促進することが示された。
Claims (4)
- 式(1)において、X及びYの一方が−CH2−であり、X及びYの他方が−O−である、請求項1に記載の損傷治療剤。
- 損傷が外傷性損傷である、請求項1又は2に記載の損傷治療剤。
- 損傷が、外傷性脳損傷である、請求項1から3の何れか一項に記載の損傷治療剤。
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