JP2015525779A - レバミピドを有効成分として含む高脂血症及びこれと関連した疾患の予防または治療用組成物 - Google Patents
レバミピドを有効成分として含む高脂血症及びこれと関連した疾患の予防または治療用組成物 Download PDFInfo
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Abstract
Description
従って、免疫疾患の多くは、このような二つの免疫細胞間のバラツキに起因するとみることができるが、例えば、Th1細胞の活性が非正常的に増加する場合は免疫疾患が発生し得て、Th2細胞の活性が非正常的に増加する場合は過敏反応による免疫疾患が発生すると知られている。
(1)高脂血症及びこれと関連した疾患の発達を阻止させる、
(2)高脂血症及びこれと関連した疾患の拡散を予防する、
(3)高脂血症及びこれと関連した疾患を軽減させる、
(4)高脂血症及びこれと関連した疾患の再発を予防する、及び
(5)高脂血症及びこれと関連した疾患の症状を緩和する(palliating)。
大食細胞にレバミピド処理による炎症性サイトカインの生成抑制効果
本発明者は、レバミピドが大食細胞に与える影響を調べるために、マウス大食細胞にレバミピドを前処理した後、LPS(lipopolysaccharide)で刺激して大食細胞から分泌する炎症性サイトカインTNF−a(tumor necrosis factor−alpha)、IL−6(interleukin−6)及びIL−1β(interleukin−1β)の生成程度をELISA分析を通じて評価した。
マウスの大食細胞株であるRAW264.7細胞は、韓国細胞株銀行(KCLB)から分譲され、細胞培養のために、10%のFBSと1%のpenicillin−streptomycinを含むDMEM(Dulbeccos Modified Eagle Medium)培地を使用した。細胞は、37℃、5%のCO2条件で培養した。
先ず、RAW264.7細胞にレバミピドを20,100μg/mlの濃度で前処理し、1時間後、LPSを100ng/ml濃度で処理して37℃のインキュベーターで48時間の間培養しながら大食細胞で炎症反応を誘導した。
レバミピドの細胞に対する毒性の測定
マウス大食細胞であるRAW264.7に対するレバミピドの細胞毒性を調べるために、MTT assayを行った。
レバミピドの処理による血管病因細胞の抑制効果
本実験では、レバミピドを血管病因細胞に処理する場合、実際に血管病因細胞の形成を抑制することができるか否かを観察した。前記「血管病因細胞」とは、動脈硬化を誘発する動脈硬化巣の前駆細胞を形成する泡沫細胞を意味し、動脈硬化を起こす原因となる細胞であるという点で、本発明で血管病因細胞であると任意に命名した。
本実験のために、ヒト大食細胞株であるTHP1細胞に160nM濃度のPMA(phorbol 12’−myristate 13’−acetate)を処理して細胞を活性させた後、PAF(platelet−activating factor)を10ug/ml処理と同時に、レバミピドを濃度別(100、250、500、1000μM)に処理して動脈硬化を誘発する動脈硬化巣の前駆細胞を形成する泡沫細胞の生成程度をOil Red O溶液(Sigma aldrich−シグマアルドリッチ)染色を通じて測定した。
レバミピドの血管病因細胞の抑制効果を現在市中で脂質低下剤(高脂血症治療薬物)として使用されているシンバスタチンと比べた。
高脂血症動物モデルにレバミピドの投与による血液脂質の改善効果
本実験では、in vivo上でレバミピドの血液脂質の改善効果を測定するために、高脂血症動物モデルにレバミピドを一定量経口投与した後、マウスの血清内の総コレステロール、LDLコレステロール及び中性脂肪数値を測定した。
高脂血症動物モデルにレバミピドの投与による脂肪肝の改善効果
本実験では、in vivo上でレバミピドの脂肪肝の改善効果を測定するために、高脂血症動物モデルにレバミピドを一定量経口投与した後、マウスの血清内のASTとALT数値を測定した。
高脂血症動物モデルにレバミピドの投与による動脈硬化巣の形成抑制効果
本実験では、in vivo上でレバミピドの動脈硬化巣の形成抑制効果を測定するために、高脂血症動物モデルにレバミピドを一定量経口投与した後、マウスのaorta branchを染色を通じて観察した。aorta branchは、動脈硬化の発生時に動脈硬化巣が形成されるところにあたる。
高脂血症動物モデルにレバミピドの投与によるB細胞抗体の免疫反応の調査
本実験では、in vivo上でレバミピドのB細胞抗体の免疫反応に与える影響を観察するために、高脂血症動物モデルにレバミピドを一定量経口投与した後、マウス血清内の総IgGとIgG1の数値を測定した。
高脂血症動物モデルにレバミピドの投与によるTh17細胞抑制及びTreg細胞誘導の同時調節反応
本実験では、in vivo上でレバミピドのTh17/Treg細胞に与える影響を観察するために、高脂血症動物モデルにレバミピドを一定量経口投与した後、マウス脾臓細胞でTh17細胞とTreg細胞の発現程度を調査した。
FACS染色は、マウスを致死させた後、マウスの脾臓細胞で行った。Th17細胞は、抗CD4抗体を先に4〜30分反応させた後、Cytofix/Cytopermを処理して30分反応させた後に洗浄し、以後、抗IL−17抗体を処理して30分反応させた後、FACScaliburでリーディング後、Flow jo programを使用して分析した。Treg細胞は、抗CD4と抗CD25抗体を処理して30分反応させた後、Treg専用Cytofix/Cytopermを処理して30分反応させ、以後洗浄した後、抗Foxp3抗体で30分反応させて、FACScaliburでリーディング後、Flow jo programを使用して分析した。
共焦点顕微鏡の分析方法は、前記マウスを致死させた後、マウスの脾臓断片を利用してOCT compoundを包埋した後、液化窒素で急速冷却した組職を冷凍切片機を利用して7mの厚さでスライドに付着した。その切片は、アセトンで固定後、10%の正常塩素血清で30分間非特異的な反応を遮断した。Th17細胞は、PE−labeled anti−CD4及びFITC−labeled anti−IL−17抗体を利用した。Treg細胞は、PE−labeled anti−CD4、FITC−labeled anti−Foxp3及びAPC−labeled anti−CD25抗体を利用した。染色した組職は、共焦点顕微鏡で分析した(LSM 510 Meta.Zeiss,Go ttingen,Germany)。
高脂血症動物モデルにレバミピドの投与によるMMP−9発現量の分析
本実験では、高脂血症動物モデルマウスのMMP−9のmRNA発現量を調査した。非線維性(non−fibrillar)コラーゲンを分解するMMP−9(matrix metalloproteinase−9)は、動脈硬化巣で発現され、動脈硬化巣の破裂に重要な病態生理学的機転に主な役割をすることが知られている。
Claims (7)
- レバミピド(rebamipide)化合物またはその薬学的に許容可能な塩を有効成分として含む高脂血症及びこれと関連した疾患の予防または治療用組成物。
- 前記レバミピドは、大食細胞で分泌する高脂血症誘発炎症性サイトカインであるTNF−a、IL−6及びIL−1bの生成を抑制させることを特徴とする請求項1に記載の高脂血症及びこれと関連した疾患の予防または治療用組成物。
- 前記レバミピドは、動脈硬化巣(Artherosclerotic plaque)の前駆細胞を形成する泡沫細胞(Foam cell)の生成抑制と共に動脈硬化巣の生成を加速化させるTh17の発現減少を通じて動脈硬化巣の形成を抑制させることを特徴とする請求項1に記載の高脂血症及びこれと関連した疾患の予防または治療用組成物。
- 前記レバミピドは、血液内の総コレステロール、LDLコレステロール及び中性脂肪数値を低くすることで、血液脂質を改善させることを特徴とする請求項1に記載の高脂血症及びこれと関連した疾患の予防または治療用組成物。
- 前記レバミピドは、組成物に0.1μM〜10000μMの濃度で含まれることを特徴とする請求項1に記載の高脂血症及びこれと関連した疾患の予防または治療用組成物。
- 前記高脂血症は、自己免疫疾患由来の高脂血症であることを特徴とする請求項1乃至請求項5のいずれか一項に記載の高脂血症及びこれと関連した疾患の予防または治療用組成物。
- 前記高脂血症と関連した疾患は、動脈硬化症、心不全症、高血圧性心臓疾患、不整脈、先天性心臓疾患、心筋梗塞症、狭心症、脳卒中及び末梢血管疾患からなる群から選択されることを特徴とする請求項1乃至5のいずれか一項に記載の高脂血症及びこれと関連した疾患の予防または治療用組成物。
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