JP4971150B2 - イクオリン−含有組成物及びその使用方法 - Google Patents
イクオリン−含有組成物及びその使用方法 Download PDFInfo
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- JP4971150B2 JP4971150B2 JP2007518179A JP2007518179A JP4971150B2 JP 4971150 B2 JP4971150 B2 JP 4971150B2 JP 2007518179 A JP2007518179 A JP 2007518179A JP 2007518179 A JP2007518179 A JP 2007518179A JP 4971150 B2 JP4971150 B2 JP 4971150B2
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- aequorin
- calcium
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Description
本発明は一般的に、カルシウムホメオスタシスの維持に有用な組成物に関する。特に、本発明は、カルシウム不均衡に関連する疾患又は症状を抑制及び/又は緩和するのに有用なイクオリン-含有医薬組成物及び栄養補助組成物に関する。
カルシウムは、ヒトの体内では5番目に豊富な元素であり、骨に主に存在する。体内のカルシウムの99%より多くが骨格に貯蔵され、常にその供給を交換しており、体液及び柔組織、例えば血液中に溶解している1%を維持している。この交換の制御は、血漿中のイオン化カルシウム濃度を感知し、この重要なバランスを維持するようにカルシウム交換を方向づける内分泌系によって主に指示されている。間質液及び柔組織中の1%のカルシウムの小分画のみがイオン化され、及び溶解され、残りは、タンパク質、特にカルシウム-結合タンパク質(CaBP)に結合している。これらのCaBPは、カルシウムホメオシタシスの維持に機能することが知られている。必須の生理的プロセスを実行するために身体は特定のカルシウム濃度を要求するので、それ故、カルシウムホメオシタシスの維持は身体の健康によって重要である。血漿及び体液中の適正なイオン性カルシウム濃度は、医学界によって、神経興奮、筋収縮、膜透過性、細胞分割、ホルモン分泌及び骨石灰化に限定されない身体機能において重要であると理解されている。カルシウムホメオシタシスの破壊、すなわちカルシウム不均衡は、例えば癌、心疾患及び神経変性疾患に限定されない多くの疾患、症候及び症状に関連する。
本発明は、カルシウム不均衡に関連する症状又は疾患の緩和及び/又は抑制に有益である医薬組成物及び栄養補助組成物を提供する。かかる組成物は、対象に様々な経路によって投与するための許容される担体と組み合わせたイクオリンを含む。従って、本発明は、許容される担体と組合せたイクオリンの有効量を含む医薬組成物に関する。他の実施態様では、本発明は、許容される担体と組合せたイクオリンの有効量を含む栄養補助組成物に関する。ある実施態様では、栄養補助組成物は、イクオリンに加えて、栄養補助効果を与えると理解されている少なくとも1つの他の成分を含む。
I. 一般論
本発明を記載する前に、本発明が記載された特定の方法及び材料は変化することがあるため、これらに限定されない、ことを理解されたい。本明細書で用いる用語が特定の実施態様のみを記載する目的のためのものであって、添付の特許請求の範囲によってのみ限定されることになる本発明の範囲を限定するものではない、ことも理解されたい。
イクオリンは、発光クラゲ及び他の海洋生物から最初に単離された発光タンパク質である。イクオリン複合体は、22,000-ダルトンのアポイクオリンタンパク質、分子酸素及び発光団コエレンテラジンを含む。3つのCa2+イオンがこの複合体に結合するときに、コエレンテラジンはコエレンテラミドに酸化されて、この際、二酸化炭素及び青色光を放出する。イクオリンが細胞によって運び出されず又は分泌されず、また、細胞内で区分又は隔離されない。従って、イクオリン測定は、比較的長期間に渡って起こるCa2+変化を検出するために用いられてきた。いくつかの実験系では、イクオリンの発光は、細胞装填後、数時間から数日で検出可能であった。イクオリンはまた細胞機能又は胚発達を妨害しない、ことが更に知られている。
一連の予備試験において、イクオリンを3種の大人ラットの海馬に直接、左右両方に注射した。ラットを麻酔した後の少なくとも24時間、ラットをケージに戻し、脳を取り除き、切断し、モノクローナル抗-イクオリン抗体を用いてイクオリンを染色した。次いで、Alexa Fluor 594との第二抗体複合体を用いて、第一抗体を視覚化した。図1は、一般的な蛍光顕微鏡を用いてイクオリン-標識海馬ニューロンの例を示す。左パネルは、CA1領域中のカニューレ先端の位置を示す海馬の顕微鏡写真である。白の四角形は、右パネルに示す2つのイクオリン標識CA3ピラミッド型ニューロンの位置を示す。海馬へのニューロンの直接導入(左パネル)が、CA1及びCA3のピラミッド形ニューロンの標識をもたらす、ことをデータは示している。3% DMSOの存在下、カルシウムを含まないaCSFにイクオリン(6% w/v)を溶解した。シリンジポンプを用いて海馬に当該溶液を直接、ゆっくり(速度 約1μL/分)注射した(体積 約1μL/側)。注射終了後に、送達カニューレを除去前の1分間、所定の位置に維持した。2種のイクオリン-含有CA3ピラミッド形ニューロンの例を右パネルに示す(4OX対物レンズ)。データは、脳へのイクオリンの直接送達を示し、また、イクオリンが海馬によって広がり、次いでCA1、CA3のニューロン及び歯状回により取られる、ことを示す。
虚血に対するカルシウム結合タンパク質イクオリンの利点を試験するために実験を行った、6% DMSO (ジメチルスルホキシド)を含むカルシウム無しの脳脊髄液にイクオリ(4%)を溶解した。2〜3時間後、ラットをイソフルランで麻酔し、首を切って殺した。温度-調節Vibratomeを用いて、400ミクロン厚の脳スライスを調製した。スライスを以下の組成物(nM):124 NaCl、2.8 KCl、2 MgSO4、2 NaH2PO4、2 CaCl2、26 NaHCO3、0.4 アスコルビン酸ナトリウム、10 D-グルコース、pH 7.4、約30℃)の酸化された(95% O2/5% CO2)人工脳脊髄液に直接置いた。1時間の再生後、スライスを5分間の虚血エピソードに供した。グルコースをフルクトースで置換し、酸素を窒素で置換することによって虚血を誘導した。5分間の虚血チャレンジ後に、スライスを、0.04%トリパンブルーを含む通常の酸化aCSFに再生し、30分間トリパンブルーaCSFでインキュベートした。トリパンブルー排除法(健常細胞はトリパンブルーを排除するが、死細胞又は死にそうな細胞はトリパンブルーを取り込み、ブルーになる)は、細胞培養又は脳スライスにおける細胞死を評価するために通常用いられる。トリパンブルーでのインキュベーション後に、切断を除き、終夜固定液に置いた後、30%スクロースで3時間インキュベーションした。低温保持装置を用いて、400μm厚スライスを約40μmの厚さに切断し、ゼラチン-被覆スライド上に固定し、カバーガラスをかぶせた。図2を参照すると、イクオリン(下パネル)注射ニューロンに対して対照(上パネル)では、トリパンブルー染色(死滅)ニューロンがより多く存在することが明らかである。図3は、虚血後の(死)神経細胞を含むトリパンブルーの平均数の棒グラフを示す。本実験は、海馬への直接のイクオリン注射が、虚血性発作に対する神経保護を与えることを証明する。
Claims (8)
- (a)イクオリン及び(b)薬学的に許容される担体を含む、脳における虚血後の神経細胞死を抑制又は緩和するための組成物。
- 追加免疫剤、抗炎症剤、抗酸化剤、抗ウイルス剤又はこれらの組合せを更に含む、請求項1記載の組成物。
- 錠剤、カプセル剤、液剤、懸濁剤、シロップ剤、飲料、経口又は眼科製剤及び注射剤からなる群より選ばれる単位投薬である、請求項1記載の組成物。
- イクオリンを含む、脳における虚血後の神経細胞死を抑制又は緩和するための医薬組成物であって、そのような治療を必要としている対象に投与される、組成物。
- 追加免疫剤、抗炎症剤、抗酸化剤、抗ウイルス剤又はこれらの組合せと一緒に提供される、請求項4記載の医薬組成物。
- 錠剤、カプセル剤、液剤、懸濁剤、シロップ剤、飲料、経口又は眼科製剤及び注射剤からなる群より選ばれる単位投薬である、請求項4記載の医薬組成物。
- イクオリンを含む、対象の脳における神経細胞の虚血損傷に対する保護を与えるための医薬組成物であって、そのような治療を必要としている対象に投与される、組成物。
- 対象の脳における神経細胞の虚血損傷に対して保護を与えるためのイクオリンを含む医薬組成物。
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JP2001240855A (ja) * | 2000-03-01 | 2001-09-04 | Masashi Sugimoto | 生物発光方法及び発光物品 |
US6800492B2 (en) * | 2000-06-01 | 2004-10-05 | Institute Pasteur | Chimeric GFP-aequorin as bioluminescent Ca++ reporters at the single cell level |
WO2001096361A1 (en) * | 2000-06-12 | 2001-12-20 | University Of Maryland Biotechnology Institute | Method of controlling the binding of calmyrin to presenilin |
US20060229243A1 (en) * | 2004-06-21 | 2006-10-12 | Quincy Resource Group, Inc. | Aequorin-containing compositions and methods of using same |
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