JP5860418B2 - クロマメノキ抽出物またはクロマメノキ分画物を有効成分として含む黄斑変性症の治療、予防または改善用組成物 - Google Patents
クロマメノキ抽出物またはクロマメノキ分画物を有効成分として含む黄斑変性症の治療、予防または改善用組成物 Download PDFInfo
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Description
これら実施例は単に本発明をより具体的に説明するためのもので、本発明の要旨によって本発明の範囲がこれら実施例に制限されないというのは当業界で通常の知識を持った者に明らかであろう。
クロマメノキの実のうち、状態の良いものを選別してきれいに洗浄した後、100gのクロマメノキに水2000mlを加え、90℃で16時間2回熱水抽出して10%クロマメノキ抽出物を得た。このように収得されたクロマメノキ抽出物は凍結乾燥してパウダー状とした後、使用前まで−40℃で保管して、クロマメノキ分画物の製造及び後述の実験に使用した。
前記実施例1で製造されたクロマメノキ抽出物パウダーを蒸留水に溶かした。また別に、二つのC18 Sep−Pakカートリッジを連結し、10mlエチルアセテート、無水メタノール(absolute methanol)で調整(precondition)した後、0.01N HCl水溶液をカートリッジに流した。
抽出物をカートリッジ内にローディング(loading)し、0.01N HCl水溶液 6mlで炭水化物、酸(acid)及びその他の水溶性化合物を溶出した。この溶出物を集めて炭水化物/酸画分とし、後の実験で比較対象として用いた。
次いで、前記カートリッジの乾燥のため、前記連結されたC18 Sep−Pakカートリッジに窒素ガスを10分間通した。続いて、乾燥したカートリッジに20mlエチルアセテートを流してフェノール性化合物(phenolic compounds)を溶出し、試験管にポリフェノール画分を収集した。
次に、0.1%HClを含む無水メタノール10mlでアントシアニンを溶出し、色素画分を得た。
全分画物は40℃で濃縮し、残留溶媒を除去した。
上記過程を経た後、炭水化物/酸画分と色素画分はそれぞれ蒸留水に溶解し、クロマメノキポリフェノール画分は50%エタノール水溶液に溶解した後、−70℃で保管し、後述する実験及び分析に用いた。
本発明の実験及び分析に用いたヒト成人のARPE細胞(ARPE−19;catalog no. CRL−2302)は、韓国カトリック医科大学視科学研究所から分譲された。前記ARPE細胞は、10%ウシ胎仔血清(FBS)、100U/mlペニシリン、及び100mg/mlストレプトマイシン(streptomycin)を添加したDMEM培地中、5%CO2、37℃で維持され、5×104個/ウェルの細胞数で6ウェルプレートに接種された。
本発明の実験及び分析に用いるA2Eは、次のようにして合成した。まず、エタノールに溶解したall−トランス−レチナールとエタノールアミン(2:1モル比)の混合物を暗室条件下で酢酸と2日間反応させた後、反応混合物を40℃で真空濃縮し、次いで、シリカゲルカラムクロマトグラフィーによって精製し、純粋なA2Eを得た。合成されたA2Eは20mMのストック濃度でDMSO(Dimethyl Sulfoxide)に溶解し、実験時まで−20℃で保管した。
A2Eの光酸化は、355nm〜375nmの照射波長を有するUVAランプ(Sankyo Denki社、Tokyo、Japan)により行った。UVAの照射前に、細胞をPBS(phosphate buffered saline)で洗浄した後、細胞が乾かない程度にPBSを除去した。ウェルプレートから蓋を除去し、強度2.35±0.3mW/cm2、エネルギー3J/cm2でUVAを照射した。
A2Eの酸化に対するクロマメノキ抽出物及びクロマメノキ分画物の抑制活性は、次の通り評価した。すなわち、96−ウェルプレートに1mM A2E 20μl(20mM A2E貯蔵液をPBSに希釈して得た)とクロマメノキ抽出物又はクロマメノキ分画物20μlを0.01%DMSO(Dimethyl Sulfoxide)が添加されたPBS 160ul中で混合した。次いで、ELISAマイクロプレートリーダーにて430nmにおける吸光度を測定した後、UVA(3J/cm2)を照射し、前記と同様に吸光度を測定した。試験試料の吸光度値をA2E対照の吸光度値と比較し、酸化されたA2Eの濃度はUVAの照射前後の吸光度差で表した。
6−ウェルプレートに、ウェル当たりARPE−19細胞を5×104個ずつ分株した後、20μl A2Eを5日間蓄積させた。その後、種々の濃度のクロマメノキ抽出物及びクロマメノキ分画物(クロマメノキ抽出物:100、250、500mg/ml;クロマメノキ分画物:12.5、25、50、100mg/ml)で処理し、UVA(3J/cm2)を照射した後、24時間インキュベートし、MTT法を用いてUVAにより誘導されたアポトーシスを測定した。MTT法によるアポトーシスの測定は、0.5mg/mlのMTTを添加したDMEMにて、光を遮断して37℃で2時間培養した後、細胞をジメチルスルホキシド(DMSO)に充分に溶解し、ELISAマイクロプレートリーダーを用いて550nmで吸光度を測定して、細胞生存率を、A2Eを蓄積せずUVAを照射しない群(正常対照群:normal control)の吸光度に対するパーセンテージ(%)で示すことにより行った。
6−ウェルプレートにウェル当たりARPE−19細胞を5×104個ずつ分株した後、種々の濃度のクロマメノキ抽出物及びクロマメノキ分画物と2日間インキュベートした後、前記と同様にA2Eを蓄積させた。その後、プロテアーゼ抑制剤(CompleteTM、Roche社、Mannheim、Germany)を含む25mM HEPESバッファに細胞を懸濁し、高速液体クロマトグラフィー(HPLC)により、細胞のA2E蓄積量を定量分析した。定量分析には、濃度既知のA2E溶液を用い、A2E量はブラッドフォード法(Bio−Rad Protein Assay、Bio−Rad、Hercules、CA)でタンパク質量を測定して補正した。試料は、HPLC定量分析の前にARPE−19細胞からCHCl3によってA2Eを抽出した後に用いた。HPLC定量分析の条件及び具体的な実験方法は下記に示した。
ウォーターズ996フォトダイオードアレイデテクターA(Waters 996 photodiode array detector A)が取り付けられ、逆相C18カラム(2504.6mm、Cosmosil 5C18、Nacalai Tesque、Osaka、Japan)を用いたウォーターズ600E HPLC(Waters600E HPLC)を使用した。A2Eは、アセトニトリルとともに0.1%トリフルオロ酢酸(TFA)溶液に溶解され、分離される。A2Eは分離後、430nmにおける吸光度を測定し、A2Eが蓄積されなかった群における吸光度に対する%で示した。
本発明のクロマメノキ抽出物及びクロマメノキ分画物のA2Eの酸化に対する抑制活性を検討するために、実験例1と同様の方法で、細胞にUVAを照射し、酸化されたA2Eの濃度を測定した(図1)。
本発明のクロマメノキ抽出物及びクロマメノキ分画物の細胞保護能を検討するために、前述した実験例2と同様に、UVAを照射した後、MTT法により細胞のアポトーシスを測定した(図2)。
本発明のクロマメノキ抽出物及びクロマメノキ分画物のA2EとisoA2Eに対する蓄積抑制活性を評価するために、実験例3と同じ方法で実験した後、A2E及びisoA2Eの濃度を測定して図3に示した。
Claims (7)
- クロマメノキ抽出物またはクロマメノキ分画物を有効成分として含む、黄斑変性症の治療、予防または改善用薬剤学的組成物の製造方法であって、
クロマメノキを、水、炭素数1〜4の低級アルコールまたはその混合溶媒によって抽出する工程、または
クロマメノキを、ポリフェノール成分分画法および/または色素成分分画法を用いて分画する工程
を含む製造方法。 - 前記クロマメノキ分画は、固相抽出法(Solid Phase Extraction;SPE)によって分画されたものである、請求項1に記載の製造方法。
- 前記ポリフェノール成分分画法を用いて分画されたポリフェノール画分は、クロマメノキ抽出物からHCl溶液で炭水化物/酸画分を除去した後、エチルアセテートで溶出させて得られた分画物である、請求項1に記載の製造方法。
- 前記色素成分分画法を用いて分画された色素画分は、クロマメノキ抽出物からHCl溶液で炭水化物/酸画分を除去し、エチルアセテートでポリフェノール画分を溶出させた後、メタノール/HCl溶液で溶出させて得られた分画物である、請求項1に記載の製造方法。
- クロマメノキ抽出物またはクロマメノキ分画物を有効成分として含む、黄斑変性症の治療、予防または改善用薬剤学的組成物であって、前記クロマメノキ抽出物およびクロマメノキ分画物は、ピリジニウムビスレチノイド(A2E)の蓄積および酸化の抑制活性を有することを特徴とする薬剤学的組成物。
- 黄斑変性症は、加齢性黄斑変性症である、請求項5に記載の薬剤学的組成物。
- 点眼剤または眼軟膏剤である、請求項5に記載の薬剤学的組成物。
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