JP2022540455A - O-環状フィトスフィンゴシン-1-フォスフェートを含むパーキンソン病の予防又は治療用組成物 - Google Patents
O-環状フィトスフィンゴシン-1-フォスフェートを含むパーキンソン病の予防又は治療用組成物 Download PDFInfo
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Abstract
Description
本発明は、O-環状フィトスフィンゴシン-1-フォスフェートを含むパーキンソン病の予防又は治療用組成物に係り、より詳しくは、O-環状フィトスフィンゴシン-1-フォスフェートを含んでドーパミン性神経細胞の死滅を抑制し、且つチロシンヒドロキシラーゼの発現を増加させることができ、パーキンソン病を予防又は治療することができる組成物に関する。
パーキンソン病(Parkinson’s disease、PD)は、中脳の黒質部位のドーパミン性神経細胞が徐々に選択的に消失しここで作られるドーパミンと呼ばれる神経伝達物質が欠乏して発生する疾病である。パーキンソン病は手、足、顔の震えや麻痺、硬直、動作緩慢などによる運動障害及び姿勢不安定などをもたらす。
〔発明が解決しようとする課題〕
本発明者らは、パーキンソン病に効果的な治療剤を開発するために鋭意研究を重ねた結果、O-環状フィトスフィンゴシン-1-フォスフェートがドーパミン性神経細胞であるSH-SY5Y神経細胞の死滅を抑制し、且つドーパミンの形成に必要な酵素であるチロシンヒドロキシラーゼの発現を増加させるという事実を見出し、本発明を完成するに至った。
本発明の一実施形態は、下記の化学式1で表される化合物又はその薬剤学的に許容される塩を含む、パーキンソン病の予防又は治療用薬剤学的組成物に関する。
本発明の薬剤学的組成物の具体的な投与量は、治療されるヒトを含む哺乳動物の種類、体重、性別、疾患の重症度、医者の判断などに応じて変わり得る。好ましくは、経口投与の場合は一日に体重1kg当たり活性成分0.01~50mgが投与され、非経口投与の場合は一日に体重1kg当たり活性成分0.01~10mgが投与される。前記一日総投与量は、疾患の重症度、医者の判断などに応じて一度に投与しても又は複数回に分けて投与してもよい。
本発明に係るO-環状フィトスフィンゴシン-1-フォスフェート又はその薬剤学的に許容される塩はロテノン又はMPP+を用いたパーキンソン病細胞モデルにおいて神経細胞の死滅を抑制し、且つ神経細胞においてドーパミンの形成を促進する酵素であるチロシンヒドロキシラーゼの発現を増加させることができ、パーキンソン病の予防、治療又は改善用組成物に効果的に用いられ得る。
〔図1〕cP1P薬物の濃度によるSH-SY5Yヒト神経細胞株の増殖効果を示したグラフである。
以下、実施例によって本発明をより具体的に説明することにする。これらの実施例は単に本発明を説明するためのものであって、本発明の範囲がこれらの実施例に限定されるものではないことは当業者にとって自明である。
ドーパミン性ヒト神経細胞の増殖に及ぼすcP1P薬物の効能を評価するために、神経細胞株としてはATCCから購入したSH-SY5Yヒト神経細胞株を用いた。神経細胞を培養する培地はダルベコ改変イーグル培地/高グルコース(Dulbeco’s Modified Eagle’s Media/high glucose)(with 10%FBS、0.5%P/S)を用い、37℃、5%CO2インキュベーターで培養した。
ロテノンは、パーキンソン病を誘発するために細胞モデルにおいて広く用いられている物質である。ロテノンを神経細胞で処理するとミトコンドリア機能を破壊して酸化的ストレスを誘発し神経細胞が死滅することはよく知られている。
MPP+(1-methyl-4-phenylpyridinium iodide、シグマ社)で酸化的ストレスを誘発してパーキンソン病細胞モデルを作るために、MPP+をリン酸緩衝溶液に溶解し、最終濃度が3mMになるように希釈して神経細胞培養培地に添加した。MPP+環境でのcP1P薬物の効能を確認するために、SH-SY5Y細胞を各10nM、100nM及び1000nMの濃度のcP1Pで1時間前処理した後、3mM MPP+で24時間処理して酸化的ストレスに露出させた。酸化的ストレスへの24時間露出後のSH-SY5Y細胞の生存に及ぼすcP1P薬物の効能はMTTアッセイによって確認した。
チロシンヒドロキシラーゼ(TH)酵素は、アミノ酸であるチロシンをドーパミンの前駆物質であるL-DOPAに転換させる酵素であって、神経細胞のドーパミンの形成に重要な役割を担う酵素である。
Claims (8)
- 前記化学式1で表される化合物又はその薬剤学的に許容される塩がチロシンヒドロキシラーゼの発現を増加させる、請求項1に記載のパーキンソン病の予防又は治療用薬剤学的組成物。
- 前記薬剤学的に許容される塩が塩酸塩である、請求項1に記載のパーキンソン病の予防又は治療用薬剤学的組成物。
- 前記化学式1で表される化合物又はその薬剤学的に許容される塩がチロシンヒドロキシラーゼの発現を増加させる、請求項4に記載のパーキンソン病の予防又は改善用健康機能食品。
- 前記薬剤学的に許容される塩が塩酸塩である、請求項4に記載のパーキンソン病の予防又は改善用健康機能食品。
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