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大学・研究所にある論文を検索できる 「パーキンソン病治療における新規標的蛋白質の探索と創薬研究」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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パーキンソン病治療における新規標的蛋白質の探索と創薬研究

芳賀 飛高 東北大学

2020.03.25

概要

【背景・目的】
パーキンソン病は進行性神経変性疾患である。薬物治療としてはドパミン神経活動を高めるドパミン補充療法が主である。しかし、副作用のため長期投与ができないため、ドパミン神経保護を目的とした新しい創薬が必要である。本研究では新規パーキンソン病治療薬開発のため、標的蛋白質の探索と創薬研究を行った。ミトコンドリア機能低下によるアデノシン三リン酸 (ATP) 産生減少はドパミン作動性神経変性を誘発する。本研究では、最初にミトコンドリア機能改善薬のパーキンソン病様症状の改善効果を検討した。次に、パーキンソン病の原因蛋白質である α-シヌクレインと結合する脂肪酸結合蛋白質 3 (FABP3) の阻害剤による治療効果について検討した。

【方法】
パーキンソン病モデルマウスは、神経毒である MPTP (25 mg/kg, i.p.) を 1 日 1 回、5 日間連投することで作成した。MPTP 最終投与の 24 時間後から、ピルビン酸エチル (EP) (25, 50, 100 mg/kg, i.p.) または sigma-1 受容体作用薬 (SA4503) (1 mg/kg, i.p.) を 1 日 1 回 4 週間投与した。次に、FABP3 阻害薬である MF8 のパーキンソン病様症状改善作用を検討し、その有効性を既存薬であるレボドパ (L-DOPA) と比較した。MPTP 最終投与の 24 時間後から、MF8 (0.3, 1.0 mg/kg, p.o.) または L-DOPA (25 mg/kg, i.p.) を 1 日 1 回 4 週間投与した。

【結果】
EP または SA4503 の慢性投与により、パーキンソン病モデルマウスの 運動機能障害及び認知機能障害の両方が改善された。また、黒質緻密部-腹側被 蓋野、線条体、および海馬 CA1 領域の ATP 含量およびドパミン作動性神経障 害は、EP または SA4503 の投与により用量依存的に改善された。さらに、パー キンソン病モデルマウスで低下した線条体のドパミン量も EP または SA4503 の投与により回復した。黒質緻密部-腹側被蓋野、線条体および海馬 CA1 領域 において MPTP 処置によって誘発された 4-hydroxy-2-nonenal (4-HNE) および ニトロチロシン反応性蛋白質レベルの上昇も、EP または SA4503 の投与によっ て抑制された。次に、FABP3 阻害剤である MF8 の効果について検討した。黒 質緻密部および腹側被蓋野において、MPTP 処置群ではドパミン作動性神経細 胞が脱落し、α-シヌクレインがドパミン作動性神経細胞の細胞体に蓄積していた。 MF8 の投与により用量依存的にドパミン作動性神経細胞死は抑制された。一方、 L-DOPA は抑制効果を示さなかった。これらの MF8 によるドパミン作動性神 経細胞保護作用はパーキンソン病様行動の改善作用と一致した。

【考察・結論】
ミトコンドリア機能改善薬である EP および SA4503 は ATP 産生能を回復させることによりドパミン作動性神経細胞死を抑制すると考えられる。一方、FABP3 阻害薬である MF8 は α-シヌクレインのドパミン作動性神経細胞での発現と凝集を抑制することにより、ドパミン作動性神経細胞死を抑制すると考えられる。これらの作用は既存薬である L-DOPA と異なることが示された。本研究により、パーキンソン病に対する新規治療法を開発するためには、ミトコンドリア機能を改善する薬剤と α-シヌクレイン凝集を抑制する薬剤が有用であることが示された。

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