イソキノリンによるパーキンソン病モデルの作成

1995 年度 実績報告書

• 研究課題/領域番号: 07264219
• 研究機関: 名古屋工業大学
• 研究代表者: 直井 信 名古屋工業大学, 工学部, 教授 (50022786)
• キーワード: パーキンソン病 / 内在性神経毒 / イソキノリン / 動物モデル / アポトーシス / 酸化的ストレス / 細胞死 / ドパミン

研究概要

ドパミンより生成されるカテコールイソキノリン、1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydro-isoquinoline[salsolinol]の光学異性体をヒトで分析したところ、脳、脳室液、脳脊髄液には(R)-体のみが存在していた。この生成酵素をヒト脳より分離精製し、ドパミンとアセトアルデヒドから(R)salsolinolを選択的に生成する酵素系があることを見い出した。(R)-salsolinolの誘導体N-methyl(R)salsolinolを線条体に注入して、ラットでパ-キソン病(PD)モデルを作成することに成功した。このモデルは寡動、振戦、異常姿勢などのヒトPDの症状に類似した行動変化が惹起された。また黒質への神経毒の特異的な蓄積と同時にドパミンとノルアドレナリンの顕著な減少と、チロシン水酸化酵素活性の低下が認められた。一方セロトニン系には影響は認められなかった。さらに線条体への持続注入により、黒質のドパミン細胞の脱落を証明した。N-methyl(R)-salsolinolはまた(R)-salsolinolより、N-メチル転移酵素によりドパミン細胞で生成されることを証明し、事実、ヒト脳でも、N-methyl(R)-salsolinolは黒質線状体に蓄積していた。
PD患者の脳脊髄液では、N-methyl(R)-salsolinolは、平均8.32±2.89nMと有為に対照群(4.53±2.08nM)より、増加していた。この結果は、PDの発症にN-methyl(R)-salsolinolの生成と代謝に関与する酵素系が内在性因子として、関与していることを示唆している。
N-methyl(R)-salsolinolがドパミン細胞に選択的な細胞死を惹起する機構として、N-methyl(R)-salsolinolの酸化にともなう水酸化ラジカルの生成と、生成物1,2-dimethyl-6,7-dihydroxyiso-quinolinium ionによるATPの生成が認められた。さらにN-methyl(R)salsolinolによりドパミン系ヒト神経芽細胞腫SH-SY5細胞に選択的に、DNA障害が起こることを見い出した。これらの結果は、N-methyl(R)-salsolinolがヒトPDの発症に関与する可能性の高いことを示している。

研究成果

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