HGFによる脳神経系の生存維持とHGFからみた神経変性疾患の病態解析

1996 年度 実績報告書

• 研究課題/領域番号: 08256220
• 研究機関: 大阪大学
• 研究代表者: 松本 邦夫 大阪大学, 医学部, 助教授 (90201780)
• 研究分担者: 船越 洋 大阪大学, 医学部, 助手 (40273685)
• キーワード: HGF / c-Met / 神経栄養因子 / 脳梗塞 / ニューロン / 脳虚血

研究概要

HGF(hepatocyte growth factor)はin vivoにおいて肝臓、腎臓、肺など臓器の再生を促すとともに臓器傷害にともなう細胞死を防止する。私達はHGFならびにそのレセプターc-Metチロシンキナーゼが脳内に広く発現され、HGFは海馬初代培養ニューロンの生存を促し、さらに脳虚血傷害にともないHGFならびにc-Metの発現が高まることを報告した(1)。HGFは新しい神経栄養因子の一つであると考えられる。HGFが脳虚血傷害によって引き起こされる海馬領域における遅発性神経細胞死を防止するかどうか検討した結果、HGFは海馬遅発性神経細胞死を強力に抑制することを見い出した。
スナネズミに5分間の脳虚血傷害を与えると7日後には海馬CAI領域におけるニューロン数はsham手術群の4%に減少し、著しい遅発性神経細胞死が引き起こされた。一方、リコンビナンHGFを脳室内に投与した場合、HGFの投与量に依存して遅発性神経細胞死が抑制され、HGFを30μg/week投与した場合、sham手術群のコントロールに比べ約66%のニューロンが生存した。また、HGFの遅発性神経細胞死に対する防止作用は脳虚血傷害を引き起こしてから6時間後より投与を開始しても有効であった。
以上の結果はHGFが脳梗塞など脳虚血傷害に対し遅発性神経細胞死を防止する有効な薬剤となりうることを示唆している。また、HGFはドーパミンニューロンなど生存/成熟を促進することが知られており(2)、各種脳神経の傷害、疾患に対し有効な治療薬となる可能性がある。
(1)Honda,S.,Kagoshima,M.Wanaka,A.,Tohyama,M.Matsumoto,K.,and Nakamura T.(1995) Mol.Brain Res.,32,197-210.
(2)Hamanoue,M.,Takemoto,N.,Matsumoto,K.,Nakamura,T.,Nakajima,K.,and Kohsaka,S.(1996) J.Neurosci.Res.,43,554-564.

研究成果

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