Neuroprotection of retinal gangalion cells mediated by the antioxidative effects and immunomodulative effects of dimethyl fumarate

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11449
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kobe University
• Principal Investigator: Kurimoto Takuji 神戸大学, 医学部附属病院, 特定助教 (50388815)
• Co-Investigator(Kenkyū-buntansha): 中村 誠 神戸大学, 医学研究科, 教授 (80273788)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 網膜神経節細胞 / 神経保護

Outline of Final Research Achievements

In the present study, we investigated the survival-promoting effects of DMF/MMF using the optic nerve crush model in mice. As a result, the daily application of both DMF and MMF dose-dependently enhanced the survival of RGCs 7 days after optic nerve crush, and both DMF and MMF at 100mg/kg concentration were maximum survival-promoting effects. Furthermore, pSTR, the component of the electrical retinogram, which reflects the activity of RGC, was significantly increased by dairy application of DMF/MMF at 100mg/kg concentration. The application of DMF/MMF upregulated the retinal expression of HO-1, one of the antioxidant enzymes. From these results, the administration of DMF / MMF promoted functionally and morphologically survival of retinal ganglion cells damaged by the optic nerve crush and was possibly accompanied by the upregulation of antioxidant effects of Keap1/ Nrf2 - HO-1.

Free Research Field

眼科学

Academic Significance and Societal Importance of the Research Achievements

本研究結果から、DMF/MMFの連日投与は、ONC後のRGCに対して神経保護効果を発揮することが明らかになった。そして、既報から明らかにされているDMF/MMFの抗酸化作用、免疫調整作用のうち、抗酸化酵素の一つであるHO-1の網膜内発現レベルを明らかに亢進させることがわかった。脂溶性エステルのDMFであるテクフィデラの多発性硬化症への臨床治験では、顔面紅潮、胃腸障害は高頻度に出現するが、重篤な副作用はほとんどなく、安全性は既に確立されている。様々な視神経変性疾患への臨床応用への可能性を示す貴重な基礎データと考えられ、緑内障をはじめとする視神経疾患の患者数を考慮すると社会的意義も高い。