Glutathione Biosynthesis via Activation of the Nuclear Factor E2–Related Factor 2 (Nrf2) – Antioxidant-Response Element (ARE) Pathway Is Essential for Neuroprotective Effects of Sulforaphane and 6-(Methylsulfinyl) Hexyl Isothiocyanate
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概要
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Oxidative stress plays pivotal roles in aging, neurodegenerative disease, and pathological conditions such as ischemia. We investigated the effect of sulforaphane and 6-(methysulfinyl) hexyl isothiocyanate (6-HITC), a naturally occurring isothiocyanate, on oxidative stress–induced cytotoxicity using primary neuronal cultures of rat striatum. Pretreatment with sulforaphane and 6-HITC significantly protected against H2O2- and paraquat-induced cytotoxicity in a concentration-dependent manner. Sulforaphane and 6-HITC induced the translocation of nuclear factor E2–related factor 2 (Nrf2) into the nucleus and increased the expression of γ-glutamylcysteine synthetase (γ-GCS), a rate-limiting enzyme in glutathione synthesis, and the intracellular glutathione content. Treatment with reduced glutathione (GSH) and N-acetyl-L-cysteine, a substance for glutathione synthesis, significantly prevented the cytotoxicity induced by H2O2 and paraquat. Moreover, exposure to L-buthionine-sulfoximine, an irreversible inhibitor of γ-GCS, suppressed the protective effects of sulforaphane and 6-HITC. In contrast, sulforaphane and 6-HITC increased heme oxygenase-1 (HO-1) expression in neurons. However, zinc-protophorphyrin IX, a competitive inhibitor of HO-1, did not influence the protective effects of sulforaphane and 6-HITC. These results suggest that sulforaphane and 6-HITC prevent oxidative stress-induced cytotoxicity in rat striatal cultures by raising the intracellular glutathione content via an increase in γ-GCS expression induced by the activation of the Nrf2-antioxidant response element pathway.
著者
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Izumi Yasuhiko
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Kyoto University
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Kume Toshiaki
京都大学 薬学研究科生体機能解析学
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Kume Toshiaki
京都大学 薬学研究科薬品作用解析学分野
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Kume Toshiaki
京都大学 薬学研究科薬品作用解析学
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Kume Toshiaki
同志社女子大学 医療薬学科薬理学
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Kume Toshiaki
Department Of Pharmaceutical Science Kyoto University Graduate School Of Pharmacology
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Akaike Akinori
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Kyoto University
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Kume Toshiaki
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Kyoto University
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Takada-Takatori Yuki
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College, Japan
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Akaike Akinori
Department Of Pharmaceutical Science Kyoto University Graduate School Of Pharmacology
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Mizuno Keita
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
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Muto Chie
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
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Sugimoto Hachiro
World-Leading Drug Discovery Research Center, Graduate School of Pharmaceutical Sciences, Kyoto Univ
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Takada-takatori Yuki
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Doshisha Women's College
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Sugimoto Hachiro
World-leading Drug Discovery Res. Center Graduate School Of Pharmaceutical Sciences Kyoto Univ. Jpn
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Muto Chie
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Kyoto University
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Kume T
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Kyoto University
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