title: 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.
abstract: 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 H(2)O(2)- 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 H(2)O(2) 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.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Mizuno
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Chie
authors.initials: C
authors.lastname: Muto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takada-Takatori
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Hachiro
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D004353:Drug Evaluation, Preclinical; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D005978:Glutathione / Q000096:biosynthesis*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements; D015398:Signal Transduction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*
chemical_list: C505386:6-(Methylsulfinyl)hexyl isothiocyanate; D000975:Antioxidants; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D013454:Sulfoxides; D013861:Thiocyanates; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; C016766:sulforaphane; D005978:Glutathione