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
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2011-01-01
|
| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319307601 |
| _version_ | 1828414669574897664 |
|---|---|
| author | Keita Mizuno Toshiaki Kume Chie Muto Yuki Takada-Takatori Yasuhiko Izumi Hachiro Sugimoto Akinori Akaike |
| author_facet | Keita Mizuno Toshiaki Kume Chie Muto Yuki Takada-Takatori Yasuhiko Izumi Hachiro Sugimoto Akinori Akaike |
| author_sort | Keita Mizuno |
| collection | DOAJ |
| description | 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. Keywords:: isothiocyanate, neuroprotection, oxidative stress, nuclear factor E2–related factor 2 (Nrf2) |
| first_indexed | 2024-12-10T13:30:45Z |
| format | Article |
| id | doaj.art-c8b9a3ea78e74902a6e1f10e82ae35b3 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-10T13:30:45Z |
| publishDate | 2011-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-c8b9a3ea78e74902a6e1f10e82ae35b32022-12-22T01:47:00ZengElsevierJournal of Pharmacological Sciences1347-86132011-01-011153320328Glutathione 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 IsothiocyanateKeita Mizuno0Toshiaki Kume1Chie Muto2Yuki Takada-Takatori3Yasuhiko Izumi4Hachiro Sugimoto5Akinori Akaike6Department of Pharmacology, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, JapanDepartment of Pharmacology, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, JapanDepartment of Pharmacology, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, JapanDepartment of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College, Kyoto 610-0395, JapanDepartment of Pharmacology, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, JapanWorld-Leading Drug Discovery Research Center, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, JapanDepartment of Pharmacology, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Corresponding author. aakaike@pharm.kyoto-u.ac.jpOxidative 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. Keywords:: isothiocyanate, neuroprotection, oxidative stress, nuclear factor E2–related factor 2 (Nrf2)http://www.sciencedirect.com/science/article/pii/S1347861319307601 |
| spellingShingle | Keita Mizuno Toshiaki Kume Chie Muto Yuki Takada-Takatori Yasuhiko Izumi Hachiro Sugimoto Akinori Akaike 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 Journal of Pharmacological Sciences |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319307601 |
| work_keys_str_mv | AT keitamizuno glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate AT toshiakikume glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate AT chiemuto glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate AT yukitakadatakatori glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate AT yasuhikoizumi glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate AT hachirosugimoto glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate AT akinoriakaike glutathionebiosynthesisviaactivationofthenuclearfactore2relatedfactor2nrf2antioxidantresponseelementarepathwayisessentialforneuroprotectiveeffectsofsulforaphaneand6methylsulfinylhexylisothiocyanate |