title: Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation.
abstract: Epalrestat (EPS), approved in Japan, is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Here we report that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH), which is important for protection against oxidative injury, through transcription regulation. Treatment of Schwann cells with EPS caused a dramatic increase in intracellular GSH levels. EPS increased the mRNA levels of γ-glutamylcysteine synthetase (γ-GCS), the enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that plays a central role in regulating the expression of γ-GCS. ELISA revealed that EPS increased nuclear Nrf2 levels. Knockdown of Nrf2 by siRNA suppressed the EPS-induced GSH biosynthesis. Furthermore, pretreatment with EPS reduced the cytotoxicity induced by H2O2, tert-butylhydroperoxide, 2,2'-azobis (2-amidinopropane) dihydrochloride, and menadione, indicating that EPS plays a role in protecting against oxidative stress. This is the first study to show that EPS induces GSH biosynthesis via the activation of Nrf2. We suggest that EPS has new beneficial properties that may prevent the development and progression of disorders caused by oxidative stress.
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sato
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yama
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Murao
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tatsunami
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tampo
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053778:Thiazolidines; C038131:epalrestat; D012236:Rhodanine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Epalrestat; Glutathione; Nuclear factor erythroid 2-related factor 2; Oxidative stress; γ-glutamylcysteine synthetase