title: Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System.
abstract: Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases.
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sato
authors.forename: Yu
authors.initials: Y
authors.lastname: Murao
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tatsunami
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tampo
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005293:Ferritins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053778:Thiazolidines; C038131:epalrestat; D012236:Rhodanine; D005293:Ferritins; D007501:Iron; D000449:Aldehyde Reductase; D002374:Catalase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase