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: Kaori Yama, Keisuke Sato, Yu Murao, Ryosuke Tatsunami, Yoshiko Tampo
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 39 Issue 9 Pg. 1523-30 (Sep 01 2016) ISSN: 1347-5215 [Electronic] Japan
• PMID: 27439473 (Publication Type: Journal Article)

Chemical References

• NF-E2-Related Factor 2
• RNA, Messenger
• RNA, Small Interfering
• Reactive Oxygen Species
• Thiazolidines
• epalrestat
• Rhodanine
• Ferritins
• Iron
• Aldehyde Reductase
• Catalase
• Heme Oxygenase-1
• Superoxide Dismutase

Topics

• Aldehyde Reductase (antagonists & inhibitors)
• Animals
• Catalase (genetics, metabolism)
• Cell Line, Tumor
• Ferritins (metabolism)
• Heme Oxygenase-1 (genetics, metabolism)
• Humans
• Iron (metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• RNA, Messenger (metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Reactive Oxygen Species (metabolism)
• Rhodanine (analogs & derivatives, pharmacology)
• Schwann Cells (drug effects, metabolism)
• Superoxide Dismutase (genetics, metabolism)
• Thiazolidines (pharmacology)
• Up-Regulation