Elucidation of novel action of epalrestat for the development of therapeutic agents for heavy metal toxicity

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K10434
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58020:Hygiene and public health-related: including laboratory approach
• Research Institution: Hokkaido University of Science
• Principal Investigator: Tatsunami Ryosuke 北海道科学大学, 薬学部, 教授 (90285552)
• Co-Investigator(Kenkyū-buntansha): 佐藤 恵亮 北海道科学大学, 薬学部, 講師 (60733946)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: エパルレスタット / カドミウム / グルタチオン / Nrf2

Outline of Final Research Achievements

Cadmium (Cd) is an environmental pollutant that targets the vascular endothelium. Recent studies have suggested a link between Cd and vascular disease, but the details of the mechanism are not clear. The aim of this study was to clarify the effect of epalrestat, a drug used in the treatment of diabetic neuropathy, on Cd-induced cytotoxicity. We revealed that epalrestat suppresses Cd-induced cell injury and increases intracellular glutathione levels. We also found that the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the above-mentioned inhibitory effect by using knockdown cells. Furthermore, this study revealed that epalrestat affects the intracellular concentrations of Cd and the Cd transporters ZIP8 and metallothionein. These results suggest that the regulation of glutathione, ZIP8, and metallothionein via the transcription factor Nrf2 by epalrestat may lead to a promising therapeutic approach for Cd poisoning.

Free Research Field

衛生薬学

Academic Significance and Societal Importance of the Research Achievements

本研究では、カドミウム誘導性の細胞傷害に対するエパルレスタットの抑制作用に検討した。今回の成果は、培養細胞による基礎研究の結果ではあるが、エパルレスタットが糖尿病性末梢神経障害のみならず、カドミウムなどの重金属中毒にも応用できる可能性を示唆している。臨床的にエパルレスタットの有用性を示すにはin vivo実験を含めたより詳細な検討が必要とされるが、本研究成果は、エパルレスタットのドラッグリパーパシングに繋がる基礎研究として、今後の適応拡大への可能性を示すものである。