Protective Effect of Epalrestat against Oxidative Stress-induced Cytotoxicity

Abstract

Epalrestat (EPS), approved in Japan, is currently the only aldose reductase inhibitor that is available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH, the most abundant non-protein thiol antioxidant in cells, is important for protection against oxidative stress. Oxidative stress is associated with the development and progression of many pathological conditions, such as atherosclerosis, diabetes, and neurodegeneration. In this study, we tested the hypothesis that EPS enhances resistance to oxidative stress, by using rat Schwann cells. To determine whether EPS protects Schwann cells from oxidative stress, we performed experiments by using radical generators, drugs, and heavy metals as the source of oxidative stress. EPS reduced the cytotoxicity induced by 2,2-azobis-[2-(2-imidazolin-2-yl) propane] dihydrochloride, 6-hydroxydopamine, cisplatin, palmitate, cadmium chloride, and manganese (II) sulfate, indicating that EPS plays a role in protecting cells from oxidative stress. We suggest that EPS has the potential to prevent the development and progression of disorders caused by oxidative stress.

Cemtirestat, an aldose reductase inhibitor and antioxidant compound, induces ocular defense against oxidative and inflammatory stress in rat models for glycotoxicity

“…Our current study has demonstrated findings supporting the ability of CMTI to restore thiol‐disulfide homeostasis 48 . Similarly, STB inhibits GSH oxidation in diabetic tissues 49 and EPA protects GSH levels rat Schwann cells 50 …”

“…48 Similarly, STB inhibits GSH oxidation in diabetic tissues 49 and EPA protects GSH levels rat Schwann cells. 50 In this study, GST was inhibited in diabetic retina and activated in diabetic lens. In addition, CMTI treatment reduced GST activity below control values in both lens and retina of F rats.…”

Elucidation and Application of Novel Action of Therapeutic Agents for Diabetic Neuropathy

“…化を介して，g-glutamate-cysteine ligase(GCL)の 発現量を増加させることを明らかにしてきた． 5,9) GCL は GSH 生 合成の 律速 酵素で あり ，EPS は 32,34,35) 細胞内への Cd の取り込みは亜鉛トラン スポーターが関与し，そのなかでも細胞外や細胞内 小器官から細胞質に亜鉛を輸送する Zrt-, Irt-like protein (ZIP)が関与していることが明らかにされ ている． 32,35,38) Cd 毒性に対して高い感受性を示すマ ウスの系統では，血管内皮細胞の ZIP8 が高発現し ていることが報告されている． 39) 血管内皮細胞を Cd で曝 露する と， ZIP8 の発 現が 強く誘 導さ れ…”