Epalrestat Stimulated Oxidative Stress, Inflammation, and Fibrogenesis in Mouse Liver

Abstract

Epalrestat (EPS), an aldose reductase inhibitor, is widely prescribed to manage diabetic neuropathy. It is generally believed that EPS is beneficial to diabetic patients because it can protect endothelial cells, Schwann cells, or other neural cells from oxidative stress. However, several clinical studies revealed that EPS therapy led to liver dysfunction, which limited its clinical applications. Currently, the underlying mechanism by which EPS causes liver dysfunction is unknown. This study aimed to investigate the mechanism responsible for EPS-induced liver injury. In mouse liver, EPS 1) increased oxidative stress, indicated by increased expression of manganese superoxide dismutase, Ho-1, and Nqo1, 2) induced inflammation, indicated by infiltration of inflammatory cells, and induced expression of tumor necrosis factor-alpha, CD11b, and CD11c, as well as 3) predisposed to induce fibrosis, evidenced by increased mRNA and protein expression of early profibrotic biomarker genes procollagen I and alpha-smooth muscle actin, and by increased collagen deposition. In cultured mouse and human hepatoma cells, EPS treatment induced oxidative stress, decreased cell viability, and triggered apoptosis evidenced by increased Caspase-3 cleavage/activation. In addition, EPS increased mRNA and protein expression of cytoglobin in mouse liver, indicating that EPS activated hepatic stellate cells (HSCs). Furthermore, EPS treatment in cultured human HSCs increased cell viability. In summary, EPS administration induced oxidative stress and inflammation in mouse liver, and stimulated liver fibrogenesis. Therefore, cautions should be exercised during EPS therapy.

Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2

“…Oxidative Medicine and Cellular Longevity whereas a very recent study reported that Epalrestat induced oxidative stress, inflammation, and fibrogenesis in the mouse liver [37].…”

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

“…Zopolrestat, an AR-specific inhibitor, improved ethanol-induced steatosis and hepatic oxidative stress by suppressing adenosine monophosphate-activated protein kinase (AMPK) activation and Srebp1c expression in C57BL/6J mice and HepG2 cells [ 99 , 100 ]. Inconsistent with these data, others have reported that epalrestat (EPS), an aldose reductase inhibitor, increased oxidative stress, as indicated by the increased expression of manganese superoxide dismutase (heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1)-induced inflammation, and the infiltration of inflammatory cells and induced the expression of tumor necrosis factor-alpha, CD11b, and CD11c, leading to fibrosis in mouse liver [ 101 ]. Further investigation should be conducted to clarify the relationship between Ar and liver dysfunction.…”

An Insight into Potential Pharmacotherapeutic Agents for Painful Diabetic Neuropathy

“…Clinical studies demonstrated the alleviation of spontaneous pain in the lower limbs of 48.6% diabetic patients [ 22 ]. Epalrestat, a carboxylic derivative, has been found beneficial in inhibiting polyol pathway and shielding against nerve damage with no side effects until recently a study conducted by Le et al highlighted the induction of liver fibrogenesis due to increased oxidative stress [ 23 , 24 ]. Studies conducted on tolrestat, zenarestat, and sorbinil suggested their withdrawal from human use because of their adverse effects, i.e., liver dysfunction, increased creatinine levels, and serious hypersensitivity, respectively [ 25 ].…”