Neurotoxic effects of iron overload under high glucose concentration

Iron overload can lead to cytotoxicity, and it is a risk factor for diabetic peripheral neuropathy. However, the underlying mechanism remains unclear. We conjectured that iron overload-induced neurotoxicity might be associated with oxidative stress and the NF-E2-related factor 2 (Nrf2)/ARE signaling pathway. As an in vitro cellular model of diabetic peripheral neuropathy, PC12 cells exposed to high glucose concentration were used in this study. PC12 cells were cultured with ferric ammonium citrate at different concentrations to create iron overload. PC12 cells cultured in ferric ammonium citrate under high glucose concentration had significantly low cell viability, a high rate of apoptosis, and elevated reactive oxygen species and malondialdehyde levels. These changes were dependent on ferric ammonium citrate concentration. Nrf2 mRNA and protein expression in the ferric ammonium citrate groups were inhibited markedly in a dose-dependent manner. All changes could be inhibited by addition of deferoxamine. These results indicate that iron overload aggravates oxidative stress injury in neural cells under high glucose concentration and that the Nrf2/ARE signaling pathway might play an important role in this process.