Effect of ferroptosis inhibitors oxindole-curcumin hybrid compound and N,N-dimethylaniline derivatives on rotenone-induced oxidative stress

Oxidative stress is common to multiple cell death pathways, including Apoptosis. We recently identified several compounds that protect against Ferroptosis, another cell death pathway associated with oxidative stress, suggesting potential efficacy against Apoptosis. The present study assessed the protective efficacies of the Ferroptosis inhibitors oxindole-curcumin hybrid compound GIF-2165X-G1, N,N-dimethylaniline derivatives GIF-2014 and GIF-2115, and ferrostatin-1 against rotenone-induced Apoptosis. Treatment of mouse hippocampal HT22 cells with the mitochondrial transport chain inhibitor rotenone for 24 h reduced mitochondrial membrane potential, increased Reactive Oxygen Species production, promoted nuclear fragmentation, and ultimately impaired cell viability, consistent with Apoptosis. Ferroptosis inhibitor cotreatment did not prevent any of these rotenone-induced apoptotic processes but did suppress delayed cell death associated with loss of plasma membrane integrity. These results suggest that GIF-2165X-G1, GIF-2014, GIF-2115, and ferrostatin-1 are selective for Ferroptosis and do not affect Apoptosis. Thus, erastin-induced Ferroptosis and rotenone-induced Apoptosis are distinct cell death pathways despite the common involvement of mitochondrial oxidative stress. Further, the cytoprotective efficacies of chemical antioxidants may depend on the specific source of oxidative stress.