Neuroprotective mechanisms of cerium oxide nanoparticles

Cerium oxide nanoparticles (nanoceria) are potent antioxidants that deactivate free radicals via a cycle of oxidation‐reduction reactions. Our previous imaging studies showed that nanoceria reduced cell death by 50% in a mouse hippocampal slice model of cerebral ischemia. The aim of the present study was to examine the mechanisms of neuroprotection of these particles by evaluating their effect on specific free radical species. Using fluorescence imaging, we show here that nanoceria (1 μg/mL) reduced the accumulation of nitric oxide (NO) and superoxide (O 2 •− ) by ~15 % and ~10%, respectively, at 2 hr post‐ischemia. Because these reductions were modest in comparison to the overall reduction in cell death, we also assessed the effects of nanoceria on peroxynitrite (ONOO •− ) and hydroxyl (HO •− ) accumulation. Using enzyme linked immunosorbent assays (ELISAs) we assessed ischemia‐induced formation of 3‐nitrotyrosine (3‐NT) and 4‐hydroxynonenal (4‐HNE), indicators of cellular damage caused by ONOO •− and HO •− , respectively. Nanoceria (1 μg/mL) had no effects on ischemia‐induced 4‐HNE accumulation but caused a greater than 50% decrease in 3‐NT levels. These findings suggest that scavenging of ONOO •− might be an important mechanism by which nanoceria mitigate ischemic brain injury and that nanoceria may be a useful therapeutic intervention for reducing oxidative/nitrosative damage following a stroke.