Our laboratory has been researching potential targets for therapeutic intervention in amyotrophic lateral sclerosis (ALS), using the SOD1G93A mouse model to test new pharmacologic strategies. This research has led us to consider cerium oxide (CeO2) nanoparticles as a potent means to mitigate oxidative stress associated with ALS neurodegeneration. These nanoparticles were developed to reduce free radical damage in the fields of materials science and manufacturing, but only recently has their biomedical potential become evident. Preliminary studies from our laboratory indicate that CeO2 nanoparticles dose-dependently protect cultured NSC-34 motor neuron-like cells from acute H2O2 toxicity, at nanoparticle concentrations in the low nanomolar range. Furthermore, nanomolar concentrations of CeO2 nanoparticles reduced protein carbonylation (oxidation) in primary astrocytes cultured from neonatal SOD1G93A mice, both in the presence and the absence of an imposed cytokine challenge. Most remarkably, preliminary studies suggest that conservative treatment with CeO2 remarkably slowed disease progression and prolonged survival in the SOD1G93A mouse. These preliminary findings motivate the following SPECIFIC AIMS that will better define the biological effects of CeO2 nanoparticles in the SOD1G93A mouse and ascertain whether nanoparticles offer a credible opportunity for clinical development. SPECIFIC AIM 1 will test the hypothesis that systemically administered CeO2 nanoparticles can slow clinical disease progression in the SOD1G93A mouse model of ALS. SPECIFIC AIM 2 will test the hypothesis that systemically administered CeO2 nanoparticles can slow motor neuron death, neuroinflammation, and oxidative stress biomarker accumulation in the SOD1G93A mutant mouse. SPECIFIC AIM 3 will test whether CeO2 nanoparticles interact with systemically administered riluzole to either improve or diminish murine clinical outcomes. Because riluzole is the current standard of care for human ALS, withholding of riluzole probably would be considered unethical in future human clinical trials, so that novel ALS therapies being explored in mice ought to be considered in the context of riluzole co- administration. PUBLIC HEALTH RELEVANCE: This project will test cerium oxide nanoparticles as a new therapeutic tool for slowing the progression of amyotrophic lateral sclerosis (ALS) in a standard, widely accepted mouse model for the disease. The project also will test the ability of these nanoparticles to act as catalytic antioxidants in the central nervous system of ALS mice.