Free radicals are thought to play a key role in the pathophysiology of traumatic brain injury (TBI). The production of free radicals and the ensuing state of oxidative stress may contribute to the chemical destruction of neuronal membranes, damage to intracellular constituents and ion channels, and apoptotic processes. The reduction of free radical activity thus remains an important avenue of treatment for TBI, yet traditional free radical scavengers may be limited by poor brain penetration, extensive dosing requirements, or both. However, new developments in the field of nanomedicine may provide treatment options not possible with traditional pharmacological approaches. This proposal is designed to determine if cerium oxide nanoparticles (CeONP) improve functional outcome and reduce oxidative stress following TBI. Recent studies suggest that CeONP are highly efficient free radical scavengers with excellent brain penetration, and CeONP have been shown to prevent neurodegeneration in response to several tissue culture models of oxidative stress. Moreover, the physicochemical properties of CeONP suggest that they are regenerative free radical scavengers that, unlike traditional antioxidants, require limited dosing. Motivated by these recent findings, we reasoned that the application of nanomedicine to the treatment of TBI would represent a novel therapeutic approach that offers unique possibilities not available with traditional pharmacological approaches. One hypothesis of this proposal is that TBI induces the production of damaging free radicals that overwhelm innate cellular defenses, resulting in a state of oxidative stress. Oxidative stress in turn results in neuronal death or dysfunction via several different pathways, ultimately resulting in poor functional outcome. Thus, the central hypothesis of this proposal is that reducing free radical activity and damage with administration of CeONP has the potential to improve functional outcome following TBI. Our preliminary studies indicate that CeONP are neuroprotective in an in vitro model of TBI. Furthermore, our preliminary work indicates that pre-injury administration of CeONP improves functional outcome following experimental TBI in rats. Thus, the specific aims of this proposal are: 1) to test the hypothesis that post-injury administration of CeONP improves functional outcome following TBI by reducing free radical damage, and 2) to test the hypothesis that delayed, post-injury administration of CeONP improves functional outcome following TBI by reducing free radical damage. The long-term objectives of these studies are to expand our knowledge of the role of free radicals in the pathophysiology of TBI, provide information on the role of oxidative stress in functional outcome following TBI, and provide novel information on the potential application of nanomedicine to the treatment of brain injury and other disease conditions involving oxidative stress.