Stroke is still one of the major killers in the United States. Head injury caused by auto accidents is also increasing. Since victims of stroke or head injury may often be paralyzed and require life-long care, they present an important socio-medical problem. Numerous studies have been done on both stroke and head injury, which propose the importance of the production of free radicals in the injury mechanisms. However, we do not have direct evidence to show that free radicals are actually involved in brain trauma. We hypothesized that free radicals are the triggering-substances causing secondary injury in brain trauma. We plan to test this hypothesis with two different types of experiments: (i) Using the spin trapping technique, we will test whether or not free radicals are produced in both ischemia- reperfusion injury and head injury. We will also determine if free radicals play an important role in the mechanism of the development of secondary injury; (ii) We will develop antioxidative drugs which could scavenge these radicals and thus protect the brain from secondary injury when either stroke or head injury takes place. We have already developed a spin trapping technique to measure free radical production in a rat ischemia-reperfusion model. We demonstrated that free radicals are indeed produced upon reperfusion, and that the amount of lipid peroxidation in the brain cortex is directly proportional to the amount of free radicals produced. This strongly supports the hypothesis that free radicals are the key factor in secondary injury . We have also synthesized new antioxidative drugs and demonstrated that they protect rats from ischemia-reperfusion injury and protect mice from head injury. Through this project, we will further verify and expand on these observations and hopefully firmly establish the hypothesis. We will also improve the efficacy of our drugs. The success of this project will deepen our understanding of injury mechanisms in brain trauma, and further help develop drugs which could reduce mortality and morbidity for these victims.