Peroxynitrite-Induced Oxidative Damage in TBI

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DESCRIPTION (provided by applicant): Extensive evidence now supports the concept that the reactive oxygen species (ROS)-mediated oxidative damage to lipids, proteins and nucleic acids plays a major role in the acute pathophysiology of traumatic brain injury (TBI), and that antioxidant drugs which inhibit this damage will reduce secondary brain injury and improve neurological recovery. However, the optimal design of antioxidant treatment for TBI requires a more complete understanding of the source and characteristics of ROS formation. Recent work indicates that mitochondria can become an important source of ROS when they become dysfunctional as a result of the massive TBI-induced rise in intracellular calcium (Ca++). Other work suggests that a key ROS formed by mitochondria is peroxynitrite (PON). PON-derived nitrogen dioxide (,NO2), carbonate (,CO3) and hydroxyl (,OH) radicals can cause oxidative damage to mitochondrial lipids (lipid peroxidation) and proteins (carbonylation, nitration) exacerbating intracellular Ca++ overload and triggering calpain-mediated cytoskeletal degradation and neurodegeneration. The specific aims of this proposal are to test the following hypotheses: 1) that post-traumatic oxidative damage in both diffuse and focal TBI is mediated by PON and that the time course of PON-mediated damage to lipids and proteins precedes calpain-mediated cytoskeletai damage and neurodegeneration, 2) that mitochondrial dysfunction is a major source of PON, and that mitochondria are an initial site of lipid and protein oxidative damage, 3) that pharmacological scavengers of PON or PON-derived oxygen radicals can protect isolated brain mitochondria from oxidative damage and dysfunction and 4) that pharmacological scavenging of PON or PON-dedved oxygen radicals will effectively inhibit post-TBI oxidative damage and dysfunction in brain mitochondria and attenuate downsteam cytoskeletal degradation and neurodegeneration. Experiments will be carried out in models of moderate and severe diffuse and focal TBI. A systematic investigation of the role of PON in acute TBI, and a careful examination of the neuroprotective efficacy of compounds which scavenge it after it is formed or that block PON-induced oxidative damage is expected to lead to a clinically effective and practical antioxidant neuroprotective strategy for acute TBI.