New small molecule targets for radiation protection

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Following detonation of a "dirty bomb," or some less sinister but equally serious nuclear accident, the majority of the ensuing casualties can be anticipated to receive relatively low-dose exposures. Consequently, emergency services will have to treat large numbers of victims (including the affected public, emergency responders and medical staff) where developing tissue damage due to "bystander effects" is of paramount importance. Post-irradiation production of reactive oxygen and reactive nitrogen species (ROS and RNS) is a chronic phenomenon that starts within minutes of the dose being received. We have recently obtained evidence from post-irradiated rat tissue for sustained production of superoxide radical days after low-level doses have been terminated. The mitochondrion is clearly implicated as the site of superoxide production as manganese supeoxide dismutase (MnSOD) expression in the pre-irradiated tissue significantly ameliorates the effect. Furthermore, the readily detectable production of peroxynitrite anion in postirradiated tissue following the stimulation of endogenous nitric oxide synthase (NOS) indicates the secondary generation of this powerful oxidant to be a major consequence of the elevated superoxide level. None of these effects are observed in control tissue taken from unirradiated animals. Specific Aims: 1) Identify the mitochondrial site of the initial superoxide production (proposed to be mtNOS) in the first few hours following irradiation (the 'early process'); 2) Identify the mitochondrial sites damaged by ROS/RNS (proposed to be complex III) resulting in further (chronic) superoxide generation (the 'later process') and devise strategies for deactivating these centers; 3) Determine the relative importance of peroxynitrite and hydrogen peroxide production in post-irradiation damage to the electron-transport chain (ETC). Within the framework of these specific aims, it is proposed to develop and test putative drugs designed to prevent the formation of key ROS/RNS at the mitochondrial sites identified as responsible for their generation. In addition to efficacy, the possible toxicity of these compounds (at the level of the ETC) will be evaluated to facilitate improvements in the characteristics of further candidate drugs produced subsequently in iterative rounds of synthesis and testing.