Abstract
Salen Mn complexes, including EUK-134, EUK-189, and the cyclized analog EUK-207, are synthetic SOD/catalase mimetics that have beneficial effects in many models of oxidative stress. As oxidative stress has been implicated by some investigators in delayed radiation injury, we are investigating whether these compounds can mitigate injury to normal tissues caused by ionizing radiation. This review describes some of this research, focusing on several tissues of interest, including the lung, kidney, and skin. These studies have demonstrated suppression of delayed radiation injury in animals treated with EUK-189 and/or EUK-207. While an antioxidant mechanism of action is postulated, it is likely that the mechanisms of radiation mitigation by these compounds in vivo are complex and may involve non-redox-related mechanisms and differ in various target tissues. It is notable, however, that indicators of oxidative stress are increased in lung and skin radiation injury models, and suppressed by salen Mn complexes. Furthermore, histological, gene expression, and other assessments suggest that salen Mn complex treatment promotes a more normalized tissue environment in irradiated animals, including preservation of microvasculature in the skin and lung. In certain experimental models, including irradiated cell cultures, salen Mn complexes have shown “mito-protective” properties, that is, attenuating mitochondrial injury. In summary, salen Mn complexes could be useful to mitigate delayed radiation injury to normal tissues following radiation therapy, accidental exposure, or radiological terrorism. Optimizing their mode of delivery and other key pharmaceutical properties, as well as gaining more understanding of their mechanism(s) of action as radiation mitigators, are key issues for future study.
Published Version
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