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Salen Manganese Complexes Mitigate Radiation Injury in Normal Tissues Through Modulation of Tissue Environment, Including Through Redox Mechanisms

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Redox-Active Therapeutics

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.

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Acknowledgements

Development of the salen Mn complexes, including EUK-207, was funded in part by GM57770 (SRD). Renal, cutaneous, and pulmonary studies and further compound development were supported by AI067734 (JEM). Some pulmonary studies were also supported by AI81294 (MM) and AI091036 (JPW). Funding for previously reviewed studies were acknowledged in [16] and the other cited primary journal articles. SRD is an inventor on patents describing salen Mn complexes. We thank Drs Eric Cohen and Richard Hill for helpful comments on the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston, MA, USA

    Susan R. Doctrow & Karl D. Huffman

  2. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

    Brian Fish, Meetha Medhora & John E. Moulder

  3. Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, USA

    Zelmira Lazarova

  4. Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA

    Jacqueline P. Williams

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  1. Susan R. Doctrow
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Correspondence to Susan R. Doctrow .

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Editors and Affiliations

  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Doctrow, S.R. et al. (2016). Salen Manganese Complexes Mitigate Radiation Injury in Normal Tissues Through Modulation of Tissue Environment, Including Through Redox Mechanisms. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_11

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