Mitochondrial uncoupler 2,4-dinitrophenol (DNP) confers protection from the acute effect of ionizing radiation by regulating redox homeostasis in radio-sensitive organs of C57BL/6 mice

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PURPOSE: The development of radiation countermeasures is an unmet need. Several cytoprotective approaches have been demonstrated to minimize ionizing radiation-induced tissue toxicity. Previously, our research indicated that mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) potentially counteract the IR-induced cell death. Herein, our investigation delves into the radio-protective efficacy of DNP following total-body irradiation (TBI) in C57BL/6 mice. METHOD: DNP was administered orally 2 h prior to TBI (7.6 Gy gamma (γ)-radiation) as a prophylactic approach against acute radiation syndrome (ARS), and survival analysis was performed for 30 days in C57BL/6 mice. Radiation-induced reactive oxygen species (ROS) and macromolecular oxidation (lipid and protein) were examined in radiation-sensitive organs, including the spleen, bone marrow, liver, and gastrointestinal tract (GI). GI damage was examined using tissue histology and correlated with the level of antioxidant catalase, superoxide dismutase, and reduced glutathione (GSH). RESULTS: DNP conferred radioprotection in mice, as evidenced by a 41% increase in survival. DNP pretreatment facilitates a substantial regulation of TBI-induced ROS production and macromolecular oxidation as early as 30 min to 24 h post-irradiation across various radiation-sensitive organs. Moreover, antioxidant analysis in GI tissue showed that DNP played a crucial role in maintaining redox homeostasis. This was evident through the elevation of catalase, superoxide dismutase, and GSH, eventually protecting from radiation-induced GI damage. CONCLUSION: The study confirms that DNP-mediated regulation of redox homeostasis in the hematopoietic and GI systems enhances survival efficacy while mitigating the risk of acute tissue damage and provides protection against ARS in C57BL/6 mice.

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