RBIO-17. The radioprotective effect of a novel brain-penetrant superoxide dismutase mimic on normal brain

Abstract BACKGROUND Cognitive deficits resulting from clinical brain radiotherapy are often long lasting and currently lack treatment options. Previous studies have shown that manganese porphyrin (MnP)-based superoxide dismutase (SOD) mimics can preserve normal brain function in preclinical models by scavenging radiation-induced deleterious free radicals. In this study, we evaluated the radioprotective potential of MnP3, a next-generation, potent SOD mimic specifically designed for enhanced blood-brain barrier penetration and favorable safety profiles, in normal mouse brains. METHODS The radioprotective potential of MnP3 against radiation-induced normal brain damage was evaluated in 10-week-old wild-type mice (C57BL/6J). Mice were exposed to either sham or 5Gy whole-brain irradiation and treated with or without MnP3. Two weeks post MnP3 administration, brain tissues were harvested after perfusion with 4% PFA to examine for DNA damage (pH2AX), apoptosis (ClCas3), oxidative stress (Cys/CySS), lipid peroxidation (4-HNE), and microglia (IBA1) distribution in three different regions including cortex (M1 and M2 regions), white matter (corpus callosum) and hippocampus. Quantification was performed using LC-MS/MS on flash-frozen tissues and immunohistochemical staining on formalin-fixed paraffin-embedded sections with standard antibody-based protocols. RESULTS Two weeks of MnP3 treatment following whole-brain irradiation in mice resulted in a significant MnP3 accumulation in normal brain and markedly reduced radiation-induced DNA damage, lipid peroxidation and apoptosis in the cortex and corpus callosum. Additionally, MnP3 attenuated microglia activation in hippocampus region. Importantly, no weight loss was observed during the treatment period, suggesting that MnP3 did not induce systemic toxicity. CONCLUSION Our findings indicate that the novel SOD mimic, MnP3, effectively penetrates the blood-brain barrier and has potential for preventing radiation-induced deleterious effects. Further studies will further evaluate its impact on cellular damage and cognitive outcomes following brain irradiation using neuro-behavior assays.