Background/Aim: Radiation mitigator, GSnitroxide, JP4-039, was evaluated for mitigation of total body irradiation (TBI) in Fanconi anemia (FA) Fancd2 −/− (129/Sv), Fancg −/− (B6), and Fanca −/− (129/Sv) mice. Materials and Methods: JP4-039 dissolved in 30% 2hydroxypropyl-β-cyclodextrin was injected intramuscularly 24 h after total body irradiation (9.25 Gy) into Fanca −/− , Fancd2 −/− and Fancg −/− mice. Irradiation survival curves were performed in vitro using bone marrow stromal cell lines derived from Fanca −/− , Fancd2 −/− and Fancg −/− mice. Results: FA mice demonstrate genotype specific differences in TBI mitigation by JP4-039. Radiation effects in derived bone marrow stromal cell lines in vitro were mitigated by drugs that block apoptosis, but not necroptosis or ferroptosis. Conclusion: FA mouse models are valuable for elucidating DNA repair pathways in cell and tissue responses to TBI, and the role of drugs that target distinct cell death pathways.
Background/Aim: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice. Materials and Methods: Fanca-/and Fanca +/+ bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and β-Galactosidase senescence analysis. Fanca-/and Fanca +/+ mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis. Results: JP4-039 reduced oral cavity ulceration in Fanca-/mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression. Conclusion: JP4-039 protected Fanca-/and Fanca +/+ cells and mouse oral cavity from both proton and photon radiation.
Background/Aim: The cause of fatal neuromuscular amyotrophic lateral sclerosis (ALS) is not known. Materials and Methods: Ninety-day-old superoxidedismutase-1 G93A (SOD1 G93A) mice demonstrating level 1 paralysis, received 9.0 Gy total body irradiation (TBI) from a cesium source at 340 cGy per minute, and intravenous transplantation with 1×10 6 C57BL/6 green fluorescent protein (GFP)+ donor bone marrow cells. Results: Paralysis-free survival was prolonged in TBI and bone marrow-transplanted SOD1 G93A mice from 100 to over 250 days (p=0.0018). Other mice transplanted with SOD1 G93A marrow or marrow treated with the free-radical scavenger MMS350 showed no therapeutic effect. GFP+ macrophage-2 (M 2) microglial cells of bone marrow origin, were seen at sites of degenerating anterior horn motor neurons. SOD1 G93A mice had a disruption in the blood-brain barrier permeability which was reversed by marrow transplant from C57BL/6 mice. SOD1 G93A marrow showed unexpected robust hematopoiesis in vitro, and radioresistance. Conclusion: After TBI, M 2 microglial cells from transplanted donor marrow extended the paralysisfree interval in SOD1 G93A mice.
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