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(PP285) Small molecule antioxidants prevent ionizing irradiation-induced fibrosis in the adult zebrafish.
Bahary, Nathan*,2, Epperly, Michael1, Quadar, Mubina1, Greenberger, Joel1, 2 Molecular Genetics and Biochemistry, Pittsburgh, PA, USA1 Radiation Oncology, Pittsburgh, PA, USA
ABSTRACT- To screen new small molecule antioxidants, we have developed a zebrafish model for irradiation-induced muscle fibrosis. To demonstrate that small molecules may be absorbed through the gills and distributed systemically, we placed adult zebrafish in the presence of increasing concentrations (0 to 200 M) of the SOD mimetic, EUK-134. Fish were sacrificed 24 hours later, the tail removed and tissue assayed for MnSOD biochemical activity. As the dose of EUK-134 increased, MnSOD biochemical activity increased and plateaued at 100 M. To determine whether small molecule antioxidants prevented muscle fibrosis, fish were incubated in the presence of each of several antioxidant small molecules, including: 100 M EUK-134, 20 M WR2721 (Amifostine), or 1 M Tempol for 24 hours. Under anesthesia, the posterior portion of the fish was irradiated to 68 Gy using a 6 MeV linear accelerator. The anterior portion containing hematopoietic as well as other vital organs was shielded from irradiation. The fish were then transferred to tanks containing water with no added antioxidants. Three months later the fish were sacrificed, and tails analyzed for irradiation-induced fibrosis. Control, irradiated fish developed extensive fibrosis of the tail including collagen and fat deposits replacing over 50% of the muscle. Zebrafish incubated in WR2721 or Tempol showed a detectable decrease in fibrosis compared to control, irradiated fish. In contrast, zebrafish incubated in EUK-134 demonstrated a significant decrease in fibrosis with minimal fat deposition detected and slight increase in collagen deposition compared to non-irradiated fish. These results indicate that EUK-134 is an effective radioprotectant and demonstrate that the adult zebrafish provides an effective model for screening new small molecule antioxidants.
Key words: antioxidants, radioprotection, zebrafish
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