Abstract
Organ specific localized administration of manganese superoxide dismutase plasmid/liposome complexes (MnSOD-PL) confers protection of the rodent lung, esophagus, oral cavity, intestine and bladder from single fraction and fractionated ionizing irradiation by a mechanism dependent upon mitochondrial localized antioxidant effects. Intravenous injection of MnSOD-PL significantly increased survival of both male and female C57BL/6NHsd mice from the LD 50/30 whole body irradiation dose of 9.5 Gy (p = 0.0001 or 0.0059, respectively). To determine if systemic MnSOD-PL mediated improved survival at the expense of a deleterious delayed increase in development of cancer, life shortening, or neurodegenerative disease we followed all survivors. Fifty male and female C57BL/6NHsd mice per group were injected intravenously with MnSOD-PL (100 μg plasmid DNA in 0.1 ml) and irradiated with control mice to 0, 1 or 9.5 Gy whole body irradiation 24 hrs later. Moribund or dying mice were sacrificed, examined for tumors and bone marrow isolated stained with Wright Geimsa, and examined for abnormal hemogram. Small intestine was fixed in formalin, sectioned and examined for intestinal changes. Female mice pretreated with MnSOD-PL prior to 9.5 Gy (LD 50/30) had an increased survival over the first 30 days which is the time frame for death due to hematopoietic or intestinal damage with 90% survival compared to 58% for the control irradiated mice (p = 0.0059). Between 30 and 530 days there was no significant change in survival rate between MnSOD-PL treated and control irradiated 9.5 Gy or 1.0 Gy groups. Beginning at day 400, all groups have a similar death rate which can be attributed of the age of the mice. Male mice pretreated with MnSOD-PL and irradiated to 9.5 Gy had 75% survival after 30 days compared to 25% for the control mice (p < 0.0001). Between 30 and 375 days after irradiation, there was no significant change in survival rate between MnSOD-PL treated compared to control irradiated 9.5 or 1.0 Gy groups. There was no detectable difference in the incidence of deaths associated with tumor (thymoma), marrow, or intestinal damage. All mice are being followed until they become moribund as a result of irradiation or old age. The data indicate, at this time, that systemic MnSOD-PL treatment is not detectably harmful to surviving total body irradiated mice.
Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle