RLIP76 protein reduces 4-HNE generated during oxidative stress and results in protection in well characterized animal models of acute radiation syndrome
European Journal of Molecular & Clinical Medicine,
2015, Volume 2, Issue 2, Pages 56-57
Ionizing radiation induces lipid peroxidation and forms reactive oxygen species (ROS) within the cell. Due to their highly reactive state, ROS have short diffusion distances and quickly transfer unbalanced electrons to neighboring molecules. This transfer cycle continues until it finally culminates in the generation of reactive alkenals such as 4-hydroxynonenal (4HNE). Under normal conditions, intracellular 4HNE levels are controlled by conjugation to glutathione and are actively transported from the cell; RLIP76 protein has been determined to be the major transport protein involved in the efflux of 4HNE-conjugates. Radiation induces significant oxidative stress, and the increased levels of 4HNE conjugates overwhelm transport capacity. When this occurs, further conjugation is inhibited and free 4HNE levels rise, triggering apoptosis. It was hypothesized that adding exogenous RLIP76 protein would reduce 4HNE levels and correspondingly increase the recovery from acute radiation syndrome (ARS) or completely protect individuals exposed to lethal doses of radiation. Methods The National Institutes of Health has developed animal models of ARS so that medical countermeasures can be tested in accordance with the FDA Animal Rule, since testing in people is clearly not ethical. One of these models, the C57BL/6 mouse, has been successfully utilized by Terapio to evaluate the efficacy of recombinant human RLIP76 encapsulated in liposomes (RLIP76-PL). These studies were 30-day survival studies of mice exposed to total body irradiation of 7.45-8.75 Gy. Administration of RLIP76-PL was subcutaneous or intramuscular on a prophylactic (administered up to 20 h prior to irradiation) or therapeutic (administered up to 36 h after irradiation) schedule.
As a prophylactic, there was 100% survival compared to 33% of the controls when mice were given three doses and exposed to 8.1 Gy. As a therapeutic, the drug is not administered until 24hrs after irradiation and remarkably, there is 92% survival compared to 8% of the controls.
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