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RLIP76 protein reduces 4-HNE generated during oxidative stress and results in protection in well characterized animal models of acute radiation syndrome

Authors:

Elizabeth K. Leffel ,

Leffel Consulting Group, LLC, Berryville, VA, USA
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Casey Cunningham,

Leffel Consulting Group, LLC, Berryville, VA, USA
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Brian R. Sloat,

Leffel Consulting Group, LLC, Berryville, VA, USA
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Henry Hebel,

Leffel Consulting Group, LLC, Berryville, VA, USA
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Curt Bilby

Leffel Consulting Group, LLC, Berryville, VA, USA
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Abstract

Background

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.

Results

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.

Conclusions

Combined data of many studies show that when compared to controls, treated mice exposed to LD50s, LD70s, or LD90s resulted in survival ranging from 50-80% over the controls. RLIP76-PL is a strong candidate to protect the population from acute radiation exposure.

How to Cite: Leffel, E.K., Cunningham, C., Sloat, B.R., Hebel, H. and Bilby, C., 2015. 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, 2(2), pp.56–57. DOI: http://doi.org/10.1016/j.nhtm.2014.11.007
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Published on 07 Feb 2015.
Peer Reviewed

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