Analysis of the metabolomic profile in serum of irradiated nonhuman primates treated with Ex-Rad, a radiation countermeasure

Abstract

To date, the United States Food and Drug Administration (FDA) has approved four drugs to mitigate hematopoietic acute radiation syndrome and all four are repurposed radiomitigators. There are several additional drug candidates currently under evaluation that may also be helpful for use during a widespread emergency. One possible candidate is Ex-Rad, also known as ON01210, a chlorobenzyl sulfone derivative (organosulfur compound), which is a novel, small-molecule kinase inhibitor with demonstrated efficacy in the murine model. In this study, we have evaluated the metabolomic and lipidomic profiles in serum samples of nonhuman primates (NHPs) treated with Ex-Rad after exposure to ionizing radiation. Two different dose administration schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation), were used and evaluated using a global molecular profiling approach. We observed alterations in biochemical pathways relating to inflammation and oxidative stress after radiation exposure that were alleviated in animals that received Ex-Rad I or Ex-Rad II. The results from this study lend credence to the possible radiomitigative effects of this drug possibly via a dampening of metabolism-based tissue injury, thus aiding in recovery of vital, radiation-injured organ systems.

Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure

“…Therefore, the NHPs were randomly divided into 3 different treatment groups and were then exposed to a single dose of 7.2 Gy of 60 Co gamma-radiation prior to drug administration. The first group received vehicle (administered 24 and 36 h post-irradiation), the second group received Ex-Rad at 24 and 36 h post-irradiation (Ex-Rad I), and the third group received Ex-Rad 48 and 60 h post-irradiation (Ex-Rad II) . Serum samples from blood were collected (samples were analyzed at 48 and 60 h post-irradiation for the Ex-Rad I group, and 96 h post-irradiation in the Ex-Rad II group) and proteomic analysis was accomplished utilizing nanoscale ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry (NanoUPLC-MS/MS profiling methods) (Figure ).…”

“…As previously published, all animals were exposed to 7.2 Gy 60 Co gamma-radiation. 28 A total of 120 serum samples were collected from three groups at study day (SD) −4 and at 24, 36, 48, and 96 h post-irradiation. However, for the proteomic profile analyses, 3 total time points (48 and 96 h for Ex-Rad I and only 1 time point, 96 h for Ex-Rad II) were analyzed.…”

“…The drug preparation and administration have been described earlier. 28 Following irradiation, the NHPs were injected according to their assigned treatment regimen. The total dose administered was 40 mg/kg; the precise injection volume was calculated based on body weight at SD0 for each individual animal.…”

“… 27 Recently, we have demonstrated using a global metabolomics molecular profiling approach with alterations in biochemical pathways relating to inflammation and oxidative stress in NHPs after irradiation that was alleviated by treatment with Ex-Rad. 28 , 29 …”

Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration

“…We conducted both targeted and untargeted metabolomics in our Metabolomics Shared Resource (Georgetown University), as previously described [ 17 ]. For untargeted analyses, an Acquity UPLC system connected to an electrospray ion source coupled with a quadrupole time-of-flight mass spectrometer (ESI-Q-TOF, Xevo-G2S (Waters Corporation, Milford, MA, USA) operating in positive and negative ionization mode was used.…”