Optimizing and Profiling Prostaglandin E-2 as a Medical Countermeasure for the Hematopoietic Acute Radiation Syndrome

Identification of medical countermeasures (MCM) to mitigate radiation damage and/or protect first responders is a compelling unmet medical need. The prostaglandin E-2 (PGE(2)) analog, 16,16 dimethyl-PGE(2) (dmPGE(2)), has shown efficacy as a radioprotectant and radiomitigator that can enhance hematopoiesis and ameliorate intestinal mucosal cell damage. In this study, we optimized the time of administration of dmPGE(2) for protection and mitigation against mortality from the hematopoietic acute radiation syndrome (H-ARS) in young adult mice, evaluated its activity in pediatric and geriatric populations, and investigated potential mechanisms of action. Windows of 30-day survival efficacy for single administration of dmPGE(2) were defined as within 3 h prior to and 6-30 h after total-body gamma irradiation (TBI). Radioprotective and radio-mitigating efficacy was also observed in 2-year-old geriatric mice and 6-week-old pediatric mice. PGE(2) receptor agonise studies suggest that signaling through EP4 is primarily responsible for the radioprotective effects. DmPGE(2) administration prior to TBI attenuated the drop in red blood cells and platelets, accelerated recovery of all peripheral blood cell types, and resulted in higher hematopoietic and mesenchymal stem cells in survivor bone marrow. Multiplex analysis of bone marrow cytokines together with RNA sequencing of hematopoielic stem cells indicated a pro-hematopoiesis cytokine milieu induced by dmPGE(2), with IL-6 and G-CSF strongly implicated in dmPGE(2)-mediated radioprotective activity. In summary, we have identified windows of administration for significant radio-mitigation and radioprotection by dmPGE(2) in H-ARS, demonstrated survival efficacy in special populations, and gained insight into radioprotective mechanisms, information useful towards development of dmPGE(2) as a MCM for first responders, military personnel, and civilians facing radiation threats. (C) 2021 by Radiation Research Society