Dose Optimization and Receptor Utilization of Prostaglandin E Analogs for Radioprotection and Radiomitigation of H-ARS and DEARE

The prostaglandin E2 (PGE2) analog 16, 16-dimethyl-PGE2 (dmPGE2) administered prior to lethal irradiation protects against mortality from the hematopoietic acute radiation syndrome (H-ARS) and the chronic delayed effects of acute radiation exposure (DEARE). DmPGE2 also enhances hematopoietic stem cells (HSC) survival and hematopoietic recovery when used as a radiomitigator for H-ARS, but with less efficacy than when used as a radioprotectant. DmPGE2 elicits dose-dependent transient locomotor depression in mice and is currently used at a near maximum tolerated dose (MTD), factors that may limit its widespread use as a medical countermeasure (MCM) for unwanted radiation exposure. To explore modalities to improve survival in radiomitigation and limit side effects in both radioprotection and radiomitigation, we sought to identify the minimum therapeutically effective dose (MTED) of dmPGE2 and related EP receptor agonists and analogs in our H-ARS and DEARE models developed in young adult C57BL/6J mice. Doses of dmPGE2 as low as 10 μg/mouse provided significant H-ARS radioprotection equivalent to 35 μg/mouse, with reduced locomotor effects. However, lower doses were less effective in mitigating hematopoietic DEARE, indicating dose-dependent long-term hematopoietic recovery. Co-stimulation of EP3 and EP4 receptors using selective agonists sulprostone (EP3) and rivenprost (EP4) showed similar radioprotective efficacy as dmPGE2, but with less locomotor effect. The PGE1 analog misoprostol also conferred robust H-ARS radioprotection with minor locomotor effect and accelerated hematopoietic recovery, presenting a cost-effective, FDA-approved alternative. Split-dose administration of dmPGE2 as a radiomitigator (20 μg/mouse at 24 and 36 h post-irradiation) significantly enhanced survival compared to a single 35 μg dose, with similar locomotor effects but shorter duration. In conclusion, our findings suggest that dose optimization and selective EP receptor targeting can enhance the therapeutic results of prostaglandin-based MCM for radiation injury while minimizing locomotor side effects, with misoprostol standing out as a candidate MCM for radioprotection and radiomitigation due to its efficacy, minor locomotor effect, stability, and existing approval status.