Posted May 24, 2022

Louis M. Pelus, Ph.D. and Christie M. Orschell, Ph.D., Indiana University

Acute exposure to ionizing radiation (e.g., X-rays, gamma rays) at high doses may cause acute and chronic injuries to various organs.¹ The hematopoietic system within bone marrow, which is responsible for generating billions of blood cells every day, is the most sensitive organ to radiation damage.² Bone marrow damage following high dose radiation manifests as hematopoietic acute radiation syndrome (H-ARS), and is one of several �Illnesses Related to Radiation Exposure,� a Fiscal Year 2014 (FY14) Peer Reviewed Medical Research Program (PRMRP) Topic Area. Loss of red blood cell and platelet production may lead to anemia and hemorrhage, while decreased white blood cell production reduces immunity and may lead to uncontrolled infection; all are contributors to death following severe radiation exposure. Currently, the U.S. Food and Drug Administration (FDA) has approved the use of only four treatments following radiation exposure. While these drugs act to mitigate injury following radiation exposure, none are approved to be administered prior to radiation exposure, i.e., for radioprotection. One drug candidate, 16,16-dimethyl prostaglandin E₂(dmPGE₂), has been shown to increase survival and reduce bone marrow damage when administered prior to radiation exposure, although its mechanism of action remained unknown, which created a hurdle for its potential use for radioprotection. Drs. Louis Pelus and Christie Orschell aimed to address these challenges through an FY14 PRMRP Investigator-Initiated Research Award - Partnering Principal Investigator Option, and they continued their studies with an FY18 Military Medical Research and Development Award through the Radiation Health Effects Research Program.

In a 2020 Stem Cell Reports publication, Drs. Pelus and Orschell reported on the molecular mechanisms of action of dmPGE₂ given prior to radiation exposure in mice. They found that mice treated with dmPGE₂ retained more bone marrow volume and healthy cells than control mice. Further, bone marrow from mice that received dmPGE₂ prior to radiation exposure could continue to produce red blood cells, white blood cells, and platelets. This was attributed to the protection of hematopoietic stem cells (HSCs), which can mature into any of these blood cell lineages. Drs. Pelus and Orschell found that HSCs in mice pre-treated with dmPGE₂ showed little DNA damage from radiation compared to untreated mice that showed significant DNA damage and increased cell death. The investigators ultimately determined that dmPGE₂ treatment inhibited or prevented upregulation of three major signaling networks induced by irradiation, which prevented cell death in irradiated HSCs.

Drs. Pelus and Orschell continued their investigation of dmPGE₂, exploring how dmPGE₂ could be used as a medical countermeasure and radioprotective agent. As described in a 2021 Radiation Research publication, they showed that mice that received dmPGE₂ between 3 hours and 15 minutes before radiation exposure were nearly completely protected from deadly radiation exposure, while those receiving doses 24 hours before were not. Specifically, dmPGE₂ treatment at 30 minutes before radiation exposure resulted in faster recovery of red blood cells and white blood cells compared to untreated mice. Treatment with dmPGE₂ at 6 and 24 hours after radiation exposure also increased survival, while treatment at 3 hours after exposure showed no benefit. Interestingly, dmPGE₂ treatment demonstrated equal levels of radioprotection in pediatric and adult mice but showed less protection in geriatric mice. Drs. Pelus and Orschell also confirmed their earlier observations that the prostaglandin E receptor EP4 is one of the PGE2 receptors involved in the radioprotective effects of dmPGE2. Overall, their data suggest that dmPGE2 treatment is effective during a specific window of time either before or after radiation exposure. Finally, in a 2022 Stem Cell Reviews and Reports publication, they further reported on the crucial role of the histone deacetylase enzyme Sirtuin 1 (Sirt1). Sirt 1 facilitates cellular protective mechanisms against oxidative stress, cell senescence, and cell death, and also stimulates autophagy, a process by which cells recycle spare or damaged parts. Their findings indicate that dmPGE2 treatment enhances Sirt1 activity, which contributes to its radioprotective effects.

These findings have advanced the understanding of dmPGE₂'s potential as a radioprotective agent and medical countermeasure. Drs. Pelus and Orschell have identified cellular and molecular mechanisms of action for dmPGE₂ in bone marrow and defined administration windows for both H-ARS radioprotective and radiation injury mitigation effects. This research moves the field closer to the goal of achieving FDA approval for the use of dmPGE₂ to both prevent and treat H-ARS and the delayed effects of acute radiation exposure. If approved, dmPGE₂ would be the first radioprotective agent and medical countermeasure available for Service Members, first responders, and others at risk for acute radiation exposure.

References:

¹ https://www.who.int/news-room/questions-and-answers/item/radiation-ionizing-radiation

² https://www.mayoclinic.org/diseases-conditions/radiation-sickness/symptoms-causes/syc-20377058

Publications:

Patterson AM, Liu L, Sampson CH, et al. 2020. A single radioprotective dose of prostaglandin E₂ blocks irradiation-induced apoptotic signaling and early cycling of hematopoietic stem cells. Stem Cell Reports 15(2):358�373.

Patterson AM, Wu T, Chua HL, et al. 2021. Optimizing and profiling prostaglandin E₂ as a medical countermeasure for the hematopoietic acute radiation syndrome. Radiation Research 195(2):115�127.

Liu L, Li H, Patterson AM, et al. 2022. Upregulation of SIRT1 contributes to dmPGE₂-dependent radioprotection of hematopoietic stem cells. Stem Cell Reviews and Reports 18:1478�1494.

Links:

Public and Technical Abstracts: Using the Prostaglandin E₂ Signaling Cascade to Mitigate the Effects of Acute and Delayed Radiation Exposure to Hematopoiesis and Blood Stem Cell Function

Public and Technical Abstracts: Further Development of dmPGE₂ as an Effective Radioprotectant and Radiomitigator for H-ARS and DEARE in Fulfillment of the Requirements for Product Development Under the Animal Rule

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