Imidazolyl ethanamide pentandioic acid promotes hematopoietic recovery following sublethal radiation in a murine model.

Abstract

Purpose: Hematopoietic acute radiation syndrome (H-ARS) results from bone marrow (BM) damage, leading to depletion of myeloid and lymphoid cells and increasing infection, hemorrhage, and mortality risks. Imidazolyl ethanamide pentandioic acid (IEPA), an orally bioavailable molecule, alleviates chemotherapy-induced myelosuppression and may similarly mitigate H-ARS. This study examines whether IEPA, alone or with granulocyte-monocyte colony-stimulating factor (GM-CSF), promotes recovery of hematopoietic stem and progenitor cells (HSCs/HPCs) after sublethal total body irradiation (TBI).

Materials and methods: Mice received 5 Gy TBI followed by vehicle, IEPA (days 1-3), GM-CSF (days 1-5), or IEPA+GM-CSF. Recovery was assessed by body weight, blood counts, flow cytometry, clonogenic assays, BM megakaryocytes, and splenic CD34⁺ cells.

Results: IEPA increased body weight 2.5-fold by day 7, while IEPA+GM-CSF showed 2.5-fold and 3.3-fold increases on days 7 and 21, respectively. IEPA promoted recovery of HSCs/HPCs, multipotent progenitors (MPP2), myeloid and lymphoid progenitors, BM megakaryocytes, and splenic CD34+ cells. IEPA+GM-CSF improved in vitro self-renewal but offered no major in vivo advantage over IEPA alone, except for a 159-fold recovery in erythroid progenitors. All treatments reduced γ-H2AX expression in Lin- and HPCs on day 21, indicating less DNA damage.

Conclusions: Our results reveal that IEPA attenuated radiation-induced DNA damage and improved recovery of HSCs/HPCs, myeloid as well as lymphoid progenitors, accompanied by increases in platelets in blood, megakaryocytes in BM and splenic CD34⁺ cells. IEPA shows promise as a radiation mitigator, with no significant benefit observed from adding GM-CSF.