An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice

Abstract

The thrombopoietin receptor agonist romiplostim (RP) was recently approved by the US Food and Drug Administration for improving survival in patients acutely exposed to myelosuppressive doses of radiation. Our previous studies with mice have shown that RP administration after lethal irradiation not only completely rescues irradiated mice but also shows mitigative effects on their hematopoiesis and multiple organ injury, including that of the lung, bone marrow, small intestine, and liver. However, the mechanism by which RP functions as a radiomitigator remains unclear. In the present study, we applied a metabolomics approach, which has the ability to reflect the status of an organism directly and accurately, helping to elucidate the biology of treatment responses. Our results showed that the disruption of several metabolites and pathways in response to total body irradiation was partially corrected by RP administration. Notably, RP-corrected metabolites and pathways have been reported to be indicators of DNA damage and lung, bone marrow, small intestine, and liver injury. Taken together, the present findings suggested that the radiomitigative effect of RP is partially involved in the recovery of organ injury, and the identified metabolites may be a useful biomarker of the survival likelihood following radiation exposure.

Metabolomics and transcriptomics based multi-omics integration reveals radiation-induced altered pathway networking and underlying mechanism

“…In the present study, we have observed upregulation of amino acid at 24 h post radiation exposure which is in concurrence with the previous studies that had also shown changes in amino acids like valine, proline, glutamate, histidine, alanine, arginine, alanine, and asparagine, tyrosine in NHP serum after IR 39 . Recently, changes in histidine metabolism have also been observed by Sato et al, though the changes observed were in contrast to our findings 41 . Some of these changes complement pathways based on transcriptomic data for their validation.…”

The Acute Radiation Syndrome-Mitigator Romiplostim and Secreted Extracellular Vesicles Improved Survival in Mice Acutely Exposed to Myelosuppressive Doses of Ionizing Radiation

“…Our previous studies showed that the thrombopoietin receptor agonist RP, a drug used for the treatment of idiopathic thrombocytopenic purpura, completely rescued mice exposed to lethal TBI [13], and the radio-mitigative effects of RP were also reported by other groups [11,12]. However, the mechanism of action of RP cannot be explained by signal transduction via the thrombopoietin receptor alone, and significant efforts were made to understand the mechanisms for achieving this life-saving effect [15][16][17][18]. In the present study, to further elucidate the radio-mitigative effect mechanism of the domestically approved drug RP, we focused on EVs that were collected from the sera of mice that overcame severe ARS and avoided mortality with the administration of RP, and performed a basic study on the radiomitigative and life-saving effects of their EVs on mice acutely exposed to myelosuppressive doses of ionizing radiation.…”

“…The thrombopoietin receptor agonist RP (Romiplate ® , Kyowa Kirin, Tokyo, Japan), as an ARS mitigator, was intraperitoneally administered once daily for 3 consecutive days to irradiated mice, starting immediately after TBI (within 2 h, 24 h, and 48 h post-TBI). The applied dose of RP was 50 µg/kg of body weight/day prepared with Normal Saline Solution (NSS; Otsuka Pharmaceutical, Tokyo, Japan) as the vehicle [13][14][15][16][17][18]. In addition to mice that received both TBI and RP (TBI + RP group), mice treated with TBI and NSS (TBI + NSS group), mice treated with RP only (0 Gy + RP group), and those treated with NSS only (0 Gy + NSS group) were prepared in this study.…”

“…The thrombopoietin receptor agonist RP was recently approved by the FDA to improve survival in patients acutely exposed to myelosuppressive doses of radiation [11][12][13][14][15][16][17][18]. To confirm the radio-mitigative and life-saving effects of RP in our mouse model of severe ARS caused by lethal TBI, we monitored the changes in body weight and the level of animal survival over a period of 30 days (Figure 1A).…”

“…Among these efforts, studies sponsored by the National Institute of Allergy and Infectious Diseases demonstrated that the administration of Nplate from Amgen (Romiplostim; RP), originally licensed in 2008 for the treatment of immune thrombocytopenia, increased platelet counts and improved survival in preclinical models of lethal radiation exposure [11,12]. We are also the first in the world to report the efficacy of RP as an ARS mitigator, and we have obtained many findings (e.g., enhanced DNA damage repair and antioxidant stress-responsive transcriptional factor, increased megakaryocyte hematopoiesis and mesenchymal stromal/stem cells (MSCs) in mouse hematopoietic tissues, and the suppression of vascular endothelial damage), in addition to dramatically improved survival rate of lethal total-body ionizing radiation (TBI)-exposed mice [13][14][15][16][17][18]. Although it was recently approved by the FDA as a medical countermeasure against radiation for hematopoietic ARS based on a series of successful, experimental, animal-based drug efficacy studies conducted under the Animal Rule, the detailed action mechanism of the radio-mitigative and life-saving effects of RP, which has a blood half-life of only several tens of hours, remains unclear.…”