Mitigative efficacy of the clinical dosage administration of granulocyte colony-stimulating factor and romiplostim in mice with severe acute radiation syndrome

Abstract Background: It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.Methods: We assessed the clinical dosage administration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival study evaluated by the log-rank test. Bone marrow and splenic cells were collected on the 21st day, when 1 week have passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assay using sera was performed for cell senescence and inflammation status analyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.Results: The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kg RP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence and inflammation markers. Conclusions: This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.

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Mitigative Efficacy of the Clinical Dosage Administration of Granulocyte Colony-stimulating Factor and Romiplostim in Mice With Severe Acute Radiation Syndrome

10.21203/rs.3.rs-34653/v1 ◽

2020 ◽

Author(s):

Masaru Yamaguchi ◽

Marino Suzuki ◽

Moeri Funaba ◽

Akane Chiba ◽

Ikuo Kashiwakura

Keyword(s):

Cell Apoptosis ◽

Cell Senescence ◽

The Body ◽

Acute Radiation ◽

Related Factor ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Acute Radiation Syndrome ◽

Stimulating Factor ◽

Dosage Administration

Abstract Background:It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.Methods:We assessed the clinical dosageadministration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival studyevaluated by the log-rank test. Bone marrow and splenic cellswere collected on the 21st day, when1 week have passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assayusing serawas performed for cell senescence and inflammationstatusanalyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.Results: The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kgRP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence and inflammation markers. Conclusions:This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.

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