Abstract
The present investigation aimed to evaluate the radiomitigative efficacy of the recombinant human erythropoietin (EPO) against acute radiation syndrome (ARS) in a rat model. Rats were irradiated with a single sublethal dose of γ-radiation (7 Gy; total body irradiation; TBI) on the 1st day of experimental course, then received EPO (5000 IU/kg; i.p.) 24 h after irradiation, and rats were observed for 30 days of survival analysis. Administration of EPO improved 30-day survival, alleviated TBI-induced myelosuppression and pancytopenia, by augmenting lymphocytes and other white blood cells in the peripheral blood of rats, while bone marrow and spleen cellularity were restored. EPO post-exposure treatment alleviated hepatotoxicity biomarkers and restored splenic function. EPO abrogated radiation-induced oxidative stress through the upregulation of the cholinergic anti-inflammatory nicotinic acetylcholine receptor (α-7-nAChR) and the pro-survival Janus kinase-2 and signal transducers and activators of transcription JAK-2/STAT-3 signaling mediated via enhancing nuclear factor erythroid-2 related factor-2 (Nrf-2) cytoprotective machinery in liver and spleen of irradiated rats. Moreover, EPO treatment prevented hepatic and splenic apoptosis. The present study establishes the implication of α-7-nAChR-JAK-2/STAT-3-Nrf-2 signaling cascade in the radiomitigative potential of EPO against ARS.
Keywords:
JAK 2; JAK-2; Nrf 2; Nrf-2; STAT 3; STAT-3; acute radiation syndrome; erythropoietin; syndrome d’irradiation aiguë; érythropoïétine; α-7-nAChR.
MeSH terms
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Acute Radiation Syndrome / drug therapy*
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Acute Radiation Syndrome / immunology
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Acute Radiation Syndrome / metabolism
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Acute Radiation Syndrome / pathology
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Animals
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Body Size / drug effects
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Body Size / radiation effects
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Cell Differentiation / drug effects
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Cell Differentiation / radiation effects
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Cholinergic Agents / pharmacology*
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Cholinergic Agents / therapeutic use
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Cytoprotection / drug effects*
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Cytoprotection / radiation effects
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Dose-Response Relationship, Drug
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Erythropoietin / pharmacology*
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Erythropoietin / therapeutic use
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Gamma Rays / adverse effects
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / radiation effects
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Humans
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Janus Kinase 2 / metabolism
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Leukocytes / cytology
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Leukocytes / drug effects
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Leukocytes / radiation effects
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Liver / drug effects
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Liver / pathology
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Liver / radiation effects
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Male
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NF-E2-Related Factor 2 / metabolism
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Radiation Tolerance / drug effects
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Radiation Tolerance / radiation effects
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Radiation-Protective Agents / pharmacology
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Rats
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Recombinant Proteins / pharmacology
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Recombinant Proteins / therapeutic use
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / radiation effects
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Survival Analysis
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Time Factors
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alpha7 Nicotinic Acetylcholine Receptor / metabolism
Substances
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Cholinergic Agents
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NF-E2-Related Factor 2
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Nfe2l2 protein, rat
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Radiation-Protective Agents
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Recombinant Proteins
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STAT3 Transcription Factor
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alpha7 Nicotinic Acetylcholine Receptor
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Erythropoietin
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Janus Kinase 2