Cholinergic and cytoprotective signaling cascades mediate the mitigative effect of erythropoietin on acute radiation syndrome

The present investigation aimed to evaluate the radiomitigative efficacy of the recombinant human erythropoietin (rhEPO) 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) at the 1st day of experimental course, then received EPO (5000 IU/kg; i.p) 24 hrs post irradiation, rats were observed for 30 days of survival analysis. Administration of EPO improved 30 days survival, alleviated TBI- induced myelosuppression and pancytopenia, by augmenting lymphocytes and WBCs in the peripheral blood of rats, while bone marrow (BM) 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. In conclusion, 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.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author