Possible Neuroprotective Effect of Erythropoietin in Acute Inflammation Induced by Exhaustive Exercise.
Authors: Papassotiriou Ioannis , Tsironi Maria , Premetis Evangelos , Kariyannis Katerina , Skenderi Katerina , Stamoulakatou Alexandra , Kattamis Antonios , Chrousos George 
Published: April 2020

Abstract
Erythropoietin is a glycoprotein hormone produced mainly by interstitial fibroblasts in the kidneys of the adult and by hepatocytes of the foetus. Released into the circulation, erythropoietin makes its way to the bone marrow, where it regulates red cell production by preventing apoptosis of erythroid progenitor cells. Recently, erythropoietin has emerged as a multifunctional growth factor that plays a significant role in the central nervous system (CNS). Both erythropoietin and its receptor are expressed throughout the brain in glial cells, neurons and endothelial cells. Hypoxia and ischaemia have been recognised as important stimuli of erythropoietin expression in the brain. Erythropoietin has potent neuroprotective properties in vivo and in vitro and appears to act in a dual way by directly protecting neurons from ischaemic damage and by stimulating endothelial cells. S-100b, a glial-derived protein is a well-established biomarker for severity of neurological injury and prognosis for recovery. Cell-based and clinical studies have implicated S-100b protein in the initiation and maintenance of a pathological, glial-mediated pro-inflammatory state in the CNS. We studied the possible association between erythropoietin and S-100b in 18 athletes participated in the ultra-distance foot race of the 246Km “Sparthathlon”. This race consists of continuous, prolonged, brisk exercise. We have reported that IL-6, CRP SAA and free plasma DNA levels markedly increased (by 8000-, 152- 108- and 10-fold, respectively) over the baseline at the end of the race1. However, IL-6 levels returned to normal by 48h, while CRP, SAA and free plasma DNA remained elevated. Erythropoietin and S-100b protein levels were determined by means of chemiluminescence (Nichols Institute Diagnostics, CA, USA and Sangtec Medical AB, Bromma, Sweden respectively). The measurements were performed before (phase I), at the end (phase II) and 48h post-race (phase III). Erythropoietin levels at phase I (13.5±6.3 IU/L), were increased significantly at phase II (52.0±52.0 IU/L) and subsequently decreased at phase III (21.0±14.6 IU/L). At the same time period S-100b protein followed the same pattern (phase I: 0.13±0.01 mg/L, phase II: 0.29±0.01 and phase III: 0.13±0.01mg/L). A significantly positive correlation between erythropoietin and S-100b protein was found at phase II (r=0.521, p&lt;0.03), while this correlation was absent in the other two phases (p&gt;0.40 and p&gt;0.08 respectively). Simultaneous measurements of haemoglobin levels showed only a significant drop of haemoglobin at phase III (143.4±12.4, 140.4±13.0 and 124.3±9.5 g/L respectively). Exhaustive exercise induces inflammation and CNS injury, promoting an erythropoietin anti-inflammatory response. We suggest that in this particular inflammatory process, erythropoietin secretion is associated with brain lesions, as they are expressed by the S-100b protein release in the circulation. This is strongly supported by the lack of any association between erythropoietin values and haemoglobin levels.