Evidence of a hormetic-like cytoprotective effect by erythropoietin in the SH-SY5Y cell model of oxygen-glucose deprivation.

Erythropoietin is recognized as a neuroprotective agent for the brain and it has been suggested that may have a biphasic hormetic-like response, with low to intermediate doses providing greater cytoprotective benefits, whereas high doses have been associated with undesirable side effects related to its systemic application; however, it is unknown whether this occurs in brain and what mechanisms could be implicated. This study investigated the potential hormetic effects of recombinant human erythropoietin (rhEPO) on SH-SY5Y cells subjected to oxygen and glucose deprivation (OGD) and reoxygenation (reox) injury. We developed an in vitro protocol to investigate the rhEPO's hormetic effect under conditions similar to ischemic stroke. Cell vitality assays were conducted, and the gene and protein expression of EPO, erythropoietin receptor (EPOR), β-common receptor (βcR), and Bcl-xL were analyzed. We found that all evaluated doses of rhEPO exhibited a cytoprotective effect on cells treated during the 24 h reox period. Notably, the intermediate 50 IU/mL dose showed significantly higher cell vitality than the high 100 IU/mL dose (p < 0.05), suggesting a potential hormetic-like effect. Interestingly, both EPO and EPOR mRNA levels increased after OGD, followed by an increase in EPOR protein levels after the reox period. However, no changes were observed in EPOR or Bcl-xL mRNA expression after 4 and 8 h of rhEPO treatment during reox. Finally, βcR mRNA expression was not detected in any group. While further research is needed, these results suggest that rhEPO treatment may exert a hormetic-like effect and offer cytoprotection against ischemic stroke-like injury.