Both heat acclimation (HA) and post-injury treatment with recombinant human
erythropoietin (Epo, rhEpo, exogenous Epo) are neuroprotective against
traumatic brain injury (TBI). Our previous data demonstrated that HA-induced neuroprotection includes improved functional recovery and reduced
cerebral edema formation. Additionally, in earlier Western-blot analyses, we found that HA mice display increased expression of the specific
erythropoietin receptor (EpoR) and of
hypoxia-inducible factor-1 alpha (HIF-1 alpha), the inducible subunit of the
transcription factor, which regulates Epo gene expression, but not of Epo itself. In light of this, the aim of the current study was threefold: (1) to assess Epo expression in the
trauma area and hippocampus following HA, rhEpo administration, or combined HA-rhEpo treatment, using immunohistochemical methods that offer enhanced anatomical resolution; (2) to examine the effects of endogenous and exogenous Epo on
edema formation in normothermic (NT) mice; and (3) to evaluate the effects of exogenous Epo administration on neuroprotective outcome measures in HA animals. HA induced enhanced expression of endogenous Epo in the
trauma area and the hippocampus. Treatment with anti-Epo antibody given to NT mice increased
edema formation, whereas rhEpo induced no beneficial effect. Cognitive performance testing and immunohistochemical findings reinforced HA and rhEpo as separate protective interventions but showed no advantage to combining the two strategies. We therefore suggest that HA-induced neuroprotection is shaped by pre-existing mediators but cannot be modified by post-injury treatment aimed at increasing the levels of
neuroprotective agents.