Intranasal Erythropoietin Protects CA1 Hippocampal Cells, Modulated by Specific Time Pattern Molecular Changes After Ischemic Damage in Rats

Erythropoietin, a multitarget molecule exhibited neuroprotective properties, especially against cerebral ischemia. However, little effort has been made to determinate both the administration pathway and doses that diminishes neuronal damage. In this study, we investigate the effect on CA1 region of different intranasal doses of rHuEPO (500, 1000 and 2500IU/kg) applied in distinct post-damage times (1, 6, and 24h) against ischemic cellular damage. Furthermore, most effective dose and time were used to evaluate gen and protein expression changes in 3 key molecules (EPO, EPOR, and beta cR). We established that CA1-region present histopathological damage in this ischemia model and that rHuEPO protects cells against damage, particularly at 1000IU dose. Molecular data shows that EPO and EPOR gene expression are upregulated in a short term after damage treatment with rHuEPO (1h); oppositely, BcR is upregulated in ischemic and Isc+EPO. Protein expression data displays no changes on EPO expression in evaluated times after treatment, but a tendency to increase 24h after damage; in the opposite way, EPOR is upregulated significantly 6h after treatment and this effect last until 24h. So, our data suggest that a single intranasal dose of rHuEPO (1h post-injury) provides histological neurorestoration in CA1 hippocampal region, even if we did not observe a dose-dependent dose effect, the medium dose evaluated (1000UI/kg of b.w.) was more effective and sufficient for induces molecular changes that provides a platform for neuroprotection.