Systemic injection of recombinant human erythropoietin after focal cerebral ischemia enhances oligodendroglial and endothelial progenitor cells in rat brain

Erythropoietin (EPO) has been demonstrated the ability of recombinant human erythropoietin (r-Hu-EPO), when administered intracerebro-ventricularly, to improve stroke outcome through the reduction of stroke damage. In a brain ischemic model, however, systemic administration of r-Hu-EPO has not been intensely investigated given that in general, large glycosylated molecules have been deemed incapable of crossing the blood-brain barrier. In this study, administration of r-Hu-EPO for 4 days, intraperitoneally aft er ischemia-reperfusion (I-R) increased the number of bromodeoxyuridine (BrdU)-positive cells in the penumbra ($10.1{\pm}1.4$, n=5, P<0.05) and in the subventricular zone (SVZ) of the lateral ventricle (LV) ($25{\pm}2.7$, n=5, P<0.05) as compared with those of I-R (penumbra: $2.5{\pm}0.7$; SVZ of LV: $3.8{\pm}1.5$). A significant increase of BrdU-positive cells in these areas was coincident with a strong immunoreactivity of oligodendrocyte progenitor cell marker (2', 3'-cyclic nucleotide 3'-phosphodiesterase). Furthermore, r-Hu-EPO administration increased the number of BrdU-positive cells in the choroid plexus ($7.8{\pm}2.3$, n=5, P<0.05) and in cerebral blood vessels ($3.5{\pm}1.3$, n=5, P<0.05) when compared with those of I-R (choroid plexus: $1.2{\pm}0.5$; cerebral blood vessels: $0.6{\pm}0.1$). These results suggest that, even when systemically administered, r-Hu-EPO may have therapeutic potential for stroke via the proliferation of oligodendroglial and endothelial progenitor cells.