Abstract: Objective To investigate the effect of intra-arterial infusion of erythropoietin alone or in combination with tissue plasminogen activator on rats following focal cerebral ischemia/reperfusion, and examine whether the effects are dependent on endoplasmic reticulum stress. Methods Sixty male rats were randomly divided into 5 groups: sham operation (sham), untreated control rats (ischemic animals), erythropoietin(EPO)-treated (onset of reperfusion, 800IU/kg), tissue plasminogen activator (tPA)-treated (onset of reperfusion, 10 mg/kg)and EPO+tPA-treated rats. Middle cerebral artery occlusion (MCAO) was induced by occluding the right middle cerebral artery. Infarct size, neurological deficits, and the levels of phosphorylated form of eukaryotic initiation factor 2α(p-eIF2α) and C/EBP-homologous protein (CHOP) were measured at 24 hours after reperfusion. Results Compared with the control animals, EPO alone (P<0.05) or in combination with tPA (P<0.05) significantly decreased infarct volume, lessened defective degree of neurological function, and reduced expression levels of p-eIF2α and CHOP. tPA+EPO(P<0.05) significantly decreased infarct volume, lessened defective degree of neurological function, and reduced expression levels of p-eIF2α and CHOP when compared with the tPA-treated animals. Immunofluorescent staining revealed co-localization of CHOP and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in cerebral cortical neurons. Conclusion Based on our data, treatment with EPO or EPO + tPA at the onset of reperfusion by intra-arterial infusion may be considered as a useful candidate to alleviate I/R injury and the potential mechanism underlying the role of EPO in a transient focal cerebral ischemia model in rats may be attributable to suppression of endoplasmic reticulum stress, which preserve neuronal cell viability and attenuate behavioral deficits.

Key words: erythropoietin, tissue plasminogen activator, eIF2α, C/EBP-homologous protein