Ischemic Preconditioning Attenuates Ischemia–Induced Cell Death Through Induction of Erythropoietin in the Rat Retina

Abstract

Abstract: : Purpose:The hematopoietic cytokine, erythropoietin (EPO), has shown to possess neuroprotective properties. We have recently demonstrated upregulation of both EPO as well as its receptor (EPOR) in a model of ischemia–reperfusion in the retina as well as its ability to ameliorate injury in this model. The purpose of this study was to determine if EPO/EPOR play a mechanistic role in the phenomena of ischemic preconditioning (PC). Methods:PC was induced in anesthetized Sprague–Dawley rats by increasing intraocular pressure above systolic arterial pressure for 8 minutes. Retinal ischemia was induced 24 hours after PC or sham PC for a period of 45 minutes. Electrophysiology (ERG) was performed at baseline and again 7 days following ischemia. TUNEL staining was used to quantitate the number of apoptotic cells. In a separate group of experiments, two groups of animals were subjected to PC followed by ischemia: 1) PC–sEPOR (an EPO inhibitor) and 2) PC–denatured sEPOR. Results:One week following ischemia, the animals subjected to PC demonstrated significant preservation of the ERG a and b waves. Similarly, the animals subjected to PC had fewer TUNEL positive cells as compared to the sham–treated controls. When administered immediately following PC, the sEPOR –treated group demonstrated significantly attenuated ERG a and b waves as compared to the denatured sEPOR–treated groups. Conclusions:These results suggest that EPO/EPOR activation is induced by PC in retinal ischemia–reperfusion and contribute to PC neuroprotection by inhibiting apoptosis.

Keywords: apoptosis/cell death • ischemia • cytokines/chemokines