Erythropoietin exerted neuroprotection against cardiac ischemic/reperfusion injury by ameliorating oxidative stress, mitochondrial dysfunction, microglial activation, apoptosis and necroptosis

Abstract

Acute cardiac ischemic/reperfusion (I/R) injury not only caused cardiac dysfunction, but also caused the development of brain dysfunction and pathology, including blood brain barrier breakdown, increased brain oxidative stress, brain mitochondrial dysfunction, brain mitochondrial dynamic imbalance, hippocampal dysplasticity, and hippocampal apoptosis. Previous studies demonstrated that erythropoietin (EPO), an important hormone for red blood cell production in response to low oxygen, exerted neuroprotective effect following cerebral ischemic-reperfusion injury. However, the effect of erythropoietin administration on brain pathology in response to cardiac I/R injury have not been investigated. Forty male Wistar rats were divided into five groups (n=8/group) including 1) control group, 2) I/R operation with vehicle (0.9% sodium chloride solution at 15 minutes prior to I/R protocol, as Vehicle), 3) I/R operation with pretreatment (5000 IU/kg at 15 minutes before I/R protocol as PEPO), 4) I/R operation with EPO administration during cardiac ischemia (5000 IU/kg at 15 minutes after left anterior descending (LAD) coronary artery ligation as DEPO), and 5) I/R operation with EPO administration at the onset of reperfusion (5000 IU/kg at the beginning of reperfusion as REPO). Acute cardiac I/R injury increased both peripheral and brain oxidative stress, caused brain mitochondrial dysfunction, increased Alzheimer's related protein, increased microglial activation, developed synaptic dysplasticity, increased apoptotic and necroptotic signaling (p<0.05, Figure 1). Given the EPO prior to I/R operation, but not during and at the onset of reperfusion, decreased both peripheral and brain oxidative stress, attenuated brain mitochondrial dysfunction, and decreased Alzheimer's related protein (p<0.05, Figure 1). Moreover, pretreatment with EPO had better efficacy to preserve microglial morphology and attenuate synaptic dysplasticity compared to given the EPO during and at the onset of reperfusion (p<0.05, Figure 1). Interestingly, administration of EPO at all time points equally decreased apoptotic and necroptotic signaling against cardiac I/R injury (p<0.05, Figure 1). These findings suggest that erythropoietin exert neuroprotection against acute cardiac ischemic/reperfusion injury through decreased oxidative stress, mitochondrial dysfunction, Alzheimer's related protein, microglial hyperactivity, synaptic dysplasticity, apoptosis and necroptosis. The present study provided information contribute to the clinical application of EPO to ameliorate brain pathologies under cardiac I/R condition.