Recombinant Human Erythropoietin Improves the Neurofunctional Recovery of Rats Following Traumatic Brain Injury via an Increase in Circulating Endothelial Progenitor Cells

Abstract

Previous studies show that circulating endothelial progenitor cells (EPCs) promote angiogenesis, which is a process associated with improved recovery in animal models of traumatic brain injury (TBI), and that recombinant human erythropoietin (rhEPO) plays a protective role following stroke. Thus, it was hypothesized that rhEPO would enhance recovery following brain injury in a rat model of TBI via an increase in the mobilization of EPCs and, subsequently, in angiogenesis. Flow cytometry assays using CD34− and CD133-specific antibodies were utilized to identify alterations in EPC levels, CD31 and CD34 antibody-stained brain tissue sections were used to quantify angiogenesis, and the Morris water maze (MWM) test and the modified Neurological Severity Score (mNSS) test were used to evaluate behavioral recovery. Compared with saline treatment, treatment with rhEPO significantly increased the number of circulating EPCs on days 1, 4, 7, and 14 (P<0.05), improved spatial learning ability on days 24 and 25 (P<0.05), and enhanced memory recovery on day 26 (P<0.05). Moreover, rhEPO treatment decreased mNSS assessment scores on days 14, 21, and 25 (P<0.05). There was a strong correlation between levels of circulating EPCs and CD34− and CD31-positive cells within the injured boundary zone (CD34+ r=0.910, P<0.01; CD31+ r=0.894, P<0.01) and the ipsilateral hippocampus (CD34+ r=0.841, P<0.01; CD31+ r=0.835, P<0.01). The present data demonstrate that rhEPO treatment improved functional outcomes in rats following TBI via an increase in the mobilization of EPCs and in subsequent angiogenesis.

Evaluation of peripheral blood CD34+ cell count in the acute phase of traumatic brain injury and chest trauma

“…Current data on CD34+ cell behaviour during TBI were obtained from five experimental rat studies and only two clinical studies [13][14][15][16][17][18][19]. Similar to this study, these two clinical studies showed that circulating EPCs were lower within the first 48 hours of injury in comparison to those in control subjects [18,19].…”

“…However, their counts increased over time, in particular between D5 and D7, peaked on the 7 th day and reached a plateau 7 days after injury at a level that was significantly higher than those of controls [18,19]. Rat studies had also shown similar results regarding CD34+ cell counts [13][14][15][16][17].…”

“…Although there are several studies which focused on CD34+ cell count after AMI and IS, studies on TBI are limited. There are only seven studies in the literature investigating the relationship between TBI and CD34 cell counts and behaviours using a different paradigm from this one [13][14][15][16][17][18][19] and five of them were experimental studies conducted in rats [13][14][15][16][17]. Most of these experimental studies demonstrated an increase in circulating CD34+ cells after traumatic brain injury (TBI) [13,17].…”

Recombinant Human Erythropoietin Augments Neovascularization Responses in a Neonatal Rat Model of Premature Brain Damage by Phosphatidylinositol 3 Kinase/Akt Pathway

“…[789] Wang et al . [10] found that the rh-EPO increased the mobilization of endothelial progenitor cells (EPCs) and subsequent promotion of angiogenesis.…”

Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Feasible Ingredient for a successful Medical Recipe

“…The recognized ability of EPO to activate protein kinase B (Akt) and subsequent phosphorylation of eNOS in endothelial cells suggests that increased formation of NO could be an important mechanism underlying the therapeutic effect of EPO, although the definitive interaction between EPO and NO is not fully injury produced in several experimental models of brain insult. In this regard, many studies have shown a neuroprotective effect of EPO in models of cerebral ischemia (21,(71)(72)(73)(74)(75), concussive brain injury (76,77), experimental autoimmune encephalomyelitis (78) and kainateinduced seizures (79). In these experimental studies, EPO has been administered both intrathecally or systemically, provoking controversy regarding the ability to cross the BBB.…”