Systemically Administered Erythropoietin Protects the Irradiated Brain Through Anti-Inflammatory Mechanisms

Abstract

Purpose/Objective: Injury of the central nervous system (CNS) represents a major cause of morbidity of clinical radiotherapy (XRT). Erythropoietin (EPO) is widely used in the treatment of anemia associated with cancer. When administered systemically, it has been shown to be neuroprotective against a wide variety of CNS insults. Materials/Methods: We recently showed that ip EPO (5000 u/Kg) administered 1 h after cranial XRT reduced both early and late behavioral and neurocognitive impairment in mice. Given the pleiotropic effects of EPO in the injured CNS, experiments were performed to determine the underlying mechanisms of these neuroprotective effects of EPO in mouse brain following cranial XRT. Adult C57BL/129S mice were given graded single doses of X-ray to the whole brain. EPO at doses of 1000, 5000 or 10,000 μ/Kg was given i.p.1 h after XRT. XRT induced a robust apoptotic response in the subgranular zone of the mouse hippocampal dentate gyrus at 8 h. EPO did not modify the apoptotic response induced by XRT. At 2 months after 17 Gy, there was inhibition of neurogenesis in the hippocampus measured by dual labeled BrdU and NeuN positive cells quantified using non-biased stereological counting. BrdU was given daily × 7 days one month after XRT to label newly born neurons. Results: EPO given 1 h after 17 Gy did not reverse the inhibition of neurogenesis. XRT induced a dose-dependent early increase in the expression of inflammatory genes in mouse brain as measured by real time PCR. These included Cox2, iNOS, Hmox1, ICAM1, E and P selectin. EPO was found to reduce the expression of these inflammatory genes at 24h after XRT compared to saline irradiated controls. At 2 months after 17 Gy, EPO also resulted in a decrease in the expression of inflammatory genes isolated from the hippocampus only compared to saline irradiated controls. Conclusions: These findings are consistent with the hypothesis that anti-inflammatory effects of EPO contribute to its neuroprotective effects following XRT. We conclude that systemically administered EPO, through anti-inflammatory mechanisms, has the potential to ameliorate the damage of the CNS induced by cranial XRT.