Erythropoietin (EPO), recognized for its central role in erythropoiesis, also mediates neuroprotection when the recombinant form (r-Hu-EPO) is directly injected into ischemic rodent brain. We observed abundant expression of the EPO receptor at brain capillaries, which could provide a route for circulating EPO to enter the brain. In confirmation of this hypothesis, systemic administration of r-Hu-EPO before or up to 6 h after focal brain ischemia reduced injury by Ϸ50 -75%. R-Hu-EPO also ameliorates the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis, and the toxicity of kainate. Given r-Hu-EPO's excellent safety profile, clinical trials evaluating systemically administered r-Hu-EPO as a general neuroprotective treatment are warranted. E rythropoietin (EPO) and its receptor (EPO-R) function as primary mediators of the normal physiologic response to hypoxia. EPO, a glycoprotein that increases red cell mass to improve tissue oxygenation, is produced by the kidney in response to hypoxia. Recombinant human EPO (r-Hu-EPO) is effective and widely used for the treatment of anemia associated with renal failure, HIV infection, cancer, and surgery. However, like other members of the cytokine superfamily to which EPO and its receptor belong, both are expressed by other tissues, including the nervous system. Similar to its regulation in the periphery, EPO within the central nervous system is inducible by hypoxia (1-4). An in vivo neuroprotective function for EPO has been demonstrated by the observation that direct intracerebraventricular injection of r-Hu-EPO in advance of hypoxic͞ ischemic stress offers significant protection of neuronal tissue (5-7). A critical neuroprotective role for endogenous EPO in the central nervous system has been confirmed by the administration of soluble EPO-R, which neutralizes EPO, consequently exacerbating ischemic stress and increasing tissue injury (7).Hypoxia may not be the only relevant stimulus for brain EPO production, however, as metabolic disturbances, including hypoglycemia and strong neuronal depolarization, generate mitochondrial reactive oxygen species that may increase brain EPO expression through hypoxia inducible factor 1 (8). EPO may thus protect nervous tissue under any condition characterized by a relative deficiency of ATP in the face of increased metabolic demands. EPO has been shown to exhibit classic neurotrophic effects in vivo and in vitro (2, 9-11). The mechanism of action of EPO in erythropoiesis, neuroprotection, and neurotrophic effects ultimately may involve activation of the bcl-x family of antiapoptotic genes, promoting survival rather than apoptosis (12)(13)(14).Despite the demonstrated benefit of intrathecally administered r-Hu-EPO in preventing ischemic neuronal damage, direct delivery of r-Hu-EPO into the brain is not a practical approach in most clinical contexts. Systemic delivery of r-Hu-EPO has not been evaluated because of the perception that the brain EPO system is parallel and distinct from the control ...
