Erythropoietin is known as the requisite cytokine for red blood cell production. Its receptor, expressed at a high level on erythroid progenitor/precursor cells, is also found on endothelial, neural, and other cell types. Erythropoietin and erythropoietin receptor expression in the developing and adult brain suggest their possible involvement in neurodevelopment and neuroprotection. During ischemic stress, erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the blood oxygen carrying capacity, stimulate nitric oxide production to modulate blood flow and contribute to the neurovascular response, or act directly on neural cells to provide neuroprotection as demonstrated in culture and animal models. Clinical studies of erythropoietin treatment in stroke and other diseases provide insight on safety and potential adverse effects and underscore the potential pleiotropic activity of erythropoietin. Herein, we summarize the roles of EPO and its receptor in the developing and adult brain during health and disease, providing first a brief overview of the well-established EPO biology and signaling, its hypoxic regulation, and role in erythropoiesis. 1. Introduction Erythropoietin (EPO) is produced primarily in the adult kidney and secreted into the circulation to regulate red blood cell production in the bone marrow. EPO stimulates erythroid progenitor cell survival, proliferation, and differentiation to satisfy the daily requirement of about 200 billion new red blood cells due in part to the limited red blood cell lifespan of 120 days. Human recombinant EPO has been used clinically for more than 2 decades to treat anemia associated with conditions such as chronic kidney disease, antiviral HIV therapy, and cancer patients on chemotherapy. EPO production is hypoxia inducible and thus increases during anemia and hypoxic stress. Interestingly, EPO production has also been detected in brain in response to hypoxic stress. The finding that EPO receptor (EpoR) expression extends beyond hematopoietic tissue to include neural and endothelial cells and the accumulating evidence for EPO antiapoptotic properties such as its neuroprotective activity have collectively led to investigations of EPO as a pleiotropic cytokine. In this paper, we review the nonhematopoietic activity of EPO in the developing as well as adult brain, and summarize its roles during health and disease. 2. EPO, EpoR Signaling, and Erythropoiesis EPO is a glycoprotein hormone consisting of a single polypeptide of 166 amino acids
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