Erythropoietin: Powerful protection of ischemic and post-ischemic brain

Ischemic brain injury inflicted by stroke and cardiac arrest ranks among the leading causes of death and long-term disability in the United States. The brain consumes large amounts of metabolic substrates and oxygen to sustain its energy requirements. Consequently, the brain is exquisitely sensitive to interruptions in its blood supply, and suffers irreversible damage after 10-15 min of severe ischemia. Effective treatments to protect the brain from stroke and cardiac arrest have proven elusive, due to the complexities of the injury cascades ignited by ischemia and reperfusion. Although recombinant tissue plasminogen activator and therapeutic hypothermia have proven efficacious for stroke and cardiac arrest, respectively, these treatments are constrained by narrow therapeutic windows, potentially detrimental side-effects and the limited availability of hypothermia equipment. Mounting evidence demonstrates the cytokine hormone erythropoietin (EPO) to be a powerful neuroprotective agent and a potential adjuvant to established therapies. Classically, EPO originating primarily in the kidneys promotes erythrocyte production by suppressing apoptosis of proerythroid progenitors in bone marrow. However, the brain is capable of producing EPO, and EPO's membrane receptors and signaling components also are expressed in neurons and astrocytes. EPO activates signaling cascades that increase the brain's resistance to ischemia-reperfusion stress by stabilizing mitochondrial membranes, limiting formation of reactive oxygen and nitrogen intermediates, and suppressing pro-inflammatory cytokine production and neutrophil infiltration. Collectively, these mechanisms preserve functional brain tissue and, thus, improve neurocognitive recovery from brain ischemia. This article reviews the mechanisms mediating EPO-induced brain protection, critiques the clinical utility of exogenous EPO to preserve brain threatened by ischemic stroke and cardiac arrest, and discusses the prospects for induction of EPO production within the brain by the intermediary metabolite, pyruvate.