Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

Abstract

Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

Editorial

“…Although EPO was believed to be produced only in the kidney and liver, Tan and colleagues 28 showed in 1992 that other organs, including the brain, produced this cytokine in response to hypoxic-ischemic stress. This finding paved the way for a plethora of studies that increasingly confirmed a number of interrelated functional roles for EPO in the mammalian brain, some of which form the basis for the studies by Mazur and colleagues 18 reported in this issue of Journal of Neurosurgery: Pediatrics.It is now appreciated that endogenously produced EPO reduces the extent of apoptotic injury following ischemia, trauma, and other insults, 9,17,23 and astrocytes may be the primary cell type responsible for this production.3 However, all resident brain cells (neurons, astrocytes, microglia, and endothelial cells) express one or more EPO receptors (EPORs). 17 Erythropoietin and EPORs play important roles in brain development.…”

“…17 Generally speaking, the expression of both EPO and EPORs in adults are upregulated in a temporally distinct, cell-specific manner 1,24 in response to many different stimuli, secondary to the stabilization of one or more isoforms of hypoxia-inducible factor, a transcription factor family responsible for inducing the expression of hundreds of survival-enhancing genes.…”

“…It is now appreciated that endogenously produced EPO reduces the extent of apoptotic injury following ischemia, trauma, and other insults, 9,17,23 and astrocytes may be the primary cell type responsible for this production. 3 However, all resident brain cells (neurons, astrocytes, microglia, and endothelial cells) express one or more EPO receptors (EPORs).…”

“…3 However, all resident brain cells (neurons, astrocytes, microglia, and endothelial cells) express one or more EPO receptors (EPORs). 17 Erythropoietin and EPORs play important roles in brain development. 5 Very high expression levels of the EPOR predominate in the fetal brain, and, as in other tissues, levels diminish during fetal development, and then rapidly after birth.…”

“…9 Expression of EPO itself increases over the time of gestation, but falls at birth as well. 17 Generally speaking, the expression of both EPO and EPORs in adults are upregulated in a temporally distinct, cell-specific manner 1,24 in response to many different stimuli, secondary to the stabilization of one or more isoforms of hypoxia-inducible factor, a transcription factor family responsible for inducing the expression of hundreds of survival-enhancing genes. 21 Accumulating evidence suggests that endogenous EPO may be a primary inducer and effector of "preconditioning"-induced cerebroprotection; 6,10 as such, elucidating the molecular basis of protection afforded by the activation of innate neuroprotective pathways promises to advance therapeutics for many cerebrovascular disorders.…”