Erythropoietin on a Tightrope: Balancing Neuronal and Vascular Protection between Intrinsic and Extrinsic Pathways

Abstract

Enthusiasm for erythropoietin (EPO) as a broad cytoprotective agent continues to increase at an almost exponential rate. The premise that EPO was required only for erythropoiesis was eventually shed by recent work demonstrating the existence of EPO and its receptor in other organs and tissues outside of the liver and the kidney, such as the brain and heart. As a result, EPO has been identified as a possible candidate in the formulation of therapeutic strategies for both cardiac and nervous system diseases. EPO has been shown to mediate an array of vital cellular functions that involve progenitor stem cell development, cellular protection, angiogenesis, DNA repair, and cellular longevity. An important requirement to achieve the goal of preventing or even reducing cellular injury by any cytoprotective agent is the ability to uncover the cellular pathways that ultimately drive a cell to its demise. We present for consideration several critical cellular pathways modulated by EPO that involve Janus kinase 2 (Jak2), the serine-threonine kinase Akt, forkhead transcription factors, glycogen synthase kinase-3β (GSK-3β), cellular calcium, protein kinase C, caspases, as well as the control of inflammatory microglial activation. As we continue to gain new insight into these pathways, EPO should emerge as a critical agent for the development, maturation, and survival of cells throughout the body.

Erythropoietin and Oxidative Stress

“…The biological activity of EPO also relies upon two disulfide bonds formed between cysteines at positions 7 and 160 and at positions 29 and 33 (Li, et al, 2004a). The requirement of these disulfide bridges has been demonstrated by the evidence that reduction of these bonds results in the loss of the biologic activity of EPO.…”

“…Replacement of asparagines 38 and 83 by glutamate or serine 126 by glycine can decrease the production and secretion of EPO (Dube, et al, 1988). The presence of the carbohydrates also are important in the control of the metabolism of EPO, since EPO molecules with high sialic acid content can be easily cleared by the body through specific binding in the liver (Tsuda, et al, 1990).The biological activity of EPO also relies upon two disulfide bonds formed between cysteines at positions 7 and 160 and at positions 29 and 33 (Li, et al, 2004a). The requirement of these disulfide bridges has been demonstrated by the evidence that reduction of these bonds results in the loss of the biologic activity of EPO.…”

“…Furthermore, EPO can block microglial cell activation and proliferation to prevent phagocytosis of injured cells through pathways that involve cellular membrane PS exposure, protein kinase B , and the regulation of caspases , Wu, et al, 2007a. EPO can directly inhibit several pro-inflammatory cytokines, such as IL-6, TNF-α, and monocyte chemoattractant protein 1 (Li, et al, 2004a, as well as reduce leukocyte inflammation (Contaldo, et al, 2007). In addition, EPO may foster the preservation of microglial cells for neuronal and vascular restructuring by preventing apoptotic injury in microglia , Vairano, et al, 2002.…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…It is the discovery of EPO and the EPO receptor (EPOR) in the nervous and vascular systems that has resulted in a heightened level of interest and enthusiasm for the potential clinical applications of EPO, such as in Alzheimer's disease, cardiac insufficiency [214,215], and cardiac transplantation [216,217]. In the nervous system, the major sites of EPO production and secretion are in the hippocampus, internal capsule, cortex, midbrain, cerebral ECs, and astrocytes [218,219]. Further work has revealed several other organs as secretory tissues for EPO that include peripheral ECs [220], myoblasts [221], insulin-producing cells [222], and cardiac tissue [133,223].…”

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

“…For example, cytokines that were previously thought to have no role in the brain, such as erythropoietin (EPO), have recently been demonstrated to regulate pathways that involve Akt and the Bcl-2 family member Bcl-x L [121,145]. EPO appears to significantly enhance the activity of Akt during oxidative stress [38,40] and prevent inflammatory activation of microglia [42].…”