Neurology Research International 1 Hindawi Publishing Corporation Neurology Research International Volume 2011, Article ID 453179, 8 pages doi:10.1155/2011/453179 Review Article Erythropoietin: Recent Developments in the Treatment of Spinal Cord Injury Stephana Carelli,1, 2 GiovanniMarfia,1, 3 AnnaMaria Di Giulio,1 Giorgio Ghilardi,4 and Alfredo Gorio1, 2 1 Laboratory of Pharmacology, Department of Medicine, Surgery and Dentistry, University of Milan, Polo H. San Paolo, Via A. di Rudin`ı 8, β014β Milan, Italy 2 Clinical Pharmacology, IRCCS Humanitas, Via Manzoni 56, Rozzano, 20089 Milan, Italy 3Cerebrovascular Unit, IRCCS, Istituto Neurologico C Besta, Via Celoria 11, 20133 Milan, Italy 4Department of Medicine, Surgery and Dentistry, University of Milan, Polo H. San Paolo, Via A. di Rudin`ı 8, β014β Milan, Italy Correspondence should be addressed to Stephana Carelli, stephana.carelli@unimi.it and Giovanni Marfia, giovanni.marfia@unimi.it Received 24 February 2011; Accepted 9 May 2011 Academic Editor: Jeff Bronstein Copyright © 2011 Stephana Carelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Erythropoietin (EPO), originally identified for its critical function in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of cells and tissues. Here is presented the analysis of EPO effects on spinal cord injury (SCI), considering both animal experiments concerning to mechanisms of neurodegeneration in SCI and EPO as a neuroprotective agent, and some evidences coming from ongoing clinical trials. The evidences underling that EPO could be a promising therapeutic agent in a variety of neurological insults, including trauma, are mounting. In particular, it is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate interesting preclinical and clinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials. Moreover the demonstration of rhEPO and its analogues’ broad neuroprotective effects in animal models of cord lesion and in human trial like stroke, should encourage scientists and clinicians to design clinical trials assessing the efficacy of these pharmacological compounds on SCI. 1. Introduction Several studies published in recent years have shown that the cytokine erythropoietin (EPO) is a crucial mediator of injury- related tissue protection in mammals following ischemic and nonischemic injuries. Severe spinal cord injury (SCI) causes an immediate paralysis of muscles innervated by motoneurons caudal to the injury site. This results not only from a loss of supraspinal tracts that subserve voluntary initiation of movement, for example, corticospinal and reticulospinal tracts that use fast glutamatergic synaptic transmission, but also from a loss of descending brainstem tracts that provide spinal motoneurons with their major source of neuromodulators, such as 5-HT. From a pathophysiological perspective, SCI has historically been divided into two distinct phases. Primary (mechanical) injury directly disrupts tissues but, in the acute phase, frequently causes only limited neuronal death surrounding the lesion epicenter and damage axons and blood vessels at the site of injury, leading to vasoconstriction, hemorrhage, and ischemia [1]. As a response to primary injury, a vigorous inflammation is initiated and is followed by a cascade of secondary events such as fluid-electrolyte imbalance, regional blood flow alterations, calcium-mediated cellular injury, free-radical generation, glutamate-induced excitotoxicity, disturbances in mitochondrion function, proinflammatory cytokine production, and apoptotic cell death. This causes the attraction of inflammatory cells such as neutrophils, macrophages, and resident microglia. The consequence of this phenomenon is the amplification of injury by releasing proinflammatory cytokines [2]. During the weeks following trauma, the site of SCI is characterized by disrupted axons and a cystic cavity encased within a glial scar. Intact tissue surrounding the lesion is found in variable amounts. It is in this intact tissue that neurons are found either uninjured or with part of their myelin sheaths lost. These neurons have the potential to regenerate axons. Nonetheless, axonal regeneration frequently fails for two reasons: first, elements within the lesion environment inhibit axonal growth and second, neurons of the CNS themselves exhibit a weak intrinsic ability to regenerate axons after trauma [3, 4]. 2. Erythropoietin Historical Background, Structure, and Signalling A century ago, it was clear that the production of erythrocytes was modulated by a humoral factor; Carnot and DeFlandre [5] named this factor hemopoietin, and successively, in 1948,