Int. J. Devl Neuroscience 29 (2011) 583–591 Contents lists available at ScienceDirect International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu Review Erythropoietin for neonatal brain injury: opportunity and challenge Tao Xiong a,b , Yi Qu a , Dezhi Mu a,c,∗ , Donna Ferriero c,d a Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China b Department of Newborn Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, China c Department of Neurology, Newborn Brain Research Institute, University of California, San Francisco, CA, USA d Department of Pediatrics, University of California, San Francisco, CA, USA article info Article history: Received 6 October 2010 Received in revised form 3 December 2010 Accepted 30 December 2010 Keywords: Erythropoietin Neonates Brain injury Hypoxia-ischemia Prematurity abstract Neonatal brain injury, caused by perinatal hypoxia-ischemia and extreme prematurity, remains a great challenge for prevention and treatment. There is no effective treatment for term hypoxic-ischemic encephalopathy (HIE) except hypothermia which by itself does not afford complete neuroprotection. Erythropoietin (EPO), a pleiotropic cytokine, has neuroprotective effects in a series of neonatal experi- mental models and recent clinical trials of HIE. However, the mechanisms, dosing, and the toxicity of EPO in these settings are inconsistently reported. This review will focus on the possible mechanisms, recent clinical advances and potential complications of EPO used in research and the clinic. In addition, optimal dose and administrative routes of EPO, and novel EPO mimetics will be discussed. © 2011 ISDN. Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction ......................................................................................................................................... 584 2. EPO–EPO receptor (EPOR) signaling in the brain ................................................................................................... 584 2.1. EPO ........................................................................................................................................... 584 2.2. EPO receptor (EPOR) ......................................................................................................................... 584 2.3. EPO–EPOR signaling ......................................................................................................................... 584 3. The neuroprotection of EPO in neonatal brain and cultured cells after HI ......................................................................... 585 3.1. Anti-apoptosis ............................................................................................................................... 585 3.2. Promotion of neural regeneration ........................................................................................................... 585 3.3. Protecting white matter from injury ........................................................................................................ 586 3.4. Anti-inflammation ........................................................................................................................... 586 3.5. Anti-neurotoxicity ........................................................................................................................... 586 3.6. Protecting the brain from edema ............................................................................................................ 587 3.7. Improvement in neurodevelopmental outcome ............................................................................................ 587 4. The effects of EPO on clinical trials .................................................................................................................. 587 4.1. EPO improves neurodevelopmental outcomes for preterm infants ........................................................................ 587 4.2. EPO improves neurological outcomes in newborns with HIE .............................................................................. 588 5. Possible side effects of EPO .......................................................................................................................... 588 5.1. Retinopathy of prematurity (ROP) .......................................................................................................... 588 5.2. Hypertension ................................................................................................................................ 588 5.3. Coagulation .................................................................................................................................. 588 Abbreviations: AQP4, water channel protein aquaporin-4; BBB, blood–brain barrier; CNS, central nervous system; ELBW, extremely low birth weight; EPO, erythropoi- etin; EPOR, erythropoietin receptor; HAWIK-III, Hamburg–Wechsler intelligence test for Children-III; HI, hypoxic-ischemic; HIE, hypoxic-ischemic encephalopathy; HIF-1, hypoxia-inducible factor 1; IVH, intraventricular hemorrhage; JAK-2, Janus family tyrosine protein kinase 2; IL-1 beta, Interleukin-1 beta; MDI, mental development index; PVL, periventricular leukomalacia; rEPO, recombinant EPO; ROP, retinopathy of prematurity; SVZ, subventricular zone. ∗ Corresponding author at: Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Lu, Chengdu, Sichuan 610041, China. Tel.: +86 28 85501512; fax: +86 28 85559065. E-mail address: dezhi.mu@ucsf.edu (D. Mu). 0736-5748/$36.00 © 2011 ISDN. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijdevneu.2010.12.007