Erythropoietin: a novel therapy for hypoxic–ischaemic encephalopathy?

Abstract

EPOErythropoietin EPO-R Erythropoietin receptor HIE Hypoxic-ischaemic encephalopathyPerinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44-53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. In this article, we review the preclinical and clinical evidence for erythropoietin (EPO) as a potential novel neuroprotective agent for the treatment of HIE. EPO is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. There is currently insufficient evidence to support the use of high-dose EPO in newborns with HIE. However, several on-going trials will provide much needed data regarding the safety and efficacy of this potential new therapy when given in conjunction with hypothermia for HIE. Novel neuroprotective therapies are needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. High-dose EPO is a promising therapy that can be administered in conjunction with hypothermia. However, additional data are needed to determine the safety and efficacy of this adjuvant therapy for HIE.Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in one to three infants per 1000 term births, 1,2 and up to 12 000 infants are affected each year in the USA. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes [3][4][5][6][7] and is the current standard of care. Yet clinical trials suggest that 44% to 53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. Therefore, novel neuroprotective therapies are urgently needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. Erythropoietin (EPO) is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. [8][9][10][11][12][13] Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. We review the preclinical and clinical evidence for EPO as a potential novel neuroprotective agent for the treatment of HIE. ERYTHROPOIETIN AND THE EPO RECEPTOR IN THE BRAINErythropoietin is a 34kDa glycoprotein that was originally identified because of its role in erythropoiesis. In the fetus, EPO is produced in the liver, and, following the...

Controversies in preterm brain injury

“…While endogenous levels of Epo appear to have minimal effect in the face of profound neural injury, pharmacological doses of exogenous Epo are neuroprotective in multiple injury models, including a preterm baboon model (Brines, Ghezzi et al 2000, Traudt and Juul 2013). Epo is under active investigation as a neuroprotective agent for both preterm brain injury (Juul, McPherson et al 2008) and as an adjunct to hypothermia treatment of term HI (Wu and Gonzalez 2015). Whether it will decrease diffuse WMI, improve myelination or improve behavioral outcomes awaits clinical trial completion (McAdams, McPherson et al 2013, Ohls, Kamath-Rayne et al 2014, O’Gorman, Bucher et al 2015).…”

Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice

“…EPO shows promise as another therapy for neonatal hypoxic-ischemic injury [22]. A nonhuman primate study [23] and small clinical trials using a multidose regimen based on animal studies have established safety and pharmacokinetics when combined with therapeutic hypothermia [24], and this suggests that EPO may result in less MRI brain injury and improve 1-year motor function [25]. …”

Delayed erythropoietin therapy improves histological and behavioral outcomes after transient neonatal stroke

“…Of many potential therapies that have been studied in an effort to both suppress early cell death but also enhance later proliferation and repair, erythropoietin (EPO) has shown promise in a number of brain injury models. EPO is a pleiotropic cytokine with a number of erythropoietic and non-erythropoietic roles 3 . EPO and EPO receptor (EPO-R) expression are elevated in the brain during gestation but decline rapidly after birth, with cell-specific endogenous EPO/ EPO-R upregulation after injury 4 .…”