Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

Abstract

BACKGROUND In the last two decades, there has been considerable evolution in the understanding role of erythropoietin (Epo) in neuroprotection. Epo has both paracrine and autocrine functions in the brain. Epo binding results in neurogenesis, oligodendrogenesis, and angiogenesis. Epo and its receptor are upregulated by exposure to hypoxia and proinflammatory cytokines following brain injury. While Epo aids in recovery of locally injured neuronal cells, it provides negative feedback to glial cells in the penumbra, thereby limiting extension of injury. This forms the rationale for use of recombinant Epo and Epo mimetics in neonatal and adult injury models of stroke, traumatic brain injury, spinal cord injury, intracerebral hemorrhage and neonatal hypoxic-ischemia. METHOD Review of published literature (Pubmed, Medline and Google scholar) RESULTS Preclinical neuroprotective data are reviewed and the rationale for proceeding to clinical trials is discussed. Results from Phase I/II trials are presented, as are updates on ongoing and upcoming clinical trials of Epo neuroprotection in neonatal populations. CONCLUSIONS The scientific rationale and preclinical data for Epo neuroprotection are promising. Phase II and III clinical trials are currently in process to determine the safety and efficacy of neuroprotective dosing of Epo for extreme prematurity and hypoxic ischemic encephalopathy in neonates.

Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair)

“…Meta-analyses combining early and late rEPO administration to prevent anemia of prematurity have raised concerns about increased rates of severe retinopathy of prematurity associated with the prolonged use of rEPO [26]. Safety issues of high-dose rEPO aimed at crossing the blood-brain barrier in preterm infants also remain a topic in recent investigations [27]. The eagerly awaited safety data from the first large phase II double-masked RCT using high-dose rEPO as a neuroprotective agent given shortly after birth (3 × 3,000 U/kg body weight (BW) rEPO or NaCl 0.9% within the first 36 h of life) to 443 very preterm infants describe no relevant differences between both groups regarding short-term outcomes, including mortality, retinopathy of prematurity and IVH incidence (ClinicalTrials.gov identifier: NCT00413946) [28].…”

Neural stem cell transplantation combined with erythropoietin for the treatment of spinal cord injury in rats

“…It was previously considered that EPO is only a endocrine hormone acting on hematopoietic cells. However, EPO has been demonstrated to be a type of tissue protection factor, which exerts neurotrophic and neuroprotective effects (2,3). Yuan et al (4) observed the effects of erythropoietin on the differentiation of embryonic cerebral cortex neural stem cells of rats cultured in vitro, the results indicated that erythropoietin is able to promote the differentiation of neural stem cells into neurons.…”

Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy

“…Erythropoietin (Epo) is a promising neuroprotective agent that reduces the initial brain damage and enhances the subsequent tissue repair. It has multiple mechanisms of action, including antiapoptotic, anti-inflammatory, antioxidative as well as angiogenic, oligodendrogenic, and neurogenic effects [71] . Epo has been studied by means of 1 H MRS during the subacute phase (at 24-72 h of age in nonhuman primates) and at longterm follow-up (at 9 months in nonhuman primates and at 25 days of age in rats).…”

“…Phase II/III clinical trials are currently underway (ClinicalTrials.gov ID: NCT01913340, NCT01732146, NCT02811263, NCT02002039). The activation of neurotrophic factors is one of the working mechanisms of Epo [71] . Interestingly, systemic administration of neurotrophic factors itself can be neuroprotective as well.…”