Elsevier

Clinics in Perinatology

Volume 42, Issue 3, September 2015, Pages 469-481
Clinics in Perinatology

Erythropoietin and Neonatal Neuroprotection

https://doi.org/10.1016/j.clp.2015.04.004Get rights and content

Section snippets

Key points

  • Neonates at known high risk of brain injury may be considered candidates for neuroprotective strategies.

  • High-risk neonates develop brain injury that is specific to developmental age and mechanism of injury.

  • Mechanisms of cell death include apoptosis, necrosis, and autophagy, and these pathways share molecular signals.

  • Erythropoietin (Epo) may provide neuroprotection for multiple different pathways of brain injury.

Infants at risk for neurodevelopmental impairment

Neonatology is a new field of medical practice, having come into its own in the 1960s. As the practice has evolved, infants who were previously destined to die now survive, yet their outcomes are frequently burdened by significant neurodevelopmental challenges. Our mandate as neonatologists is to ensure that survivors of these previously fatal conditions can lead fully functional lives without impairment. Examples of infants who previously had little or no hope for survival include those born

Mechanisms of cell death

There are 3 known mechanisms of cell death: apoptosis, necrosis, and autophagy. These cell death programs are complex and interrelated and involve signaling pathways that can potentially be inhibited, interrupted, or modified, allowing for targeted neuroprotective strategies (Fig. 1). Apoptosis is a form of programmed cell death characterized by immunologically silent cell shrinkage with nuclear pyknosis and intact plasma membranes. It can be activated by intrinsic or extrinsic pathways. The

Erythropoietin as a neuroprotective agent for neonatal neuroprotection

Epo is a 30.4-kDa cytokine originally recognized for its role in erythropoiesis. Prenatally it is produced primarily in the liver, whereas postnatally it is produced primarily in the kidney. The switch in production site is thought to occur at approximately term postconceptual age. Epo is also produced in developing brain where it functions as both an important growth factor and neuroprotective agent for the central nervous system.52, 53, 54, 55 Epo is produced in brain by multiple cells types,

Mechanism of action

Epo binds to 2 cell surface Epo receptors (EpoR) to form a homodimer, which activates Jak2 kinase to phosphorylate Jak2 and EpoR; this activates multiple signaling cascades, including MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinases), PI3K (phosphoinositide 3-kinase)/Akt, Stat5, and nuclear factor kappa B (NFkB). NFkB and Stat5 move into the nucleus and act as transcription factors for Bcl-2 and Bcl-xL, which are antiapoptotic genes. Epo also acts indirectly,

Clinical trials of erythropoietin in neonatal populations

In the past 8 years, clinical trials to evaluate the safety and efficacy of Epo in various neonatal conditions have emerged. Neonatal patient populations that have been targeted include preterm infants (Box 2)84, 85, 86, 87 and term infants with HIE,88, 89 stroke,90 and cyanotic heart disease (Box 3).91 Pharmacokinetic and safety studies have shown that Epo dosed from 500 to 3000 U/kg is safe in preterm and term neonates. Two phase I/II studies evaluating the safety85 and pharmacokinetics84 of

Summary of animal and human studies

Epo has shown significant potential in in vitro and in vivo studies of brain injury.81, 97 It has specific cell receptor-mediated effects that are neuroprotective, as well as effects that are independent of the EpoR,98 and more general systemic effects (anti-inflammatory, erythropoietic, angiogenic), all of which may be beneficial in the face of brain injury. These basic science studies are now being translated to the bedside. The translation of dose, dosing interval, and duration of treatment

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    Disclosures: None.

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