Taking Stock After Another Negative Erythropoietin Neuroprotection Trial.

Erythropoietin is a glycoprotein originally identified and named for its role in erythropoiesis. Interest in erythropoietin as a neurotherapeutic began in 1993, with preclinical studies 1 showing protective effects of erythropoietin, including decreased apoptosis, inflammation, excitotoxicity, and glutamate toxicity.Erythropoietinwasalsothoughttobeimportantforlatebrainrecoverybecauseitstimulates neurogenesis, angiogenesis, and migration of regenerating neurons. Erythropoietin decreases oxidative stress via upregulation of antioxidant enzymes, inhibition of nitric oxide production, and a decrease in lipid peroxidation. These properties of erythropoietin were thought to be particularly relevant to neuroprotection in newborns, when antioxidant systems are immature. Phase 1 and 2 clinical trials of erythropoietin neuroprotection for both encephalopathy of prematurity and neonatal hypoxic-ischemic encephalopathy demonstrated safety with the promise of efficacy, as demonstrated by meta-analyses of these small studies. Phase 3 randomized clinical trials followed, using a variety of dosing strategies and gestational ages.