Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury

Abstract

Brain injury from preterm birth predisposes children to cerebral palsy, epilepsy, cognitive delay, and behavioral abnormalities. The CNS injury often begins before the early birth, which hinders diagnosis and concurrent treatment. Safe, effective postnatal interventions are urgently needed to minimize these chronic neurological deficits. Erythropoietin (EPO) is a pleiotropic neuroprotective cytokine, but the biological basis of its efficacy in the damaged developing brain remains unclear. Coordinated expression of EPO ligand and receptor expression occurs during CNS development to promote neural cell survival. The authors propose that prenatal third trimester global hypoxia-ischemia disrupts the developmentally regulated expression of neural cell EPO signaling, and predisposes neural cells to death. Furthermore, the authors suggest that neonatal exogenous recombinant human EPO (rhEPO) administration can restore the mismatch of EPO ligand and receptor levels, and enhance neural cell survival. Transient systemic hypoxia-ischemia (TSHI) on embryonic Day 18 in rats mimics human early-third trimester placental insufficiency. This model was used to test the authors' hypothesis using a novel clinically relevant paradigm of prenatal injury on embryonic Day 18, neonatal systemic rhEPO administration initiated 4 days after injury on postnatal Day 1, and histological, biochemical, and functional analyses in neonatal, juvenile, and adult rats. The results showed that prenatal TSHI upregulates brain EPO receptors, but not EPO ligand. Sustained EPO receptor upregulation was pronounced on oligodendroglial lineage cells and neurons, neural cell populations particularly prone to loss from CNS injury due to preterm birth. Postnatal rhEPO administration after prenatal TSHI minimized histological damage and rescued oligodendrocytes and gamma-aminobutyric acidergic interneurons. Myelin basic protein expression in adult rats after insult was reduced compared with sham controls, but could be restored to near normal levels by neonatal rhEPO treatment. Erythropoietin-treated TSHI rats performed significantly better than their saline-treated peers as adults in motor skills tests, and showed significant seizure threshold restoration using a pentylenetetrazole increasing-dose paradigm. These data demonstrate that neonatal rhEPO administration in a novel clinically relevant paradigm initiated 4 days after a global prenatal hypoxic-ischemic insult in rats rescues neural cells, and induces lasting histological and functional improvement in adult rats.