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

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>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 hypoxiaischemia 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.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Transient systemic hypoxia-ischemia (TSHI) on embryonic Day 18 in rats mimics human early-thirdtrimester 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.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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 γ-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.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p></jats:sec>

Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury

“…from P1 to P5) normalizes the seizure threshold and motor function in adult rats that suffered prenatal TSHI (Mazur et al, 2010). Here, KCC2 protein expression was quantified at P11 and P28 following prenatal TSHI using the same protocol of postnatal EPO administration.…”

Recombinant Human Erythropoietin Augments Angiogenic Responses in a Neonatal Rat Model of Cerebral Unilateral Hypoxia-Ischemia

“…Recently, it has been reported that EPO has many unexpected nonhematopoietic functions, including reducing the incidence of bronchopulmonary dysplasia [6], neuroprotection and angiogenesis [7]. Results of studies on injured prenatal brains have shown that neonatal rh-EPO administration is beneficial to myelination [8], rescues neural cells and induces lasting histological and functional improvements [9]. In addition, a retrospective cohort study on premature infants found a dose-response relationship between rh-EPO treatment and improved Mental Developmental Index scores [10].…”

Editorial

“…Although EPO was believed to be produced only in the kidney and liver, Tan and colleagues 28 showed in 1992 that other organs, including the brain, produced this cytokine in response to hypoxic-ischemic stress. This finding paved the way for a plethora of studies that increasingly confirmed a number of interrelated functional roles for EPO in the mammalian brain, some of which form the basis for the studies by Mazur and colleagues 18 reported in this issue of Journal of Neurosurgery: Pediatrics.…”