Selective Inhibition of Nitric Oxide in Hypoxic-Ischemic Brain Model in Newborn Rats: Is It an Explanation for the Protective Role of Erythropoietin?

Abstract

Erythropoietin (Epo) exerts neuroprotection against neuronal death induced by ischemia and hypoxia in vitro and in vivo. Recent studies suggest that the neuroprotective effects of Epo may depend upon different mechanisms, including the inhibition of nitric oxide (NO). We recently demonstrated that Epo exerts neuroprotection in a model of neonatal hypoxic-ischemic brain damage. In the present study, we directly determined whether systemic administration of recombinant Epo modulates cerebral NO production in a neonatal rat model of hypoxic-ischemic brain injury. Seven-day-old Wistar rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. Brain nitrite levels were evaluated in both hemispheres (carotid ligated or nonligated) by Griess reagent 72 h after the hypoxic-ischemic insult. Our results show that hypoxic-ischemic insult results a significant increase in NO production as compared with NO levels in hypoxic hemispheres and control animals. A single dose of Epo treatment (1,000 U/kg i.p.) significantly decreased NO overproduction in the hypoxic-ischemic hemisphere, whereas no significant change appeared in hypoxia alone or in controls. These data suggest that the selective inhibitory effect of Epo on NO overproduction could have a neuroprotective effect in neonatal hypoxic-ischemic brain injury.

Erythropoietin after Focal Cerebral Ischemia Activates the Janus Kinase–Signal Transducer and Activator of Transcription Signaling Pathway and Improves Brain Injury in Postnatal Day 7 Rats

“…In neonatal rat models, Epo prevents intrauterine ischemiareperfusion-or N-methyl-D-aspartate receptor antagonistinduced brain injury (11,12) and reduces brain injury in a hypoxic-ischemic model of the postnatal day 7 (P7) rat (13,14). The latter neonatal rat model requires both unilateral carotid artery ligation and systemic hypoxia (15,16) but does not accurately reproduce the pathogenesis of focal stroke in human neonates.…”

Erythropoietin Protects Dopaminergic Neurons and Improves Neurobehavioral Outcomes in Juvenile Rats after Neonatal Hypoxia-Ischemia

“…Epo receptors (EpoR) are present on many cell types in brain, and their activation by Epo results in cell-specific effects (8). Stimulation of neurons with recombinant Epo (rEpo) decreases glutamate toxicity (both N-methyl-D-aspartate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid mediated) (9,10), up-regulates antiapoptotic factors Bcl-x L and Bcl-2 (4,11), and decreases nitric oxide-mediated injury (12)(13)(14). In addition, rEpo preserves blood-brain barrier integrity (15), enhances proliferation/ differentiation of oligodendrocyte precursors (16), and promotes neurogenesis from neural stem cells (17).…”

A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants

“…15,[33][34][35][36][37][38][39][40][41] In addition to stimulating erythropoiesis, ESAs are protective in the developing brain, making it possibly beneficial for very premature infants who are at risk for intraventricular hemorrhage, hypoxicischemic injury, and developmental delay. 37 The neuroprotective mechanisms of ESAs include decreased neuronal apoptosis, decreased inflammation, increased neurogenesis, promotion of oligodendrocyte differentiation and maturation, and improved white matter survival.…”

“…37 The neuroprotective mechanisms of ESAs include decreased neuronal apoptosis, decreased inflammation, increased neurogenesis, promotion of oligodendrocyte differentiation and maturation, and improved white matter survival. [35][36][37][38][39][40][41] Recent clinical studies suggest a strong potential for neuroprotection. [42][43][44][45] Our group previously reported an improved cognitive outcome in former ELBW infants with serum Epo concentrations $500 mU/mL.…”