Safety of high-dose recombinant erythropoietin in a neonatal rat model.
BACKGROUND
High-dose recombinant erythropoietin (rEpo) is neuroprotective in neonatal animal models of brain injury, but the long-term consequences of neonatal exposure have not been studied.


OBJECTIVE
We hypothesized that multiple injections of high-dose rEpo during the neonatal period would be safe, and would improve neurologic outcomes after exposure to neonatal hypoxia or hypoxic-ischemic injury.


METHODS
Three experimental groups of Sprague-Dawley rats were assessed: (1) normoxia, (2) hypoxia and (3) hypoxia-ischemia. Groups 1 and 2 were given 0, 2,500 or 5,000 U/kg rEpo subcutaneously for the first 5 days of life (P1-P5). Group 2 animals also underwent 2 h of hypoxia (8% O(2)) daily from P1-P3. Group 3 animals underwent right carotid artery ligation followed by hypoxia (8% O(2) x 90 min) on P7, followed by either vehicle or rEpo (2,500 U/kg subcutaneously QD x3). We evaluated short- and long-term physiologic and behavioral outcomes. Major organs were evaluated grossly and histologically.


RESULTS
rEpo treatment transiently raised hematocrit, prevented hypoxia-induced delays in geotaxis and growth, improved forelimb strength, promoted liver growth in males, lowered the adult platelet count, but did not alter other CBC indices or histology. rEpo prevented hypoxia-ischemia-induced learning impairment and substantia nigra neuron loss.


CONCLUSIONS
Repeated treatment of newborn rats with high-dose rEpo was safe under all conditions tested. rEpo treatment improved the development of hypoxia-exposed newborns and prevented the learning impairment and dopamine neuron loss due to unilateral hypoxic-ischemic brain injury.
McPherson
Ronald J
RJ
Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, WA98195-6320, USA.
Demers
Eric J
EJ
Juul
Sandra E
SE
D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D006400:Hematocrit; D000860:Hypoxia / Q000139:chemically induced; D020925:Hypoxia-Ischemia, Brain / Q000139:chemically induced; D008099:Liver / Q000187:drug effects; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D015430:Weight Gain / Q000187:drug effects
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D004298:Dopamine