Injury to the brain during the perinatal period is a leading cause of death and disability in children. We currently do not have successful therapeutic regimens for the treatment of brain injury in children. However, recent research has shown that erythropoietin (Epo) may be of therapeutic benefit. Recombinant Epo (rEpo) has been shown to provide significant neuroprotection in many adult animal models of brain injury, including hypoxia-ischemia and trauma. Indeed, when rodents are subjected to a variety of experimental brain injuries, rEpo administration, even up to 6 hr after the event, reduces subsequent brain injury by 50-70 percent. Although the mechanism of rEpo action is not fully understood, it is known to decrease apoptotic cell death in neurons; it has direct antioxidant effects, and it may also reduce peri-neuronal inflammation. rEpo was previously thought to have limited clinical applicability, as it was not thought to cross the blood brain barrier (BBB) due to its large size (37 kD) and highly glycosylated structure. Recently, however, it has been shown that when very high dose rEpo (5000 U/kg) is given systemically, it protects the brain from a variety of mechanisms of injury. This suggests that a proportion of systemically administered rEpo crosses the BBB, or that systemically administered rEpo is neuroprotective through secondary mechanisms. No studies have applied this therapy to a neonatal model of injury. rEpo is commonly used in premature infants to stimulate erythropoiesis and reduce erythrocyte transfusions (200-400 U/kg/dose), but the dose of rEpo required for neuroprotective effects (5000 U/kg/dose) is much higher than those traditionally used for erythropoiesis. We hypothesize that neonatal hypoxic-ischemic brain injury can be ameliorated by the early administration of systemic (intravenous) high dose rEpo, and furthermore, that it will be safe both in the short and long-term. We will use the well-established model of perinatal hypoxia-ischemia developed by Vannucci (unilateral carotid artery ligation followed by hypoxia) to test these hypotheses.
The specific aims of the current proposal are to determine: 1) the time course and degree of rEpo penetration across the BBB of neonatal rats, 2) the optimal rEpo treatment parameters for neuroprotection following hypoxia-ischemia, 3) mechanism(s) by which rEpo decreases neuronal injury, and 4) the short and long-term safety of systemically administered high dose rEpo in the neonatal rat. If high dose rEpo treatment of human neonates following birth asphyxia indeed resulted in a 50 percent reduction in brain damage (as it does in laboratory animals) this treatment could annually save up to 1 million lives world wide while substantially lessening the financial and emotional consequences of birth asphyxia.
| Juul, Sandra E; McPherson, Ronald J; Bammler, Theodor K et al. (2008) Recombinant erythropoietin is neuroprotective in a novel mouse oxidative injury model. Dev Neurosci 30:231-42 |
| McPherson, Ronald J; Juul, Sandra E (2008) Recent trends in erythropoietin-mediated neuroprotection. Int J Dev Neurosci 26:103-11 |
| Juul, Sandra; Felderhoff-Mueser, Ursula (2007) Epo and other hematopoietic factors. Semin Fetal Neonatal Med 12:250-8 |
| McPherson, Ronald J; Demers, Eric J; Juul, Sandra E (2007) Safety of high-dose recombinant erythropoietin in a neonatal rat model. Neonatology 91:36-43 |
