No abstract

There are mixed reports on the neuroprotective properties of erythropoietin (EPO) in animal models of birth asphyxia. We investigated the effect of EPO on short-and long-term outcome after neonatal hypoxic-ischemic (HI) brain injury in mice and compared the effect of two different dose regimens of EPO. Nine-day-old mice were subjected to HI, and EPO was injected i.p. at 0, 24, and 48 h after HI in a dose of either 5 or 20 kU/kg. Paw preference in the cylinder rearing test (CRT) was used as a measure of sensorimotor function. Only in female mice, administration of EPO at 5 kU/kg but not 20 kU/kg improved sensorimotor function, reduced striatum atrophy and hippocampal lesion volume, and enhanced myelin basic protein (MBP) staining as determined at 4 and 9 wk after HI. In addition, at 72 h after HI, more Ki67 cells were found in the subventricular zone and dentate gyrus after EPO 5 kU/kg treatment, indicating an increase in progenitor cell proliferation. In conclusion, EPO improves sensorimotor function after neonatal HI and protects against striatum atrophy, hippocampus injury, and white matter loss. per 1000 live-born infants and is an important cause of cerebral palsy, epilepsy, and adverse developmental outcome (1,2). Experimental studies in newborn animals with HI showed that antioxidative, anti-inflammatory, and neurotrophic agents are neuroprotective (3,4). However, in clinical studies with newborns with HI encephalopathy, only mild hypothermia showed a modest neuroprotective effect if started within 6 h after birth in asphyxiated term newborns with moderate encephalopathy (5,6).Erythropoietin (EPO), a glycoprotein primarily recognized as a mediator promoting maturation and proliferation of erythroid progenitor cells (7,8), is an attractive drug for this purpose. EPO has been proven to cross the blood-brain barrier after systemic administration at a high dose and to reduce free radical formation and proinflammatory and apoptotic activity in models of brain damage (8 -11). EPO has also been shown to stimulate formation of new neurons because of its actions as a neurotrophic factor (12,13). The effects of EPO are mediated by binding of EPO to its receptor (EPOR), which is present in the brain at relatively high levels in regions known to be sensitive to hypoxia (14,15). Most studies in neonatal animals treated with EPO after HI indeed showed an improved histological outcome (8,16), although our study in rats with neonatal HI brain damage showed no histological improvement (17). However, Spandou et al. (18) reported that in a similar rat model, using a shorter duration of hypoxia, EPO induced effective regeneration of brain tissue.In human studies, no adverse effects of EPO treatment have been reported indicating that EPO is a safe drug for neonates (19). EPO has been increasingly used in preterm infants to treat neonatal anemia or to improve neurodevelopmental outcome, at a low (0.4 kU/kg) or a relatively high dose (3 kU/kg) (19 -21). Furthermore, EPO treatment (0.3-0.5 kU/kg) of perinatally asphyxi...