Abstract
The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia.
Highlights
Perinatal hypoxia-ischemia (HI) remains a major contributor to infant mortality and morbidity, and a considerable number of children who suffer from perinatal HI-induced brain inflammation and brain injury develop long term neurological disabilities, including behavioral alterations, motor disturbances and learning deficits [1,2]
We have previously reported that HI led to reductions of the ipsilateral brain volume and neuron density in the hippocampal CA1 area in the P14 rat [3], similar to injuries found in newborn infants with cerebral dysmaturation disorder [4]
EPO has been shown to be neuroprotective in animal models of brain injury induced by perinatal HI in Postnatal Day 7 (P7)–P10 rodents, at which age the developmental stage of oligodendrocytes is equivalent to near-term to term infants [11,12,13,14,15,16] recombinant EPO is considered a potentially promising therapeutic treatment following perinatal HI [6,7,8,9,10]
Summary
Perinatal hypoxia-ischemia (HI) remains a major contributor to infant mortality and morbidity, and a considerable number of children who suffer from perinatal HI-induced brain inflammation and brain injury develop long term neurological disabilities, including behavioral alterations, motor disturbances and learning deficits [1,2]. Our previous studies have developed a neonatal rat model to mimic the HI condition by ligating unilateral carotid artery followed by exposure to hypoxia (8% oxygen for 1.5 h) in Postnatal Day 7 P7 rats. EPO has been shown to be neuroprotective in animal models of brain injury induced by perinatal HI in P7–P10 rodents, at which age the developmental stage of oligodendrocytes is equivalent to near-term to term infants [11,12,13,14,15,16] recombinant EPO (rEPO) is considered a potentially promising therapeutic treatment following perinatal HI [6,7,8,9,10]. The associated neurobehaviors, including sensorimotor, locomotor activity and cognitive ability, were determined in juvenile rats
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