Long-Term Pharmacologic Neuroprotection after Birth Asphyxia: Where Do We Stand?

Bel, Frank van; Groenendaal, Floris

doi:10.1159/000143723

Cited by 41 publications

(32 citation statements)

References 138 publications

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“…The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10)(11)(12)(13).…”

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Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

et al. 2012

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Background: Both hypothermia and erythropoietin (ePO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (hI). We investigated a possible additive effect of the use of a combination of hypothermia-ePO in a rat model of neonatal hI. Methods: at postnatal day 7, rats were subjected to hI and then randomized to 3 h of hypothermia, ePO, or both. sensorimotor function was assessed by the cylinder-rearing test (cRT) at 2 and 5 wk after hI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. results: Multivariable analysis using general linear modeling showed that hypothermia, ePO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after hI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the cRT. Maximal improvement in males was 26% after combined treatment with hypothermia and ePO. histological outcome was improved by hypothermia only with no additional effect of ePO or gender. conclusion: hypothermia after hI improved sensorimotor function in females more than in males. There was a borderline additive effect of ePO when combined with hypothermia. histology of brain lesion volume and white matter damage was improved only by hypothermia.P erinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury and is associated with long-term neurological sequelae such as cognitive dysfunction, developmental delay, seizures, and sensory and/or motor impairment (1,2). Several studies in newborn rodents indicate that reduction of brain temperature by 2-5 °C even for 3 h, when started within 6 h after HI, provides neuroprotection and improved behavioral outcome (3-6).The neuroprotective effects of hypothermia of mildly asphyxiated newborns have been demonstrated, but in clinical practice, morbidity and mortality remain considerable (30-45%) (7,8). The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10-13). In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14). In recent studies with a rodent model, females appear to benefit more from neuroprotective interventions after HI, such as hypothermia, EPO,.The aim of the present study was to test whether the addition of EPO to hypothermia has additive neuroprotective effects as compared with a single treatment and to examine possible gender effects. Results HypothermiaSham-treated rats did not show a paw preference in the cylinder-rearing test (CRT) (paw preference < ±5%, data not shown). A significant paw preference of the unimpaired forepaw in the normothermia groups was observed at both 2 and 5 wk after HI (Figure 1). Differences between males and females in the normothermia group were not statistically significant. In fema...

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Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

et al. 2012

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“…N eonatal hypoxic-ischemic (HI) brain injury occurs in [1][2][3][4] 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).…”

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“…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).…”

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Beneficial Effect of Erythropoietin on Sensorimotor Function and White Matter After Hypoxia-Ischemia in Neonatal Mice

et al. 2011

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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...

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“…H ypothermia (HT) is one of the most promising neuroprotective modalities against hypoxic ischemic encephalopathy (HIE) in neonatal brain (1). However, in neonates with severe HIE, little neuroprotection could be achieved using current HT protocols in which whole-body or head cooling is performed for 48 to 72 h by maintaining the core temperature within a range of 33.5 to 34.5°C (2)(3)(4)(5).…”

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Long-Term Neuroprotective Effect of Postischemic Hypothermia in a Neonatal Rat Model of Severe Hypoxic Ischemic Encephalopathy: A Comparative Study on the Duration and Depth of Hypothermia

2010

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ABSTRACT:It is not known whether deeper or longer hypothermia (HT) can achieve better neuroprotection against hypoxic ischemic encephalopathy (HIE) in neonates. To compare the neuroprotective effects of different durations and temperatures of postischemic HT in neonatal rats with severe HIE, 7-d-old rats were subjected to the Rice-Vannucci model for 150 min hypoxia. Only the rats with identified brain lesions in diffusion-weighted MRI were assigned to normothermia (NT, 36°C/48 h) or four HT (HT-30°C/48 h; HT-30°C/24 h; HT-33°C/48 h; and HT-33°C/24 h) groups.1 H-magnetic resonance spectroscopy ( 1 H-MRS) and T2-weighted MRI were obtained serially, and functional studies were performed. HT groups showed significantly greater residual hemispheric volume and better rotarod and cylinder tests than did the NT group at 5 wk postischemia. HT groups also showed lower lactate-plus-lipid level in 1 H-MRS than did the NT group at 7 d postischemia. All of these outcome variables, however, did not differ among the 4 HT subgroups, despite a trend toward greater residual brain volume in the 48-h HT versus 24-h HT subgroups. In conclusion, neither reducing the target temperature from 33 to 30°C nor prolonging the duration from 24 to 48 h produced further improvements in neurologic outcomes in neonatal rat with HIE. (Pediatr Res 68: 303-308, 2010) H ypothermia (HT) is one of the most promising neuroprotective modalities against hypoxic ischemic encephalopathy (HIE) in neonatal brain (1). However, in neonates with severe HIE, little neuroprotection could be achieved using current HT protocols in which whole-body or head cooling is performed for 48 to 72 h by maintaining the core temperature within a range of 33.5 to 34.5°C (2-5). In animal studies, the efficacy of postischemic HT was also limited in the subgroup with severe ischemic injury (6,7). To treat severe HIE by HT, a recent review suggested a "deeper" and "more prolonged" cooling (8). However, no controlled clinical trials have tested this supposition and several experimental studies failed to clearly demonstrate an effect of postischemic HT protocols with different target temperatures or duration in a perinatal HIE model (9 -11).The 7-d-old rat with unilateral carotid artery ligation and subsequent exposure to 8% hypoxia is the most commonly used model to evaluate the efficacy of therapeutic interventions in the developing brain (12), and several studies have used this Rice-Vannucci model (RVM) to test the effects of HT (10,11,(13)(14)(15)(16)(17)(18)(19). However, an experimental design composed of a shorter duration of hypoxia, representing "mild" ischemic lesions, is not appropriate for evaluating the neuroprotective effect of HT against severe HIE. To date, few experimental studies have used the RVM with hypoxia exposure longer than 120 min (10,13,19), but none of these have reported the long-term neuroprotective effect of postischemic HT.The aim of this study was to investigate the long-term neuroprotective effect of various postischemic HT protocols with different t...

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Long-Term Pharmacologic Neuroprotection after Birth Asphyxia: Where Do We Stand?

Cited by 41 publications

References 138 publications

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Beneficial Effect of Erythropoietin on Sensorimotor Function and White Matter After Hypoxia-Ischemia in Neonatal Mice

Long-Term Neuroprotective Effect of Postischemic Hypothermia in a Neonatal Rat Model of Severe Hypoxic Ischemic Encephalopathy: A Comparative Study on the Duration and Depth of Hypothermia

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