Neuronal damage after moderate hypoxia and erythropoietin

Weber, A Ioana; Dzietko, Mark; Berns, Monika; Felderhoff‐Mueser, Ursula; Heinemann, Uwe; Maier, Rolf F.; Obladen, Michael; Ikonomidou, Chrissanthi; Bührer, Christoph

doi:10.1016/j.nbd.2005.04.016

Cited by 54 publications

(34 citation statements)

References 39 publications

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“…In the current model, we observed no neuronal cell death in any examined region: cortex, striatum, or hippocampus. This is in line with Weber et al (24) who reported no increase in neuronal death even after 8% O 2 for two 8-h periods in the newborn rat brain. Our group has shown that 100% O 2 increases the extent of cerebral injury when …”

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confidence: 93%

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

et al. 2013

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Background: Supplemental oxygen used during resuscitation can be detrimental to the newborn brain. The aim was to determine how different oxygen therapies affect gene transcription in a hypoxia-reoxygenation model. Methods: C57BL/6 mice (n = 56), postnatal day 7, were randomized either to 120 min of hypoxia 8% O 2 followed by 30 min of reoxygenation with 21, 40, 60, or 100% O 2 , or to normoxia followed by 30 min of 21 or 100% O 2 . Affymetrix 750k expression array was applied with RT-PCR used for validation. Histopathology and immunohistochemistry 3 d after hypoxiareoxygenation compared groups reoxygenated with 21 or 100% O 2 with normoxic controls (n = 22). results: In total, ~81% of the gene expression changes were altered in response to reoxygenation with 60 or 100% O 2 and constituted many inflammatory-responsive genes (i.e., C5ar2, Stat3, and Ccl12). Oxidative phosphorylation was downregulated after 60 or 100% O 2 . Iba1 + cells were significantly increased in the striatum and hippocampal CA1 after both 21 and 100% O 2 . conclusion: In the present model, hypoxia-reoxygenation induces microglial accumulation in subregions of the brain. The transcriptional changes dominating after applying hyperoxic reoxygenation regimes include upregulating genes related to inflammatory responses and suppressing the oxidative phosphorylation pathway.

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Section: Discussionsupporting

confidence: 93%

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

et al. 2013

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“…One limitation of this study is that small numbers of subjects were used in the groups testing multiple injections of 30,000 U/kg at 48h and 1 wk. Our data showing no benefit at the highest rEpo doses is consistent with a recent study published by Weber et al (26), in which extremely high-dose rEpo (40 U/mL) had neurotoxic effects using in vitro neuronal culture and brain slice models of mild hypoxia. This was also apparent in vivo when neonatal rats with mild brain injury were treated with 2 ϫ 20,000 U/kg i.p.…”

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confidence: 93%

A Comparison of High-Dose Recombinant Erythropoietin Treatment Regimens in Brain-Injured Neonatal Rats

2007

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Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of hypoxic-ischemic brain injury. However, the optimal rEpo dose, dosing interval, and number of doses for reducing brain injury are still undetermined. We compared the neuroprotective efficacy of several subcutaneous rEpo treatment regimens. Seven-day-old rats underwent unilateral carotid ligation plus 90 min 8% hypoxia. Treatment began immediately after injury. Treatment regimens examined included 1, 3, or 7 daily subcutaneous injections of either 0 (vehicle), 2,500, 5,000, or 30,000 U/kg rEpo. Gross brain injury, neuronal apoptosis (TUNEL), and gliosis (glial fibrillary acidic protein) were assessed at 48 h or 1 wk post injury. Immunoreactive cells and brain injury were quantified for statistical comparison to vehicle controls. rEpo treatment reduced brain injury, apoptosis, and gliosis, in a dose-dependent U-shaped manner at both 48 h and 1 wk. Neither one injection of 2,500, seven injections of 5,000, or three injections of 30,000 U/kg rEpo were protective. Three doses of 5,000 and one dose of 30,000 U/kg rEpo were most protective at both time intervals. rEpo provides dose-dependent neuroprotection. Of the regimens tested, three doses of 5,000 U/kg was optimal because it provided maximal benefit with limited total exposure. (Pediatr Res 61: [451][452][453][454][455] 2007) N eonatal brain injury continues to affect the lives of thousands of infants in the United States and worldwide. In fact, perinatal asphyxia accounts for 23% of deaths globally (1). Hypothermia following hypoxia-ischemia offers promise of improved neurodevelopmental outcomes, however, thus far, the therapeutic benefit has been modest (2). When strict entry criteria are defined, up to 60% of untreated infants exposed to moderate to severe perinatal hypoxia-ischemia die or have significant neurodevelopmental sequelae (3,4). Erythropoietin (Epo), a hematopoietic cytokine known best for its erythropoietic effects, has neuroprotective effects in many animal models of brain injury, including hypoxia-ischemia, trauma, and excitotoxic injury (5-12). Although many neuroprotective strategies appeared promising in animal models, most have failed clinically (often due to toxicity). In contrast, rEpo is a safe treatment for anemia (13) and, more importantly, the neuroprotective effects of rEpo have translated well from bench to clinical trials for both amyotrophic lateral sclerosis (ALS) (14) and middle cerebral artery stroke (15).Initial studies provided no evidence that the 37 kD charged glycoprotein rEpo could cross the blood-brain barrier (BBB) (16 -18). Therefore, early rEpo neuroprotection experiments used either in vitro application (19,20) or direct intracerebral injection (21). More recently, robust neuroprotection was produced after systemic injection of high-dose rEpo (5,000 U/kg i.p.) (5). Although the neuroprotective rEpo dose is clearly above the anemia treatment range, there is no consensus as to the optimal neuroprotective dose, dose number, or in...

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“…In a neonatal rat HI model, administration of EPO at 20 kU/kg significantly increased the number of degenerating cerebral neurons (35). However, in our female animals, a mild improvement of sensorimotor function was shown at 4 wk post-HI after EPO treatment with 20 kU/kg, but the improvement did not last into the adult period (9 wk post-HI).…”

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confidence: 53%

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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Neuronal damage after moderate hypoxia and erythropoietin

Cited by 54 publications

References 39 publications

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

A Comparison of High-Dose Recombinant Erythropoietin Treatment Regimens in Brain-Injured Neonatal Rats

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

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