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See detailHypoxia and hypercapnia during incubation of chicken eggs on development and subsequent performance
Decuypere, E.; Onagbesan, O.; De Smit, L. et al

Conference (2006)

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See detailHypoxia in macrophytodetritus accumulation: Species specific harpacticoid copepod adaptation?
Mascart, Thibaud ULg; De Troch, Marleen; Gobert, Sylvie ULg et al

Poster (2014, May 05)

Mediterranean Posidonia oceanica seagrass meadows generate high primary production and support large biodiversity of associated fauna and flora. The majority of the foliar material falls on the ... [more ▼]

Mediterranean Posidonia oceanica seagrass meadows generate high primary production and support large biodiversity of associated fauna and flora. The majority of the foliar material falls on the unvegetated sea floor during the autumnal leaf senescence, fuelling the detrital food web. Whilst laying on the sea floor the freshly formed macrophytodetritus pile up into accumulations according to the local hydrodynamics and seafloor geomorphology. In these litter accumulations, harpacticoid copepods (Crustacea, Copepoda) are the main meiofaunal players (metazoans in the size range of 38µm – 1mm) and show a high specific diversity. They are primarily grazers, but their high specific diversity suggests that they occupy also a large variety of trophic niches. This large morphological and trophic diversity can partly be promoted by the complexity of the phytodetritus in seagrass accumulations. On the other hand, macrophytodetritus degradation and flux of reduced compounds from the sediments is responsible for oxygen consumption inside the accumulation of seagrass litter. Therefore, concentration of oxygen inside the accumulation is very variable and often under the concentration observed in the water column just above the litter. Frequently, oxygen levels reach very low values. The present study aims to link the oxygen variability inside the accumulation to the densities of the five most dominant harpacticoid copepods found living in the P. oceanica litter. Standardized samples were collected seasonally in two contrasting sites of the Calvi Bay (Corsica) during one year. Our results showed no correlation between the oxygen concentrations and harpacticoid community diversity or their total abundances. The five most dominant species showed divergent results, but none had a clear correlation with the oxygen concentration. This contrasts with observation done for sediment meiofaunal community where most harpacticoid copepods are sensitive to oxygen level and where nematodes often dominate the community. This could be explained by their high mobility and the patchiness and variability of the oxygen concentrations present in the accumulations. Harpacticoid copepods, whilst being sensitive to hypoxia and anoxia developed a strategy to live in this fast oxygen changing environment. To conclude, our results underline the importance of species-specific analysis of correlation data. Especially in complex and dynamic environments where a variety of potential trophic niches are present and species competition is very likely to occur. The overall abundance pattern and diversity of the copepod community showed no relation to the oxygen concentration while the most abundant copepod species did not responded to fluctuating oxygen concentrations. [less ▲]

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See detailHypoxia in the Black Sea northwestern shelf: From eutrophication to climatic stressors.
Capet, Arthur ULg; Beckers, Jean-Marie ULg; Grégoire, Marilaure ULg

in 40th CIESM congress proceedings (2013, October)

Abstract The dynamics of seasonal hypoxia, which affects the Black Sea north-western shelf since the mid 1970's until present days, is investigated by means of a 3D biogeochemical model. Comparison of the ... [more ▼]

Abstract The dynamics of seasonal hypoxia, which affects the Black Sea north-western shelf since the mid 1970's until present days, is investigated by means of a 3D biogeochemical model. Comparison of the model results with in -situ data reveals that the phenomenon may have been underestimated after the mid 1990's due to the distribution of observations. We investigate the mechanism of hypoxia at seasonal scale, and identify the main drivers of its interannual variability. While high nutrients discharge caused severe hypoxia in the 1980's, it was sustained in the 1990's by the pool of organic matter accumulated during the previous years in the sediments layer. With an increasing intensity, climatic stressors intensifies the response of hypoxia to nutrient discharge, and affect the seasonal dynamics of hypoxia by extending its temporal scale. [less ▲]

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See detailHypoxia induces a phase transition within a kinase signaling network in cancer cells
Wei, Wei; Shia, Qihui; Remacle, Françoise ULg et al

in Proc. Natl. Acad. Sci. USA (2013)

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See detailHypoxia induces protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor activity
Sermeus, Audrey; Cosse, Jean-Philippe ULg; Crespin, Marianne et al

in Molecular Cancer (2008), 7

Background: it is now well established that hypoxia renders tumor cells resistant to radio- but also chemotherapy. However, few elements are currently available as for the mechanisms underlying this ... [more ▼]

Background: it is now well established that hypoxia renders tumor cells resistant to radio- but also chemotherapy. However, few elements are currently available as for the mechanisms underlying this protection. Results: in this study, physiological hypoxia was shown to inhibit apoptosis induced in HepG2 cells by etoposide. Indeed, hypoxia reduced DNA fragmentation, caspase activation and PARP cleavage. The DNA binding activity of 10 transcription factors was followed while the actual transcriptional activity was measured using specific reporter plasmids. Of note is the inhibition of the etoposideinduced activation of p53 under hypoxia. In parallel, data from low density DNA microarrays indicate that the expression of several pro- and anti-apoptotic genes was modified, among which are Bax and Bak whose expression profile paralleled p53 activity. Cluster analysis of data unravels several possible pathways involved in the hypoxia-induced protection against etoposide-induced apoptosis: one of them could be the inhibition of p53 activity under hypoxia since caspase 3 activity parallels Bax and Bak expression profile. Moreover, specific downregulation of HIF-1α by RNA interference significantly enhanced apoptosis under hypoxia possibly by preventing the hypoxia mediated decrease in Bak expression without altering Bax expression. Conclusion: these results are a clear demonstration that hypoxia has a direct protective effect on apoptotic cell death. Moreover, molecular profiling points to putative pathways responsible for tumor growth in challenging environmental conditions and cancer cell resistance to chemotherapeutic agents. [less ▲]

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See detailHypoxia induces translational regulation of VEGFC
Morfoisse, Florent ULg; Frainay, Clément; Pujol, Françoise et al

Poster (2012, October 29)

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See detailHypoxia Induces VEGF-C Expression in Metastatic Tumor Cells via a HIF-1a-Independent Translation-Mediated Mechanism
Morfoisse, Florent ULg; Kuchnio, Anna; Frainay, Clément et al

in Cell Reports (2014), 6

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See detailHypoxia is not required for human endometrial breakdown or repair in a xenograft model of menstruation.
Coudyzer, Pauline; Lemoine, Pascale; Jordan, Benedicte F. et al

in FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2013), sous presse

Menstrual endometrial breakdown induced by estradiol and progesterone withdrawal is regularly attributed to vasospasm of spiral arteries causing ischemia and hypoxia. We investigated whether hypoxia ... [more ▼]

Menstrual endometrial breakdown induced by estradiol and progesterone withdrawal is regularly attributed to vasospasm of spiral arteries causing ischemia and hypoxia. We investigated whether hypoxia actually occurred in an in vivo model of menstruation. Three complementary approaches were used to look for signs of hypoxia in fragments of human functionalis xenografted to ovariectomized immunodeficient mice bearing pellets-releasing estradiol and progesterone, and then deprived of ovarian steroids. Hormone withdrawal 21 d after grafting induced menstrual breakdown and MMP expression within 4 d. Local partial oxygen pressure (pO2) was measured by electron paramagnetic resonance using implanted lithium phtalocyanine crystals. In mice with hormone maintenance until sacrifice, pO2 was low one week after grafting (14.8+/-3.4 mmHg) but increased twofold from the second week when tissue was largely revascularized. After 3 wk, pO2 was not modified by hormone withdrawal but was slightly increased on hormone reimpregnation 4 d after removal (34.7+/-6.1 mmHg) by comparison with hormone maintenance (27.1+/-8.6 mmHg). These results were confirmed using fluorescence quenching-based OxyLite measurements. In a further search for signs of hypoxia, we did not find significant HIF1-alpha immunostaining, nor pimonidazole adducts after hormone withdrawal. We conclude that hypoxia is not needed to trigger menstrual-like tissue breakdown or repair in human endometrial xenograft.-Coudyzer, P., Lemoine, P., Jordan, B. F., Gallez, B., Galant, C., Nisolle, M., Courtoy, P. J., Henriet, P., and Marbaix, E. Hypoxia is not required for human endometrial breakdown or repair in a xenograft model of menstruation. [less ▲]

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See detailHypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast
Munaut, Carine ULg; Lorquet, Sophie ULg; Pequeux, Christel ULg et al

in Human Reproduction (2008), 23(6), 1407-15

BACKGROUND: Pre-eclampsia is a pregnancy disorder characterized by a maternal endothelial cell dysfunction associated with low levels of circulating placental growth factor (PlGF) and increased levels of ... [more ▼]

BACKGROUND: Pre-eclampsia is a pregnancy disorder characterized by a maternal endothelial cell dysfunction associated with low levels of circulating placental growth factor (PlGF) and increased levels of total vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1), and soluble endoglin, a transforming growth factor b1 and 3 coreceptor. Here, we tested the hypothesis that these altered levels of angiogenic cytokines and of the anti-angiogenic soluble forms of cytokine receptors could be the consequence of hypoxia. METHODS: Normal human umbilical vein endothelial cells, immortalized first trimester extravillous trophoblast cells (HTR8/SVneo) and first trimester placental villi explants (8–14 weeks) were used for culture under normoxia (20% O2) or hypoxia (1% O2). Culture media were collected for the measurement of cytokines by enzyme-linked immunosorbent assay. Total RNA was extracted for RT-PCR analysis. RESULTS: Under hypoxia, villous trophoblast expressed higher levels of VEGF, VEGFR-1, sVEGFR-1 and VEGFR-2 mRNAs (P < 0.001), and secreted more VEGF and sVEGFR-1 proteins (P < 0.05). In contrast, PlGF mRNA and protein were decreased in 1% O2 (P < 0.001), whereas endoglin (Eng) was not modulated. Additionally, sVEGFR-1 directly abolished VEGF/PlGF-induced angiogenesis in the rat aortic ring assay. CONCLUSIONS: Our results support the hypotheses that, in pre-eclampsia, (i) overproduction of VEGF family factors by pre-eclamptic placenta is a consequence of induced hypoxia; (ii) overproduction of sVEGFR-1 by hypoxic villous trophoblast accounts for maternal free VEGF depletion; (iii) low circulating level of free PlGF is not only related to sVEGFR-1 overproduction, but also to hypoxia induced mRNA down-regulation; (iv) Eng is not modulated by hypoxia.. [less ▲]

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See detailHypoxia promotes resistance to etoposide by regulating p53 stability and c-jun DNA-binding activity
Cosse, Jean-Philippe ULg; Ronvaux, Marie; Ninane, Noelle et al

Poster (2008)

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See detailHypoxia promotes resistance to etoposide by regulating p53 stability and c-jun DNA-binding activity
Cosse, Jean-Philippe ULg; Ronvaux, Marie; Ninane, Noelle et al

Conference (2008)

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See detailHypoxia protects HepG2 cells against etoposide-induced apoptosis VIA a HIF-1-independent pathway
Piret, Jean-Pascal; Cosse, Jean-Philippe ULg; Ninane, Noelle et al

in Experimental Cell Research (2006), 312

Tumor hypoxia has been described to increase the resistance of cancer cells to radiation therapy and chemotherapy. It also supports the invasiveness and metastatic potential of the tumor. However, few ... [more ▼]

Tumor hypoxia has been described to increase the resistance of cancer cells to radiation therapy and chemotherapy. It also supports the invasiveness and metastatic potential of the tumor. However, few data are available on the transduction pathway set up under hypoxia and leading to this resistance against anti-cancer therapies. HIF-1, the main transcription factor activated by hypoxia, has been recently shown to participate to this process although its role as an anti- or a pro-apoptotic protein is still controversy. In this study, we showed that hypoxia protected HepG2 cells against etoposide-induced apoptosis. The effect of hypoxia on cell death was assayed by measuring different parameters of the apoptotic pathway, like DNA fragmentation, caspase activity and PARP-1 cleavage. The possible implication of HIF-1 in the anti-apoptotic role of hypoxia was investigated using HIF-1α siRNA. Our results indicated that HIF-1 is not involved in the hypoxia-induced antiapoptotic pathway. Another transcription factor, AP-1, was studied for its potential role in the hypoxia-induced protection against apoptosis. Specific inhibition of AP-1 decreased the protection effect of hypoxia against etoposide-induced apoptosis. Together, all these data underline that hypoxia could mediate its anti-apoptotic role via different transcription factors depending on the cellular context and pro-apoptotic stimuli. [less ▲]

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See detailHypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction.
Minet, E.; Mottet, Denis ULg; Michel, G. et al

in FEBS Letters (1999), 460(2), 251-6

The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear ... [more ▼]

The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear translocator (ARNT)-Sim (PAS) factors Sim and aryl hydrocarbon receptor (Ahr). The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), involved in the response to hypoxia, also belongs to the bHLH-PAS family. This work was aimed to investigate the putative role of Hsp90 in HIF-1 activation by hypoxia. Using a EGFP-HIF-1alpha fusion protein, co-immunoprecipitation experiments evidenced that the chimeric protein expressed in COS-7 cells interacts with Hsp90 in normoxia but not in hypoxia. We also demonstrated that Hsp90 interacts with the bHLH-PAS domain of HIF-1alpha. Moreover, Hsp90 is not co-translocated with HIF-1alpha into the nucleus. At last, we showed that Hsp90 activity is essential for HIF-1 activation in hypoxia since it is inhibited in the presence of geldanamycin. These results indicate that Hsp90 is a major regulator in HIF-1alpha activation. [less ▲]

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See detailHypoxia-Induced Decrease in p53 Protein Level and Increase in c-jun DNA Binding Activity Results in Cancer Cell Resistance to Etoposide
Cosse, Jean-Philippe ULg; Ronvaux, Marie; Ninane, Noelle et al

in Neoplasia : An International Journal for Oncology Research (2009), 11

Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance in particular by cellular adaptations that modulate the apoptotic process. However, the mechanisms ... [more ▼]

Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance in particular by cellular adaptations that modulate the apoptotic process. However, the mechanisms involved in this resistance still need deeper understanding. In this study, we investigated the involvement of four transcription factors, c-Myc, nuclear factor κB (NF-κB), p53, and c-jun/activator protein 1 (AP-1) in the hypoxia-induced resistance to etoposide in HepG2 cells. Whereas the profile of c-Myc and NF-κB activity did not fit the effect of hypoxia on caspase 3 activity, hypoxia decreased basal p53 abundance and DNA binding activity as well as p53 etoposide-induced activation. Short interfering RNA (siRNA) silencing evidenced that p53 was required for etoposide-induced apoptosis under normoxia. An inhibition of its activity under hypoxia could thus be responsible at least in part for the protection observed under hypoxic conditions. Moreover, p53 was found to induce the expression of Bak1. We showed that Bak1 was involved in the etoposide-induced apoptosis because Bak1 siRNA decreased it. Conversely, hypoxia increased c-jun DNA binding activity in the presence of etoposide. siRNA-mediated silencing of c-jun increased the responsiveness of cells to etoposide under hypoxia, as shown by an increase in caspase 3 activity and lactate dehydrogenase release. These effects occurred in a p53-independent manner. These data evidenced that hypoxia decreased the responsiveness of HepG2 cells to etoposide at least by two independent pathways involving p53 inhibition and c-jun activation. [less ▲]

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See detailThe hypoxia-inducible factor HIF-1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects.
Qing, Ma; Gorlach, Agnes; SCHUMACHER, Katharina ULg et al

in Basic Research in Cardiology (2007), 102(3), 224-232

OBJECTIVES: The response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) which leads to the induction of a variety of adaptive gene products including ... [more ▼]

OBJECTIVES: The response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) which leads to the induction of a variety of adaptive gene products including vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). This study was designed to test the hypothesis that HIF-1 and its target genes would be upregulated in the ventricular myocardium of infants with cyanotic congenital cardiac defects. METHODS: 14 infants with cyanotic (n = 7) or acyanotic cardiac defects (n = 7) were investigated. Samples from the right ventricular myocardium taken immediately after aortic clamping were studied for protein expression and DNA-binding activity. RESULTS: Protein levels of HIF-1alpha were significantly elevated in patients with cyanotic compared to acyanotic congenital heart disease and inversely correlated with the degree of hypoxemia. This response was accompanied by significantly enhanced HIF-1 DNA binding activity. Furthermore, protein levels of VEGF and eNOS were significantly higher in the myocardium of cyanotic than of acyanotic infants. To test the potential involvement of upstream regulatory pathways, activation of MAP kinases was determined. Intramyocardial levels of phosphorylated p38 MAP kinase, but not of ERK1/2 were significantly higher in infants with cyanotic compared to those with acyanotic congenital heart disease and inversely correlated to hypoxemia. CONCLUSIONS: These findings show that chronic hypoxemia is associated with the induction and stabilization of the transcription factor HIF-1 as well as its target genes VEGF and eNOS in the myocardium of infants with cyanotic cardiac defects. Thus, stabilization of HIF-1 and induction of the adaptive hypoxia response could particularly participate in myocardial remodeling in children with congenital cardiac defects and chronic hypoxemia. [less ▲]

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See detailHypoxia-inducible Factor-1-dependent Overexpression of Myeloid Cell Factor-1 Protects Hypoxic Cells against tert-Butyl Hydroperoxide-induced Apoptosis
Piret, Jean-Pascal; Minet, Emmanuel; Cosse, Jean-Philippe ULg et al

in Journal of Biological Chemistry (2005), 280

Increased levels of Mcl-1 (myeloid cell factor-1) have been reported in several cancers, suggesting an important role played by Mcl-1 in cancer cell survival. Mcl-1 is an anti-apoptotic protein shown to ... [more ▼]

Increased levels of Mcl-1 (myeloid cell factor-1) have been reported in several cancers, suggesting an important role played by Mcl-1 in cancer cell survival. Mcl-1 is an anti-apoptotic protein shown to delay or block apoptosis. In this work, using semiquantitative immunofluorescence, real-time PCR, and RNase protection assay, an increase in Mcl-1 expression was detected in hepatoma HepG2 cells incubated under hypoxia or in the presence of cobalt chloride. Through analysis of the Mcl-1 promoter sequence, a putative HIF-1 (hypoxiainducible factor-1) binding site was identified. A Mcl-1 promoter fragment containing this hypoxia-responsive element was able to bind HIF-1 in vitro. It also induced hypoxia-dependent transcription of a luciferase reporter gene, which was suppressed by anti-HIF-1 short interfering RNA. Finally, overexpression of Mcl-1 protected HepG2 cells against apoptosis induced by tertbutyl hydroperoxide as shown by inhibition of caspase-3 activation and DNA fragmentation. All these data suggest a potential anti-apoptotic role of HIF-1 that could protect cells against apoptosis under hypoxia by overexpression of the Mcl-1 protein. [less ▲]

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See detailHypoxic ischemic encephalopathy : new insights in neuroprotection
VIELLEVOYE, Renaud ULg

Conference (2015, September 26)

Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal morbidity and mortality and is a common cause of disability with devastating impact on individuals and families. During the acute ... [more ▼]

Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal morbidity and mortality and is a common cause of disability with devastating impact on individuals and families. During the acute phase, HIE is initially characterized by an excitotoxic cascade with hypoxic membrane depolarization, cytotoxic edema, glutamate release and intracellular accumulation of calcium leading to necrotic cell death and production of proinflammatory cytokines through the NF-κB pathway. In a second phase, reperfusion leads to production of free radicals, activation of proteases and phospholipases, exacerbing the damage to cell membrane and DNA and mitochondrial dysfunction causing caspase mediated apoptotic cell death. In a third phase, growth factors and inflammatory cytokines produced during the early phase of HIE attempt to repair damage induced by hypoxia–ischemia. Although the utility of therapeutic hypothermia induced in the 6 hours following HIE in the reduction of death or major neurodevelopmental disability is now well established in the neonate with moderate or severe encephalopathy, almost half of these children still die or have abnormal outcomes [1]. Protocols attempting to optimize cooling with deeper hypothermia (33.5°C vs 32.0°C) and/or longer duration (72h vs 120h), as well protocols studying neuroprotective effect of late hypothermia (6-24h) or hypothermia for 33-35 week GA preterm babies are currently performed. Furthermore, experimental data suggest that hypothermia extends the duration of the therapeutic window [2] and that certain drugs given during this time may improve neuroprotection either additively or synergistically. Xenon is a noble gas with anaesthetic and neuroprotective properties. It inhibits NMDA receptor, promotes cell survival and induces the production of erythropoietin and vascular endothelial growth factor through the hypoxia inducible factor 1 alpha (HIF-1α) pathway. Data from experimental piglet models of hypoxia-ischemia (HI) demonstrate a synergy when Xenon is administered in combination with mild therapeutic hypothermia [3]. In the human newborn, a phase-1 trial recently established that breathing 50% Xenon for up to 18 hours with 72 hours of cooling was feasible, with no adverse effects seen with 18 months’ follow-up [4]. A monocentric phase-3 trial is currently under process in England. Melatonin is a remarkable natural antioxidant but also exhibits antiapoptotic and anti-inflammatory properties in vitro. In animal models, melatonin administration prior or after the onset of HI significantly reduced infarct volume demonstrating both prophylactic and therapeutic effect [5-6]. When combined with hypothermia, melatonin enhances neuroprotection by reduction of the H–I-induced increase in clinically relevant biomarkers in the deep grey matter of newborn piglets [7]. Clinical studies confirmed its safety profile and its ability to reduce biomarkers level of HI in the human newborn [8]. Recently, a randomized controlled trial showed that the combination of melatonin and hypothermia administered to infants with moderate-to-severe H–I brain injury was efficacious in reducing oxidative stress, neonatal seizures and MRI brain lesions as well as in improving neurological outcomes at 6 months of age [9]. Erythropoietin (EPO) and its receptor are expressed in the developing central nervous system and are required for normal brain development. EPO is up-regulated in umbilical cord blood from babies who have suffered HI, which may be an endogenous repair mechanism. In vitro and in vivo neuroprotection induced by EPO is achieved by several mechanisms such as direct neurotrophic effect, direct antioxidant effects, decreased inflammation or regulation between pro-apoptotic and anti-apoptotic factors. Safety profile of EPO administration during hypothermia for newborns with HIE has been established in Phase I trials [10]. In a randomized prospective pase-2 trial, repeated low-dose rEPO reduced the risk of disability for infants with moderate but not severe HIE at 18 months, without apparent side effects [11]. A double-blind randomized controlled phase-3 trial is currently performed in France. Allopurinol is a xantine-oxidase inhibitor. In high concentrations it also scavenges hydroxyl radicals and prevents free radical formation. Allopurinol provides neuroprotection in rat and piglets models of HIE. In the human, a systematic review and meta-analysis of three studies on 114 newborns did not reveal statistically difference in the risk of death or a composite of death or severe neurodevelopmental disability between groups [12]. It was hypothesized that postnatal allopurinol treatment started too late to reduce reperfusion-induced free radical surge. However, in a recent study, allopurinol given to mothers during labor with fetal hypoxia did not significantly lower neuronal damage markers in cord blood even if post hoc analysis revealed a potential beneficial treatment effect in girls [13]. Magnesium sulfate (MgSO4) is a naturally occurring NMDA receptor antagonist. MgSO4 given to mothers at risk for preterm birth is associated with a reduced risk of cerebral palsy and gross motor dysfunction in their children. Its role as an adjuvant to therapeutic hypothermia in the asphyxiated term infant remains unclear. A recent review of preclinical studies using MgSO4 in HIE highlights the inconsistent impact between studies related to a lack of temperature control during and after HI, along with variability in the dose, timing of treatment [14]. A metaanalysis of five randomized controlled trials that compared magnesium to control in newborns with HIE showed a significant improvement in short term outcomes but no difference in the composite outcome of death or moderate to severe disability at 18 months [15]. Other NMDA and AMPA antagonist such as topiramate and memantine also exhibited neuroprotective properties in animal models but safety and efficacy in the human newborn with HIE still needs to be clarified [16]. N-acetyl cysteine (NAC) acts as a glutathione precursor with antioxidant, antiapoptotic, and anti-inflammatory properties. In a piglet model of HIE, NAC reduced cerebral oxidative stress, reduced cerebral lactate accumulation and improved cerebral perfusion. When combined with hypothermia in the asphyxiated rodent, NAC decreased infarct volume, improved myelin expression and functional outcomes on a synergistic pattern. NF-κB inhibitors and NO synthase inhibitors are other therapeutic options currently under investigation in in vitro and in vivo preclinical studies. Moreover, recent research performed at the University of Liege also suggests that Estetrol (E4), an estrogen synthetized exclusively by the human foetus, has neuroprotective properties in a rat model of HIE. Translation to clinical use in humans still needs to be studied [17]. Several therapies have also been suggested in order to improve mechanisms of repair and regeneration observed after the HI insult. Growth factors such as BDNF, IGF-1, EGF or bFGF can improve cell viability, stimulate the growth of new neurons or promotes oligodendroglial differentiation and myelination. Recent advances in regenerative medicine suggest that stem cell transplantation may improve repair of the damaged brain after HIE through the replacement of dead cells as well as through the release of trophic factors [18]. Animal preclinical data are promising. However many questions need to be answered with well-designed controlled trials before clinical application in daily practice. References [1] Edwards AD et al. (2010) Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 340:c363. [2] O'Brien F et al. (2006) Delayed whole-body cooling to 33 or 35 degrees c and the development of impaired energy generation consequential to transient cerebral hypoxia-ischemia in the newborn piglet. Pediatrics 117:1549–59. [3] Chakkarapani, E. et al. (2010) Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Ann. Neurol. 68, 330–341 [4] Dingley, J. et al. (2014) Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics 133, 809–818 [5] Carloni, S. et al. (2008) Melatonin protects from the long-term consequences of a neonatal hypoxic–ischemic brain injury in rats. J. Pineal. Res. 44, 157–164 [6] Hutton, L.C. et al. (2009) Neuroprotective properties of melatonin in a model of birth asphyxia in the spiny mouse (Acomyscahirinus). Dev. Neurosci. 31, 437–451 [7] Robertson, N.J. et al. (2013) Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 136, 90–105 [8] Fulia, G. et al. (2001) Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. Journal of Pineal Research; 31(4):343–349. [9] Aly, H. et al. (2015) Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J. Perinatol. 35, 186–191 [10] Wu, Y.W. et al. (2012) Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 130, 683–691 [11] Zhu, C. et al. (2009) Erythropoietin improved neurologic outcomes in newborns with hypoxic–ischemic encephalopathy. Pediatrics 124, 218–226 [12] Chaudhari, T. and McGuire, W. (2012) Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic–ischaemic encephalopathy. Cochrane Database Syst. Rev. 7, Cd006817 [13] Kaandorp, J.J. et al. (2015) Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch. Dis. Child Fetal Neonatal Ed. 100, F216–F223 [14] Galinsky, R. et al. (2014) Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in term-equivalent models in preclinical studies: a systematic review. Dev. Neurosci. 36, 73–82 [15] Tagin, M. et al. (2013) Magnesium for newborns with hypoxic–ischemic encephalopathy: a systematic review and meta-analysis. J. Perinatol. 33, 663–669 [16] Wu, Q et al. (2015) Neuroprotective agents for neonatal hypoxic–ischemic brain injury. Drug Discovery Today. [17] Tskitishvili, E et al. (2014). Estetrol attenuates neonatal hypoxic–ischemic brain injury. Experimental Neurology, 261, 298-307. [18] Kelen, D and Robertson, NJ. (2010) Experimental treatments for hypoxic ischaemic encephalopathy. Early Human Development 86; 369–377. [less ▲]

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See detailHypoxic pulmonary vasoconstriction and anaesthesia
Brichant, Jean-François ULg

Conference (2002, April)

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See detailHypoxic-Ischemic Encephalopathy and Premature Babies Brain Damage: Impact of Estetrol
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 11th Congress of the European Society of Gynecology, Prague 21-24 October, 2015 (2015)

Neonatal hypoxic-ischemic brain injury remains a main problem of perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities ... [more ▼]

Neonatal hypoxic-ischemic brain injury remains a main problem of perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities mostly in the form of motor and cognitive delays. The nature of the deficits is dependent on the gestational age and severity of the insult, though it is s seldom reported in preterm infants. No medical treatment provides important neuroprotection against HIE. Studies in animal models of HIE may provide important information for the development of treatment for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. In this study, we defined the antioxidative effect of E4 in primary hippocampal cell cultures taken from newborn rat pups (in vitro) and evaluated its neuroprotective and therapeutic potency in neonatal HIE model of the immature newborn rat (in vivo). Lactate Dehydrogenase (LDH) and cell survival (MTS) assays were performed on primary neuronal cell cultures. Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of two markers of brain damage (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate that E4 has a significant neuroprotective and therapeutic dose-dependent effects. Estetrol has powerful antioxidative and cell survival effects in vitro. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, Estetrol might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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