Oxygen causes cell death in the developing brain

Felderhoff‐Mueser, Ursula; Bittigau, Petra; Sifringer, Marco; Jarosz, Bożena; Korobowicz, E; Mahler, Lieselotte; Piening, Turid; Moysich, Axel; Grune, Tilman; Thor, Friederike; Heumann, Rolf; Bührer, Christoph; Ikonomidou, Chrysanthy

doi:10.1016/j.nbd.2004.07.019

Cited by 213 publications

(250 citation statements)

References 45 publications

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“…In previous studies, we demonstrated that hyperoxia-induced cell death displays morphological features similar to physiological apoptotic cell death and occurs in a disseminated fashion throughout the immature rat brain. 9 The extent of brain damage depends both on the duration of an exposure to high oxygen levels and on the age of hyperoxiaexposed rodents; vulnerability is significantly increased in neonatal rodents and subsides by P14. 9 To further confirm that the observed changes in brain proteome reflect increased production of ROS and resulting oxidative stress, we examined brains of 7-day-old mice following hyperoxia or normoxia (controls) for proteins modified by ROS.…”

Section: Histological Featuresmentioning

confidence: 99%

“…9 The extent of brain damage depends both on the duration of an exposure to high oxygen levels and on the age of hyperoxiaexposed rodents; vulnerability is significantly increased in neonatal rodents and subsides by P14. 9 To further confirm that the observed changes in brain proteome reflect increased production of ROS and resulting oxidative stress, we examined brains of 7-day-old mice following hyperoxia or normoxia (controls) for proteins modified by ROS. Analysis of brain lysates revealed elevated levels of protein carbonyls, a general marker of oxidative stress ( Figure 4).…”

Section: Histological Featuresmentioning

confidence: 99%

“…However, in many cases, there is neither an obvious clinical explanation nor a corollary on conventional imaging studies for the neuropsychologic morbidity. Recent work has emphasized the role of intrauterine and neonatal infections, 5 pharmacologic agents 6,7 and oxygen [8][9][10] in triggering neuronal death in the developing mammalian brain.…”

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated that increased oxygen tension is a powerful trigger for widespread apoptotic cell death in the developing rodent brain. 9 This hyperoxiainduced apoptosis is associated with oxidative stress, upregulation of inflammatory cytokines, decreased expression of neurotrophins and decreased activation of neurotrophin-regulated pathways. 9,10 The timing of greatest vulnerability coincides with the peak of the brain growth spurt, which starts at about midpregnancy in humans and extends well into the third postnatal year.…”

Section: Introductionmentioning

confidence: 99%

“…9 This hyperoxiainduced apoptosis is associated with oxidative stress, upregulation of inflammatory cytokines, decreased expression of neurotrophins and decreased activation of neurotrophin-regulated pathways. 9,10 The timing of greatest vulnerability coincides with the peak of the brain growth spurt, which starts at about midpregnancy in humans and extends well into the third postnatal year. In mice and rats, this developmental period occurs within the first three postnatal weeks; 13 cross-species extrapolation with regard to the timing of the main brain growth spurt period thereby renders 6-dayold mice a model for preterm human infants.…”

Section: Introductionmentioning

confidence: 99%

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Acute and long-term proteome changes induced by oxidative stress in the developing brain

et al. 2005

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The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.

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Section: Histological Featuresmentioning

confidence: 99%

Section: Histological Featuresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute and long-term proteome changes induced by oxidative stress in the developing brain

et al. 2005

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Caspase‐1–processed interleukins in hyperoxia‐induced cell death in the developing brain

Felderhoff‐Mueser

Sifringer

Polley

et al. 2004

Annals of Neurology

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Infants born prematurely may develop neurocognitive deficits without an obvious cause. Oxygen, which is widely used in neonatal medicine, constitutes one possible contributing neurotoxic factor, because it can trigger neuronal apoptosis in the developing brain of rodents. We hypothesized that two caspase-1-processed cytokines, interleukin (IL)-1␤ and IL-18, are involved in oxygen-induced neuronal cell death. Six-day-old Wistar rats or C57/BL6 mice were exposed to 80% oxygen for various time periods (2, 6, 12, 24, and 48 hours). Neuronal cell death in the brain, as assessed by Fluoro-Jade B and silver staining, peaked at 12 to 24 hours and was preceded by a marked increase in mRNA and protein levels of caspase 1, IL-1␤, IL-18, and IL-18 receptor ␣ (IL-18R␣). Intraperitoneal injection of recombinant human IL-18 -binding protein, a specific inhibitor of IL-18, attenuated hyperoxic brain injury. Mice deficient in IL-1 receptor-associated kinase 4 (IRAK-4), which is pivotal for both IL-1␤ and IL-18 signal transduction, were protected against oxygen-mediated neurotoxicity. These findings causally link IL-1␤ and IL-18 to hyperoxia-induced cell death in the immature brain. These cytokines might serve as useful targets for therapeutic approaches aimed at preserving neuronal function in the immature brain, which is exquisitely sensitive to a variety of iatrogenic measures including oxygen. Neurol 2005;57:50 -59 Advances in the understanding of fetal physiology have resulted in markedly increased survival rates of premature infants. Ann

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Protection with estradiol in developmental models of apoptotic neurodegeneration

Asimiadou

Bittigau

Felderhoff‐Mueser

et al. 2005

Annals of Neurology

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Medical measures that bear no known danger for the adult brain may trigger active neuronal death in the developing brain. Pharmacological blockade of N-methyl-D-aspartate or activation of GABA(A) receptors, blockade of voltage-dependent sodium channels, and oxygen induce widespread apoptotic neurodegeneration during the period of rapid brain growth in rodents. Because such measures are often necessary in critically ill infants and toddlers, search for adjunctive neuroprotective strategies is warranted. We report that 17beta-estradiol ameliorates neurotoxicity of drugs that block N-methyl-D-aspartate receptors, activate GABA(A) receptors, or block voltage-gated sodium channels and reduces neurotoxicity of oxygen in the infant rat brain. This neuroprotective effect is reversed by tamoxifen and cannot be reproduced by 17alpha-estradiol. 17Beta-estradiol did not affect GABA(A) or N-methyl-D-aspartate currents in hippocampal neuronal cultures, indicating that direct modulation of neurotransmitter receptor/channel properties by this compound cannot explain neuroprotective effect. 17beta-Estradiol did, however, increase levels of phosphorylated extracellular signal-regulated kinase 1/2 and AKT, suggesting that activation of these prosurvival proteins may represent one mechanism for its neuroprotective action. 17Beta-estradiol and related compounds may be neuroprotective agents suitable for use in critically ill infants and toddlers. Its supplementation may particularly help to improve neurocognitive outcome in preterm infants who are prematurely deprived of maternal estrogen.

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Oxygen causes cell death in the developing brain

Cited by 213 publications

References 45 publications

Acute and long-term proteome changes induced by oxidative stress in the developing brain

Acute and long-term proteome changes induced by oxidative stress in the developing brain

Caspase‐1–processed interleukins in hyperoxia‐induced cell death in the developing brain

Protection with estradiol in developmental models of apoptotic neurodegeneration

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