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| 2. |
- Fukuda, Hirotsugu, et al.
(author)
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Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition
- 2004
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In: Cell Death Differ. - Univ Gothenburg, Dept Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. Osaka Univ, Sch Med, Dept Obstet & Gynecol, Suita, Osaka 5650871, Japan. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Uppsala Univ, Dept Neurosci, SE-75123 Uppsala, Sweden. Sahlgrens Univ Hosp, Dept Radiat Phys, SE-41345 Gothenburg, Sweden. H Lundbeck & Co AS, Mol Dis Biol, DK-2500 Copenhagen, Denmark. Sahlgrens Univ Hosp, Dept Oncol, SE-41345 Gothenburg, Sweden. Queen Silvia Childrens Hosp, Dept Pediat, SE-41685 Gothenburg, Sweden. : NATURE PUBLISHING GROUP. - 1350-9047 .- 1476-5403. ; 11:11, s. 1166-78
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Journal article (peer-reviewed)abstract
- One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.
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| 3. |
- Hagberg, Henrik, 1955, et al.
(author)
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PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury
- 2004
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In: J Neurochem. ; 90:5, s. 1068-75
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Journal article (peer-reviewed)abstract
- Poly(ADP-ribose) polymerase-1 is over-activated in the adult brain in response to ischemia and contributes to neuronal death, but its role in perinatal brain injury remains uncertain. To address this issue, 7-day-old wild-type (wt) and PARP-1 gene deficient (parp+/- and parp-/-) Sv129/CD-1 hybrid mice were subjected to unilateral hypoxia-ischemia and histologic damage was assessed 10 days later by two evaluators. Poly(ADP-ribose) polymerase-1 knockout produced moderate but significant (p < 0.05) protection in the total group of animals, but analysis by sex revealed that males were strongly protected (p < 0.05) in contrast to females in which there was no significant effect. Separate experiments demonstrated that PARP-1 was activated over 1-24 h in both females and males after the insult in neonatal wt mice and rats using immnocytochemistry and western blotting for poly(ADP-ribose). Brain levels of NAD+ were also significantly reduced, but the decrease of NAD+ during the early post-hypoxia-ischemia (HI) phase was only seen in males. The results indicate that hypoxia-ischemia activates Poly(ADP-ribose) polymerase-1 in the neonatal brain and that the sex of the animal strongly influences its role in the pathogenesis of brain injury.
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| 4. |
- Plesnila, N., et al.
(author)
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Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia
- 2004
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In: J Cereb Blood Flow Metab. ; 24:4, s. 458-66
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Journal article (peer-reviewed)abstract
- Signaling cascades associated with apoptosis contribute to cell death after focal cerebral ischemia. Cytochrome c release from mitochondria and the subsequent activation of caspases 9 and 3 are critical steps. Recently, a novel mitochondrial protein, apoptosis-inducing factor (AIF), has been implicated in caspase-independent programmed cell death following its translocation to the nucleus. We, therefore, addressed the question whether AIF also plays a role in cell death after focal cerebral ischemia. We detected AIF relocation from mitochondria to nucleus in primary cultured rat neurons 4 and 8 hours after 4 hours of oxygen/glucose deprivation. In ischemic mouse brain, AIF was detected within the nucleus 1 hour after reperfusion after 45 minutes occlusion of the middle cerebral artery. AIF translocation preceded cell death, occurred before or at the time when cytochrome c was released from mitochondria, and was evident within cells showing apoptosis-related DNA fragmentation. From these findings, we infer that AIF may be involved in neuronal cell death after focal cerebral ischemia and that caspase-independent signaling pathways downstream of mitochondria may play a role in apoptotic-like cell death after experimental stroke.
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| 5. |
- Wang, Xiaoyang, 1965, et al.
(author)
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The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin.
- 2004
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In: Journal of neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 91:4, s. 900-10
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Journal article (peer-reviewed)abstract
- Recently, erythropoietin (EPO) and the nonerythropoietic derivative asialoEPO have been linked to tissue protection in the nervous system. In this study, we tested their effects in a model of neonatal hypoxia-ischemia (HI) in 7-day-old rats (unilateral carotid ligation and exposure to 7.7% O(2) for 50 min). EPO (10 U/g body weight = 80 ng/g; n = 24), asialoEPO (80 ng/g; n = 23) or vehicle (phosphate-buffered saline with 0.1% human serum albumin; n = 24) was injected intraperitoneally 4 h before HI. Both drugs were protective, as judged by measuring the infarct volumes, neuropathological score and gross morphological score. The infarct volumes were significantly reduced by both EPO (52%) and asialoEPO (55%) treatment, even though the plasma levels of asialoEPO had dropped below the detection limit (1 pm) at the onset of HI, while those of EPO were in the nanomolar range. Thus, a brief trigger by asialoEPO before the insult appears to be sufficient for protection. Proteomics analysis after asialoEPO treatment alone (no HI) revealed at least one differentially up-regulated protein, synaptosome-associated protein of 25 kDa (SNAP-25). Activation (phosphorylation) of ERK was significantly reduced in asialoEPO-treated animals after HI. EPO and the nonerythropoietic asialoEPO both provided significant and equal neuroprotection when administered 4 h prior to HI in 7-day-old rats. The protection might be related to reduced ERK activation and up-regulation of SNAP-25.
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| 6. |
- Wang, Xiaoyang, 1965, et al.
(author)
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X-linked inhibitor of apoptosis (XIAP) protein protects against caspase activation and tissue loss after neonatal hypoxia-ischemia
- 2004
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In: Neurobiol Dis. - Univ Gothenburg, Dept Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Obstet & Gynecol, SE-41685 Gothenburg, Sweden. Uppsala Univ, Dept Neurosci, SE-75123 Uppsala, Sweden. Univ Gothenburg, Dept Med Biophys, SE-40530 Gothenburg, Sweden. Univ Gothenburg, Queen Silvia Childrens Hosp, Dept Pediat, SE-41685 Gothenburg, Sweden. : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 16:1, s. 179-89
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Journal article (peer-reviewed)abstract
- Nine-day-old transgenic XIAP overexpressing (TG-XIAP) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 60 min, leading to widespread infarctions in the ipsilateral hemisphere during reperfusion. The activation of caspase-3 and -9 seen in wild-type animals was virtually abolished in TG-XIAP mice. Tissue loss was significantly reduced from 54.4 +/- 4.1 mm(3) (mean +/- SEM) in wild-type mice to 33.1 +/- 2.1 mm(3) in the TG-XIAP mice. Injured neurons displayed stronger XIAP staining during reperfusion, particularly in the nuclei. XIAP was colocalized with XAF-1, Smac, and HtrA2 in injured neurons after hypoxia-ischemia (HI). XIAP was cleaved after HI, and Smac immunoprecipitation co-precipitated a 25-kDa C-terminal fragment of XIAP, indicating that Smac preferentially bound to cleaved XIAP. These findings provide the first evidence that increased XIAP levels protect the neonatal brain against HI.
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| 7. |
- Zhu, Changlian, 1964
(author)
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Caspase-dependent and caspase-independent neuronal injury in the developing brain
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Aims: To investigate the mechanisms of neuronal cell death after hypoxia-ischemia in the developing brain.Methods: Rats or mice were subjected to left common carotid artery ligation plus hypoxia. Animals were sacrificed at certain time points after hypoxia-ischemia. The brains were collected for immunohistochemistry, western blotting, enzyme activity measurement and brain injury assessment.Results: Caspase-3 was activated after HI, and reached a peak level at 24 h post-HI. Immunoreactivity for active caspase-3 corresponded well with hybridization with an oligonucleotide hairpin probe, a marker of double-stranded DNA breaks with one nucleotide overhang in the 3 end. Calpain activation and, subsequently, Caspase-3 activation occurred after HI. Calpain inhibitors reduced cleavage of pro-caspase-3 into a 29 kDa product and decreased the activation of caspase-3. Calpain activation facilitated further activation of caspase-3. After HI, AIF was lost from mitochondria and the levels increased in nuclei (translocation) and, subsequently, signs of caspase-independent DNA damage occurred. AIF release occurred earlier than that of cytochrome c and correlated with tissue damage. A broad spectrum caspase inhibitor markedly reduced activation of caspase activity after HI, but still did not confer tissue protection. Nitrotyrosine formation preceded AIF release and caspase-3 activation. Nitrotyrosine is an early marker of cellular injury. Combined inhibition of nNOS and iNOS by 2-iminobiotin(a known neuroprotectant)reduced nitrotyrosine formation and caspase-3 activation. Immaturity greatly influences the outcome of HI, but not in a linear fashion. Apoptosis-related mechanisms of neuronal cell death after HI are much more prevalent in the developing brain, including both caspase-dependent and caspase-independent pathways.Conclusions: Several apoptotic mechanisms are activated in neonatal brain after HI. Inhibition of apoptotic mechanisms may be a fruitful neuroprotective strategy. Brain injury and neuronal cell death after hypoxia-ischemia is age-related and prevention and treatment of brain injury need to be adjusted to the developmental level.
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| 8. |
- Zhu, Changlian, 1964, et al.
(author)
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Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia
- 2004
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In: J Neurochem. ; 90:2, s. 462-71
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Journal article (peer-reviewed)abstract
- Excessive nitric oxide (NO) production after cerebral hypoxia-ischaemia (HI) may induce cellular injury in various ways, including reaction with superoxide to form the highly reactive peroxynitrite. We characterized the spatial and temporal formation of peroxynitrite through immunohistochemical detection of nitrosylated proteins. Nitrotyrosine immunoreactivity peaked around 3 h post-HI and was detected in areas of injury, as judged by the loss of microtubule-associated protein-2 (MAP-2) staining, in neurones, glia and endothelial cells. Nitrotyrosine staining co-localized with three other cellular markers of injury, active caspase-3, nuclear translocation of apoptosis-inducing factor (AIF) and an oligonucleotide hairpin probe detecting specific DNA strand breaks. The number of nitrotyrosine-positive cells at early time points outnumbered the cells positive for the other three markers of injury, indicating that nitrosylation preceded caspase-3 activation. Pharmacological inhibition of neuronal and inducible nitric oxide synthase (nNOS and iNOS) using 2-iminobiotin, which has been demonstrated earlier to be neuroprotective, significantly reduced nitrotyrosine formation and caspase-3 activation, but not nuclear translocation of AIF, in cortex and striatum of the ipsilatral hemisphere. In summary, nitrotyrosine is an early marker of cellular injury and inhibition of nNOS and iNOS is a promising strategy for neuroprotection after perinatal HI.
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| 9. |
- Zhu, Changlian, 1964, et al.
(author)
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Post-ischemic hypothermia-induced tissue protection and diminished apoptosis after neonatal cerebral hypoxia-ischemia
- 2004
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In: Brain Res. ; 996:1, s. 67-75
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Journal article (peer-reviewed)abstract
- Hypothermia is possibly the single most effective method of neuroprotection developed to date. However, the mechanisms are not completely understood. The aim of this study was to investigate the effects of post-ischemic hypothermia on brain injury and apoptotic neuronal cell death as well as related biochemical changes after neonatal hypoxia-ischemia (HI). Seven-day-old rats were subjected to left common carotid artery ligation and hypoxia (7.8%) for 1 h. Systemic hypothermia was induced immediately after hypoxia-ischemia, and body temperature was maintained at 30 degrees C for 10 h. The normothermic group was kept at 36 degrees C. Brain infarct volumes and neuronal loss in the CA1 area of the hippocampus were significantly reduced at 72 h post-HI in the hypothermia group. Cytochrome c release and activation of caspase-3 and -2 at 24 h post-HI were significantly diminished by hypothermia. The numbers of cytochrome c- and TUNEL-positive cells in the cortex and dentate gyrus of the hippocampus were significantly reduced in the hypothermia group compared with the normothermia group at 72 h post-HI. These results indicate that hypothermia may, at least partially, act through inhibition of the intrinsic pathway of caspase activation in the neonatal brain, thereby preventing apoptotic cell death.
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