Evidence of Nuclear DNA Fragmentation Following Hypoxia‐Ischemia in the Infant Rat Brain, and Transient Forebrain Ischemia in the Adult Gerbil

Ferrer, Isidró; Tortosa, Avelina; Macaya, Alfons; Sierra, Àngels; Moreno, Dolores; Munell, Francina; Blanco, Rosa; Squier, Waney

doi:10.1111/j.1750-3639.1994.tb00821.x

Cited by 145 publications

(67 citation statements)

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“…The injury resulting is similar to that seen in the term human infant that has been exposed to an H-I insult. We have found recently that BDNF markedly protects against the H-I injury in this model, a portion of which has features of apoptotic-like death (Ferrer et al, 1994;Mehmet et al, 1994;Hill et al, 1995;Sidhu et al, 1997;Silverstein et al, 1997;Hasegawa et al, 1998;Pulera et al, 1998) and is caspase dependent (Cheng et al, 1998;Han et al, 2000). Our results in the present study supporting the involvement of the ERK pathway in this protection may have important clinical implications.…”

Section: Discussionmentioning

confidence: 99%

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Han¹,

2000

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Neurotrophins activate several different intracellular signaling pathways that in some way exert neuroprotective effects. In vitro studies of sympathetic and cerebellar granule neurons have demonstrated that the survival effects of neurotrophins can be mediated via activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway. Neurotrophin-mediated protection of other neuronal types in vitro can be mediated via the extracellular signalrelated protein kinase (ERK) pathway. Whether either of these pathways contributes to the neuroprotective effects of neurotrophins in the brain in vivo has not been determined. Brain-derived neurotrophic factor (BDNF) is markedly neuroprotective against neonatal hypoxic-ischemic (H-I) brain injury in vivo. We assessed the role of the ERK and PI3-kinase pathways in neonatal H-I brain injury in the presence and absence of BDNF. Intracerebroventricular administration of BDNF to postnatal day 7 rats resulted in phosphorylation of ERK1/2 and the PI3-kinase substrate AKT within minutes. Effects were greater on ERK activation and occurred in neurons. Pharmacological inhibition of ERK, but not the PI3-kinase pathway, inhibited the ability of BDNF to block H-Iinduced caspase-3 activation and tissue loss. These findings suggest that neuronal ERK activation in the neonatal brain mediates neuroprotection against H-I brain injury, a model of cerebral palsy.

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Section: Discussionmentioning

confidence: 99%

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Han¹,

2000

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“…Neurons are thus thought to be fragile and very sensitive to such stress, and, as a consequence, apoptotic cell death occurs (2,3). Several studies have shown that caspases are involved in this neuronal apoptosis triggered by brain ischemia.…”

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confidence: 99%

Up-regulation of Protein-disulfide Isomerase in Response to Hypoxia/Brain Ischemia and Its Protective Effect against Apoptotic Cell Death

Tanaka

Uehara

Nomura

2000

Journal of Biological Chemistry

247

182

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We isolated and identified a stress protein that is upregulated in response to hypoxia in primary-cultured glial cells. Protein-disulfide isomerase (PDI) was up-regulated not only by hypoxia in glia in vitro, but also by transient forebrain ischemia in rats in vivo. To determine whether newly synthesized PDI is involved in tolerance to ischemic stress, we carried out two procedures to induce PDI gene expression in human neuroblastoma SK-N-MC cells, as well as intrahippocampal injection following electroporation of an expression vector capable of overexpressing PDI in rats. Overexpression of this gene resulted in attenuation of the loss of cell viability induced by hypoxia in neuroblastoma SK-N-MC cells and a reduction in the number of DNAfragmented cells in the CA1 area of the hippocampus in brain ischemic rats, respectively. These findings suggest that up-regulated PDI may play a critical role in resistance to ischemic damage, and that the elevation of levels of this protein in the brain may have beneficial effects against brain stroke.Two distinct phenomena are observed in the CA1 subfield of the hippocampus after transient forebrain ischemia in rodents: the death of neurons, which is referred to as "delayed neuronal death," and the proliferation of glial cells, which is termed "gliosis" (1). Neurons are thus thought to be fragile and very sensitive to such stress, and, as a consequence, apoptotic cell death occurs (2, 3). Several studies have shown that caspases are involved in this neuronal apoptosis triggered by brain ischemia. Transgenic mice expressing dominant-negative mutants of caspase-1 and caspase-1-deficient mice show a reduced neuronal cell death induced by ischemic brain injury (4 -6). Caspase inhibitors such as Z-VAD-fmk, 1 YVAD-fmk, and DEVD-fmk also significantly reduce the neuronal cell death induced by ischemia (7-9). Furthermore, overexpression of Bcl-2 in transgenic mice as well as of neuronal apoptosis inhibitory protein, a member of the inhibitor of apoptosis protein family, by injection of adenovirus expression vectors has a protective effect against the neuronal cell death induced by focal cerebral or transient forebrain ischemia (10, 11). These results suggest that caspases are involved in ischemia-induced neuronal death in an anti-apoptotic protein-dependent manner.On the other hand, glial cells show tolerance to ischemic stress, and their numbers are increased in areas originally containing neurons. Due to their abundance and ability to sustain environmental perturbations, glia play a critical role in maintaining neuronal function under both physiological and pathological conditions (12). Glial cells subjected to hypoxia express stress proteins such as a 70-kDa heat shock protein (HSP70), a 78-kDa glucose-regulated protein (GRP78), a 150-kDa oxygen-regulated protein (ORP150), a 36-kDa putative RNA-binding protein (RA301), and a 70-kDa putative vesicle transport-related protein (RA410) (13-16). Hori et al. (17) have reported that the inhibition of protein synthesis during early reoxy...

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“…Because it is considered that this period provides a therapeutic window after ischemic injury, there have been attempts to elucidate the exact mechanism of ischemia-induced neuronal cell death. Recently, evidence emerged that neurons are very fragile and sensitive to ischemic stress compared to glial cells and consequently undergo apoptotic cell death (Ferrer et al, 1994;Nitatori et al, 1995). The molecular mechanisms that trigger delayed neuronal cell death are not fully understood; however, hypotheses include the excitotoxicity of glutamate, a disturbed calcium homeostasis, an altered lipid metabolism, free radicals, and mitochondrial involvement (Abe et al, 1995;Juurlink and Sweeney, 1997).…”

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confidence: 99%

Correlation between Delayed Neuronal Cell Death and Selective Decrease in Phosphatidylinositol 4-Kinase Expression in the CA1 Subfield of the Hippocampus after Transient Forebrain Ischemia

Furuta

Uehara

Nomura

2003

J Cereb Blood Flow Metab

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Summary:Transient forebrain ischemia induces a delayed neuronal death in the CA1 area of the hippocampus. However, the mechanism leading to this phenomenon has yet to be established. The authors used an mRNA differential-display method to isolate genes for which mRNA levels change only in the hippocampus during ischemia/reperfusion. They succeeded in identifying the product of one down-regulated gene as phosphatidylinositol 4-kinase (PI 4-K). Compared with control levels, PI 4-K mRNA expression in the hippocampus, but not the cerebral cortex, was significantly decreased by 30% and about 80% 1 and 7 days after ischemia/reperfusion, respectively. Interestingly, PI 4-K and PI bisphosphate levels were selectively decreased in the CA1 region, but not other regions, whereas TUNEL-positive cells could be detected 3 days after ischemia. Consistent with these results, PI 4-K expression was suppressed by hypoxia in SK-N-MC neuroblastoma cells before loss of cell viability. Overexpression of wild-type PI 4-K, but not the kinase-negative mutant of PI 4-K (K1789A), recovered the loss of viability induced by hypoxia. These findings strongly suggest that a prior decrease in PI 4-K and PI bisphosphate levels caused by brain ischemia/hypoxia is partly involved in delayed neuronal cell death.

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Evidence of Nuclear DNA Fragmentation Following Hypoxia‐Ischemia in the Infant Rat Brain, and Transient Forebrain Ischemia in the Adult Gerbil

Cited by 145 publications

References 45 publications

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Up-regulation of Protein-disulfide Isomerase in Response to Hypoxia/Brain Ischemia and Its Protective Effect against Apoptotic Cell Death

Correlation between Delayed Neuronal Cell Death and Selective Decrease in Phosphatidylinositol 4-Kinase Expression in the CA1 Subfield of the Hippocampus after Transient Forebrain Ischemia

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