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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis has drawn attention in ischemic neuronal death recently. However, studies of apoptosis in cerebral ischemia have concentrated largely in DNA fragmentation, a late phase in apoptotic nuclei, at the expense of possible primary ischemic targets at the subcellular level and of upstream apoptotic signalling. To assess those issues, we used an intraluminal middle cerebral artery occlusion model in mice with or without reperfusion, and examined sequential changes of Bcl-2 family proteins modulating apoptotic signalling immunohistochemically and studied nuclear DNA fragmentation, to compare their chronology in relation to the development of infarct as detected by loss of microtubule-associated protein-2, an early marker of cytoplasmic damage. In the centre of the lesion, Bax protein increased and Bcl-2 and Bcl-x proteins decreased after loss of microtubule-associated protein-2 antigenicity occurred, but at the border of the lesion, the former changes preceded loss of microtubule-associated protein-2 antigenicity. Additionally, close morphologic analysis of DNA fragmentation in situ indicated that transient ischemia predominantly induced apoptotic cells but permanent ischemia produced necrosis of cells in the centre of the lesion. The contrasting cell death mechanisms, apoptosis and necrosis, are selectively involved in the pathology of cerebral ischemia, depending on its severity.
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PMID:Alterations of Bcl-2 family proteins precede cytoskeletal proteolysis in the penumbra, but not in infarct centres following focal cerebral ischemia in mice. 946 Jul 52

It has been reported that programmed cell death (apoptosis) occurs during myocardial infarction. The influence of age on programmed cell death or DNA fragmentation after coronary occlusion has not been extensively characterized. To test the hypothesis that there are age-related differences in susceptibility to DNA fragmentation during ischemia-infarction, we studied DNA fragmentation in young adult and old male F344 rat hearts after acute coronary artery occlusion. Hearts were studied at 1, 3, and 5 h and 1 and 7 days after coronary ligation. The percentage of apoptotic cells was determined by the in situ end-labeling technique, and internucleosomal fragmentation (DNA laddering) pattern was also analyzed. Our results show that 1) DNA fragmentation began earlier and peaked earlier in the old compared with young adult hearts during infarction; 2) there was heightened expression of both Bcl-2 and Bax in the old hearts at baseline; and 3) the Bcl-2-to-Bax ratio was higher in the older heart after coronary ligation. These results suggest that, compared with the young adult heart, the aged heart may be more susceptible to ischemia-induced DNA fragmentation.
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PMID:Bcl-2 and Bax expression in adult rat hearts after coronary occlusion: age-associated differences. 968 94

Delayed neuronal death was produced in the CA1 area of the hippocampus following 5 min of forebrain ischemia in adult gerbils. Immunohistochemistry and Western blotting to Bcl-2, Bax, and Bcl-x was examined in control (age-matched, non-operated and sham-operated) and ischemic gerbils. Bcl-2 immunoreactivity was low in CA1 neurons, but Bax was highly expressed in CA1 neurons of control gerbils. Moderate Bcl-x immunoreactivity was observed in control CA1 neurons. Strong Bcl-2 and Bcl-x immunoreactivity was found in CA1 neurons following ischemia. Bcl-2, Bax, and Bcl-x were localized in dying cells, thus suggesting that expression of Bcl-2 was not sufficient to prevent nerve cells from dying. Although the Bcl-x antibody does not discriminate between Bcl-xL and Bcl-xS content in tissue sections, Western blots disclosed a marked increase in the intensity of the band corresponding to Bcl-xS, but not of the band corresponding to Bcl-xL in ischemic hippocampi, thus indicating that the increase in Bcl-xS is associated with delayed cell death following transient forebrain ischemia in the adult gerbil.
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PMID:Bcl-2, Bax, and Bcl-x expression in the CA1 area of the hippocampus following transient forebrain ischemia in the adult gerbil. 969 85

Oxidative stress affecting DNA integrity may be an important mediator of cell death induced by cerebral ischemia followed by reperfusion. Genes involved in the DNA repair processes may play an important role in cell viability. We studied the spatial expression of the DNA damage inducible gene p53 and its transcriptional targets p21WAF1/CIP1, cyclin G1, and Bax and compared their expression with markers of early DNA damage following 10 min of transient forebrain ischemia in rats. Cyclin G1 and p21WAF1/CIP1 mRNA levels increased significantly between 2.5 and 4-fold in neurons of the hippocampus, cortex, and striatum during the first 24 hr after reperfusion and decreased at 48 hr of reperfusion. Significant increases in the protein levels of Cyclin G1 and p21 WAF1/CIP1 were only seen in the striatum at 48 hr of reperfusion. The mRNA levels of the p21 family members p27KIP1 or p57KIP2 demonstrated no significant changes. p53, baxalpha, and bcl-xl mRNA levels increased in all areas of the hippocampus by 12 to 24 hr and decreased over the next 2 days of reperfusion. baxalpha mRNA was specifically induced in neurons of the outer cortical layers at 12 and 24 hr after reperfusion, and protein levels increased in the striatum at 48 hr. No changes in protein levels of p53, Bcl-xl, or Bcl-2 were detected in the cerebral cortex, hippocampus, or striatum at any time point following reperfusion. Single-stranded DNA breaks detected with DNA polymerase I-mediated in situ nick translation partly overlapped with nuclear cyclin G1 protein in the striatum, cortex, and hippocampus at 24 hr, however at 48 hr cyclin G1 remained elevated only in neurons bordering areas exhibiting DNA damage. Nuclear p53 protein, p21 mRNA, and baxalpha mRNA were absent in cells stained with the in situ nick translation method but p21 mRNA and baxalpha mRNA were increased in neurons adjacent to those with detectable DNA nick ends at 24 and 48 hr following reperfusion. The enhanced expression of cyclin G1, p21WAF1/CIP1, and baxalpha in neurons surviving transient forebrain ischemia may indicate their participation in an adaptive response to cerebral ischemia and reperfusion.
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PMID:Increased expression of cyclin G1 and p21WAF1/CIP1 in neurons following transient forebrain ischemia: comparison with early DNA damage. 969 56

Delayed neuronal death in the gerbil hippocampal CA1 sector occurs 48 to 72 hours after severe forebrain ischemia. DNA fragmentation is observed in the hippocampal CA1 neurons at around that time. We show here that an inhibitor of proteolytic process of apoptosis, N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK), protected hippocampal neuronal damage by inhibition of the DNA fragmentation in a dose-dependent manner and that TPCK induced an apoptosis-regulating molecule, Bcl-2 protein, in the surviving neurons. These results suggest the prevention of apoptosis-related DNA fragmentation by TPCK may be an attractive therapeutic strategy for preserving hippocampal neurons from ischemic insult.
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PMID:Protective effect of apoptosis-inhibitory agent, N-tosyl-L-phenylalanyl chloromethyl ketone against ischemia-induced hippocampal neuronal damage. 970 42

Five minutes of bilateral common carotid artery occlusion in the Mongolian gerbil results in a selective, delayed death of CA1 pyramidal neurons. Although Bcl-2 appears to protect a variety of cells from cell death, the precise role of this apoptosis-regulating protein is complicated. We used immunoblots to estimate levels of Bcl-2, Bcl-x(l), and Bax at various times after carotid occlusion. Rather than Bcl-2, Bcl-x(l) appears to be the predominant neuroprotective form of this family of proto-oncogenes in the gerbil hippocampus. After transient ischemia, Bcl-2 and Bcl-x(l) protein levels remained the same. However, Bax levels were dramatically increased at 6 hours after ischemia, compared with sham-operated animals, and were still elevated at 72 hours after ischemia. To monitor dimerization interactions among theses apoptosis-regulating molecules, immunoprecipitation studies were conducted. These studies demonstrated that Bcl-x(l) association with Bax increases after ischemia. Therefore, Bax may disrupt the more favorable Bcl-x(l) (Bcl-2) interactions necessary for normal neuronal functioning and thus promote transient ischemic death.
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PMID:Bcl-x(l) Bax interaction after transient global ischemia. 970 49

In the central nervous system, interleukin (IL)-3 has been shown to exert a trophic action only on septal cholinergic neurons in vitro and in vivo, but a widespread distribution of IL-3 receptor (IL-3R) in the brain does not conform to such a selective central action of the ligand. Moreover, the mechanism(s) underlying the neurotrophic action of IL-3 has not been elucidated, although an erythroleukemic cell line is known to enter apoptosis after IL-3 starvation possibly due to a rapid decrease in Bcl-2 expression. This in vivo study focused on whether IL-3 rescued noncholinergic hippocampal neurons from lethal ischemic damage by modulating the expression of Bcl-xL, a Bcl-2 family protein produced in the mature brain. 7-d IL-3 infusion into the lateral ventricle of gerbils with transient forebrain ischemia prevented significantly hippocampal CA1 neuron death and ischemia-induced learning disability. TUNEL (terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling) staining revealed that IL-3 infusion caused a significant reduction in the number of CA1 neurons exhibiting DNA fragmentation 7 d after ischemia. The neuroprotective action of IL-3 appeared to be mediated by a postischemic transient upregulation of the IL-3R alpha subunit in the hippocampal CA1 field where IL-3Ralpha was barely detectable under normal conditions. In situ hybridization histochemistry and immunoblot analysis demonstrated that Bcl-xL mRNA expression, even though upregulated transiently in CA1 pyramidal neurons after ischemia, did not lead to the production of Bcl-xL protein in ischemic gerbils infused with vehicle. However, IL-3 infusion prevented the decrease in Bcl-xL protein expression in the CA1 field of ischemic gerbils. Subsequent in vitro experiments showed that IL-3 induced the expression of Bcl-xL mRNA and protein in cultured neurons with IL-3Ralpha and attenuated neuronal damage caused by a free radical-producing agent FeSO4. These findings suggest that IL-3 prevents delayed neuronal death in the hippocampal CA1 field through a receptor-mediated expression of Bcl-xL protein, which is known to facilitate neuron survival. Since IL-3Ralpha in the hippocampal CA1 region, even though upregulated in response to ischemic insult, is much less intensely expressed than that in the CA3 region tolerant to ischemia, the paucity of IL-3R interacting with the ligand may account for the vulnerability of CA1 neurons to ischemia.
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PMID:Interleukin 3 prevents delayed neuronal death in the hippocampal CA1 field. 970 46

Apoptosis of retinal ganglion cells has been observed in experimental glaucomatous models and human glaucomatous eyes in recent pathological studies. It seems that retinal ganglion cells in glaucomatous optic neuropathy die by a process similar to programmed cell death. Deprivation of neurotrophic factors, ischemia, chronic elevation of glutamate, and disorganized NO metabolism are suspected to be factors affecting neuronal loss in glaucoma, and most of these factors are known to activate the mechanism of cellular suicidal death. One of the common switches for the death mechanism seems to be in the mitochondria and to be controlled by Bcl-2 family proteins. A major goal of neuronal cell death research in glaucomatous neuropathy is to identify its molecular components and mechanisms of regulation. This information will lead to therapeutic agents that can modulate the cell death process in the treatment of glaucomatous neuropathy.
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PMID:[Neuronal cell death mechanism in glaucomatous optic neuropathy]. 983 6

After an ischemic episode induced by the electrocoagulation of the left middle cerebral artery (MCA) in mouse, neurons within the damaged territory die either by an apoptotic or by a necrotic process. Most of the cortical neurons within the ischemic area display both morphological and biochemical signs of programmed cell death: nuclear condensation, DNA degradation, formation of apoptotic bodies, and glutathione depletion. In fact, apoptosis essentially contributes to the expansion of the ischemic lesion and the maximum of damaged territory is reached 24 h postocclusion. Several potentially neuroprotective pathways have been evidenced in different experimental models of ischemia including the activation of antioxidant enzyme activities and/or the recruitment of neurotrophic as well as antiapoptotic factors. In our model of permanent focal ischemia induced by MCA occlusion, we measured the temporal synthesis of nerve growth factor (NGF) and examined the status of antioxidant enzymes as well as Bcl-2 antiapoptotic product. We detected in both cortices a transient increase of NGF which peaks at 6 h. Moreover, we reported that glutathione peroxidase is recruited with a time course which parallels NGF synthesis. Finally, we observed the induction of Bcl-2 in safe neurons; this may represent a self-protective response against ischemia-induced apoptosis. We provide evidence that in a model of permanent focal ischemia, several neuroprotective pathways could be coactivated.
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PMID:Recruitment of several neuroprotective pathways after permanent focal ischemia in mice. 987 75

Investigation of death pathways during cell injury in vivo caused by ischemia and reperfusion is of clinical importance, but technically difficult. Heterogeneity of cell types, differences between organ systems, diversity of death paradigms and exacerbation of tissue damage caused by inflammation are only some of the variables that need to be taken into account. With respect to the identification of necrosis and apoptosis in affected organs, technical issues related to preparation artifacts, occurrence of internucleosomal DNA cleavage in necrotic as well as apoptotic cells and other overlaps in death pathways bear consideration. In that caspase independent as well as caspase dependent processes cause cell death and that caspase inhibitors can act as anti-inflammatory agents, evaluation of ischemic death mechanisms in parenchymal cells needs to be performed with caution. When the effects of inflammation are removed by appropriate in vitro studies using purified or cultured cells, several mitochondrial factors that lead to cell death can be studied. Substantial evidence exists for the participation of electron transport defects, mitochondrial permeability transitions (MPT) and release of cytochrome c from mitochondria, effected by pro-apoptotic proteins such as Bax. The anti-apoptotic protein Bcl-2 exerts an overriding protective role in this type of injury by preserving mitochondrial structure and function. In contrast, caspase inhibitors cannot offer long-term protection to ischemically injured parenchymal cells regardless of how effectively they can inhibit apoptotic events, if the cells have suffered permanent mitochondrial damage impairing respiration.
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PMID:Mechanisms of cell death in hypoxia/reoxygenation injury. 991 96


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