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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protooncogene bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that the mechanism of action of Bcl-2 involves antioxidant activity. The involvement of free radicals in ischemia/reperfusion injury to neural cells has led us to investigate the effect of Bcl-2 in a model of delayed neural cell death. We have examined the survival of control and bcl-2 transfectants of a hypothalamic tumor cell line, GT1-7, exposed to potassium cyanide in the absence of glucose (chemical hypoxia/aglycemia). After 30 min of treatment, no loss of viability was evident in control or bcl-2 transfectants; however, Bcl-2-expressing cells were protected from delayed cell death measured following 24-72 h of reoxygenation. Under these conditions, the rate and extent of ATP depletion in response to treatment with cyanide in the absence of glucose and the rate of recovery of ATP during reenergization were similar in control and Bcl-2-expressing cells. Bcl-2-expressing cells were protected from oxidative damage resulting from this treatment, as indicated by significantly lower levels of oxidized lipids. Mitochondrial respiration in control but not Bcl-2-expressing cells was compromised immediately following hypoxic treatment. These results indicate that Bcl-2 can protect neural cells from delayed death resulting from chemical hypoxia and reenergization, and may do so by an antioxidant mechanism. The results thereby provide evidence that Bcl-2 or a Bcl-2 mimetic has potential therapeutic application in the treatment of neuropathologies involving oxidative stress, including focal and global cerebral ischemia.
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PMID:Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability. 759 37

Oxidative stress is believed to play important roles in neuronal cell death associated with many different neurodegenerative conditions (e.g., Alzheimer's disease, Parkinson's disease, and cerebral ischemia), and it is believed also that apoptosis is an important mode of cell death in these disorders. Membrane lipid peroxidation has been documented in the brain regions affected in these disorders as well as in cell culture and in vivo models. We now provide evidence that 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, is a key mediator of neuronal apoptosis induced by oxidative stress. HNE induced apoptosis in PC12 cells and primary rat hippocampal neurons. Oxidative insults (FeSO4 and amyloid beta-peptide) induced lipid peroxidation, cellular accumulation of HNE, and apoptosis. Bcl-2 prevented apoptosis of PC12 cells induced by oxidative stress and HNE. Antioxidants that suppress lipid peroxidation protected against apoptosis induced by oxidative insults, but not that induced by HNE. Glutathione, which binds HNE, protected neurons against apoptosis induced by oxidative stress and HNE. PC12 cells expressing Bcl-2 exhibited higher levels of glutathione and lower levels of HNE after oxidative stress. Collectively, the data identify that HNE is a novel nonprotein mediator of oxidative stress-induced neuronal apoptosis and suggest that the antiapoptotic action of glutathione may involve detoxification of HNE.
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PMID:Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. 918 46

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

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

Gap junctions are conductive channels that connect the interiors of coupled cells. We determined whether gap junctions propagate transcellular signals during metabolic stress and whether such signaling exacerbates cell injury. Although overexpression of the human proto-oncogene bcl2 in C6 glioma cells normally increased their resistance to injury, the relative resistance of bcl2+ cells to calcium overload, oxidative stress and metabolic inhibition was compromised when they formed gap junctions with more vulnerable cells. The likelihood of death was in direct proportion to the number and density of gap junctions with their less resistant neighbors. Thus, dying glia killed neighboring cells that would otherwise have escaped injury. This process of glial 'fratricide' may provide a basis for the secondary propagation of brain injury in cerebral ischemia.
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PMID:Gap-junction-mediated propagation and amplification of cell injury. 1019 36

Caspase-9 is critical for cytochrome c (cyto-c)-dependent apoptosis and normal brain development. We determined that this apical protease in the cyto-c pathway for apoptosis resides inside mitochondria in several types of cells, including cardiomyocytes and many neurons. Caspase-9 is released from isolated mitochondria on treatment with Ca2+ or Bax, stimuli implicated in ischemic neuronal cell death that are known to induce cyto-c release from mitochondria. In neuronal cell culture models, apoptosis-inducing agents trigger translocation of caspase-9 from mitochondria to the nucleus, which is inhibitable by Bcl-2. Similarly, in an animal model of transient global cerebral ischemia, caspase-9 release from mitochondria and accumulation in nuclei was observed in hippocampal and other vulnerable neurons exhibiting early postischemic changes preceding apoptosis. Loss of mitochondrial barrier function during neuronal damage from ischemia or other insults therefore may play an important role in making certain caspases available to participate in apoptosis.
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PMID:Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. 1031 56

Protective effects after focal cerebral ischemia were assessed in transgenic mice that overexpress in a neuron-specific fashion mouse Bcl-XL or human Bcl-2. Both Bcl genes were under the control of the same mouse Thy-1 regulatory sequences resulting in very similar expression patterns in cortical neurons. Furthermore, these sequences direct lateonset (i.e. around birth) expression in brain, thus minimizing effects of transgene expression during brain development. Effects on infarct volume were measured using MRI after permanent occlusion of the middle cerebral artery (MCA). When compared to their non-transgenic littermates, Thy1mbcl-XL mice showed a significant 21% reduction in infarct size whereas Thy1hbcl-2 mice did not reveal any reduction. These findings suggest a selective protective advantage of Bcl-XL as compared with Bcl-2 in this mouse model for human stroke.
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PMID:Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. 1040 19

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.
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PMID:Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. 1041 67

In experimental models of cerebral ischemia, cells within the damaged territory die by necrosis and by apoptosis that contributes to the expansion of the insult. Apoptotic machinery mobilizes intracellular processes such as induction of Bcl-2 family members, activation of the proteolytic cascade including the caspases, and cleavage of caspase substrates, such as poly(ADP-ribose) polymerase or PARP. Mitochondria play a pivotal role in controlling apoptosis by releasing cytochrome c and modulating redox state, both under the regulation of manganese superoxide dismutase (Mn SOD) via superoxide anion detoxification. The implication and the kinetics of such events in apoptosis induced after focal permanent ischemia in mice remains to be studied. In a paradigm of ischemic insult induced by occlusion of the middle cerebral artery (MCAO) in mice, we showed by immunohistochemistry a constitutive expression of caspase-3 that is enhanced after MCAO in neurons localized within the infarcted zone. As a function of time intervals after MCAO, the cytochrome c amount increased in the cytosolic fraction of ischemic cortical extracts. The kinetics of the release was in concordance with the expression of caspase-3 and the subsequent cleavage of PARP appearing before the internucleosomal fragmentation of DNA, the ultimate step of apoptosis. When the apoptotic markers progressively appeared, no changes of Mn SOD activity or Mn SOD expression were detected after MCAO. We can therefore speculate that the recruitment of Mn SOD did not participate per se in the release of cytochrome c elicited after permanent focal ischemia.
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PMID:Early and sequential recruitment of apoptotic effectors after focal permanent ischemia in mice. 1067 15

Previous studies have suggested that various apoptotic-related proteins could be involved in the death process induced by cerebral ischaemia. In order to further clarify their role and examine how the anti-apoptotic protein Bcl-2 could influence this process, the time-course of mRNA expression of various cell death genes was studied from 1 to 14 days following permanent occlusion of the middle cerebral artery in wild-type (WT) and Bcl-2 transgenic mice, within and outside the area of infarction. No differences of the infarct sizes were observed between the two groups of mice, showing that the extent of neuronal injury could not have been lowered by the Bcl-2 transgene. Seven days after the ischaemic insult, the mRNA expression of the cell death gene effector cpp32 was dramatically upregulated in the penumbra of WT and Bcl-2 transgenic mice. Interestingly, the cpp32 transcript was markedly induced from 3 days in the ipsilateral thalamus of the two groups of mice. However, apoptotic bodies were observed in the thalamic field of WT but not transgenic mice. This suggests that cpp32 mRNA may be induced in an attempt to kill the injured cells and, in contrast to the penumbra, cell death in the thalamus may be prevented in Bcl-2 transgenic mice. Based on these results, the pathophysiological mechanisms that underly neuronal damage following ischaemia need consideration in order to evaluate the extent of neuroprotection that may be afforded by the Bcl-2 anti-apoptotic protein. Although the present study does not confirm previous data showing a protective role of Bcl-2 in neocortical infarcted areas, it suggests that anti-apoptotic therapies may constitute a possible treatment for areas of the brain remote from those directly affected by ischaemia.
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PMID:Cell death is prevented in thalamic fields but not in injured neocortical areas after permanent focal ischaemia in mice overexpressing the anti-apoptotic protein Bcl-2. 1076 22


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