Global ischemia induces apoptosis-associated genes in hippocampus

Honkaniemi, Jari; Massa, Stephen M.; Breckinridge, Mary; Sharp, Frank R.

doi:10.1016/s0169-328x(96)00121-0

Cited by 128 publications

(70 citation statements)

References 48 publications

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“…In these experiments, bcl-2 mRNA levels were similar in the nonischemic hemisphere of stressed and unstressed animals, suggesting that stress does not alter baseline bcl-2 expression. In unstressed animals, bcl-2 mRNA levels were also similar in ischemic and nonischemic hemispheres at 24 h. This was not unexpected, as bcl-2 expression is thought to be either increased after stroke or, at minimum, preferentially preserved in injured cells with restricted protein synthesis (18)(19)(20)(21)(22). The similar bcl-2 levels in infarcted and noninfarcted tissue of unstressed animals argues against the notion that decreased bcl-2 levels merely reflects a larger infarct relative to unstressed animals.…”

Section: Discussionmentioning

confidence: 81%

“…Increased bcl-2 expression promotes cell survival and protects against apoptosis and cellular necrosis in numerous neurodegenerative disorders (17). Under ischemic conditions, bcl-2 expression is selectively increased in the peri-infarct region (18)(19)(20)(21)(22). Alterations in bcl-2 expression by either genetic (23)(24)(25)(26)(27)(28)(29)(30) or pharmacological (18,(31)(32)(33) manipulations ultimately affect tissue infarction; treatments that increase bcl-2 expression tend to be neuroprotective.…”

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confidence: 99%

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Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

DeVries

Joh

Bernard

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

139

113

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The relationship between stressful life events and the onset of disease is well documented. However, the role of psychological stress as a risk factor for life-threatening cerebrovascular insults such as stroke remains unspecified, but could explain individual variation in stroke outcome. To discover the mechanisms through which psychological stress may alter stroke outcome, we modeled the effects of chronic social intimidation and stress on ischemiainduced bcl-2 expression and early neuronal cell loss resulting from cerebral artery occlusion in mice (C57BL͞6). The bcl-2 protooncogene promotes cell survival and protects against apoptosis and cellular necrosis in numerous neurodegenerative disorders, including stroke. In our study, male mice were chronically exposed to aggressive social stimuli before induction of a controlled, mild ischemic insult. Stressed mice expressed Ϸ70% less bcl-2 mRNA than unstressed mice after ischemia. In addition, social stress greatly exacerbated infarct in wild-type mice but not in transgenic mice that constitutively express increased neuronal bcl-2. Despite similar postischemic concentrations of corticosterone, the major stress hormone in mice, high corticosterone concentrations were significantly correlated with larger infarcts in wild-type mice but not bcl-2 transgenic mice. Thus, enhanced bcl-2 expression offsets the potentially deleterious consequences of high postischemic plasma corticosterone concentrations. Taken together, these data demonstrate that stressful prestroke social milieu strongly compromises an endogenous molecular mechanism of neuroprotection in injured brain and offer a new behavioral target for stroke therapy.

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

DeVries

Joh

Bernard

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

139

113

View full text Add to dashboard Cite

show abstract

“…Because all mitochondrial toxins used in this study cause energy failure, which in turn induces calcium influx into mitochondria, this is one possible mechanism of mitochondrial dysfunction, which would explain why activation of DNA repair enzymes can paradoxically enhance cell death (31), presumably through energy depletion, and would imply that other types of mitochondrial malfunction may well trigger similar cascades. This hypothetical mechanism would also explain the relationship between energy failure and excitotoxicity, both of which might trigger calcium accumulation and cytochrome c release, and the reports of a necrotic morphology (7,8) and an apoptotic-like biochemistry (32)(33)(34)(35) in pathological situations characterized by depletion of energy reserves, such as cerebral ischemia.…”

Section: Discussionmentioning

confidence: 96%

Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

Niquet

Baldwin

Allen

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxic necrosis of dentate gyrus neurons in primary culture required the activation of an orderly cell death program independent of protein synthesis. Early mitochondrial swelling and loss of the mitochondrial membrane potential were accompanied by release of cytochrome c and followed by caspase-9-dependent activation of caspase-3. Caspase-3 and -9 inhibitors reduced neuronal necrosis. Calcium directly induced cytochrome c release from isolated mitochondria. Hypoxic neuronal necrosis may be an active process in which the direct effect of hypoxia on mitochondria may lead to the final common pathway of caspase-3-mediated neuronal death.

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“…This process, also referred to as ischemic preconditioning, is supported in part by the activation of the hypoxia-inducible factor (HIF-1α) and an array of immediate early transcription factors with diverse biological functions including c-Jun and Egr-1/Krox-24 (Collaco-Moraes et al, 1994;Herdegen and Leah, 1998;Hsu et al, 1993). Stroke-induced gene expression also plays a critical role in promoting delayed neuron loss after ischemia (Honkaniemi et al, 1996). In this regard, pre-treatment with the macromolecular synthesis inhibitor cycloheximide confers neuroprotection (Du et al, 1996;Gwag et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Halterman

Jesus

Rempe

et al. 2008

Molecular and Cellular Neuroscience

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Understanding the mechanisms governing the switch between hypoxia-induced adaptive and pathological transcription may reveal novel therapeutic targets for stroke. Using an in vitro hypoxia model that temporally separates these divergent responses, we found apoptotic signaling was preceded by a decline in c/EBP-β activity and was associated with markers of ER-stress including transient eIF2α phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2α phosphatase inhibitor salubrinal blocked the activation of caspase-3, indicating that ER-related stress responses are integral to this transition. Delivery of either full-length, or a transcriptionally inactive form of c/EBP-β protected cultures from hypoxic challenge, in part by inducing levels of the anti-apoptotic protein Bcl-2. These data indicate that the pathologic response in cortical neurons induced by hypoxia involves both the loss of c/EBP-β-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.

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Global ischemia induces apoptosis-associated genes in hippocampus

Cited by 128 publications

References 48 publications

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

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