Apoptosis and Necrosis in Cerebrovascular Disease

Snider, B. Joy; Gottron, Frank J.; Choi, Dennis W.

doi:10.1111/j.1749-6632.1999.tb07829.x

Cited by 113 publications

(62 citation statements)

References 78 publications

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“…Whether the regulation of the Cdc2 and JNK signaling pathways in activity-deprived neurons is coordinated remains to be determined. Finally, because neuronal death is thought to be a major pathophysiologic feature of several common neurologic disorders, including neurodegenerative diseases and stroke (Cotman, 1998;Pettmann and Henderson, 1998;Snider et al, 1999), it will also be interesting to determine whether the E2F-Cdc2 cell-cycle pathway contributes to neuronal apoptosis in these neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

The E2F–Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons

Konishi

Bonni

2003

J. Neurosci.

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Neuronal apoptosis plays a critical role in the normal development of the mammalian brain and is thought to contribute to the pathogenesis of several neurologic disorders. However, the intracellular mechanisms underlying apoptosis of neurons remain incompletely understood. In the present study, we characterized a cell-cycle-based mechanism by which neuronal activity deprivation induces apoptosis of postmitotic neurons. Activity deprivation, but not growth factor withdrawal, was found to induce Cdc2 expression and consequent Cdc2-mediated apoptosis in granule neurons of the developing rat cerebellum. We found that activity deprivation induces cdc2 transcription in neurons via an E2F-binding element (EBE) within the cdc2 promoter. The transcription factor E2F1 that is expressed in granule neurons was found in DNA binding assays to bind to the EBE of the cdc2 gene. In chromatin immunoprecipitation analysis, endogenous E2F1 forms a complex with the promoter of the endogenous cdc2 gene in granule neurons, indicating that endogenous E2F1 is poised to activate transcription of the endogenous cdc2 gene in neurons. Consistent with this conclusion, a dominant interfering form of E2F, when expressed in granule neurons, blocked activity deprivation-induced cdc2 transcription. In other experiments, we found that the expression of E2F1 in granule neurons induces Cdc2 expression and promotes neuronal apoptosis via the activation of Cdc2. Remarkably, in contrast to inducing the E2F-mediated expression and activation of Cdc2 in granule neurons, activity deprivation fails to stimulate the expression of E2F-target genes that trigger DNA synthesis and replication. Together, our findings define a novel apoptotic mechanism whereby E2F selectively couples an activity deprivation-induced signal to cdc2 transcription in the absence of stimulating DNA synthesis and thus culminating in Cdc2-mediated apoptosis of postmitotic neurons.

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Section: Discussionmentioning

confidence: 99%

The E2F–Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons

Konishi

Bonni

2003

J. Neurosci.

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“…The expression of Bax is increased selectively in neurons undergoing apoptosis after global forebrain ischemia and focal cerebral ischemia (Krajewski et al, 1995;Isenmann et al, 1998). The cerebral infarct, and the delayed neuronal death in the hippocampus, are significantly reduced in mice and gerbil that over-express Bcl-2, respectively (Martinou et al, 1994;Snider et al, 1999;Antonawich et al, 1999). Hypoxic-ischemia can activate the pro-apoptotic Bcl-2 family, possibly through two separate routes.…”

Section: Fas Receptormentioning

confidence: 99%

Cellular and Molecular Pathways of Ischemic Neuronal Death

Won¹,

Kim²,

Gwag³

2002

BMB Reports

201

172

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Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of Ca 2+ and Na + that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.

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“…Both necrotic and apoptotic cell death mechanisms have been implicated in the pathogenesis of ischemic (Graham and Chen, 2001;Kirino, 1982;Liu et al, 1999;Martin et al, 2000;Snider et al, 1999) and traumatic brain injury (Clark et al, 2000;Conti et al, 1998;Eldadah and Faden, 2000;Kotapka et al, 1991;Yakovlev et al, 1997). The brain is vulnerable to oxidative stress due to its high rate of oxidative metabolic activity (Maier and Chan, 2002).…”

Section: Cell Death Mechanismsmentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

567

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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Apoptosis and Necrosis in Cerebrovascular Disease

Cited by 113 publications

References 78 publications

The E2F–Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons

The E2F–Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons

Cellular and Molecular Pathways of Ischemic Neuronal Death

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

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