Late Calcium EDTA Rescues Hippocampal CA1 Neurons from Global Ischemia-Induced Death

Calderone, Agata; Jover, Teresa; Mashiko, Toshihiro; Noh, Kyang Min; Tanaka, Hidetaka; Bennett, Michael V. L.; Zukin, R. Suzanne

doi:10.1523/jneurosci.1713-04.2004

Cited by 132 publications

(174 citation statements)

References 54 publications

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“…Male Sprague-Dawley rats (150-200 g; Charles River Laboratories) were subjected to transient global ischemia or sham operation by four-vessel occlusion as described (11,61).…”

Section: Methodsmentioning

confidence: 99%

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Noh¹,

Hwang²,

Follenzi³

et al. 2012

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

163

180

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Dysregulation of the transcriptional repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor is important in a broad range of diseases, including cancer, diabetes, and heart disease. The role of REST-dependent epigenetic modifications in neurodegeneration is less clear. Here, we show that neuronal insults trigger activation of REST and CoREST in a clinically relevant model of ischemic stroke and that REST binds a subset of "transcriptionally responsive" genes (gria2, grin1, chrnb2, nefh, nfκb2, trpv1, chrm4, and syt6), of which the AMPA receptor subunit GluA2 is a top hit. Genes with enriched REST exhibited decreased mRNA and protein. We further show that REST assembles with CoREST, mSin3A, histone deacetylases 1 and 2, histone methyl-transferase G9a, and methyl CpG binding protein 2 at the promoters of target genes, where it orchestrates epigenetic remodeling and gene silencing. RNAi-mediated depletion of REST or administration of dominant-negative REST delivered directly into the hippocampus in vivo prevents epigenetic modifications, restores gene expression, and rescues hippocampal neurons. These findings document a causal role for REST-dependent epigenetic remodeling in the neurodegeneration associated with ischemic stroke and identify unique therapeutic targets for the amelioration of hippocampal injury and cognitive deficits.chromatin remodeling | global ischemia | CA1 | synaptic plasticity

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“…Male Sprague-Dawley rats (150-200 g; Charles River Laboratories) were subjected to transient global ischemia or sham operation by four-vessel occlusion as described (11,61).…”

Section: Methodsmentioning

confidence: 99%

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Noh¹,

Hwang²,

Follenzi³

et al. 2012

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

163

180

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“…130,136 Treatment with zinc chelators has been shown to reduce neuronal death in animal models of cerebral ischemia, trauma, hypoglycemia, and neurodegenerative disorders. [137][138][139][140][141][142] These effects may be due in part to suppression of zinc-mediated microglial activation. Zinc has been shown to induce activation of microglia in culture and in brain, and injection of the zinc chelator CaEDTA prevents ischemia-induced microglial activation.…”

Section: Zincmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…Regulation of Ca 2þ -A=K channel composition after ischemic injury may also involve Zn 2þ -dependent signaling. In an in vivo model of stroke, application of the cell-impermeant Zn 2þ chelator CaEDTA 30 min before global ischemia attenuated the ischemic downregulation of GluR2, the delayed rise in neuronal Zn 2þ , and neuronal death (16). Ischemic downregulation of GluR2 occurs via the Zn 2þ -dependent expression of the nine Zn 2þ -finger transcription factor restrictive element-1 silencing transcription factor (REST-1), which suppresses neuronal-specific targets, including GluR2 (16,17).…”

Section: Translocation Of Vesicular Zincmentioning

confidence: 99%

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

Aras

Aizenman

2011

Antioxidants & Redox Signaling

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Zn2+ has emerged as a major regulator of neuronal physiology, as well as an important signaling agent in neural injury. The intracellular concentration of this metal is tightly regulated through the actions of Zn 2+ transporters and the thiol-rich metal binding protein metallothionein, closely linking the redox status of the cell to cellular availability of Zn 2+ . Accordingly, oxidative and nitrosative stress during ischemic injury leads to an accumulation of neuronal free Zn 2+ and the activation of several downstream cell death processes. While this Zn 2+ rise is an established signaling event in neuronal cell death, recent evidence suggests that a transient, sublethal accumulation of free Zn 2+ can also play a critical role in neuroprotective pathways activated during ischemic preconditioning. Thus, redox-sensitive proteins, like metallothioneins, may play a critical role in determining neuronal cell fate by regulating the localization and concentration of intracellular free Zn 2+

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Late Calcium EDTA Rescues Hippocampal CA1 Neurons from Global Ischemia-Induced Death

Abstract: Transient global ischemia induces a delayed rise in intracellular Zn

Cited by 132 publications

References 54 publications

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Microglial Activation in Stroke: Therapeutic Targets

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

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