HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption

Roy, Michael S.; Hom, JJ; Sapolsky, R. M.

doi:10.1038/sj.gt.3301642

Cited by 28 publications

(22 citation statements)

References 47 publications

(64 reference statements)

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“…In pursuing how neurons die following seizures, we and others have shown that several caspases and auxiliary effectors of programmed cell death are activated, and that molecular and pharmacological manipulations of these are neuroprotective (8,10,11,13) and may be able to modify epileptogenesis (12,13). Although Bcl-2 family proteins are key regulators of such pathways, their involvement in epileptic brain injury remains little understood, because seizure-induced expressional changes of Bcl-2 family proteins often either are minimal or emerge beyond a time at which cell death could still be influenced (7).…”

Section: Discussionmentioning

confidence: 99%

“…Following anesthesia, intubation, and vein catheterization, animals were placed in a stereotaxic frame. Two electrodes (Plastics One Inc., Roanoke, Virginia, USA) were then affixed to the skull bitemporally over the hippocampi and a third was placed across the frontal cortex for electroencephalogram (EEG) recordings (Grass model [8][9][10][11][12][13][14][15][16]; Astro-Med Inc., West Warwick, Rhode Island, USA). A craniectomy was also performed for placement of the injection cannula.…”

Section: Seizure Model In Vivomentioning

confidence: 99%

“…Data from experimental seizure models and now human studies reveal the activation of several effectors of apoptosis in the brain (8)(9)(10)(11). Further, molecular or pharmacological intervention in these pathways can reduce seizure-induced neuronal loss (8)(9)(10)(11) and may modify the emergent epilepsy phenotype after seizures (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Shinoda

Schindler²,

Meller³

et al. 2004

J. Clin. Invest.

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Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.Nonstandard abbreviations used: B cell lymphoma (Bcl); Bcl-2-associated death promoter (Bad); Bcl-2-associated X protein (Bax); Bcl-2-homologous antagonist/ killer (Bak); Bcl-2 homology domain 3 (BH3); Bcl-2-interacting mediator of cell death (Bim); BH3-interacting domain death agonist (Bid); cornu ammonis (CA); electroencephalogram (EEG); forkhead in rhabdomyosarcoma (FKHR); kainic acid (KA); 27-kDa Cdk-inhibitory protein 1 (p27 Kip1 ); lactate dehydrogenase (LDH); maximal electroshock seizure (MES); sodium orthovanadate (SOV).

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Section: Discussionmentioning

confidence: 99%

Section: Seizure Model In Vivomentioning

confidence: 99%

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Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Shinoda

Schindler²,

Meller³

et al. 2004

J. Clin. Invest.

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“…P35 is a pan caspase inhibitor, which inhibits caspases 1, 3, 6, 7, 8, and 10 while crmA selectively inhibits caspases 1 and 8 (Bump et al, 1995, Zhou et al, 1997. Using the HSV vector system and primary neuronal cultures, we have demonstrated the neuroprotective ability of p35 and crmA after excitotoxic stimuli (Roy et al, 2001, Roy et al, 2002, Roy and Sapolsky, 2003. In this study we further compare the protective effects of p35 and crmA.…”

Section: Introductionmentioning

confidence: 99%

“…First, virally-derived caspase inhibitors are more physiological compared with synthesized peptides, and they are homologs of some mammalian genes; thus gene therapy using such virally-derived caspase inhibitors may provide insights into the action of the endogenous genes and clarify the underlying mechanisms (Roy et al, 2001, Roy et al, 2002. We intended to compare the neuroprotective effects of two well known caspase inhibitors, baculoviral p35 and cowpox virus crmA.…”

Section: Introductionmentioning

confidence: 99%

Viral caspase inhibitor p35, but not crmA, is neuroprotective in the ischemic penumbra following experimental stroke

et al. 2007

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Apoptosis, a predominant cause of neuronal death after stroke, can be executed in a caspasedependent or apoptosis inducing factor (AIF)-dependent manner. Herpes Simplex Virus (HSV) vectors expressing caspase inhibitors p35 and crmA have been shown to be neuroprotective against various excitotoxic insults. Here we further evaluated the possible neuroprotective role of p35 and crmA in a rat stroke model. Overexpression of p35, but not crmA, significantly increased neuronal survival. Results of double immunofluorescence staining indicate that compared with neurons infected with crmA or control vectors, p35-infected neurons had less active caspase-3 expression, cytosolic cytochrome c and nuclear AIF translocation.

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Death‐associated protein kinase expression in human temporal lobe epilepsy

Henshall

Schindler

So³

et al. 2004

Annals of Neurology

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Experimental and human data suggest programmed (active) cell death may contribute to the progressive hippocampal atrophy seen in patients with refractory temporal lobe epilepsy. Death-associated protein (DAP) kinase is a novel calcium/calmodulin-activated kinase that functions in apoptosis mediated by death receptors. Because seizure-induced neuronal death involves both death receptor activation and calcium, we examined DAP kinase expression, localization, and interactions in hippocampal resections from patients with intractable temporal lobe epilepsy (n = 10) and autopsy controls (n = 6). Expression and phosphorylation of DAP kinase was significantly increased in epilepsy brain compared with control. DAP kinase and DAP kinase-interacting protein 1 (DIP-1) localized to mitochondria in control brain, whereas levels of both were increased in the cytoplasm and microsomal (endoplasmic reticulum) fraction in epilepsy samples. Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin, DIP-1, and the Fas-associated protein with death domain (FADD) in epilepsy samples. Finally, immunohistochemistry determined DAP kinase was coexpressed with DIP-1 in neurons. This study provides the first description of DAP kinase and DIP-1 in human brain and suggests DAP kinase is a novel molecular regulator of neuronal death in epilepsy.

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HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption

Cited by 28 publications

References 47 publications

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Viral caspase inhibitor p35, but not crmA, is neuroprotective in the ischemic penumbra following experimental stroke

Death‐associated protein kinase expression in human temporal lobe epilepsy

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