Role of caspase-3 in ethanol-induced developmental neurodegeneration

Young, Chainllie; Roth, Kevin A.; Klocke, Barbara J.; West, Tim; Holtzman, David M.; Labruyere, Joann; Qin, Yue-Qin; Dikranian, Krikor; Olney, John W.

doi:10.1016/j.nbd.2005.04.014

Cited by 110 publications

(103 citation statements)

References 39 publications

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“…The absence of TUNEL staining and other evidence of apoptotic sequelae also argue against classical apoptosis as the mechanism of neuronal death in this model. Our results are surprising because whereas activation of initiator caspases has been reported as a chronic event preceding neuronal death in a model of familial amyotrophic lateral sclerosis (Pasinelli et al, 2000), executioner caspase activation is viewed as a direct and inevitable path toward apoptotic cell death that occurs within hours (Chang et al, 2002;Young et al, 2005). Our results indicate that initiator and executioner caspases appear to be activated in tangle-bearing neurons, but longitudinal in vivo imaging uncovers a dissociation between caspase activation and acute neuronal death.…”

Section: Discussionmentioning

confidence: 52%

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Spires‐Jones¹,

Calignon²,

Matsui³

et al. 2008

J. Neurosci.

121

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Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.

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Section: Discussionmentioning

confidence: 52%

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Spires‐Jones¹,

Calignon²,

Matsui³

et al. 2008

J. Neurosci.

121

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“…Yoon et al (2003) reported that in a mouse cortical cell culture preparation, glutamate receptor blockade with a combination of MK-801 and CNQX (MK-801/CNQX) induced caspase-3 activation and cell death, which was significantly reduced by 100 mM of zVAD-fmk. Caspase-3 activation has also been reported after repeated doses of 20 mg/kg ketamine (Scallet et al, 2004) or a single dose of 40 mg/kg ketamine (Young et al, 2005). After ethanol exposure, cultured cortical neurons showed caspase-3 activation and apoptosis, which was prevented by the caspase-3 inhibitor Ac-ABPDEVD-CHO (Takadera and Ohyashiki, 2004).…”

Section: Discussionmentioning

confidence: 85%

“…Active caspase-3 cleaves many substrates such as poly(ADPribose) polymerase-1 (PARP) and ICAD (inhibitor of caspase-activated DNase) that result in key morphological alterations involved in apoptosis (Fischer et al, 2003). Caspase-3 activation in postnatal rodent brain has been reported after administration of NMDA antagonists (Adams et al, 2004;Monti and Contestabile, 2000;Yoon et al, 2003;Scallet et al, 2004;Young et al, 2005). However, the precise relationship between caspase-3 activation and postnatal neuronal death following NMDAR blockade is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

Wang

Johnson

2006

Neuropsychopharmacol

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This study determined the role of caspase-3 in phencyclidine (PCP)-induced neurodegeneration in postnatal rats. PCP administration to postnatal day 7 rats induced a dose-dependent increase in caspase-3 enzymatic activity in frontal cortex, striatum, and hippocampus. Enzymatic activation was present at 4 h, peaked between 6 and 12 h, and disappeared by 24 h. Further, cleaved caspase-3-immunoreactive neurons were detected as early as 2 h in the cortex, and were found throughout the brain, including, in addition, the thalamus and striatum. Within the cingulate, frontal, parietal, and retrosplenial cortices, immunoreactivity was specific for layers II-IV (especially layer II). Neurons positive for both silver staining and terminal deoxynucleotidyl transferase biotin-d-UTP nick-end labeling (TUNEL) were found in the same brain regions and subregions. Double labeling experiments confirmed that cleaved caspase-3 and TUNEL were coexpressed in many neurons in all brain regions and subregions studied. Temporal studies revealed that procaspase-3 cleavage preceded TUNEL staining by about 3 h, with many neurons being positive for both caspase-3 and TUNEL 9 h after PCP treatment. In organotypic corticostriatal slices, PCP caused a concentration-and time-dependent cleavage of procaspase-3 that was also colocalized with TUNEL staining in layers II-IV of the parietal cortex. Caspase-3 activation again preceded PCP-induced DNA damage assessed by TUNEL. PCP-induced neuronal death in vitro as measured by TUNEL staining was blocked 85% by Ac-AAVALLPAVLLALLAPDEVD-CHO, a cell-permeable selective caspase-3 inhibitor. These data demonstrate that caspase-3 activation plays a necessary role in the regionally selective neuronal death induced by PCP in the developing rat brain.

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“…The ethanolinduced neuronal loss may partially explain neuropathological conditions in rodents similar to those found in human fetal alcohol spectrum disorders (FASD). This rodent model of FASD has been widely used for elucidating mechanisms of ethanol-induced toxicity in the developing brain [3][4][5]. It has been shown that ethanol induces Bax-mediated disruption of mitochondrial membranes, cytochrome c release, and caspase-3 activation, leading to neurodegeneration in P7 mouse brains [6].…”

Section: Introductionmentioning

confidence: 99%

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Chakraborty

Shimada

Mao

et al. 2008

Biochemical and Biophysical Research Communications

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Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3β (GSK-3β), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanolinduced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3β and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and Nacylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3β, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.

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Role of caspase-3 in ethanol-induced developmental neurodegeneration

Cited by 110 publications

References 39 publications

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

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