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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear changes, including internucleosomal DNA fragmentation, are characteristic features of neuronal apoptosis resulting from transient cerebral ischemia and related brain insults for which the molecular mechanism has not been elucidated. Recent studies suggest that a caspase-3-mediated mechanism may be involved in the process of nuclear degradation in ischemic neurons. In this study, we cloned from rat brain a homolog cDNA encoding caspase-activated deoxyribonuclease (CAD)/DNA fragmentation factor 40 (DFF40), a 40 kDa nuclear enzyme that is activated by caspase-3 and promotes apoptotic DNA degradation. Subsequently, we investigated the role of CAD/DFF40 in the induction of internucleosomal DNA fragmentation in the hippocampus in a rat model of transient global ischemia and in primary neuronal cultures under ischemia-like conditions. At 8-72 hr after ischemia, CAD/DFF40 mRNA and protein were induced in the degenerating hippocampal CA1 neurons. CAD/DFF40 formed a heterodimeric complex in the nucleus with its natural inhibitor CAD (ICAD) and was activated after ischemia in a delayed manner (>24 hr) by caspase-3, which translocated into the nucleus and cleaved ICAD. Furthermore, an induced CAD/DFF40 activity was detected in nuclear extracts in both in vivo and in vitro models, and the DNA degradation activity of CAD/DFF40 was inhibited by purified ICAD protein. These results strongly suggest that CAD/DFF40 is the endogenous endonuclease that mediates caspase-3-dependent internucleosomal DNA degradation and related nuclear alterations in ischemic neurons.
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PMID:Caspase-activated DNase/DNA fragmentation factor 40 mediates apoptotic DNA fragmentation in transient cerebral ischemia and in neuronal cultures. 1142 95

An excessive activation of poly(ADP-ribose) polymerase (PARP) has been proposed to play a key role in post-ischemic neuronal death. We examined the neuroprotective effects of the PARP inhibitors benzamide, 6(5H)-phenanthridinone, and 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinone in three rodent models of cerebral ischemia. Increasing concentrations of the three PARP inhibitors attenuated neuronal injury induced by 60 min oxygen-glucose deprivation (OGD) in mixed cortical cell cultures, but were unable to reduce CA1 pyramidal cell loss in organotypic hippocampal slices exposed to 30 min OGD or in gerbils following 5 min bilateral carotid occlusion. We then examined the necrotic and apoptotic features of OGD-induced neurodegeneration in cortical cells and hippocampal slices using biochemical and morphological approaches. Cortical cells exposed to OGD released lactate dehydrogenase into the medium and displayed ultrastructural features of necrotic cell death, whereas no caspase-3 activation nor morphological characteristics of apoptosis were observed at any time point after OGD. In contrast, a marked increase in caspase-3 activity was observed in organotypic hippocampal slices after OGD, together with fluorescence and electron microscope evidence of apoptotic neuronal death in the CA1 subregion. Moreover, the caspase inhibitor Z-VAD-FMK reduced OGD-induced CA1 pyramidal cell loss. These findings suggest that PARP overactivation may be an important mechanism leading to post-ischemic neurodegeneration of the necrotic but not of the apoptotic type.
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PMID:Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. 1152 47

In the last decade, the molecular mechanisms of apoptosis, a major type of active cell death (type I cell death) have largely been clarified in mammalian cells. Particularly, the caspase family of proteinases has been shown to play crucial roles in the execution of apoptosis. Differing from apoptosis, type II cell death is known to be associated with autophagosomes/autolysosomes and appear in the developing nervous system (CLARKE, 1990). We have previously shown that delayed neuronal death occurring in the CA1 pyramidal layer of the gerbil hippocampus after brief forebrain ischemia is apoptotic in nature and autophagosomes/autolysosomes abundantly appear in the neurons before DNA fragmentation. To further understand the roles of autophagosomes/autolysosomes in active cell death, we examined the apoptosis of PC12 cells using morphological and biochemical techniques. PC12 cells are known to undergo apoptosis when cultured in the absence of serum. In such an environment, the mitochondrial pathway of apoptosis is activated; cytochrome c is released from mitochondria, and caspase-9/caspase-3 are activated. We have first examined morphological features of PC12 cells during the apoptotic process following serum deprivation, and found that autophagy is induced from the early stage of the process in the cells before typical nuclear changes. When autophagy is inhibited in the cells by 3-methyladenine, an autophagy inhibitor, they are largely protected from apoptosis. In relation to the induction of autophagy in PC12 cells following serum deprivation, immunoreactivity, protein amounts, and the proteolytic activity of lysosomal proteinases, particularly cathepsins B and D, are all greatly altered; those of cathepsin B drastically decrease in the cells from the early stage of serum-deprived cultures, whereas those of cathepsin D increase. Moreover, PC12 cells overexpressing cathepsin D undergo apoptosis more rapidly in serum-deprived cultures than wild-type cells, whereas those overexpressing cathepsin B increase the viability. These lines of evidence suggest that autophagy is involved in PC12 cell death following serum deprivation, this type of cell death being regulated by lysosomal proteinases, cathepsins B and D, downstream autophagy.
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PMID:Autophagic cell death and its execution by lysosomal cathepsins. 1157 20

Kainate-induced status epilepticus is associated with both apoptotic and necrotic cell death and induction of heat shock proteins (HSPs) in hippocampal and cortical regions of the rodent brain. In the present study we have examined the temporal, spatial and cellular expression patterns of mRNAs for the highly inducible HSPs, HSP70 and HSP27, together with the apoptotic marker, caspase 3 (CPP32) in rat brain after systemic administration of kainate. HSP70 mRNA was transiently induced in the forebrain by kainate, principally in the CA1, CA3 and hilar cells of the hippocampal formation, in piriform cortex and discrete thalamic nuclei. Maximal expression was seen at 8 h after kainate which then declined to background levels by 7 days. Labelling was predominantly neuronal. In contrast, HSP27 mRNA expression was more widespread. Intense labelling was observed in CA1, CA3 and the hilar region at 8 h after kainate but the expression profile for HSP27 mRNA expanded considerably with intense signals seen in corpus callosum, cortex and thalamus at 24 h post kainate. Emulsion autoradiographs indicated a predominantly glial localisation for HSP27 mRNA. In the hilus, a distinct subpopulation of interneurones were found to express HSP27 mRNA. CPP32 mRNA was upregulated in CA1, CA3 and hilus of the hippocampal formation and in piriform cortex. CPP32 mRNA expression was more restricted and similar in distribution to HSP70 mRNA being localised to neurones. The present study demonstrates the unique early expression of HSP27 mRNA by glial cells and distinct populations of neurones which extends beyond those in which HSP70 and CPP32 induction occurs with subsequent cell loss.
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PMID:Heat shock protein 27 shows a distinctive widespread spatial and temporal pattern of induction in CNS glial and neuronal cells compared to heat shock protein 70 and caspase 3 following kainate administration. 1158 92

Domoic acid (DA), a potent neurotoxin, administered intravenously (0.75 mg/kg body weight) in adult rats evoked seizures accompanied by nerve cell damage in the present study. Neuronal degeneration and microglial reaction in the hippocampus were investigated, and the temporal profile of bcl-2, bax, and caspase-3 genes in cell death or survival was assessed following the administration of DA. Nissl staining showed darkly stained degenerating neurons in the hippocampus following the administration of DA at 1-21 days, the degeneration being most severe at 5 days. Ultrastructural study in CA1 and CA3 regions of hippocampus revealed two types of neuronal degeneration, cells that exhibited swollen morphology and shrunken electron-dense cells. Immunoreactivity of Bcl-2 and Bax was increased considerably at 16 hr and 24 hr in the neurons of the hippocampus following DA administration. No significant change was observed in the immunoreactivity of caspase-3 in the controls and DA-treated rats at any time interval. Microglial cells in the hippocampus showed intense immunoreaction with the antibodies OX-42 and OX-6 at 1-21 days after DA administration, indicating the up-regulation of complement type 3 receptors and major histocompatibility complex type II antigens for increased phagocytic activity and antigen presentation, respectively. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) showed occasional positive neurons in the CA1 and CA3 regions at 5 days after DA administration, with no positive cells in the controls. RT-PCR analysis revealed that bcl-2 and bax mRNA transcripts in the hippocampus were significantly increased at 16 hr and gradually decreased at 24 hr following the administration of DA. Although bax and bcl-2 mRNA expression is rapidly induced at early stages, in situ hybridization analysis revealed complete loss of bcl-2, bax, and caspase-3 mRNA at 24 hr after DA administration in the region of neuronal degeneration in the hippocampus. These results indicate that the pattern of neuronal degeneration observed during DA-induced excitotoxic damage is mostly necrotic.
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PMID:Domoic acid-induced neuronal damage in the rat hippocampus: changes in apoptosis related genes (bcl-2, bax, caspase-3) and microglial response. 1159 13

Caspases are believed to play a key role in the delayed neuronal cell death observed in the rat brain after hypoxic-ischemic (HI) insult. Caspase inhibitors have been developed as antiapoptotic agents. Hippocampal damage after HI insult is strongly related to tissue temperature, and systemic hypothermia has been introduced clinically for brain protection. In this study, we examined the effects of a caspase inhibitor and systemic hypothermia on neuronal protection in the developing rat brain. Postnatal d 7 rat pups were subjected to the Rice model of hypoxia for 1 h. Systemic hypothermia was induced with a water bath at 29 degrees C. Before HI insult, a pan-caspase inhibitor, boc-aspartyl-(OMe)-fluoromethyl-ketone (BAF), was injected into the cerebral ventricle. The ipsilateral hippocampus was subjected to caspase assays and histologic assessment. The HI group at 37 degrees C (HI-37 degrees C) showed a peak of caspase-3 activity 16 h after insult. This activity was significantly reduced in the presence of BAF or hypothermia (HI-29 degrees C group, p < 0.05) or by the combination of HI-29 degrees C + BAF (p < 0.01 versus HI-37 degrees C). The number of neuronal cells in the ipsilateral hippocampal CA1 region in the HI-37 degrees C group was significantly decreased (62.9% versus control). The number of neuronal cells was maintained in the HI-37 degrees C + BAF group (82.7%), the HI-29 degrees C group (78.7%), and the combination group (95.2%) (p < 0.05 versus HI-37 degrees C). A combination of systemic hypothermia and BAF produced a strong protective effect against neuronal damage in the developing rat brain, along with a reduction in caspase-3 activity.
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PMID:Combination effect of systemic hypothermia and caspase inhibitor administration against hypoxic-ischemic brain damage in neonatal rats. 1164 53

It has been documented that alpha-phenyl-N-tert-butyl-nitron (PBN) possesses a potent neuroprotective effect when administered after transient focal cerebral ischemia. However, contradicting results were reported regarding its effect in transient global ischemia. To further elucidate the mechanism of PBN action, we have studied the effect of PBN on animal survival, histopathological outcome, and activation of caspase-3 following 30 min of global ischemia in vehicle- and PBN-treated rats. The results showed that 30 min of global ischemia was such a severe insult that no animal could survive beyond 2 d of reperfusion. Histopathological evaluation showed severe tissue edema and microinfarct foci in the neocortex and thalamus. Close to 100% damage was observed in the stratum and hippocampal CA1, CA3, and dentate gyrus subregions. Postischemic PBN treatment significantly enhanced animal survival and reduced damage in the neocortex, thalamus, and hippocampus. Immunohistochemistry demonstrated that caspase-3 was activated following ischemia in the striatum and the neocortex. PBN suppressed the activation of caspase-3 in both structures. It is concluded that PBN is a potent neuroprotectant against both focal and global ischemia; besides its function as a free radical scavenger, PBN may reduce ischemic brain damage by blocking cell death pathways that involve caspase-3 activation.
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PMID:Free radical spin trap alpha-phenyl-N-tert-butyl-nitron inhibits caspase-3 activation and reduces brain damage following a severe forebrain ischemic injury. 1170 97

The aim of this study was to determine whether hypoxic-ischemia from asphyxial cardiac arrest activates brain caspases-1 and -3, and the anti-apoptotic protein, XIAP. Asphyxial cardiac arrest in rats was used to induce hypoxic-ischemia. A pan-caspase inhibitor (zVAD) was given in the treatment group. At 72 h after reperfusion, caspase-3 and XIAP expression were present in multiple vulnerable brain regions, whereas caspase-1 was predominantly found in the CA1 hippocampus. zVAD significantly reduced expression of caspases and XIAP and the number of ischemic neurons in the CA1 hippocampus while neurological deficit scores were improved. We conclude that hypoxic-ischemia increases caspases-1 and-3, and XIAP expression. Treatment with zVAD significantly decreases caspase and XIAP expression in these brain regions and improves neurological outcome.
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PMID:Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats. 1172 87

Cell death-regulatory genes like caspases and bcl-2 family genes are involved in delayed cell death in the CA1 sector of hippocampus after global cerebral ischemia, but little is known about the mechanisms that trigger their expression. The authors found that expression of Fas and Fas-ligand messenger ribonucleic acid and protein was induced in vulnerable CA1 neurons at 24 and 72 hours after global ischemia. Fas-associating protein with a novel death domain (FADD) also was upregulated and immunoprecipitated and co-localized with Fas. Caspase-10 was activated and interacted with FADD protein to an increasing extent as the duration of ischemia increased. Moreover, caspase-10 co-localized with both FADD and caspase-3. These findings suggest that Fas-mediated death signaling may play an important role in signaling hippocampal neuronal death in CA1 after global cerebral ischemia.
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PMID:Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia. 1174 Feb 2

The paired-pulse paradigm was used to study the maturation of CA1 population spikes (PS) in the hippocampal slices of Wistar rats. Measurements were taken daily, from postnatal day (PN) 14 to PN27. In the slices from younger animals, inputs exhibit strong paired-pulse profile, which may be associated with low synaptic efficacy. Both responses increased during the third week of life, however, PS1 increased faster so that the PS1/PS2 ratio increased during the early period and remained increased thereafter. This may reflect postnatal modifications of synaptic transmission mediating the increase in hippocampal responses. Modifications of synaptic efficacy are prevailing during early phases while other mechanisms take over at later stages. Partial correlation analysis suggests that the decline of PS amplitude after PN19 may be due to the decrease in the number of connected neurons rather than to modifications of the synaptic efficacy. Thus, the actual direction and magnitude of postnatal PS maturation is suggested to depend on the balance of these two factors. The transient decline of PS amplitude coincided with a period of caspase-3 activation. There was a clear general trend for caspase-3 activity to decrease before PN17, while the inverse trend was observed during next period up to PN21.
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PMID:Periods of postnatal maturation of hippocampus: synaptic modifications and neuronal disconnection. 1174 15


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