Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed hippocampal neurodegeneration after transient global ischemia is mediated, at least in part, through the activation of terminal caspases, particularly caspase-3, and the subsequent proteolytic degradation of critical cellular proteins. Caspase-3 may be activated by the membrane receptor-initiated caspase-8-dependent extrinsic pathway and the mitochondria-initiated caspase-9-dependent intrinsic pathway; however, the precise role of these deduced apoptosis-signaling pathways in activating caspase-3 in ischemic neurons remains elusive. The authors cloned the caspase-9 gene from the rat brain and investigated its potential role in mediating ischemic neuronal death in a rat model of transient global ischemia. Caspase-9 gene expression and protease activity were extremely low in the adult brain, whereas they were developmentally upregulated in newborn rats, especially at postnatal 12 weeks, a finding consistent with the theory of an essential role for caspase-9 in neuronal apoptosis during brain development. After 15-minute transient global ischemia, caspase-9 was overexpressed and proteolytically activated in the hippocampal CA1 neurons at 8 to 72 hours of reperfusion. The temporal profile of caspase-9 activation coincided with that of cytochrome c release and caspase-3 activation, but preceded CA1 neuronal death. Immunoprecipitation experiments revealed that there was enhanced formation of Apaf-1/caspase-9 complex in the hippocampus 8 and 24 hours after ischemia. Furthermore, intracerebral ventricular infusion of the relatively specific caspase-9 inhibitor N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoro-methylketone before ischemia attenuated caspase-3-like activity and significantly enhanced neuronal survival in the CA1 sector. In contrast, inhibition of caspase-8 activity had no significant effect on caspase-3 activation or neuronal survival. These results suggest that the caspase-9-dependent intrinsic pathway may be the primary mechanism responsible for the activation of caspase-3 in ischemic hippocampal neurons.
J Cereb Blood Flow Metab 2002 May
PMID:Cloning and characterization of rat caspase-9: implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia. 1197 26

The role of the tumor necrosis factor (TNF)-alpha convertase (TACE/ADAM17) in the adult nervous system remains poorly understood. The authors have previously demonstrated that TACE is upregulated in rat forebrain slices exposed to oxygen-glucose deprivation (OGD). They have now used rat mixed cortical cultures exposed to OGD or glutamate to study (1) TACE expression and localization, and (2) the effects of TNF-alpha release on cell viability. OGD-or glutamate-caused TNF-alpha release, an effect that was blocked by the TACE inhibitor BB3103 (BB) (0.1-1 micromol/L; control: 1.67 +/- 0.59; OGD: 6.59 +/- 1.52; glutamate: 3.38 +/- 0.66; OGD +/- BB0.1: 3.23 +/- 0.67; OGD +/- BB1: 1.33 +/- 0.22 pg/mL, n = 6, P < 0.05). Assay of TACE activity as well as Western blot showed that TACE expression is increased in OGD-or glutamate-exposed cells. In control cultures, TACE immunoreactivity was present in some microglial cells, whereas, after OGD or glutamate, TACE immunostaining appeared in most microglial cells and in some astrocytes. Conversely, BB3103 (0.1 micromol/L) caused apoptosis after glutamate exposure as shown by annexin and Hoechst 33342 staining and caspase-3 activity, an effect mimicked by the proteasome inhibitor MG-132 (caspase activity: glutamate: 5.1 +/- 0.1; glutamate + BB: 7.8 +/- 0.8; glutamate + MG: 11.9 +/- 0.5 pmol. min(-1) mg(-1) protein, n = 4, P < 0.05), suggesting that translocation of the transcription factor NF-kappaB mediates TNF-alpha-induced antiapoptotic effect. Taken together, these data demonstrate that, in rat mixed neuronal-glial cortical cultures exposed to OGD or glutamate, (1) TACE/ADAM17 activity accounts for the majority of TNF-alpha shedding, (2) an increase in glial TACE expression contributes to the rise in TNF-alpha, and (3) TNF-alpha release in this setting inhibits apoptosis via activation of the transcription factor NF-kappaB.
J Cereb Blood Flow Metab 2002 May
PMID:TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate. 1197 30

Citicoline has been demonstrated to be beneficial in several models of cerebral ischaemia. We tested the hypothesis that citicoline may provide apoptotic pathways following focal cerebral ischaemia. Focal cerebral ischaemia was produced by distal, permanent middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. The animals were randomised into four groups: (B+A) Citicoline 500 mg/kg IP 24 and 1 h before MCAO, and 23 h after MCAO; (A) citicoline 500 mg/kg IP, within 30 min after MCAO, and 23 h after MCAO; (C) vehicle IP; and (D) sham-operated. The animals were sacrificed at 12 h (n=8 per group) and 24 h (n=8 per group) after MCAO. Immunohistochemistry was performed on free-floating tissue sections with goat polyclonal antibodies to procaspase-1, -2, -3, -6 and -8, and in paraffin-embedded sections processed for cleaved caspase-3 (17 kDa) immunohistochemistry. Finally, some sections were stained with the method of in situ end-labelling of nuclear DNA fragmentation. For gel electrophoresis and Western blotting, antibodies to poly (ADP-ribose) polymerase (PARP) products of 89 kDa were used to reveal specific cleavage substrates of caspases. MCAO induced the expression of all procaspases and the expression of PARP products of 89 kDa, as well as cells with nuclear DNA fragmentation, at 12 and 24 h, in the infarcted core and penumbra. Citicoline reduced the expression of all procaspases at 12 and 24 h after MCAO, as well as the expression of cleaved caspase-3 in cells in the penumbra area. This was accompanied by a reduction in the number of cells bearing nuclear DNA fragments. The expression of caspase-cleaved products of PARP (PARP 89 kDa) was reduced in citicoline-treated ischaemic rats. These results show that citicoline inhibits the expression of proteins involved in apoptosis following MCAO.
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PMID:CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat. 1201 11

The authors used cultured mouse cortical neurons to study mechanisms of DNA damage-induced apoptosis in immature and mature neurons. Neurons were maintained viably for 60 days in vitro (DIV60). The increased levels of glutamate receptors, synaptic proteins, and glycolytic enzyme were used to track maturation. Exposure of neurons to the DNA-damaging agent camptothecin induced apoptosis in immature (DIV5) and mature (DIV25-30) neurons. Internucleosomal fragmentation of DNA emerged more rapidly in mature neurons than in immature neurons. Immunoblotting revealed that cleaved caspase-3 increased in apoptotic DIV5 neurons but not in DIV30 neurons, but immunolocalization showed accumulation of cleaved caspase-3 in DIV5 and DIV30 neurons. A reversible caspase-3 inhibitor blocked apoptosis in DIV5 neurons but not in DIV30 neurons. Phosphorylation of extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAP kinase)-42/44 occurred preapoptotically in mature but not immature neurons, while Erk54 nuclear translocation and MAP kinase kinase kinase-1 cleavage into putative caspase-3-generated proapoptotic fragments occurred in DIV5 but not DIV30 neurons. Inhibition of Erk activation with MAP kinase kinase inhibitor blocked apoptosis at both ages. The results show that immature and mature cortical neurons engage different signaling mechanisms in MAP kinase and caspase pathways during apoptosis; thus, neuron age influences the mechanisms and progression of apoptosis.
J Cereb Blood Flow Metab 2002 Aug
PMID:Immature and mature cortical neurons engage different apoptotic mechanisms involving caspase-3 and the mitogen-activated protein kinase pathway. 1217 79

A previous study demonstrated that cross-desensitization experiments performed with the lysophosphatidic acid (LPA) analogues (R)- and (S)-N-palmitoyl-norleucinol 1-phosphate (PNPAs) inhibited LPA-induced platelet aggregation without any stereospecificity. Here we report opposite biological effects of the two enantiomers on mitogenesis of IMR-90 fibroblasts in relation to their respective metabolism. (R)PNPA was proliferative, while (S)PNPA induced apoptosis by specifically inhibiting phosphatidylcholine biosynthesis at the last step of the CDP-choline pathway controlled by cholinephosphotransferase. This effect was not direct but required dephosphorylation of PNPAs by ecto-lipid phosphate phosphatase before cellular uptake of the generated N-palmitoyl-norleucinols (PNOHs). Inhibition of cholinephosphotransferase by the derivative (S)PNOH was confirmed by an in vitro assay. (S)PNPA proapoptotic effects led us to clarify the mechanism linking cholinephosphotransferase inhibition to apoptosis. Three proapoptotic responses were observed: the activation of caspase-3, the production of ceramides from newly synthesized pools (as demonstrated by the inhibitor Fumonisin B1) and finally the activation of stress-activated protein kinase, p38 and c-Jun N-terminal kinases 1/2, as a result of ceramide increase. Thus our data demonstrate that synthetic analogues of LPA might display stereospecific effects leading to apoptosis independently of classical LPA-activated pathways.
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PMID:A lysophosphatidic acid analogue is revealed as a potent inhibitor of phosphatidylcholine synthesis, inducing apoptosis. 1219 36

Citicoline, or CDP-choline, is an essential endogenous intermediate in the biosynthesis of phosphatidylcholine that may act as a neuroprotector in several models of neurodegeneration. The present study analyses the effects of citicoline in the paradigm of staurosporine-induced cell death in human SH-SY5Y neuroblastoma cells. Citicoline reduces apoptosis induced by 100 nM staurosporine for 12 h in SH-SY5Y cells. This effect is higher with pre-treatment of 60 mM citicoline for 24 h after staurosporine challenge. Moreover, citicoline treatment restores glutathione redox ratio diminished after staurosporine challenge. Finally, citicoline also reduces the expression levels of active caspase-3 and specific PARP-cleaved products of 89 kDa resulting from staurosporine exposure when citicoline is added to the culture medium 24 h before staurosporine. These findings demonstrate that citicoline affects the staurosporine-induced apoptosis cell-signalling pathway by interacting with the glutathione system and by inhibiting caspase-3 in SH-SY5Y human neuroblastoma cells.
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PMID:Citicoline increases glutathione redox ratio and reduces caspase-3 activation and cell death in staurosporine-treated SH-SY5Y human neuroblastoma cells. 1244 83

Erythropoietin (EPO) plays a prominent role in the regulation of the hematopoietic system, but the potential function of this trophic factor as a cytoprotectant in the cerebral vascular system is not known. The authors examined the ability of EPO to modulate a series of death-related cellular pathways during free radical-induced injury in cerebral microvascular endothelial cells (ECs). Endothelial cell injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, apoptotic protease-activating factor-1 (Apaf-1), and Bcl-XL expression, mitochondrial membrane potential, cytochrome c release, and cysteine protease activity. They show that constitutive EPO is present in ECs but is insufficient to prevent cellular injury. Signaling through the EPO receptor, however, remains biologically responsive to exogenous EPO administration to offer significant protection against nitric oxide-induced injury. Exogenous EPO maintains both genomic DNA integrity and cellular membrane asymmetry through parallel pathways that prevent the induction of Apaf-1 and preserve mitochondrial membrane potential in conjunction with enhanced Bcl-XL expression. Consistent with the modulation of Apaf-1 and the release of cytochrome c, EPO also inhibits the activation of caspase-9 and caspase-3-like activities. Identification of novel cytoprotective pathways used by EPO may serve as therapeutic targets for cerebral vascular disease.
J Cereb Blood Flow Metab 2003 Mar
PMID:Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin. 1262 7

Insulin-like growth factor (IGF-1) markedly increases myelination and glial numbers in white matter after ischemia in near-term fetal sheep; however, it is unclear whether this is due to reduced cell loss or increased secondary proliferation. Brain injury was induced in near-term fetal sheep by 30 minutes of bilateral carotid artery occlusion. Ninety minutes after the occlusion, fetuses were given, intracerebroventricularly, either a single dose of IGF-1 (either 3 or 30 micro g), or 3 micro g followed by 3 micro g over 24 hours (3 + 3 micro g). White matter was assessed 4 days after reperfusion. Three micrograms, but not 30 micro g of IGF-1 prevented loss of oligodendrocytes and myelin basic protein density (P < 0.001) compared to the vehicle-treated ischemia controls. No additional effect was observed in the 3 + 3 micro g group. IGF-1 treatment was associated with reduced caspase-3 activation and increased glial proliferation in a similar dose-dependent manner. Caspase-3 was only expressed in oligodendrocytes that showed apoptotic morphology. Proliferating cell nuclear antigen co-localized with both oligodendrocytes and astrocytes and microglia. Thus, increased oligodendrocyte numbers after IGF-1 treatment is partly due to suppression of apoptosis, and partly to increased proliferation. In contrast, the increase in reactive glia was related only to proliferation. Speculatively, reactive glia may partly mediate IGF-1 white matter protection.
J Cereb Blood Flow Metab 2003 Jun
PMID:Insulin-like growth factor (IGF)-1 suppresses oligodendrocyte caspase-3 activation and increases glial proliferation after ischemia in near-term fetal sheep. 1279 22

The hypothesis was tested that hyperbaric oxygen therapy (HBO) reduced brain infarction by preventing apoptotic death in ischemic cortex in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and subsequently were exposed to HBO (2.5 atmospheres absolute) for 2 h, at 6 h after reperfusion. Rats were killed and brain samples were collected at 24, 48, 72 h, and 7 days after reperfusion. Neurologic deficits, infarction area, and apoptotic changes were evaluated by clinical scores, 2,3,7-triphenyltetrazolium chloride staining, caspase-3 expression, DNA fragmentation assay, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL)-hematoxylin and eosin (H&E) costaining. In MCAO/R without HBO treatment animals, DNA fragmentation was observed in injured cortex at 24, 48, and 72 h but not in samples at 7 days after reperfusion. Double labeling of brain slides with NeuN and caspase-3 demonstrated neurons in the injured cortex labeled with caspase-3. TUNEL+H&E costaining revealed morphologic apoptotic changes at 24, 48, and 72 h after reperfusion. Hyperbaric oxygen therapy abolished DNA fragmentation and reduced the number of TUNEL-positive cells. Hyperbaric oxygen therapy reduced infarct area and improved neurologic scores at 7 days after reperfusion. One of the molecular mechanisms of HBO-induced brain protection is to prevent apoptosis, and this effect of HBO might preserve more brain tissues and promote neurologic functional recovery.
J Cereb Blood Flow Metab 2003 Jul
PMID:Inhibition of apoptosis by hyperbaric oxygen in a rat focal cerebral ischemic model. 1284 89

Loss of mitochondrial membrane integrity and the resulting release of apoptogenic factors may play a critical role in mediating hippocampal neurodegeneration after transient global ischemia. In the present study, the authors have cloned and characterized the rat cDNA encoding apoptosis-inducing factor (AIF), an intramitochondrial protein that promotes cell death in a caspase-independent manner upon release into nonmitochondrial compartments. In contrast to the expression patterns of a number of apoptosis-regulatory gene products during brain development, the expression of AIF protein increases gradually with brain maturation and peaks in adulthood. In a rat model of transient global ischemia, AIF was found to translocate from mitochondria to the nucleus in the hippocampal CA1 neurons after ischemia and to manifest a DNA-degrading activity that mimicked the purified AIF protein and was inhibitable by AIF immunodepletion. The temporal profile of AIF translocation after ischemia (24 to 72 hours) coincided with the induction of large-scale DNA fragmentation at the size of 50 kbp, a well-characterized hallmark of AIF-like activity but preceded the formation of internucleosomal DNA fragmentation (72 hours), a DNA degradation associated with the terminal stage of cell death. Further, the nuclear translocation of AIF after ischemia was not blocked by inhibiting caspase-3/-7 activities, but, as shown in neuronal cultures that were challenged with transient oxygen-glucose deprivation, it can be prevented by intracellular delivery of the mitochondria-associated antiapoptotic protein Bcl-xL. The results presented here strongly suggest that mitochondrial release of AIF may be an important factor, in addition to the previously reported cytochrome c and Smac, which could contribute to the selective vulnerability of CA1 neurons to transient global ischemic injury.
J Cereb Blood Flow Metab 2003 Oct
PMID:Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. 1452 24


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