Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Retinal cell death induced by over-stimulation of glutamate receptors is related to the programmed cell death or apoptosis. However, little is known about the intracellular events that lead to this cell death process in the retina. In this study, we asked if caspase-3 family cysteine proteases regulate cell death in an explant culture of adult rat retina after exposure to excessive glutamate. Cells with DNA fragmentation were first detected in the ganglion cell layer 3 h after a brief exposure to 20 mM glutamate; whilst those in the inner nuclear layer were first observed 6 h after the glutamate lesion. Caspase-3-like activity, as indicated by immunostaining of the fractin antibody that recognizes actin fragments generated by caspase-3 family proteases, was seen 40 min after glutamate treatment. Staining was first detected in the ganglion cell layer and then in the inner nuclear layer, preceding the appearance of cells with DNA fragmentation in these layers. Colocalization study showed that all cells with DNA breaks were fractin positive, indicating that caspase-3 family activity was involved in the glutamate-induced cell death in the adult rat retina. Furthermore, DEVD-CHO, a tetrapeptide inhibitor for caspase-3 family members, reduced dramatically the fractin staining and significantly alleviated glutamate-induced cell death and DNA fragmentation in the ganglion cell layer and inner nuclear layer. Inhibitor for caspase-1-like activity, YVAD-CHO, neither reduced the fractin staining nor showed comparable neuroprotective effects to the retina. We conclude that glutamate-induced apoptotic cell death in adult rat retina is mediated by a specific activation of cysteine proteases related to the caspase-3 family, and an intervention to the caspase-3 proteases provides effective protection to retinal neurons against glutamate excitotoxicity.
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PMID:Inhibition of caspase-3-like activity reduces glutamate induced cell death in adult rat retina. 1151 28

Apoptosis of neuronal cells is a proposed cause of certain neurological disorders. Here, we report on a 5- to 6-fold increase in apoptosis by exposure to prostaglandin D2 synthase (PGD2S) in PC12 neuronal cells. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and appears to be mediated via caspase-3 activation. Neutralization with anti-PGD2S antibody or pre-treatment with selenium, which inhibits PGD2S enzymatic activity, both significantly inhibited the PGD2S-induced apoptosis, however, neither had any effect on the apoptosis induced by the known neuronal apoptotic inducer, glutamate. In addition, prostaglandins E1, E2, and F2alpha all inhibited the PGD2S-induced apoptosis while prostaglandin H2 had no significant effect. Furthermore, PGD2S isolated from human serum was more effective at inducing apoptosis then recombinantly expressed protein, presumably due to glycosylation. This novel role of PGD2S, as an inducer of apoptosis, may have implications in PC12 differentiation and possibly some neurological disorders.
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PMID:Prostaglandin D2 synthase induces apoptosis in PC12 neuronal cells. 1152 37

The mitogen-activated protein kinase (MAPK) cascades are thought to be important mediators in the transduction of extracellular signals into cellular responses. The p38 kinase, a member of the MAPK superfamily, is activated by a wide variety of extracellular stimuli and has been implicated in neuronal apoptosis induced by glutamate. In this study we have examined the role of p38 kinase in the potassium deprivation model of apoptosis in rat cerebellar granule neurons (CGN). An increase in p38 kinase activity was observed with a 15-minute potassium deprivation when compared to the basal level. We also found that SB203580 and PD169316, specific p38 kinase inhibitors, significantly attenuated apoptosis in potassium-deprived cells in a dose dependent manner. A decrease in caspase-3 mediated DEVD-MCA, substrate hydrolysis and the appearance of the 120 kDa-spectrin breakdown product in cells treated with SB203580 further suggests that the p38 kinase acts upstream of caspase-3 in the apoptosis cascade. The data provides evidence for an essential role of p38 kinase in mediating apoptotic cell death in CGN and the inhibition of p38 kinase mimics the suppression of apoptosis provided by natural survival signals.
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PMID:Inhibition of p38 kinase mimics survival signal-linked protection against apoptosis in rat cerebellar granule neurons. 1154 39

Excitotoxic glutamate CNS stimulation can result in neuronal cell death. Contributing mechanisms and markers of cell death are the activation of caspase-3 and DNA fragmentation. It remains to be resolved to which extent both cellular reactions overlap and/or indicate different processes of neurodegeneration. In this study, mixed neuronal cultures from newborn mice pubs (0-24 h) were stimulated with glutamate, and the co-localization of active caspase-3 and DNA fragmentation was investigated by immunocytochemistry and the TUNEL nick-end labelling. In untreated cultures, 8% scattered neurons (marked by MAP-2) displayed activated caspase-3 at different morphological stages of degeneration. TUNEL staining was detected in 5% of cell nuclei including GFAP-positive astrocytes. However, co-localization of active caspase-3 with TUNEL was less than 2%. After glutamate stimulation (125 microM), the majority of neurons was dying between 12 and 24 h. The absolute number of active caspase-3 neurons increased only moderately but in relation of surviving neurons after 24 h from 8 to 36% (125 microM), to 53% (250 microM) or to 32% (500 microM). TUNEL staining also increased after 24 h following glutamate treatment to 37% but the co-localization with active caspase-3 remained at the basal low level of 2%. In our system, glutamate-mediated excitotoxicity effects the DNA fragmentation and caspase-3 activation. Co-localization of both parameters, however, is very poor. Active caspase-3 in the absence of TUNEL indicates a dynamic degenerative process, whereas TUNEL marks the end stage of severe irreversible cell damage regardless to the origin of the cell.
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PMID:Caspase-3 activation and DNA fragmentation in primary hippocampal neurons following glutamate excitotoxicity. 1159 62

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, have been examined following intracortical injection of the glutamate analogue quinolinic acid (QA). Increased JNK(P) and p38(P) immunoreactivity has been found in the core at 1 h following QA injection, whereas increased MAPK(P) immunoreactivity occurs in neurons and glial cells localised around the lesion and in neurons in remote cortical regions. This is accompanied by strong phosphorylated Ser63 c-Jun (c-Jun(P)) immunoreactivity in the core at 3 h, and by strong phosphorylated CREB, Elk-1 and ATF-2 (CREB(P), Elk-1(P) and ATF-2(P)) immunoreactivity mainly in neurons around the core at 24 h following QA injection. Examination with the method of in situ end-labelling of nuclear DNA fragmentation has revealed large numbers of positive cells with no apoptotic morphology in the core at 24 h, thus indicating that JNK(P), p38(P) and c-Jun(P) over-expression precedes cell death. In contrast, MAPK(P), CREB(P), Elk-1(P) and ATF-2(P), but not phosphorylated c-Myc (c-Myc(P)), over-expression correlates with cell survival. Examination of cleaved, active caspase-3 has shown specific immunoreactivity restricted to a few hematogenous cells in the area of injection. Since cleaved caspase-3 is not expressed by dying cells in the present paradigm, JNK(P), p38(P) and c-Jun(P) expression is not associated with caspase-3 activation. The present results demonstrate selective activation of specific MAPK signals which are involved either in cell death or cell survival triggered by excitotoxic insult.
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PMID:Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. 1159 64

Hypoxia-ischemia (HI) is a leading cause of white matter damage, a major contributor to cerebral palsy in premature infants. Preferential white matter damage is believed to result from vulnerability of the immature oligodendrocyte (the pro-OL) to factors elevated during ischemic damage, such as oxygen free radicals and glutamate. In order to determine whether pro-OLs undergo apoptotic death after HI, we analyzed periventricular white matter OLs in P7 rats 4, 12 and 24 h after HI to analyze the time course and mode of cell death. DNA fragmentation was seen at 12 and 24 h of recovery after HI, representing a 17-fold increase over control. In addition, caspase-3 activation was found in NG2+ pro-OLs at 12 h. Electron-microscopic analysis of cell death in the white matter revealed a transition from early necrotic deaths to hybrid cell deaths to classical apoptosis between 4 and 24 h of recovery from HI. The delayed time course of apoptosis in pro-OLs supports the feasibility of interventions to improve clinical outcomes for newborns surviving birth asphyxia.
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PMID:Perinatal hypoxia-ischemia induces apoptotic and excitotoxic death of periventricular white matter oligodendrocyte progenitors. 1159 21

Activation of ionotropic glutamate receptors can induce neuronal apoptosis in vitro and in vivo. We showed previously that activation of the N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptors in a low Ca(2+) and low Na(+) condition induced apoptotic neuronal death, and that the K(+) efflux via NMDA receptor channels was likely a key event in NMDA-induced apoptosis. Since non-NMDA receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and kainate receptors, are also permeable to K(+), we tested the hypothesis that stimulating K(+) efflux via non-NMDA receptor channels could induce apoptosis in cultured cortical neurons. Using a Ca(2+)-free and Na(+)-free external solution, application of kainate revealed outward membrane currents carried by K(+) efflux. In a low Ca(2+)/low Na(+) medium, a 5-h exposure to 50-500 microM AMPA in the presence of the NMDA receptor antagonist MK801 induced dose-dependent neuronal death 24 h after the onset of the insult, accompanied by intracellular K(+) reduction and caspase-3 activation. The AMPA-induced cell death was attenuated by the caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-FMK) and by the protein synthesis inhibitor cycloheximide. Reducing K(+) efflux by raising extracellular K(+) concentration from 5 to 25 mM attenuated AMPA-triggered cell death, the Ca(2+) channel antagonist nifedipine showed no effect on the AMPA toxicity. Kainate induced similar neuronal death sensitive to attenuation by Z-VAD-FMK or elevated extracellular K(+).We suggest that the non-NMDA receptor-mediated K(+) efflux may participate in apoptotic process and that blocking excessive K(+) efflux mediated by NMDA and non-NMDA receptors may selectively prevent neuronal apoptosis under certain pathological conditions.
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PMID:Role of K(+) efflux in apoptosis induced by AMPA and kainate in mouse cortical neurons. 1173 31

Hypoxic-ischemic encephalopathy (HIE) in neonates is a disorder of excessive neuronal excitation that includes seizures, abnormal EEG activity, and delayed failure of oxidative metabolism with elevated levels of lactic acid in the brain. Evidence from experimental models and clinical investigation indicates that HIE is triggered by a profound disruption in the function of glutamate synapses so that re-uptake of glutamate from the synapse is impaired and post-synaptic membranes containing glutamate receptors are depolarized. Severe hypoxemia preferentially depolarizes neuronal membranes, while ischemia probably has greater impact on the activity of glial glutamate re-uptake. Together, severe hypoxia and ischemia trigger a delayed cascade of events that may result in cell death by necrosis and/or apoptosis. Apoptosis is far more prominent in the neonate than in the adult and activation of cysteine proteases such as caspase-3 is a very important pathway in excitotoxic neonatal injury. Understanding the complex molecular networks triggered by an excitotoxic insult in the neonate provides insight into patterns of selective neuronal vulnerability and potential therapeutic strategies.
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PMID:Excitotoxicity in neonatal hypoxia. 1175 16

Studies on the cellular and molecular mechanism of neurotransmitter receptor-signaling and of neuronal and glial cell responses to stresses seem to be important to elucidate the action mechanism of centrally-acting drugs and to develop novel therapeutics against several diseases in the brain. The present review shows our findings with regard to the membrane receptor-signaling mechanism including serotonin, noradrenaline, glutamate receptors, ion channels, G-proteins, protein kinases and drug actions in Xenopus oocytes injected with rat brain mRNA, NG108-15 cells and brain membranes. Regarding the results of studies on the inter- and intra-cellular mechanism of neurons and glial cells against cerebral ischemia/hypoxia, we review the involvement of a transcription factor NF-kappa B in LPS-elicited inducible NO synthase (iNOS) expression in rat astroglial cells. Then we describe possible involvement of: 1) ADP-ribosylation/nitrosylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 2) decrease in mitochondrial membrane potential, release of caspase-3 from mitochondria and degradation of the inhibitor of caspase-activated DNase by activated caspase in NO-induced neuronal apoptosis. We observed that hypoxia results in expression of a molecular chaperon such as protein disulfide isomerase (PDI) and HSP70 in astroglial cells. Our recent findings indicate that overexpression of PDI in the rat hippocampus (in vivo) and in neuroblastoma SK-N-MC cells (in vitro) significantly suppress the hypoxia-induced neuronal death. From physiological/pathophysiological and pharmacological aspects, we review the importance of studies on the cellular and molecular mechanism of membrane receptor-signaling and of stress-responses in the brain to identify functional roles of neuro-glial- as well as neuro-neuronal interaction in the brain.
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PMID:[Cellular and molecular pharmacological studies on membrane receptor-signaling and stress-responses in the brain]. 1176 4

The present study is directed to study: (a) bax translocation and cytochrome c release as mediators of the mitochondrial pathway of apoptosis; (b) Fas-L (Fas-ligand) expression as an indicator of the possible involvement of the Fas/Fas-L signaling pathway; and (c) active caspase-3 expression as the main executioner of caspase-mediated apoptosis, in rats receiving an intraperitoneal injection of the glutamate analogue kainic acid (KA) at a dose of 9 mg/kg, which is sufficient to produce generalized seizures and excitotoxic cell death in the entorhinal cortex. Sub-fractionation studies of entorhinal cortex homogenates have shown cytochrome c and cytochrome oxidase IV localized in the mitochondrial fraction, and Bax localized in the cytosolic fraction. No modifications in the sub-cellular distribution of cytochrome c and Bax have been observed at 6 h and 24 h in KA-treated rats. Morphological studies have shown cytoplasmic shrinkage and nuclear condensation consistent with necrosis in the entorhinal cortex. Many neurons (about 30% of dying cells) are stained with the method of in situ end-labeling of nuclear DNA fragmentation. Yet only about 5% of dying cells have apoptotic morphology. A percentage of dying cells (5% at 6 h and 40% at 24 h) over-express Fas-L but only about 2% of dying cells at 24 h post-injection express cleaved caspase-3 (17 kD). The present data further support the concept that necrosis is the predominant form of cell death in the entorhinal cortex, although caspase-3-dependent apoptotic cell death may play a limited role, in the present paradigm of KA-induced excitotoxicity.
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PMID:Caspase-3-associated apoptotic cell death in excitotoxic necrosis of the entorhinal cortex following intraperitoneal injection of kainic acid in the rat. 1188 Feb 2


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