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

Previous studies showed that 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, produced neuronal death secondary to perturbed intracellular calcium homeostasis. However, the response of intramitochondrial calcium ([Ca(2+)](m)) to 3-nitropropionic acid remains unknown. In this study, we investigated the roles of and relationships among [Ca(2+)](m) overload, mitochondrial reactive oxygen species, and mitochondrial membrane depolarization in 3-nitropropionic acid-induced neuronal death. Following 1 mM 3-nitropropionic acid treatment on primary rat neuronal cultures, there was a gradual increase of [Ca(2+)](m) beginning at 2-4 h post 3-nitropropionic acid application, and a twofold increase of mitochondrial reactive oxygen species at 4 h. These were followed by mitochondrial membrane depolarization at 6-8 h post-treatment. By inhibiting [Ca(2+)](m) uptake, Ruthenium Red attenuated the production of reactive oxygen species, and prevented the 3-nitropropionic acid-induced mitochondrial membrane depolarization and 70% of apoptotic neuronal death (P<0.001). Inhibition of caspase activation attenuated the elevation of [Ca(2+)](m) (P<0.001), indicating that caspase activation plays a role in the elevation of [Ca(2+)](m). MK-801, an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, prevented 3-nitropropionic acid-induced [Ca(2+)](m) elevation, caspase-3 activation, mitochondrial depolarization, and neuronal death. We conclude that the activation of NMDA glutamate receptor contributes to mitochondrial alterations induced by 3-nitropropionic acid. Inhibition of its activation and [Ca(2+)](m) overload with subsequent mitochondrial membrane depolarization can therefore attenuate the neuronal death induced by 3-nitropropionic acid.
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PMID:The mechanisms of neuronal death produced by mitochondrial toxin 3-nitropropionic acid: the roles of N-methyl-D-aspartate glutamate receptors and mitochondrial calcium overload. 1207 12

Colchicine, a potent microtubule-depolymerizing agent, is well known to selectively kill dentate granule cells in the hippocampal formation in vivo. Using organotypic cultures of rat entorhino-hippocampal slices, we confirmed that in vitro exposure to 1 microM and 10 microM of colchicine reproduced a specific degeneration of the granule cells after 24 h. Similar results were obtained with other types of microtubule-disrupting agents, i.e., nocodazole, vinblastine, and Taxol. Interestingly, the actin-depolymerizing agents cytochalasin D and latrunculin A also elicited selective neurotoxicity in the dentate gyrus without affecting survival of hippocampal pyramidal cells. The selective pattern of degeneration was observable 24 h after a brief treatment with the toxins as short as 5 min, but this delayed neuronal death was unlikely to be a result of excitotoxicity because it was virtually unaffected by glutamate receptor antagonists, tetrodotoxin, or extracellular Ca(2+)-free conditions. The damaged tissues contained a large number of TUNEL-positive neurons and exhibited an increased level in caspase-3-like activity, suggesting that cytoskeleton disruption triggers an apoptosis-like process in dentate granule cells. Thus, this study may provide a basis for understanding the distinctive mechanism that supports granule cell survival.
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PMID:Cytoskeleton disruption causes apoptotic degeneration of dentate granule cells in hippocampal slice cultures. 1212 12

Transient global ischemia reportedly results in glutamate receptor stimulation and harmful Ca(2+)-overloading, then activates some proteins involved in cell apoptosis in vivo and in vitro, but underlying mechanisms remain to be elucidated. Here we evaluated the role of N-methyl-D-aspartate (NMDA) receptor antagonist and L-type voltage-gated Ca(2+) channel (L-VGCC) antagonist in mediating the release of cytochrome c and the expression of caspase-3 precursor protein (procaspase-3). Cytochrome c release from mitochondria is a critical step in the cell apoptotic process. We examined whether cytochrome c was translocated from mitochondria to the cytosol by Western blot in rat hippocampus after 15 min global ischemia. Released cytochrome c interacts with apoptotic protease activating factor-1 and caspase-9, both of which play important roles in the cytochrome c-dependent mitochondrial pathway of apoptosis by activating caspase-3. Our studies demonstrated that the inactive precursor and active cleaved subunits of caspase-3 protease increased dramatically with the extent of reperfusion time. Following pretreatment with ketamine (a non-competitive NMDA receptor antagonist) and nifedipine (L-VGCC antagonist), cytosolic cytochrome c and the expression of procaspase-3 dramatically decreased, which might result in less neuron damage after ischemia.
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PMID:N-methyl-D-aspartate receptor and L-type voltage-gated Ca(2+) channel antagonists suppress the release of cytochrome c and the expression of procaspase-3 in rat hippocampus after global brain ischemia. 1214 22

Neuronal apoptosis is induced prominently in the newborn rodent brain by glutamate receptor excitotoxicity and related insults, including trauma and hypoxia-ischemia. However, the molecular mechanisms of this neurodegeneration are unclear. We tested the hypothesis that changes in the subcellular distribution of the proapoptotic protein Bax precede the activation of downstream apoptosis-effector mechanisms such as caspase-3 cleavage and endonuclease activation during the progression of excitotoxic neuronal apoptosis in the striatum of newborn rat. Kainic acid (4 nmol) was injected into striatum of anesthetized 7-day-old rats, and the animals were killed at 2, 6, 12, and 24 h postinsult. Controls were age-matched, vehicle-injected, or naive rats. Counts of ultrastructurally confirmed striatal neuron apoptosis in brain sections were highest at 24 h. Striatal tissue was microdissected and fractionated into cytosolic, mitochondrial-, and nuclear-enriched compartments. Immunoblots showed that Bax translocates from the cytosol fraction to the mitochondrial fraction, with maximal translocation by 2 h in the absence of changes in mitochondrial accumulation. Cleaved caspase-3 levels increase progressively in both cytosolic and mitochondrial fractions between 6 and 24 h. Cleaved caspase-3 accumulates in apoptotic striatal neurons as shown by immunolocalization. Internucleosomal fragmentation of DNA coincides with caspase-3 cleavage. We conclude that rapid translocation of Bax to mitochondria precedes caspase-3 and endonuclease activation during excitotoxic neuronal apoptosis in newborn rat brain and that initiation of this death cascade occurs within 2 h after glutamate receptor activation.
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PMID:Rapid subcellular redistribution of Bax precedes caspase-3 and endonuclease activation during excitotoxic neuronal apoptosis in rat brain. 1218 52

Caspases are proteases involved in various physiological and pathological processes in the nervous system, including development and pathogenesis. GRASP-1 is a recently identified neuronal substrate of caspase-3-subfamily caspases. It is a Ras-guanine nucleotide exchange factor (RasGEF) that interacts with the glutamate receptor interacting protein (GRIP). This alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor/GRIP protein complex has been proposed to be involved in AMPA receptor synaptic targeting. The caspase-3 cleavage of GRASP-1 separates the N-terminal RasGEF catalytic domain from the C-terminal GRIP-interacting region, potentially disrupting regulation of the RasGEF activity by GRIP. To examine the regulation and regional distribution of the caspase-3 cleavage of GRASP-1 in vivo, we generated a cleavage site-specific antibody, termed CGP, against the cleaved N-terminal fragment of GRASP-1. Using this antibody, we have examined the caspase cleavage of GRASP-1 during postnatal development and following ischemia in mice. We found that caspase cleavage of GRASP-1 occurs in specific brain regions in a time-dependent manner during development and ischemia. This data provides an important account of the brain areas that might require caspase-3 activity in postnatal development and ischemic damage, which has not been documented. It also demonstrates that the CGP antibody is a powerful tool for studying neuronal activity of the caspase-3-subfamily caspases in vivo.
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PMID:Physiological and pathological caspase cleavage of the neuronal RasGEF GRASP-1 as detected using a cleavage site-specific antibody. 1220 67

The molecular events initiating apoptosis following traumatic spinal cord injury (SCI) remain poorly understood. Soon after injury, the spinal cord is exposed to numerous secondary insults, including elevated levels of glutamate, that contribute to cell dysfunction and death. In the present study, we attempted to mimic the actions of glutamate by subdural infusion of the selective glutamate receptor agonist, kainic acid, into the uninjured rat spinal cord. Immunohistochemical colocalization studies revealed that activated caspase-3 was present in ventral horn motor neurons at 24 hours, but not 4 hours or 96 hours, following kainic acid treatment. However, at no time point examined was there evidence of significant neuronal loss. Kainic acid resulted in caspase-3 activation in several glial cell populations at all time points examined, with the most pronounced effect occurring at 24 hours following infusion. In particular, caspase-3 activation was observed in a significant number of oligodendroglia in the dorsal and ventral funiculi, and there was a pronounced loss of oligodendroglia at 96 hours following treatment. The results of these experiments indicate a role for glutamate as a mediator of oligodendroglial apoptosis in traumatic SCI. In addition, understanding the apoptotic signaling events activated by glutamate will be important for developing therapies targeting this cell death process.
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PMID:Temporal and spatial distribution of activated caspase-3 after subdural kainic acid infusions in rat spinal cord. 1290 Sep 17

Oligodendrocytes are vulnerable to excitotoxic signals mediated by AMPA receptors and by high- and low-affinity kainate receptors. Here we investigated the nature of the cell death triggered by activation of these receptors in primary cultures of oligodendrocytes from the rat optic nerve. Activation of AMPA receptors at both submaximal and maximal concentrations of the agonist induced massive calcium entry, mitochondrial depolarization, and a rise in the level of reactive oxygen species that correlated with a decrease in the levels of reduced glutathione. In addition, excitotoxicity initiated by submaximal, but not maximal, activation of AMPA receptors was prevented by caspase-3 blockade and by the concomitant blockade of caspases 8 and 9. In turn, maximal activation of high- or low-affinity kainate receptors induced mitochondrial events and toxicity levels similar to those observed with submaximal activation of AMPA receptors. In contrast to AMPA receptor-mediated insults, calcineurin inhibition or caspase-9 blockade was sufficient to prevent cell death triggered by both types of kainate receptors. Consistent with these results, prolonged glutamate receptor activation in freshly isolated optic nerves caused selective activation of caspase-3 and chromatin condensation in oligodendrocytes. Overall, the evidence presented here indicates that oligodendrocyte death by excitotoxicity is mediated by caspase-dependent and -independent mechanisms.
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PMID:Caspase-dependent and caspase-independent oligodendrocyte death mediated by AMPA and kainate receptors. 1457 31

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme activated by DNA breaks and serves a role in DNA repair through the formation of polymers (poly(ADP)ribosylation) at sites of DNA damage. PARP-1 is activated by DNA damage in neurons of the hippocampus and cerebral cortex following excessive exposure to glutamate receptor agonists such as NMDA or kainic acid. In addition, recent studies suggest that degradation of PARP-1 occurs in cells that undergo apoptotic versus nonapoptotic forms of cell death. To investigate this process further, we examined the spatiotemporal aspects of excitotoxic injury in the rodent visual cortex by making focal intracerebral injections of kainic acid. These injections resulted in DNA damage, PARP-1 activation, and neuronal cell death over a 5-day period. Rapid neuronal cell injury assessed by Fluoro-Jade staining appeared within hours, but increased TUNEL staining occurred only after 24 h. A dramatic increase in caspase-3 activity, as well as an increase in the number of neurons containing active caspase-3, peaked 2 days after injury. Last, increased PARP-1 immunoreactivity and PARP-1 cleavage reached peak levels 2 to 3 days after delivering the excitotoxin. These findings suggest that increased caspase-3 activity may regulate the degradation of PARP-1 in subsets of cortical neurons during excitotoxic cell death.
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PMID:PARP cleavage, DNA fragmentation, and pyknosis during excitotoxin-induced neuronal death. 1463 6

To examine the possible role of inflammatory cytokines in mediating neonatal brain injury, we investigated effects of intracerebral injection of IL-1beta (IL-1beta) or tumor necrosis factor-alpha (TNFalpha) on brain injury in the neonatal rat. A stereotaxic intracerebral injection of IL-1beta or TNFalpha (10 ng per pup) was performed in postnatal day 5 (P5) SD rats. Although no necrosis of neurons was found, increased astrogliosis, as indicated by GFAP positive staining was observed 24 and 72 h following the injection of IL-1beta or TNFalpha. IL-1beta induced apoptotic cell death in the rat brain 24 h after the injection, as indicated by increases in positive TUNEL staining and caspase-3 activity, and apoptotic cell death was partially blocked by systemic administration of NBQX, an antagonist of the AMPA glutamate receptor. IL-1beta also significantly reduced the number of developing oligodendrocytes (OLs) 24 h after the injection and this impairment was not prevented by NBQX. On the contrary, TNFalpha induced a much smaller increase in the number of TUNEL positive cells and did not reduce the number of developing OLs. By P8, myelin basic protein (MBP) was clearly detected in the control rat brain, while MBP positive staining was very weak, if any, in the IL-1beta treated rat brain. MBP expression in the TNFalpha treated rat brain was less affected. The overall results indicate that IL-1beta may directly cause injuries to developing OLs and impair myelination in the neonatal rat brain and TNFalpha may have different roles in mediating brain injury.
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PMID:Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat. 1520 1

The purpose of this study was to determine the efficacy and putative mechanisms of action of tetracycline and minocycline in inhibiting retinal cell apoptosis after glutamate-induced excitotoxicity and trophic factor deprivation in a retinal cell line (E1A-NR.3) and in primary mixed retinal cell cultures. In addition, a differentiated PC-12 cell line was used to determine whether minocycline was neuroprotective after trophic withdrawal in a pure neuronal cell line devoid of glia. Results from this study demonstrated that minocycline, but not tetracycline, is protective in in vitro models of excitotoxicity-induced retinal cell apoptosis. Moreover, the protective effects provided by minocycline in retinal cells seemed independent of actions on N-methyl-D-aspartate receptors (NMDARs) and glutamate receptor-mediated Ca(2+) influx. Doses of the NMDAR antagonist MK-801 (dizocilpine) and minocycline that alone provided no significant neuroprotection resulted in enhanced retinal cell survival when applied concurrently, suggestive of distinct signaling pathways, and minocycline was without effect on glutamate-induced Ca(2+) influx, as assessed by calcium imaging. Minocycline was also neuroprotective after trophic factor withdrawal, producing a decrease in apoptosis and caspase-3 activation in both retinal cells and the PC-12 neuronal-like cell line. These results support a role for minocycline as a retinal neuroprotectant and demonstrate that the antiapoptotic actions of minocycline in retinal cells do not arise from the blockage of NMDARs or glutamate receptor-mediated Ca(2+) influx but do involve inhibition of caspase-3 activation. In addition, the survival-promoting actions of minocycline may arise via actions on both neuronal and non-neuronal cell targets.
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PMID:An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. 1530 47


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