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)

Senile plaques of Alzheimer's brain are characterized by activated microglia and immunoreactivity for the peptide chromogranin A. We have investigated the mechanisms by which chromogranin A activates microglia, producing modulators of neuronal survival. Primary cultures of rat brain-derived microglia display a reactive phenotype within 24 h of exposure to 10 nM chromogranin A, culminating in microglial death via apoptotic mechanisms mediated by interleukin-1beta converting enzyme. The signalling cascade initiated by chromogranin A triggers nitric oxide production followed by enhanced microglial glutamate release, inhibition of which prevents microglial death. The plasma membrane carrier inhibitor aminoadipate and the type II/III metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-sulphonophenylglycine are equally protective. A significant amount of the released glutamate occurs from bafilomycin-sensitive stores, suggesting a vesicular mode of release. Inhibition of this component of release affords significant microglial protection. Conditioned medium from activated microglia kills cerebellar granule cells by inducing caspase-3-dependent neuronal apoptosis. Brain-derived neurotrophic factor is partially neuroprotective, as are ionotropic glutamate receptor antagonists, and, when combined with boiling of conditioned medium, full protection is achieved; nitric oxide synthase inhibitors are ineffective.
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PMID:Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation. 1042 49

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare and uniformly fatal disorder of early childhood characterized by fever, hepatosplenomegaly, cytopenia and widespread infiltration of vital organs by activated lymphocytes and macrophages. In order to test whether the massive accumulation of immune cells in these patients is associated with a perturbation of apoptosis, lymphocytes were isolated from eight patients and subjected to the chemotherapeutic agent etoposide or agonistic anti-Fas monoclonal antibodies in vitro. These stimuli elicited a normal apoptotic response in FHL patient cells when compared to healthy controls, as determined by phosphatidylserine exposure, DNA fragmentation, in vitro cleavage of the caspase-3-like substrate aspartate-glutamate-valine-aspartate-7-amino-4-methyl-coumarin (DEVD-AMC) and proteolysis of the anti-apoptotic protein Bcl-2. In addition, the degree of constitutive and Fas-triggered apoptosis in freshly isolated neutrophils was monitored in three children, with similar results. These studies indicate that immune cells derived from FHL patients are not inherently resistant to apoptosis induction. Specifically, etoposide-induced and Fas-triggered activation of intracellular caspases appears to remain intact in these individuals. However, the degree of spontaneous activation of caspase-3-like enzymes in activated lymphocytes was attenuated in three of the four patients tested prior to initiation of therapy, suggesting a possible biological deficiency in these individuals.
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PMID:Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients. 1046 May 99

Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.
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PMID:Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene. 1051 82

By using flow-cytometric analysis, we examined the involvement of p53, c-Myc, Bcl-2 and Bax in the glutamate-induced cell death in cultured cortical neurons. The activities of caspase-1-like and caspase-3-like proteases were also measured after the glutamate treatment. The apoptosis rate of the cells increased after 12 h and 24 h treatment with glutamate. The temporal profile of p53, c-Myc, Bcl-2, Bax expression and caspases activation after glutamate treatment suggest that Bcl-2, c-Myc and caspase-3 play important roles in the excitotoxic neuronal cell death. The down-regulation of Bcl-2 may be an important early stage event, which may cause the activation of caspase-3. c-Myc is also involved in the process of apoptosis though its precise role remains elusive. bFGF exhibited the capability to antagonize the neuronal apoptosis caused by glutamate. The antiapoptotic potential of bFGF may result from its attenuating effect on the down-regulation of Bcl-2 induced by glutamate and, subsequently, blockade of apoptosis cascade. This may provide a possible explanation for its neuroprotective effect against ischemic cell death.
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PMID:Roles of p53, c-Myc, Bcl-2, Bax and caspases in glutamate-induced neuronal apoptosis and the possible neuroprotective mechanism of basic fibroblast growth factor. 1052 75

Twelve and twenty-four hours after intraperitoneal administration of thioacetamide (200 mg/kg body weight) to rats, caspase-3 activity in the liver and plasma of the treated rats increased significantly compared with that of the control group. These results demonstrated that thioacetamide caused apoptosis, which involved activation of caspase-3, although there may be a number of pathways to apoptosis in the liver that may or may not involve the activation of this protein. The results also indicated that the activated caspase-3 was released in plasma along with glutamate-oxaloacetate transaminase (GOT) by successive necrosis. This is the first study that shows an increase of caspase-3 activity in plasma.
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PMID:Increase of caspase-3 activity in rat liver and plasma by thioacetamide. 1059 Nov 48

Excessive activation of glutamate receptors mediates neuronal death in a number of neurodegenerative diseases. The intracellular signaling pathways that mediate this type of neuronal death are only partly understood. Following mild insults via NMDA receptor activation, central neurons undergo apoptosis, but with more fulminant insults, necrosis intervenes. Caspases are important in several forms of apoptosis in vivo and in vitro. Previously, we have demonstrated that caspases are important in excitotoxicity-mediated apoptosis of cerebrocortical neurons. To determine the possible activation of caspase-3 in NMDA-induced neuronal apoptosis, we used an affinity-labeling technique: Biotinylated N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD.CHO) preferentially labels conformationally active caspase-3-like proteases, allowing us to visualize affinity-labeled caspases with streptavidin-fluorescein isothiocyanate under confocal microscopy. NMDA-induced apoptosis of cerebrocortical neurons was associated with a time-dependent increase in conformationally active caspase-3-like proteases. The activation of caspases was apparent within 20 min of NMDA stimulation and was localized primarily in the cytosol. However, following incubation of neurons for 18-24 h, conformationally active caspase-3-like proteases were also detectable in nuclei. Double labeling with propidium iodide to detect chromatin condensation indicated that affinity-labeled caspase-3-like proteases were specifically expressed in apoptotic cells. To further confirm this, we used an antibody specific for the conformationally active fragment of caspase-3 and found largely concordant results. Moreover, preincubation with DEVD.CHO prevented NMDA-induced apoptosis. Our results suggest that caspase-3-like proteases play a major role in excitotoxin-induced neuronal apoptosis.
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PMID:Involvement of activated caspase-3-like proteases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons. 1061 14

Glial cell line-derived neurotrophic factor (GDNF) provides neuroprotection, but its neuroprotective mechanism has not been resolved. We investigated the neuroprotective mechanism of GDNF using primary culture of the rat mesencephalon. Bleomycin sulfate (BLM) and L-buthionine-[S,R]-sulfoximine (BSO) caused apoptosis in both dopaminergic and nondopaminergic neurons, as revealed by the presence of chromatin condensation, and positive staining by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL). GDNF preincubation blocked the neurotoxicity and reduced the number of the TUNEL-positive cells caused by BLM and BSO exposure. In contrast, GDNF did not provide neuroprotection against glutamate toxicity, which was not accompanied by these apoptotic features. The neuroprotection was mediated by phosphatidylinositol 3-kinase, an effector downstream from c-Ret, because it was blocked by LY294002. GDNF pretreatment caused up-regulation of Bcl-2 and Bcl-x. Furthermore, GDNF suppressed oxygen radical accumulation caused by BLM. Apoptosis induced by BLM and BSO was blocked by a caspase-3 inhibitor. Caspase-3 activity was elevated by BLM and suppressed by GDNF pretreatment. These findings indicate that GDNF has no effect on necrosis but exerts protection against apoptosis by activation of phosphatidylinositol 3-kinase and the subsequent up-regulation of Bcl-2 and Bcl-x, which suppresses accumulation of oxygen radicals followed by caspase-3 activation.
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PMID:Neuroprotective mechanism of glial cell line-derived neurotrophic factor in mesencephalic neurons. 1069 50

In the present study, extracellular glutamate (Glu) was monitored in real time using an enzyme electrode biosensor following traumatic brain injury (TBI) either with or without inducing hypoxia in the rat. We also measured the cortical contusion volume at 3 days after insult by staining with 2,3,5-triphenyltetrazolium chloride (TTC). Male Sprague-Dawley rats (300-400 g) were anesthetized and then subjected to lateral fluid percussion (FP) brain injury of moderate severity (3.5-4.0 atm), using the Dragonfly device model (no. HPD-1700). The experimental animals were divided into four groups. Group 1 (n = 10) was subjected to TBI only, group 2 (n = 10) to TBI followed by 20 min of moderate hypoxia (FiO2: 10%), group 3 (n = 4) to 20 min of moderate hypoxia without TBI, and group 4 (n = 4) to sham. Seventy-two hours after the insults, the animals were sacrificed, their brains were stained with TTC, and the lesion volumes were calculated. A surge in the extracellular Glu concentration occurred immediately after TBI in groups 1 and 2. There was no significant difference between the two groups. Group 2 showed a prolonged efflux of Glu during hypoxia ( < 0.05). In group 3, Glu continued to show a mild increase. The cortical contusion volume in group 2 was significantly larger than that in group 1. To evaluate the possible involvement of apoptosis in groups 1 and 2, separate rats were sacrificed under the same procedures after 1, 6, 24, and 72 h after insult (n = 2/group). Immunohistochemical analysis demonstrated an increased number of both the cysteine protease caspase-3-positive cells at 24 h and TUNEL-positive cells at 72 h in group 2. These results suggest that TBI with moderate hypoxia induced the prolonged efflux of Glu, which thus resulted in more cortical damage due to necrosis and apoptosis.
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PMID:Real-time monitoring of glutamate following fluid percussion brain injury with hypoxia in the rat. 1070 72

Neuroprotective effects of a Group II metabotropic glutamate receptor agonist, LY379268, were examined in a neonatal rat model of hypoxia-ischemia (unilateral common carotid artery ligation followed by hypoxic exposure for 1.5h in 7-day-old rat pups). LY379268 administered 5 min after hypoxic exposure (2, 5, or 10 mg/kg, i.p.) significantly reduced brain injury as measured by reductions in the ipsilateral brain weight and in CA1 hippocampal neuron density. The significant neuroprotective effects were also observed when this compound (5 mg/kg) was administered 30 min, but not 60 min, after hypoxic exposure. The neonatal hypoxia-ischemia (HI) procedure significantly increased caspase-3 activity and induced DNA fragmentation in the ipsilateral cortex compared with that in the contralateral cortex 24 and 72h after the insult, respectively. LY379268 did not prevent this increase in caspase-3 activity and DNA fragmentation in the ipsilateral cortex. These results suggest that activation of Group II metabotropic glutamate receptors may provide neuroprotection against HI brain injury. However, blockade of caspase-3 activation and the apoptotic pathway appears not to be involved in the neuroprotective effects of LY379268 observed in the neonatal rat model of HI.
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PMID:Protection of neonatal rat brain from hypoxic-ischemic injury by LY379268, a Group II metabotropic glutamate receptor agonist. 1071 35

Studies examined the phenotypic characteristics of glutamate-induced cell death and their relationship to calpain and caspase-3 activation. Cell viability was assessed by fluorescein diacetate and propidium iodide staining and lactate dehydrogenase release. Calpain and caspase-3 activity was inferred from signature proteolytic fragmentation of alpha-spectrin. Characterization of cell death phenotypes was assessed by Hoechst 33258 and DNA fragmentation assays. Exposure of septohippocampal cultures to 1.0, 2.0, and 4.0 mmol/L glutamate induced a dose-dependent cell death with an LD50 of 2.0 mmol/L glutamate after 24 hours of incubation. Glutamate treatment induced cell death in neurons and astroglia and produced morphological alterations that differed from necrotic or apoptotic changes observed after maitotoxin or staurosporine exposure, respectively. After glutamate treatment, cell nuclei were enlarged and eccentrically shaped, and aggregated chromatin appeared in a diffusely speckled pattern. Furthermore, no dose of glutamate produced evidence of internucleosomal DNA fragmentation. Incubation with varying doses of glutamate produced calpain and caspase-3 activation. Calpain inhibitor II (N-acetyl-Leu-Leu-methionyl) provided protection only with a narrow dose range, whereas carbobenzoxy-Asp-CH2-OC(O)-2,6-dichlorobenzene (Z-D-DCB; pan-caspase inhibitor) and MK-801 (N-methyl-D-aspartate receptor antagonist) were potently effective across a wider dose range. Cycloheximide did not reduce cell death or protease activation.
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PMID:Novel characteristics of glutamate-induced cell death in primary septohippocampal cultures: relationship to calpain and caspase-3 protease activation. 1072 20


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