UNIPROT:P42574 - FACTA Search

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

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

The exact molecular mechanism of ischemic neuronal death still remains unclear from rodents to primates. A number of studies using lower species animals have suggested implication of apoptosis cascade, while using monkeys the authors recently claimed necrosis cascade by calpain-induced leakage of lysosomal cathepsins (calpain-cathepsin hypothesis). This paper is to study implications of apoptotic versus necrotic cascades for the development of hippocampal CA1 neuronal death in the primate brain undergoing complete global ischemia. Here, we focused on two terminal cell death effectors; caspase-activated DNase (CAD) and lysosomal enzyme DNase II, in the monkey CA1 sector undergoing 18 min ischemia. The expressions of their mRNA and proteins, and the subcellular localizations as well as ultrastructure and specific DNA gel electrophoresis were examined. Expression of CAD was much less in the normal brain, compared with the lymph node or heart tissues. On day 1 after ischemia, however, CAD mRNA and protein were significantly increased in the CA1 sector, and then CAD protein immunohistochemically showed a translocation from the perikarya into the nucleus. Activated DNase II protein was significantly increased on days 2 and 3 after ischemia, and also showed a similar translocation indicating lysosomal leakage. Although the post-ischemic CA1 neurons showed positive terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining on days 3-5, they showed eosinophilic coagulation necrosis on light microscopy, and frank membrane disruption and mild chromatin condensation on electron microscopy. Furthermore, DNA smear pattern typical for necrosis was observed instead of DNA laddering. These data altogether suggest that the post-ischemic CA1 neuronal death of the monkey occurs not by apoptosis but by necrosis with participations of lysosomal enzymes DNase II and cathepsins as well as CAD. The interactions between apoptotic (caspase-3 and CAD) and necrotic (calpain, cathepsin and DNase II) cascades should be studied further.
...
PMID:Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus. 1175 60

Mitochondria are known to be involved in the early stage of apoptosis by releasing cytochrome c, caspase-9, and the second mitochondria-derived activator of caspases (Smac). We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduced superoxide production and ameliorated neuronal injury in the hippocampal CA1 subregion after global ischemia. However, the role of oxygen free radicals produced after ischemia/reperfusion in the mitochondrial signaling pathway has not been clarified. Five minutes of global ischemia was induced in male SOD1-transgenic (Tg) and wild-type (Wt) littermate rats. Cytosolic expression of cytochrome c and Smac and activation of caspases were evaluated by immunohistochemistry, Western blot, and caspase activity assay. Apoptotic cell death was characterized by DNA nick end and single-stranded DNA labeling. In the Wt animals, early superoxide production, mitochondrial release of cytochrome c, Smac, and cleaved caspase-9 were observed after ischemia. Active caspase-3 was subsequently increased, and 85% of the hippocampal CA1 neurons showed apoptotic DNA damage 3 d after ischemia. Tg animals showed less superoxide production and cytochrome c and Smac release. Subsequent active caspase-3 expression was not evident, and only 45% of the neurons showed apoptotic DNA damage. A caspase-3 inhibitor (N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone) reduced cell death only in Wt animals. These results suggest that overexpression of SOD1 reduced oxidative stress, thereby attenuating the mitochondrial release of cytochrome c and Smac, resulting in less caspase activation and apoptotic cell death. Oxygen free radicals may play a pivotal role in the mitochondrial signaling pathway of apoptotic cell death in hippocampal CA1 neurons after global ischemia.
...
PMID:Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. 1175 4

Male Wistar rats were subjected to intraperitoneal (i.p.) streptozotocin (STZ) administration (85 mg/kg) to evoke diabetes. Cerebral ischaemia was produced by injection of 0.03 ml of air into the left carotid followed by bilateral common carotid ligation. We studied the effect of application of two antioxidants--coenzyme Q10 (CoQ10, 10 mg/kg b.w., i.p. for seven days) and lipoic acid (LA, 100 mg/kg b.w., i.p. for seven days) on neurones and on the apoptosis-related enzyme--caspase-3 activity in the hippocampus and dentate gyrus. Ischaemia and diabetes lead to a decrease of nuclear and perikaryon diameters as well as neuronal density in the CA1, CA2, CA3 and dentate gyrus. Application of CoQ10 or LA for seven days improved the mean nucleus area and perikaryon area in almost all investigated structures. Both antioxidants diminished neuronal loss in the diabetes complicated with ischaemia but not in the animals with diabetes only. Activity of one of the key enzymes in apoptotic cell death, caspase-3 (CPP32), increased in hippocampus in the diabetic rats, in the animals with cerebral ischaemia and in the rats with both diabetes and ischaemia by about 80%, 33% and 53%, respectively. Either the CoQ10 or the LA treatment led to a significant decrease of the CPP32 activity in all experimental groups. Our results confirm the presence of neuronal damage and death in the hippocampus and dentate gyrus in the experimental STZ-diabetes and its aggravation by the additional cerebral ischaemia. The effects of the antioxidative treatment support the hypothesis of an important role of oxidative stress and free radicals in neuronal pathology in diabetes and ischaemia. The above results of CPP32 activity suggest an important role of apoptosis as a mechanism of cell death and demonstrate the positive effect of the CoQ10 and the LA treatment.
...
PMID:Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. 1177 Jan 25

We conducted this study to determine whether high physiological levels of estradiol (proestrus) could protect the hippocampal CA1 neurons following transient global ischemia. Ovariectomized or ovary-intact female rats were subjected to 20 min of ischemia and allowed to survive for 96 h. Estradiol was administered subcutaneously in a group of ovariectomized rats 24 h before ischemia induction. Ending serum estrogen levels were correlated to cerebral blood flow (CBF), histologic assessment and immunofluorescent caspase-3 active peptide (C-3AP) positive cell count. Estradiol administration significantly improved CBF in the hippocampus (compared with intact or ovariectomized rats) but not in the parietal cortex. No significant differences in CBF between intact or ovariectomized rats were noted. Estradiol administration maintained serum levels of the steroid in estradiol-treated rats-about 10 times that of intact animals and more than 20 times that of ovariectomized animals. Morphologically, live cell counts in estradiol-treated rats were significantly higher than in intact or ovariectomized rats. Live cell counts were also significantly higher in intact than ovariectomized rats. C-3AP positive cell counts were much higher in ovariectomized rats than in intact and estradiol-treated rats. In conclusion, proestrus levels of 17beta-estradiol protect hippocampal CA1 neurons against transient global ischemia, through mechanisms that appear to involve improvement of perfusion and inhibition of caspase-3 activity.
...
PMID:Proestrus levels of estradiol during transient global cerebral ischemia improves the histological outcome of the hippocampal CA1 region: perfusion-dependent and-independent mechanisms. 1179 Mar 87

The importance of postmenopausal estrogen replacement therapy in affording protection against the selective and delayed neuronal death associated with cardiac arrest or cardiac surgery in women remains controversial. Here we report that exogenous estrogen at levels that are physiological for hormone replacement in postmenopausal women affords protection against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1 of male gerbils. Global ischemia induced a marked increase in activated caspase-3 in CA1, evident at 6 hr after ischemia. Global ischemia induced a marked upregulation of the proapoptotic neurotrophin receptor p75(NTR) in CA1, evident at 48 hr. p75(NTR) expression was induced primarily in terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling-positive cells, indicating expression in neurons undergoing apoptosis. Global ischemia also induced a marked downregulation of mRNA encoding the AMPA receptor GluR2 subunit in CA1. Caspase-3, p75(NTR), and GluR2 were not significantly changed in CA3 and dentate gyrus, indicating that the ischemia-induced changes in gene expression were cell specific. Exogenous estrogen attenuated the ischemia-induced increases in activated caspase-3 and blocked the increase in p75(NTR) in post-ischemic CA1 neurons but did not prevent ischemia-induced downregulation of GluR2. These findings demonstrate that long-term estrogen at physiological levels ameliorates ischemia-induced hippocampal injury and indicate that estrogen intervenes at the level of apoptotic signaling cascades to prevent onset of death in neurons otherwise "destined to die."
...
PMID:Estrogen protects against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1. 1189 51

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.
...
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

Granulovacuolar degeneration (GVD) is a diagnostic neuropathological feature of Alzheimer's disease (AD). In some neurons, apoptosis has been hypothesized to be a primary mechanism causing neuronal cell death in AD. In this study we investigated CA1 neurons with GVD in AD and Down's syndrome (DS) brain. We demonstrated that activated caspase-3 and a caspase-cleaved cleavage product of the amyloid precursor protein (cAPP) are co-localized in GVD granules, and that these same cells often show nuclear DNA damage. In contrast, activated caspase-8 is present in the cytoplasm but not within the granules of GVD neurons. A caspase-cleavage product of fodrin that accumulates in many AD and DS neurons is not present in GVD granules. These data support a role for the activation of apoptotic mechanisms in selective compartments exhibiting GVD.
...
PMID:Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain. 1207 Jun 57

Research into the molecular mechanisms of epileptic brain injury is hampered by the resistance of key mouse strains to seizure-induced neuronal death evoked by systemically administered excitotoxins such as kainic acid. Because C57BL/6 mice are extensively employed as the genetic background for transgenic/knockout modeling in cell death research but are seizure resistant, we sought to develop a seizure model in this strain characterized by injury to the hippocampal CA subfields. Adult male C57BL/6 mice underwent focally evoked seizures induced by intraamygdala microinjection of kainic acid. Kainic acid (KA) effectively elicited ipsilateral CA3 pyramidal neuronal death within a narrow dose range of 0.1-0.3 microg, with mortality < 10%. With employment of the most consistent (0.3 microg) dose, seizures were terminated 15, 30, 60, or 90 min after KA by diazepam. Damage was largely restricted to the ipsilateral CA3 subfield of the hippocampus, but injury was also consistent within CA1, suggesting that this mouse model better reflects the hippocampal neuropathology of human temporal lobe epilepsy than does the rat, in which CA1 is typically spared. Confirming this CA1 injury as seizure specific and not a consequence of ischemia, we used laser-Doppler flowmetry to determine that cerebral perfusion did not significantly change (97% to 118%) over control. Degenerating cells were > 95% neuronal as determined by neuron-specific nuclear protein (NeuN) counterstaining of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeled (TUNEL) brain sections. Furthermore, TUNEL-positive cells often exhibited the morphological features of apoptosis, and small numbers were positive for cleaved caspase-3. These data establish a mouse model of focally evoked seizures in the C57BL/6 strain associated with a restricted pattern of apoptotic neurodegeneration within the hippocampal subfields that may be applied to research into the molecular basis of neuronal death after seizures.
...
PMID:Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse. 1221 Aug 27

Male Wistar rats received unilateral intrahippocampal injections of 3 nmol (3.18 microg) aggregated Abeta(25-35), intracerebroventricular bilateral injections of 0.5 microg human recombinant TNFalpha or both (Abeta(25-35) + TNFalpha-treated animals). Seven days after the surgery brain sections were stained with cresyl violet (Nissl), for fragmented DNA (TUNEL), glial fibrillar acidic protein (GFAP) and isolectin B4-reactive microglia. In addition, caspase-3 activity in brain regions was measured fluorometrically. The morphology of the hippocampus after the injection of Abeta(25-35) or both Abeta(25-35) and TNFalpha (but not TNFalpha alone) showed cell loss in the CA1 pyramidal cell layer. The extension of neuronal degeneration measured in the CA1 field was significantly larger in Abeta(25-35)-treated groups compared to the contralateral hemisphere of both vehicle-treated controls and animals injected with TNFalpha alone. TNFalpha augmented the Abeta(25-35)-induced damage, significantly increasing the extension of degenerating area. Administration of Abeta(25-35) caused reactive gliosis in the ipsilateral hemisphere as demonstrated by upregulation of GFAP expression and the presence of hypertrophic astrocytes in the hippocampus. This effect was much more prominent in the hippocampi of rats treated with Abeta(25-35) + TNFalpha but absent after administration of TNFalpha alone. In both Abeta(25-35)-treated groups, the damaged area of the hippocampal CA1 field and lateral band of dentate gyrus displayed many darkly stained round isolectin B4-positive phagocyte-like microglial cells. Sparse TUNEL-positive nuclei were found in the hippocampi of rats treated with Abeta(25-35) alone or together with TNFalpha, but not in the control brain sections or in brain sections of TNFalpha-injected animals. The activity of caspase-3 increased significantly in the ipsilateral hippocampus after the injection of Abeta(25-35). Surprisingly, administration of TNFalpha into the cerebral ventricles prevented this Abeta(25-35)-induced increase in hippocampal caspase-3 activity. The results are discussed from the perspective of dual (neuroprotective and neurodestructive) roles of TNF in the brain.
...
PMID:Effects of tumor necrosis factor-alpha central administration on hippocampal damage in rat induced by amyloid beta-peptide (25-35). 1247 19

Reports on non-neural cells have shown that enhanced activity of the Ca(2+)-dependent/ATP-independent phospholipid scramblase (PLSCR1) is, at least in part, responsible for surface exposure of phosphatidylserine and the collapse of plasma membrane asymmetry in injured or apoptotic cells. To shed some light on mechanisms with a potential to lead to apoptotic death of human neurones following ischemic/hypoxic injury, we examined the immunoreactivity of hippocampal neurones for PLSCR1, caspase-3, cytochrome c and DNA-fragmentation in 22 individuals with clinically symptomatic cerebral ischemia after cardiac arrest or severe hypotension. WE FOUND: (1) significant differences in the percentage of PLSCR1-immunoreactive neurones between controls and short survivors; statistically strong differences between the frequency of immunoreactive neurones among the subfields studied with lowest levels in the CA3; preferential distribution of immunoreactive neurones in controls within the regio entorhinalis, subfield CA1, and hilum. Additionally, these areas exhibited staining of fibre bundles which probably correspond to perforant path, alvear path and collateral's of Schaffer, (2) caspase-3 was upregulated in a region-specific manner with marked activation in the selectively vulnerable hippocampal areas, (3) cytochrome c was redistributed, (4) DNA-fragmentation represented by scattered TUNEL-positive cells increased predominantly during the first 3 days after ischemia, and particularly in the regions of greatest susceptibility to hypoxic injury. This study presents the first evidence that PLSCR1, and probably remodelling of plasma membrane phospholipids (PL), plays a role in ischemic injury in the human hippocampus.
...
PMID:Spatial resolution of phospholipid scramblase 1 (PLSCR1), caspase-3 activation and DNA-fragmentation in the human hippocampus after cerebral ischemia. 1260 85

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>