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)

Preclinical studies have identified numerous neuroprotective drugs that attenuate brain damage and improve functional outcome after cerebral ischemia. Despite this success in animal models, neuroprotective therapies in the clinical setting have been unsuccessful. Identification of biochemical markers common to preclinical and clinical cerebral ischemia will provide a more sensitive and objective measure of injury severity and outcome to facilitate clinical management and treatment. However, there are currently no effective biomarkers available for assessment of stroke. Nonerythroid alphaII-spectrin is a cytoskeletal protein that is cleaved by calpain and caspase-3 proteases to signature alphaII-spectrin breakdown products (alphaII-SBDPs) after cerebral ischemia in rodents. This investigation examined accumulation of calpain- and caspase-3-cleaved alphaII-SBDPs in cerebrospinal fluid (CSF) of rodents subjected to 2 hours of transient focal cerebral ischemia produced by middle cerebral artery occlusion (MCAO) followed by reperfusion. After MCAO injury, full-length alphaII-spectrin protein was decreased in brain tissue and increased in CSF from 24 to 72 hours after injury. Whereas alphaII-SBDPs were undetectable in sham-injured control animals, calpain but not caspase-3 specific alphaII-SBDPs were significantly increased in CSF after injury. However, caspase-3 alphaII-SBDPS were observed in CSF of some injured animals. These results indicate that alphaII-SBDPs detected in CSF after injury, particularly those mediated by calpain, may be useful diagnostic indicators of cerebral infarction that can provide important information about specific neurochemical events that have occurred in the brain after acute stroke.
J Cereb Blood Flow Metab 2004 Jan
PMID:Accumulation of calpain and caspase-3 proteolytic fragments of brain-derived alphaII-spectrin in cerebral spinal fluid after middle cerebral artery occlusion in rats. 1468 21

Caspase-3 has been identified as a key protease in the execution of apoptosis and appears to be an important downstream event after hypoxia-ischemia in the immature brain. The efficacy of a pan-caspase inhibitor, boc-aspartyl-(Ome)-fluoromethyl-ketone (BAF), was tested in a model of unilateral focal ischemia with reperfusion in 7-day-old rats. The BAF inhibitor was given intraperitoneally 5 minutes before reperfusion via the carotid artery. This procedure reduced the activity of caspase-3 by 79% but did not induce a significant reduction in infarct volume (23.8 +/- 7.5% versus 30.1 +/- 6.4%). Animals were distributed in two populations. One population exhibited an infarct, whereas the other appeared to be fully protected. BAF-treated animals exhibiting an infarct mostly displayed necrotic cell death, whereas apoptotic nuclei were observed in untreated or vehicle-treated animals. Repeated dose of BAF (5 minutes before and 9 hours after reperfusion) did not also provide benefit after neonatal ischemia, although a general trend to reduce lesion was observed (20.5 +/- 3.7% versus 34.4 +/- 5.9%). These findings raise critical questions about the use of peptide ketone apoptotic inhibitors in improving histopathologic outcomes after neonatal stroke.
J Cereb Blood Flow Metab 2004 Jan
PMID:Caspase inhibition after neonatal ischemia in the rat brain. 1468 24

Apoptosis in the endothelium of major cerebral arteries may play a role in the initiation and maintenance of cerebral vasospasm after subarachnoid hemorrhage (SAH). We tested the therapeutic effect of caspase inhibitors on endothelial apoptosis and on cerebral vasospasm in an established dog double-hemorrhage model. Thirty-one mongrel dogs were divided into five groups: control; SAH; SAH treated with vehicle [DMSO]; SAH treated with Ac-DEVD-CHO [a specific caspase-3 inhibitor]; and SAH treated with Z-VAD-FMK [a broad caspase inhibitor]. The inhibitors (100 microM) were injected into the cisterna magna daily from Day 0 through Day 3. Angiography was performed on Day 0 and Day 7. Histology, TUNEL staining, and immunohistochemistry were conducted on basilar arteries collected on Day 7 after SAH. Positive staining of TUNEL, poly(ADP)-ribose polymerase (PARP), caspase-3, and caspase-8 was observed in the endothelial cells of the spastic arteries. Double fluorescence labeling demonstrated co-localization of TUNEL with caspase-3 and TNFalpha receptor-1 (TNFR1). Ac-DEVD-CHO and Z-VAD-FMK prevented endothelial apoptosis and reduced angiographic vasospasm. The mechanism of apoptosis in endothelial cells involves TNFR1 and the caspase-8 and caspase-3 pathways. Caspase inhibitors may have potential in the treatment of cerebral vasospasm.
J Cereb Blood Flow Metab 2004 Apr
PMID:Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage. 1508 11

In this immunohistochemical study, the age- and stage-dependent accumulation of advanced glycation end-products (AGEs) in Alzheimer's disease (AD) and their relation to the formation of neurofibrillary tangles and neuronal cell death was investigated. For this purpose, the distribution of AGEs in neurons and glia was analyzed in the auditory association area of superior temporal gyrus (Brodmann area 22) of young and old non-demented controls and compared with early- and late-stage AD. A possible co-localization of AGEs with typical hallmarks of AD, such as hyperphosphorylated tau (as a marker for disturbed kinase/phosphatase activity), nNOS (as a marker for nitroxidative stress) and caspase-3 (as a marker of apoptotic cell death), was also investigated. Our results show that the percentage of AGE-positive neurons (and astroglia) increase both with age and, in AD patients, with the progression of the disease (Braak stages). Interestingly, nearly all if those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphoryated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles. Many, but not all, neurons show a co-localization of AGEs with other markers of neurodegeneration, such as nNOS and caspase-3.
Cereb Cortex 2005 Feb
PMID:Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains. 1523 35

Matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral ischemia by degrading matrix components in the neurovascular unit. In this study, the authors document a pathway by which MMPs interfere with cell-matrix interactions and trigger caspase-mediated cytotoxicity in brain endothelial cells. Hypoxia-reoxygenation induced endothelial cytotoxicity. Cytoprotection with zDEVD-fmk confirmed that cell death was partly caspase mediated. The temporal profile of caspase-3 activation was matched by elevations in MMP-2 and MMP-9. MMP inhibitors significantly decreased caspase-3 activation and reduced endothelial cell death. Degradation of matrix fibronectin confirmed the presence of extracellular proteolysis. Increasing integrin-linked kinase signaling with the beta1 integrin-activating antibody (8A2) ameliorated endothelial cytotoxicity. The results suggest that MMP-9 and MMP-2 contribute to caspase-mediated brain endothelial cell death after hypoxia-reoxygenation by disrupting cell-matrix interactions and homeostatic integrin signaling.
J Cereb Blood Flow Metab 2004 Jul
PMID:Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. 1524 Nov 80

Nicotinamide, a beta-nicotinamide adenine dinucleotide (NAD) precursor and an essential nutrient for cell growth and function, may offer critical insights into the specific cellular mechanisms that determine neuronal survival, since this agent significantly impacts upon both neuronal and vascular integrity in the central nervous system. The authors show that nicotinamide provides broad, but concentration-specific, protection against apoptotic genomic DNA fragmentation and membrane phosphatidylserine exposure during oxidative stress to secure cellular integrity and prevent phagocytic cellular demise. Activation of the protein kinase B (Akt1) pathway is a necessary requirement for nicotinamide protection, because transfection of primary hippocampal neurons with a plasmid encoding a kinase-deficient dominant-negative Akt1 as well as pharmacologic inhibition of phosphatidylinositol-3-kinase phosphorylation of Akt1 eliminates cytoprotection by nicotinamide. Nicotinamide fosters neuronal survival through a series of intimately associated pathways. At one level, nicotinamide directly modulates mitochondrial membrane potential and pore formation to prevent cytochrome c release and caspase-3-and 9-like activities through mechanisms that are independent of the apoptotic protease activating factor-1. At a second level, nicotinamide maintains an inhibitory phosphorylation of the forkhead transcription factor FOXO3a at the regulatory sites of Thr and Ser and governs a unique regulatory loop that prevents the degradation of phosphorylated FOXO3a by caspase-3. Their work elucidates some of the unique neuro-protective pathways used by the essential cellular nutrient nicotinamide that may direct future therapeutic approaches for neurodegenerative disorders.
J Cereb Blood Flow Metab 2004 Jul
PMID:The NAD+ precursor nicotinamide governs neuronal survival during oxidative stress through protein kinase B coupled to FOXO3a and mitochondrial membrane potential. 1524 Nov 81

Perinatal hypoxic-ischemic (H/I) brain injury remains a major cause of neurologic disability. Because we have previously demonstrated that this insult depletes cells from the subventricular zone (SVZ), the goal of the present investigation was to compare the relative vulnerability to H/I of neural stem cells versus progenitors. The dorsolateral SVZs of P6 rats were examined at 2 to 48 hours of recovery from H/I using hematoxylin and eosin, in situ end labeling (ISEL), terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL), electron microscopy, and immunofluorescence. Pyknotic nuclei and ISEL cells were observed by 4 hours of recovery, peaked at 12 hours, and persisted for at least 48 hours. Many active-caspase-3 cells were observed at 12 hours and they comprised one third of the total TUNEL population. Electron microscopy revealed that hybrid cell deaths predominated at 12 hours of recovery. Importantly, few dying cells were observed in the medial SVZ, where putative stem cells reside, and no nestin medial SVZ cells showed caspase-3 activation. By contrast, active-caspase-3/PSA-NCAM progenitors were prominent in the lateral SVZ. These data demonstrate that early progenitors are vulnerable to H/I, whereas neural stem cells are resilient. The demise of these early progenitors may lead to the depletion of neuronal and late oligodendrocyte progenitors, contributing to cerebral dysgenesis after perinatal insults.
J Cereb Blood Flow Metab 2004 Jul
PMID:Neural stem cells in the subventricular zone are resilient to hypoxia/ischemia whereas progenitors are vulnerable. 1524 Nov 90

DNA repair plays a critical, but imprecisely defined role in neuronal survival during cortical neurogenesis. We examined cortical development in mice deficient for the DNA end-joining protein, Ku70. At gestational day 14.5, corresponding to the peak of neurogenesis, the Ku70(-/-) embryonic cerebral cortex displayed 25- to 30-fold more cell death than heterozygous littermates, as judged by DNA breaks, pyknosis and active caspase-3. In Ku70(-/-) embryos only, large clusters of dying neurons were found in the intermediate zone. Cell death declined until P4, when the number of dying cells became comparable to that in heterozygous mice. Two groups of dying cells were evident: a GLAST(+) neural progenitor population in the subventricular and ventricular zones, and a doublecortin(+) immature neuron population in the intermediate zone, the latter exhibiting strong staining for oxidative DNA damage. Antioxidants and lower oxygen tension reduced the high levels of neuronal death in primary cortical cultures derived from Ku70(-/-) mice, but not the low levels of cell death in wildtype cortical cultures. Results indicate migrating cortical neurons undergo oxidative DNA damage, which is normally repaired by non-homologous end joining. Failure to repair oxidative damage triggers a form of apoptosis involving caspase-3 activation.
Cereb Cortex 2005 Jun
PMID:Oxidative damage and defective DNA repair is linked to apoptosis of migrating neurons and progenitors during cerebral cortex development in Ku70-deficient mice. 1534 28

Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.1 degrees C to between 30 and 33 degrees C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41 +/- 20 vs 18 +/- 11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14 +/- 12 vs 91 +/- 51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4 +/- 6 vs 38 +/- 18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24 +/- 12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.
J Cereb Blood Flow Metab 2004 Aug
PMID:Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep. 1536 18

Neonatal hypoxia-ischemia (HI) is a major contributor to many perinatal neurologic disorders and, thus, the search for therapies and effective treatments for the associated brain damage has become increasingly important. The tetracycline derivative, doxycycline (DOXY), has been reported to be neuroprotective in adult animal models of cerebral ischemia. To investigate the putative neuroprotective effects of DOXY in an animal model of neonatal HI, a time-course study was run such that pups received either DOXY (10 mg/kg) or VEH immediately before hypoxia, 1, 2, or 3 hours after HI (n=6). At 7 days after injury, the pups were euthanized, and the brains were removed and processed for immunohistochemical and Western blot analyses using antibodies against specific markers for neurons, apoptotic markers, microglia, oligodendrocytes, and astrocytes. Results showed that in vulnerable brain regions including the hippocampal formation, thalamus, striatum, cerebral cortex and white matter tracts, DOXY significantly decreased caspase-3 immunoreactivity (a marker of apoptosis), promoted neuronal survival, inhibited microglial activation and reduced reactive astrocytosis compared with VEH-treated HI pups. These effects were found to occur in a time-dependent manner. Taken together, these results strongly suggest that doxycycline has potential as a pharmacological treatment for mild HI in neonates.
J Cereb Blood Flow Metab 2005 Mar
PMID:Doxycycline reduces cleaved caspase-3 and microglial activation in an animal model of neonatal hypoxia-ischemia. 1564 41


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