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)

Even though cerebral vasospasm after subarachnoid hemorrhage (SAH) causes cerebral ischemia or infarction, the metabolic alterations in cerebrospinal fluids (CSF) after SAH have not been studied. This study was undertaken to measure the levels of glucose, lactate, pyruvate and glutamate in CSF from double hemorrhage dog models. Thirty-two mongrel dogs of either sex, weighing 18-24 kg, underwent double hemorrhage by percutaneous needle puncture of the cistema magna and injection of autologous blood on day 0 and day 2. The dogs were then sacrificed on day 3, 5 and 7, after collecting CSF. In another study, the dogs were treated with mitogen-activated protein kinase (MAPK) inhibitors PD98059 and U0126, and caspase-2 and caspase-3 inhibitors from day 3 to day 6 after initial blood injection. CSF was collected on day 7 before dogs were sacrificed. The concentration of glucose, lactate, pyruvate and glutamate in CSF was measured by photometrical method. Compared with CSF collected on day 0, glucose was decreased on days 5-7, lactate was increased on days 2-7, pyruvate was increased on days 2-7, and glutamate was increased on days 3-7 (p < 0.05). In the groups treated with MAPK or caspase inhibitors, most of the metabolic alterations remained unchanged as compared with CSF from untreated dogs. Clinically, caspase inhibitors-2 and -3, and MAPK inhibitor U0126 all failed to prevent vasospasm. MAPK inhibitor PD98059 partially prevented vasospasm. Our data demonstrated a metabolic alteration of glucose, glutamate, lactate and pyruvate in CSF during cerebral vasospasm. This metabolic change in consistent with the time course of cerebral vasospasm. This study suggests that brain energy metabolites and excitative amino acids are altered during cerebral vasospasm.
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PMID:Metabolic alterations in cerebrospinal fluid from double hemorrhage model of dogs. 1121 Apr 38

This preliminary study was undertaken to explore the possible protective effect of caspase inhibitors Z-VDVAD-FMK and Z-DEVD-FMK in apoptosis and vasospasm in penetrating arteries during cerebral vasospasm. Experimental subarachnoid hemorrhage (SAH) was induced in 16 dogs by an intracisternal injection of autologous arterial blood (0.4 ml/kg) on Day 0 and Day 2. The dogs were then randomly divided into four groups: control-SAH, vehicle-control, and two treatment groups. In the treatment groups, caspase inhibitors (10 microM) were intracisternally injected each day beginning on Day 2 until Day 6. Effects of the inhibitors were analyzed utilizing angiography, the clinical status of the dogs (activity, appetite, and neurological deficits), and transmission electron microscopy of the penetrating arteries. All the dogs were sacrificed on Day 7. In control-SAH and vehicle-control groups, severe angiographic vasospasm, poor clinical status, and penetrating vasospasm were registered in all the dogs. In the treatment groups, all the dogs developed angiographic vasospasm and vasospasm in penetrating arteries, however, with benign clinical statues. The occurrence of apoptosis in endothelial cells was reduced by caspase-2 but not by caspase-3 inhibitor. Caspase inhibitors failed to prevent vasospasm either in major or in penetrating arteries. The improvement of clinical scores by the caspase inhibitors may be related to their protection of the endothelial cells. Further investigations using more rigorous clinical scoring system and quantitative information on the degree of apoptosis in the vessels, as well as in the brain parenchyma are recommended.
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PMID:Preliminary study of the effects of caspase inhibitors on vasospasm in dog penetrating arteries. 1213 14

One of the important histological changes in cerebral vasospasm after subarachnoid hemorrhage (SAH) is endothelial cell damage, which involves apoptosis. The current study was undertaken to determine whether anti-apoptosis therapy prevents apoptosis and reverses vasospasm in a dog SAH model. Twenty-three mongrel dogs of either sex, weighing 17-25 kg, were subjected to autologous arterial blood injection into the cisterna magna on day 0 and day 2, and sacrificed on day 7. Angiography was performed on day 0 before blood injection and on day 7 before sacrifice. Caspase-2 (Z-VDVAD-FMK, 10 microM) inhibitor, caspase-3 (Z-DEVD-FMK, 10 microM) inhibitor, or vehicle (DMSO) were injected intrathecally from day 2 to day 6. The effects of caspase inhibitors on apoptosis and vasospasm were evaluated by angiography and transmission electron microscopy. The residual diameter of the basilar artery on day 7 in SAH dogs without treatment was 53.4+/-5.5% of the day 0 diameter. Marked damage to the endothelial cells, including apoptotic like changes, was observed in these arteries. Both caspase inhibitors prevented apoptosis in the endothelial cells. Only caspase-3 inhibitor, however, had a near-significant effect on reducing 13.3% of angiographic vasospasm. Higher doses and early treatment, as well as other more potent apoptosis inhibitors, are recommended for future studies.
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PMID:Therapeutic effect of caspase inhibitors in the prevention of apoptosis and reversal of chronic cerebral vasospasm. 1260 82

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.
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PMID:Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage. 1508 11

While the intraluminal thread technique to induce middle cerebral artery occlusion is widely used in animal models of focal cerebral ischemia, it has several drawbacks. The present study describes a new technique involving transfemoral selective intraluminal wiring, and evaluates its technical feasibility, effectiveness, and safety. Twenty-four Wistar rats were used in this work: two for a vascular anatomy study and 22 subjected to middle cerebral artery occlusion for 1 h by our new transfemoral selective "intraluminal wiring" technique. After 24 h of reperfusion, the animals were evaluated neurologically, and then were sacrificed. Macroscopic, histological (2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin-eosin and TUNEL), and biochemical (DNA fragmentation and caspase-3 activity) studies were performed to assess the extent of brain damage produced by focal ischemia. Technical success was obtained in all 22 animals. Signs of focal ischemia and reperfusion, such as necrosis and apoptosis, were detected in the middle cerebral artery territory. No subarachnoid hemorrhage was noticed in any animal. Transfemoral selective intraluminal wiring appears to be a reliable, safe, and minimally invasive technique to induce transient focal cerebral ischemia in rats.
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PMID:Transfemoral selective "intraluminal wiring" technique for transient middle cerebral artery occlusion in rats. 1597 62

The c-Jun N-terminal kinase (JNK) is induced by cerebral ischemia and injurious blood components acutely after subarachnoid hemorrhage (SAH). We hypothesized that inhibition of JNK will prevent damage to the neurovascular unit in the early brain injury period after SAH. Ninety-nine male SD rats (300-350 g) were randomly assigned to sham, SAH, and SAH treated with JNK inhibitor groups. SAH was induced by endovascular perforation. The JNK inhibitor SP600125 was administered intraperitoneally at 1 hr before and 6 hr after SAH. At 24 hr after SAH, we observed increased phosphorylation of JNK and c-Jun. Signs of neurovascular damage were observed in the hemorrhagic brains; these included the increases of aquaporin (AQP)-1 expression and brain water content as well as enhanced matrix metalloproteinase (MMP)-9 activity, vascular collagen IV loss, increased VEGF tissue level, and Evans blue extravasation. The appearances of cleaved caspase-3 expression, TUNEL-positive cells, and apoptotic morphology in cerebral tissues were associated with neurological deficit after SAH. JNK inhibition prevented c-Jun phosphorylation and suppressed AQP1, MMP-9, VEGF, and caspase-3 activation, with concomitant diminution of neuronal injury, blood-brain barrier preservation, reduced brain swelling, and improved neurological deficit in rats after SAH. This study demonstrates a multitude of beneficial effects of JNK inhibition, including protection of the neurovascular unit in early brain injury after SAH.
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PMID:Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. 1741 Jun

Clinical evidence suggests that factors other than cerebral vasospasm, such as delayed neuronal and astrocytic cell death, may play a role in the poor prognosis of patients with subarachnoid hemorrhage (SAH). Here we examined this using immunohistochemistry and confocal microscopy in 3 different brain areas in a dog model of SAH. Using antibodies against neuronal marker neuronal nuclear protein (NeuN) and astrocyte marker glial fibrillary acidic protein (GFAP) in conjunction with apoptosis marker (cleaved caspase-3), we quantified neurons and astrocytes to monitor the degree of apoptosis in both groups. Experimental SAH group showed 44 +/- 1% caspase-3 positive neurons in comparison to the 2.0 +/- 0.1% in the control group (P < 0.001, 6 animals each group). For astrocytes, a total 25 +/- 1% were caspase-3 positive in day 7 SAH group, as compared to 0.40 +/- 0.01% for controls (P < 0.001). Regional analysis revealed that neuronal caspase-3 immunoreactivity in all 3 regions were significantly higher (P < 0.001) in SAH animals than that in the control animals. However, the analysis of total area, size and signal co-localization of GFAP with caspase-3 indicated that astrocytic reactivity and proliferation are seen primarily in the hippocampal area, with the least changes detectable in the brainstem. We conclude that in the dog model, there was a significant increase of neuronal and astrocytic cleaved caspase-3, possibly reflecting apoptosis, following SAH induction. These changes coupled with neurological deterioration seen in patients may present a possible reason for the poor outcome in SAH patients.
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PMID:Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: a possible cause for poor prognosis. 1878 13

Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-alpha (TNFalpha) and nuclear factor (NF)kappaB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFalpha. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFalpha and NFkappaB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.
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PMID:Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. 1885 40

This study was designed to explore the role of simvastatin and its effects on the Akt/GSK3beta survival signal and apoptosis pathway after experimental subarachnoid hemorrhage (SAH). SAH was induced by blood injection into the cisterna magna in New Zealand white rabbits. Increased expression of phospho-Akt and phospho-GSK3beta was observed in brain tissue after SAH. Apoptosis and related proteins, including P53, apoptosis-inducing factor (AIF), cytochrome C, and cleaved caspase-3, were also activated. Simvastatin, at both low dose (10 mg/kg) and high dose (40 mg/kg), further increased expression of phospho-Akt and phospho-GSK3beta, decreased activation of caspase-3, and inhibited apoptosis. Preserved blood-brain barrier and attenuated brain edema were observed following simvastatin treatment. In addition, the neuroprotective effects of simvastatin were blocked by wortmannin (2.5 microg/kg/min), an irreversible PIK3 inhibitor. P53, AIF, and cytochrome C were not affected by simvastatin treatment. Findings from the present study suggest that simvastatin ameliorates acute brain injury after SAH. The potential mechanisms of action include activation of the Akt/GSK3beta survival signal and inhibition of caspase-dependent apoptosis pathway.
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PMID:Simvastatin activates Akt/glycogen synthase kinase-3beta signal and inhibits caspase-3 activation after experimental subarachnoid hemorrhage. 2000 38

Stroke is the second leading cause of death worldwide and the number one cause of adult disability in the United States and Europe. A subtype of stroke, subarachnoid hemorrhage (SAH), accounts for 7% of all strokes each year and claims one of the highest mortalities and morbidities. Many therapeutic interventions have been used to treat brain injury following SAH but none have reached the level of effectiveness needed to clinically reduce mortality. Ginsenoside Rb1 (GRb1), a major component of the Chinese traditional medicine Panax Ginseng, has been shown to reduce ischemic brain injury and myocardial injury via anti-apoptotic pathways. In the present study, we investigated the use of GRb1 on SAH induced brain injury in rats. Four groups were used: sham, vehicle (SAH), low dose treatment (SAH+ 5mg/kg GRb1), and high dose treatment (SAH+ 20mg/kg GRb1). Post assessment included wall thickness and mean cross-section area of basilar artery were measured for evaluating cerebral vasospasm, Evans blue extravasations to assess blood brain barrier (BBB) permeability, immunohistochemistry and Western Blot analysis looking for specific pro-apoptotic markers, and tunnel staining for cell death assessment. In addition, mortality, neurological function and brain edema were investigated. The results showed that high dose GRb1 treatment significantly enlarged mean cross-sectional area and decreased wall thickness of basilar artery, reduced neurological deficits, brain edema, BBB disruption, and TUNEL positive cell expression. Same time, we found that the proteins expression of P53, Bax and Caspase-3 were significantly reduced, whereas the expression of bcl-2 was up-regulated in Rb1 treatment. The results of this study suggest that GRb1 could relieve cerebral vasospasm and potentially provide neuroprotection in SAH victims. The underlying mechanisms may be partly related to inhibition of P53 and Bax dependent proapoptosis pathway. More studies will be needed to confirm these results and determine its potential as a long term agent.
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PMID:Ginsenoside Rbeta1 reduces neurologic damage, is anti-apoptotic, and down-regulates p53 and BAX in subarachnoid hemorrhage. 2035 83


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