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)

During influenza epidemics in Japan, the number of children with acute encephalopathies and encephalitis has recently increased. Although the pathophysiologies remain unclear, there is usually brain edema with evidence of damage to the blood-brain-barrier (BBB). We investigated the glial reaction and apoptosis in brains of eight such cases comprising two of acute necrotizing encephalopathy and six of influenza encephalopathy, and compared the results with those in five control brains. Apoptosis, evidenced by chromatin condensation and fragmentation in hematoxylin sections, in situ end labeling of fragmented DNA (TUNEL) and DNA laddering, was observed in neurons and glial cells in four brains with influenza encephalopathy. In the TUNEL-positive brains, the increase in microglia was greater than in the TUNEL-negative brains. Immunoreactivity for active-caspase 3, demonstrated by immunohistochemistry, and the overexpression of a caspase-cleaved fragment of poly(ADP-ribose) polymerase, demonstrated by Western blotting, indicated that activation of caspase 3 is involved in the apoptotic pathway in the brains of influenza encephalopathy cases. Apoptosis or specific pathological processes that cause apoptosis may give rise to aggravated encephalopathy.
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PMID:Apoptosis and microglial activation in influenza encephalopathy. 1255 9

Experimental models of traumatic brain injury have been developed to replicate selected aspects of human head injury, such as contusion, concussion, and/or diffuse axonal injury. Although diffuse axonal injury is a major feature of clinical head injury, relatively few experimental models of diffuse traumatic brain injury (TBI) have been developed, particularly in smaller animals such as rodents. Here, we describe the pathophysiological consequences of moderate diffuse TBI in rats generated by a newly developed, highly controlled, and reproducible model. This model of TBI caused brain edema beginning 20 min after injury and peaking at 24 h post-trauma, as shown by wet weight/dry weight ratios and diffusion-weighted magnetic resonance imaging. Increased permeability of the blood-brain barrier was present up to 4 h post-injury as evaluated using Evans blue dye. Phosphorus magnetic resonance spectroscopy showed significant declines in brain-free magnesium concentration and reduced cytosolic phosphorylation potential at 4 h post-injury. Diffuse axonal damage was demonstrated using manganese-enhanced magnetic resonance imaging, and intracerebral injection of a fluorescent vital dye (Fluoro-Ruby) at 24-h and 7-day post-injury. Morphological evidence of apoptosis and caspase-3 activation were also found in the cerebral hemisphere and brainstem at 24 h after trauma. These results show that this model is capable of reproducing major biochemical and neurological changes of diffuse clinical TBI.
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PMID:The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats. 1535 Sep 63

Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) is a clinically promising strategy in ischaemic disease. The pathophysiological consequences of enhanced vessel formation, however, are poorly understood. We established mice overexpressing human VEGF165 under a neuron-specific promoter, which exhibited an increased density of brain vessels under physiological conditions and enhanced angiogenesis after brain ischaemia. Following transient intraluminal middle cerebral artery (MCA) occlusions, VEGF overexpression significantly alleviated neurological deficits and infarct volume, and reduced disseminated neuronal injury and caspase-3 activity, confirming earlier observations that VEGF has neuroprotective properties. Brain swelling was not influenced in VEGF-overexpressing animals, while sodium fluorescein extravasation was moderately increased, suggesting that VEGF induces a mild blood-brain barrier leakage. To elucidate whether enhanced angiogenesis improves regional cerebral blood flow in the ischaemic brain, [14C]iodoantipyrine autoradiography was performed. Autoradiographies revealed that VEGF induces haemodynamic steal phenomena with reduced blood flow in ischaemic areas and increased flow values only outside the MCA territory. Our data demonstrate that VEGF protects neurons from ischaemic cell death by a direct action rather than by promoting angiogenesis, and suggest that strategies aiming at increasing vascular density in the whole brain, e.g. by VEGF overexpression, may worsen rather than improve cerebral haemodynamics after stroke.
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PMID:VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. 1550 18

The purpose of this study was to compare the relative effects of mannitol and hypertonic saline (HTS) on calpain activity, apoptosis and neuroinflammatory response induced by experimental cortical contusion. Four groups of 5 Sprague-Dawley male rats were submitted to focal brain injury produced by exposing the parietal cortex to dynamic cortical deformation. Groups were defined by rescucitation fluids administered 30 min post-injury as follows: group 1-0.9% normal saline 2 ml/kg; group 2-mannitol 20% 0.5 g/kg; group 3-HTS 2 ml/kg; group 4-HTS 4 ml/kg. At 72 h, animals were sacrificed. Paraffin-mounted sections of were stained for mu-Calpain, TUNEL, active caspase 3 and myeloperoxidase. There was no difference in the lesion size between the different groups. In contrast, there was a significant reduction in calpain and apoptosis activity and in the neuroinflammatory response in animals receiving HTS. Although mannitol proved to significantly decrease the neuroinflammatory response and calpain activity, it did not affect apoptosis, and its effect was significantly less than that of HTS. Importantly, the effect of HTS was mostly independent from the infused volume. Our results show that HTS promotes cell survival and reduces secondary brain damage following TBI. This protective effect was evidenced at rather small infused volumes, proved to encompass several cellular and molecular mechanisms involved in secondary cell death and could not be related to relief of intracranial pressure. These findings suggest that the high osmolality of HTS may have protective effects besides its impact on brain edema.
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PMID:Relative effects of mannitol and hypertonic saline on calpain activity, apoptosis and polymorphonuclear infiltration in traumatic focal brain injury. 1678 40

Calpains and cathepsins are two families of proteases that play an important role in ischemic cell death. In this study, we investigated the effect of E64d, a mu-calpain and cathepsin B inhibitor, in the prevention of neuronal and endothelial apoptotic cell death after focal cerebral ischemia in rats. Rats underwent 2 hr of transient focal ischemia from middle cerebral artery occlusion (MCAO) and were sacrificed 24 hr later. E64d (5 mg/ kg intraperitoneally) was administered 30 min before MCAO. Assessment included neurological function, infarction volume, brain water content, blood-brain barrier permeability, histology, and immunohistochemistry. The E64d-treated rats had significant brain protection against ischemic damage. We observed a reduction of infarction volume, brain edema, and improved neurological scores in E64d-treated rats compared with the nontreated control. Furthermore, there was a remarkable reduction in both proteases and caspase-3 activation and apoptotic changes in both neurons and endothelial cells in E64d-treated rats. These results suggest that E64d protects the brain against ischemic/reperfusion injury by attenuating neuronal and endothelial apoptosis.
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PMID:Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats. 1680 20

Studies have illustrated that fatty acids, especially polyunsaturated fatty acids (PUFA), have a role in regulating oxidative stress via the enhancement of antioxidative defense capacity or the augmentation of oxidative burden. Elevated oxidative stress has been implicated in the pathogenesis of brain injury associated with cerebral ischemia/reperfusion (I/R). The objective of this study was to assess whether treatment with fatty acids after focal cerebral I/R induced by occlusion of the common carotid arteries and the middle cerebral artery has effects on brain injury in a rat model. PUFA, including arachidonic acid (AA) and docosahexaenoic acid (DHA), and the saturated fatty acid, stearic acid (SA), were administrated 60 min after reperfusion via intraperitoneal injection. AA and DHA aggravated cerebral ischemic injury, which manifested as enlargement of areas of cerebral infarction and increased impairment of motor activity, in a concentration-dependent manner. However, there were no remarkable differences in post-ischemic alterations between the SA and saline groups. The post-ischemic augmentation of injury in AA and DHA treatment groups was accompanied by increases in the permeability of the blood-brain barrier (BBB), brain edema, metalloproteinase (MMP) activity, inflammatory cell infiltration, cyclooxygenase 2 (COX-2) expression, caspase 3 activity, and malondialdehyde (MDA) production, and by a decrease in the brain glutathione (GSH) content. Furthermore, we found that either AA or DHA alone had little effect on free radical generation in neuroglia, but they greatly increased the hydrogen peroxide-induced oxidative burden. Taken together, these findings demonstrate the detrimental effect of PUFA such as AA and DHA in post-ischemic progression and brain injury after cerebral I/R is associated with augmentation of cerebral I/R-induced alterations, including oxidative changes.
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PMID:Detrimental effects of post-treatment with fatty acids on brain injury in ischemic rats. 1785 1

Surgical resection of brain tissue is associated with tissue damage at the resection margin. Studies of ischemic brain injury in rodents have shown that administration of L-histidine and thioperamide reduces ischemic tissue loss, in part by inhibition of apoptotic cell death. In this study we tested administration of L-histidine and thioperamide in surgical brain injury in mice. Mice were randomized to one of three groups: Sham surgery (n=18), surgical brain injury without treatment (SBI) (n=33), and surgical brain injury with combined l-histidine and thioperamide treatment (SBI+H) (n=29). Surgical brain injury was induced via right frontal craniotomy with resection of the right frontal lobe. L-histidine (1000 mg/kg) and thioperamide (5 mg/kg) were administered to the SBI+H group immediately following surgical resection. Postoperative assessment included neurobehavioral scores, Evans blue measurement of blood-brain barrier breakdown, brain water content, Nissl histology, and immunohistochemistry for IgG and cleaved caspase 3. Postoperative findings included equivalent neurobehavioral outcomes at 24 and 72 h in the SBI and SBI+H groups, similar histological outcomes between SBI and SBI+H, and similar qualitative staining for cleaved caspase 3. SBI+H had increased BBB breakdown on Evans blue analysis and a trend towards increased brain edema which was significant at 72 h. We conclude that combined treatment with l-histidine and thioperamide leads to increased BBB breakdown and brain edema in surgical brain injury.
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PMID:Role of histamine in brain protection in surgical brain injury in mice. 1834 55

Evidence suggests that inactivation of cell-damaging mechanisms and/or activation of cell-survival mechanisms may provide effective preventive or therapeutic interventions to reduce cerebral ischemia/reperfusion (I/R) injuries. Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid in the central nervous system that has been shown to possess neuroprotective effects. We examined whether different preadministrative protocols of DHA have effects on brain injury after focal cerebral I/R and investigated the potential neuroactive mechanisms involved. Sprague-Dawley rats were intraperitoneally pretreated with DHA once 1 h or 3 days being subjected to focal cerebral I/R or daily for 6 weeks before being subjected to focal cerebral I/R. Reduction of brain infarction was found in all three DHA-pretreated groups. The beneficial effect of DHA on the treatment groups was accompanied by decreases in blood-brain barrier disruption, brain edema, malondialdehyde (MDA) production, inflammatory cell infiltration, interleukin-6 (IL-6) expression and caspase-3 activity. Elevation of antioxidative capacity, as evidenced by decreased MDA level and increased superoxide dismutase activity and glutathione level, was detected only in the chronic daily-administration group. The two single-administration groups showed increased phosphorylation of extracellular-signal-regulated kinase (ERK). Elevation of Bcl-2 expression was detected in the chronic daily-administration and 3-day-administration groups. In vitro study demonstrated that DHA attenuated IL-6 production from stimulated glial cells involving nuclear factor kappaB inactivation. Therefore, the data suggest that the neuroprotective mechanisms of DHA pretreatment are, in part, mediated by attenuating damaging mechanisms through reduction of cytotoxic factor production and by strengthening survival mechanisms through ERK-mediated and/or Bcl-2-mediated prosurvival cascade.
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PMID:Protective effect of docosahexaenoic acid against brain injury in ischemic rats. 1880 85

Ketone bodies have been shown to be favorable alternative metabolic substrates and are protective under neuropathologies. At the same time, cytochrome c release has been reported following traumatic brain injury (TBI) and precipitates apoptosis via the mitochondrial pathway. The present study investigated the effects of a ketogenic diet (KD) on TBI. TBI was produced using the Feeney weight-drop model and the animals were fed either normal diet (ND) or KD. Brain edema was estimated by wet/dry weight ratio; cytochrome c was detected by Western blotting; cellular apoptosis in the penumbra area was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and active caspase-3 immunohistochemical staining. The results show that brain edema, cytochrome c release, and cellular apoptosis were induced after TBI and that KD reduced these changes dramatically. These findings suggest that KD has potential therapeutic benefit in TBI.
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PMID:Ketogenic diet reduces cytochrome c release and cellular apoptosis following traumatic brain injury in juvenile rats. 1920 46

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


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