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)

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

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

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

Erythropoietin (Epo) is an endogenous cytokine that regulates hematopoiesis and is widely used to treat anemia. In addition, it has recently increased interest in the neurosciences since the new concept of Epo as a neuroprotective agent has emerged. The potential protective effect of human recombinant Epo (r-hu-Epo) on a hypoxic-ischemic (HI) pup rat model was studied. Cerebral HI was obtained by permanent left carotid artery ligature of pups followed by a 2-h hypoxia. Three hours after carotid occlusion, brain lesions were assessed by magnetic resonance diffusion weighted imaging. Intraperitoneal administration of r-hu-Epo (30,000 U/kg dose) limited both the HI-induced brain lesion area and the decrease in apparent diffusion coefficient (ADC) in the lesion. To identify potential mechanisms underlying the effects of Epo, immunohistochemical detection of caspase-3 and water channel protein aquaporin-4 (AQP4) were performed. No early apoptosis was detected, but up-regulation of AQP4 expression was observed in HI pups that received r-hu-Epo compared with HI animals without treatment. This study demonstrates an early neuroprotective effect of Epo with regard to brain lesion area and ADC values. One possible mechanism of Epo for decreasing brain edema and cellular swelling could be a better clearance of water excess in brain tissue, a process possibly mediated by AQP4.
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PMID:Short-term effect of erythropoietin on brain lesions and aquaporin-4 expression in a hypoxic-ischemic neonatal rat model assessed by magnetic resonance diffusion weighted imaging and immunohistochemistry. 2046 Oct 24

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype accounting for approximately 3 to 7% of cases each year. Despite its rarity among the various stroke types, SAH is still responsible for approximately 25% of all stroke fatalities. Although various preventative and therapeutic interventions have been explored for potential neuroprotection after SAH, a considerable percentage of patients still experience serious neurologic and/or cognitive impairments as a result of the primary hemorrhage and/or secondary brain damage that occurs. Z-ligustilide (LIG), the primary lipophilic component of the Chinese traditional medicine radix Angelica sinensis, has been shown to reduce ischemic brain injury via antiapoptotic pathways. Accordingly, in our study, we investigated the neuroprotective potential of LIG after experimental SAH in rats. Rats with SAH that was induced using the established double hemorrhage model were studied with and without LIG treatment. Mortality, neurobehavioral evaluation, brain water content, blood-brain barrier (BBB) permeability, and vasospasm assessment of the basilar artery were measured on days 3 and 7 after injury. Additional testing was done to evaluate for apoptosis using TdT-mediated dUTP-biotin nick end labeling staining as well as immunohistochemistry and Western blotting to identify key proapoptotic/survival proteins, i.e., p53, Bax, Bcl-2, and cleaved caspase-3. The results showed that LIG treatment reduced mortality, neurobehavioral deficits, brain edema, BBB permeability, and cerebral vasospasm. In addition, treatment reduced the number of apoptotic cells in the surrounding brain injury site, which accompanied a marked down-regulation of proapoptotic proteins, p53, and cleaved caspase-3. Our data suggest that LIG may be an effective therapeutic modality for SAH victims by altering apoptotic mechanisms.
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PMID:Treatment with Z-ligustilide, a component of Angelica sinensis, reduces brain injury after a subarachnoid hemorrhage in rats. 2139 13

Semi-quantitative neuroradiologic studies, quantitative neuron density studies and immunocytochemistry markers of oxidative stress and neuroinflammation indicate neuronal injury and deficits in young patients with chronic poorly controlled type 1 diabetes mellitus (T1DM). Present data suggest that pathogenesis of the neuronal deficits in young patients, who die as the result of diabetic ketoacidosis (DKA) and brain edema (BE), does not involve apoptosis, a prominent form of regulated cell death in many disease states. To further address this we studied mediators of macroautophagy, endoplasmic reticulum (ER) stress and apoptosis. In all areas studied we demonstrated increased levels of macroautophagy-associated proteins including light chain-3 (LC3) and autophagy related protein-4 (Atg4), as well as increased levels of the ER-associated glucose-regulated protein78/binding immunoglobulin protein (GRP78/BiP) in T1DM. In contrast, cleaved caspase-3 was rarely detected in any T1DM brain regions. These results suggest that chronic metabolic instability and oxidative stress may cause alterations in the autophagy-lysosomal pathway but not apoptosis, and macroautophagy-associated molecules may serve as useful candidates for further study in the pathogenesis of early neuronal deficits in T1DM.
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PMID:Autophagy in the brains of young patients with poorly controlled T1DM and fatal diabetic ketoacidosis. 2207 79

Autophagy, the bulk intracellular degradation of cytoplasmic constituents, can be a pro-survival or a pro-death mechanism depending on the context. A recent study showed that autophagy was activated in the phase of early brain injury following subarachnoid hemorrhage (SAH). However, whether autophagy activation after SAH is protective or harmful is still elusive. This study was undertaken to determine the potential role of autophagy pathway activation in early brain injury following SAH. The rats were pretreated with intracerebral ventricular infusion of either the autophagy inducer rapamycin (RAP) or inhibitor 3-methyladenine (3-MA) before SAH onset. The results from electron microscopic examinations showed that RAP administration caused the formation of autophagosomal vacuoles, and 3-MA induced neuronal apoptosis. RAP treatment significantly increased the expression of autophagic proteins Atg5 and Beclin 1, the ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I and reduced caspase-3 activity, the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells, brain edema and neurological deficits after SAH. Conversely, 3-MA treatment exacerbated early brain injury. RAP treatment significantly increased the expression of the autophagic proteins Atg5 and Beclin 1, the ratio of LC3-II to LC3-I and reduced caspase-3 activity, the number of TUNEL-positive cells, brain edema and neurological deficits after SAH. Conversely, 3-MA treatment reversed these changes and exacerbated early brain injury. To further clarify the mechanism of autophagy protection, we investigated the expression levels of key apoptosis-related molecules. The results showed that RAP administration decreased Bax translocation to the mitochondria and downstream cytochrome c release from the mitochondria to the cytosol. Taken together, our study indicates that activation of autophagic pathways reduces early brain injury after SAH. This neuroprotective effect is likely exerted by anti-apoptotic mechanisms.
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PMID:Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. 2252 19


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