Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we evaluated the time-course of caspase-3 activation, and the evolution of cell death following focal cerebral ischemia produced by transient middle cerebral artery occlusion in rats. Ischemia-induced active caspase-3 immunoreactivity in the striatum but not the cortex at 3 and 6 h time points post-reperfusion. Furthermore, using a novel approach to visualize enzymatic activity, deltaC-APP, a C-terminal cleavage product of APP generated by caspase-3, was found to immunolocalize to the same areas as active caspase-3. Double-labeling studies demonstrated co-localization of these two proteins at the cellular level. Further double-labeling experiments revealed that active caspase-3 was confined to neuronal cells which were still viable and thus immunoreactive for NeuN. DNA fragmentation, assessed histologically by terminal dUTP nick-end labeling (TUNEL), was observed in a small number of cells in the striatum as early as 3 h, but only began to appear in the cortex by 6 h. DNA fragmentation was progressive, and by 24 h post-reperfusion, large portions of both the striatum and cortex showed TUNEL positive cells. However, double-labeling of active caspase-3 with TUNEL showed only minimal co-localization at all time-points. Thus, caspase-3 activation is an event that appears to occur prior to DNA fragmentation. As a confirmation of the histological TUNEL data, 24 h ischemia also induced the generation of nucleosome fragments, evidenced by cell death enzyme-linked immunosorbent assay. Using a novel ischemia-induced substrate cleavage biochemical approach, spectrin P120 fragment, a caspase-specific cleavage product of alpha II spectrin, a cytoskeletal protein, was shown to be elevated by western blotting. Brain concentrations of both nucleosomes and spectrin P120 correlate with the degree of injury previously assessed by triphenyltetrazolium chloride staining and infarct volume calculation. Together, our findings suggest a possible association between caspase-3 activation and ischemic cell death following middle cerebral artery occlusion brain injury.
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PMID:Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat. 1240 27

The transition from reversible to irreversible ischemic injury (ischemia-reperfusion, I/R) occurs coincident with the loss of vinculin, a cytoskeletal protein involved in the attachment of the myofibrils to the sarcolemmal membrane. If the loss of vinculin were critical to the development of I/R, then increased levels of vinculin would be predicted to delay the onset of irreversible injury assuming that the protein is functional and localized to the proper subcellular site. The present study determined whether increased expression of vinculin, specifically in the cytoskeletal compartment, would provide protection from I/R injury. Neonatal rat myocytes were cultured and infected with a newly created replication-deficient adenovirus driving the expression of vinculin. I/R was induced with chemical inhibitors of glycolysis and mitochondrial respiration. Irreversible cell injury was assessed with lactate dehydrogenase (LDH) release. Virus-infected myocytes expressed significantly more vinculin in the cytoskeletal fraction and increased the expression of paxillin but sustained the same amount of injury in response to simulated I/R as control cells (n = 4; P = not significant, paired t-test). Hypothermic I/R (ischemia at 25 degrees C) resulted in a significant reduction in LDH release (P </= 0.02; n = 4). Virus-mediated overexpression of vinculin does not appear to represent a rational approach to overcoming I/R injury.
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PMID:Effect of increased expression of cytoskeletal protein vinculin on ischemia-reperfusion injury in ventricular myocytes. 1257 17

Because of observations that cultured neurons from mice deficient in the transcription factor E2F1 exhibit resistance after treatment with a wide variety of cell-death inducers, the authors investigated whether resistance extended to a cerebral ischemic insult. No differences in cerebral blood flow or physiologic parameters were observed in the mutant E2F1 littermates after the focal ligation. After 2 hours of left middle cerebral artery occlusion and 1 day of reperfusion, a 33% smaller infarct (P < 0.05) was observed by 2,3,5-triphenyltetrazolium staining in the brains of E2F1-null mice compared with their E2F1+/+ and +/- littermates. A milder ischemic insult produced by 20 minutes of middle cerebral artery occlusion and 7 days of reperfusion produced a greater difference in the E2F1-null animals with a 71% smaller infarct (P < 0.001) compared to littermate controls. A decrease in neuronal damage after mild ischemia in E2F1-null mice was observed by immunohistochemical monitoring of the loss in neuronal-specific microtubule-associated protein 2 cytoskeletal protein and the appearance of nuclear DNA fragmentation by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling. This decreased brain damage was evidenced by improved behavior in motor function of E2F1 -/- mice compared with their E2F1 +/+ littermates by 7 days of reperfusion. In an effort to address the underlying molecular mechanism of the resistance of E2F1-null mice, the expression of several downstream proapoptotic target genes (p73, Apaf1, Arf) of the E2F1 transcription factor was measured by quantitative polymerase chain reaction. Although an attenuated increase in Hsp68 mRNA was found in E2F1 -/- mice, no changes in the proapoptotic transcripts were found after ischemia, and a mechanistic inference was not possible. The authors conclude that the transcription factor E2F1 does modulate neuronal viability in brain after cerebral ischemia and corroborates the findings with cultured neurons.
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PMID:Absence of the transcription factor E2F1 attenuates brain injury and improves behavior after focal ischemia in mice. 1297 18

Astrogliosis, consisting in astroglial proliferation and increased expression of the specific cytoskeletal protein glial fibrillary acid protein (GFAP) is common in several situations of brain damage. Arterial hypertension, which induces cerebrovascular changes, can cause also brain damage, neurodegeneration and dementia (vascular dementia). This study was designed to assess astroglial reaction in different brain areas (frontal cortex, occipital cortex, hippocampus and striatum) of spontaneously hypertensive rats (SHR) in the pre-hypertensive phase (2 months of age), in the developing phase of hypertension (4 months of age) and in established hypertension (6 months of age). SHR were compared to age-matched normotensive Wistar-Kyoto (WKY) rats. Analysis included reverse transcription-polymerase chain reaction (RT-PCR) of GFAP mRNA, GFAP immunochemistry (Western blot analysis) and immunohistochemistry. A significant increase of GFAP mRNA and an increase of GFAP immunoreactivity were noticeable in different brain areas of SHR compared to normotensive WKY rats at 6, but not at 2 or 4 months of age. Immunohistochemistry revealed a numerical augmentation (hyperplasia) and an increase in size (hypertrophy) of GFAP-immunoreactive astrocytes in frontal cortex, occipital cortex and striatum of SHR. In the hippocampus of SHR only a numerical increase of GFAP-immunoreactive astrocytes was found. These finding demonstrating the occurrence of astrogliosis in the brain of SHR with established hypertension suggest that hypertension induces a condition of brain suffering enough to increase biosynthesis and expression of GFAP similarly as reported in several neurodegenerative disorders and in brain ischemia.
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PMID:Increased expression of glial fibrillary acidic protein in the brain of spontaneously hypertensive rats. 1519 88

Severe hemolysis or myolysis occurring during pathological states, such as sickle cell disease, ischemia reperfusion, and malaria results in high levels of free heme, causing undesirable toxicity leading to organ, tissue, and cellular injury. Free heme catalyzes the oxidation, covalent cross-linking and aggregate formation of protein and its degradation to small peptides. It also catalyzes the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Heme being a lipophilic molecule intercalates in the membrane and impairs lipid bilayers and organelles, such as mitochondria and nuclei, and destabilizes the cytoskeleton. Heme is a potent hemolytic agent and alters the conformation of cytoskeletal protein in red cells. Free heme causes endothelial cell injury, leading to vascular inflammatory disorders and stimulates the expression of intracellular adhesion molecules. Heme acts as a pro-inflammatory molecule and heme-induced inflammation is involved in the pathology of diverse conditions; such as renal failure, arteriosclerosis, and complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure. Heme offers severe toxic effects to kidney, liver, central nervous system and cardiac tissue. Although heme oxygenase is primarily responsible to detoxify free heme but other extra heme oxygenase systems also play a significant role to detoxify heme. A brief account of free heme toxicity and its detoxification systems along with mechanistic details are presented.
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PMID:Free heme toxicity and its detoxification systems in human. 1591 43

TNF-alpha modulates EC proliferation and thereby plays a central role in new blood vessel formation in physiologic and pathologic circumstances. TNF-alpha is known to downregulate cyclin A, a key cell cycle regulatory protein, but little else is known about how TNF-alpha modulates EC cell cycle and angiogenesis. Using primary ECs, we show that ezrin, previously considered to act primarily as a cytoskeletal protein and in cytoplasmic signaling, is a TNF-alpha-induced transcriptional repressor. TNF-alpha exposure leads to Rho kinase-mediated phosphorylation of ezrin, which translocates to the nucleus and binds to cell cycle homology region repressor elements within the cyclin A promoter. Overexpression of dominant-negative ezrin blocks TNF-alpha-induced modulation of ezrin function and rescues cyclin A expression and EC proliferation. In vivo, blockade of ezrin leads to enhanced transplanted EC proliferation and angiogenesis in a mouse hind limb ischemia model. These observations suggest that TNF-alpha regulates angiogenesis via Rho kinase induction of a transcriptional repressor function of the cytoskeletal protein ezrin and that ezrin may represent a suitable therapeutic target for processes dependent on EC proliferation.
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PMID:The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A. 1596

In this study we examined whether expression of microtubule-associated protein 2 (MAP2) after transient global cerebral ischemia can be influenced by behavioral experience and if the changes are associated with functional improvement. Rats received either ischemia or sham surgery then assigned to: complex environment housing (EC) or social housing (SC) as controls for 14 days followed by water maze testing. Upregulation of MAP2 was seen in all ischemic animals with a significant overall increase evident in the EC housed rats. Behaviorally, all animals learned to perform the water maze task over time but the ischemia SC rats had the worst performance overall while all the EC housed animals demonstrated the best performance in general. Regression analysis showed that increase MAP2 expression was able to explain some of the variance in the behavioral parameters in the water maze suggesting that this cytoskeletal protein probably played a role in mediating enhanced functional outcomes.
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PMID:Amelioration of cognitive impairment and changes in microtubule-associated protein 2 after transient global cerebral ischemia are influenced by complex environment experience. 1635 57

Cannabinoid CB1 receptors are the most abundant G-protein-coupled receptors in the brain. Its presynaptic location suggests a role for cannabinoids in modulating the release of neurotransmitters from axon terminals by retrograde signaling. The neuroprotective effects of cannabinoid agonists in animal models of ischemia, seizures, hypoxia, Multiple Sclerosis, Huntington and Parkinson disease have been demonstrated in several reports. The proposed mechanism for the neuroprotection ranges from antioxidant effects, reduction of microglial activation and anti-inflammatory reaction to receptor-mediated reduction of glutamate release. In the present work, we analyzed the morphological changes induced by a chronic treatment with the synthetic cannabinoid receptor agonist, WIN 55,212-2, in four brain regions where the CB1 cannabinoid receptor is present in high density: the CA1 hippocampal area, corpus striatum, cerebellum and frontal cortex. After a twice-daily treatment for 14 days with the cannabinoid receptor agonist (3 mg/kg sc, each dose) to male Wistar rats (150-170 g), the expression of neurofilaments (Nf-160 and Nf-200), microtubule-associated protein-2 (MAP-2), synaptophysin (Syn) and glial fibrillary acidic protein (GFAP) was studied by immunohistochemistry and digital image analysis. Ultrastructural study of the synapses was done using electron microscopy. After the treatment, a significant increase in the expression of neuronal cytoskeletal proteins (Nf-160, Nf-200, MAP-2) was observed, but we did not find changes in the expression of GFAP, the main astroglial cytoskeletal protein. In cerebellum, there was an increase in Syn expression and in the number of synaptic vesicles, while, in the hippocampus, an increase in the Syn expression and in the thickness of the postsynaptic densities was observed. The results obtained from these studies provide evidences on the absence of astroglial reaction and a sprouting phenomena induced by the WIN treatment that might be a key contributor to the long-term neuroprotective effects observed after cannabinoid treatments in different models of central nervous system (CNS) injury reported in the literature.
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PMID:Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2. 1656 7

Proteolytic processing plays an important role in regulating a wide range of important cellular functions, including processing of cytoskeletal proteins. Loss of cytoskeletal proteins such as spectrin is an important characteristic in a variety of acute central nervous system injuries including ischemia, spinal cord injury and traumatic brain injury (TBI). The literature contains extensive information on the proteolytic degradation of alpha-II-spectrin after TBI in the adult brain. By contrast, there is limited knowledge on the characteristics and relevance of these important processes in the immature brain. The present experiments examine TBI-induced proteolytic processing of alpha-II-spectrin after TBI in the immature rat brain. Distinct proteolytic products resulting from the degradation of the cytoskeletal protein alpha-II-spectrin by calpain and caspase 3 were readily detectable in cortical brain parenchyma and cerebrospinal fluid after TBI in immature rats.
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PMID:Alpha-II-spectrin after controlled cortical impact in the immature rat brain. 1694 68

Controversy surrounds proper classification of neurodegeneration occurring acutely following neonatal hypoxia-ischemia (HI). By ultrastructural classification, in the first 24 h after neonatal hypoxia-ischemia in the 7-day-old (p7) rat, the majority of striatal cells die having both apoptotic and necrotic features. There is formation of a functional apoptosome, and activation of caspases-9 and -3 occurring simultaneously with loss of structurally intact mitochondria to 34.7+/-25% and loss of mitochondrial cytochrome c oxidase activity to 34.7+/-12.7% of control levels by 3 h after hypoxia-ischemia. There is also loss of the mitochondrial motor protein, kinesin. This combination of activation of apoptosis pathways simultaneous with significant mitochondrial dysfunction may cause incomplete packaging of nuclear and cytoplasmic contents and a hybrid of necrotic and apoptotic features. Evidence for an intermediate biochemistry of cell death including expression of the 17 kDa isoform of caspase-3 in dying neurons lacking a classic apoptotic morphology and degradation of the neuronal cytoskeletal protein spectrin by caspase-3 and calcium-activated calpains yielding 120 kDa and 145/150 kDa fragments, respectively, is also found. In summary, neonatal hypoxia-ischemia triggers apoptotic cascades, and simultaneously causes mitochondrial structural and functional failure. The presence of a "continuum" phenotype of cell death that varies on a cell-by-cell basis suggests that the phenotype of cell death is dependent on the energy available to drive the apoptotic pathways to completion.
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PMID:Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as "continuum" phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. 1796 29


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