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)

The authors report two cases of ischemic stroke secondary to occlusive vasculopathy two decades after radiation therapy (RT) for medulloblastoma. Both patients underwent posterior fossa medulloblastoma partial resection, followed by craniospinal RT in which a cobalt 60 source was used; 40 Gy were given to the whole brain plus a 15-Gy boost to the posterior fossa. Both patients received multiagent chemotherapy, immediately following radiation therapy in the first case and after repeated craniotomy for recurrence 13 years after radiation in the second case. They experienced multiple sequelae from radiation and chemotherapy, including growth retardation and psychomotor delay. However, 20 years after treatment, they remained tumor free and able to work, until they presented with focal neurological deficits and seizures. Computerized tomography and magnetic resonance imaging of the brain in both cases showed no tumor recurrence, but did demonstrate ischemia in a posterior cerebral artery distribution. Cerebral angiography revealed multiple mid-sized arterial wall irregularities as well as focal stenoses consistent with a postirradiation vasculopathy. The pathophysiological mechanisms, radiological appearance, and incidence of this syndrome are reviewed from the literature.
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PMID:Late postirradiation occlusive vasculopathy in childhood medulloblastoma. Report of two cases. 972 22

Like other areas of the central nervous system, the retina is highly vulnerable to ischemia. In particular, neurons in the inner nuclear layer, including gamma-amino butyric acid (GABA)-ergic amacrine neurons, are highly vulnerable. Since excitotoxicity is likely a major mechanism of ischemic retinal injury, using rat retinal cell culture, we examined whether GABAergic retinal neurons are differentially vulnerable to particular excitotoxins. The neuronal population as a whole, identified by anti-microtubule associated protein-2 (MAP-2) immunocytochemistry, was equally vulnerable to kainate, but more resistant to N-methyl-d-aspartate (NMDA) than cultured cortical neurons. Compared to Thy-1 immunoreactive neurons, GABA immunoreactive neurons were more vulnerable to kainate, but more resistant to NMDA neurotoxicity. Double staining of cultures with anti-GABA immunocytochemistry and the kainate-stimulated cobalt uptake method, revealed a close correlation between the two. However, unlike in other neuronal cells, there was no clear correlation between GluR2 immunoreactivity and the cobalt staining. The heightened vulnerability of GABAergic neurons to kainate, as compared to the general neuronal population, may be due to the calcium-permeable AMPA/kainate receptors they have, as identified functionally by the kainate-stimulated cobalt uptake staining. Since these neurons are preferentially injured in ischemia, AMPA/kainate receptor-mediated neurotoxicity may contribute significantly to ischemic retinal injury.
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PMID:High vulnerability of GABA-immunoreactive neurons to kainate in rat retinal cultures: correlation with the kainate-stimulated cobalt uptake. 1009 9

Intracellular and single-electrode voltage-clamp recordings were made to investigate the process of membrane dysfunction induced by superfusion with oxygen and glucose-deprived (ischemia-simulating) medium in hippocampal CA1 pyramidal neurons of rat tissue slices. To assess correlation between potential change and membrane dysfunction, the recorded neurons were stained intracellularly with biocytin. A rapid depolarization was produced approximately 6 min after starting superfusion with ischemia-simulating medium. When oxygen and glucose were reintroduced to the bathing medium immediately after generating the rapid depolarization, the membrane did not repolarize but depolarized further, the potential reaching 0 mV approximately 5 min after the reintroduction. In single-electrode voltage-clamp recording, a corresponding rapid inward current was observed when the membrane potential was held at -70 mV. After the reintroduction of oxygen and glucose, the current induced by ischemia-simulating medium partially returned to preexposure levels. These results suggest that the membrane depolarization is involved with the membrane dysfunction. The morphological aspects of biocytin-stained neurons during ischemic exposure were not significantly different from control neurons before the rapid depolarization. On the other hand, small blebs were observed on the surface of the neuron within 0.5 min of generating the rapid depolarization, and blebs increased in size after 1 min. After 3 min, neurons became larger and swollen. The long and transverse axes and area of the cross-sectional cell body were increased significantly 1 and 3 min after the rapid depolarization. When Ca2+-free (0 mM) with Co2+ (2.5 mM)-containing medium including oxygen and glucose was applied within 1 min after the rapid depolarization, the membrane potential was restored completely to the preexposure level in the majority of neurons. In these neurons, the long axis was lengthened without any blebs being apparent on the membrane surface. These results suggest that the membrane dysfunction induced by in vitro ischemia may be due to a Ca2+-dependent process that commences approximately 1.5 min after and is completed 3 min after the onset of the rapid depolarization. Because small blebs occurred immediately after the rapid depolarization and large blebs appeared 1.5-3 min after, it is likely that the transformation from small to large blebs may result in the observed irreversible membrane dysfunction.
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PMID:Membrane dysfunction induced by in vitro ischemia in rat hippocampal CA1 pyramidal neurons. 1020 Feb 22

We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy-induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation.
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PMID:Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. 1058 8

In rat hippocampal CA1 neurons recorded intracellularly from tissue slices, a rapid depolarization occurred approximately 5 min after application of ischemia-simulating medium. In extracellular recordings obtained from CA1 region, a rapid negative-going DC potential (rapid DC potential) was recorded, corresponding to a rapid depolarization. When oxygen and glucose were reintroduced after generating the rapid depolarization, the membrane further depolarized and the potential became 0 mV after 5 min. Contrary, the DC potential began to repolarize slowly and subsequently a slow negative-going DC potential (slow DC potential) occurred within 1 min. A prolonged application of ischemia-simulating medium suppressed the slow DC potential. Addition of a high concentration of ouabain in normoxic medium reproduced a rapid but not a slow DC potential. The slow DC potential was reduced in low Na+- or Co2+-containing medium, but was not affected in low Cl-, high K+ or K+-free medium, suggesting that the slow DC potential is Na+-and Ca2+-dependent. Ni2+ (Ca2+ channel blocker as well as the Na+/Ca2+ exchanger blocker) and benzamil hydrochloride (Na+/Ca2+ exchanger blocker) reduced the slow DC potential dose-dependently. These results suggest that the slow DC potential is mediated by forward mode operation of Na+/Ca2+ exchangers in non-neuronal cells, and that reactivation of Na+, K+-ATPase is necessary to the Na+/Ca2 +exchanger activity.
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PMID:Na+/Ca2+ exchanger activity induces a slow DC potential after in vitro ischemia in rat hippocampal CA1 region. 1071 10

Erythropoietin (Epo), the major hormone controlling the hypoxia-induced increase in the number of erythrocytes, has also a functional role in the brain. However, few data exist as to the cellular source of brain-derived Epo as well as to the molecular mechanisms that control Epo expression in the central nervous system. Using patch-clamp and RT-PCR methods, we provide direct evidence that, besides astrocytes, neurons are a source of Epo in the brain. Both the astrocytic and neuronal expression of Epo mRNA are induced not only by hypoxia, but also by desferrioxamine (DFX) and cobalt chloride (CoCl(2)), two agents known to mimic the hypoxic induction of Epo in hepatoma cells. This induction is blocked by cycloheximide suggesting that de novo protein synthesis is required. Furthermore, the addition of H(2)O(2) decreases the hypoxia-induced Epo mRNA levels. These data indicate that, following hypoxia, a common oxygen sensing and signaling pathway leads to increased Epo gene expression in both nervous and hepatoma cells; this pathway would be dependent on the redox-state of the brain. Furthermore, we show that the in vivo administration of CoCl(2) and DFX to mice induces an increased Epo mRNA level in the neocortex. As Epo protects the brain against ischemia, our in vivo experiments suggest that the use of molecules such as CoCl(2) or DFX, that provoke an increased Epo gene expression in the brain, could be useful in the development of potential therapeutic strategies for the treatment of hypoxic or ischemic brain injury.
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PMID:Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. 1075 76

Hypoxia-inducible factor-1 (HIF-1) is a heterodimer composed of HIF-1alpha and HIF-1beta protein subunits. This transcription factor is essential for the activation of hypoxia-inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2 for 3 hours), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. To support the role of HIF-1 in protective preconditioning, we also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1alpha and HIF-1beta protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl2 or DFX 24 hours before hypoxia-ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle-injected littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning, which could be used in high-risk deliveries and other clinical situations.
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PMID:Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. 1097 34

Adrenomedullin is a potent vasodilator peptide originally isolated from pheochromocytoma. Adrenomedullin is produced by various types of cells including neurons and astrocytes. To explore possible pathophysiological roles of adrenomedullin in hypoxic brain, we studied the effects of hypoxia on the expression of adrenomedullin in T98G human glioblastoma cells by radioimmunoassay and northern blot analysis. Expression levels of adrenomedullin mRNA and immunoreactive adrenomedullin levels in the culture medium were increased by hypoxia about six- and about threefold, respectively. Treatment with cobalt chloride increased expression levels of adrenomedullin mRNA about threefold and immunoreactive adrenomedullin levels in the culture medium about threefold in T98G cells. Using actinomycin D, we showed that hypoxia did not cause the stabilization of the adrenomedullin mRNA, suggesting that the increased adrenomedullin mRNA levels in response to hypoxia are caused mainly by increased transcription. Treatment with cycloheximide caused increases in adrenomedullin mRNA levels in both normoxic and hypoxic states, raising the possibility that some protein(s) may act as a suppressor of adrenomedullin gene expression in T98G cells. These findings indicate that adrenomedullin is highly induced during hypoxia in T98G glioblastoma cells and suggest that increased expression of adrenomedullin during hypoxia may be important in the defense against hypoxia or ischemia in the brain.
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PMID:Induction of adrenomedullin during hypoxia in cultured human glioblastoma cells. 1103 71

We initially observed a phenomenon of reduced in vitro binding of exogenous cobalt [Co(II)] to the N-terminus of human serum albumin (HSA) in emergency chest pain patients with early onset unstable angina and myocardial infarction. We then developed a colorimetric assay to measure cobalt-HSA binding and record the results in absorbance units (ABSU). In a preliminary clinical study of 139 emergency patients with acute chest pain, 99 patients with evidence of myocardial ischemia (Group 1) had elevated assay levels (mean ABSU +/- SD; 0.519 +/- 0.086) compared to 40 patients (Group 2) with no evidence of ischemia (0.316 +/- 0.092) (p < 0.00001). In Group 1, 95 of 99 (96.0%) patients had levels higher than a decision threshold of 0.400 ABSU and in Group 2, 37 of 40 (92.5%) samples had higher cobalt binding capacity (ABSU </= 0.400). Further studies are warranted to determine if an assay measuring altered cobalt-HSA binding is a clinically useful diagnostic test to rule out myocardial ischemia.
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PMID:A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. 1107 21

The pathogenesis of late-onset epileptic seizures after thrombo-embolic cerebral infarction is poorly understood. Our previous positron emission tomographic (PET) studies with 15O have demonstrated that post-apoplectic epilepsy is associated with more severe brain ischemia, but we were unable to determine if this was the cause or the consequence of the seizures. Using cobalt-55 (55Co) as PET tracer we can now distinguish recurrent, recent infarction in patients with a previous old infarct in the same vascular territory. In seven out of twelve patients with post-apoplectic seizures an increased uptake of 55Co was observed in the border area and in two of them also within the old infarct core. In the control group, composed of eight seizure-free patients with also an old infarct involving the cortical territory of the middle cerebral artery, no increase in 55Co uptake was observed on PET examination. The present study indicates that in a significant number of patients late-onset epilepsy is the clinical expression of recurrent strokes, occurring in the same vascular territory.
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PMID:Cobalt-55 positron emission tomography in late-onset epileptic seizures after thrombo-embolic middle cerebral artery infarction. 1109 6


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