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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of glutamate antagonists and GABA agonists may protect neurons from the effects of transient ischemia. Felbamate is a new antiepileptic drug with glutamate antagonist and GABA agonist properties. We tested the efficacy of felbamate in a gerbil model of transient forebrain ischemia. Damage assessment was done with silver staining at 7 and 28 days after 5 min of bilateral carotid occlusion. Cerebral cortex, hippocampus (CA1 and CA4), thalamus and striatum were evaluated on a 4-point scoring system. The animals sacrificed at 28 days were also tested in a water-maze task to assess recovery of function. The initial dose of felbamate (300 mg/kg) was given 30 min before the ischemic insult in one set of animals and 30 min after the insult in another set of animals. There were 8 animals tested per group (total: 48 animals). There was significant neuronal protection with the use of felbamate, both before and after ischemia in all regions of the brain. Protection was seen in animals sacrificed at 7 and 28 days. Protection was moderate when felbamate was used before ischemia. It was highly significant when felbamate was given 30 min after the insult. Behavioral studies however did not show any difference in the felbamate treated animals versus the saline treated controls. The structural protection with felbamate was very significant when used in the post-ischemic period. This window for protection merits further evaluation in relation to the clinical setting of stroke.
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PMID:Neuroprotection with felbamate: a 7- and 28-day study in transient forebrain ischemia in gerbils. 884 83

The metabotropic glutamate receptors (mGluRs) can be classified into three families based on amino acid sequence homology, signal transduction mechanisms and pharmacological properties. Generally, class I mGluRs mediate an excitation of neurons while activation of class II and III mGluRs results in a depression of synaptic transmission. In this study we have analyzed the expression pattern of mGluRs in human hippocampus using a panel of polyclonal antibodies specific for mGluR1b, mGluR2/3, mGluR4a, and mGluR5. Immunoreactivity for mGluR1b and mGluR5, i.e., the subtypes representing class I mGluRs, was found in all hippocampal neurons. The mGluR1b antiserum stained perikarya and proximal dendrites, whereas immunoreactivity for mGluR5 was also detectable in the distal dendritic compartments. Immunoreactivity for mGluR2/3, members of class II mGluRs, was present in all principle neurons in the dentate gyrus as well as in the CA4, CA3 and CA2 regions. Pyramidal cells of the CA1 region exhibited only weak labeling for mGluR2/3. Glial cells were also mGluR2/3-immunoreactive. The reaction obtained with an antiserum directed against mGluR4a, a member of class III mGluRs, was confined to the mossy fiber projection field in CA3 stratum lucidum. These data demonstrate differential expression of mGluR variants in the human hippocampus and may provide an important basis for future studies of mGluRs under various neuropathological conditions such as temporal lobe epilepsy, ischemia and neurodegenerative disorders.
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PMID:Immunohistochemical distribution of metabotropic glutamate receptor subtypes mGluR1b, mGluR2/3, mGluR4a and mGluR5 in human hippocampus. 893 Mar 27

Wistar rats were subjected to transient forebrain ischemia for 30 min. After a survival period of two to three days their brains were fixed and sections were processed for Nauta suppressive method (26) to study postischemic degenerative changes and for glial fibrillary acidic protein (GFAP) to study glial reaction. After two days somatodendritic argyrophilia was evident in the CA1a and CA4 areas. The somata and dendrites of CA1 a pyramidal neurons were intensely argyrophilic, and a clear border zone which separated these neurons from undamaged CA1b neurons was detected. In the CA4 area a few degenerating, probably mossy cells were found. Neuronal degeneration then proceeded rapidly during a 72 h survival period, when the somata and dendrites of complete CA1 and CA2 pyramidal cells became intensively argyrophilic. The area of CA4 was full of degenerated neurons, but the CA3 neurons remained intact. Postischemic glial changes were observed after 48h survival. The rostral part of CA1a area contained a higher concentration of astrocytes in the dendritic layer as well as in the pyramidal layer. These astrocytes revealed features of reactive astrocytes. An intense GFAP immunoreactivity with heavily stained astrocytic figures appeared in the CA2, CA3 dendritic layers, stratum molecular of the DG and hilus. The central region of CA4 area contained various vacuoles with clearly stained astrocytes. By 72 h after ischemia the tissue structure changed in all areas since the pyramidal layer contained shrunken neurons and large vacuoles. The GFAP immunoreactivity in the hippocampus was the same or even higher as observed after two days postischemia, but the astrocytes were seen more closely in the relation with the pyramidal cell layer.
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PMID:Ischemic damage in the hippocampus: a silver impregnation and immunocytochemical study in the rat. 893 16

Cerebral ischemia/hypoxia induces histopathological changes characterized by nuclear and cytoplasmic condensation and sustained c-fos expression. The ischemic changes are thought to be initiated by excessive glutamate released by the ischemic neurons. However, no comparative study has been made between the pathological and molecular changes caused by local injection of excitotoxin and by ischemia. In the present study, we investigated the histopathological changes in rat brains induced by an intracerebral microinjection of kainic acid, a potent analogue of glutamate using two newly available markers for ischemic neurons: Fos immunohistochemistry and EA 50 stain. The rats were sacrificed at intervals from 1 hour (h) to 28 days. We demonstrated that the neurons at the site of injection developed changes typical of ischemia 1 h post-lesion: nuclear and cytoplasmic condensation, strong Fos immunoreactivity and positive EA 50 stain. By 1 day, the neurons underwent necrosis and an infarct-like picture was produced. The neuronal degeneration rapidly spread to the bilateral neocortex, CA3 and CA4 regions of hippocampus, piriform gyrus, amygdala and cerebellar Purkinje cells. After 3 days, there was neovascularization and macrophage production in the lesion center and astrocytic proliferation at the lesion periphery. The CA1 of hippocampus showed delayed neuronal necrosis typical of ischemia. Thus, intracerebral microinjection of KA induces similar histopathological and molecular changes as those occurring in brain infarct and is a simple and reliable model for studying changes related to focal brain infarct.
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PMID:Kainate-induced brain lesion: similar local and remote histopathological and molecular changes as in ischemic brain infarct. 896 94

Cerebral hypoxia-ischemia causes encephalopathy and neurologic disabilities in newborns by unclear mechanisms. We tested the hypothesis that hypoxia-ischemia causes brain damage in newborns that is system-preferential and related to regional oxidative metabolism. One-week-old piglets were subjected to 30 minutes of hypoxia and then seven minutes of airway occlusion, producing asphyxic cardiac arrest, followed by cardiopulmonary resuscitation and four-day recovery. Brain injury in hypoxic-ischemia piglets (n = 6) compared to controls (n = 5) was analyzed by hematoxylin-eosin, Nissl, and silver staining, relationships between regional vulnerability and oxidative metabolism were evaluated by cytochrome oxidase histochemistry. Profile counting-based estimates showed that 13% and 27% of neurons in layers II/III and layers of somatosensory cortex had ischemic cytopathology, respectively; CA1 neuronal perikarya appeared undamaged, and < 10% of CA3 and CA4 neurons were injured; and neuronal damage was 79% in putamen, 17% in caudate, but nucleus accumbens was undamaged. Injury was found preferentially in primary sensory neocortices (particularly somatosensory cortex), basal ganglia (predominantly putamen, subthalamic nucleus, and substantia nigra reticulata), ventral thalamus, geniculate nuclei, and tectal nuclei. In sham piglets, vulnerable region generally had higher cytochrome oxidase levels than less vulnerable areas. Postischemic alterations in cytochrome oxidase were regional and laminar, with reductions (31-66%) occurring in vulnerable regions and increases (20%) in less vulnerable areas. We conclude that neonatal hypoxia-ischemia causes highly organized, system-preferential and topographic encephalopathy, targeting regions that function in sensorimotor integration and movement control. This distribution of neonatal encephalopathy is dictated possibly by regional function, mitochondrial activity, and connectivity.
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PMID:Primary sensory and forebrain motor systems in the newborn brain are preferentially damaged by hypoxia-ischemia. 898 85

Ubiquitin (Ub) is a small 76-residue protein, involved in intracellular protein degradation through a specific ATP-dependent system, which uses Ub as a tag to label proteins committed to be hydrolyzed by a specific 26 S protease. PGP-9.5 is another important component of the Ub system, i.e. a neuron-specific carboxyl-terminal hydrolase, which recycles Ub from Ub-polypeptide complexes. We have investigated the expression of Ub and PGP-9.5 in rat hippocampal neurons in an early phase of reperfusion in a model of transient global brain ischemia/hypoxia (bilateral occlusion of common carotid arteries for 10 min accompanied by mild hypoxia-15% O2-for 20 min), by means of immunohistochemical methods using light and electron microscopy. The intensity of Ub and PGP-9.5 immunoreactivity was evaluated by image analysis. We have detected a marked increase of Ub immunoreactivity (UIR) in neurons of CA1, CA2, CA3, CA4, and dentate gyrus subfields 1 hr after ischemia/hypoxia (but not after hypoxia only), statistically significant as confirmed by image analysis. Such increase in immunoreactivity in ischemic/hypoxic rats was localized essentially in the nuclei of hippocampal neurons. There were no changes in PGP-9.5 immunoreactivity. The data suggest that in the present model of rat brain ischemia/hypoxia Ub is involved in the neuronal stress response.
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PMID:Ubiquitin-mediated stress response in a rat model of brain transient ischemia/hypoxia. 902 69

Ischemia-induced delayed neuronal death can be mediated by apoptosis, and (-)deprenyl has been shown to block apoptosis in dopaminergic and cholinergic neurons. This study has investigated whether (-)deprenyl can prevent delayed neuronal death of hippocampal pyramidal cells. Rats were subjected to unilateral hypoxia-ischemia and treated with (-)deprenyl (0.25 mg/kg, s.c.) or saline daily. After sacrifice the left and right hippocampi were examined histologically. Unilateral delayed neuronal death was seen in the CA1, CA3 and CA4 fields up to 14 days after the ischemia. After 14 days' treatment with (-)deprenyl there was 66%, 91% and 96% reduction in delayed neuronal death in the CA1, CA3 and CA4 fields, respectively. (-)Deprenyl was effective when given at the onset or after ischemia, but not when given 2 h before ischemia. The reduction in ischemia-induced delayed neuronal death is consistent with an anti-apoptotic mechanism of (-)deprenyl.
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PMID:(-)Deprenyl reduces delayed neuronal death of hippocampal pyramidal cells. 906 41

Morphofunctional effects of combined moderate forebrain ischemia due to permanent bilateral carotid artery ligation and short-term systemic hypoxia in rats were investigated. Moreover, a putative effect of brain protection by Cerebrolysin (Cerebrolysin, EBEWE, Austria), a brain tissue hydrolysate containing a mixture of 85% free amino acids and 15% small peptides (MW < 10,000), was studied. Eighty-seven adult Wistar rats (24 Cerebrolysin treated and 63 controls) were subjected to chronic moderate forebrain ischemia by permanent bilateral carotid artery ligation for 7 days. Twenty-four hours after the onset of ischemia, 56 of them underwent an additional hypoxic hypoxia (FiO2 = 0.08) of 15 min. A first group (19 out of 56 animals) received Cerebrolysin (every dose 2.5 ml/kg body weight s.c.) after ligation, after hypoxia and then daily. A second group (6 out of 56 animals) received an equal volume of physiological saline after ligation and Cerebrolysin the first time after hypoxia and then once a day. An untreated control group (31 out 56 animals) received physiological saline. Changes in behavior were scored and electrophysiological activity was quantified by spectral ECoG analysis before carotid artery ligation, before and after hypoxia, and once a day during the following 7 days. On the 7th day after hypoxia, the animals were sacrificed and the grade of histological damage was quantified by morphometry. After permanent carotid artery ligation, 20 out of 63 (31.7%) untreated control animals died within 24 h but only 4 out of 20 (16.7%) Cerebrolysin treated animals. However, Cerebrolysin had not detectable effect on mortality after the additional acute hypoxia. Within 24 h after hypoxia, ECoG power of the higher frequency ranges remained low (p < 0.05). Surviving animals showed a significantly higher ECoG power during and 15 min after hypoxia than those animals that died within 48 h after hypoxia (p < 0.05). All animals showed reduced behavioral activity (p < 0.01) 20 min after hypoxia, however, basal reflex responses were not altered. The major patterns of neuronal damage were coagulation necrosis and general sponginess of the neuropil which is a sign of brain edema. These changes occurred predominantly within the superolateral convexities of the parietal cortex, in the entorhinal and in the piriform cortex as well as in the CA1 and CA4 region and in the dentate gyrus of the hippocampus. The striatum and the origin nuclei of the brain nerves were also affected. We did not observe a relationship between behavior, ECoG depression and the extent of morphological damage after hypoxia nor did we find any protective effects of Cerebrolysin on these parameters. Rather it is suggested that the degree of ECoG depression immediately after hypoxic hypoxia could be a predictor for prognosis of animal survival. Cerebrolysin reduced the amount of early mortality which was caused by moderate global forebrain ischemia. However, no protective influences of the amount of brain tissue damage could be shown.
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PMID:Morphofunctional effects of moderate forebrain ischemia combined with short-term hypoxia in rats--protective effects of Cerebrolysin. 908 71

We examined the immunohistochemical regional distribution of calcineurin (Ca2+/calmodulin-dependent protein phosphatase) in the adult rat hippocampus, following various regional destruction. In the normal adult rat hippocampus, the calcineurin immunoreactivity showed a characteristic pattern. This protein phosphatase was detected in all layers of the CA1 subfield, including the cytoplasm of the pyramidal cells, whereas it was strongly evident in the stratum lucidum and moderately so in the cytoplasm of pyramidal cells in the CA3 subfield. Seven days after transient forebrain ischemia, which induced destruction of CA1 pyramidal cells, the calcineurin immunoreactivity decreased in all layers of the CA1 subfield, while the immunoreactivity for synapsin I, a marker of the presynaptic site, was preserved. Seven days after the intraventricular injection of kainate, which induced destruction of CA3 pyramidal cells, the calcineurin immunoreactivity in the stratum lucidum was preserved, although the immunostaining pattern of the stratum lucidum changed when CA3 pyramidal cells were destroyed. Seven days after mechanical destruction of the dentate gyrus and CA4 subfield, which induced destruction of mossy fibers, the calcineurin immunoreactivity in the stratum lucidum was lost, except in the far site of the stratum lucidum. In the CA1 subfield, calcineurin was mainly located in postsynaptic sites, while it was mainly located in the presynaptic sites in the mossy fibers of the CA3 subfield. The immunohistochemistry of adjacent sections with antibodies of microtubule-associated protein 2 and synapsin I, which are markers of postsynaptic and presynaptic sites respectively, supports these results. Thus, calcineurin has a different synaptical distribution in the rat hippocampus.
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PMID:Calcineurin in the adult rat hippocampus: different distribution in CA1 and CA3 subfields. 915 50

The mRNA expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1beta mRNA and eventually synthesize IL-1 protein and which cells respond to this signaling by producing IL-1 receptors during ischemia. To clarify this question, rats were subjected to global ischemia by bilateral carotid occlusion and hypotension for 20 minutes, followed by reperfusion for 2 hours (n = 7), 8 hours (n = 7), or 24 hours (n = 7). Cryostat sections were hybridized using antisense oligonucleotide probes (30 dimer). Multiple cell markers were used in immunohistochemical staining to identify the cells expressing IL-1beta and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1beta mRNA. The number of IL-1beta mRNA-expressing cells was significantly increased by 2 hours of reperfusion in several brain areas including cortex (12-fold compared with sham) and caudate-putamen (14-fold), and was maximally increased in most hippocampal regions by 8 hours of reperfusion (mean +/- SD of positive cells/field versus sham equivalent being 37.9 +/- 12.3 versus 4.0 +/- 3.3; 30.6 +/- 9.0 versus 3.1 +/- 2.3; 41.3 +/- 17.5 versus 2.9 +/- 1.9; in CA1; CA2; CA3/CA4 regions of the hippocampus, respectively). IL-1beta mRNA signal was also intensified in the white matter areas. Changes in IL-1R mRNA were seen in the hippocampus (after 2 hours CA1: 16-fold; CA2: 17-fold; DG: 24-fold increase; and CA3/CA4: 10-fold increase after 8 hours), and the expression was prolonged especially in CA1 and CA2 regions up to 24 hours of reperfusion. The major cellular source of IL-1beta protein was glia (astrocytes, oligodendrocytes, microglia, and scattered perivascular macrophages/monocytes), while neurons and sporadic microvascular endothelia showed IL-1R immunoreactivity. The data suggest that neurons in discrete areas vulnerable for selective neuronal death, and possibly the vascular endothelium, are target cells for ischemia-induced glial IL-1beta production.
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PMID:Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. 934 36


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