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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent investigations have demonstrated internucleosomal DNA fragmentation in ischemic neuronal tissue. This type of fragmentation is characteristic of programmed cell death or apoptosis and suggests that neuronal death in stroke may be more complex than simple necrotic death. The present experiments provide a detailed examination of the regional localization and time course for apoptotic DNA fragmentation in the cerebral cortex following focal cerebral ischemia. Spontaneously hypertensive rats were subjected to permanent right middle cerebral artery occlusion and the cerebral cortices were examined for evidence of DNA fragmentation using electrophoretic, flow cytometric, and histological approaches. An electrophoretic examination of cortical DNA at 24 h after the occlusion indicated that the majority of nucleosomal ladders were in the transition zone or penumbra and the core of the infarction, with no fragmentation apparent in the contralateral normal cortex. A flow cytometric analysis of DNA fragmentation in intact cells revealed a similar pattern, with increased fragmentation observed in ischemic cortex vs. the contralateral cortex. Saggital sections taken 1.5 mm lateral to midline were collected from animals at 1, 4, and 24 h after the infarction and DNA fragmentation was examined histologically by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) staining. Quantitative analysis of these sections indicated that DNA fragmentation can be observed in the anterior and central area of the infarctions as soon as 1 h after the occlusion and that the extent and magnitude of the fragmentation increases at 4 and 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1995 Aug
PMID:Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. 749 49

Loss of intracellular calcium homeostasis has been regarded an important factor underlying neuron cell death after cerebral ischemic insult. In the brain, a major mechanism for regulation of intracellular calcium is through the signal transduction pathway involving hydrolysis of poly-phosphoinositides and release of the second messenger, inositol 1,4,5-trisphosphate (IP3). IP3 mobilizes calcium by interacting with an intracellular receptor. Upon its release after agonist stimulation, this second messenger is catabolized by a 3-kinase and a 5-phosphatase. In this study, in situ hybridization was carried out to examine the mRNA expression of IP3, receptor (IP3R) and IP3 3-kinase (IP3K) in rat brain cortex after transient focal cerebral ischemia induced by temporary occlusion of the middle cerebral artery (MCA) and the common carotid arteries (CCAs). Results indicate a large decrease (52%) in IP3R mRNA levels in the ischemic cortex as compared to that in the contralateral side at 4 h after a 45 min ischemic insult. By 16 h, practically no IP3R mRNA could be detected in the ischemic cortex. On the other hand, IP3K mRNA levels remained unaltered until 16 h after reperfusion, during which time, expression in the infarct core decreased but that surrounding the core area increased instead. Hybridization of adjacent brain sections with probes for neuron specific enolase (NSE) and beta-actin indicated also a time-dependent decrease in mRNA levels after ischemia, but these changes were less dramatic as compared to IP3R. At 16 and 24 h after reperfusion, there was an increase in beta-actin mRNA in cortical areas outside the MCA cortex, suggesting of reactive gliosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1995 Sep
PMID:In situ hybridization of mRNA expression for IP3 receptor and IP3-3-kinase in rat brain after transient focal cerebral ischemia. 750 Aug 36

N-methyl-D-aspartate (NMDA) receptor antagonists have been demonstrated widely to be neuroprotective in cerebral ischemia, hypoxia, and traumatic brain injury. However, although noncompetitive NMDA antagonists have typically proven efficacious under all of these conditions, competitive antagonists have not been shown to be beneficial following moderate traumatic brain injury. The present study has used phosphorus magnetic resonance spectroscopy ([31P]MRS) to examine the effects of the competitive antagonist cis-4-(phosphonomethyl) piperidine-2-carboxylic acid (CGS-19755) and the noncompetitive antagonist dextromethorphan on biochemical outcome following fluid percussion-induced traumatic brain injury in rats. Five minutes prior to induction of moderate (2.8 +/- 0.2 atm) fluid percussion brain injury, animals received either CGS-19755 (10 mg/kg iv), dextromethorphan (10 mg/kg iv), or equal volume saline vehicle. [31P]MRS spectra were then acquired for 4 h post-trauma and intracellular pH, free magnesium concentration, cytosolic phosphorylation potential, and oxidative capacity determined. Both CGS-19755-treated animals and saline treated controls demonstrated significant and sustained declines in intracellular free magnesium concentration and bioenergetic status following trauma. In contrast, administration of dextromethorphan significantly attenuated free magnesium decline and improved bioenergetic state during the post-traumatic monitoring period. These results suggest that the neuroprotective actions of NMDA antagonists following traumatic brain injury are associated with attenuation of free magnesium decline and that such actions seem to be preferentially mediated by noncompetitive blockers.
Mol Chem Neuropathol
PMID:Efficacy of competitive vs noncompetitive blockade of the NMDA channel following traumatic brain injury. 763 18

We have previously shown that somatostatin (SS) immunoreactive (-i) neurons, located in the rat dentate hilus, are vulnerable to cerebral ischemia (Johansen et al., 1987). Within 40 h after ischemia, the cells show clear signs of cell death. At the same time, we observed that dying cells, located in the projection field of the mossy fibers (dentate hilus and CA3 mossy fiber layer), accumulate free zinc. We now demonstrate that the hilar cells, accumulating zinc after ischemia, are SS-i cells. Since it is known that hypothermia can ameliorate ischemic brain damage, we furthermore studied whether hypothermia (29 degrees C) protects the vulnerable SS-i neurons in hilus from zinc accumulation and ischemic cell death. We found that hypothermia both prevented ischemia-induced neuronal zinc accumulation and cell death. We speculate that hilar SS-i cells are highly vulnerable to ischemia, and develop rapid ischemic cell death, because they accumulate zinc shortly after ischemia.
Mol Chem Neuropathol
PMID:Hypothermia protects somatostatinergic neurons in rat dentate hilus from zinc accumulation and cell death after cerebral ischemia. 768 76

Brains from 5 mice subjected to focal ischemia (2 hours)--reperfusion (22 h), revealed a significant increase (P < 0.01) in cells exhibiting DNA fragmentation (100-200 per section)--ipsilateral hemisphere compared to 0-3 per section found in the contralateral hemisphere and normal (n = 5) and sham operated (n = 5) mice. Neurons were the predominant cells (90-95%) exhibiting DNA fragmentation, and were primarily located in the inner boundary zone to the infarct. Apoptosis may contribute to the development of infarct after transient focal cerebral ischemia.
Brain Res Mol Brain Res 1995 Jan
PMID:In situ detection of DNA fragmentation after focal cerebral ischemia in mice. 770 71

Levels of mRNAs encoding the proto-oncogene, c-fos, and the 70 kDa stress protein, hsp70, were evaluated in gerbil brain following transient cerebral ischemia of varied duration by in situ and blot hybridization techniques. Blots of total hippocampal RNA obtained after 5 min ischemic insults confirmed a characteristic, transient time course of c-fos expression with a striking elevation within 1 h and a return to control levels by 3 h recirculation. Hsp70 hybridization was significant at 1 h and continued to increase until 3-6 h after the insult. Striking accumulation of c-fos mRNA was detected within 15 min recirculation in dentate granule cells, persisting through 1 h, and a weaker signal was evident in CA1 and CA3 pyramidal neurons of hippocampus, as well as in prepiriform/entorhinal cortex and neocortical regions, during the same interval. Hsp70 hybridization showed an identical distribution at 1 h recirculation. Ischemic insults of 1 min duration resulted in no detectable increase of either mRNA, while 2 min ischemia resulted in changes comparable to those seen after 5 min insults. This common threshold corresponds to the ischemic interval required for energy depletion and resultant failure of intracellular ion homeostasis. In contrast, expression of hsp70 mRNA was not observed under conditions of brief depolarization accompanying cortical or hippocampal spreading depression that were shown to induce c-fos. A delayed component of c-fos mRNA expression was not detected in this model, while persistent hsp70 hybridization, restricted to hippocampal CA1 neurons, was evident at 48 h after either 2 min or 5 min ischemic insults. The parallels in c-fos and hsp70 mRNA expression during early recirculation suggest that overlapping mechanisms triggered following postischemic depolarization contribute to their induction after transient ischemia.
Brain Res Mol Brain Res 1994 Oct
PMID:Coexpression of c-fos and hsp70 mRNAs in gerbil brain after ischemia: induction threshold, distribution and time course evaluated by in situ hybridization. 785 54

Regional changes in the mRNA accumulations for cytoskeletal proteins alpha-tubulin and beta-actin were examined by in situ hybridization and Northern blot analysis in spontaneously hypertensive rat brains at chronic stages after 3 hours of transient ischemia. alpha-Tubulin mRNA accumulations showed no significant change at 2 weeks after transient ischemia except for a significant decrease in the frontal cortex (9.7%, p < 0.01) coinciding with ischemia induced histological changes. beta-Actin mRNA level was significantly increased in the parietal cortex (8.5%), septum (10.0%), amygdala (11.0%), CA4 area (5.8%) and the dentate gyrus (7.5%) of the hippocampus at 2 weeks after recirculation compared with a sham-operated control group (p < 0.01). The ischemic areas of hippocampal and frontocortical lesions receive afferent neurons from those regions where beta-actin mRNA was increased, suggesting that ischemia-induced increases in beta-actin mRNA may reflect actin synthesis in these neurons to compensate for lost synaptic connections. Two cytoskeletal mRNA concentrations reacted differently to cerebral ischemia, and did not parallel histological signs of ischemia either temporally or spatially.
Res Commun Mol Pathol Pharmacol 1994 Nov
PMID:Regional changes in alpha-tubulin and beta-actin mRNA accumulations after transient ischemia in spontaneously hypertensive rat brains. 788 65

The redistribution of glutamate and GABA in postischemic brains was examined immunocytochemically using the gerbil model of unilateral 1 h cerebral ischemia. In the cerebral neocortex, the majority of neurons underwent recovery processes after 5 h of recirculation, while neurons in the hippocampus were irreversibly damaged. Glutamate-like immunoreactivity (LI) was highly increased in the degenerating hippocampal CA3 pyramidal cells after recirculation, while in the neocortex and the hippocampal CA1 sector, the pyramidal cells showed only slightly increased glutamate-LI. GABA-LI-positive punctae in the neuropil, corresponding to neuronal processes of GABAergic neurons, were accentuated after recirculation both in the cerebral neocortex and the hippocampus. Although the astrocytes on the nonischemic side showed neither glutamate-LI nor GABA-LI, the swollen astrocytes and their foot processes, which were observed after recirculation, often showed strong glutamate-LI and GABA-LI. These data suggest (1) the accumulation of glutamate or glutamate-like substances, especially in the CA3 pyramidal cells, (2) the excitation of the GABAergic neurons and their subsequent uptake of GABA, and (3) the sequestration of the extracellular neurotransmitters by astrocytes in the postischemic period.
Mol Chem Neuropathol 1994 May
PMID:Redistribution of glutamate and GABA in the cerebral neocortex and hippocampus of the Mongolian gerbil after transient ischemia. An immunocytochemical study. 791 66

Many pharmacotherapies for stroke that have been successful in the laboratory have proven to be ineffective in the clinical setting, often because patients do not arrive for treatment until hours after the onset of the ischemic insult. Kappa opioid treatment of cerebral ischemia has been successful in the cat and mouse with treatment delays of up to 6 h. The purpose of the present study was to develop a model of delayed kappa opioid treatment of cerebral ischemia in the rabbit. Fourteen rabbits underwent permanent, unilateral occlusion of the internal carotid, middle cerebral, and anterior cerebral arteries via a transorbital, microsurgical approach. At 6 h postocclusion, animals received a blinded bolus injection and continuous infusion of either saline or the kappa agonist, U50488. Survival was not improved after U50488 treatment. U50488 treatment did, however, reduce areas of severe tissue damage and increase areas of modest tissue damage. This suggests U50488 arrested the progression of damage from noninfarcted to fully infarcted tissue. The present results show beneficial effects of delayed treatment with kappa agonists in a species similar in vasculature to humans, and much less costly than primates or cats.
Mol Chem Neuropathol 1994 Aug
PMID:U50488 reduces the severity of tissue damage in a rabbit model of focal cerebral ischemia. 799 29

To study the roles of bFGF and its receptor in the process of neuronal cell death and the wound repair response, we induced 10 min of transient global cerebral ischemia in rats and measured changes in expression of both bFGF and the FGF receptor, flg. CA1 pyramidal cells are selectively vulnerable to ischemia and die one to 3 days after 10 min of ischemia. In these cells, bFGF mRNA was induced by 6 hours, reached a maximal level by 24 h after ischemia, and subsequently decreased. Message for the FGF receptor, flg, was present in the pyramidal cells layer, and vanished almost completely in parallel with neuronal death. In the granule cell layer of dentate gyrus, the expression of bFGF mRNA increased more rapidly. It was maximal by 6 h and returned to the basal level by 3 days. In the hilus of the dentate gyrus, bFGF expression was maximal at 24 h and returned to control levels by 3 days. Despite the rapid changes in expression of bFGF mRNA, there was no significant change of bFGF immunoreactivity in either the CA1 pyramidal cell layer or in the granule cell layer of dentate gyrus within 3 days after ischemia. The apparent failure of the message to be efficiently translated supports the idea that translation is impaired under conditions where ischemia leads to delayed neuronal cell death. Expression of bFGF mRNA, FGFR mRNA and bFGF immunoreactivity increased dramatically in a broad area of CA1 subfield from 7 days until 30 days after ischemia because of increased expression by reactive glial cells. We suggest that these rapid and complex changes in the expression of bFGF mRNA and bFGF protein may be part of a coordinated response to ischemic injury that is designed to minimize the severity of neuron death.
Brain Res Mol Brain Res 1994 Mar
PMID:Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor. 801 96


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