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

Changes in astrocyte glutamine synthetase (GS) in postischemic rat brain were evaluated and correlated with regional neuronal vulnerability or resistance to ischemia. Rats subjected to 20 or 30 min of cerebral ischemia were allowed to survive for 3 or 24 h after ischemia; normal animals served as controls. Resultant neuronal necrosis was severe in the striatum by 24 h and in the CA1 region of the hippocampus at 72 h; neurons in paramedian cortex and CA3 region of the hippocampus were not permanently damaged. Glutamine synthetase (GS) immunocytochemistry was performed on vibratome sections of paraformaldehyde-fixed brains and enzyme activity was assayed in frozen samples of cerebral cortex, striatum and hippocampus. At 3 and 24 h after ischemia, GS immunoreactivity increased and was secondary to enlargement of GS-positive cell bodies and processes as well as to increased numbers of GS-positive astrocytes. Enzyme activity also increased in cortex, striatum and hippocampus at 3 and 24 h (P less than or equal to 0.03). This study shows that increase in astrocyte GS occurs rapidly after ischemia, and prior studies indicate that this increase occurs in parallel with proliferative changes in astrocyte organelles. The results also suggest that astrocyte metabolism of glutamate increases after ischemia. The increased capacity for glutamine synthetase may be important in normalizing extracellular glutamate following ischemia and protecting brain from the neurotoxic effects of this excitatory amino acid.
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PMID:Brain glutamine synthetase increases following cerebral ischemia in the rat. 134 43

An immunohistochemical method was used to study the distribution and changes with time of the astrocytic reaction in the gerbil hippocampus following transient ischemia. Three markers were investigated with specific antibodies to glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and S-100 protein. On Day 2 after ischemia, and more prominently on Day 3, reactive astrocytes were intensely stained for GFAP in the hippocampal formation, especially in the CA1 region and dentate gyrus. This response by astrocytes preceded CA1 pyramidal cell degeneration, which became apparent on Day 5. On Day 5, immunoreactive cells were not stained as intensely as on Day 3, but cells in the CA1 region and dentate gyrus were still more intensely stained than those in normal animals. GS and S-100 showed similar changes in distribution after ischemia, although the change in GS was less prominent: the hilus of the dentate gyrus was most intensely stained. Both immunoreactivities seemed to increase rather transiently on Day 2 or 3 and to decrease to the initial level on Day 5. The fact that reactive astrocytes appeared in CA1 before the onset of visible neural degeneration indicates that signals from indisposed neurons may be transmitted to astrocytes for their quick functioning. It is also suggested that degenerative changes occur in the dentate gyrus and may be involved in the delayed neural death of CA1 pyramidal cells. These observations indicate that astrocytes play a role in the neural degeneration induced by ischemia and that several types of astrocytes seem to react differently.
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PMID:Reaction of astrocytes in the gerbil hippocampus following transient ischemia: immunohistochemical observations with antibodies against glial fibrillary acidic protein, glutamine synthetase, and S-100 protein. 135 Feb 52

The concentration of glutamate as well as the hydroxylation of salicylate, as an index of hydroxyl free radical formation, has been determined in the abdominal aorta and heart of gerbils undergoing an ischemia/reperfusion insult (IRI) and compared to control sham-operated gerbils. The amount of glutamate and hydroxylated salicylate (dihydroxybenzoic acid, DHBA) was significantly increased in both the aorta and heart of IRI-treated gerbils as compared to the aorta and in the heart of sham-operated gerbils. Vitamin E (90 mg/kg at 24 and 1 h prior to an IRI) pretreatment prevented the increase of both glutamate and DHBA in both the aorta and heart of IRI-lesioned gerbils. The results suggest that increases in glutamate, perhaps due to the decreased activities of glutamine synthetase, are correlated with increased oxygen free radical formation during an ischemia/reperfusion insult to the heart.
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PMID:Glutamate accumulation and increased hydroxyl free radical formation in the abdominal aorta and heart of gerbil after ischemia/reperfusion insult. 135 62

Iron mediates damage to proteins and DNA. The mechanisms of damage not only involve iron but also oxygen free radical intermediates. Oxidative damage to DNA causes not only strand breaks, but also formation of specific base adducts, such as 8-hydroxy-2'-deoxyguanosine. Oxidative damage also inactivates certain enzymes such as glutamine synthetase. Novel methods of assessing oxidative damage to tissue, including quantitation of salicylate hydroxylation as an index of hydroxyl free radical flux as well as specific lesions to proteins and DNA, have yielded results that clearly show that ischemia/reperfusion injury to mongolian gerbil brain involves oxidatively damaging events. Aging in gerbil as well as human brain is also associated with increased oxidative damage. Recent novel observations have shown that the spin-trapping agent phenyl alpha-tert-butylnitrone (PBN) offers protection in gerbil brain during ischemia/reperfusion injury. We also show that oxidative damage to brain during aging is decreased by chronic administration of PBN. The mechanism of action of PBN may be related to its trapping of specific free radicals, which triggers a cascade of oxidative events that eventually lead to tissue injury.
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PMID:Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. 151 Mar 77

Oxygen free radicals and oxidative events have been implicated as playing a role in bringing about the changes in cellular function that occur during aging. Brain readily undergoes oxidative damage, so it is important to determine if aging-induced changes in brain may be associated with oxidative events. Previously we demonstrated that brain damage caused by an ischemia/reperfusion insult involved oxidative events. In addition, pretreatment with the spin-trapping compound N-tert-butyl-alpha-phenylnitrone (PBN) diminished the increase in oxidized protein and the loss of glutamine synthetase (GS) activity that accompanied ischemia/reperfusion injury in brain. We report here that aged gerbils had a significantly higher level of oxidized protein as assessed by carbonyl residues and decreased GS and neutral protease activities as compared to young adult gerbils. We also found that chronic treatment with the spin-trapping compound PBN caused a decrease in the level of oxidized protein and an increase in both GS and neutral protease activity in aged Mongolian gerbil brain. In contrast to aged gerbils, PBN treatment of young adult gerbils had no significant effect on brain oxidized protein content or GS activity. Male gerbils, young adults (3 months of age) and retired breeders (15-18 months of age), were treated with PBN for 14 days with twice daily dosages of 32 mg/kg. If PBN administration was ceased after 2 weeks, the significantly decreased level of oxidized protein and increased GS and neutral protease activities in old gerbils changed in a monotonic fashion back to the levels observed in aged gerbils prior to PBN administration. We also report that old gerbils make more errors than young animals and that older gerbils treated with PBN made fewer errors in a radial arm maze test for temporal and spatial memory than the untreated aged controls. These data can be interpreted to indicate that oxidation of cellular proteins may be a critical determinant of brain function. Moreover, it also implies that there is an age-related increase in vulnerability of tissue to oxidation that can be modified by free radical trapping compounds.
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PMID:Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. 167 89

At present in vivo NMR spectroscopic studies of brain glutamate and glutamine concentrations relative to encephalopathy have mainly been performed in hepatic encephalopathy (HE). In vivo proton NMR studies were performed in rats with hyperammonemia and acute HE due to acute liver ischemia as well as in rats with hyperammonemia due to either repeated urease i.p. injection or i.p. administration of methionine sulfoximine, a well known inhibitor of glutamine synthetase. In man, in vivo proton NMR is described in patients with chronic liver disease: cirrhosis of different etiology and associated with different degrees of HE. In the experimental models proton NMR spectroscopy of the cerebral cortex revealed an increase in glutamine concentration, a decrease in glutamate concentration and a decrease in phosphocholine compounds. In humans no clear distinction between cerebral cortex glutamate and glutamine concentration could be made by in vivo 1H NMR spectroscopy. However, the combined glutamate/glutamine peak increased in a way compatible with an increased cerebral cortex glutamine concentration during chronic HE. In the cirrhotic patients too a decrease in cerebral cortex phosphocholine compounds was observed, the explanation of which is unclear. Both the experimental work and the clinical observations support the hypothesis that impairment of the glutamate/glutamine cycle between astrocytes and neurons plays a role in the pathogenesis of hepatic encephalopathy.
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PMID:What the clinician can learn from MR glutamine/glutamate assays. 167 85

Brain is extremely susceptible to oxidative damage. Utilizing a series of novel approaches, we have demonstrated that oxidative damage occurs during an ischemia/reperfusion insult (IRI) to brain. Thus, we have demonstrated that an IRI to Mongolian gerbil brain results in: (1) an enhanced rate of salicylate hydroxylation, implicating an increased flux of hydroxyl free radicals; (2) an enhanced flux of free radicals as determined by spin-trapping; (3) an enhanced level of endogenous protein oxidation; (4) a decrease in glutamine synthetase (GS) activity, an enzyme very sensitive to oxidative damage; and (5) demonstration of protection from an IRI by administering the spin-trapping agent alpha-phenyl-tert-butyl nitrone (PBN). The novel observation that PBN offers protection from the lethality brought on by a brain IRI appears to be clearly linked to the ability of the administered spin-trap to inhibit oxidative damage as evidenced by the decreased amount of brain protein oxidation and the prevention of an IRI-mediated loss of GS activity in treated animals. Aged gerbils are more sensitive to the lethal action of a brain IRI than younger animals, but they are protected by PBN administration as are the younger animals. Older gerbils have a significantly higher level of oxidized protein in the brain. Older gerbils have decreased activities of GS and neutral protease, the enzyme that removes oxidized protein, than younger animals. Chronic twice daily administration of PBN (32 mg/kg) for 14 days to older animals significantly lowered brain oxidized protein levels and raised GS and neutral protease activity to those observed in younger animals. Cessation of PBN administration resulted in a time-dependent restoration of protein oxidation levels and enzyme activities back to those observed prior to spin-trap administration. Older gerbils exhibit significantly higher errors in a radial arm maze than younger animals, but older gerbils that had received chronic daily treatments of PBN (32 mg/kg) for 14 days committed significantly less errors than untreated controls. The errors committed in PBN-treated animals was decreased down to the level of those observed in younger animals. Clearly the spin-trapping agent, PBN, appears to have promise in: (1) elucidation of the role of oxidative damage in normal brain function during aging, (2) understanding the development of pathological conditions, and (3) development of treatment regimens for prevention of damage that occurs during the development of pathological conditions and in aging.
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PMID:Protection against oxidative damage to CNS by alpha-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: a novel series of nonlipid free radical scavengers. 167 44

Free radical-mediated oxidative damage has been implicated in tissue injury resulting from ischemia/reperfusion events. Global cortical ischemia/reperfusion injury to Mongolian gerbil brains was produced by transient occlusion of both common carotid arteries. Protein oxidation, as measured by protein carbonyl content, increased significantly during the reperfusion phase that followed 10 min of ischemia. The activity of glutamine synthetase, an enzyme known to be inactivated by metal-catalyzed oxidation reactions, decreased to 65% of control levels after 2 hr of reperfusion that followed 10 min of ischemia. We also report that the free radical spin trap N-tert-butyl-alpha-phenylnitrone [300 mg/kg (body weight)] administered 60 min before ischemia/reperfusion is initiated, partially prevents protein oxidation and protects from loss of glutamine synthetase activity. In addition, we report a N-tert-butyl-alpha-phenylnitrone-dependent nitroxide radical obtained in the lipid fraction of the ischemia/reperfusion-lesioned brains, but there was very little radical present in the comparable sham-operated control brains. These data strengthen the previous observation utilizing in vivo-trapping methods, that free radical flux is increased during the reperfusion phase of the ischemia-lesioned gerbil brain. The loss of glutamine synthetase would be expected to increase the levels of brain L-glutamate. Thus, the oxidative inactivation of glutamine synthetase may be a critical factor in the neurotoxicity produced after cerebral ischemia/reperfusion injury.
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PMID:Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. 197 1

Astrocytes are important in regulating the microenvironment of neurons both by catabolic and synthetic pathways. The glutamine synthetase (GS) activity observed in astrocytes affects neurons by removing toxic substances, NH3 and glutamate; and by providing an important neuronal substrate, glutamine. This glutamate cycle might play a critical role during periods of hypoxia and ischemia, when an increase in extracellular excitatory amino acids is observed. It was previously shown in our laboratory that fructose-1,6-bisphosphate (FBP) protected cortical astrocyte cultures from hypoxic insult and reduced ATP loss following a prolonged (18-30 hrs) hypoxia. In the present study we established the effects of FBP on the level of glutamate uptake and GS activity under normoxic and hypoxic conditions. Under normoxic conditions, [U-14C]glutamate uptake and glutamine production were independent of FBP treatment; whereas under hypoxic conditions, the initial increase in glutamate uptake and an overall increase in glutamine production in astrocytes were FBP-dependent. Glutamine synthetase activity was dependent on FBP added during the 22 hours of either normoxic- or hypoxic-treatment, hence significant increases in activity were observed due to FBP regardless of the oxygen/ATP levels in situ. These studies suggest that activation of GS by FBP may provide astrocytic protection against hypoxic injury.
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PMID:Effect of fructose-1,6-bisphosphate on glutamate uptake and glutamine synthetase activity in hypoxic astrocyte cultures. 791 Mar 81

Recent results suggest that even relatively brief periods of ischemia in gerbils (10 min) lead to oxidative damage to brain proteins, reflected in an increased carbonyl content in the soluble protein fraction and a decreased glutamine synthetase (GS) activity. Since we failed to reproduce these findings in rats subjected to 15 min of transient ischemia, we explored whether oxidative damage to proteins could be observed after longer ischemic periods. To that end, one middle cerebral artery was occluded in rats for either 1 or 3 h, with recirculation periods of 0 min, 15 min, 1 h, and 6 h. Protein carbonyl content and GS activity were determined in focal and perifocal tissues and compared with values obtained in the same areas on the contralateral side. Ischemia, particularly of 3-h duration, followed by various reperfusion periods was accompanied by a significant (16-35%) decrease in the concentration of proteins of the soluble protein fraction. However, in no group was there an increased carbonyl content of the remaining proteins in this fraction. When expressed per milligram of protein, GS activity remained unchanged or rose somewhat. An inconsistent (and moderate) decrease in GS activity was present only if GS activity was expressed per milligram of wet tissue. The present findings, which fail to document oxidative damage to proteins following focal ischemia of 1- or 3-h duration, are thus radically different from those obtained in gerbils. The results suggest that appreciable species differences exist and raise the question of whether free radical-mediated oxidation of proteins is an invariable component of ischemic brain damage.
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PMID:Does ischemia with reperfusion lead to oxidative damage to proteins in the brain? 809 49


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