| 1. |
- Deshpande, J. K., et al.
(författare)
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Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia
- 1987
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 7:1, s. 89-95
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to correlate calcium accumulation with the development of neuronal necrosis following transient ischemia. After 10 min of forebrain ischemia in the rat—a period that leads to reproducible damage of CA1 pyramidal cells—determination of calcium concentration and evaluation of morphological signs of cell body necrosis in the dorsal hippocampus were performed at various recirculation times. Tissue calcium concentration was not different from control at the end of ischemic period and did not change after 3, 6, 12, or 24 h of recirculation. However, after 48 h, calcium content increased significantly, with a further increase being seen after 72 h. At early recovery periods, only scattered necrotic neurons were observed. after 48 h, only 2 of 12 hemispheres showed more than 25 necrotic cells per section. More conspicuous neuronal death was observed after 72 h. The results thus demonstrate that net accumulation of calcium in regio superior of the hippocampus precedes marked necrosis of CA1 pyramidal cells. The results suggest that one primary event in the delayed death of these cells is membrane dysfunction with increased calcium cycling.
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| 2. |
- Agardh, Carl-David, et al.
(författare)
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The influence of hypothermia on hypoglycemia-induced brain damage in the rat
- 1992
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Ingår i: Acta Neuropathologica. - 1432-0533. ; 83:4, s. 379-385
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Tidskriftsartikel (refereegranskat)abstract
- The effects of hypothermia on hypoglycemic brain damage were studied in rats after a 30-min period of hypoglycemic coma, defined as cessation of spontaneous EEG activity. The rats were either normothermic (37 degrees C) or moderately hypothermic (33 degrees C). Morphological brain damage was evaluated after various periods of recovery. Hypothermic animals with halothane anesthesia never resumed spontaneous respiration, thus requiring artificial ventilation during recovery (maximally 8 h). In contrast, when isoflurane was used as the anesthetic agent, all animals survived and were examined after 1 week of recovery. There was a tendency towards gradually higher arterial plasma glucose levels during hypoglycemia with lower body temperature. The time period from insulin injection until isoelectric EEG appeared was gradually prolonged by hypothermia, and was shorter when isoflurane was used for anesthesia. Brain damage was examined within the neocortex, caudoputamen and hippocampus (CA1, subiculum and the tip of the dentate gyrus). Damage to neurons was found to be of two types, namely condensed dark purple neurons (pre-acidophilic) and shrunken bright red-staining neurons (acidophilic). In the neocortex, no clear influence of temperature on the degree of injury was seen. In the caudoputamen, the number of injured neurons clearly decreased at lower temperature (33 degrees C, P less than 0.001) when halothane was used, while no such difference was seen when isoflurane was used as the anesthetic agent. Likewise, a protective effect of hypothermia was seen in subiculum (P less than 0.01) when halothane, but not isoflurane was used.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 3. |
- Cardell, M., et al.
(författare)
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Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia
- 1991
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 11:1, s. 122-128
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Tidskriftsartikel (refereegranskat)abstract
- The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 7.1 ± 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes after glucose-induced recovery, the PDHC activity had decreased by 33% compared to control levels, and remained significantly depressed after 3 h of recovery. This decrease in activity was not due to a decrease in the total PDHC activity. At 24 h of recovery, PDHC activity had returned to control levels. We conclude that the activation of PDHC during hypoglycemic coma is probably the result of an increased PDH phosphatase activity following depolarization and calcium influx, and allosteric inhibition of PDH kinase due to increased ADP/ATP ratio. The depression of PDHC activity following hypoglycemic coma is probably due to an increased phosphorylation of the enzyme, as a consequence of an imbalance between PDH phosphatase and kinase activities. Since some reduction of the ATP/ADP ratio persisted and since the lactate pyruvate ratio had normalized by 3 h of recovery, the depression of PDHC most likely reflects a decrease in PDH phosphatase activity, probably due to a decrease in intramitochondrial Ca2+.
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| 4. |
- Harris, R. J., et al.
(författare)
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Cerebral extracellular calcium activity in severe hypoglycemia : Relation to extracellular potassium and energy state
- 1984
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 4:2, s. 187-193
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Tidskriftsartikel (refereegranskat)abstract
- The changes in extracellular Ca2+ (Cae) and K+ (Ke) activities were studied in the rat brain during insulin-induced hypoglycemia. At about the time of onset of isoelectric EEG in severe insulin-induced hypoglycemia (300-g male Wistar rats under 70% N2O anaesthesia), there was an increase in Ke which, at ∼13 mM, was associated with a fall in Cae. Ke peaked at 48 ± 12 mM, and Cae at 0.18 ± 0.28 mM. This ion change began to normalise, but before recovery was complete a second ion change, of magnitude similar to that of the first, occurred from which the cells did not recover. The Cae recovered to only 66% of normal in the time available before the second depolarisation. Measurements on brains frozen at different stages during the sequence of ion changes revealed that ATP and phosphocreatine (PCr) concentrations and energy charge (EC) were not reduced before the first depolarisation. During the first depolarisation there was a 72% decrease in PCr and a 37% fall in ATP level, leading to a 23% drop in EC. These levels decreased further by the 10th minute of isoelectricity, but only the fall in ATP concentration was significant. The results indicate that the first ion change was a spreading depression and that cellular energy state was not the only factor in determining the response of tissue in the early stages of the comatose state.The changes in extracellular Ca2+ (Cae) and K+ (Ke) activities were studied in the rat brain during insulin-induced hypoglycemia. At about the time of onset of isoelectric EEG in severe insulin-induced hypoglycemia (300-g male Wistar rats under 70% N2O anaesthesia), there was an increase in Ke which, at ∼13 mM, was associated with a fall in Cae. Ke peaked at 48 ± 12 mM, and Cae at 0.18 ± 0.28 mM. This ion change began to normalise, but before recovery was complete a second ion change, of magnitude similar to that of the first, occurred from which the cells did not recover. The Cae recovered to only 66% of normal in the time available before the second depolarisation. Measurements on brains frozen at different stages during the sequence of ion changes revealed that ATP and phosphocreatine (PCr) concentrations and energy charge (EC) were not reduced before the first depolarisation. During the first depolarisation there was a 72% decrease in PCr and a 37% fall in ATP level, leading to a 23% drop in EC. These levels decreased further by the 10th minute of isoelectricity, but only the fall in ATP concentration was significant. The results indicate that the first ion change was a spreading depression and that cellular energy state was not the only factor in determining the response of tissue in the early stages of the comatose state.The changes in extracellular Ca2+ (Cae) and K+ (Ke) activities were studied in the rat brain during insulin-induced hypoglycemia. At about the time of onset of isoelectric EEG in severe insulin-induced hypoglycemia (300-g male Wistar rats under 70% N2O anaesthesia), there was an increase in Ke which, at ∼13 mM, was associated with a fall in Cae. Ke peaked at 48 ± 12 mM, and Cae at 0.18 ± 0.28 mM. This ion change began to normalise, but before recovery was complete a second ion change, of magnitude similar to that of the first, occurred from which the cells did not recover. The Cae recovered to only 66% of normal in the time available before the second depolarisation. Measurements on brains frozen at different stages during the sequence of ion changes revealed that ATP and phosphocreatine (PCr) concentrations and energy charge (EC) were not reduced before the first depolarisation. During the first depolarisation there was a 72% decrease in PCr and a 37% fall in ATP level, leading to a 23% drop in EC. These levels decreased further by the 10th minute of isoelectricity, but only the fall in ATP concentration was significant. The results indicate that the first ion change was a spreading depression and that cellular energy state was not the only factor in determining the response of tissue in the early stages of the comatose state.
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| 5. |
- Koide, T., et al.
(författare)
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Chronic dexamethasone pretreatment aggravates ischemic neuronal necrosis
- 1986
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 6:4, s. 395-404
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Tidskriftsartikel (refereegranskat)abstract
- This study addresses the question of whether the cyclooxygenase inhibitors indomethacin and diclofenac and the glucocorticosteroid dexamethasone ameliorate neuronal necrosis following cerebral ischemia. In addition, since these drugs inhibit the production of prostaglandins and depress phospholipase A2 activity, respectively, the importance of free fatty acids (FFAs) on the development of ischemic neuronal damage was assessed. Neuronal damage was determined in the rat brain at 1 week following 10 min of forebrain ischemia. The cyclooxygenase inhibitors, whether given before or after ischemia, failed to alter the brain damage incurred. Animals given dexamethasone were divided into three groups and the drug was administered at a constant dosage of 2 mg/kg: (a) 2 days, 1 day, and 3 h intraperitoneally before (chronic pretreatment), (b) 3 h intraperitoneally before (acute pretreatment), and (c) 5 min intravenously and 6 h and 1 day intraperitoneally after (chronic posttreatment) induction of ischemia. Acute pretreatment did not affect the histopathological outcome. Chronic posttreatment of animals with dexamethasone ameliorated the damage inflicted on the caudate nucleus, but had no effect on other brain areas investigated. Unexpectedly, the chronic pretreatment aggravated the brain damage and caused seizures following ischemia. Histopathological data showed massive neuronal damage in these brains. The accumulation of FFA levels during ischemia was markedly suppressed, and the decrease in the energy charge was curtailed by chronic pretreatment with dexamethasone. However, brain glucose levels in control animals and lactic acid concentrations following 10 min of ischemia were significantly higher both in the cerebral cortex and in the hippocampus of dexamethasone-treated animals. These results suggest that aggravation of neuronal necrosis by chronic dexamethasone pretreatment could be ascribed to lactic acidosis due to hyperglycemia in combination with an action of dexamethasone on glucocorticoid receptors in the brain.
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| 6. |
- Koide, T., et al.
(författare)
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Circulating catecholamines modulate ischemic brain damage
- 1986
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 6:5, s. 559-565
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Tidskriftsartikel (refereegranskat)abstract
- In search of factors influencing the outcome of an ischemic insult, we induced 10 min of forebrain ischemia in rats and assessed neuronal necrosis by quantitative histopathology after 1 week of recovery. Procedures for inducing ischemia included bilateral carotid artery clamping and reduction of blood pressure to 40–50 mm Hg by bleeding. To facilitate rapid lowering of blood pressure, a ganglionic blocker, trimethaphan (TMP), was administered at the onset of ischemia. Omission of the ganglionic blocker proved to markedly ameliorate neuronal damage. Similarly favorable effects were obtained when a mixture of adrenaline and noradrenaline (1 μg kg−1 min−1 each) was infused during the early recirculation period in animals previously given TMP. Infusion of noradrenaline alone also ameliorated the damage, though the efficacy was somewhat less. The results suggest that catecholamines, released as a response to stress, ameliorate ischemic brain damage.
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| 7. |
- Kokaia, Zaal, et al.
(författare)
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Regional brain-derived neurotrophic factor mRNA and protein levels following transient forebrain ischemia in the rat
- 1996
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Ingår i: Brain Research. Molecular Brain Research. - 0169-328X. ; 38:1, s. 139-144
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Tidskriftsartikel (refereegranskat)abstract
- Levels of BDNF mRNA and protein were measured in the rat brain using in situ hybridization and a two-site enzyme immunoassay. Under basal conditions, the highest BDNF concentration was found in the dentate gyrus (88 ng/g), while the levels in CA3 (50 ng/g), CA1 (18 ng/g) and parietal cortex (8 ng/g) were markedly lower. Following 10 min of forebrain ischemia, BDNF protein increased transiently in the dentate gyrus (to 124% of control at 6 h after the insult) and CA3 region (to 131% of control, at 1 week after the insult). In CA1 and parietal cortex, BDNF protein decreased to 73-75% of control at 24 h. In contrast, BDNF mRNA expression in dentate granule cells and CA3 pyramidal layer was transiently elevated to 287 and 293% of control, respectively, at 2 h, whereas no change was detected in CA1 or neocortex. The regional BDNF protein levels shown here correlate at least partly with regional differences in cellular resistance to ischemic damage, which is consistent with the hypothesis of a neuroprotective role of BDNF.
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| 8. |
- Lundgren, J., et al.
(författare)
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Preischemic hyperglycemia and postischemic alteration of rat brain pyruvate dehydrogenase activity
- 1990
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 10:4, s. 536-541
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Tidskriftsartikel (refereegranskat)abstract
- Transient cerebral ischemia in normoglycemic animals is followed by a decrease in glucose utilization, reflecting a postischemic cerebral metabolic depression and a reduction in the activity of the pyruvate dehydrogenase complex (PDHC). Preischemic hyperglycemia, which aggravates ischemic brain damage and invariably causes seizure, is known to further reduce cerebral metabolic rate. To investigate whether these effects are accompanied by changes in PDHC activity, the postischemic cerebral cortical activity of this enzyme was investigated in rats with preischemic hyperglycemia (plasma glucose 20-25 mM). The results were compared with those obtained in normoglycemic animals (plasma glucose 5-10 mM). The activated portion of PDHC and total PDHC activity were measured in neocortical samples as the rate of decarboxylation of [14C]pyruvate in crude brain mitochondrial homogenates after 5 min, 15 min, 1 h, 6 h, and 18 h of recirculation following 15 min of incomplete cerebral ischemia. In normoglycemic animals the fraction of activated PDHC, which rises abruptly during ischemia, was reduced to 19-25% during recirculation compared with 30% in sham-operated controls. In hyperglycemic rats the fraction of activated PDHC was higher during the first 15 min of recirculation. However, after 1 and 6 h of recirculation, the fraction was reduced to values similar to those measured in normoglycemic animals. Fifteen of 26 rats experienced early (1-4 h post ischemia) seizures in the recovery period. The PDHC activity appeared unchanged prior to these early postischemic seizures. We conclude that the accentuated depression of postischemic metabolic rate observed in hyperglycemic animals is not coupled to a corresponding postischemic depression of PDHC. The relative increase in the fraction of activated PDHC in the early recovery phase in hyperglycemic animals probably reflects either increased intramitochondrial calcium levels or persistent increases in the NADH/NAD and/or ADP/ATP ratios.
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| 9. |
- Siesjo, B. K., et al.
(författare)
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Influence of acidosis on lipid peroxidation in brain tissues in vitro
- 1985
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 5:2, s. 253-258
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Tidskriftsartikel (refereegranskat)abstract
- To study the influence of acidosis on free radical formation and lipid peroxidation in brain tissues, homogenates fortified with ferrous ions and, in some experiments, with ascorbic acid were equilibrated with 5–15% O2 at pH values of 7.0, 6.5, 6.0, and 5.0, with subsequent measurements of thiobarbituric acid-reactive (TBAR) material, as well as of water- and lipid-soluble antioxidants (glutathione, ascorbate, and α-tocopherol) and phospholipid-bound fatty acids (FAs). Moderate to marked acidosis (pH 6.5–6.0) was found to grossly exaggerate the formation of TBAR material and the decrease in α-tocopherol content and to enhance degradation of phospholipid-bound, polyenoic FAs. These effects were reversed at pH 5.0, suggesting a pH optimum at pH 6.0–6.5. It is concluded that acidosis of a degree encountered in ischemic brain tissues has the potential of triggering increased free radical formation. This effect may involve increased formation of the protonated form of superoxide radicals, which is strongly prooxidant and lipid soluble, and/or the decompartmentalization of iron bound to cellular macromolecules like ferritin.
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| 10. |
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