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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dramatic increase in the arachidonic acid (AA) level in the brain is a well-known molecular event during cerebral ischemia. As mitochondria are known to be one possible site of the cell damage, the effects of AA on the respiratory activity of rat brain mitochondria were investigated in vitro using an oxygen electrode. In NAD-linked respiration, respiratory control ratio was decreased significantly by AA, with an IC50 of 6.0 microM. AA had the dual effect on mitochondrial respiration, a decrease in state 3 and uncoupled state and an increase in state 4 (i.e., uncoupling) as reported by Hillered and Chan (J. Neurosci. Res. 19, 94-100, 1988). Furthermore, we found that other unsaturated long-chain free fatty acids (C18:1-C18:3, C20:1-C20:5) also showed such a dual effect. Cyclooxygenase metabolites of AA such as prostaglandins (D2, E2, F2 alpha, E1) and thromboxane B2, and lipoxygenase metabolites such as leukotrienes (D4, B4) and 5- or 12-hydroperoxyeicosatetraenoic acid had no significant effect. The inhibition of the uncoupled state by AA was more marked in NAD-linked than that in FAD-linked respiration, while the degree of uncoupling by AA were the same in both respirations. In spectrophotometrical measurement, the reduction of cytochromes and flavo-protein was markedly inhibited by AA in NAD-linked respiration, but not in the FAD-linked one. In addition, the activity of cytochrome c oxidase was scarcely inhibited by AA. These data suggest that AA itself, not its metabolites, may inhibit mitochondrial ATP production during brain ischemia and that AA may act on the site(s) closely related to NAD-linked respiration, but not the FAD-linked one, in addition to its uncoupling effect.
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PMID:A possible mechanism of mitochondrial dysfunction during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid. 165 47

Mitochondrial pyruvate-supported respiration was studied in vitro under conditions known to exist following ischemia, i.e., elevated extramitochondrial Ca2+, Na+, and peroxide. Ca2+ alone (7-10 nmol/mg) decreased state 3 and increased state 4 respiration to 81 and 141% of control values, respectively. Sodium (15 mM) and/or tert-butyl hydroperoxide (tBOOH; up to 2,000 nmol/mg protein) alone had no effect on respiration; however, Na+ or tBOOH in combination with Ca2+ dramatically altered respiration. Respiratory inhibition induced by Ca2+ and tBOOH does not involve pyruvate dehydrogenase (PDH) inhibition since PDH flux increased linearly with tBOOH concentration (R = 0.96). Calcium potentiated tBOOH-induced mitochondrial NAD(P)H oxidation and shifted the redox state of cytochrome b from 67 to 47% reduced. Calcium (5.5 nmol/mg) plus Na+ (15 mM) decreased state 3 and increased state 4 respiratory rates to 55 and 202% of control values, respectively. Sodium- as well as tBOOH-induced state 3 inhibition required mitochondrial Ca2+ uptake because ruthenium red addition before Ca2+ addition negated the effect. The increase in state 4 respiration involved Ca2+ cycling since ruthenium red immediately returned state 4 rates back to control values. The mechanisms for the observed Ca2(+)-, Na(+)-, and tBOOH-induced alterations in pyruvate-supported respiration in vitro are discussed and a multifactorial etiology for mitochondrial respiratory dysfunction following cerebral ischemia in vivo is proposed.
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PMID:Effect of peroxide, sodium, and calcium on brain mitochondrial respiration in vitro: potential role in cerebral ischemia and reperfusion. 231 94

The peculiarities of brain energy metabolism were studied in male rats before and during cerebral ischemia of various severity elicited by bilateral common carotid arteries ligation. A multidimensional analysis was applied. In the rats which died after the ischemia, the NAD + NADH+/phosphocreatine (PCr) ratio and ATP content before ligation were higher than those in the surviving group. Also the strength of relationships between parameters of NMR spectra in each correlation matrix were 10 times higher and the variability of elements in each matrix was significantly lower in victims than those in the surviving group. The development of severe ischemia and the animals death were accompanied by an increase in the inorganic phosphate content, decrease in pH and stepwise disappearing of PCr and ATP. In animals surviving the same brain ischemia model, the changes in 31P spectra parameters pointed to some increase in the ratio of NAD + NADH+ only to ATP + ADP but not to PCr, and to an increase in summarized strength of correlation between 31P spectra parameters with the variability of elements decreased within each correlation matrix. Detection of these changes can be helpful in the diagnosis of mild ischemia without neurological deficit which already needs preventive therapy against more severe ischemia.
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PMID:[Changes in energy metabolism in the brain in experimental cerebral ischemia of different degree of severity (nuclear magnetic resonance-spectroscopic study)]. 260 23

The effect of the ganglioside GM1 was studied in a focal cerebral ischemia model in 30 cats consisting of 2 hours of middle cerebral artery occlusion followed by 4 hours of recirculation. The cerebrocortical electrical activity, extracellular potassium activity, and microcirculation indicated by NAD/NADH fluorescence were measured during occlusion as well as during recirculation in the core of the middle cerebral artery territory, while the cerebral metabolic rate for glucose (ICMRgl) was measured at the end of recirculation. The cats were classified into either mildly or moderately severe stroke groups based on the depression of the cerebrocortical electrical activity on the occluded side. Of 12 cats with only a mild stroke, six were administered GM1 intravenously 30 minutes after occlusion, while six cats were not treated. Of 12 cats with a moderate stroke, six were treated and six were left untreated. In six additional cats, only a sham insult was undertaken. In the cats with mild stroke, GM1 treatment significantly increased lCMRgl in the peripheral middle cerebral artery territory compared with the untreated cats; for the six treated cats, lCMRgl was normalized toward the control level, whereas it was depressed in the six untreated cats. There were no other significant effects of GM1 treatment on the other measured parameters. A potential protective effect of anesthesia is discussed.
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PMID:Effect of GM1 ganglioside after focal cerebral ischemia in halothane-anesthetized cats. 272 48

To verify the lipid peroxidation in the focal cerebral ischemia, the levels of alpha-tocopherol, ubiquinone and ascorbate were measured in the ischemic center in rats. The former two were endogeneous lipid soluble antioxidants and the last was a water soluble antioxidant. alpha-Tocopherol, reduced ubiquinone-9 and -10, and reduced ascorbate decreased to 79%, 73%, 66%, and 76% 0.5 hour after ischemia, respectively. alpha-Tocopherol decreased to 63% 6 hours after ischemia, and then reached a plateau, while reduced ubiquinones and reduced ascorbate declined further to 16% and 10% 12 hours after ischemia, respectively, and then reached plateau levels. These results suggest their functional and durational differences as antioxidants against lipid peroxidation in this ischemic model. Although the reciprocal increase in oxidized ubiquinones during ischemia was not observed, that in oxidized ascorbate was noted. The complementary antioxidant system between cytoplasmic and membranous components, the combination alpha-tocopherol/ascorbate, was estimated from the calculated consumption ratio of these antioxidants, assuming that the loss of these reduced antioxidants is due to neutralization of free radicals. This system was suggested to play an important role in an early ischemic period. Urate also markedly increased during ischemia. Therefore, xanthine oxidase activity was measured in rats both in normal brain and in ischemic brain induced by four-vessel occlusion method. In the control rat, the enzyme activity was 0.87 +/- 0.13 nmol/g wet brain/min at 25 degrees C (mean +/- S.D.): 92.4% was associated with the NAD-dependent dehydrogenase form and only 7.6% with the oxygen-dependent superoxide-producing oxidase form. However, the ratio of the latter form increased to 43.7% after 0.5 hour of global ischemia despite the same level in total xanthine oxidase activity. This result suggests the involvement of the oxygen free radicals generated from the xanthine oxidase pathway in the pathogenesis of the ischemic injury of the rat brain.
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PMID:[Lipid peroxidation and changes in xanthine oxidase in cerebral ischemia]. 280 15

An increase in cytosolic free calcium concentration ([Ca2+]i) may trigger irreversible cell injury following cerebral ischemia. We have measured changes in [Ca2+]i in cat cortex in vivo during ischemia produced by 1 hour of middle cerebral artery occlusion and during 30 minutes of reperfusion. Indo-1, a fluorescent Ca2+ indicator, was loaded into the exposed cortex by superfusion, and changes in the [Ca2+]i signal (400/506 nm ratio) were measured microfluorometrically during ultraviolet excitation (340 nm). The nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD/NADH) redox state and hemodynamic changes were measured simultaneously. The animals showing severe deterioration in their electroencephalograms (EEG) showed a progressive increase in the [Ca2+]i signal during ischemia (baseline: 1.46 +/- 0.05; 60 minutes after occlusion: 2.99 +/- 0.37; n = 7). At 30 minutes following reperfusion, the animals showing little recovery in their EEG exhibited a further increase in [Ca2+]i (4.71 +/- 0.87, n = 3), whereas animals showing significant recovery in their EEG also showed recovery of [Ca2+]i (1.55 +/- 0.09, n = 4). By contrast, the moderate or mild stroke animals with less deterioration in their EEGs showed no increase in [Ca2+]i during either ischemia or reperfusion. These data suggest that the increase in [Ca2+]i might be closely related not only to deterioration of brain function during ischemia but also to poor recovery during the reperfusion period.
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PMID:In vivo measurement of cytosolic free calcium during cerebral ischemia and reperfusion. 314 14

Mitochondrial function was examined in cats after 1 h of complete cerebral ischemia and subsequent recirculation periods from 15 min to 56 h. During ischemia the NAD-linked respiratory control ratio and the maximal phosphorylation capacity of "free" and synaptosomal mitochondria decreased to 53% to 76% of control values. During postischemic reperfusion to 6 h, mitochondrial function was restored to 80%, remaining less than control throughout the entire investigated recirculation period with a tendency of secondary deterioration from 12 h of reperfusion onward. ADP: O ratios were unaffected during ischemia, but decreased significantly during early recirculation (15 to 30 min), and were completely restored from 45 min reperfusion onward. Correlation with electrophysiologic recordings revealed that mitochondrial dysfunction was not a limiting factor for neurophysiologic recovery during early recirculation (15 to 90 min). When the recirculation period was extended (greater than 3 h), good neurophysiologic recovery was associated with a return of mitochondrial function to control levels; inversely, poor mitochondrial function was correlated with poor neurophysiologic recovery.
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PMID:Mitochondrial respiration during recirculation after prolonged ischemia in cat brain. 356 58

Brain levels of NADH and NAD+ were measured in three models of cerebral ischemia to determine whether degradation of the pyridine nucleotides is enhanced in models that generate high concentrations of lactic acid. Complete ischemia (decapitation), in which lactate increased to 14 mmol/kg, caused a gradual decrease in the NAD pool to 50% of control by 2 h. During focal ischemia (occlusion of the middle cerebral artery), the decrease in the NAD pool was less pronounced (82% of control at 2 h) despite the accentuated accumulation of lactate to 33 mmol/kg. In a third model (unilateral hypoxia-ischemia), pretreatment of animals with glucose augmented the ischemic elevation of lactate from 30 mmol/kg to 40 mmol/kg and greatly impaired restoration of energy metabolites during recirculation. However, glucose pretreatment had no effect on the size of the NAD pool during ischemia or early recovery. These results, therefore, demonstrate that the pyridine nucleotide pool is not rapidly degraded during ischemic insults that accumulate high concentrations of lactic acid. The stability of the NAD pool may have been enhanced by the limited increase in brain levels of NADH that occurred in these models of incomplete ischemia.
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PMID:Effect of lactacidosis on pyridine nucleotide stability during ischemia in mouse brain. 361 29

Cerebral ischemia was induced in cats using bilateral carotid artery occlusion coupled with hemorrhagic hypotension. Thirty minutes of ischemia, which depleted levels of ATP and phosphocreatine throughout the cerebral cortex, was followed by 2-4 hours of recirculation. During the recovery period, cortical perfusion and NADH fluorescence were monitored through a cranial window. Postischemic perfusion, as indicated by transit time, was initially higher than control, but declined to subnormal levels by 60 minutes. NADH fluorescence transients, induced by brief anoxia, also decreased steadily during recirculation, indicating a failure of oxidation-reduction capability. The disappearance of anoxic-NADH transients usually preceded the decline of flow, suggesting that O2 delivery was not the factor limiting redox reactions. Furthermore, tissue levels of NADH, which were nearly normal after 2-4 hours of recirculation, did not indicate tissue hypoxia. In spite of normalization of NADH, resynthesis of high energy phosphates were severely impaired. The degree of ATP recovery varied widely in different cortical regions; however, there were two general groups of ATP values--one at 5% and the other at 70% of control levels. In the energy-depleted areas, NADH levels were normal, but the total pool of NAD (NADH + NAD+) and the tissue content of K+ were 43% lower than control. In contrast, the NAD pool and K+ content were only slightly diminished in the regions with greater ATP restitution. The results suggest that postischemic resynthesis of ATP may be limited not by inadequate delivery of O2, but rather by defective production of NADH.
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PMID:Factors limiting regeneration of ATP following temporary ischemia in cat brain. 706 95

The effect of reperfusion following 30 min of cerebral ischaemia on brain mitochondrial respiratory chain activity has been studied in the gerbil. The state 3 respiration rates with both FAD- and NAD-linked substrates were reduced after ischaemia. After 5 min of reperfusion, state 3 respiration with FAD-linked substrates was restored, but levels of NAD-linked substrates did not return to control values until 30 min of reperfusion. By 120 min of reperfusion state 3 respiration decreased relative to control values with all substrates studied. Measurement of the individual respiratory chain complexes showed that complex I, complex II-III, and complex V activities were reduced after ischaemia. By 5 min of reperfusion complex II-III activity was restored, but the activities of complexes I and V did not return to control values until 30 min of reperfusion. In contrast, complex IV activity was unaffected by ischaemia or 5 and 30 min of reperfusion but was significantly reduced after 120 min of reperfusion, possibly owing to free radical production and lipid peroxidation.
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PMID:Effect of reperfusion following cerebral ischaemia on the activity of the mitochondrial respiratory chain in the gerbil brain. 756 67


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