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

In some animal models of reversible ischemia, there is a therapeutic window during early recovery when glutamate receptor antagonists can rescue neurons from injury. We have previously reported that organotypic cultures of the hippocampus can be protected by NMDA-receptor antagonists during recovery from a brief period of simulated ischemia. To model ischemia, we have used potassium cyanide to inhibit oxidative metabolism and 2-deoxyglucose to inhibit glycolysis. To study the time course and mechanisms of delayed NMDA-receptor toxicity in more detail, we have extended these studies to dissociated cortical cultures. Injury was assessed by release of lactate dehydrogenase into the culture medium. Metabolic inhibition for 15 min caused dose-dependent injury. Morphologic signs of neuronal toxicity were delayed until the recovery period. MK-801 reduced injury significantly when present throughout the experiment. Surprisingly, MK-801 provided the same protection when administration was delayed until after the end of the metabolic inhibition, blocking NMDA receptors only during recovery. To examine NMDA toxicity during metabolic inhibition, the competitive NMDA-receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid was added during exposure. The protective effect of NMDA-receptor blockade was completely lost if the antagonist was removed during 1 min of continuing selective inhibition of oxidative metabolism. The toxic potency and effectiveness of glutamate were enhanced during metabolic inhibition, showing that receptors were not inactivated by simulated ischemia. These results are consistent with the specific hypothesis that return of oxidative metabolism triggers a critical period of toxic NMDA-receptor activation.
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PMID:Toxic NMDA-receptor activation occurs during recovery in a tissue culture model of ischemia. 756 65

The effect of energy failure on Cl(-)-dependent L-glutamate (L-Glu) transport was examined with an in vitro preparation. Rat brain slices were incubated in low oxygen and glucose-deprived medium (in vitro ischemia), and a synaptic membrane fraction was prepared from the slices. Cl(-)-dependent L-[3H]Glu uptake into vesicles increased about twofold after 20 min of in vitro ischemia. The increased L-[3H]Glu uptake was inhibited by L-Glu, DL-2-amino-4-phosphonobutyrate, L-homocysteic acid, L-cystine, 4,4'-diisothiocyano-2,2'-disulfonic stilbene, and removal of Cl-. Uptakes of Na(+)-dependent L-[3H]Glu, [3H]GABA, and [3H]taurine were not changed by the in vitro ischemia. In vitro ischemia increased the Vmax value without affecting the Km value. The increased L-[3H]Glu uptake by in vitro ischemia was reduced by subsequent incubation in a normoxic glucose-containing solution. ATP content in brain slices decreased to < 10% of control values by in vitro ischemia for 10 min. The decrease in ATP content was restored by subsequent incubation in normoxic glucose-containing solution. Treatment with veratrine, 2,4-dinitrophenol, carbonyl cyanide m-chlorophenylhydrazone, and NaCN in normoxic conditions increased L-[3H]Glu uptake with a concomitant decrease in ATP content in slices. These results suggest that Cl(-)-dependent L-Glu transport activity in synaptic membranes increases in ischemia- or hypoxia-induced brain energy failures.
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PMID:Increase in chloride-dependent L-glutamate transport activity in synaptic membrane after in vitro ischemic treatment. 756 78

We studied the effects of ATP depletion on neurotransmitter release in the rat brain using the microdialysis method. Ringer's solution containing 2 mM sodium cyanide (NaCN) was perfused into the hippocampus and striatum for 60 min via a microdialysis probe, and changes in serotonin (5-HT) and amino acids (glutamate, aspartate and taurine) levels in dialysates were investigated. NaCN perfusion induced a transient 3.9-fold increase in 5-HT levels in the hippocampal dialysate. Amino acid levels in dialysates also increased during NaCN perfusion, but differently in the striatum and hippocampus (glutamate: 1.3- and 2.4-fold, taurine: 2.3- and 1.3-fold, respectively). Perfusion of Ca(2+)-free Ringer's solution remarkably suppressed the NaCN-induced increase in 5-HT but not the increases in amino acid levels. Depolarization by 100 mM KCl perfusion could induce increases in 5-HT and amino acids in dialysates at 3 hr after NaCN perfusion similarly with that of control. These findings indicate that the sensitivity of nerve terminals to energy failure are different between neurons containing different neurotransmitters and also between brain regions, and suggest that this regionally different sensitivity of amino acid neurons might be involved in the underlying mechanism of the localized vulnerability to transient ischemia.
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PMID:[Increase in extracellular levels of serotonin and amino acids in the rat brain following cyanide-induced energy failure]. 758 27

The protooncogene bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that the mechanism of action of Bcl-2 involves antioxidant activity. The involvement of free radicals in ischemia/reperfusion injury to neural cells has led us to investigate the effect of Bcl-2 in a model of delayed neural cell death. We have examined the survival of control and bcl-2 transfectants of a hypothalamic tumor cell line, GT1-7, exposed to potassium cyanide in the absence of glucose (chemical hypoxia/aglycemia). After 30 min of treatment, no loss of viability was evident in control or bcl-2 transfectants; however, Bcl-2-expressing cells were protected from delayed cell death measured following 24-72 h of reoxygenation. Under these conditions, the rate and extent of ATP depletion in response to treatment with cyanide in the absence of glucose and the rate of recovery of ATP during reenergization were similar in control and Bcl-2-expressing cells. Bcl-2-expressing cells were protected from oxidative damage resulting from this treatment, as indicated by significantly lower levels of oxidized lipids. Mitochondrial respiration in control but not Bcl-2-expressing cells was compromised immediately following hypoxic treatment. These results indicate that Bcl-2 can protect neural cells from delayed death resulting from chemical hypoxia and reenergization, and may do so by an antioxidant mechanism. The results thereby provide evidence that Bcl-2 or a Bcl-2 mimetic has potential therapeutic application in the treatment of neuropathologies involving oxidative stress, including focal and global cerebral ischemia.
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PMID:Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability. 759 37

Extravasation of leukocytes at sites of ischemia may mediate tissue injury. To determine how leukocyte accumulation may be induced by ischemia, effects of hypoxia on basal neutrophil expression of adhesion and activation receptors were examined. Effects of hypoxia upon preactivated cells were also studied. To determine whether regulation of expression is dependent on oxygen availability or on mitochondrial respiration, the effects of physical hypoxia (substitution of O2 by nitrogen) were compared with those of chemical hypoxia with sodium cyanide (NaCN). Leukocytes in whole blood (eight volunteers) were exposed either to hypoxia alone or to priming concentrations of lipopolysaccharide (LPS, 1 microgram/ml) followed by chemical hypoxia (NaCN, 1 mM) or physical hypoxia (PO2 of 1-10 torr) for various time intervals. Room air was controlled and hypoxic cells were labeled with fluorescent monoclonal antibodies to integrins CD18 and CD11b or to the 55-kDa TNF alpha cell surface receptor (TNFR). Receptor concentrations were measured by flow cytometry. Data were analyzed by ANOVA/Student's t test. Physical hypoxia increased expression of both CD11b and CD18 over time and augmented their LPS-induced up-regulation. Isolated chemical hypoxia did not change neutrophil expression of CD11b or CD18, but partially inhibited neutrophil CD11b and CD18 up-regulation by LPS. LPS-induced TNFR down-regulation was not affected by physical hypoxia, which failed to alter TNFR expression in this model.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypoxia-induced alterations of neutrophil membrane receptors. 763 Jan 18

The cerebral protective effects of VA-045, a novel apovincaminic acid derivative, were investigated in mice under conditions of normobaric hypoxia, histotoxic anoxia by potassium cyanide (KCN), and complete ischemia. VA-045 and thyrotropin releasing hormone (TRH) showed a significant protective effect on normobaric hypoxia. The duration of action of the protective effect of VA-045 was longer than that of TRH. VA-045 but not TRH significantly prolonged the survival time following administration of KCN. VA-045 and TRH showed a positive effect on complete ischemia, and the duration of the protective effect of VA-045 was longer than that of TRH. Beneficial effects of VA-045 for treating cerebral hypoxia, anoxia and ischemia will be discussed.
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PMID:Cerebral protective effects of VA-045, a novel apovincaminic acid derivative, in mice. 785 Feb 59

In the present study the hypothesis was tested that local noradrenaline release contributes to adenosine formation in myocardial ischemia. Therefore, in ischemic non-working rat hearts either adrenergic receptors or ischemia-evoked noradrenaline release were blocked. Noradrenaline and adenosine were determined in the effluent using HPLC-methods. Following 20 min of stop of perfusion flow both the beta-adrenergic receptor antagonist bisoprolol (91.6 +/- 10.5 nmol/g) and the inhibitor of ischemia-induced noradrenaline release desipramine (108.5 +/- 12.5 nmol/g) caused a suppression of adenosine release (control: 140.9 +/- 7.3 nmol/g). To examine the time-course of the release, further experiments were performed at constant perfusion flow with energy metabolism blocked by cyanide together with removal of glucose from the perfusion buffer. This condition resulted in a nearly simultaneous release of adenosine and noradrenaline from the hearts. The beta-adrenoceptor blocking agents atenolol and bisoprolol postponed the release of adenosine, whereas the alpha-antagonists prazosin and yohimbine had no effect on adenosine release induced by cyanide. None of the adrenergic receptor blockers affected the release of noradrenaline. The inhibitors of the neuronal noradrenaline carrier (uptake1) desipramine, oxaprotiline, and cocaine suppressed the release of noradrenaline during cyanide administration, indicating a carrier-mediated efflux of noradrenaline. Reduction of extracellular noradrenaline by these agents coincided with a delay of adenosine release (cumulative release within 20 min--control: 251.2 +/- 13.9, desipramine: 172.1 +/- 15.3, oxaprotiline 36.5 +/- 5.8, cocaine: 111.8 +/- 23.6 nmol/g). Desipramine and cocaine were also used during administration of exogenous noradrenaline in normoxic hearts, to confirm specificity of their action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiac noradrenaline release accelerates adenosine formation in the ischemic rat heart: role of neuronal noradrenaline carrier and adrenergic receptors. 786 92

The acute anti-ischemic and anti-anoxic effects of dextrorphan (DX) were compared with those of dizocilpine (MK-801) in a variety of animal models, and in vivo and in vitro testings under anoxic conditions. DX reduced the incidence of death in ischemic mice and improved the rotarod performance of mice with brain ischemia. The ischemically-impaired memory of mice treated with DX markedly improved, as shown in the step-through type passive avoidance test, Morris water maze and in the habituation of exploratory behavior test. MK-801 likewise improved the water maze performance of the ischemically-impaired mice, but to a lesser extent. The step-through type passive avoidance performance of ischemic mice was not improved by MK-801. In the passive avoidance task with normal mice, DX, like MK-801, produced anterograde amnesia at doses higher than those needed to attenuate the behavioral effects of ischemia. DX, intravenously or centrally administered, markedly and dose-dependently reduced the incidence of death in mice receiving potassium cyanide (KCN). DX lessened the reduction in adenosine triphosphate (ATP) and increased lactate contents in mice dosed with KCN and also lessened the reduction in ATP in the TCA cycle and oxidative phosphorylation reactions caused by KCN (0.58 mmol/l), whereas MK-801 failed to show any effect on ATP formation pathways in vivo and in vitro, and failed to protect mice against KCN-induced lethal toxicity in vivo. In the in vitro studies, DX increased the adenylate kinase activity of the rat brain homogenate. DX was found to be a cerebroprotectant with anti-ischemic and anti-anoxic actions, the effects probably stemming from its N-methyl-d-aspartate receptor antagonistic property in cooperation with its ATP replenishing action.
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PMID:Dextrorphan attenuates the behavioral consequences of ischemia and the biochemical consequences of anoxia: possible role of N-methyl-d-aspartate receptor antagonism and ATP replenishing action in its cerebroprotecting profile. 787 Sep 46

Ischemia/reperfusion mechanisms contribute to lung injury after transplantation, pulmonary embolism, and resolution of atelectasis. Alveolar tissue becomes hypoxic and deprived of substrate only when both ventilation and perfusion are interrupted, a situation modeled in vivo by complete, unilateral lung collapse. Because previously hypoxic mitochondria may be an important intracellular source of superoxide and hydrogen peroxide (H2O2) during reperfusion and re-oxygenation, the authors, in this study, investigated whether mitochondrial H2O2 release changed as a result of lung hypoxia/hypoperfusion resulting from collapse. Mitochondria were isolated from hypoxic (previously collapsed) right or contralateral left rabbits' lungs and from control rabbits' lungs. Mitochondrial H2O2 release, a marker of superoxide production, was measured fluorometrically after incubation with or without 1 mmol/L cyanide and 0.1 mmol/L nicotinamide adenine dinucleotide. Mitochondrial recovery was determined by assaying succinate dehydrogenase activity in mitochondrial preparations and lung homogenates. Lung succinate dehydrogenase activity and mitochondrial recovery were comparable among groups. Calculated lung mitochondrial content did not change (control subjects: left 7.9 +/- 0.5, right 13.8 +/- 1.7; hypoxic: left 10.3 +/- 1.3, right 10.5 +/- 2.4, all mg mitochondrial protein/lung). Mitochondria released hydrogen peroxide at approximately 5.6 nmol/h/mg pro in buffer alone and 14.8 nmol/h/mg pro in buffer with cyanide and nicotinamide adenine dinucleotide. However, lung collapse and resulting hypoxia caused no change in mitochondrial number or capacity to release H2O2 in vitro. Based on these findings, it is suggested that other sources of reactive oxygen metabolites, including xanthine oxidase and activated neutrophils, contribute to the oxidant injury observed in this model.
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PMID:Hydrogen peroxide release by mitochondria from normal and hypoxic lungs. 794 83

Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, exacerbate neuronal death in the hippocampus during ischemia. Since ischemia brain damage is ascribed to an elevated level of extracellular excitatory amino acids (EAAs), this study was undertaken to investigate the effect of GCs on EAA homeostasis in hippocampal cell cultures during the insult of cyanide exposure. Using D-[2,3-3H]aspartic acid ([3H]D-Asp) as a tracer, we found that corticosterone (CORT, the physiological GC in rats) increased the accumulation of extracellular [3H]D-Asp by 25% in hippocampal cultures during cyanide-induced ischemia. CORT had no effect on the release of [3H]D-Asp. Instead, analysis of [3H]D-Asp uptake kinetics indicates that CORT decreased the maximum uptake rate and the Michaelis constant by 44% and 50%, respectively, in cells treated with cyanide. It is concluded that, during cyanide-induced ischemia, CORT might enhance extracellular overflow of [3H]D-Asp by decreasing its uptake, thereby endangering neurons.
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PMID:Glucocorticoids increase extracellular [3H]D-aspartate overflow in hippocampal cultures during cyanide-induced ischemia. 798 1


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