Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors have used intracerebral microdialysis to develop a method for routine monitoring of disturbances in brain energy metabolism in patients in the neurosurgical intensive care unit. Microdialysis was conducted for periods ranging from 2.3 to 8.3 days in four patients (three with severe head injuries and one with severe subarachnoid hemorrhage). Altogether, 4447 chemical analyses from 587 dialysis samples were carried out. Concentrations of the energy-related metabolites lactate, pyruvate, and hypoxanthine were measured, and the lactate:pyruvate ratio was calculated. In addition, the acids glutamate, aspartate, taurine, glutamine, asparagine, and glycine were measured in one patient. The microdialysis data were matched with various clinical events, including intracranial hypertension and therapeutic interventions such as initiation or withdrawal of barbiturates and cerebrospinal fluid drainage. The present study shows that microdialysis can be used for long-term measurement of extracellular fluid (ECF) energy-related metabolites and amino acids in the frontal cortex of neurosurgical patients in a clinical setting. Fluctuations of the measured ECF energy-related substances corresponded to various clinical events presumably involving hypoxia/ischemia. The authors found a 25-fold increase in ECF glutamate, aspartate, and taurine under conditions of energy perturbation, as indicated by high levels of the lactate:pyruvate ratio, lactate, and hypoxanthine. The use of long-term intracerebral microdialysis in patients opens a new field of clinical research, with many possibilities for improving insight into intracranial dynamics in acute cerebral conditions.
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PMID:Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. 172 72

We used in vivo microdialysis to determine the impact of a focal hypoxic-ischemic insult on striatal amino acid efflux in the immature brain. Microdialysis probes were inserted into the right striatum of postnatal day 7 rats. To induce hypoxic-ischemic injury, the right carotid artery was ligated and the animals were exposed to 8% oxygen for 2.5 hours (n = 22). Rats exposed to ligation alone (n = 10) or hypoxia alone (n = 8) and untreated controls (n = 17) were also studied. Two hours after probe insertion, a 30-minute baseline microdialysis sample was obtained. After arterial ligation, two additional baseline samples were collected. Five more samples were collected over the next 2.5 hours (in 8% oxygen or room air). Eight amino acids (glutamate, aspartate, taurine, glutamine, alanine, serine, glycine, and asparagine) were consistently detected in dialysates using a high-performance liquid chromatography assay with electrochemical detection. In untreated controls, amino acid efflux did not change over 4 hours. During hypoxia-ischemia, efflux values fluctuated widely, with marked intra-animal and interanimal variability. Efflux peaks for each amino acid were defined as values greater than the highest control mean value plus two standard deviations. Glutamate efflux peaks (greater than 7 pmol/min compared with 2 pmol/min at baseline) were detected in no controls and in eight hypoxic-ischemic rats (p = 0.006, Fisher's two-tailed exact test). Taurine efflux peaks (greater than 75 pmol/min compared with 10 pmol/min for controls at baseline) were detected in 10 hypoxic-ischemic rats and one control (p = 0.01) and in seven of the eight animals in which glutamate efflux peaks occurred (p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of perinatal stroke on striatal amino acid efflux in rats studied with in vivo microdialysis. 185 13

Excitatory amino acids have been implicated in the production of calcium mediated neuronal death following central nervous system ischemia. We have used microdialysis to investigate changes in the extracellular concentrations of amino acids in the spinal cord after aortic occlusion in the rabbit. Glutamate, aspartate, glutamine, asparagine, glycine, taurine, valine, and leucine were measured in the microdialysis perfusate by high pressure liquid chromatography. The concentrations of glutamate, glycine, and taurine were significantly higher during ischemia and reperfusion than controls. Delayed elevations in the concentrations of asparagine and valine were also detected. The elevation of glutamate is consistent with the hypothesis that excitotoxins may mediate neuronal damage in the ischemic spinal cord. Increased extracellular concentrations of asparagine and valine may reflect preferential use of amino acids for energy metabolism under ischemic conditions. The significance of increased concentrations of inhibitory amino acid neurotransmitters is unclear.
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PMID:Spinal cord ischemia-induced elevation of amino acids: extracellular measurement with microdialysis. 197 91

It is well established that excitatory amino acid neurotransmitters are extensively liberated during ischemia and that they have neurotoxic properties contributing to neuronal injury. To study changes in the liberation of excitatory and other amino acids during cerebral ischemia, we measured their extracellular concentrations and related them to blood flow levels and electrophysiologic activity (electrocorticogram and auditory evoked potentials) before and for up to 2 hours after multiple cerebral vessel occlusion in 14 anesthetized cats. Blood flow levels between 0 and 43 ml/100 g/min were reached. Concentrations of the excitatory amino acid neurotransmitters increased most (aspartate 10-fold, glutamate 30-fold, and gamma-aminobutyric acid 300-fold compared with control values) below a blood flow threshold of 20 ml/100 g/min. The total power of the electrocorticogram and the amplitude of the auditory evoked potentials were affected below the same blood flow threshold. In contrast, concentrations of the nontransmitter amino acids taurine, alanine, asparagine, serine, and glutamine increased 1.5-5-fold as blood flow decreased, while concentrations of the essential amino acids phenylalanine, valine, leucine, and isoleucine did not change during cerebral ischemia. The great increases in concentrations of the excitatory amino acid neurotransmitters below a blood flow threshold close to that for functional disturbance is in accordance with the role of these amino acids in ischemic cell damage. Their release at blood flow levels compatible with cell survival and the increase in their concentrations with severity and duration of cerebral ischemia imply that excitotoxic antagonists may have potential as therapeutic agents.
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PMID:Differences in ischemia-induced accumulation of amino acids in the cat cortex. 197 18

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.
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PMID:Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. 228 87

Isolated rat hearts were, after a retrograde perfusion by the Langendorff procedure, rendered ischemic by lowering the aortic pressure to zero. The rate of proteolysis and temporal patterns of the changes in the concentrations of the metabolites of the tricarboxylic acid cycle, related amino acids, ammonia, and breakdown products of the adenine nucleotides were determined. The most significant change in the amino acid metabolism was a decrease of the proteolysis to one-tenth and a large accumulation of alanine, which was almost stoichiometric to the degradation of aspartate plus asparagine. The accumulation of malate and succinate was small compared with the metabolic net fluxes of aspartate and alanine. The metabolic balance sheet suggests that aspartate was converted to alanine. A prerequisite for this would be a feed in of carbon of aspartate to the tricarboxylic acid cycle as oxalacetate, reversal of the malate dehydrogenase, and production of pyruvate by the malic enzyme reaction. Alanine accumulating during ischemia is not glycolytic in origin but occurs through a concerted operation of anaplerotic reactions and tricarboxylic acid cycle metabolite disposal. The data also suggest that the potentially energy-yielding reduction of fumarate to succinate is not significant in the ischemic myocardium.
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PMID:Tricarboxylic acid cycle metabolites during ischemia in isolated perfused rat heart. 682 95

Extracellular concentrations of amino acids in halothane-anesthetized rats were measured using a microdialysis fiber inserted transversely through the dorsal spinal cord at the level of the lumbar enlargement in conjunction with HPLC and ultraviolet detection. After a 2-h washout and a 1-h control period, 20 min of reversible spinal cord ischemia was achieved by the inflation of a Fogarty F2 catheter passed through the femoral artery to the descending thoracic aorta. After 2 h of postischemic reperfusion, animals were transcardially perfused with saline followed by 10% formalin or 4% paraformaldehyde. The glutamate concentration in the dialysate was significantly elevated after 10 min of occlusion and returned to near-baseline during the first 30 min of reperfusion. Taurine was elevated significantly 0.5 h postocclusion and continued to increase throughout the 2 h of reperfusion. Glycine concentrations showed a tendency to be slightly above baseline during the reperfusion period. Glutamine concentrations modestly increased following 2 h of reperfusion. No significant changes in aspartate, asparagine, and serine were detected. In control animals no significant changes in any amino acids were detected. To assess the role of complete spinal ischemia on spinal glutamate release, studies were carried out using cardiac arrest. Twenty minutes after induction of cardiac arrest, the glutamate concentration was increased about 350-400%. In a separate group of animals, spinal cord blood flow (SCBF) and its response to decreased CO2 were measured using a laser probe implanted into the epidural space at the level of the L2 vertebral segment. SCBF decreased to 5-6% of the control during aortic occlusion. After reversible ischemia, marked hyperemia was seen for the first 15 min, followed by hypoperfusion at 60 min. Under control-preischemic conditions a decrease in arterial CO2 content caused a decrease in SCBF of about 25%. This autoregulatory response was almost completely absent when assessed 60 min after a 20-min interval of aortic occlusion. Histopathological analysis of spinal cord tissue from these animals demonstrated heavy neuronal argyrophilia affecting small and medium-sized neurons located predominantly in laminae III-V. These changes corresponded to signs of irreversible damage at the ultrastructural level. Occasionally, small areas of focal necrosis, located in the dorsolateral part of the dorsal horn and anterolateral part of the ventral horn, were found. The results are consistent with a role for glutamate in ischemically induced spinal cord damage and suggest that taurine elevation detected during the early reperfusion period may serve as an important indicator of irreversible spinal cord neuronal damage.
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PMID:Transient spinal ischemia in rat: characterization of spinal cord blood flow, extracellular amino acid release, and concurrent histopathological damage. 801 7

The carbohydrate moieties of glycoprotein hormones or growth factor molecules may have a variety of effects that impact biological potency. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a 45 kD heparin-binding, endothelial cell (EC) specific mitogen with a putative N-linked glycosylation site. Recent studies have shown that VEGF/VPF may successfully augment collateral development in animal models of myocardial and hindlimb ischemia. The extent to which glycosylation of the 75 asparagine site affects the angiogenic properties of VEGF/VPF has not been studied in vivo. Specifically unaddressed to date is the concern that nonglycosylated VEGF/VPF may be less stable, and therefore characterized by a shorter half-life, reducing its utility for therapeutic angiogenesis. Accordingly, the purpose of this study was to investigate the extent to which posttranslational modification, specifically glycosylation, mofies the angiogenic properties of VEGF/VPF in vivo. Glycosylated (g+) recombinant human VEGF165 was purified from media conditioned by Chinese hamster ovary (CHO) cells. Nonglycosylated (g-) VEGF165 was expressed, purified and refolded from E. coli. The purity of both materials was assessed by silver-stained SDS/PAGE and characterized by the presence of a single amino terminal sequence as indicated by Edman degradation. Tryptic mapping by reverse-phase HPLC confirmed that the potential glycosylation site at 75 asparagine was occupied by N-linked carbohydrate for the Chinese hamster ovary-derived VEGF/VPF, but not for E. coli-derived VEGF/VPF. The mitogenic effects of Chinese hamster ovary-derived (g+) VEGF165 and E. coli-derived (g-) VEGF165 wre studied in vitro using microvascular EC. At concentrations of VEGF/VPF ranging from 10(-4) to 10(2) nM, both produced similar concentration-dependent effects on EC proliferation. For in vivo studies, (g-) (n = 8) and (g+) (n = 8) formulations of VEGF/VPF were administered to New Zealand white rabbits with unilateral hindlimb ischemia. For (g-) versus (g+) VEGF/VPF-treated groups, respectively, calf blood pressure ratio was 0.40 +/- 0.04 versus 0.37 +/- 0.04; angiographic score (of collateral vessels) was 0.37 +/- 0.04 versus 0.35 +/- 0.04; capillary density (capillaries/mm2) at necropsy was 246.9 +/- 21.5 versus 253.9 +/- 18.8; and tissue perfusion (colored microspheres) was 92.8 +/- 5.5 versus 90.30 +/- 13.47 (all p = ns). Moreover, intravascular Doppler-based analyses of resting, maximum, and endothelium-dependent flow was similar for (g-) and (g+) VEGF/VPF. These in vitro and in vivo findings establish that the potential for VEGF/VPF to stimulate therapeutic angiogenesis persists unaltered in the nonglycosylated state.
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PMID:The in vivo bioactivity of vascular endothelial growth factor/vascular permeability factor is independent of N-linked glycosylation. 878 Jan 72

Hypothermia has been reported to be beneficial in CNS physical injury and ischemia. We previously reported that posttraumatic cooling to 17 degrees C for 2 h increased survival of mouse spinal cord (SC) neurons subjected to physical injury (dendrite transection) but that cooling below 17 degrees C caused a lethal NMDA receptor-linked stress to both lesioned and uninjured neurons. The present study tested whether cooling below 17 degrees C increases extracellular levels of excitatory amino acids (EAA). SC cultures were placed at 10 degrees C or 37 degrees C. Glutamate (Glu) and aspartate (Asp) levels were higher in the medium of the cooled cultures after 0.5 h (23 +/- 4 nM/microgram vs. 4 +/- 1 nM/microgram and 4 +/- 1 nM/microgram vs. 1 +/- 0 nM/microgram, respectively). The concentration of each EAA then declined and reached a plateau at 2-4 h that was still significantly higher than control levels (p < 0.0001, two-factor ANOVA, three cultures per group). Other amino acids (glycine, asparagine, glutamine, serine) showed an opposite pattern, with higher levels in the 37 degrees C group. Both NMDA and non-NMDA antagonists prevented the lethal cold injury. Survival of SC neurons cooled at 10 degrees C for 2 h and rewarmed for 22 h was 58% +/- 25% in the control group, 94% +/- 5% in the CNQX-treated group, 97% +/- 5% in the DAPV-treated group, and 99% +/- 2% in the group treated with both antagonists [p < 0.0006, one factor ANOVA, five cultures (> 120 neurons) per group]. These results show that death of neurons cooled to 10 degrees C is caused by elevated extracellular Glu and Asp and requires activation of both the NMDA and non-NMDA receptor subtypes.
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PMID:The role of excitatory amino acids in hypothermic injury to mammalian spinal cord neurons. 900 66

We evaluated in rats, the effect of moderate hypothermia (30-31 degrees C) on extracellular levels of amino acids, with special emphasis on the excitatory amino acids (EAAs) glutamate and aspartate, lactate and pyruvate, after severe spinal cord compression. A laminectomy of Th7 and Th8 was made. A probe was inserted in a dorsal horn and microdialysis was performed for 1.5 h before and 4 h after applying severe compression for 5 min. Dialysate samples were collected at intervals of 10 min and analyzed by high-performance liquid chromatography. In normothermic (37.5 degrees C) animals there was a several-fold rise of glutamate that peaked in the first 10 min fraction after trauma. Hypothermic animals showed a similar increase after trauma, which was statistically significant until 20 min after injury. The level of glutamate was significantly higher in hypothermic animals from 20 to 70 min after injury, compared with normothermic animals. Aspartate also showed a marked increase following injury. The peak concentration was similar for both groups, whereas recovery was delayed in hypothermic animals. There was no significant difference between the normothermic and hypothermic animals for arginine, taurine, alanine, glutamine, histadine, glycine, threonine, tyrosine, and asparagine. No significant effect of hypothermia on lactate or lactate/pyruvate was noted. However, the mean level of lactate tended to be lower and recovery was quicker in hypothermic animals. The results of the present study suggest that moderate hypothermia does not attenuate extracellular accumulation of EAAs or markedly improve energy metabolism in our model. Instead, our findings raise the possibility that moderate hypothermia prolongs the duration of glutamate receptor overactivation. Since hypothermia effectively attenuates glutamate release in CNS and spinal cord ischemia models our results suggest different mechanisms of extracellular accumulation of EAAs in ischemia and trauma.
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PMID:Effects of moderate hypothermia on extracellular lactic acid and amino acids after severe compression injury of rat spinal cord. 904 12


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