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)

U-74006F, 21-(4-(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl)-16 alpha-methylpregan-1,4,9(11)-triene monomethane sulfonate, is currently under development for the treatment of human central nervous system trauma and ischemia. The iv pharmacokinetics and excretion of 14CU-74006F (labeled in the 16 alpha-methyl group) and 3HU-74006F (labeled in a pyrrolidine ring) were investigated in the young adult Sprague-Dawley rat and the perfused rat liver. Following a 3 mg/kg iv bolus dose, plasma levels of 14CU-74006F declined biexponentially with alpha and beta half-times of 8 and 70 min, respectively. The terminal phase volume of distribution was 5.1 liters/kg and the plasma clearance was 51 ml/min/kg, which is similar to the in vivo hepatic plasma flow. Plasma levels of total 14C-labeled metabolites quickly exceeded levels of parent drug and declined with a terminal phase half-time of 50 hr. Greater than 90% of the 14C and 3H doses was excreted in feces with terminal phase half-times of 107 and 46 hr, respectively. Consistent with high hepatic clearance, the oral solution bioavailability of U-74006F was 16%, and the hepatic extraction efficiency of U-74006F from 3% bovine serum albumin (w/v) medium in the perfused liver was 80-86% under nonsaturating conditions at physiological flows. U-74006F was rapidly metabolized in the perfused liver and excreted in bile as metabolites. The biliary excretion mechanism was more easily saturated than hepatic uptake and metabolism, with the consequence that, at pharmacologically relevant perfusate levels of drug, metabolites accumulated in the liver and effluxed into the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetics and excretion of the 21-aminosteroid antioxidant U-74006F in rat and perfused rat liver. 257 75

Ischemic neuronal injury is supposed to be caused in part by the extracellular accumulation of excitatory amino acids (EAA). Neurotransmitter and metabolic EAA can be released from synaptic vesicles and cytoplasm of neurones and glial cells. In this study the release of the glutamate analogue [3H]D-aspartate ([3H]D-ASP), loaded into 500 microns slices of rat hippocampus, was investigated. The efflux of the label was measured during anoxic-aglycemic ("ischemic") and normoxic K+ depolarization. To identify the pools from which [3H]D-ASP is released we have estimated its calcium dependence and the effects of inhibitors of: (1) Na(+)-dependent transporter of amino acids (100 microM L-trans-pyrrolidine-2,4-dicarboxylic acid/L-trans-PDC/), (2) sodium channel (1 microM tetrodotoxin TTX), and (3) anion channel (1 mM furosemide). [3H]D-ASP released upon normoxic depolarization was 40% inhibited by TTX, nearly 40% by L-trans-PDC and over 50% by furosemide. The "ischemic" release was in 40% calcium dependent, completely TTX independent and in approximately 50% blocked by furosemide treatment. Our data suggest that EAA accumulated in the synaptic cleft during ischemia are mainly released from the cytosolic compartment by mechanisms which are connected with the ischemic increase of extracellular potassium concentration.
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PMID:Enhancement of 3[H]D-aspartate release during ischemia like conditions in rat hippocampal slices: source of excitatory amino acids. 878 12

The redox status of the cell plays an essential role in regulating signal transduction, transcription factor activity, and expression of cell surface molecules. In this study, we show that pyrrolidine dithiocarbamate (PDTC), a potent antioxidant agent, upregulated the cell surface expression of intercellular adhesion molecule-1 (ICAM-1) in human endothelial cells (EC). Further analysis of PDTC-mediated ICAM-1 up-regulation revealed that PDTC increased ICAM-1 mRNA levels and augmented its gene promoter activity. Transfection experiments in EC with reporter constructs harboring nested deletion fragments of the ICAM-1 promoter indicated the presence of a functional PDTC-responsive region located between positions -136 to -353 of the promoter. Gel retardation assays together with supershift analysis revealed that PDTC induced the binding of c-fos and c-jun to a consensus activating protein-1 (AP-1) binding site located at position -284. PDTC alone or in combination with TNF-alpha enhanced AP-1-dependent transactivation in HUVEC, as determined by DNA binding assays. The functional implication of AP-1 in the transcription of the ICAM-1 gene was further demonstrated by cotransfection experiments in which a c-jun expression vector induced the promoter activity of the PDTC-responsive element of the ICAM-1 promoter. Taken together, these results indicate that the antioxidant PDTC induces transcriptional activation of ICAM-1 and that this induction is mediated at least in part by the transcription factor AP-1. This mechanism might be operative in pathologic conditions in which a redox imbalance plays a key role, such as ischemia/reperfusion injury or arteriosclerosis.
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PMID:Transcriptional up-regulation of intracellular adhesion molecule-1 in human endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves the activation of activating protein-1. 887 59

There was a large release of endogenous glutamate and of pre-accumulated [3H]-D-aspartate from rat hippocampal slices during deprivation of oxygen and glucose (in vitro ischemia). The role of Na(+)-dependent glutamate transporters in this process was investigated. The release of both glutamate and [3H]-D-aspartate was largely blocked by two competitive substrate analogues of the Na(+)-dependent glutamate transporters (L-trans-pyrrolidine-2,4-dicarboxylate and D,L-threo-B-hydroxyaspartate) if the substrate analogues were intracellularly loaded prior to the ischemia. The pre-loaded analogue, D,L-threo-B-hydroxyaspartate, did not block exocytotic release of glutamate, induced by high-potassium. Dihydrokainate, an inhibitor of a subset of the Na(+)-dependent transporters, did not inhibit ischemia-induced release of glutamate or [3H]-D-aspartate. However, it did block release induced by veratridine, which was also blocked by the pre-loaded substrate analogues. Dihydrokainate could still inhibit veratridine-induced release during ischemia, showing that conditions during ischemia did not reduce its efficacy. It is concluded that release of glutamate during ischemia is largely via reversal of the Na(+)-dependent glutamate transport system. The differential effects of dihydrokainate and the competitive substrate analogues on ischemia-induced release indicate that this release occurs via a subset of the glutamate transporters that are present in the hippocampus.
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PMID:Mechanism of glutamate release from rat hippocampal slices during in vitro ischemia. 895 64

The extracellular concentration of glutamate increases during hypoxia/ischemia probably due to deficient uptake. Glutamate might contribute to neuronal damage associated with this disorder and to neurodegeneration during aging. In the present study, we have tested the effect of two inhibitors of glutamate transport, L-trans-pyrrolidine-2,4-dicarboxylate and dihydrokainate, on the extracellular levels of glutamate and on neuronal damage, which was quantitatively studied by image analysis of histological brain sections. Drugs were administered by microdialysis and glutamate concentration was determined by HPLC in the striatum and the hippocampus of 3-month-old and 22-24-month-old rats. In both regions studied, the basal concentration of extracellular glutamate was higher in aged than in young rats. Pyrrolidine dicarboxylate induced a substantial elevation of extracellular glutamate in both regions, and although this increase was almost twofold higher in old than in young animals, no neuronal damage was observed. In contrast, dihydrokainate had a poor effect on glutamate levels, but induced clear neuronal damage in the striatum and the hippocampus in both groups of rats. The present results suggest that age appears not to be a significant factor in the sensitivity of neurons to the toxic effect of extracellular glutamate increase via blockade of its transport system.
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PMID:Glutamate uptake impairment and neuronal damage in young and aged rats in vivo. 928 38

To study the effects of glutamate transporters on the pathogenesis of brain infarct, pharmacological and histological analyses were carried out on the thrombotic focal ischemic model. Expression of mRNA coding for the glutamate transporter GLAST increased significantly in the penumbra at 72 h following the ischemia. Combined with confocal laser scanning microscopic analysis, double staining showed expression of GLAST mRNA in both neurons and glial cells in the penumbra. L-trans-Pyrrolidine-2,4-dicarboxylate (L-trans-PDC), a glutamate uptake inhibitor, dose-dependently enhanced the volume of the infarct induced by the ischemia. The results suggest that a compensatory increase in the activity of glutamate transporter may accompany pathological changes after ischemic injury.
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PMID:Effect of glutamate transporter on neuronal damage induced by photochemical thrombotic brain ischemia. 951 87

Activation of N-methyl-D-aspartate (NMDA) receptors is known to produce arachidonic acid release, which has been implicated in excitotoxicity. Antagonists and partial agonists at the glycine site of the NMDA receptor, despite exhibiting functional differences in electrophysiological studies, inhibit glutamate-induced neurotoxicity and ischemia-induced neurodegeneration. The objective of this study was to investigate the effects of both glycine site antagonists and partial agonists on NMDA receptor-mediated [3H]arachidonic acid (AA) release evoked by glutamate, NMDA or a competitive inhibitor of the glutamate/aspartate uptake carrier. The [3H]AA release evoked by a maximally effective concentration of glutamate (100 microM) was blocked by the glycine site antagonists 7-chlorokynurenic acid (7-CKYN) and 5,7-dichlorokynurenic acid (5,7-DCKYN) and by a low intrinsic efficacy glycine partial agonist (+)-1-hydroxy-3-aminopyrrolid-2-one [(+)-HA-966]. 1-Aminocyclopropanecarboxylic acid (ACPC), a high intrinsic efficacy glycine partial agonist, did not modify [3H]AA release evoked by 100 microM glutamate. However, ACPC blocked (in a glycine reversible manner) the [3H]AA release induced by NMDA (100 microM) with an IC50 of 131 +/- 2 microM. Furthermore, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a competitive inhibitor of the glutamate transporter, also released [3H]AA (Emax and EC50 of 127 +/- 4% and 30 +/- 1 microM, respectively). ACPC, 7-CKYN and (+/-)-2-amino-7-phosphonoheptanoic acid (AP-7), a competitive NMDA receptor antagonist, inhibited [3H]AA release evoked by PDC. These results demonstrate that both glycine site antagonists and partial agonists can inhibit NMDA receptor-mediated [3H]AA release in cerebellar granule cells, an action consistent with the neuroprotective effects of these compounds.
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PMID:Glycine site antagonists and partial agonists inhibit N-methyl-D-aspartate receptor-mediated [3H]arachidonic acid release in cerebellar granule cells. 958 May 93

Formation of free radicals during reperfusion of the isolated ischemic heart has often been demonstrated by detecting hydroxyl radical spin adducts of the nitrone 5,5-dimethyl-1-pyrroline N-oxide (DMPO) in coronary effluents. However, questions still remain regarding (a) whether the reported cardiovascular effects of nitrone perfusion may affect the formation of spin adducts, and (b) the primary generation of superoxide (O2.-), because of the short persistency of O2.-/DMPO spin adduct. We therefore compared the effects of perfusing 5 mM of two nitrones, DMPO and 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) or the two structurally related pyrrolidines, diethyl (2-methyl-2-pyrrolidinyl) phosphonate (DEPMPH) and pyrrolidine (PyH), on postischemic functional recovery of rat hearts subjected to 10 min of low-flow ischemia, 30 min of global ischemia and 60 min of reperfusion. All compounds were added to the perfusate before ischemia, throughout low-flow ischemia and during the initial 10 min of reflow. In one additional group, hearts received DEPMPO only at reflow. Hemodynamic and in vitro ESR evidence is presented indicating that the phosphonate group of DEPMPO and DEPMPH confers these molecules with an enhanced cardioprotective efficacy, unrelated to radical scavenging, acting in synergy with the intrinsic radical trapping effects of the nitronyl group. Continuous-flow ESR spin trapping using 5.7 mM DEPMPO administered at reflow, but not before ischemia, demonstrated for the first time extended formation of O2.- in the reperfused myocardium.
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PMID:Nitrone spin traps and their pyrrolidine analogs in myocardial reperfusion injury: hemodynamic and ESR implications--evidence for a cardioprotective phosphonate effect for 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide in rat hearts. 966 Jan 78

Impairment of glutamate transport during ischemia might be related to the elevation of the extracellular concentration of glutamate and ischemic neuronal damage. Additionally, impairment of energy metabolism in vivo leads to neurodegeneration apparently mediated by a secondary excitotoxic mechanism. In vitro observations show that glucose deprivation and inhibition of energy metabolism exacerbate the toxic effects of glutamate. We have previously shown that glutamate uptake inhibition in vivo by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) leads to a substantial elevation in the extracellular concentration of excitatory amino acids that is not associated with cell death. These observations suggest that energy depletion during ischemia might be determinant of ischemic neuronal damage. To investigate whether impairment of energy metabolism in vivo increases neuronal susceptibility to glutamate uptake inhibition, we studied the effect of glutamate accumulation induced by the intrahippocampal or intrastriatal administration of PDC in energy-deficient rats chronically treated with 3-nitropropionic acid (3-NP), which irreversibly inhibits the tricarboxylic acid cycle and electron transport chain. Extracellular glutamate levels were monitored by HPLC from fractions collected from microdialysis probes, and neuronal damage was evaluated by histological analysis. Our results show that glutamate uptake inhibition leads to marked neuronal damage in energy-deficient rats but not in intact animals, which apparently is not related to an additional elevation of glutamate levels induced by 3-NP.
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PMID:Transient inhibition of glutamate uptake in vivo induces neurodegeneration when energy metabolism is impaired. 988 63

The transcription factor nuclear factor kappaB (NF-kappaB) regulates multiple immediate-early gene expressions involved in immune and inflammatory responses and cellular defenses. Ischemia-reperfusion induces many immediate-early gene expressions, but little is known about the NF-kappaB activation in myocardium during ischemia and reperfusion. This study demonstrated that ischemia alone rapidly induced NF-kappaB activation in the myocardium of isolated working rat hearts. Electrophoretic mobility shift assay showed that NF-kappaB binding activity significantly increased in the nucleus after 5 min of ischemia and remained elevated for up to 30 min. Western blot analysis suggested that the levels of inhibitory IkappaBalpha protein in the cytoplasm became markedly decreased at 4, 5, 7.5, and 10 min of ischemia but were gradually restored following 10 min of ischemia. Reduction of IkappaBalpha protein in the cytoplasm by ischemia resulted in NF-kappaB translocation to the nucleus. Northern blot hybridization showed that IkappaBalpha mRNA levels were not significantly elevated during myocardial ischemia. Pyrrolidine dithiocarbamate, an antioxidant, significantly inhibited the loss of IkappaBalpha protein from the cytoplasm and prevented NF-kappaB binding activity in the nucleus. Reperfusion following short periods of ischemia augmented NF-kappaB binding activity in the nucleus induced by ischemia. The results suggest that early activation of NF-kappaB induced by ischemia in the myocardium could be a signal mechanism for controlling and regulating immediate-early gene expression during ischemia-reperfusion.
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PMID:Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. 995 Aug 56


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