Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine (DA), serotonin (5-HT), tryptophan (TRP), 5-hydroxyindole acetic acid (5-HIAA), and GABA were assayed spectrofluorometrically in various regions of 16 human post-mortem brains with acute and old cerebral infarction. In both recent and older strokes a total depletion of DA and 5-HT in the necrotic tissue was associated with mild reduction of these compounds in remote non-ischemic areas of the injured, and less of the contralateral cerebral hemispheres. 5-HIAA was significantly reduced in acute ischemic necrosis, while the perifocal edema zone showed considerable accumulation of both 5-HT and 5-HIAA. Marked elevation of the 5-HT precursor TRP and of GABA was present in both the necrotic center and perifocal edema of acute infarcts, which also showed a mild reduction of total proteins. The degradation zone surrounding old infarcts showed a mild decrease of both 5-HT and 5-HIAA with normal TRP levels, indicating normalization of the previously increased 5-HT metabolism and turnover after decrease of acute cerebral edema. These data which confirm previous studies in experimental cerebral ischemia and stroke indicate that disorders in the metabolism of brain monoamines and other putative neurotransmitters contribute to the development of postischemic brain damage and the complicating cerebral edema. They are also in keeping with the concept that unilateral focal ischemia produces bilateral effects on brain monoamines.
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PMID:Changes of some putative neurotransmitters in human cerebral infarction. 3 76

Cerebral ischemia was induced in normothermic, artificially ventilated rats, anesthetized with 70% N2O or 150 mg/kg of phenobarbitone, by bilateral occlusion of the common carotid arteries and by simultaneous depression of the mean arterial blood pressure to 50 mm Hg. The levels of tyrosine, dopamine (DA), noradrenaline (NA), tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured after 15 min of ischemia as well as after 30 min of recirculation. In separate experiments (70% N2O) the rate of accumulation of DOPA and 5-hydroxytryptophan (5-HTP) was determined in three different brain regions (striatum, limbic forebrain and hemispheres) during recirculation. During ischemia, the monoamine pattern was unaffected. Following recirculation, increases in DA, 5-HIAA, tyrosine and tryptophan were found irrespective of the type of anesthesia used. Pronounced postischemic decreases in NA and 5-HT were observed in animals anesthetized with nitrous oxide but not in those given phenobarbitone. During recirculation the rate of tyrosine hydroxylation increased in all three brain regions while tryptophan hydroxylation was reduced. It is tentatively concluded that following transient, global cerebral ischemia, neuronal activity is low or eliminated in dopaminergic and serotoninergic neurons and high in noradrenergic neurons.
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PMID:Influence of transient ischemia on monoamine metabolism in the rat brain during nitrous oxide and phenobarbitone anaesthesia. 30 81

The effects of gamma-hydroxybutyrate (GHB) on 1) monoamine metabolism, and 2) protein synthesis were examined in a gerbil stroke model. The monoamine metabolism was studied by occluding bilateral common carotid arteries for 15 minutes followed by GHB administered intravenously 3 hours later. Tissue monoamine concentration was examined up to 8 hours after recirculation. Three hours after GHB administration, dopamine (DA) had increased to almost twice that of the non-treated group, whereas homovanillic acid, a metabolite of DA, did not show any significant difference. These results may mean that GHB will facilitate DA synthesis but that it has no influence on its release. Therefore, a DA-mediated increase in cerebral blood flow in the cerebral cortex cannot be expected. Tryptophan, a precursor of 5-hydroxytryptamine (5HT), started to increase just after recirculation reaching a level of over four times that of the control value at 2 to 3 hours, and then starting to decrease in the non-treated group. This decline in tryptophan was markedly facilitated by GHB administration within 1 hour. On the other hand, 5HT administration within 1 hour. On the other hand, 5HT increased only very slightly in the cerebral cortex 1 hour after GHB administration, the change ratio being 1/30 of tryptophan. It can therefore be speculated, that the decrease in tryptophan brought about by GHB administration is due to the improvement in disturbed protein synthesis rather than to stimulation of 5HT synthesis. Protein synthesis was studied by administering GHB 2 minutes prior to a 5-minute temporal common carotid artery occlusion. Ninety minutes after recirculation animals were given a single dose of 14C-leucine and further 60 minutes were allowed to pass before sacrifice. Autoradiographs of the GHB-treated group were compared with those of the non-treated group. With GHB pretreatment, autoradiographs showed an increased uptake of 14C-leucine in at least the hippocampus, thalamus, and hypothalamus, and in two out of three animals, there was diffusely increased uptake. Thus, it is speculated that GHB is effective in improving the protein synthesis in the postischemic period. The favorable function of GHB during cerebral ischemia is regarded by many to be prevention of energy failure by reducing cerebral metabolism. On the other hand, the results derived from the present study suggest that GHB may improve protein synthesis in the postischemic period. Thus, we suggest that GHB is useful if given at the acute stage of cerebral ischemia such as during internal carotid artery or middle cerebral artery occlusion.
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PMID:[Effects of gamma-hydroxybutyrate on monoamine metabolism and protein synthesis after transient global cerebral ischemia]. 140 58

Excessive activity or release of excitatory amino acids has been implicated in the neuronal injury that follows transient cerebral ischemia. To investigate the metabolism of the endogenous excitotoxin, quinolinic acid, and its potential for mediating cell loss following ischemia, the concentrations of quinolinic acid, L-tryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were quantified in gerbil brain regions at different times after 5 or 15 min of ischemia induced by bilateral carotid artery occlusion. Significant elevation of brain tryptophan levels, accompanied by increased 5-hydroxyindoleacetic acid concentrations, occurred during the first several hours of recirculation, but regional brain quinolinic acid concentrations were found either to decrease or remain unchanged during the first 24 h after the ischemic insult. However, significant increases in quinolinic acid concentrations occurred in striatum and hippocampus at 2 days of recirculation after 5 min of ischemia. After a further 4 and 7 days, strikingly large increases in quinolinic acid concentrations were observed in all regions examined, with the highest levels observed in the hippocampus and striatum, regions that also show the most severe ischemic injury. These delayed increases in brain quinolinic acid concentrations are suggested to reflect the presence of activated macrophages, reactive astrocytes, and/or microglia in vulnerable regions during and subsequent to ischemic injury. While the results do not support a role for increased quinolinic acid concentrations in early excitotoxic neuronal damage, the role of the delayed increases in brain quinolinic acid in the progression of postischemic injury and its relevance to postischemic brain function remain to be established.
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PMID:Delayed increases in regional brain quinolinic acid follow transient ischemia in the gerbil. 169 82

Changes in cerebral free amino acids, catecholamines and uric acid levels were explored for up to 7 days after cerebral ischemia in the rat. Fifty male Sprague-Dawley rats were subjected to occlusion of the middle cerebral artery on the olfactory tract, under halothane anesthesia. The animals were decapitated at 2, 4, 6, 12, 24 hours and 2, 3, 5, 7 days after the surgery, respectively. The brains were rapidly removed. The cerebral hemispheres were divided into right and left halves, and homogenized in sulfosalicylic acid solution. Free amino acids were analyzed by colormetric method. Cathecholamines and uric acid were analyzed by high-performance liquid chromatography. Each parameters were measured both on the ischemic and contralateral hemispheres. The time course of changes in each parameters were observed by means of the ratio, which is the value of ischemic side divided by that of contralateral side. Free amino acids Dicarboxylic group; Decreases in glutamate and increases in glutamine suggest one aspect of detoxication of ammonia within the ischemia tissue. Monocarboxylic group; GABA, glycine, alanine were increased in early ischemic state, and gradually lowered to the normal values. These suggest the impairment of tricarboxylic acid (TCA) cycle in the ischemic tissues, since these amino acids are closely related to TCA cycle. Essential amino acids, except for tryptophan, were increased until the end of study. These increases suggest the utilization of essential amino acids for protein synthesis might be disturbed in the ischemic tissues. Catecholamines and precursors; Norepinephrine and dopamine were lowered gradually. On the other hand, phenylalanine and tyrosine were increased during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Biochemical studies of the cerebral ischemia in the rat--changes in cerebral free amino acids, catecholamines and uric acid]. 370 75

Male gerbils (Meronies ungulata) were treated with various doses of tryptophan and the changes in spontaneous motor activity determined. Tryptophan decreased behavior at a dose of 200 mg/kg. Cerebral ischemia was produced by bilateral carotid occlusion for 5 min. This duration of ischemia produced a large increase in activity at both 6 h and 24 h postischemia. Tryptophan (200 mg/kg) prevented the ischemia-induced increases in locomotor activity. These data suggest that dietary amino acids may play a role in determining the effects of ischemia.
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PMID:Acute tryptophan pretreatment protects against behavioral changes caused by cerebral ischemia. 372 76

The excitotoxic hypothesis postulates a central role for the excitatory amino acids (EAAs) and their receptors in the neuronal damage that ensues cerebral ischemia-hypoxia and numerous other brain disorders. A major premise of the excitotoxic hypothesis is that neuronal protection can be achieved via blockade of EAA receptors with specific antagonists. This paper describes the use of the rat hippocampal slice preparation in the evaluation of various EAAs and their analogues for their potency as excitotoxins (agonists) and antagonists of the NMDA and the kainate/AMPA glutamate receptor subtypes. The hypersensitivity of hypoxic hippocampal slices to the presence of excitotoxins provided us with an inexpensive, sensitive tool to distinguish between structurally similar compounds. Moreover, these studies indicate that hypoxic neuronal damage cannot solely result from an excitotoxic mechanism; the involvement of voltage-dependent calcium channels in such damage is likely, as is evident from experiments performed in calcium-depleted medium and with the non-competitive NMDA antagonist MK-801. At sub-toxic doses, quinolinate, a tryptophan metabolite implicated in Huntington's disease, appears to be a strong potentiator of the toxicity of all excitotoxins tested.
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PMID:Hypoxia, excitotoxicity, and neuroprotection in the hippocampal slice preparation. 747 43

Accumulation of L-kynurenine and quinolinic acid (QUIN) in the brain occurs after either ischemic brain injury or after systemic administration of pokeweed mitogen. Although conversion of L-[13C6]tryptophan to [13C6]-QUIN has not been demonstrated in brain either from normal gerbils or from gerbils given pokeweed mitogen, direct conversion in brain tissue does occur 4 days after transient cerebral ischemia. Increased activities of enzymes distal to indoleamine-2,3-dioxygenase may determine whether L-kynurenine is converted to QUIN. One day after 10 min of cerebral ischemia, the activities of kynureninase and 3-hydroxy-3,4-dioxygenase were increased in the hippocampus, but local QUIN levels and the activities of the indoleamine-2,3-dioxygenase and kynurenine-3-hydroxylase were unchanged. By days 2 and 4 after ischemia, however, the activities of all these enzymes in the hippocampus as well as QUIN levels were significantly increased. Kynurenine aminotransferase activity in the hippocampus was unchanged on days 1 and 2 after ischemia but was decreased on day 4, at a time when local kynurenic acid levels were unchanged. A putative precursor of QUIN, [13C6]anthranilic acid, was not converted to [13C6]QUIN in the hippocampus of either normal or 4-day post-ischemic gerbils. Gerbil macrophages stimulated by endotoxin in vitro converted L-[13C6]tryptophan to [13C6]QUIN. Kinetic analysis of kynurenine-3-hydroxylase activity in the cerebral cortex of postischemic gerbils showed that Vmax increased, without changes in Km. Systemic administration of pokeweed mitogen increased indoleamine-2,3-dioxygenase and kynureninase activities in the brain without significant changes in kynurenine-3-hydroxylase or 3-hydroxyanthranilate-3,4-dioxygenase activities. Increases in kynurenine-3-hydroxylase activity, in conjunction with induction of indoleamine-2,3-dioxygenase, kynureninase, and 3-hydroxyanthranilate-3,4-dioxygenase in macrophage infiltrates at the site of brain injury, may explain the ability of postischemic hippocampus to convert L-[13C6]tryptophan to [13C6]QUIN.
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PMID:Kynurenine pathway enzymes in brain: responses to ischemic brain injury versus systemic immune activation. 824 62

Delayed increases in the levels of an endogenous N-methyl-D-aspartate receptor agonist, quinolinic acid (QUIN), have been demonstrated following transient ischemia in the gerbil and were postulated to be secondary to induction of indoleamine-2,3-dioxygenase (IDO) and other enzymes of the L-tryptophan-kynurenine pathway. In the present study, proportional increases in IDO activity and QUIN concentrations were found 4 days after 10 min of cerebral ischemia, with both responses in hippocampus > striatum > cerebral cortex > thalamus. These increases paralleled the severity of local brain injury and inflammation. IDO activity and QUIN concentrations were unchanged in the cerebellum of postischemic gerbils, which is consistent with the preservation of blood flow and resultant absence of pathology in this region. Blood QUIN and L-kynurenine concentrations were not affected by ischemia. Brain tissue QUIN levels at 4 days postischemia exceeded blood concentrations, minimizing a role for breakdown of the blood-brain barrier. Marked increases in the activity of kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase were also detected in hippocampus but not in cerebellum on day 4 of recirculation. In vivo synthesis of [13C6]QUIN was demonstrated, using mass spectrometry, in hippocampus but not in cerebellum of 4-day postischemic animals 1 h after intracisternal administration of L-[13C6]tryptophan. However, accumulation of QUIN was demonstrated in both cerebellum and hippocampus of control gerbils following an intracisternal injection of 3-hydroxyanthranilic acid, which verifies the availability of precursor to both regions when administered intracisternally. Notably, although IDO activity and QUIN concentrations were unchanged in the cerebellum of ischemic gerbils, both IDO activity and QUIN content were increased in cerebellum to approximately the same degree as in hippocampus, striatum, cerebral cortex, and thalamus 24 h after immune stimulation by systemic pokeweed mitogen administration, demonstrating that the cerebellum can increase IDO activity and QUIN content in response to immune activation. No changes in kynurenic acid concentrations in either hippocampus, cerebellum, or cerebrospinal fluid were observed in the postischemic gerbils compared with controls, in accordance with the unaffected activity of kynurenine aminotransferase activity. Collectively, these results support roles for IDO, kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase in accelerating the conversion of L-tryptophan and other substrates to QUIN in damaged brain regions following transient cerebral ischemia. Immunocytochemical results demonstrated the presence of macrophage infiltrates in hippocampus and other brain regions that parallel the extent of these biochemical changes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of delayed increases in kynurenine pathway metabolism in damaged brain regions following transient cerebral ischemia. 841 38

Quinolinic acid is an excitotoxic kynurenine pathway metabolite, the concentration of which increases in human brain during immune activation. The present study compared quinolinate responses to systemic and brain immune activation in gerbils and rats. Global cerebral ischemia in gerbils, but not rats, increased hippocampus indoleamine-2,3-dioxygenase activity and quinolinate levels 4 days postinjury. In a rat focal ischemia model, small increases in quinolinate concentrations occurred in infarcted regions on days 1, 3, and 7, although concentrations remained below serum values. In gerbils, systemic immune activation by an intraperitoneal injection of endotoxin (1 mg/kg of body weight) increased quinolinate levels in brain, blood, lung, liver, and spleen, with proportional increases in lung indoleamine-2,3-dioxygenase activity at 24 h postinjection. In rats, however, no significant quinolinate content changes occurred, whereas lung indoleamine-2,3-dioxygenase activity increased slightly. Gerbil, but not rat, brain microglia and peritoneal monocytes produced large quantities of [13C(6)]-quinolinate from L-[13C(6)]tryptophan. Gerbil astrocytes produced relatively small quantities of quinolinate, whereas rat astrocytes produced no detectable amounts. These results demonstrate that the limited capacity of rats to replicate elevations in brain and blood quinolinic acid levels in response to immune activation is attributable to blunted increases in local indoleamine-2,3-dioxygenase activity and a low capacity of microglia, astrocytes, and macrophages to convert L-tryptophan to quinolinate.
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PMID:Species heterogeneity between gerbils and rats: quinolinate production by microglia and astrocytes and accumulations in response to ischemic brain injury and systemic immune activation. 932 81


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