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

Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy-compromised cells since the NMDA receptor-linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy-deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Furthermore the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium-related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks "fast" excitation and Na+ influx, an "upstream" event which causes "downstream" calcium influx via multiple pathways. In the perifocal ("penumbra") zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium-carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.
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PMID:Neurocytotoxicity: pharmacological implications. 168 4

In situ hybridization was used to study expression of mRNAs for members of the nerve growth factor (NGF) family in the rat brain after 2 and 10 min of forebrain ischemia and 1 and 30 min of insulin-induced hypoglycemic coma. Two hours after the ischemic insults, the level of brain-derived neurotrophic factor (BDNF) mRNA was markedly increased in the granule cells of the dentate gyrus, and at 24 h it was still significantly elevated. NGF mRNA showed a pronounced increase 4 h after 2 min of ischemia but had returned to a control level at 24 h. Both 2 and 10 min of ischemia caused a clear reduction of the level of mRNA for neurotrophin 3 (NT-3) in the dentate granule cells and in regions CA2 and medial CA1 of the hippocampus 2 and 4 h after the insults. The increase of BDNF mRNA could be partially blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist NBQX but was not influenced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Both NBQX and MK-801 attenuated the decrease of NT-3 mRNA after ischemia. One and 30 min of hypoglycemic coma also induced marked increases in BDNF and NGF mRNA in dentate granule cells with maximal levels at 2 h. If the changes of mRNA expression lead to alterations in the relative availability of neurotrophic factors, this could influence functional outcome and neuronal necrosis following ischemic and hypoglycemic insults.
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PMID:Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. 173 36

The experiments were designed to test the possibility that calcium influx into neurons via voltage sensitive calcium channels (VSCCs) contribute to brain damage in two conditions in which any amelioration of neuronal necrosis may be assumed not to occur through an improvement of blood flow, viz., hypoglycemic coma and brief transient ischemia. Hypoglycemic coma is thought to lead to neuronal necrosis by release of glutamate and cellular influx of calcium during the insult, while damage due to brief transient ischemia may, at least in part, result from increased calcium cycling across cell membranes in the postinsult period. The insults were delivered to anesthetized rats, and the localization and density of neuronal necrosis were evaluated by histopathology following 1 week of recovery. One dihydropyridine calcium antagonist (isradipine), given in doses which have been reported to ameliorate ischemic damage due to stroke, failed to reduce damage incurred by 30 min of hypoglycemic coma, or 15 min of transient forebrain ischemia. Provided that it can be assumed that isradipine in the doses employed reduced calcium influx via VSCCs, the results support the notion that calcium influx through VSCCs plays only a minor pathogenetic role in global/forebrain ischemia or in hypoglycemia, and they suggest that the effect of blockers of VSCCs in stroke, if any, is due to both blockade of VSCCs and increase in blood flow.
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PMID:The effect of a dihydropyridine calcium antagonist (isradipine) on selective neuronal necrosis. 183 Aug 97

Fructose-1,6-diphosphate has been shown to improve neurologic recovery following resuscitation from cardiac arrest and to restore brain electrical activity during hypoglycemic coma in rabbits. In view of these findings, we determined whether fructose-1,6-diphosphate protects the brain during ischemia-hypoxia. We subjected 16 rabbits to hypotension, hypoxemia, and bilateral common carotid artery occlusion. Five minutes after the onset of isoelectric electroencephalograms, seven randomly selected rabbits received 10% fructose-1,6-diphosphate (350 mg/kg bolus followed by 10 mg/kg/min infusion for 90 minutes) and the remaining nine rabbits (controls) received an equal volume of 1.5% NaCl (3.5 ml/kg bolus followed by 0.1 ml/kg/min infusion for 90 minutes). After isoelectricity lasting 7.86 +/- 0.8 minutes (mean +/- SEM) in the treated group and 6.44 +/- 0.38 minutes in the control group, the rabbits were reinfused with autologous shed blood and reoxygenated and the carotid artery occluders were removed. Treated rabbits recovered electrical activity more rapidly than the controls (p less than 0.005), and all seven treated rabbits survived. Only two controls (22%) survived (p less than 0.001), and they were severely disabled. Histology showed extensive cortical necrosis and focal necrosis in the hippocampi and cerebellum of brains from the two surviving controls. Brains from two treated rabbits exhibited minimal neuronal loss limited to the neocortex, and the brains from the remaining five treated rabbits were normal. This study suggests that fructose-1,6-diphosphate protects the brain from ischemic-hypoxic insults.
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PMID:Prevention of ischemic-hypoxic brain injury and death in rabbits with fructose-1,6-diphosphate. 232 42

In this chapter, the pathophysiology and neurochemical pathology of epileptic brain damage is discussed on the basis of an integrative approach in which a comparison is made to cell necrosis resulting from ischemia and hypoglycemia. Two main questions are asked. First, is the brain damage resulting from these three disorders of cerebral energy metabolism similar in distribution and structural characteristics, as previously proposed? Second, is it possible to identify one or several neurochemical events, at the cellular and subcellular level, that qualify as the final common pathways leading to neuronal necrosis? A related question is, will seizures cause structural damage even if they do not critically curtail cellular oxygen supply? A review of the literature and of recent results obtained in animals with long-term recovery following status epilepticus of known duration suggests that although brain damage caused by epilepsy shows some similarities to that incurred due to ischemic and hypoglycemic insults, it is far from identical. In well oxygenated animals with an adequate cardiovascular function, 2 hr of status epilepticus causes moderate neuronal necrosis in the cerebral cortex (layers 3-4), the hippocampus (CA4 and CA1 pyramidal cells), and the thalamus (ventromedial nuclei). In rats, status epilepticus of 30 min duration or longer invariably causes infarction of the substantia nigra (pars reticularis), with some affectation of globus pallidus as well. Notably, CA3 pyramids and dentate neurons are spared, as is the pars compacta of the substantia nigra. Neurochemical events in ischemia, hypoglycemia, and status epilepticus show some striking dissimilarities, yet all three conditions lead to neuronal necrosis. In complete or near-complete ischemia, in which metabolic rate virtually ceases; deterioration of tissue energy state is rapid and extensive, with dramatic loss of ion homeostasis; cellular redox systems are reduced; and acidosis is marked to excessive. In hypoglycemic coma, oxygen consumption continues, albeit at a reduced rate; loss of high energy phosphates is extensive but less than complete, as is loss of ion homeostasis; cellular redox system become oxidized; and acidosis is absent. In epileptic seizures, finally, metabolic rate is markedly enhanced; perturbation of tissue energy state and of ion homeostasis is minimal to small; and acidosis is moderate. Results obtained in experimental animals suggest that neuronal necrosis, when incurred, is unrelated to energy failure and occurs in spite of adequate cellular oxygenation. Four neurochemical events are common to all three conditions discussed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epileptic brain damage: pathophysiology and neurochemical pathology. 287 25

This article provides a brief review of recent developments regarding the pathophysiology of ischemic brain damage, and offers hypotheses explaining the pathogenesis of selective neuronal vulnerability and of tissue infarction, respectively. It is suggested that selective neuronal vulnerability, observed after brief periods of ischemia and after hypoglycemic coma, qualifies as an excitotoxic lesion, which causes postsynaptic damage to neurons innervated by excitatory amino acids by enhancing calcium influx. However, ischemic damage often involves glial and vascular cells as well, and causes infarction. It is hypothesized that this type of brain damage is related to acidosis and that enhanced acidosis is detrimental because it accelerates delocalization of protein-bound iron, with an ensuing free-radical damage to membrane lipids and proteins.
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PMID:Mechanisms of ischemic brain damage. 304 96

Selective lesions of the noradrenergic locus coeruleus (LC) system have recently been shown to aggravate both ischemic and epileptic brain damage. This study explores the possibility that the LC system also influences hypoglycemic brain injury. Bilateral 6-hydroxydopamine lesions of the LC projection to the forebrain were found to cause no change in the degree of neuronal necrosis in the neocortex, hippocampal formation and caudate-putamen following 30 min of reversible insulin-induced hypoglycemic coma. We propose that selective neuronal necrosis in ischemia and status epilepticus is due to the action of excitatory amino acids at synaptic sites, which can be partly counteracted by noradrenaline release from inhibitory LC terminals. In hypoglycemia, excitatory amino acids probably cause brain damage via a local and more diffuse toxic effect which is not significantly influenced by the activation of the LC system.
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PMID:Mechanisms of hypoglycemic brain damage. Evidence against a significant role of the noradrenergic locus coeruleus system. 314 10

A persistent vegetative state (severe dementia) developed in a 30-year-old man following hypoglycemic coma. Despite the poor clinical outcome, sensory evoked response recovered between 6 and 34 months after the insult. The cerebral blood flow level at rest after 34 months was slightly above the normal range. This finding contrasts with the low cerebral blood flow regularly reported in patients who are comatose or stuporous following severe brain hypoxia-ischemia.
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PMID:Persistent vegetative state with high cerebral blood flow following profound hypoglycemia. 663 60

The present experiments were designed to provide information on brain calcium metabolism during hypoglycemic coma. We specifically wished to evaluate changes in extracellular calcium concentration (Ca2+e) during prolonged hypoglycemic coma and recovery and to assess whether Ca2+e falls to similar values during hypoglycemia and ischemia. To that end, Ca2+e and K+e in neocortical tissue were recorded by ion-sensitive microelectrodes during hypoglycemic coma of 30 min duration and during 15 min of recovery. Cardiac arrest ischemia was induced either at the end of the period of hypoglycemia or after 15 min of recovery. Hypoglycemic coma, as reflected by a DC potential shift and by cellular release of K+, was accompanied by a sustained decrease in Ca2+e from approximately 1.2 to approximately 0.02 mM, i.e., to approximately 1% of control. Infusion of glucose was followed by a biphasic recovery of Ca2+e, starting within 2 min of infusion. During the first phase, completed within the initial 3-4 min, Ca2+e rose to about 25% of control. During the second phase, Ca2+e slowly increased toward normal within 25-30 min. Ischemia, when induced at the end of the period of hypoglycemia, was accompanied by a rise in Ca2+e to about 0.1 mM, i.e., about 10% of control. A similar value was recorded when ischemia was induced after 15 min of recovery following a 30-min hypoglycemic coma. Although the present results do not give information on Ca2+i during hypoglycemic coma, it is tempting to conclude that partial preservation of the nucleoside triphosphate stores, and absence of acidosis, allow some binding and sequestration of the calcium entering the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Brain calcium metabolism in hypoglycemic coma. 840 20

The present article is concerned with mechanisms which are responsible for the exaggerated brain damage observed in hyperglycemic animals subjected to transient global or forebrain ischemia. Since hyperglycemia enchances the production of lactate plus H+ during ischemia, it seems likely that aggravation of damage is due to exaggerated intra- and extracellular acidosis. This contention is supported by results showing a detrimental effect of extreme hypercapnia in normoglycemic rats subjected to transient ischemia or to hypoglycemic coma. Enhanced acidosis may exaggerate ischemic damage by one of three mechanisms: (i) accelerating free radical production via H(+)-dependent reactions, some of which are catalyzed by iron released from protein bindings by a lowering of pH, (ii) by perturbing the intracellular signal transduction pathway, leading to changes in gene expression or protein synthesis, or (iii) by activating endonucleases which cause DNA fragmentation. While activation of endonucleases must affect the nucleus, the targets of free radical attack are not known. Microvessels are considered likely targets of such attack in sustained ischemia and in trauma; however, enhanced acidosis is not known to aggravate microvascular dysfunction, or to induce inflammatory responses at the endothelial-blood interface. A more likely target is the mitochondrion. Thus, if the ischemia is of long duration (30 min) hyperglycemia triggers rapidly developing mitochondrial failure. It is speculated that this is because free radicals damage components of the respiratory chain, leading to a secondary deterioration of oxidative phosphorylation.
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PMID:Molecular mechanisms of acidosis-mediated damage. 878 Jul 90


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