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

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

Hypoxia-ischemia, hypoglycemia, and status epilepticus damage specific regions in the developing brain. The factors which determine selective neuronal vulnerability have remained obscure but recent research suggests that the patterns may be related to dysfunction of specific sets of synapses. An important current hypothesis suggests that hyperactivity of excitatory synapses, which use neurotransmitters such as glutamate, may cause excessive transmitter release and lead to damage of adjacent neurons. Excessive stimulation of excitatory neurotransmitter receptors triggers a cascade of biochemical reactions and potentially lethal ionic shifts. Recent observations suggest that drugs acting at these receptors could be used to reduce brain injury caused by a variety of insults to the developing brain.
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PMID:New insights into mechanisms of neuronal damage in the developing brain. 287 53

The effect of insulin-induced hypoglycemia following 10.5 minutes of forebrain ischemia was studied in the rat. All groups received preischemic glucose loading (2 gm/kg) to promote brain infarction. Following completion of ischemia, rats received either 2 to 3 IU/kg (low-dose group) or 8 to 20 IU/kg (high-dose group) insulin. During the survival period, blood glucose concentrations were maintained in the ranges of 1.2 to 2.9 mM and 2.9 to 4.9 mM, respectively, for the low-dose and high-dose insulin groups. Control rats were given 2 gm/kg glucose immediately following ischemia. During the recovery period, until perfusion at 7 days, they were given glucose, 2 gm/kg, twice daily by intraperitoneal injection, and their drinking water was supplemented with 25% glucose. Mortality (p less than 0.05) and postischemic seizure incidence (p less than 0.01) were significantly reduced in the low-dose insulin group compared to the control group. Mortality was increased in the high-dose insulin group compared to the control group and was associated with an increased incidence of postischemic seizures. Neuropathological examination revealed no cortical infarction in the low-dose or high-dose insulin-treated rats compared to a 60% incidence of cortical infarction in the control group. In addition, the high-dose insulin-treated group showed a significant reduction in striatal and hippocampal CA1 selective neuronal necrosis compared to control rats with comparable survivals (p less than 0.05). The findings suggest that postischemic blood glucose concentrations play an important role in modulating both ischemic infarction and selective neuronal necrosis.
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PMID:The effect of postischemic blood glucose levels on ischemic brain damage in the rat. 305 89

Ischemia, hypoglycemia, and epilepsy have long been thought to produce similar or identical brain damage. Furthermore, these insults have been assumed to be additive in their damaging effects. These notions have been based on neuropathological observations in the hippocampus and cerebral cortex, and on the tenet that energy failure (ischemia, hypoglycemia) and increased demand for energy (epilepsy) similarly give rise to selective neuronal necrosis. Recently, other bases for considering these three insults identical have grown out of observations that loss of calcium homeostasis is common to all and that an excitotoxic mechanism of selective neuronal necrosis exists in all three conditions. Fundamental differences between ischemia, hypoglycemia, and epilepsy include the underlying neurochemical changes induced, the neuronal revival times, the time course of neuronal death, the distribution of selective neuronal necrosis, and the likely excitotoxins released. Lactic acid accumulation, implicated in damage to the neuropil as well as to neuronal cell bodies, also occurs to different degrees and in different distributions in the three conditions. The degree and distribution of pannecrosis is thus also different in ischemia, hypoglycemia, and epilepsy.
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PMID:Biological differences between ischemia, hypoglycemia, and epilepsy. 306 62

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

In 27 cats treated to vary arterial serum glucose concentrations, we measured cerebral high-energy phosphate metabolite concentration and intracellular pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy during transient global cerebral ischemia and reperfusion. Hypoglycemia was induced with 4 units/kg i.v. insulin in six cats before ischemia; hyperglycemia was induced with 1.5 g/kg i.v. glucose in six cats before and in six cats during ischemia. Nine untreated cats subjected to ischemia without manipulation of blood glucose concentration served as controls. During ischemia, intracellular pH fell to similar levels in the control and both hyperglycemic groups. During reperfusion, the hyperglycemic before ischemia group initially exhibited a severe further decline in intracellular pH (p less than 0.003); this further decline was not observed in the control or the hyperglycemic during ischemia groups. Intracellular acidosis was attenuated both during ischemia and early after reperfusion in the hypoglycemic before ischemia group. In all groups, cerebral high-energy phosphate metabolite concentrations were depleted during ischemia and then recovered to the same degree during reperfusion. Our data suggest that brain glucose stores before ischemia determine the severity and time course of intracellular acidosis during ischemia and reperfusion.
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PMID:Global cerebral ischemia and intracellular pH during hyperglycemia and hypoglycemia in cats. 318 23

This study was designed to determine the effect of fasting upon cerebral hypoxic-ischemic injury. In the first part of the study the effect of fasting was determined for survival, brain tissue water and kation contents, and blood-brain barrier integrity. In the second part of the study the administration of the substrates beta-hydroxybutyrate (BHB) and glucose has been evaluated regarding their influence upon the effect of fasting. The study used the Levine-Klein model of unilateral carotid occlusion and hypoxia because it mimics clinical situations of ischemia with hypoxia. The data show that fasting did protect rats from developing brain infarction following hypoxia-ischemia. Hypoglycemia seems to be involved in the mitigation of ischemic blood-brain barrier disruption. The plasma glucose level seems to be not the only factor involved in the genesis of the tissue kation changes. Starvation-induced ketosis probably does not play a role in the protection mechanism.
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PMID:Protective effect of fasting upon cerebral hypoxic-ischemic injury. 324 3

Hypoglycemia was induced by intracarotid insulin infusions in adult Lewis rats. Electron microscopy of the acoustic cortices in these animals revealed that hypoglycemia provoked marked morphological and morphometric alterations in the pre- and postsynaptic terminals present, as well as in the astrocytic processes seen. The number of the synaptic vesicles in the "active zone" of the synapses was dramatically decreased, with most of the vesicles loosely dispersed in the entire presynaptic profile. Some of the pre- and postsynaptic terminals were enlarged and contained dilated cisternae of smooth endoplasmic reticulum, as well as mitochondria exhibiting a marked internal disorganization. The synaptic clefts in a large number of synapses were dilated and contained fibrillary material. The most striking morphological alterations seen involved a membrane discontinuity of the postsynaptic terminal and was found mostly in the synapses of the superficial layer of the acoustic cortex. Most of the morphological alterations observed in the acoustic cortex following uncomplicated hypoglycemia are seen in sensitive areas of the brain after ischemia or hypoxia.
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PMID:Synaptic alterations in the acoustic cortex of the rat following insulin-induced hypoglycemia. 330 32

Focal cerebral ischemia was produced by occlusion of the middle cerebral artery in rats. Cerebral blood flow measured with [14C]iodoantipyrine was severely reduced in the lateral portion of neostriatum. This area of dense ischemia was sharply demarcated against the surroundings. The adjacent cortex was perfused at one-third of normal, whereas blood flow in the medial neostriatum was only slightly reduced. This pattern of perfusion was independent of the plasma glucose concentration of the animal. In contrast, the glucose utilization calculated from the 2-[3H]deoxyglucose accumulation depended on the plasma glucose concentration. Enhanced glucose utilization was evident in the border areas surrounding the ischemic focus in normoglycemic animals. Neither acutely nor chronically diabetic animals had such an increase of metabolism in the borderzone. Moderately hyperglycemic rats had a narrow rim of enhanced glucose utilization immediately surrounding the ischemic core, whereas animals with plasma glucose values above 22 mmol/L had no such rim. In mild hypoglycemia (2-4 mmol/L), the glucose utilization was slightly enhanced in the border areas, but during severe hypoglycemia (less than 2.5 mmol/L), the glucose utilization declined gradually toward the ischemic core. Glucose content, and thereby the lumped constant (measured by 3-0-[14C]methylglucose) showed little regional variation, except in the ischemic core. These findings indicate that blood flow alterations after occlusion of the middle cerebral artery in rats are not influenced by the plasma glucose utilizations. In contrast, glucose utilization depends on a combination of plasma glucose concentration and blood flow instead of blood flow per se.
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PMID:Autoradiographic determination of cerebral glucose content, blood flow, and glucose utilization in focal ischemia of the rat brain: influence of the plasma glucose concentration. 333

Flurothyl-induced status epilepticus was studied by light and electron microscopy (LM, EM) to determine the time course and structural features of neuronal necrosis in the vulnerable brain regions in epilepsy. The cerebral cortex, hippocampus and thalamus were examined after closely spaced recovery periods of up to 1 week. The results showed that acidophilic neurons appeared simultaneously in neurons of the neocortex, hippocampus and thalamus, and that this occurred within 1 h following the end of the epilepsy. The corresponding features of acidophilic neurons by EM were mitochondrial flocculent densities and large discontinuities in cell and nuclear membranes. Dark neurons were ubiquitous during the epilepsy, but recovered almost universally. A few dark neuronal forms persisted and underwent cytorrhexis after 12-h recovery or longer. Axon-sparing dendritic lesions characteristic of excitotoxic neuronal death were found in the neuropil of the neocortex, and in both vulnerable CA1 and resistant CA3 neurons of the hippocampus. Other than acute edema, glial changes were absent. The findings support an excitotoxic mechanism in epilepsy-induced selective neuronal necrosis also in brain regions outside the hippocampus, and contrast with previous reports in ischemia and hypoglycemia in that neuronal necrosis occurs virtually immediately after an epileptic insult. No "maturation" of cell damage, as described in ischemia, was seen. Furthermore, even exceedingly dark neuronal forms and massive dendritic swelling must be considered sub-lethal or prelethal cellular changes. Lethal cellular changes include acidophilia by LM, cell membrane breaks, and mitochondrial flocculent densities by EM.
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PMID:The nature and timing of excitotoxic neuronal necrosis in the cerebral cortex, hippocampus and thalamus due to flurothyl-induced status epilepticus. 336 60


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