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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues can be salvaged only by recirculation, and any brain damage incurred is delayed, suggesting that the calcium transient gives rise to sustained changes in membrane function and metabolism. If the ischemia is less dense, as in the penumbral zone of a focal ischemic lesion, pump failure may be moderate and the leak may be only slightly or intermittently enhanced. These differences in the pump/leak relationship for calcium explain why calcium and glutamate antagonists may lack effect on the cardiac arrest type of ischemia, while decreasing infarct size in focal ischemia. The adverse effects of acidosis may be exerted by several mechanisms. When the ischemia is sustained, acidosis may promote edema formation by inducing Na+ and Cl- accumulation via coupled Na+/H+ and Cl-/HCO3- exchange; however, it may also prevent recovery of mitochondrial metabolism and resumption of H+ extrusion. If the ischemia is transient, pronounced intraischemic acidosis triggers delayed damage characterized by gross edema and seizures. Possibly, this is a result of free-radical formation. If the ischemia is moderate, as in the penumbral zone of a focal ischemic lesion, the effect of acidosis is controversial. In fact, enhanced glucolysis may then be beneficial. Although free radicals have long been assumed to be mediators of ischemic cell death, it is only recently that more substantial evidence of their participation has been produced. It now seems likely that one major target of free radicals is the microvasculature, and that free radicals and other mediators of inflammatory reactions (such as platelet-activating factor) aggravate the ischemic lesion by causing microvascular dysfunction and blood-brain barrier disruption.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. 150 80

The responses to the glutamate agonist N-methyl-D-aspartate (NMDA) were studied in the sensori-motor cortex of rats with petit mal-like seizures. In a first study, the changes in extracellular concentration of calcium elicited through ionophoretic application of NMDA at various depths in the cortex were measured in vivo. The results show that in the cortex of epileptic rats the NMDA responses are much more widely distributed than in the cortex of control rats. In a second study, a current-source density analysis of the responses elicited through electrical stimulation of the white matter was performed in slices of neocortex in vitro. These findings show that the NMDA-dependent component of the synaptic responses are more widely distributed and of longer duration in the cortex of epileptic rats than in that of control rats. Taken together, these results suggest that in this model of absence epilepsy NMDA-dependent mechanisms are important in the triggering and maintenance of epileptic activity.
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PMID:Responses to N-methyl-D-aspartate are enhanced in rats with petit mal-like seizures. 151 97

A semi-quantitative estimation has been made of the effect of anaesthetics, anticonvulsants and glutamate antagonists on the extent of neuronal loss in the hippocampus caused by the local injection of the excitotoxin kainic acid, and on the vulnerability of neurons in various extrahippocampal regions due to the resulting seizure activity. Following the intrahippocampal injection of 0.47 nmol kainic acid (a submaximal dose), the amount of neuronal loss in the dorsal hippocampus was greater when given under the short-acting anaesthetics halothane and ketamine (a non-competitive glutamate antagonist), than when given under pentobarbital anaesthesia (with or without co-administration of ketamine (30 mg/kg)). When kainic acid was injected under halothane or ketamine anaesthesia a greater number of extrahippocampal limbic regions (distal toxicity) were also affected, usually on the ipsilateral side, and the extent of damage in each of these regions was generally more extensive. The anticonvulsants MK 801 and diazepam, or multiple injections of ketamine over a period of 5 h, decreased both the local and distal toxicity of kainic acid injected under short duration anaesthesia, to levels similar to those found under pentobarbital anaesthesia. However, these compounds, even at high doses, could not reliably prevent all seizure-related damage in extrahippocampal areas.
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PMID:Effects of anaesthetics, anticonvulsants and glutamate antagonists on kainic acid-induced local and distal neuronal loss. 151 56

This overview presents data showing that glucose use increases and that excitatory amino acids (i.e., glutamate, aspartate), taurine and ascorbate increase in the extracellular fluid during seizures. During the cellular hyperactive state taurine appears to serve as an osmoregulator and ascorbate may serve as either an antioxidant or as a pro-oxidant. Finally, a unifying hypothesis is given for seizure-induced brain damage. This unifying hypothesis states that during seizures there is a release of excitatory amino acids which act on glutamatergic receptors, increasing neuronal activity and thereby increasing glucose use. This hyperactivity of cells causes an influx of calcium (i.e., calcium stress) and water movements (i.e., osmotic stress) into the cells that culminate in brain damage mediated by reactive oxygen species.
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PMID:The osmotic/calcium stress theory of brain damage: are free radicals involved? 153 23

Magnetic resonance spectroscopy (MRS) is a flexible tool with real clinical utility. Examples from our experience in over 250 cases of clinical proton MRS are presented. Shorter echo time and reproducible water suppression increases the number of metabolites which can be detected and identified. Case reports illustrate the significance of altered ratios of N-acetylaspartate, choline, total creatine, myo-inositol, glutamate, glutamine, lactate, glucose, ketones, and, as an incidental finding, ethanol. Significant new information has resulted by applying proton MRS in chronic hepatic encephalopathy, diabetes mellitus and severe hypoxic encephalopathy ('near-drowning'). Potentially useful measurements have been made in normal brain maturation, ethanol related diseases, dementia (normal-pressure hydrocephalus), urea cycle defect and neuronal disease presenting as seizures. Metabolite imaging, particularly with proton, is clinically valuable, documenting the heterogeneity of biochemical disorders in seemingly focal lesions. A new method of specific 31-phosphorus--phosphocreatine imaging provides information in partially denervated skeletal muscle and is expected to have applications in brain.
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PMID:Clinical tools for the 90s: magnetic resonance spectroscopy and metabolite imaging. 156 13

Administration of 1-methyl-4-phenyl-pyridinium ion (MPP+) into the lateral ventricle of mice induced clonic convulsions and lethality in a dose- and age-dependent manner. MPP+ failed to induce seizures in 4-day-old mice, and the convulsant response to MPP+ was enhanced in aged mice. The seizures triggered by MPP+ in adult mice were blocked by coadministration of L-glutamate antagonists active at kainate/AMPA receptors such as gamma-D-glutamylaminomethylsulphonate and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline. The N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate, but not kynurenate, also protected mice against MPP+ convulsions. Similarly, the benzodiazepine midazolam and the adenosine A1 agonist 2-chloroadenosine, but not antiepileptic drugs such as phenobarbital, trimethadione, ethosuximide, or acetazolamide, showed a protective efficacy against seizures. Additionally, the excitatory amino acid antagonists as well as phenobarbital, midazolam and 2-chloroadenosine protected mice against MPP+ lethality. These data suggest that convulsant action of MPP+ and its lethality in rodents may be mediated by excitatory amino acids.
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PMID:Excitatory amino acid antagonists protect mice against MPP+ seizures. 158 55

Quinolinic acid (QUI), a structural analogue of neurotransmitters such as L-glutamate and L-aspartate, may act as an 'excitotoxin' when it is abundant in the brain. The compound has been causally related to various neurodegenerative disorders, including epilepsy. We tested the capacity of the brains of epilepsy-prone El mice to synthesize QUI. The activity of 3-hydroxyanthranilate 3,4-dioxygenase in the cerebral cortex of El mice was about 17 times that of ddY mice, the parent strain of El mice. The activity of this enzyme was undetectable in brains of BALB/cA mice and C3H/HeN mice. In El mice the sexes had comparable enzyme activity. The enzyme activity increased gradually as the animals aged. An injection of endotoxin caused a further increase in the enzyme activity. The enzyme activity in the spleen of El mice did not differ from that of ddY mice, and endotoxin did not affect the enzyme activity in the spleen. No strain-difference was observed in the activity of quinolinate phosphoribosyltransferase, a QUI-degrading enzyme, in the cerebral cortex. These results suggest that an increase in the synthesis of QUI in the brain is involved in the pathogenesis of epileptic seizures in El mice.
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PMID:Abnormally high activity of 3-hydroxyanthranilate 3,4-dioxygenase in brain of epilepsy-prone El mice. 161 5

Laminer analysis of the distribution of GABA and GAD in the superior colliculus has shown that the distribution pattern of GABA within the SC is similar in rabbit, cat, and guinea pig. The highest levels of GABA were found in the superficial gray layer (SGL), averaging 37-40 mmol/kg dry weight. The GABA concentrations in the deep layers were each only half that of the levels in the SGL. The concentrations of both GABA and GAD in the upper half of SGL are the same as those in the substantia nigra and medial forebrain bundle which have the highest amounts of GABA in the CNS. Denervation studies of the fibers projecting to SGL suggest that the GABA concentrated in the SGL is intrinsic to the layer. The results obtained from immunohistochemical and electron microscopic studies on the localization of GABA neurons corresponds well with the regional distribution pattern of GABA and GAD reported here. However, pharmacological and electrophysiological studies do not necessarily accord well with the GABA distribution studies because they indicate that there are many GABA sensitive neurons in both the SGL and DGL. To investigate the role of GABA in the SGL, the effect of GABA and its agonists and antagonists on neurotransmission in SGL has been studied in SC slices in a perfusion system. Bath applied GABA (100 microM to 1 mM) enhanced the amplitude of postsynaptic field potentials (PSP) in SGL in a dose-dependent fashion and at concentrations above 1 mM it depressed the PSP in a dose-dependent fashion. A similar response pattern was obtained with muscimol (0.1-10 microM excitation; greater than 10 microM inhibition). However (-)-baclofen only inhibited the PSP. Bicuculline (1 microM) shifted the dose-response inhibitory curve of GABA to the right, while the excitatory effect was enhanced. These results indicate that GABA has an excitatory and inhibitory action on neurotransmission in the SGL. The nigro-tectal GABAergic fibers terminate in the intermediate and deep layers of SC. Inhibition of GABAergic activity in the SC causes irrepressible saccades made toward the center of the movement field while GABA activation delays and slows saccadic eye movements. Thus, GABA in the SC plays an important role in the control of eye movements. The same GABAergic projection is also related to the propagation of generalized seizures. There exist collicular neurons which suppress the propagation of seizures.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The distribution and function of gamma-aminobutyric acid (GABA) in the superior colliculus. 163 1

Ralitoline and CI-953 are anticonvulsant compounds active in both maximal electroshock and kindling models of seizures with rodents. CI-953 (IC50 = 5 microM) and ralitoline (IC50 = 2 microM) both blocked sustained repetitive firing of sodium action potentials with effects on firing activity triggered by spontaneous excitatory postsynaptic potentials at higher concentrations. No effects on iontophoretic GABA and glutamate responses were noted. Both compounds inhibited the binding of tritiated batrachotoxinin A 20-alpha-benzoate ([3H]BTX-b) to rat brain synaptosomes with apparent Kd values of 29 microM (CI-953) and 25 microM (ralitoline). Our results suggest that effects on voltage-dependent sodium channels may underlie the anticonvulsant action of these compounds.
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PMID:Ralitoline (CI-946) and CI-953 block sustained repetitive sodium action potentials in cultured mouse spinal cord neurons and displace batrachotoxinin A 20-alpha-benzoate binding in vitro. 165 Dec 26

The effects of some dipeptides, analogues of N-acetyl-alpha-L-aspartyl-L-glutamate, were studied after i.c.v. administration into mice in acute experiments. N-Acetyl-alpha-L-aspartyl-L-glutamate itself did not induce seizures in animals, but prevented glutamate-induced convulsions. All other dipeptides possessed excitatory glutamate-like actions. Some structural requirements for the excitatory effects of the dipeptides are discussed.
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PMID:Excitatory action of some aspartate- and glutamate-containing dipeptides after intracerebroventricular injection in mice. 165 72


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