Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014544 (epilepsy)
 64,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since glutamine synthetase (GS) has been proposed as the primary enzyme in the regulation of glutamate metabolism in the central nervous system and since inhibition of the activity of this enzyme in vivo leads to seizures, it has been proposed that an abnormality in the structure or function of this enzyme could be responsible for the induction of seizures in epilepsy prone rats. To test this hypothesis the glutamine synthetases were purified from the brains of both genetically epilepsy prone rats (GEPR) and their progenitors, genetically epilepsy resistant rats (GERR). The enzymes were compared using both SDS-PAGE and isoelectric focusing. The immunoreactivities of equal amounts of protein were determined using the ELISA technique, and the regulation of the glutamine synthetase activities by Mn2+/Mg2+ ratios were compared. The only difference found between the glutamine synthetases from the two strains was a slightly lower specific activity of the enzyme from the epilepsy prone animals.
 ...
PMID:Comparison of glutamine synthetases from brains of genetically epilepsy prone and genetically epilepsy resistant rats. 135 42

The purpose of this study was to determine the effects of two experimental models of chronic epilepsy in rats on the activity of the astroglial enzyme glutamine synthetase. FeCl2-induced cortical lesions that increased the sensitivity to pentylenetetrazol-induced generalized seizures also significantly increased glutamine synthetase activity in the homotopic site of the contralateral cortex. A decrease in cortical glutamine synthetase was found in the cortex ipsilateral to the stimulated amygdala in electrically kindled animals. These findings provide evidence that increased glutamine synthetase activity is associated with developing, submaximal seizures and that decreased activity is characteristic of mature, chronic seizure states such as that associated with kindled amygdala seizures.
 ...
PMID:Alterations in glutamine synthetase activity by FeCl2-induced focal and kindled amygdaloid seizures. 196 96

The effects of cortical kindling in rats on [3H]D-aspartate uptake and on glutaminase and glutamine synthetase activities has been studied. The high affinity uptake of [3H]D-aspartate in control cortical tissue (Km approximately 2 microM) was undetectable in the kindled tissue, whilst the enzyme activities were unchanged. A loss of the high-affinity uptake sites for excitatory amino acids may be a contributing factor to the kindling phenomenon.
Epilepsy Res 1987 Mar
PMID:Effect of cortical kindling on [3H]D-aspartate uptake and glutamate metabolism in rats. 290 63

The cerebral concentrations of pyridoxal-5'-phosphate and divalent transition metal ions (Cu2+ and Zn2+) are appreciably higher in the seizure-susceptible strain of mouse (DBA/2J) than those in normal strains (CBA/Ca and Parkes ). By injecting metal ions intracranially and pyridoxal-5'-phosphate intraperitoneally, we could render the normal mouse prone to sound-induced epilepsy. The behaviour of the treated seizure-susceptible strain of mouse. The levels of glutamate and aspartate in its inferior colliculus were elevated and the concentration of gamma-aminobutyrate was lowered. Glutaminase inhibitors, 6-diazo-5-oxo-L-norleucine (DON) and 0-diazo-acetyl-L-serine (azaserine), and a transaminase inhibitor, 4-amino-3- isoxazolidone (L-cycloserine), when injected intraperitoneally, protected the seizure-susceptible mouse from undergoing convulsions, whereas pyridoxal-5'-phosphate and methionine sulphoximine, a glutamine synthetase inhibitor, exacerbated its epileptic condition. We propose a possible sequence of biochemical events associated with susceptibility to audiogenic seizures.
 ...
PMID:Studies on sound-induced epilepsy in mice. 614 59

Previous investigations in seizure-prone mice have suggested that an abnormally elevated production of the astrocyte-derived neuroexcitant, quinolinic acid (QUIN), plays a role in seizure susceptibility. In order to evaluate further the role of QUIN metabolism in genetic murine seizure models, the activities of its biosynthetic enzyme 3-hydroxyanthranilic acid oxygenase (3HAO), and of two other astrocytic enzymes, kynurenine aminotransferase (KAT) and glutamine synthetase (GS), were measured in the brains of seizure-prone EL and DBA/2 mice and two non-epileptic strains (BALB/c and Swiss-Webster). 3HAO activity was found to be markedly higher in both EL and DBA/2 mice than in the non-epileptic strains in all brain regions examined. The activity of 3HAO was not modified by the tossing procedure employed to promote seizures in EL mice. While some strain differences were noted in the activities of KAT and GS, these enzymes did not distinguish seizure-prone from the non-epileptic mice. In order to delineate better the relationship between glial activation and 3HAO, KAT and GS, further studies were performed in the ibotenate-lesioned hippocampus. In mice (but not in rats), the activity of 3HAO was selectively increased in gliotic tissue. These data demonstrate substantial species and strain differences in astroglial enzymes and in their response to brain injury. The observation of widespread abnormally high 3HAO activity in two distinct seizure-prone mouse strains strengthens the hypothesis that enhanced production of QUIN contributes to seizure susceptibility in mice.
Epilepsy Res 1994 Jul
PMID:Differential expression of the astrocytic enzymes 3-hydroxyanthranilic acid oxygenase, kynurenine aminotransferase and glutamine synthetase in seizure-prone and non-epileptic mice. 780 40

Human and experimental animal studies suggest a relationship between low Mn status and seizures. The genetically epilepsy prone rat (GEPR), which has low tissue Mn levels, was studied in the context of Mn supplementation. Manganese was provided at 45 micrograms/g diet (control) or 1000 micrograms/g diet (supplemented) to dams during pregnancy and lactation, then to the offspring after weaning. Offspring were tested for seizure susceptibility as young adults; tissue trace elements, brain monoamines and brain glutamine synthetase activity were measured as endpoint biochemical indices. Supplementation, although developmentally encompassing and highly effective in elevating tissue Mn levels, had no effect on seizure latency or severity. Similarly, brain monoamine concentrations and glutamine synthetase activities were resistant to Mn supplementation. Notably, the GEPR was confirmed to have low whole brain glutamine synthetase activity. These findings suggest that seizure activity in the GEPR does not stem from an increased nutritional/metabolic need for Mn.
Epilepsy Res 1993 Jan
PMID:The influence of manganese supplementation on seizure onset and severity, and brain monoamines in the genetically epilepsy prone rat. 809 51

Low blood manganese (Mn2+) concentration is associated with epilepsy in humans and rats. The low Mn2+ concentration is attributed by some investigators to the seizure activity associated with the epilepsy, whereas others propose that the low Mn2+ concentration may be secondary to genetic mechanisms underlying the epilepsy. To begin to differentiate between these possibilities, Mn(2+)-binding enzymes of liver and brain (i.e., arginase and glutamine synthetase, respectively) were assayed in rats exposed to chronically induced seizures and in genetically epilepsy-prone rats (GEPRs). Chronic seizures caused a decrease in whole blood Mn2+ levels but did not affect brain Mn2+ concentrations. Arginase activity was increased in livers of rats with chronic seizure as compared with controls, but this difference was eliminated when Mn2+ was added to the assay. Brain glutamine synthetase activity was unaffected by chronic seizures, but the activity of this enzyme was significantly lower in GEPR brain than in control brain. Liver arginase activity tended to be lower in GEPRs, although the difference was not statistically significant. These data indicate that seizures affect liver arginase activity through changes in liver Mn2+ concentration, but GEPRs show abnormalities in Mn(2+)-dependent enzymes apparently independent of seizure activity.
 ...
PMID:Manganese and epilepsy: brain glutamine synthetase and liver arginase activities in genetically epilepsy prone and chronically seizured rats. 809 25

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
Epilepsy Res 1995 Sep
PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

Biological effects of tiagabine, a new antiepileptic drug, were analyzed on cultures of rat's cortical astrocytes. Tiagabine was added to the cultures at concentrations of 1 and 10 microg/ml, correspondent to therapeutic range; cell viability (tetrazolium salt assay and lactic dehydrogenase release), maturation and differentiation (glutamine synthetase activity) and presence of stress conditions (reactive oxygen species formation, inducible nitric oxide synthetase expression and 70 kDa heath shock protein production) were tested. Our results indicate that the addition of Tiagabine to primary astrocytes not only did not change significantly the examined metabolic activities but also seems to exert a protective action against oxidative stress. Thus, our data reinforce the idea that Tiagabine may be considered an effective promising drug in the treatment of epilepsy.
 ...
PMID:Biological effects of tiagabine on primary cortical astrocyte cultures of rat. 1086 13

Astrocytes play a predominant role in energy metabolism and in the catabolism of gamma-aminobutyric acid (GABA) and glutamate, neurotransmitters critically involved in epileptic processes. We show specific astrocytic alterations in the genetic absence epilepsy rats from Strasbourg (GAERS). Spontaneous absence seizures appear in this strain in the cortex and thalamus after the age of 1 month. In these brain structures, we demonstrate increased GFAP expression in both adult and young GAERS, suggesting that reactive astrocytes are already present before the onset of seizures. Glutamate dehydrogenase (GDH) and glutamine synthetase (GS), which are localized mainly in astrocytes and involved in glutamate catabolism, are shown to be differentially altered. GDH expression was increased in the thalamus of both young and adult GAERS and in the cortex of young GAERS. GS expression was slightly decreased in the thalamus of young GAERS. These astrocytic modifications are not adaptive responses to seizures, as the modifications appear before the development of absence seizures. Thus, astrocytes might be involved in the neuronal processes giving rise to epileptic seizures in this strain.
 ...
PMID:Specific alteration in the expression of glial fibrillary acidic protein, glutamate dehydrogenase, and glutamine synthetase in rats with genetic absence epilepsy. 1097 7


1 2 3 4 5 6 Next >>