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

The levels of preprosomatostatin (preproSS) mRNA, somatostatin-like immunoactivity (SS-LI) (also known as somatotropin-release inhibitory factor, or SRIF), glutamic acid decarboxylase (GAD) activity and GAD mRNA were determined in several brain regions of amygdaloid-kindled rats. SS mRNA and SS increased in the cortex and striatum, while only SS increased in the hippocampus. No changes were detected in either GAD activity or GAD mRNA in any brain region. The data suggest that somatostatin may be one of the factors involved in the chain of events leading to kindled seizures.
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PMID:Amygdaloid kindling of rats increases preprosomatostatin mRNA and somatostatin without affecting glutamic acid decarboxylase (GAD) mRNA or GAD. 256 84

Studies of various parameters of amino acid and catecholamine metabolism in human cerebral cortex have provided a number of biochemical markers that appear to delineate areas of focal epileptic activity. These observations have been consolidated further by investigations of a number of experimental models of epilepsy in animals. In appraising this data, it is important to take into consideration whether the tissue samples were obtained during an actual seizure state or in an interictal period. It is also important when possible to assess the extent of astrogliosis and neuronal loss. Sites of spontaneously active epileptic spiking in the cerebral neocortex have a somewhat different amino acid profile when compared to gray matter obtained from surrounding nonspiking gyri several centimeters away. There is an elevation in glycine content, a relative diminution in taurine, and a trend towards lowered glutamic acid levels. However, the concentrations of the eight amino acids measured appear in both the foci and surround to still be within the general range for normal tissue. Measurements of key enzymes involved in the synthesis and regulation of neurotransmitters provide a complementary method of evaluating functional changes in epileptic brain as they are generally less labile than their substrates. There is a moderate increase in the activity of glutamic acid dehydrogenase, an enzyme that plays an important role in the synthesis of glutamic acid from glucose. In some patients a decrease in glutamic acid decarboxylase has also been reported: this enzyme forms gamma-aminobutyric acid (GABA) from glutamic acid and is thus important for inhibition in the central nervous system. Moreover, there is a striking increase in the activity of tyrosine hydroxylase, the rate-limiting enzyme responsible for catecholamine synthesis. The possibility of a focal abnormality in catecholamine metabolism is reinforced by the simultaneous finding of a relative decrease in the number of alpha-1 postsynaptic receptor sites. An important marker of energy metabolism in neural tissue, Na+,K+-ATPase activity, has also been found to be decreased in actively spiking human cerebral cortex. Data from experimental animal foci produced by topical application of convulsant agents show a consistent drop in glutamic acid tissue content. This can be matched to an efflux of glutamic acid from the cortical surface, which in turn is proportional to the electrographic activity of the spike focus. In addition, there is often also a decrease in taurine and GABA in such foci, as well as an increase in the levels of a number of neutral amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amino acid and catecholamine markers of metabolic abnormalities in human focal epilepsy. 287 18

In view of finding a new gamma-aminobutyric acid (GABA) receptor ligand we synthesized an arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride]. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 microM and a Hill number near 1.0. SR 95103 (1-100 microM) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities. Intraperitoneally administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that St 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable.
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PMID:An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site. 298 69

We have tested several compounds interfering with the brain monoamine (noradrenaline, dopamine, serotonin) and acetylcholine systems for their effects on limbic seizures produced by systemically (s.c.) injected kainic acid as well as on neurochemical changes in amygdala/pyriform cortex resulting from the kainic acid treatment. The characteristic neurochemical changes induced by s.c. kainic acid were a decrease in noradrenaline and an increase in 5-hydroxyindoleacetic acid in the acute (3 h after kainic acid injection) suggesting strongly increased neurotransmitter turnover in noradrenergic and serotonergic neurons. This was followed by a reduction of glutamic acid decarboxylase and choline acetyltransferase activities during the chronic phase (3 days) of the kainic acid action, indicating destruction of GABAergic and cholinergic neurons. The compounds tested in this model of limbic epilepsy included 1-propranolol, prazosin, clonidine, yohimbine, metergoline, atropine and haloperidol. Among these compounds the alpha 2-adrenergic agonist clonidine (0.1 mg/kg, i.p.) exhibited a powerful protective action on kainic acid-induced limbic seizures as well as on the neurochemical changes in the amygdala and pyriform cortex. In addition, the adrenoceptor antagonists prazosin (alpha 1) and propranolol (beta) as well as the dopamine receptor antagonist haloperidol had significant but less potent - protective actions upon kainic acid-induced seizures and subsequent neurochemical changes. On the other hand, yohimbine (alpha 2-antagonist) and metergoline (serotonin-antagonist) potentiated the limbic seizure syndrome and no effect was found with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha 2-adrenoceptors modulate kainic acid-induced limbic seizures. 299 67

Although animal models consistently indicate that gamma-amino-butyric acid (GABA) synaptic function (GABA levels, synthesis, uptake and/or receptors) is decreased in seizure states, there is little evidence to date in support of such a hypothesis for human epilepsy. This chapter presents the results of an in-depth study of the activity of the GABA-synthesizing enzyme L-glutamic acid decarboxylase (GAD) in brain tissue removed during neurosurgical resection for intractable epilepsy. The tissue studied is unique in that identified (by stereo EEG) foci were excised (rather than large blocks of tissue containing mixtures of foci and nonepileptic material) and compared with nonepileptic (stereo EEG and morphological definitions) tissue from the same patients. In patients in which there was no indication of a tumor, GAD activity in the foci was low in more than 50% of the patients examined. Furthermore, when the population distribution of GAD was compared in epileptic versus nonepileptic tissue fragments from all patients, the peak distribution of epileptic tissue fragments occurred at much lower GAD activities than for the nonepileptic fragments (0-20 versus 41-80 nmol CO2/mg protein X hr, respectively). A small subgroup of epileptic fragments occurred with a normal GAD distribution, indicating that the presence of an epileptic focus was not invariably associated with low GAD activity. When the low levels of GABA "A" binding sites in these epileptic tissue fragments are taken into consideration in combination with the low GAD levels, then it can be estimated that 60 to 70% of the present patient population had deficient GABAergic transmission in epileptic foci as compared to nonepileptic brain tissue from the same patients. It follows that the GABA hypothesis of human epilepsy is not an exclusive or unitary hypothesis, and some patients appear to have normally functioning GABA synapses (as assessed biochemically) in epileptogenic areas. Thus, other neurotransmitter and neurohumoral systems certainly play a role in the epileptic process.
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PMID:Alterations of GABA-mediated synaptic transmission in human epilepsy. 301 Jun 75

The seizure state induced in the rat by cerebral cortical implantation of cobalt metal has been increasingly used to study a variety of neurochemical parameters. This experimental model of epilepsy affords the opportunity to study events prior to the development of seizures, during the period of intense seizure activity, and during the period when seizure activity has essentially terminated. The seizures that occur in this model are intermittent and paroxysmal and share many other similarities with human epilepsy. The crucial question with this model, and indeed with any experimental model of epilepsy, is whether the basic seizure-producing mechanism(s) is similar. This question remains to be answered. There have been studies that show that changes in certain neurochemical parameters parallel the onset, intensity, and decline of seizure activity in cobalt-epileptic animals. Although extremely interesting, by themselves they do not prove a cause-and-effect relationship. Such parallelism is more apparent in the case of GABA than in the cases of lipids and gangliosides. GABA and its synthetic enzyme, glutamic acid decarboxylase (GAD), are both at normal levels prior to the development of seizures, are significantly decreased during the period of seizures, and return toward control values at a time when seizures are no longer apparent. On the other hand, there is no change in postsynaptic GABA binding sites (Bmax) prior to seizures, a significant increase in Bmax during seizure activity, and a return toward normal by 21 days (when seizure activity has terminated). Studies that have been carried out on lipids and gangliosides in cobalt-induced epilepsy are not nearly as extensive nor are the results as positive as those that have been obtained in the case of GABA. They do, however, provide provocative findings that may well be related to the genesis of epilepsy.
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PMID:GABA receptors, lipids, and gangliosides in cobalt epileptic focus. 301 Jun 78

Immunocytochemical localization of glutamic acid decarboxylase (GAD), the synthesizing enzyme for the neurotransmitter gamma-aminobutyric acid (GABA), has been used to study the time course of the decrease in putative GABAergic synaptic terminals that occurs in an alumina gel-induced model of focal epilepsy. Monkeys were studied at progressive intervals following unilateral application of alumina gel to sensorimotor cerebral cortex, and were categorized into 3 different experimental groups depending upon their clinical status. These groups respectively exhibited: (1) no abnormal bioelectrical (EEG and ECoG) activity; (2) abnormal bioelectrical activity, but no clinical seizures; and (3) both abnormal bioelectrical activity and clinical seizures. Normal and sham-operated monkeys were also studied. The amounts of GAD-positive terminal-like structures were determined on control and experimental sides of motor cortex (layer V) of all specimens with an image analysis system. This quantitative study revealed that monkeys from the 3 experimental groups showed reductions of GAD-positive terminals on the experimental cortical side, with greater losses occurring at progressively longer times following alumina gel implants. Statistical tests showed that there were no significant cortical side differences for the normal and sham groups, but that cortical side variations were significantly different for each of the 3 experimental groups. Conventional electron microscopy of an early experimental stage revealed degenerating axon terminals in layer V of motor cortex, as well as phagocytosis of degenerating material and astrogliosis. Similar findings were obtained from a chronically epileptic specimen, except that degenerating terminals were observed less often and fibrous astrocytic scarring was more prevalent, especially surrounding the somata of pyramidal neurons. The main conclusion drawn from the results of this investigation is that significant decreases of GAD-positive terminals occur prior to the onset of clinical seizures, and this is consistent with a causal role for a loss of GABAergic innervation in the development of seizure activity in this primate model of focal epilepsy.
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PMID:Time course of the reduction of GABA terminals in a model of focal epilepsy: a glutamic acid decarboxylase immunocytochemical study. 309 29

The effect of long-term treatment with valproic acid (VPA) on zinc (Zn) metabolism was studied in 15 children with absence seizures. During treatment with VPA the erythrocyte Zn content was significantly lower than that found in controls matched for sex and age. Plasma and urine values of Zn and of copper were within normal limits. It is suggested that the anticonvulsive action of VPA may be mediated through its effect on the metabolism of Zn in the brain and the concomitant changes in the activity of the enzymes glutamic acid decarboxylase and carbonic anhydrase.
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PMID:Effect of valproic acid therapy on zinc metabolism in children with primary epilepsy. 310 54

The brains of seizure-sensitive (SS) and seizure-resistant (SR) gerbils were studied with an immunocytochemical method to localize glutamic acid decarboxylase (GAD) to determine whether a defect existed in the inhibitory GABAergic system similar to that which has been reported in animal models of focal epilepsy in which GABAergic cell bodies and terminals are decreased in number. A major difference between the two strains of gerbils was found in the number of GABAergic neurons in the hippocampal formation. Specifically, a paradoxical increase occurred in the number of glutamate decarboxylase GAD-immunoreactive neurons: there were approximately 65% more GABAergic cells within the dentate gyrus and the CA3 region of the hippocampus in the SS gerbils. Furthermore, the density of GAD-immunoreactive puncta, the light microscopic correlates of synaptic boutons, was greater in the SS animals. Other histological methods were used to determine if the difference between SS and SR gerbils was specific for the GABAergic system. Nissl-stained preparations showed that the number of granule cells in the dentate gyrus was 20% greater in SS gerbils than in SR gerbils. An examination of some hippocampal afferents, efferents, and intrinsic connections with acetylcholinesterase histochemistry and the Timm's stain for heavy metals demonstrated no differences between the two strains. In addition, Golgi-stained preparations of the dentate gyrus indicated that the morphology of basket cells did not differ between the two strains nor between the gerbil and the rat. Several brain regions in addition to the hippocampus were studied to determine whether or not the increased number of GAD-immunoreactive neurons was specific for the hippocampal formation. These regions included the substantia nigra, motor cortex, and nucleus reticularis thalami and were selected because they contain large populations of GABAergic neurons and have been implicated in seizure activity. No differences between the two strains were detected in any of these regions. Therefore, a major morphological difference between the brains of SS and SR gerbils exists in the hippocampal formation of SS gerbils in which an increase occurs in the number of GABAergic neurons and granule cells. If these additional inhibitory neurons act mainly to inhibit other inhibitory neurons, the net effect would be increased disinhibition of the principal excitatory neurons of the hippocampal formation. This could lead to seizure activity within the hippocampal formation and at distant sites through multiple synaptic connections.
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PMID:Hippocampus of the seizure-sensitive gerbil is a specific site for anatomical changes in the GABAergic system. 361 18

1 The rate of synthesis of gamma-aminobutyric acid (GABA) in the cortex, hippocampus and striatum of rat brain was assessed by measuring the linear rate of accumulation of GABA following injection of amino-oxyacetic acid (AOAA). 2 Five min after a single electrically induced seizure there was a rise in GABA content in these brain regions and an almost total inhibition of the rate of synthesis. 3 Five min after seizure induced by the inhalant convulsant flurothyl there was no rise in GABA content in these brain regions but a similar marked degree of inhibition of GABA synthesis. 4 Two hours after the convulsion the rate of GABA synthesis had returned to control values in all three brain regions. 5 A single convulsion did not alter the glutamic acid decarboxylase activity in these brain regions either in the absence or presence of added co-factor (pyridoxal phosphate). 6 Evidence for an inhibition of GABA release following a convulsion which may be associated with the inhibition of GABA synthesis is presented in the following paper.
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PMID:Inhibition of the rate of GABA synthesis in regions of rat brain following a convulsion. 366 92


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