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

Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
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PMID:Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. 370 28

Morphological analysis of brains from rats receiving a convulsant dose of the muscarinic cholinergic agonist, pilocarpine hydrochloride (380 mg/kg), revealed a widespread damage to the forebrain as assessed by light microscopy 5-7 days after seizures. The substantia nigra, olfactory cortex, amygdala, hippocampus, septum, temporal cortex and thalamus underwent prominent morphological injury and cell loss. A concurrent assessment of the activity of L-glutamate decarboxylase (GAD), the gamma-aminobutyrate (GABA) synthesizing enzyme, demonstrated marked deficits in GAD activity in the brain regions undergoing morphological insult. Diazepam, 10 mg/kg, and scopolamine hydrochloride, 10 mg/kg, administered 30 min prior to the injection of pilocarpine, 380 mg/kg, prevented acute behavioral and electrographic, and long-term morphological and biochemical sequelae of seizures. These findings suggest that the muscarinic antagonist, scopolamine, and the anticonvulsant benzodiazepine, diazepam, may aid in preventing extensive brain damage related to pathological muscarinic cholinergic overactivity. The similarity of the topography of the damage and deficits in the GAD activity in brains of rats treated with pilocarpine indicates that GABAergic neurons are lost in the subregions of the brain preferentially sensitive to the convulsant action of pilocarpine.
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PMID:Seizures produced by pilocarpine: neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. 380 99

A procedure is described for the rapid preparation of nerve ending particles (synaptosomes) from 11 regions of one rat brain. The synaptosomal fractions have been characterized by electron microscopy and determination of four marker enzymes, i.e., glutamate decarboxylase (GAD), acetylcholinesterase, succinate dehydrogenase, and glycerol 3-phosphate dehydrogenase. Comparison with a much lengthier standard (Ficoll-sucrose) preparation showed that the synaptosomal yield of the new procedure was substantially better as judged by both morphological evaluation and protein recovery. The improved synaptosome preparation was used for determination of regional gamma-aminobutyric acid (GABA) levels in synaptosomal fractions. The postmortem increase in GABA level during removal and dissection of brain tissue and homogenization and fractionation procedures could be minimized by rapid processing of the tissue at low temperatures and inclusion of the GAD inhibitor 3-mercaptopropionic acid (3-MP; 1 mM) in the homogenizing medium. The addition of GABA (0.2 mM) to the homogenizing medium did not alter the GABA levels in the synaptosomes, indicating that no significant redistribution of GABA occurred during subcellular fractionation in sodium-free media. Synaptosomal GABA levels determined in the 11 rat brain areas showed the same regional distribution as the GABA-synthesizing enzyme GAD. On the basis of these findings, it was suggested that the synaptosome preparation could be used to evaluate the in vivo effects of drugs on nerve terminal GABA. Treatment of rats with a convulsant dose of 3-MP (50 mg/kg i.p.) 3 min before decapitation significantly lowered synaptosomal GABA levels in olfactory bulb, hippocampus, thalamus, tectum, and cerebellum. The 3-MP-induced seizures and reduction of GABA levels could be prevented by administration of valproic acid (200 mg/kg i.p.) 15 min before the 3-MP injection. The data indicate that the improved synaptosome preparation offers a convenient method of preparing highly purified synaptosomes from a large number of small tissue samples and can provide useful information on the in vivo effects of drugs on regional GABA levels in nerve terminals.
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PMID:Improved method for isolating synaptosomes from 11 regions of one rat brain: electron microscopic and biochemical characterization and use in the study of drug effects on nerve terminal gamma-aminobutyric acid in vivo. 392 10

Amino acid concentrations were measured in the cortex, cerebellum and hippocampus of the mouse brain before and during seizures induced by isoniazid (250 mg/kg i.p.), an inhibitor of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). Valproate sodium and diazepam dose-dependently delay the onset of convulsive fits caused by isoniazid. However, neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone. Also, these antiepileptic drugs did not modify the rate of GABA depletion elicited by isoniazid. These results, observed in four different brain structures, strengthen those first obtained with beta-vinyllactic acid, another inhibitor of GAD.
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PMID:The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels. 393 Jun 61

A single intraperitoneal injection of pyridoxal-5'-phosphate (PLP) in a species of mouse, DBA/2J, that is normally susceptible to sound-induced convulsion exacerbated its epileptic condition. The effect of injection was most pronounced about 30 min after the administration and subsided gradually within the following 4 h. Correlated with this increased seizure susceptibility were enhanced levels of synaptosomal aspartate and glutamate, and a diminished gamma-aminobutyric acid (GABA) level. The concentrations of nonneuroactive amino acids remained unchanged. When stimulated with veratrine, synaptosomes prepared from PLP-injected mice showed an increased release of aspartate and glutamate and a decreased release of GABA compared to those prepared from control mice. The activity of glutamate decarboxylase in the brains of PLP-treated mice was lowered, whereas the activity of GABA-transaminase was enhanced. Finally, the epileptic condition of DBA mice could be ameliorated by maintenance on a diet composed of vitamin B6-deficient feed and cellulose.
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PMID:Alteration of amino acid metabolism in epileptogenic mice by elevation of brain pyridoxal phosphate. 398 38

1. DL-C-Allyglycine, 4-deoxypyridoxine hydrochloride and 3-mercaptopropionic acid have been studied with reference to their convulsant effects in mice and in baboons (Papio papio) with photosensitive epilepsy, and their action on the cerebral enzyme synthesizing gamma-aminobutyric acid (L-glutamate-1-carboxy-lyase).2. In mice, the ED(50) values for seizures following intraperitoneal injection were allylglycine 1.0 mmol/kg body weight, 4-deoxypyridoxine 1.1 mmol/kg and 3-mercaptopropionic acid 0.27 mmol/kg. Latency to seizure onset was longest after allylglycine (44-240 min), intermediate after 4-deoxypyridoxine (9-114 min) and shortest after 3-mercaptopropionic acid (2.5-8 min).3. In Papio papio intravenous administration of subconvulsant doses of allylglycine (0.87-3.1 mmol/kg), or of 4-deoxypyridoxine (0.21-0.53 mmol/kg) enhanced the occurrence and persistence of myoclonic responses to intermittent photic stimulation, and augmented the associated electroencephalographic abnormalities, without modifying their character or distribution. Higher doses produced brief seizures recurring at regular intervals, between 2-14 h after allylglycine (4.0-4.3 mmol/kg) or 1-4 h after 4-deoxypyridoxine (0.53-0.87 mmol/kg). Electroencephalographically these seizures originated unilaterally in the occipital or posterior parietal cortex.4. In Papio papio photically-induced epileptic responses were enhanced 5-10 min after the intravenous injection of 3-mercaptopropionic acid (0.09-0.28 mmol/kg). A sequence of brief generalized seizures followed by complete recovery occurred 4-17 min after the injection of 3-mercaptopropionic acid (0.28-0.38 mmol/kg). Fatal status epilepticus followed the injection of 3-mercaptopropionic acid (0.57-0.75 mmol/kg). E.E.G. records showed generalized cortical involvement at the onset of the seizures.5. L-Glutamate 1-carboxy-lyase (GAD) activity was determined in whole brain homogenates from mice killed at various intervals after receiving i.p. a convulsant dose of one of the compounds. Inhibition of GAD activity was evident 30-60 min before seizure onset following allylglycine or 4-deoxypyridoxine administration, and was maximal (40-60%) just before or during seizure activity. Addition of pyridoxal phosphate to the brain homogenate relieved inhibition produced by 4-deoxypyridoxine but not that produced by allylglycine. Inhibition of GAD activity in brain homogenates from animals killed 2 or 4 min after injection of a convulsant dose of 3-mercaptopropionic acid varied from 0-49% depending on the dose of 3-mercaptopropionic acid and the concentration of substrate in the assay system.6. Kinetic analysis of the inhibition of GAD activity following direct addition of the compounds to mouse brain homogenates indicated that 3-mercaptopropionic acid (0.01-0.5 mM) was competitive with respect to the substrate. A comparable percentage inhibition of GAD activity was obtained only with much higher concentrations of 4-deoxypyridoxne, i.e. 10-50 mM. Allylglycine in vitro was a very weak inhibitor of GAD activity.7. Three biochemically different mechanisms underlie the inhibition of cerebral GAD activity that precedes seizures induced by ailylglycine, 4-deoxypyridoxine and 3-mercaptopropionic acid. The data are consistent with a critical reduction in the rate of synthesis of gamma-aminobutyric acid being responsible for the onset of seizures.
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PMID:Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxine in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase. 420 45

The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydrofolic acid (THF) and dihydrofolic acid (DHF) to mimic the actions of kainic acid (KA) in a number of in vitro and in vivo systems known to be sensitive to KA was examined. None of the three folate derivatives at 100 microM concentration significantly inhibited the specific binding of [3H]-KA to striatal membranes although 2 microM L-glutamate produced a 40% inhibition. None of the three folate derivatives stimulated the formation of cyclic GMP in cerebellar slices incubated in vitro although KA (0.5 mM) increased cyclic GMP levels by 2.5-fold. Whereas intrahippocampal injection of 2.3 nmoles of KA produces prolonged abnormalities of the EEG, limbic-type seizures and a characteristic pattern of neuronal degeneration in the hippocampal formation and related structures, intrahippocampal injection of a 100-fold greater dose of THF caused only minor and transient EEG abnormalities, no overt seizures and a highly restricted lesion. Whereas intrastriatal injection of 5.6 nmoles of KA caused a profound reduction in the specific activities of choline acetyltransferase and glutamate decarboxylase, markers for striatal intrinsic cholinergic and GABAergic neurons, 50-fold greater doses of MTHF did not affect either enzyme although this high dose of THF did cause a significant 33% reduction in choline acetyltransferase activity. These findings support the suggestion that THF may have weak neurotoxic effects in brain but indicate that the actions of this compound and the related MTHF and DHF are not mediated through KA-specific receptors.
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PMID:Failure of folic acid derivatives to mimic the actions of kainic acid in brain in vitro or in vivo. 612 82

Behavioural, histopathological and neurochemical changes induced by systemic injection of kainic acid (10 mg/kg, s.c.) were investigated in rats. The most pronounced behavioural changes were strong immobility ("catatonia"), increased incidence of "wet dog shakes", and long-lasting generalized tonic-clonic convulsions. The behavioural symptoms were fast in their onset and lasted for several hours. Two distinct phases of histopathological and neurochemical changes were observed. (1) Early partially reversible changes were seen up to 3 h after kainic acid injection. They consisted of shrinkage and pyknosis of neuronal perikarya together with swelling of dendrites and axon terminals. These changes were accompanied by generalized signs of edema throughout the whole brain. Neurochemically, there was a marked decrease in noradrenaline levels (up to 70%) and an increase in levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid (up to 200%) in all analysed brain regions, suggesting a strongly increased firing rate of aminergic neurones during the period of generalized seizures. These histological and neurochemical changes were found in all the brain regions examined; they were greatly reduced or only sporadically seen after 1-3 days, when the animals had recovered from the seizures. (2) Late irreversible changes developed 24 h and later following kainic acid injection. They consisted of incomplete tissue necrosis with loss of nerve cells and oligodendrocytes, demyelination, astroglial scar formation, small perivenous hemorrhages and extensive vascular sprouting. The changes were restricted to the pyriform cortex, amygdala, hippocampus (most pronounced in the CA1 sector), gyrus olfactorius lateralis, bulbus olfactorius and tuberculum olfactorium. Neurochemically, a selective decrease was seen in choline acetyltransferase activity (40%) of the amygdala/pyriform cortex area, and of glutamate decarboxylase activity in the dorsal hippocampus (45%) and amygdala/pyriform cortex (55%). No such changes were found in the frontal cortex and the striatum/pallidum. Since at these later time periods the widespread early changes in monoamine metabolism were mostly normalized, loss of acetylcholine and gamma-aminobutyric acid neurons in the affected brain regions represented a selective neurochemical change typical for this stage of kainic acid action. The observed neurochemical and histopathological changes may be directly related to the excitotoxic and convulsive properties of kainic acid. However, brain edema resulting in herniation damage of the basal portions of the brain in addition to disturbances of microcirculation and +
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PMID:Kainic acid induced seizures: neurochemical and histopathological changes. 614 39

Four catalytic inhibitors of GABA-aminotransferase (GABA-T), viz. gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA, and ethanolamine O-sulphate (EOS), as well as the unspecific enzyme inhibitor aminooxyacetic acid (AOAA), sodium valproate (VPA), and GABA itself were studied for anticonvulsant, biochemical, and toxic effects in mice. Elevations of the electroconvulsive threshold by 30 V were produced at the time of their maximal effect by the i.p. injection (AOAA s.c.) of 13 mg/kg AOAA, 37 mg/kg gabaculine, 65 mg/kg gamma-acetylenic GABA, 125 mg/kg VPA, 1,440 mg/kg EOS, 1,900 mg/kg gamma-vinyl GABA and 2,800 mg/kg GABA. At these doses, all drugs except GABA and VPA increased the clonic pentetrazole threshold to a similar extent, but differed in their increases in the brain content of GABA, which varied from 70% (EOS) to 300% (gamma vinyl GABA) as a consequence of decreases in the activity of GABA-T. The activity of the GABA-synthesizing enzyme glutamate decarboxylase was decreased only by gamma-acetylenic GABA. When determining the anticonvulsant effect of the different drugs against the convulsant ED 97 of pentetrazole, 3-mercaptopropionic acid, strychnine and maximal electroshock seizures, gabaculine, AOAA, VPA and in part gamma-vinyl GABA and GABA were efficacious enough to allow the determination of ED50 values, whereas gamma-acetylenic GABA and EOS showed no clear activity in any of these seizure models. Gabaculine and AOAA at their anticonvulsant ED50 were toxic or lethal. All inhibitors of GABA-T except EOS caused numerous side effects which cast doubt on the specificity of these drugs. The present results indicate that inhibitors of GABA-T hardly seem to be suited for treatment of convulsive disorders in human but are useful tools in studies of experimental epilepsy.
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PMID:A comparative study of the pharmacology of inhibitors of GABA-metabolism. 678 93

The concentration of gamma-aminobutyrate (GABA) and the activity of glutamate decarboxylase and GABA-transaminase were measured in extracts of mouse brain before the onset and during the course of generalized seizures induced by systemic administration of homocysteine thiolactone. The results indicate that whole brain GABA metabolism is unaffected by subconvulsive and convulsive doses of homocysteine at all stages of the generalized seizure. Electroencephalographic monitoring of rat brain electrical activity via hippocampal electrode implantation allowed the course homocysteine-induced seizures to be followed and afforded a means of quantifying such seizures.
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PMID:Hippocampal electrical activity and gamma-aminobutyrate metabolism in brain tissue following administration of homocysteine. 682 71


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