Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Biochemical and pharmacological effects of gamma-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as alpha-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.
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PMID:Gamma-vinyl GABA: comparison of neurochemical and anticonvulsant effects in mice. 341 34

The ability of discrete brainstem injections of gamma-vinyl-gamma-aminobutyric acid (GVG), an irreversible inhibitor of gamma-aminobutyric acid transaminase, to prevent pentylenetetrazol (PTZ) seizures and maximal electroshock seizures (MES) was studied and compared in rats. PTZ seizures were prevented by GVG injections in the anterior thalamus, the caudal hypothalamus, the superior colliculus, cerebellar nuclei, and in a large area of the medial medullary, pontine, and mesencephalic tegmentum encompassing the vestibular nuclei, the reticular formation, and portions of the central gray. GVG injections in the substantia nigra did not protect against PTZ seizures. In contrast, tonic hindlimb extension in MES was prevented consistently by injections in the substantia nigra. A minority of injections in the vestibular nuclei, cerebellar nuclei, and parts of the reticular formation also protected against tonic hindlimb extension of MES. These results indicate a striking difference in the functional anatomy of PTZ-induced seizures and MES. PTZ seizures appear to be mediated by an extensive system involving the reticular formation, diencephalic regions in the vicinity of the anterior medial thalamus and caudal hypothalamus, and bulbar regions which give rise to descending motor pathways to the spinal cord. In contrast to PTZ seizures, MES appears to be mediated by a different neuroanatomical substrate with the present data implicating only the substantia nigra definitely in that process.
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PMID:Functional anatomy of pentylenetetrazol and electroshock seizures in the rat brainstem. 342 67

The effects of microinjection of various neuroactive compounds into the anterior thalamic nucleus (AN) and other selected subcortical regions of guinea pig brain on the expression of pentylenetetrazol (PTZ)-induced behavioral and electrical seizure activity were examined. Excitatory agents, kainic acid (KA), bicuculline (BIC) or PTZ, injected into the AN or other thalamic nuclei, striatum, but not the mammillary bodies (MB), facilitated the EEG convulsant action of systemically administered PTZ. Injection of muscimol into the AN protected against the expression of PTZ-induced repetitive high-voltage EEG seizure discharges and inhibited the facilitatory effects of subcortically applied KA or BIC. Injection of muscimol into the AN was also able to terminate established ongoing seizure discharges. Unilateral application of muscimol to the AN did not prevent the repetitive hypersynchronous EEG discharges following systemic PTZ but did result in the delay in the onset of cortical hypersynchrony in the ipsilateral hemisphere. Muscimol injections into other thalamic nuclei, MB, cortex, striatum or directly into the CSF space had no anticonvulsant effect, however. Microinjection of gamma-vinyl-gamma-aminobutyric acid, a selective GABA transaminase inhibitor, resulted in protection from the behavioral convulsant action and lethal effects of PTZ when administered into the thalamus, especially the AN, but not when injected into the striatum or CSF. These data demonstrate that the AN is an important subcortical nucleus for the mediation of both cortical EEG synchrony and behavioral seizure expression induced by PTZ. In light of previous results establishing a role for the brainstem and diencephalon in PTZ seizure expression, the AN may serve, in part, as a gating mechanism for the propagation of paroxysmal activity between subcortical areas and the cerebral cortex.
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PMID:Anterior thalamic mediation of generalized pentylenetetrazol seizures. 354 79

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

The high seizure susceptibility in epileptic chickens is due to an autosomal recessive mutation. In 3-day-old chicks homozygous for the epilepsy gene (epileptics), elevation of body temperature using microwave diathermy evoked an initial febrile seizure resembling the clonic seizures evoked in epileptic chicks by photic stimulation. After complete recovery, this was followed by a clonic-tonic seizure. In nonepileptic heterozygote hatchmates (carriers) of the same age, only the latter seizure pattern was observed. In 16- to 17-day-old chicks of either phenotype, both seizure patterns were observed during hyperthermia. In all cases, the temperature at which seizures occurred was significantly lower in epileptic than in nonepileptic chicks, indicating a lower threshold for febrile seizures when there is an inherited predisposition to convulse. The occurrence of seizures was dependent on the body temperature and not on the rate of rise of temperature. Elevation of the brain gamma-aminobutyric acid (GABA) concentrations by administration of the GABA transaminase inhibitor gamma-vinyl GABA reduced the incidence of the initial febrile seizures and increased the latency in those birds that were not fully protected.
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PMID:Experimental febrile convulsions in epileptic chickens: the anticonvulsant effect of elevated gamma-aminobutyric acid concentrations. 404 16

Alterations in gamma-aminobutyric acid (GABA) metabolism have been investigated in the kindling model of epilepsy. Numerous generalized seizures were induced by amygdala-kindling stimulations in rats. One week after the last stimulation, there were no changes in GABA levels nor in the activity of enzymes responsible for the synthesis (glutamic acid decarboxylase) and catabolism (GABA transaminase and succinyl semialdehyde dehydrogenase). These results do not exclude other changes in GABA function as modifications of transport or receptors.
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PMID:Absence of modifications in gamma-aminobutyric acid metabolism after repeated generalized seizures in amygdala-kindled rats. 408 36

gamma-Acetylenic GABA (GAG, RMI 71.645), a potent irreversible inhibitor of gamma-aminobutyric acid transaminase, was given orally in various dosage schedules to 14 patients with Huntington disease. The biochemical effects of the drug on cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA) and the GABA-containing dipeptide, homocarnosine, were measured in 10 of 14 patients. Treatment with GAG increased CSF concentrations of GABA and homocarnosine as compared to pretreatment values, suggesting that the drug increased brain GABA concentration. Despite this neurochemical effect, the clinical state was not improved. Except for single seizure episodes in five patients, GAG therapy was well tolerated. These results do not exclude the possibility that agents that augment CNS GABAergic function may prove useful in therapy of Huntington disease.
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PMID:Treatment of Huntington disease with gamma-acetylenic GABA an irreversible inhibitor of GABA-transaminase: increased CSF GABA and homocarnosine without clinical amelioration. 625 6

Intraperitoneal injection of ethanol (1-2 g/kg) and chlordiazepoxide (2-16 mg/kg) suppressed susceptibility to audiogenically induced, clonic-tonic seizures and antagonized forelimb tremor in rats undergoing ethanol withdrawal, 30 min after treatment. However, a smaller dose of ethanol (0.5 g/kg) actually increased clonic seizure frequency, suggesting that ethanol exerts a biphasic proconvulsant/anticonvulsant action. Direct activation of gamma-aminobutyric acid (GABA) receptors by intracisternal administration of GABA (100-1000 micrograms), muscimol (0.3-1.0 micrograms) or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) (0.3-3.0 micrograms) 5 to 10 min before testing also reduced susceptibility to audiogenic clonic-tonic seizures. In sharp contrast to these anticonvulsant actions, GABA, muscimol and THIP had no effect on withdrawal-induced forelimb tremors. Blockade of GABA uptake with 1-2,4-diaminobutyric acid (300 and 600 mg/kg i.p.) and inhibition of GABA transaminase with aminooxyacetic acid (12.5 and 25.0 mg/kg i.p.) both reduced susceptibility to seizures. However, anticonvulsant doses of these two drugs, unlike GABA, muscimol and THIP, also reduced forelimb tremor. Three other GABA transaminase inhibitors, gamma-vinyl GABA (450 and 900 mg/kg i.p.), gamma-acetylenic GABA (50-150 mg/kg i.p.) and ethanolamine-O-sulfate (250-750 mg/kg i.p.), were inactive against ethanol withdrawal audiogenic seizures and forelimb tremors. These results indicate that direct GABA receptor activation can selectively suppress one type of ethanol withdrawal response (i.e., audiogenic seizure susceptibility) while failing to influence another (forelimb tremors).
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PMID:Differential sensitivity of ethanol withdrawal signs in the rat to gamma-aminobutyric acid (GABA)mimetics: blockade of audiogenic seizures but not forelimb tremors. 631 80

One of the defects in human epilepsy appears to be the suboptimal functioning of at least certain central gamma-aminobutyric acid (GABA)-mediated synapses. Of the several approaches for the manipulation of the functional state of such synapses that have been investigated, the possibility of interference with GABA metabolism and GABA transport processes is reviewed. It is concluded that the efficiency of inhibitors of the GABA-metabolizing enzyme, GABA transaminase, as antiepileptic drugs is related to the ability of the inhibitors to increase selectively the synaptic or transmitter-related GABA levels. Whether or not this reflects different modes of action of these inhibitors on neuronal and glial GABA transaminase remains to be established. Inhibition of the GABA transport mechanisms seems to represent an alternative approach to increase synaptic GABA levels. Evidence is presented that inhibitors of glial GABA uptake possess anticonvulsant activity. A comparison of drugs that inhibit both neuronal and glial GABA uptake with selective glial GABA uptake inhibitors indicates that the latter type of inhibitor most effectively blocks seizure activity. Such a drug is 4,5,6,7-tetrahydroisoxazolo[4,5c]pyridin-3-ol (THPO), which unfortunately lacks the important property of easy penetration of the blood-brain barrier. Prodrugs of this glial-selective GABA uptake inhibitor may have pharmacological and therapeutic interest.
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PMID:Transport and metabolism of gamma-aminobutyric acid in neurons and glia: implications for epilepsy. 631 24

Seven patients with Huntington disease were treated with aminooxyacetic acid (AOAA), an inhibitor of gamma-aminobutyric acid aminotransferase (GABA-T), in an effort to alleviate symptoms by increasing brain GABA content. AOAA was given orally in a placebo-controlled crossover trial in which patients, relatives, and three of the evaluating physicians remained blind. Toxic symptoms occurred in all seven patients when AOAA dosage was increased beyond 2 mg per kilogram per day, and included drowsiness, ataxia, seizures, and psychotic behavior. In five patients who took AOAA for 4 months, no clinical improvement was observed. Biochemical monitoring showed that less inhibition of hepatic GABA-T enzyme activity was achieved than in patients treated with large doses of isoniazid. Results of this trial neither support nor exclude the possible therapeutic usefulness of increasing brain GABA content in Huntington disease.
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PMID:Failure of aminooxyacetic acid therapy in Huntington disease. 644 91


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