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)

The influence that the amygdala may exert on the development of hippocampal kindling was investigated using three different approaches: (i) after uni- or bilateral amygdalectomy by thermocoagulation, (ii) after prestimulation of the amygdala until the appearance of masticatory movements, and (iii) after increasing the GABA concentration in the amygdala with gamma-vinyl GABA. Hippocampal kindling was not significantly modified in amygdalectomized animals. On the contrary, prestimulation of the ipsilateral amygdala facilitated the subsequent hippocampal kindling. Finally, microinjection of gamma-vinyl GABA in both amygdalae either reduced the seizures to a prekindled level or strongly delayed the appearance of the motor signs of kindling. It is suggested that hippocampal kindling may develop preferentially through the amygdala.
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PMID:Role of the amygdala in development of hippocampal kindling in the rat. 662 30

Changes in gamma-aminobutyric acid (GABA) occurring in the presence and in the absence of GABA-containing nerve terminals were estimated in rats in which the dense GABA projection to the substantia nigra was surgically destroyed on one side of the brain. The net increase in GABA of the denervated nigra was compared with that of the intact nigra at various times after a single injection of gama-vinyl-GABA, which irreversibly inhibits GABA transaminase. Total GABA reached a maximum within 12 hours, but the GABA pool associated with nerve terminals did not increase until 36 hours and peaked at 60 hours. The onset and peak of anticonvulsant activity against maximal electroshock seizures directly paralleled the time course for the increase in GABA in nerve terminals, but was not positively correlated with that independent of the terminals. This result supports the concept that elevating GABA in nerve terminals facilitates GABA-mediated synaptic transmission and predicts anticonvulsant activity.
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PMID:Seizure protection and increased nerve-terminal GABA: delayed effects of GABA transaminase inhibition. 676 30

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

Mice were treated with different doses of the GABA aminotransferase (GABA-T) inhibitors aminooxyacetic acid, gamma-acetylenic acid, gamma-vinyl GABA and ethanolamine-O-sulphate via the drinking water for periods of 1-12. All drugs caused marked elevations of whole brain GABA concentrations within 4 days of treatment which were associated with increases in the electroconvulsive threshold. However, the effect on seizure threshold could not be enhanced by an increase in the daily dosage of the GABA-T inhibitors and, especially with higher doses, tolerance to the anticonvulsant effect developed. At least in part, this finding may be attributed to a decrease in the activity of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. On the other hand, with valproic acid (VPA) no tendency towards a reduced anticonvulsant effectiveness during medication was observed. VPA caused only non-significant increases in cerebral GABA levels but elevated brain GAD activity significantly. No behavioral changes were seen following subchronic administration of GABA-T inhibitors and VPA except in cases where the daily fluid intake was markedly reduced. Our data suggest that the anticonvulsant efficacy of long term treatment with GABA-T inhibitors is limited by the development of compensatory mechanisms, such as reduction of GAD activity, which in turn reduce the amount of GABA available for synaptic transmission, though overall GABA concentrations in the brain are highly elevated. Drug such as VPA which cause only moderate effects on GABA metabolism seem superior in this respect.
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PMID:Anticonvulsant and biochemical effects of inhibitors of GABA aminotransferase and valproic acid during subchronic treatment in mice. 680 73

The effects of microinjection of a GABA-elevating substance (gamma-vinyl-GABA) in the substantia nigra were assessed on kindled convulsive seizures induced by daily appropriate amygdaloid stimulation in the rat. Bilateral administration of 20 micrograms of gamma-vinyl-GABA strongly reduced the afterdischarge duration of the seizures without significantly modifying the motor convulsions. This effect was noted 24 h after injection and lasted for up to 48 h. Administration of gamma-vinyl-GABA in structures 1.5 mm distant from the substantia nigra had no effect on kindled seizures. It is suggested that the substantia nigra may intervene in a negative feedback system that tends to suppress the paroxysmal activity initiated from the amygdala.
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PMID:Abortive amygdaloid kindled seizures following microinjection of gamma-vinyl-GABA in the vicinity of substantia nigra in rats. 685 5

The rate of cortical gamma-aminobutyric acid (GABA) turnover was estimated by determining the rate of GABA accumulation following inhibition of GABA transaminase by gamma-vinyl-GABA (1.5 g/kg, i.v.) in paralysed, ventilated rats. During 1 h of bicuculline-induced seizures (1.2 mg/kg, i.v.) the rate of accumulation of cortical GABA level is approximately threefold greater than in the control group receiving gamma-vinyl-GABA alone, suggesting that the GABA shunt activity increases in parallel with the increase in overall cortical metabolic rate observed during bicuculline seizures. Pretreatment with gamma-vinyl-GABA did not affect the bicuculline-induced changes in other major cortical amino acids.
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PMID:Cortical GABA turnover during bicuculline seizures in rats. 687 71

The effects of GABA-modulating drugs were assessed in a pharmacological study of amygdala-kindled seizures in the rat. Fully-kindled subjects were tested with a randomized dose regimen, including drug vehicle, for each of seven drugs. Afterdischarge duration, motor seizure latency, motor seizure duration and motor seizure stage were scored. The GABA synthesis inhibitor, 3-mercaptopropionic acid, the GABA antagonist, bicuculline, and the chloride ionophore blocker, picrotoxin, all decreased motor seizure latency, but did not otherwise alter the kindled seizure duration or seizure stage. The inhibitor of GABA metabolism, gamma-vinyl-GABA, and pentobarbital, which competes for the picrotoxin binding site, both antagonized kindled seizures. Gamma-vinyl-GABA, however, did not appear to antagonize kindled seizures by a specific effect on GABA neurotransmission. The GABA agonists, imidazole acetic acid and [alpha-(chloro-4'phenyl)fluoro-5-hydroxy-2-benzylidene-amino]-4-butyramide (SL 76-002), did not alter the kindled seizures. The results of these experiments are not consistent with the hypothesis that kindled seizures result from a loss of GABA-mediated inhibition; however, GABA may have a role in the modulation of kindled seizure activity.
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PMID:Pharmacological investigation of gamma-aminobutyric acid (GABA) and fully-developed generalized seizures in the amygdala-kindled rat. 706 9

The relative ability of 16 direct and indirect GABAmimetic drugs to elevate the threshold for electroconvulsions and pentetrazole seizures was studied in mice. The following drugs were tested: GABA and its pro drug cetyl GABA, the GABA agonists muscimol, THIP and progabide, the inhibitors of the high affinity GABA uptake (-)- and (+)-nipecotic acid ethyl ester, (+/-)-nipecotic acid methyl ester, (+/-)-cis-4-hydroxynipecotic acid methyl ester and guvacine methyl ester, and the inhibitors of GABA degradation aminooxyacetic acid, gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA and ethanolamine-O-sulphate. Valproic acid was induced as a reference standard. All drugs were administered intraperitoneally and their anticonvulsant potencies were compared at the previously established time of peak drug effect. All GABAmimetics gave rise to significant, dose-dependent threshold elevations. Most potent were muscimol, THIP and Cetyl GABA, and least potent were gamma-vinyl GABA and ethanolamine-O-sulphate. Determination of minimal neurotoxicity by means of the chimney test indicated that the anticonvulsant effect of most GABAmimetics was impaired by a narrow margin of safety. Only cetyl GABA, aminooxyacetic acid and progabide exhibited satisfactory margins of safety similar to those of valproic acid in any particular test. Based on the present data, cetyl GABA and progabide appear to be the most interesting compounds examined besides valproic acid and both GABAmimetics may be interesting as potential antiepileptic drugs.
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PMID:Comparative assay of anticonvulsant and toxic potencies of sixteen GABAmimetic drugs. 712 52

Postictal immobility (IP) following chemically (pictrotoxin, metrazol) and electrically-induced (maximal electroshock, MES) convulsions has behavioral features close to neuroleptic-type catalepsy. EEG, monitored postictally, showed that catalepsy is accompanied by a variety of EEG patterns. Cataleptic behavior extended beyond the period of "postictal EEG depression". During PI rats had vivid righting and corneal reflexes. Like haloperidol-pretreated rats they were able to maintain uncomfortable postures on the vertical grid or horizontal bar; although signs of rigidity were noticed, the rats would fail to remain self-supporting when placed across metal bookends ("bridge" test). All rats reacted to the tail-pinch immediately when the seizure would halt. However, 10-15 min later when PI was minimal or not detectable, animals became totally unresponsive to pressure applied to the tail ("delayed analgesia"). Examination of VEP recovery after MES showed that the secondary slow negativity and sensory after discharge were well developed irrespective of the score of the tail-pinch test. Pharmacological profile of PI suggests that the endogenous opiate system might contribute to this syndrome. Similar to morphine-induced catalepsy/catatonia: (1) PI is insensitive to atropine and scopolamine; (2) neither haloperidol nor alpha-methyl-p-tyrosine was able to potentiate it; (3) PI is reduced by apomorphine, naloxone, and physostigmine. Also, drugs acting via GABA system (gamma-vinyl GABA, diazepam, sodium valproate) reduce PI intensity. It is hypothesized that PI system (1) is controlled by GABA carrying fibers and (2) uses neuropeptide with neuroleptic properties.
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PMID:Pharmacologic analysis of the postictal immobility syndrome in the rat. 729 Dec 36

The intraperitoneal administration of gabaculine, aminooxyacetic acid (s.c.), gamma-acetylenic GABA, gamma-vinyl GABA, ethanolamine-O-sulphate, sodium valproate and GABA caused significant increases in the GABA content of both the whole brain and brain nerve endings (synaptosomes) in mice, a linear relationship being observed between the two parameters. When the relative effects on GABA concentrations were compared with the potency of the different drugs to elevate the thresholds for electroconvulsions and clonic pentetrazole seizures, only the increase in the pentetrazole seizure threshold was significantly correlated with the elevation of brain and synaptosomal GABA content. The present results indicate that the threshold for pentetrazole seizures is an appropriate test-system to study the relationship between alterations of overall GABA levels in the brain and nerve terminals and anticonvulsant activity of GABA-elevating agents.
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PMID:Relationship between drug-induced changes in seizure thresholds and the GABA content of brain and brain nerve endings. 730 Sep 16


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