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)

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."
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PMID:GABA and epilepsy: their complex relationship and the evolution of our understanding. 131 57

The effects of some GABAergic agents on seizures induced by quinine were studied in mice. Muscimol, AOAA, DABA and baclofen significantly protected mice against quinine-induced convulsions. Bicuculline effectively enhanced quinine-induced convulsions, and significantly attenuated the protective effects of muscimol, AOAA and DABA against convulsions induced by quinine. Diazepam and phenobarbitone significantly protected mice against convulsions induced by quinine. However, phenytoin did not affect quinine-induced seizures to any significant degree. These results indicate that the convulsant effect of quinine may be due to a disturbance in the status of the GABAergic system.
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PMID:Effects of some GABAergic agents on quinine-induced seizures in mice. 132 22

In mice, tonic convulsive seizure induced by intravenous administration of caffeine (adenosine A1, A2 receptors antagonist) was significantly potentiated by any one of L-PIA (adenosine A1 receptor agonist), NECA (adenosine A2 receptor agonist) and 2-ClAd (adenosine A1, A2 receptors agonist). The caffeine-induced seizure was unaffected by diazepam (benzodiazepine receptor agonist), but was inhibited by Ro 15-1788 (antagonist or partial agonist). beta-DMCM (antagonist or inverse agonist) increased the seizure. Muscimol (GABA-a receptor agonist), baclofen (GABA-b receptor agonist) and AOAA (GABA transaminase inhibitor) did not show significant effect on caffeine-induced convulsion. Bicuculline (GABA-a receptor antagonist) and picrotoxin (chloride channel blocker) significantly potentiated the convulsion at the doses which did not induce it. Caffeine-induced convulsion was potentiated by NMDA with its non-convulsive dose. CPP (competitive NMDA receptor antagonist) and MK-801 (non-competitive NMDA receptor antagonist) significantly inhibited the seizures. These results suggest that caffeine-induced seizure is not caused by blockade of adenosine receptors. Caffeine may act to beta-carboline sensitive benzodiazepine receptor (Type 1) which has no linkage with GABA-a receptor. Furthermore, it is implied that caffeine plays some role at NMDA receptor calcium ion channel complex.
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PMID:[Effects of agonists and antagonists of benzodiazepine, GABA and NMDA receptors, on caffeine-induced seizures in mice]. 132 1

1. The influence of some GABAergic agents on tonic seizures elicited by chloroquine was investigated in mice. 2. Chloroquine (45-100 mg/kg) elicited seizures in mice in a dose related manner. 3. Muscimol (1-2 mg/kg), DABA (8-16 mg/kg) and baclofen (4-16 mg/kg) profoundly delayed the onset of chloroquine (65 mg/kg)-induced seizures. The incidence of the seizures was also significantly reduced by muscimol (1-2 mg/kg), DABA (8 mg/kg) and baclofen (4-8 mg/kg). 4. AOAA (10 mg/kg) profoundly reduced the proportion of mice that convulsed while AOAA (20 mg/kg) completely protected mice against chloroquine (65 mg/kg)-induced seizures. 5. Bicuculline (5 mg/kg) and picrotoxin (0.5-1 mg/kg) significantly potentiated chloroquine (50 mg/kg)-induced seizures. The onset of seizures and the number of mice that convulsed were shortened and increased respectively. The onset of chloroquine (65 mg/kg)-elicited seizures was also profoundly shortened. Bicuculline (5 mg/kg) and picrotoxin (0.5 mg/kg) effectively antagonised the protective effects of muscimol (2 mg/kg), AOAA (10 mg/kg) and DABA (8 mg/kg) against chloroquine (65 mg/kg)-elicited seizures. 6. Diazepam (1 mg/kg) and phenobarbitone (20 mg/kg) significantly antagonised chloroquine (65 mg/kg) seizures. The onset of seizures was significantly delayed by both diazepam (0.25-1 mg/kg) and phenobarbitone (10-20 mg/kg). 7. These data suggest that enhancement and inhibition of GABAergic neurotransmission respectively attenuate and potentiate chloroquine seizures in mice.
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PMID:Involvement of GABAergic mechanisms in chloroquine-induced seizures in mice. 163 37

To determine whether genetic differences in development of ethanol dependence are related to changes in gamma-aminobutyric acidA (GABAA) receptor function, we measured 36Cl- uptake by brain cortical membrane vesicles from withdrawal seizure prone and withdrawal seizure resistant (WSP/WSR) mice treated chronically with ethanol. Muscimol-stimulated chloride flux was not different between WSP and WSR mice before or after ethanol treatment. Also, augmentation of muscimol action by flunitrazepam or inhibition of muscimol action by the inverse agonists Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]- [1,4]benzodiazepine-3-carboxylate) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) was not different for ethanol-naive WSP and WSR mice. However, chronic ethanol administration enhanced the inhibitory actions of DMCM and Ro 15-4513 on membranes from WSP but not WSR mice. Conversely, chronic ethanol treatment attenuated the action of flunitrazepam on membranes from WSR but not WSP mice, suggesting that the actions of benzodiazepine agonists and inverse agonists are under separate genetic control. These genetic differences in actions of DMCM and Ro 15-4513 indicate that sensitization to benzodiazepine inverse agonists produced by chronic ethanol treatment may be related to development of withdrawal seizures and suggest that differences in the GABA/benzodiazepine receptor complex represent alleles that have segregated during the selection of the WSP/WSR mice.
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PMID:Modulation of gamma-aminobutyric acidA receptor-operated chloride channels by benzodiazepine inverse agonists is related to genetic differences in ethanol withdrawal seizure severity. 165 34

The role of inhibitory systems in the initiation and termination of seizures in limbic circuits of the rat was tested by measuring the time to onset and duration of maximal dentate activation before and after the administration of GABAergic agents. Both 0.1 and 0.3 mg/kg of the GABAA receptor antagonist bicuculline lengthened maximal dentate activation while 0.3 mg/kg was needed to reversibly decrease the time to onset. Picrotoxin, an antagonist at the GABAA receptor/channel complex, lengthened maximal dentate activation, but did not alter the time to onset. Muscimol, a GABAA receptor agonist, shortened maximal dentate activation, but did not lengthen the time to onset. Baclofen, a GABAB receptor agonist (3 and 10 mg/kg), had no effect on the time to onset of maximal dentate activation, while 10 mg/kg baclofen shortened maximal dentate activation. These results demonstrate that agents that have selective action at both GABAA and GABAB synapses alter the duration of maximal dentate activation more than they influence the time to onset of maximal dentate activation and suggest that GABAergic mechanisms are critical in the termination of seizures.
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PMID:Pharmacological evidence indicating a role of GABAergic systems in termination of limbic seizures. 170 25

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the gamma-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-[+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists. gamma-D-Glutamylaminomethylsulphonate (gamma-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), gamma-D-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus.2+ the pathogenesis of seizures triggered by bicuculline in mice.
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PMID:Excitatory amino acid antagonists protect mice against seizures induced by bicuculline. 216 7

The repeated administration of N-methyl-beta-carboline-3-carboxamide (FG 7142) to mice leads to 'chemical kindling', i.e. the development of seizures in response to doses which were initially insufficient to produce convulsive activity. To determine if chemical kindling produced changes in the GABAA receptor/chloride channel complex, we measured the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the convulsant site of the complex by quantitative autoradiography. As a measure of chloride channel function, we studied muscimol-stimulated uptake of 36Cl- by isolated brain synaptosomes. Kindling decreased the Bmax of [35S]TBPS binding in cortex but not in cerebellum or hippocampus. Kindling did not alter binding affinities in any of these brain regions. Some mice injected with FG 7142 did not kindle despite receiving the same treatment as kindled mice. These 'injected but not kindled' mice did not display decreased receptor binding in any of these brain areas. Muscimol-stimulated 36Cl- uptake into cortical synaptosomes was also diminished by chemical kindling. These findings suggest that a decrease in functioning GABA-regulated chloride channels may be responsible for chemical kindling with FG 7142.
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PMID:Chemical kindling decreases GABA-activated chloride channels of mouse brain. 246 90

Chronic treatment with benzodiazepine receptor agonists increases sensitivity to the convulsant action of FG 7142, an inverse agonist. We investigated whether or not changes in the number and function of GABA-gated chloride channels accompanies this increased sensitivity. Diazepam, 5 mg.kg-1, was administered to mice daily for five days, and mice were then tested with a single injection of FG 7142, 40 mg.kg-1, at several intervals thereafter. At 24 hours after the last diazepam dose, 10 of 15 mice had clonic seizures following FG 7142 and four of the remaining five had myoclonic jerks. At 48 hours, only one of six mice developed a clonic seizure, and none were observed in mice tested at 96 or 144 hours. Muscimol-stimulated chloride flux was reduced in cortical synaptosomes from diazepam-treated mice at 24 hours but not at 48 or 96 hours. However, the binding of [35S]TBPS, a ligand closely associated with the chloride channel, was unchanged at 24 hours. These results suggest that a transient diminution in GABA-gated chloride channel function; unaccompanied by a reduction in channel number, may underlie the sensitization to the convulsant action of FG 7142 observed after withdrawal from chronic diazepam treatment.
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PMID:Diazepam sensitizes mice to FG 7142 and reduces muscimol-stimulated 36Cl- flux. 247 37

Bath application of muscimol (10-20 microM) to hippocampal slices obtained from rats on postnatal days 10-15 produced epileptiform activity in the form of multiple population spikes in 20% of slices tested, concurrent with marked disinhibition. The disinhibition occurred in nearly 100% of cases tested at muscimol concentrations that produced epileptiform activity. Paired pulse analysis of GABAergic recurrent inhibition revealed a muscimol-induced disinhibitory effect involving a decrease in maximum possible inhibition. Spontaneous and antidromically elicited inhibitory postsynaptic potentials (IPSPs) recorded intracellularly were suppressed by muscimol. Current-voltage analysis of the recurrent IPSPs suggests that muscimol acted at a number of sites to produce disinhibition. The input conductance of the postsynaptic pyramidal cell increased due to muscimol, creating a current shunt which likely decreased the efficacy of synaptic currents. Muscimol also caused a decrease in the conductance due to the IPSP as well as a shift in the depolarizing direction of the equilibrium potential of the IPSP. The data indicate that muscimol, a GABAA agonist, can produce disinhibition resulting from the multiple consequences of its action. We conclude that the physiologic consequences of GABAA agonist treatment are complex. On the other hand, neurons are likely to be inhibited by a tonic increase in membrane conductance. However, since recurrent inhibition is simultaneously compromised, excitatory vollies of sufficient intensity may overcome the tonic inhibition and produce a hyperexcitable state. In some cases, this disinhibition may induce epileptiform activity. These observations are relevant in light of the proposed use of GABA agonists clinically to control seizures.
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PMID:Disinhibitory actions of the GABAA agonist muscimol in immature hippocampus. 255 27


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