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)

GABAA receptors are multisubunit inhibitory chloride channels in the brain which open in response to binding of gamma-aminobutyric acid (GABA) and are thought to be involved in some forms of seizures. We compare the sequence and expression of the GABAA receptor delta subunit in audiogenic seizure prone (DBA/2J) and seizure resistant (C57BL/6J) inbred strains of mice and also report this subunit's postnatal developmental profile. We did not detect any unique features in the delta subunits of DBA/2J mice which might explain their seizure susceptibility, but did detect in some clones from both DBA/2J mice and C57BL/6J mice an unusual substitution of His for a conserved Tyr in the delta subunit's first putative transmembrane region.
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PMID:Strain comparisons and developmental profile of the delta subunit of the murine GABAA receptor. 132 97

The effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.
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PMID:Inhibition of GABA-gated chloride channel function by arachidonic acid. 132 73

Intracellular recordings were obtained from the basolateral amygdala in in vitro rat brain slice preparations to examine whether gamma-aminobutyric acid (GABA)B receptors are altered after in vivo kindling-induced epileptogenesis. Stimulating the stria terminalis evoked excitatory (EPSPs) and inhibitory (IPSPs) postsynaptic potentials in control neurons, and epileptiform bursting or enhanced EPSPs, but no IPSPs, in neurons from animals, 4 to 8 weeks after the last kindled seizure. Baclofen (0.1 nM-100 microM) depressed EPSPs in control and kindled basolateral amygdala neurons, but the EC50 appeared to be shifted 100-fold from 5 nM in control to 500 nM in kindled neurons. Further analysis suggested a high-affinity component may be affected in kind led neurons. The absence of IPSPs in kindled neurons could not account for this shift, because effects of baclofen on EPSP amplitude were reduced in kindled animals even when GABAA receptors were blocked with bicuculline methiodide (30 microM) and postsynpatic GABAB receptors with intracellular guanosine 5'-O-3-thiotriphosphate (10 mM); 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (10 microM) was also present to block bicuculline methiodide-induced bursting. Membrane responses to exogenously applied N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid were not affected by baclofen. Baclofen also hyperpolarized basolateral amygdala neurons and reduced membrane input resistance with an EC50 of 1 microM in control and kindled neurons. Post- but not presynaptic effects of baclofen were blocked by 2-hydroxy-saclofen (100 microM) and pertussis toxin pretreatment. In conclusion, kindling-induced epileptogenesis reduces the sensitivity of presynaptic GABAB receptors, an effect which may contribute to the enhancement of excitatory transmission in kindled animals. Furthermore, different pharmacological properties of pre- and postsynaptic receptors in the amygdala suggest two distinct populations of GABAB receptors whose long-lasting responses to kindling-induced seizures are different.
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PMID:Epileptogenesis reduces the sensitivity of presynaptic gamma-aminobutyric acidB receptors on glutamatergic afferents in the amygdala. 132 20

The substantia nigra gamma-aminobutyric acid (GABA) system is crucial for seizure control. Our previous work indicates that in 16-day-old rat pups, nigral administration of the GABAA receptor agonist muscimol facilitates flurothyl-induced seizures, whereas it suppresses seizures in adult rats. To determine whether the proconvulsant effect of muscimol in rat pups may be mediated by nigral GABAA receptors, in the present study we applied a selective GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Bilateral nigral infusions of THIP (500 or 700 ng) significantly decreased the thresholds for flurothyl seizures in a dose-dependent fashion. Doses of 350 ng or less did not significantly modify the susceptibility to seizures. An anticonvulsant action of THIP could not be detected at any dose. Administration of an effective THIP dose (500 ng) 2 mm dorsal to the SNR had no influence on seizures. These findings suggest that in rat pups the proconvulsant effect of nigral GABAA receptor agonists may be attributed to unique pharmacologic characteristics of GABAA receptors during development.
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PMID:The proconvulsant effect of nigral infusions of THIP on flurothyl-induced seizures in rat pups. 132 81

The role of gamma-aminobutyric acid (GABA) transmission in the control of convulsive epileptic seizures is considered from the perspective of the actions of drugs that augment GABA transmission in the brain. In particular, the effects of a directly acting GABAA receptor agonist, muscimol, is compared with the effects of a GABA-elevating agent, gamma-vinyl GABA (GVG, vigabatrin), in animal models of convulsive seizures. Evidence indicates that there are certain regions of the brain where enhanced GABA transmission is anticonvulsant; in other regions, blockade of GABA transmission exerts anticonvulsant actions. In addition, there are brain areas in which the effects of muscimol and GVG are distinct from one another, owing to a relatively low level of endogenous GABA transmission in those areas. The direct stimulation of postsynaptic GABA receptors (by direct receptor agonists) bypasses normal mechanisms of synaptic transmission and can evoke abnormal neurological symptoms, whereas the enhancement of presynaptic availability of GABA avoids these complications. GVG acts to boost presynaptic GABA stores, which can then be utilized physiologically; this may account for the relatively low incidence of CNS-related side effects with anticonvulsant doses of GVG. It is suggested that greater attention be focused on ways of enhancing endogenous GABA availability in future drug development for the control of seizure disorders.
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PMID:GABA and epilepsy: basic concepts from preclinical research. 133 May 9

The basket cells are an important cell type in the dentate gyrus because their axon terminals form a prominent plexus with the somata of the principal cells, the granule cells. The basket cells consist of five morphological types that have different dendritic arborizations and somal positions. All five types of basket cell display immunoreactivity for glutamate decarboxylase, the synthesizing enzyme for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Electron microscopy has shown that basket cells have similar ultrastructural features including smooth dendrites, infolded nuclei, intranuclear rods, prominent Nissl bodies, and a thick rim of perikaryal cytoplasm. The axon terminals of basket cells form symmetric synapses with the somata and proximal dendrites of granule cells. Since the somata, basal dendrites and proximal apical dendrites of basket cells are postsynaptic to granule cell axon collaterals, the basket cells are linked to granule cells in a powerful feedback inhibitory circuit. The basket cells are also involved in feedforward inhibition as a result of being postsynaptic to perforant path and commissural axons. The calcium-binding protein, parvalbumin, is found in each type of basket cell but less than 40% of the basket endings display parvalbumin-immunoreactivity. In contrast, virtually all cortical basket cells contain parvalbumin, and this difference for basket cells between neocortex and hippocampus may contribute to the lower seizure threshold for the hippocampal formation as compared to the neocortex. Studies show that basket cells play a role in at least two experimental models of epilepsy.
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PMID:Local circuitry of GABAergic basket cells in the dentate gyrus. 133 68

The postsynaptic actions of glutamate, gamma-aminobutyric acid (GABA), acetylcholine, norepinephrine, serotonin, and histamine in the cerebral cortex and thalamus and their relevance to the control of thalamocortical activity are reviewed. Excitatory and inhibitory amino acids (such as glutamate and GABA) are proposed to form the neurotransmitters by which the executative neural networks of the neocortex and thalamus process synaptic information. In contrast, the more slowly acting neurotransmitters, acetylcholine, norepinephrine, serotonin, and histamine, are proposed to control the state of activity and excitability of thalamic and cortical neurons and thereby modulate the state of thalamocortical activity. Specific examples of the involvement of fast and slow transmitter actions in the genesis of epileptic seizures and the determination of sleep-wake cycles are given.
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PMID:Neurotransmitter actions in the thalamus and cerebral cortex. 135 May 91

Extracellular concentrations of gamma-aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) were determined by microdialysis in rat hippocampus during various amygdaloid kindled stages. The values of GABA and Glu were increased 3-4 times in C2-C3 stages in comparison with the values in control animals. After reaching the C5 stages, these values were increased 3-7 times. However, the concentration of Asp decreased depending on the kindling stage, reaching the lowest value of 33% in comparison with the normal value. The observed changes may be related to kindling induced seizures.
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PMID:In vivo microdialysis of amino acid neurotransmitters in the hippocampus in amygdaloid kindled rat. 135 51

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in brain, opens chloride channels through actions on GABAA receptors. We now report base and amino acid sequences of the alpha 1, alpha 2, and alpha 3 subunits from GABAA receptors of audiogenic seizure-prone (DBA/2J) and -resistant (C57BL/6J) inbred strains of mice. Inbreeding had fixed different alleles of the alpha 1 subunit in the two strains, giving five base differences in the cDNAs. None of these affected amino acid sequence, but one did create a NsiI restriction site potentially useful in mapping genomic DNA. No base or amino acid sequence differences between the strains were detected for the other two subunits. Northern blots revealed no apparent strain differences in message levels for these three subunits in whole brains of the mice at 3 weeks of age, the peak of seizure susceptibility in DBA/2J, but did reveal distinct regional and developmental patterns of expression among the subunits in mouse brain.
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PMID:The alpha 1, alpha 2, and alpha 3 subunits of GABAA receptors: comparison in seizure-prone and -resistant mice and during development. 135 7

Alcohol withdrawal is associated with a decrease in gamma-aminobutyric acid neurotransmission. This explains the efficacy of benzodiazepines. However, an increase in adrenergic activity may also play a part in alcohol withdrawal symptoms, suggesting a potential efficacy of beta-blocking drugs. A double-blind comparative study of propranolol and diazepam was carried out in 28 patients suffering from moderate uncomplicated alcohol withdrawal. Patients were treated for 15 days with either 75 mg of propranolol or 30 mg of diazepam. The results show that both drugs at the dosages used are equipotent in reducing physical withdrawal symptoms and anxiety symptoms. This suggests that most likely the central as well as the peripheral effects determine the clinical usefulness of propranolol in the management of alcohol withdrawal. However, propranolol is ineffective in preventing major motor seizures, suggesting that different neurobiological mechanisms underlie the alcohol withdrawal symptoms.
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PMID:Effects of beta-blocking drugs in alcohol withdrawal: a double-blind comparative study with propranolol and diazepam. 136 75


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