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)

1. The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L-687,414 (R(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one) have been investigated in rodents. 2. L-687,414 dose-dependently antagonized seizures induced by N-methyl-D,L- aspartic acid (NMDLA, ED50 = 19.7 mg kg-1), pentylenetetrazol (PTZ, ED50 = 13.0 mg kg-1) and electroshock (ED50 = 26.1 mg kg-1) when given intravenously 15 min before test, in male Swiss Webster mice but was most potent against audiogenic seizures induced by a 120 dB bell in DBA/2 mice (ED50 = 5.1 mg kg-1, i.p., 30 min before test). 3. L-687,414 also induced impairments of performance in a rotarod test in both Swiss Webster and DBA/2 mice and the ratio [rotarod MED:anticonvulsant ED50] varied between 0.9 and 5, depending on the convulsant used. 4. Similar behaviours to those seen after administration of the non-competitive NMDA receptor antagonist, MK-801 (head weaving, body rolling, hyperlocomotion) were seen in the mouse after giving L-687,414, although the peak effect occurred at a dose (100 mg kg-1) which was 5-20 times the anticonvulsant ED50S, depending on the convulsant used. Unlike MK-801, however, doses of L-687,414 that were behaviourally stimulant did not increase dopamine turnover in the nucleus accumbens. 5. Consistent with the interaction of L-687,414 with the glycine/NMDA receptor, the anticonvulsant, ataxic and motor stimulant effects of the compound were significantly attenuated by the glycine/NMDA receptor agonist, D-serine (10-100 micrograms per mouse, i.c.v.). 6. The results show that L-687,414 is a potent, orally active anticonvulsant with a more benign pharmacological profile than antagonists acting at the ion channel of the NMDA receptor complex. The compound is a useful tool with which to probe the functional role of the glycine co-agonist site in vivo.
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PMID:The anticonvulsant and behavioural profile of L-687,414, a partial agonist acting at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor complex. 785 61

Previous studies have shown that potassium-evoked, calcium-dependent, endogenous aspartate release is greater from hippocampal slices of adult epileptic (EL) mice than from nonepileptic control C57BL/6J (B6) mice. To examine further the association between epilepsy and enhanced aspartate release in EL mice, endogenous neurotransmitter release from hippocampal slices was studied in young, seizure-free EL mice and in two nonseizure control mouse strains, DDY and B6. DDY is the parental strain from which EL arose, and it has a genetic background similar to EL. Released amino acid neurotransmitters were quantitated by HPLC with fluorescent detection and were expressed as picomoles of amino acid released per minute of incubation per slice +/- SEM. Aspartate release was significantly higher in EL mice (15.8 +/- 0.8) than in either the control B6 or DDY mice (8.5 +/- 1.4 and 8.4 +/- 1.7, respectively). No significant differences were found among the B6, DDY, and EL mice for the release of glutamate (23.0 +/- 2.0, 32.3 +/- 5.8, and 25.9 +/- 2.6, respectively) or GABA (23.5 +/- 0.7, 19.5 +/- 3.2, and 21.8 +/- 3.2, respectively). Thus, enhanced aspartate release precedes the onset of EL seizures and may be related to the cause rather than to the effects of seizure activity.
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PMID:Enhanced aspartate release related to epilepsy in (EL) mice. 791 88

Extracellular levels of aspartate, glutamate and glutamine were monitored by microdialysis in the dorsal hippocampus of freely moving rats following the administration of a convulsant dose of pilocarpine (400 mg/kg, i.p.). Rats were either pretreated with the glutamate uptake inhibitor, 1-trans-pyrrolidine-2,4-dicarboxylic acid (PDC, 1 mM in the perfusion medium, -25 min), or received pilocarpine directly. All rats injected with pilocarpine (with or without PDC pretreatment) developed limbic seizures (latency 15.4 +/- 2.4 min). Without PDC pretreatment there were no significant changes in extracellular levels of aspartate, glutamate and glutamine following pilocarpine administration until the onset of limbic seizures when glutamine levels fell by 35%. Following PDC pretreatment there were large and sustained increases in extracellular hippocampal aspartate (250%) and glutamate (55%) levels, but no significant change in the glutamine level. When pilocarpine was administered to this group of rats, there were further selective, significant, transient increases in the extracellular levels of aspartate (31%) and glutamate (18%) which preceded the onset of seizures. Aspartate and glutamate levels were not significantly increased (relative to PDC controls) during seizures. The conditions for pilocarpine-induced increases in aspartate and glutamate release were established in parallel groups of anaesthetised rats where pilocarpine was administered via a microdialysis probe in the dorsal hippocampus. Following the infusion of 10 mM pilocarpine there were large and rapid increases in the levels of aspartate (143%) and glutamate (179%), which were completely abolished by the absence of calcium in the perfusion medium, or by the presence of atropine (20 mM) or tetrodotoxin (1 microM).
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PMID:Extracellular amino acid levels in hippocampus during pilocarpine-induced seizures. 809 93

The aim of this investigation was to determine the incidence of seizure activity in the acute phase following traumatic brain injury. Compression contusion trauma was produced in the right parietal cortex in 19 artificially ventilated rats. Electroencephalographic recordings were carried out in 17 of the animals for 2 h following the impact. The extracellular levels of neuroactive amino acids were simultaneously monitored in 9 of the experiments using microdialysis. In 14 of the 17 animals a generalized seizure activity with an average duration of 59 s (range 30-101 s) was recorded. The mean time lag between trauma and seizure onset was 67 s (range 26-90 s). The seizure activity was consistently followed by post-ictal depression. The trauma was accompanied by a transient increase of aspartate, taurine, glutamate and glycine, in decreasing rank order. The seizure activity occurred when the levels of these neuroactive amino acids were elevated. It is concluded that the high incidence of seizure activity observed may be an important factor contributing to secondary ischemia after traumatic brain injury. Aspartate and glutamate, potentiated by glycine, may play a role in post-traumatic seizure activity.
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PMID:Epileptic seizure activity in the acute phase following cortical impact trauma in rat. 818 Aug

We report the isolation, characterization, and total synthesis of a small peptide ligand for nicotinic acetylcholine receptors (nAChRs). It is highly active against the neuromuscular receptor in frog but not in mice. In contrast, it induces seizures when injected centrally in mice and rats, suggesting that it may target neuronal nAChRs in mammals. Although such receptors may be important in both normal cognition and the pathophysiology of several neuropsychiatric disorders, there are few ligands to discriminate between the multiple receptor subtypes. The new peptide is a highly divergent alpha-conotoxin from the snail Conus imperialis, which preys on polychaete worms. In this article, the purification, structural analysis, synthesis, and preliminary physiological characterization of alpha-conotoxin ImI (alpha-CTx-ImI) are reported. The sequence of the peptide is: Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2. The peptide shows striking sequence differences from all alpha-conotoxins of fish-hunting Conus, but its disulfide-bridging is similar: [2-8; 3-12]. We suggest that cone venoms may provide an array of ligands with selectivity for various neuronal nAChR subtypes.
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PMID:A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI. 820 95

The metabolism of GABA and other amino acids was studied in the substantia nigra, the hippocampus and the parietal cortex of rats following microinjections of GAMMA-vinyl-GABA during status epilepticus induced by lithium and pilocarpine. GABA metabolism showed striking regional variations. In controls, both GABA concentration and rate of GABA synthesis were highest in the substantia nigra and lowest in cortex, as expected. In substantia nigra, status epilepticus resulted in a 2 1/2 fold decline in the rate of GABA synthesis and in a 307% increase in the turnover time of the GABA pool. In hippocampus, the rate of GABA synthesis was not altered significantly, but the turnover time of the GABA pool was 284% of controls, and the size of that pool increased to 208% of controls. By contrast, in cortex, where seizure activity is limited in this model, the rate of GABA synthesis increased to 230% of controls while pool size and turnover time did not change. Aspartate concentration decreased in all three brain regions. These data suggest that the observed reduction of the rate of GABA synthesis in substantia nigra could play a key role in seizure spread in this model of status epilepticus.
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PMID:GABA metabolism in the substantia nigra, cortex, and hippocampus during status epilepticus. 847 71

Germline mutations in the presenilin 1 (PS1) gene apparently account for the majority of early-onset, familial Alzheimer's disease (AD). Using a mutation-screening strategy (denaturing gradient gel electrophoresis; DGGE), we analyzed a large family with early onset AD and seizures. The patients in this family showed a novel missense mutation in exon 5 of the PS1 gene (A to T change in codon 120, altering glutamine to aspartic acid). This novel mutation is located within the second hydrophilic domain of the molecule, a region not particularly involved in previously described germline mutations, and is of unknown biological significance. These results also demonstrate that DGGE can be used effectively to screen for mutations within this gene.
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PMID:A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. 893 4

Dichloromethane, methanol and water extracts of Viscum sapense L.f., of the Loranthaceae family, were tested for antimicrobial activities against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. Methanol extract was also tested for activity against seizures in albino mice induced by pentylenetetrazole (PTZ), bicuculline and N-methyl-DL-aspartic acid (NMDLA). Methanol extract of V. capense inhibited the growth of S. aureus. Methanol extract also protected the mice against PTZ- and bicuculline-induced tonic seizures but did not significantly alter NMDLA-induced tonic seizures. The data indicate that the extract of V. capense has antibacterial activity against S. aureus and also anticonvulsant activity.
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PMID:Antimicrobial and anticonvulsant activities of Viscum capense. 970 15

Excitotoxic mechanisms are believed to be involved in the death of neurons after trauma, epileptic seizures and cerebral ischaemia. We investigated the role of mitochondrial superoxide production in excitotoxic cell death of cultured rat hippocampal neurons. Brief exposure to the selective glutamate agonist N-methyl-D-aspartate (NMDA; 100-300 microM, 10 min) induced significant neuronal death, which was sensitive to cycloheximide (1 microM) and the caspase-1 inhibitor, acetyl-Tyr-Val-Ala-Asp-chloromethylketone (10 microM). Intracellular superoxide production was monitored semiquantitatively on sister cultures from the same platings using the oxidation-sensitive probe, hydroethidine. Brief exposures to toxic NMDA concentrations induced significant increases in superoxide production which correlated with the degree of neuronal injury. However, subtoxic NMDA exposures also produced moderate, yet statistically significant increases in superoxide production. Both NMDA-induced superoxide production and neurotoxicity were reduced by inhibition of mitochondrial electron transport using either sodium cyanide (1 mM), or a combination of rotenone (2 microM) and oligomycin (2 microM). The mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone (FCCP, 1 microM) mimicked the effect of NMDA on mitochondrial superoxide production. Both NMDA-induced superoxide production and neurotoxicity were potentiated by FCCP (1 microM). Exposure to FCCP alone (1-10 microM, 10 min), however, failed to produce any toxicity. Our data suggest that mitochondrial superoxide production per se is not sufficient to trigger the degeneration of cultured hippocampal neurons, but that manipulation of mitochondrial activity alters NMDA-induced superoxide production and neurotoxicity.
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PMID:NMDA-induced superoxide production and neurotoxicity in cultured rat hippocampal neurons: role of mitochondria. 975 Nov 60

A rational, chemical, synthetic effort to identify promising low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists for use as antiepileptic drugs led to the discovery of AR-R 15035AR, or [RS]-alpha-phenyl-2-pyridine-ethanamine.2HCl. Chiral separation followed by intensive in vivo screening resulted in the selection of the [S] enantiomer, AR-R 15896AR, as the best compound for further preclinical development. AR-R 15896AR prevented tonic seizures in rodents for up to 6 to 8 h in response to maximal electroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as characteristic seizures following injections of N-methyl-DL-aspartic or kainic acids. AR-R 15896AR was ineffective in two kindling models of epilepsy, did not produce tolerance to MES, and was devoid of proconvulsant and phencyclidine-like properties in mice and rats, respectively. Therapeutic indices for AR-R 15896AR were comparable to or exceeded those for standard anticonvulsants. Orally administered AR-R 15896AR rapidly entered the rat brain and was eliminated in parallel from the plasma and plasma-free compartment. A dose-response relationship between plasma and brain levels after p.o. or i.v. administration of AR-R 15896AR and protection against MES was highly correlative. The time course for loss of protection against MES mirrored the elimination of the compound from brain and plasma. The total brain concentration (25 microM) of drug at the ED50 value (approximately 3 mg/kg) for protection against MES seizures was consistent with the reported affinity of AR-R 15896AR at the N-methyl-D- aspartic acid binding site (IC50 value = 1.3 microM). The present findings demonstrated the attractiveness of AR-R 15896AR as a candidate for further development to treat epilepsy.
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PMID:[S]-AR-R 15896AR-A novel anticonvulsant: acute safety, pharmacokinetic and pharmacodynamic properties. 986 62


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