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)

To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered dextrorphan and dizocilpine, non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared. Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of NMDA, but also showed a broad spectrum of anticonvulsant activities against tonic convulsions caused by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), bicuculline, pentylenetetrazole or electroconvulsive shock. The anticonvulsant action of dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of dextrorphan. Dizocilpine, unlike dextrorphan, impaired motor function at doses showing its anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced seizures were not antagonized by dextrorphan. Dextrorphan and dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of glutamate receptors, as death caused by NMDA but not by AMPA and KA was selectively and markedly inhibited by both dextrorphan and dizocilpine. In view of these results, the efficacy of dextrorphan and dizocilpine as antagonists of convulsant effects appears to be consistent with the interpretation that a variety of convulsants cause tonic convulsions via direct or indirect interaction with the NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+) binding proteins, are not directly modified by the administration of dextrorphan, itself.
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PMID:Antagonism of various tonic convulsions in mice by dextrorphan and dizocilpine. 768 6

Propofol (i.v. and i.p.) exhibited anticonvulsant activity in three models of seizure in the mouse, induced by bicuculline, kainic acid and N-methyl-DL-aspartic acid (NMDLA). Morphine, pethidine and fentanyl, which showed a biphasic dose-response relationship with respect to seizure modulation, abolished the anticonvulsant activity of propofol to exhibit their own intrinsic activity in proconvulsant doses. This occurred with very low doses of fentanyl and pethidine (15 micrograms kg-1 and 0.5 mg kg-1, respectively) in the NMDLA model. Thus it appears that propofol has anticonvulsant activity only when a convulsion is elicited directly; it does not prevent the actions of compounds that lower seizure threshold to convulsant stimuli. The anticonvulsant doses of morphine and fentanyl did not summate with the anticonvulsant activity of propofol. However, there was some evidence of summation of anticonvulsant activity between pethidine and propofol in the NMDLA model.
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PMID:Interactions between opioid drugs and propofol in laboratory models of seizures. 771 78

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

D-CPP-ene[3-(2-carboxy-piperazine-4-yl)-1-propenyl-1-phosphonic acid; a competitive antagonist of N-methyl-D-aspartic acid] in a dose of 2 mg/kg (i.p.) significantly increased the threshold for electroconvulsions. When given in a dose half that affecting the electroconvulsive threshold, D-CPP-ene potentiated the anticonvulsant activity of carbamazepine, diazepam, diphenylhydantoin, phenobarbital and valproate against maximal electroshock (50 mA)-induced seizures in mice. However, this NMDA antagonist did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction, in terms of total plasma levels at least, is not probable. The chimney test and retention test in mice revealed that the combined treatment of D-CPP-ene at 1.0 mg/kg (i.p.) with either diazepam, diphenylhydantoin, phenobarbital or valproate (providing a 50% protection against maximal electroshock convulsions) resulted in motor impairment and caused impairment of long-term memory. On the other hand, a combination of D-CPP-ene and carbamazepine was devoid of adverse effects. It can be concluded that the potential utility of D-CPP-ene in combination with conventional antiepileptic drugs does not seem promising, except for carbamazepine.
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PMID:The competitive NMDA antagonist, D-CPP-ene, potentiates the anticonvulsant activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. 793 96

DNA binding activities of several transcription factors were evaluated in nuclear extracts from brains of mice which were intracerebroventricularly injected with N-methyl-D-aspartic acid (NMDA) using gel retardation electrophoresis. An injection of NMDA increased binding of both probes for activator protein 1 (AP1) and cyclic AMP response element binding protein (CREB) 1 to 5 h after the injection compared with that of saline, in a dose-dependent manner at doses from 0.05 to 0.4 micrograms. However, no significant alterations were found in binding of probes for other 4 different transcription factors tested following the injection of NMDA up to 4 h after the administration. These included promoter-specific transcription factor, nuclear factor kappa B, activator protein 2 and octamer binding protein. Potentiation of the AP1 and CREB binding was prevented in a dose-dependent manner by the administration of either of the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, the NMDA antagonist D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid, the glycine antagonist 5,7-dichlorokynurenic acid, or the proposed polyamine antagonist ifenprodil. In contrast, the AP1 binding was not consistently affected up to 4 h following intracerebroventricular injections of other agonists including DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic, kainic, and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acids, in contrast to the severity of convulsive seizures by the former 2 excitants. These results support the proposal that an intracerebroventricular injection of NMDA may selectively potentiate DNA binding activities of both AP1 and CREB through in vivo activation of the NMDA receptor complex in the murine brain.
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PMID:Molecular biological studies on nuclear transcription factors expressed through the N-methyl-D-aspartate receptor complex. 797 30

Felbamate and selected compounds were evaluated for their ability to protect against N-methyl-D-aspartic acid (NMDA)-induced convulsions and lethality in mice. Convulsions produced by intracerebroventricular administration of NMDA (0.8 micrograms per mouse) were antagonized by felbamate, phenytoin, carbamazepine, phenobarbital, valproate, diazepam, 2-amino-5-phosphonovalergic acid (APV), dextromethorphan and ketamine. NMDA (350 mg kg-1 intraperitoneally) produced 100% lethality in mice. Felbamate, phenytoin, and phenobarbital were ineffective in preventing NMDA-induced lethalities, whereas diazepam, APV, ketamine and dextromethorphan were the most potent compounds in preventing lethalities. Any relationship between the protective effects of felbamate against NMDA-induced seizures and competitive or non-competitive antagonism of NMDA receptor sites, however, cannot be established until further experimentation is carried out.
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PMID:Comparative effects of felbamate and other compounds on N-methyl-D-aspartic acid-induced convulsions and lethality in mice. 805 87

Because multiple withdrawals from chronic ethanol treatment facilitate the rate of kindling from the inferior collicular cortex, the following studies sought to identify potential sources of this long-term change in seizure sensitivity. When rats received 6 or 10 withdrawals from a 5-day ethanol liquid diet, a significant decrease was found in the threshold frequency for seizure genesis, 6-7 days post-withdrawal. The magnitude of this change was related to the number of withdrawals (6 withdrawals, -2.0 +/- 0.3 Hz; 10 withdrawals, -3.2 +/- 1.2 Hz). Thus, multiple ethanol withdrawals increased seizure sensitivity within the inferior collicular cortex. On the following day in the same animals, changes in inhibitory or excitatory function were evaluated within the inferior collicular cortex. We found a withdrawal-related increase in the effectiveness of bicuculline to reduce the seizure threshold current within the inferior collicular cortex. Seizure sensitivity to collicular N-methyl-D-aspartic acid (NMDA) microinjection was decreased after 6 ethanol withdrawals, and increased after 10 withdrawals, but control liquid diet animals exhibited similar responses to collicular NMDA microinjection. Therefore, multiple withdrawals from ethanol alters the seizure sensitivity within the inferior collicular cortex. One possible contribution to this change is a local decrease in GABA inhibitory function.
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PMID:A potential contribution to ethanol withdrawal kindling: reduced GABA function in the inferior collicular cortex. 811 44

The electroencephalographic and histopathological changes following intra-amygdaloid injection of excitatory amino acids were examined in rats. Limbic seizure status was induced after injection of kainic acid (KA), domoic acid (DA), quisqualic acid (QA), alpha-allo-kainic acid (ALLO-KA) and D-glutamic acid (D-GA). The excitatory effect was found to be in the following order: KA > DA >> QA > ALLO-KA >> D-GA. D-GA caused only a transient paroxysmal discharge on EEG. However, seizure was not induced by an injection of L-glutamic acid (L-GA), D-aspartic acid (D-AA) and L-aspartic acid (L-AA). The minimum epileptogenic doses of these amino acids were defined and intra-amygdaloid injection of these doses were performed. Seven days following the injections, histopathological study was performed. These injection resulted in various degree of degeneration and neuronal cell loss of the pyramidal cells in the ipsilateral hippocampus in the following order of severity: DA > or = KA > D-GA > ALLO-KA > QA. These results indicate absence of correlation between epileptogenicity and histopathological changes. Non epileptogenic amino acids induced no pathological changes of hippocampus or the injected site. These results suggest that the severity of hippocampal damage induced by intra-amygdaloid injection of amino acids depends not only on the magnitude of the induced limbic seizure status but also on the difference of neuropharmacological properties of those amino acids in terms of the interaction with their receptors. Further studies are necessary to elucidate the mechanism of actions of these excitatory amino acids in relation to their receptor subtypes.
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PMID:[Epileptogenicity and neurotoxicity induced by intra-amygdaloid injection of various excitatory amino acids in rats]. 832 16

Mice genetically selected to be resistant (withdrawal-seizure resistant, WSR) or prone (withdrawal-seizure prone, WSP) to handling-induced convulsions during ethanol withdrawal were tested for sensitivity to convulsions induced by timed intravenous (i.v.) infusion of N-methyl-D-aspartic acid (NMDA). WSR mice displayed convulsions at infused doses of NMDA that averaged 20% lower than WSP mice. This result was present in both genetically independent replicates of the WSR and WSP mice and provides strong evidence for an involvement of the NMDA system in the difference in withdrawal seizures present in these lines.
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PMID:Sensitivity to N-methyl-D-aspartic acid-induced convulsions is genetically associated with resistance to ethanol withdrawal seizures. 851 27

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.
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PMID:Structure-activity relationships in a series of 2(1H)-quinolones bearing different acidic function in the 3-position: 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid, a new potent and selective AMPA/kainate antagonist with neuroprotective properties. 856 8


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