Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anticonvulsant effects of felbamate (10-300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5-7 dichlorokynurenic acid (5-7DCKA; 0.6-30 nmol/mouse, intracerebroventricularly, ICV), and 2, 3-dihydroxy-6 nitro-7-sulfamoylbenzo (F) quinoxoline (NBQX; 1.1-33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1, 4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1-40 mg/kg IP) was uneffective, while 5,7DCKA (5-90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K+ channels using alpha-dendrotoxin, with ED50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by alpha-dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.
 ...
PMID:Anticonvulsant activity of 5,7DCKA, NBQX, and felbamate against some chemoconvulsants in DBA/2 mice. 895 66

Hypoxia is the most common cause of neonatal seizures and encephalopathy. We have previously developed an in vivo experimental model of perinatal hypoxia which exhibits age-dependent acute and chronic epileptogenic effects. Between postnatal day (P) 10-12, the rat exhibits acute seizure activity during global hypoxia, while no seizures are induced at earlier (P5) or older (P60) ages. Rats exposed to hypoxia between P10-12 have reduced seizure thresholds to chemical convulsants in adulthood. The nonNMDA antagonists NBQX appears to suppress both the acute and long term epileptogenic effects of hypoxia. The age-dependency of the hyperexcitable response to hypoxia in vivo can be reproduced in vitro using hippocampal slices. In Mg(2+)-free media, hypoxia induced ictal discharges within 60 s of onset in 79% of slices from normal P10 rat pups compared to 11% of adult slices (p < 0.001). Model systems such as that described here allow for correlation of in vitro and in vivo electrophysiology and should provide data regarding the pharmacological and physiological characteristics of hypoxia-induced seizure activity in the immature brain which could ultimately be applied to therapeutic strategies.
 ...
PMID:Hypoxia-induced hyperexcitability in vivo and in vitro in the immature hippocampus. 898 95

Deep prepiriform cortex modulates excitatory activity in the limbic system during seizures. We therefore studied a potential role for this system in another process involving excitatory neurotransmission: global ischemia in the rat. The non-NMDA antagonist NBQX was microinjected bilaterally into deep prepiriform cortex prior to 10 min of global ischemia. Hippocampal cell injury was then assessed by heath shock protein (HSP) expression 24 h after ischemia. NBQX significantly decreased the number of HSP positive cells in both CA1 and CA3 hippocampal subsectors, suggesting the possibility that pathways from deep prepiriform cortex to hippocampus modulate excitotoxicity in target neurons during ischemia.
 ...
PMID:Pharmacologic blockade of non-NMDA receptors at deep prepiriform cortex attenuates heat shock protein expression in global ischemia. 903 84

The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the initiation and propagation of limbic motor seizures in rats was examined by the intracerebral and systemic administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline (NBQX), a selective antagonist of the AMPA subtype of glutamate receptor. Limbic motor seizures were evoked focally by the application of the gamma-aminobutyric acid receptor antagonist, bicuculline, into area tempestas, an epileptogenic site in the deep anterior piriform cortex. Before eliciting seizures, NBQX was applied focally into either 1) area tempestas or 2) perirhinal or posterior piriform cortex ipsilateral to the area tempestas from which seizures were evoked. In addition, pretreatment with i.p. NBQX was evaluated for anticonvulsant actions against area tempestas-evoked clonic or systemically evoked tonic seizures. In all conditions, a dose-dependent decrease in the severity of seizures was obtained with NBQX. With focal intracerebral administration, a dose of 500 pmol of NBQX consistently protected against limbic motor seizures, with partial protection achieved with 100 pmol. After i.p. administration, 2.5 and 5.0 mg/kg significantly protected the rats from both limbic motor seizures and tonic extensor seizures. No overt disturbance of spontaneous behavior was associated with the anticonvulsant doses of NBQX. Moreover, both forebrain substrates of limbic motor seizures and hindbrain substrates of tonic extensor seizures were highly susceptible to disruption by NBQX. The results indicate that AMPA subtype of glutamate receptors are crucial mediators of seizure propagation via perirhinal and piriform cortics.
 ...
PMID:A crucial role of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures. 906 29

Deep prepiriform cortex has an important role in modulating neurotransmission during limbic seizures. We used pharmacologic blockade of non-N-methyl-D-aspartate (NMDA) receptors to study excitatory circuitry from the deep prepiriform cortex to the hippocampus during global ischemia in rat. NBQX, a potent non-NMDA glutamate receptor antagonist, was microinjected stereotactically into the deep prepiriform cortex before global ischemia for 10 min. Neuronal cell death in the hippocampus was evaluated quantitatively 72 h after ischemia. The NBQX-injected rats had a greater number of surviving cells in CA1 sector of hippocampus than did saline-injected controls or rats that received NBQX injections 1 mm from the target. Thus, excitatory amino acid-mediated circuitry emanating from deep prepiriform cortex modulates ischemic neuronal injury in the hippocampus.
 ...
PMID:Deep prepiriform cortex modulates neuronal cell death in global ischemia. 911 8

The present study investigates the role of pharmacologic blockade of NMDA (N-methyl-D-aspartate) and non-NMDA receptors at deep prepiriform cortex (area tempestas, AT) in neuronal injury during prolonged seizures in rat. Status epilepticus was induced by intravenous kainate (15 mg/kg) and neuronal death was assessed in hippocampal CA3 sector 72 h following status epilepticus. Unilateral equimolar microinjections of 2-amino-7-phosphonoheptanoic acid (AP-7), an NMDA receptor antagonist, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), a non-NMDA receptor antagonist, into AT were given prior to kainate administration. Counts of surviving cells in CA3 ipsilateral to NBQX-injected AT were significantly greater than on the contralateral control-side, but no significant difference between the AP-7-injected and saline-injected side was found. These results indicate that neurotransmission via non-NMDA receptors is more important than that via NMDA receptors at AT in the genesis of neuronal injury in hippocampus during kainate-induced status epilepticus.
 ...
PMID:Non-NMDA but not NMDA blockade at deep prepiriform cortex protects against hippocampal cell death in status epilepticus. 912 42

Seizures were induced in immature 18-day-old rats by i.p. administration of homocysteine (11 mmol/kg) and the effects of selected antagonists of NMDA receptors [MK-801 (0.5 mg/kg), AP7 (0.33 mmol/kg), CGP 40116 (10 mg/kg)] and non-NMDA receptors [GDEE (4 mmol/kg), NBQX (two doses, 30 mg/kg each)] were studied. The effect of MgSO4 (two doses, 2 mmol/kg each) was also tested. The anticonvulsant effect was evaluated not only from the behavioral manifestations of seizures, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding to 16-45 min after homocysteine administration. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. In contrast to neonatal rats, in which only NMDA antagonists could prevent homocysteine-induced seizures, both NMDA and non-NMDA receptor antagonists exerted an anticonvulsant effect in 18-day-old rats. In addition, the pronounced anticonvulsant effect could be achieved by the combined treatment with low subthreshold doses of NMDA (MK-801) and non-NMDA (NBQX) receptor antagonists. The protection was evident not only in suppressing behavioral symptoms of seizures, but also in preventing most of the metabolic changes accompanying seizures, mainly glycogen degradation. More than a sevenfold accumulation of lactate occurring during seizures was markedly reduced by all the tested drugs, but was not completely eliminated. All antagonists, when given alone in the same doses as those used for seizure protection, remained without any effect on lactate levels. Comparison of the present data with previous findings concerning neonatal rats suggests that there may be a developmental change in anticonvulsant efficacy of non-NMDA receptor antagonists against homocysteine-induced seizures in rats.
 ...
PMID:Anticonvulsant action of both NMDA and non-NMDA receptor antagonists against seizures induced by homocysteine in immature rats. 921 80

A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and approximately 2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 microM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have Kb values of 0.63 and 0.31 microM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg i.v., respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (approximately -2.7). Separate studies indicate that QXs 12a and 12e are also active in vivo as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted-QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.
 ...
PMID:5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors. 935 35

N-Methyl-D-aspartate (NMDA)/glycine site antagonists were tested for their ability to prevent cocaine-induced convulsions and lethality in Swiss Webster mice. Pre-treatment of mice with the novel NMDA/glycine site antagonists ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione) or ACEA-1328 (5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione) attenuated cocaine-induced convulsions; these effects were pharmacologically antagonized with D-cycloserine. The structurally-related NMDA/glycine site antagonist DCQX (6,7-dichloroquinoxaline-2,3-dione) and the structurally-unrelated NMDA/glycine site partial agonist HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) also attenuated cocaine-induced convulsions, with the R(+)-isomer of HA-966 being more effective than the S(-)-isomer. In contrast, the selective alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist, NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide) , failed to provide statistically significant protection although it shares the 2,3-quinoxalinedione structure of DCQX and the ACEA compounds. Pre-treatment with ACEA-1021, ACEA-1328, DCQX, or R(+)-HA-966 also attenuated cocaine-induced lethality in mice. Significantly, post-treatment with ACEA-1021, immediately prior to or after the onset of seizures, prevented death in up to 86% of mice receiving a lethal dose of cocaine; post-treatment with vehicle resulted in death of all mice. The results suggest the utility of targeting excitatory mechanisms for the treatment of cocaine overdose and offer a novel base structure from which effective pharmacotherapies can be developed.
 ...
PMID:Novel NMDA/glycine site antagonists attenuate cocaine-induced behavioral toxicity. 942 17

The effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists were compared on audiogenic seizures in the rats neonatally exposed to propylthiouracil (PTU). The rats treated with 0.02% PTU through mother's milk during days 0-19 after delivery showed a high incidence of audiogenic seizures consisting of running fit (RF) followed by generalized tonic-clonic seizure (GTCS) after matured. The systemic administration with MK-801, a NMDA receptor antagonist dose-dependently inhibited both RF and GTCS. NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione), a non-NMDA receptor antagonist, when systemically administered, failed to block audiogenic seizures. Audiogenic seizures caused a marked induction of c-fos messenger RNA (mRNA) in septal nucleus, bed nucleus of stria terminalis, amygdaloid nuclei, peripeduncular nucleus, and inferior colliculus, which was almost completely blocked by the pretreatment with MK-801. Bilateral microinjection of MK-801 into the inferior colliculus showed a tendency for inhibiting GTCS, but not RF, whereas CPP (3-(R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid), a competitive NMDA receptor antagonist produced a significant inhibition against both RF and GTCS. These NMDA receptor antagonists administered into cisterna ambience, the floor of which is composed of inferior colliculus and neighboring structures, have shown potent blocking effects on both RF and GTCS. The present results suggest that NMDA receptors in the inferior colliculus, presumably in the subnucleus of external cortex may play the critical role in the initiation of audiogenic seizures in PTU-treated rats.
 ...
PMID:NMDA receptors in the inferior colliculus are critically involved in audiogenic seizures in the adult rats with neonatal hypothyroidism. 974 70


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>