Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) was studied following intravenous administration to mice. Maximal electroshock seizures were suppressed by low doses of NBQX (ED50 = 13 mg/kg) but effects had dissipated by 10 min after a dose of 25 mg/kg. Coadministration of the transport inhibitor probenecid (p-(dipropylsulphamoyl)-benzoic acid) enhanced and prolonged the anticonvulsant action of NBQX and also enhanced and prolonged ataxia. NBQX may be rapidly eliminated by a process sensitive to probenecid.
 ...
PMID:Probenecid pretreatment enhances anticonvulsant action of NBQX in mice. 149 53

1. GYKI 52466 is a benzodiazepine derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 benzodiazepine derivative GYKI 52466 and 1,4-benzodiazepines such as diazepam, the benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2. Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10-20 mg kg-1), NBQX (80-120 mg kg-1) and diazepam (5 mg kg-1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing themyoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect.3. With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment.4. Flumazenil (5-20 mg kg-1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test.5. The data indicate that the GABAA receptor-associated benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment,thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
 ...
PMID:Effects of the non-NMDA antagonists NBQX and the 2,3-benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil. 788 91

Locomotor activity, ataxia, and stereotypy were assessed in the open field after administration of NMDA and AMPA antagonists acting by different mechanisms. The interaction with glutamatergic receptors was confirmed in the binding assay. (+)MK-801 and phencyclidine (PCP) produced similar changes in horizontal activity, i.e., a strong increase from the beginning of the test. Ketamine, and to a lesser extent, memantine, enhanced horizontal activity at the later observation periods only. Amantadine and NBQX produced a slight inhibition, while GYKI-52466, d-cycloserine, (+R)-HA-966, CGP-37849, and dextromethorphan were ineffective. Vertical activity (rearings) were inhibited by most agents except GYKI-52466 and gly-B partial agonists. At higher doses ataxia was seen after: MK-801, PCP, ketamine, memantine, amantadine, CGP-37849, dextromethorphan, and GYKI-52466. Hence, the inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.
 ...
PMID:Glutamate antagonists have different effects on spontaneous locomotor activity in rats. 802 81

The cerebroprotective effect of the non-N-methyl-D-aspartate antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline.NA) on neurological deficit and infarct volume (visualised with 2,3,5-triphenyltetrazolium) 24 h after permanent middle cerebral artery (MCA) occlusion in Fischer rats (n = 6 per dose) was studied. NBQX (10, 20 or 30 mg Kg-1, i.p., 0,30,60 min) immediately after MCA occlusion reduced cortical infarct volume by 45% (not significant), 70% (p < 0.05) or 75% (p < 0.05) respectively. NBQX (30 mg Kg-1, i.p., 60, 90, 120 min) reduced cortical infarct volume by 58% (p < 0.05). With a 2 h delay NBQX was ineffective. Neurological deficits (with blinded assessment) were improved with immediate or delayed NBQX (3 x 30 mg Kg-1, i.p.). The main adverse behavioral effect of NBQX (3 x 20 or 3 x 30 mg Kg-1, p.i.) was ataxia. The cerebroprotective effect of NBQX in rats suggests a possible therapeutic role for non-N-methyl-D-aspartate antagonists given shortly after stroke onset.
 ...
PMID:Cerebroprotective effect of a non-N-methyl-D-aspartate antagonist, NBQX, after focal ischaemia in the rat. 833 Jul 53

In mice injected with formalin into the hindpaw, the 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, equipotently inhibited the early phase (EP) and late phase (LP) of licking. At higher doses, they provoked ataxia and inhibited the writhing elicited by intra-abdominal acetic acid. The antagonists, (-)-alprenolol, (-)-tertatolol, WAY-100,135 and S 15931 were more potent against the LP than the EP. They also inhibited writhing, and only at very high doses did they elicit ataxia. In rats, 8-OH-DPAT and flesinoxan increased the current required to elicit vocalisation upon electrical stimulation of the tail. The action of 8-OH-DPAT was blocked by WAY-100,135, which, like other antagonists, was inactive alone. Interestingly, a low dose of 8-OH-DPAT partially inhibited the antinociceptive action of the mu-opioid agonist, morphine, the action of which was dose-dependently facilitated by (-)-alprenolol and S 15931. Administered s.c., 8-OH-DPAT elicited spontaneous tail-flicks (STFs) in rats: these were abolished by WAY-100,135, (-)-tertatolol, (-)-alprenolol and S 15931. STFs were also eliminated by s.c. or i.t. administration of the alpha 2-adrenergic receptor agonist, clonidine, the GABAA agonist, muscimol or the GABAB agonist, baclofen. The mu-opioid, morphine, blocked STFs only at high doses and the kappa-opioid agonists, U 50,488 and U 69,593, even at supra-ataxic doses, were inactive. Antagonists at neurokinin (NK)1 (RP 67580), NK2 (SR 48,968) and bradykinin (BK)2 (Hoe 140) receptors, as well as aspirin, did not block STFs, though indomethacin was effective. Antagonists at the glycine B site coupled to the NMDA receptor, L 687,414, L 701,324 and (+)-HA966, blocked STFs. Furthermore, (+)-HA 966 and the competitive NMDA receptor antagonist, CPP, were active upon i.t. administration. STFs were also blocked by s.c. or i.t. administration of the AMPA antagonists, YM 900 and NBQX. In conclusion, the influence of 5-HT1A ligands upon nociception is dependent upon the algesiometric paradigm. Intriguingly, modulation of 5-HT1A receptor-mediated STFs reveals parallels to neuropathic pain.
 ...
PMID:Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm. 878 80

Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency of dizocilpine > TCP > (-)-MK-801 > SKF 10,047 > dextrorphan > PCP. There was a positive correlation between the potencies of the compounds that substituted for dizocilpine and their previously reported affinities for the [3H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABAA receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17742, (+/-)CPP and LY 233536 dose-dependently substituted for dizocilpine. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive NMDA blockers.
 ...
PMID:Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice. 933 79

NBQX, a specific and potent AMPA receptor antagonist has been found to be neuroprotective in various models of ischemia and to have anticonvulsant properties in different models of epilepsy. In this experiment, the neurobehavioral effects of NBQX were studied. In an open field, an important ataxia was emphasized at a dose of 60 mg/kg. In a swimming task, an increase of the escape latencies was noted on the third day at a dose of 40 mg/kg. In a Morris water maze task, doses devoid of effects on locomotion were used (10, 20, and 30 mg/kg). There was no effect on the acquisition of the task at 10 mg/kg and a slight impairment at 20 mg/kg, but the rats did not learn the task at 30 mg/kg. This impairment was reversible, as shown by the increasing performance of this group without treatment. No impairment was noted in the retention phase of the Morris water maze task. The results are discussed relative to the role of the AMPA receptor in memory processes.
 ...
PMID:Behavioral effects of NBQX, a competitive antagonist of the AMPA receptors. 958 71

In order to study the roles of the AMPA and kainate subtypes of non-NMDA glutamate receptors in the processing of persistent nociceptive information, compounds with varying activities at these receptors were examined for effects on the formalin-induced paw-licking behavior in rats. The selective AMPA antagonist, LY300164 and the mixed AMPA/kainate antagonist, NBQX, were compared for their effects on formalin-induced pain behavior. NBQX (3, 10, 20 mg/kg, i.p.), caused antinociception as well as ataxia whereas the selective AMPA antagonist, LY300164 (3,5,10 mg/kg, i.p.), did not cause antinociception at doses that did not produce ataxia. In view of the well documented distribution of kainate receptors on C fibres and of the kainate-preferring iGluR5 subtype on dorsal root ganglia (DRG), we tested a series of three decahydroisoquinolines with different profiles of activity between iGluR5 and AMPA receptors and all without activity on iGluR6, iGluR7 or KA2 subtypes. LY293558 (0.1, 1, 3, 5 mg/kg, i.p.), which had low micromolar affinity for both iGluR5 and 2 caused, like NBQX, both antinociceptive and ataxic effects. However, the selective iGluR5 antagonist LY382884 (5, 10, 30, 100 mg/kg, i.p.), exhibited antinociceptive actions without ataxia while the iGluR2 preferring antagonist LY302679 (5 mg/kg, i.p), caused ataxia but did not produce antinociceptive effects at that dose. These actions were stereoselective since the enantiomeric compounds, LY293559 and LY302680, were ineffective in these tests. The data strongly suggest an involvement of iGluR5 in the processing of nociceptive information.
 ...
PMID:Kainate GluR5 receptor subtype mediates the nociceptive response to formalin in the rat. 968 Feb 56

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.
 ...
PMID:LU 73068, a new non-NMDA and glycine/NMDA receptor antagonist: pharmacological characterization and comparison with NBQX and L-701,324 in the kindling model of epilepsy. 986 55

Though the AMPA receptor has been implicated in several neurodegenerative processes (epilepsy, ischemia, spasticity), its role in cognition is yet to be clarified. The aim of this study was to assess in the rat the effects of the AMPA receptor antagonist NBQX (3.5, 7, 10, 20 and 30 mgkg(-1), i.p.) on learning and memory. For this purpose, the object recognition task was chosen. NBQX, at the higher doses used (20 and 30 mgkg(-1)) caused respectively, depression of motility and ataxia, while given at lower doses (3.5, 7 and 10 mgkg(-1)) it did not influence animals performance in the object recognition paradigm. All rats acquired similarly well the task. In conclusion, these results would support and broaden previous observations on the lack of major involvement of AMPA receptors in the rat working memory mechanisms.
 ...
PMID:The non-NMDA receptor antagonist NBQX does not affect rats performance in the object recognition task. 1182 Aug 60


1 2 Next >>