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)

DL-beta-N-methylamino-alanine (DL-BMAA; 1-10 mumol i.c.v.) in mice induced a syndrome of: ataxia, ptosis, scratching, jumping, myoclonic jerks, clonic muscle spasms and tonic seizure, which was unaffected by pretreatment with D(-)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylate (D(-)-CPPene; i.p.), or by co-administration of gamma-D-glutamylamino-methylsulphonate (gamma-D-GAMS with DL-BMAA; i.c.v.). Pretreatment with 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; i.v.) decreased the incidence of clonic seizures for DL-BMAA, kainic acid and RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (RS-AMPA; i.c.v.). These results suggest an involvement of the AMPA/quisqualate subtype of excitatory amino acid receptors in acute BMAA toxicity.
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PMID:Receptor site specificity for the acute effects of beta-N-methylamino-alanine in mice. 198 Feb 47

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.
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PMID:Glutamate antagonists have different effects on spontaneous locomotor activity in rats. 802 81

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.
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PMID:Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm. 878 80

Topiramate is a new antiepileptic drug which has recently become available in the United States and in a number of European countries. Pharmacological studies suggest that its mode of action is multifactorial and involves blockade of voltage-dependent sodium channels, potentiation of GABAergic transmission and inhibition of excitatory pathways through an action at AMPA receptor sites. Carbonic anhydrase inhibiting properties have also been demonstrated but they are considered not to be relevant to anticonvulsant activity. Topiramate is well absorbed from the gastrointestinal tract, peak plasma levels being usually attained in 2-3 hours. The drug is negligibly (9-17%) bound to plasma proteins and is eliminated partly by renal excretion in unchanged form and partly by oxidation and hydrolysis. In healthy volunteers, the half-life is about 20-30 hours, but elimination rate is accelerated in patients taking concomitant enzyme inducing drugs such as phenytoin, carbamazepine and barbiturates. Topiramate has no major effects on plasma levels of concurrent anticonvulsants, except for a rise in plasma phenytoin in occasional patients. In double-blind add-on trials in refractory partial epilepsy, a significant reduction in seizure frequency has been demonstrated in over 40% of topiramate-treated patients (vs about 10% of those treated with placebo), a response rate which compares favourably with that observed with other new antiepileptic drugs. Dosages found to be effective in add-on controlled trials range between 200 and 1000 mg day-1, although most patients are likely to benefit from receiving 400 mg day-1 or less. Preliminary data suggest that topiramate may be effective also in generalized epilepsies, but this needs to be confirmed in prospective studies. The most common adverse effects of topiramate are CNS-related and include dizziness, fatigue, visual disturbances, ataxia, mental slowing and impaired concentration. Paresthesias, anorexia, weight loss and increased risk of nephrolithiasis have been also reported. Many of these effects are related to dose and/or to rate of dose titration. Based on these data, topiramate appears to be a valuable new drug, whose main current indication is in the add-on management of refractory partial and secondarily generalized seizures. Studies on its potential-value as monotherapy are in progress.
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PMID:A pharmacological and clinical review on topiramate, a new antiepileptic drug. 926 38

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.
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PMID:Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice. 933 79

In this study, we examined the acute anticonvulsant spectrum of (1) dizocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynurenic acid (1-100 nmol) (NMDA receptor/ionophore complex antagonists); (2) muscimol (0.1-10 nmol; direct GABA(A) agonist); (3) YM90K (3-10 mg/kg; AMPA receptor antagonist); and (4) diazepam (2 and 5 mg/kg) and carbamazepine (5 and 20 mg/kg), two standard anticonvulsants, using the partially-kindled hippocampal model for epileptic seizures in freely moving rats. The anticonvulsant effect of these compounds were assessed by determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) the pulse number threshold (PNT), which is indicative of the seizure threshold or initiation. In addition, ataxia, a measure of CNS dysfunction, was assessed for each compound. Overall, our results indicated that the anticonvulsant compounds examined could be classified into three categories based on effects on the AD and PNT: (1) elevation of PNT (carbamazepine, dizocilpine, CGS 19755 and 7-chlorokynurenic acid); (2) reduction of AD (diazepam and muscimol); and (3) mixed action, i.e., increased PNT and decreased AD (YM90K). Behavioral data indicated that all compounds, except carbamazepine, produced a dose- or concentration-dependent ataxia. Overall, our results suggest that NMDA receptors play a role in seizure initiation, whereas the GABA(A) receptors appear to be involved in seizure maintenance and AMPA receptors may be involved in both phenomena.
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PMID:Acute effects of various GABA receptor agonists and glutamate antagonists on focal hippocampal seizures in freely moving rats elicited by low-frequency stimulation. 941 23

The antiepileptic drug (AED) topiramate is a monosaccharide derivative with a sulfamate functionality. It modulates voltage-dependent sodium conductance, potentiates gamma-aminobutyric acid-evoked currents, and blocks the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of the glutamate receptor. Topiramate is rapidly absorbed and has linear, proportional, steady-state pharmacokinetics. It has no known clinically significant effect on plasma levels of carbamazepine, valproic acid, or phenobarbital, although it may increase plasma concentrations of phenytoin in some patients. When topiramate is used with hepatic enzyme-inducing AEDs, its plasma concentrations are approximately 50% lower than when it is administered alone. The efficacy of topiramate 200 to 1000 mg/d administered in two divided doses as adjunctive therapy for partial-onset seizures was investigated in five double-masked, placebo-controlled trials. The median percentage reduction in average monthly seizure frequency from baseline was 12% for placebo, compared with 30% for the 200-mg/d group and 48% for the 400-mg/d group. At a dosage of 400 mg/d, a seizure reduction of 75% or greater was seen in 22% of topiramate patients, compared with 7% of those receiving placebo; up to 9% of topiramate patients, compared with none of those receiving placebo, became seizure free. Although little additional efficacy was seen at dosages of 600, 800, and 1000 mg/d, dosing should be individualized, because some patients may respond to higher dosages. When topiramate is combined with other AEDs, the most common side effects at dosages of 200 to 400 mg/d are somnolence, dizziness, ataxia, psychomotor slowing, hesitant speech, and wordfinding difficulties. Most patients who experienced adverse events during the first 8 weeks of the trials no longer experienced them by their last visit. Although there was a 1.5% incidence of renal stones that may be associated with carbonic anhydrase inhibition, more than 75% of patients experiencing a stone continued on therapy.
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PMID:Topiramate: a review of preclinical, pharmacokinetic, and clinical data. 944 41

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.
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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.
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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.
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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


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