2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Ataxia

The neural cell adhesion molecule NCAM and its dynamically regulated posttranslational modification polysialic acid (PSA) are major determinants of cellular interactions during ontogeny. While NCAM in the absence of PSA stabilizes cell-cell interactions, the attachment of the large and polyanionic PSA negatively influences cell adhesion and promotes plasticity. Disease-associated changes in the polysialylation state of NCAM raise the question whether the PSA-NCAM system can affect CNS pharmacology. Here we investigated the pharmacological effects of the competitive AMPA antagonist NBQX in genetic mouse models either lacking NCAM and PSA (female NCAM knockout mice) or being drastically reduced in the level of PSA expression (female ST8SiaIV knockout mice). Studies were carried out with the respective wildtype littermate controls. In mice lacking NCAM and PSA, NBQX-induced ataxia proved to be more intense as compared with wild-type mice. On both mutant backgrounds, NBQX significantly elevated seizure thresholds during i.v. infusion of the chemoconvulsant pentylenetetrazole. In summary, the data demonstrate that the PSA-NCAM system impacts AMPA receptor pharmacology under in vivo conditions. The fact that comparable effects were observed in NCAM- and ST8SiaIV-knockout mice indicates that this impact is not due to a stabilizing effect of NCAM in the absence of PSA. Thus, disease-related changes in the polysialylation of NCAM are likely to be associated with effects on the efficacy and tolerability of AMPA receptor antagonists.

Topics: Analysis of Variance; Animals; Ataxia; Behavior, Animal; Disease Models, Animal; Excitatory Amino Acid Antagonists; Female; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Cell Adhesion Molecules; Pentylenetetrazole; Quinoxalines; Seizures; Sialyltransferases

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline), a novel and selective AMPA antagonist, was tested to evaluate its influence upon anticonvulsant activity of common antiepileptic drugs in mice. NBQX (10, 20, 40 mg/kg, i.p.) had no influence upon the threshold for electroconvulsions. NBQX (10 mg/kg) enhanced the activity of anticonvulsant drugs decreasing their ED50S against maximal electroshock from 321 to 190 mg/kg for valproate, from 19.5 to 14.5 mg/kg for carbamazepine, from 31.0 to 21.4 mg/kg for phenobarbital, from 17.8 to 9.5 mg/kg for diphenylhydantoin and from 19.5 to 10.5 mg/kg for diazepam. In addition, NBQX (10 mg/kg) failed to impair motor performance and long-term memory determined in the chimney test and passive avoidance task. The combinations of NBQX (10 mg/kg) and carbamazepine, diphenylhydantoin or phenobarbital resulted in no adverse effects. Diazepam (10.5 mg/kg) alone impaired the motor performance and long-term memory and so it did when combined with NBQX. Also retention of the passive avoidance task and motor performance were impaired by valproate alone or given together with NBQX. Finally, NBQX (10 mg/kg) did not affect the plasma level of any antiepileptic drug. It is concluded that non-NMDA glutamate receptor blockade results in the considerable enhancement of the efficacy of common antiepileptic drugs.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Ataxia; Avoidance Learning; Behavior, Animal; Drug Synergism; Electroshock; Male; Memory; Mice; Motor Activity; Psychomotor Performance; Quinoxalines; Seizures

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.

Topics: Animals; Anticonvulsants; Ataxia; Drug Synergism; Injections, Intravenous; Male; Mice; Motor Activity; Probenecid; Quinoxalines; Seizures