Topiramate modulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism.

Purpose: These studies further investigate the ability of topiramate (TPM) to enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a benzodiazepine-insensitive pathway.

Methods: Topiramate (30 and 100 microM) enhancement of GABA (1 microM)-evoked currents in primary cultures of mouse cortical neurons was studied by using whole-cell electrophysiologic techniques. Results obtained with TPM (30 microM) were compared with those obtained with clonazepam (CZP; 1 microM).

Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound.

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy)benzylamino)propanamide methanesulfonate], a new anticonvulsant that displays a wide therapeutic window, has a potency comparable or superior to that of most classic anticonvulsants. PNU-151774E is chemically unrelated to current antiepileptics. In animal seizure models it possesses a broad spectrum of action.

Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold.

The anticonvulsant topiramate is effective in laboratory animals against maximal electroshock seizures, amygdala kindling, and spike-wave discharges and has demonstrated efficacy in humans for the treatment of complex partial seizures. However, its mechanism of action has yet to be clearly elucidated. When the chloride-sensitive fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) was used as a tool for estimating the effect of anticonvulsant drugs on GABA receptor function, topiramate was observed to enhance GABA-stimulated chloride (Cl-) flux.

The dihydropyridine nitrendipine inhibits [3H]MK 801 binding to mouse brain sections.

The L-type Ca2+ channel antagonist nitrendipine inhibits N-methyl-D-aspartate (NMDA)-activated Ca2+ flux into cerebellar granule cells, and [3H]dibenzocyclohepteneimine ([3H]MK 801) binding to mouse cerebral cortical and hippocampal membranes. To further study this interaction between nitrendipine and NMDA-activated channels, the effects of several L-channel active agents on [3H]MK 801 binding to mouse brain were investigated in an autoradiographic assay. Serial slide-mounted sagittal sections of mouse brain were labeled with [3H]MK 801 in the presence of varying concentrations of the L-channel active agents nitrendipine, nimodipine, nifedipine, Bay K 8644, and verapami.

The dihydropyridine nitrendipine reduces N-methyl-D-aspartate (NMDA)-evoked currents of rodent cortical neurons through a direct interaction with the NMDA receptor-associated ion channel.

The 1,4-dihydropyridine (DHP) nitrendipine was previously shown to concentration-dependently (0.1-1 microM) reduce N-methyl-D-aspartate (NMDA)-evoked calcium influx and single-channel activity of mouse cerebellar granule cells and to reduce [3H]dizocilpine (MK-801) binding to mouse cortical and hippocampal membranes. Using patch-clamp electrophysiology, the present study was designed to understand further the specific mechanism of interaction between nitrendipine and NMDA receptors.

The dihydropyridine nitrendipine modulates N-methyl-D-aspartate receptor channel function in mammalian neurons.

Nitrendipine and other dihydropyridine voltage-sensitive calcium channel (VSCC) antagonists have been demonstrated to possess anticonvulsant and neuroprotectant activity in a variety of model systems. Likewise, antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype act as potent anticonvulsant and neuroprotective agents. Both VSCC and NMDA antagonists exert their effects by inhibiting the neuronal influx of calcium associated with activation of VSCCs or the NMDA receptor, respectively.

Characterization of the anticonvulsant properties of F-721.

The anticonvulsant properties of F-721 (3-diethylamino-2,2-dimethylpropyl-5-[p-trifluoromethylphenyl]-2-f uroate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N-methyl-D-aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.

A neuropharmacological evaluation of felbamate as a novel anticonvulsant.

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) was subjected to a series of carefully selected in vivo and in vitro tests to provide additional insight into mechanism of action, margin of safety, and clinical potential. FBM was effective against intracerebroventricular (i.c.