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Purpose: These studies further investigate the ability of topiramate (TPM) to enhance y-aminobutyric acid (GABA)-mediated inhibition through a benzodiazepineinsensitive pathway.Methods: Topiramate (30 and 100 pM) enhancement of GABA (1 pM)-evoked currents in primary cultures of mouse cortical neurons was studied by using whole-cell electrophysiologic techniques. Results obtained with TPM (30 pM) were compared with those obtained with clonazepam (CZP; 1 pM).Results: Topiramate enhanced GABA currents in a subset of cortical neurons tested. In addition, TPM enhanced GABAevoked currents in CZP-insensitive neurons, and CZP was effective in a subset of TPM-insensitive neurons. Related studies in vivo demonstrated that intraperitoneal (i.p.) administration of either TPM (25 mg/kg) or CZP (0.012 mg/kg) increases pentylenetetrazol (PTZ) seizure threshold. This effect of CZP, but not TPM, was reversed by the benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mgkg, i.p.).Conclusions: These results indicate that GABA,-receptor sensitivity to TPM is not dependent on the presence of BZD sensitivity. Enhancement of GABA-mediated inhibition through a BZD-insensitive pathway may represent one mechanism through which TPM exerts its anticonvulsant action. Key Words: Topiraniate-Glutamate-GABA-Antiepileptic drugs-Epilepsy .Studies conducted in this laboratory have found that topiramate (TPM) enhances y-aminobutyric acid (GABA)-evoked C1-flux of cerebellar granule neurons and GABA-evoked whole-cell currents of cortical neurons (1). Preliminary results obtained from singlechannel patch-clamp studies (2) suggest that the effect of TPM on GABA-evoked currents is similar to that of the benzodiaaepines (BZDs; e.g., TPM enhances the frequency of opening rather than the open-channel duration of the GABA, receptor). TPM differs from the benLodiazepines, however, in that its effect was not reversed by the BZD antagonist flumazenil (FMZ) (2). Numerous investigations have demonstrated that anticonvulsant drugs (AEDs) that enhance GABA-mediated inhibition (e.g., the BZDs and barbiturates) also elevate seizure threshold (3). Thus if TPM enhances GABA-evoked currents, it may also increase seizure threshold.Our studies further investigated the ability of TPM to enhance GABA-mediated inhibition through a BZDinsensitive pathway. Here we extend previous studies on

Summary: Purpose:The studies presented here represent our efforts to investigate the anticonvulsant activity of N-methyltetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity.Methods: The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague-Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acidinduced neural tube defects.Results: In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED 50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES-and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED 50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED 50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice.Conclusions: The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential.

Summary:Purpose: We sought to investigate the anticonvulsant activity of the new antiepileptic drug (AED), valrocemide or TV1901 (VGD) in various animal (rodent) models of human epilepsy to determine its anticonvulsant profile and safety margin.Methods: VGD was administered intraperitoneally to CF no. 1 mice and orally or intraperitoneally to Sprague-Dawley rats. The anticonvulsant activity of VGD was examined in nine different animal models of epilepsy for its ability to block electrically, chemically, or sensorily induced seizures.Results: In mice VGD afforded complete protection against maximal electroshock (MES)-, pentylenetetrazole-, picrotoxin-, and bicuculline-induced seizures and 6-Hz "psychomotor" seizures with median effective dose (ED 50 ) values of 151, 132, 275, 248, and 237 mg/kg, respectively. VGD was also effective in preventing sound-induced seizures in Frings audiogenic-seizure susceptible mice (ED 50 , 52 mg/kg). The median neurotoxic dose in mice was 332 mg/kg. After oral administration to rats, VGD was active in the MES test, with an ED 50 of 73 mg/kg, and the median neurotoxic dose was 1,000 mg/kg. Intraperitoneal administration of 300 mg/kg of VGD to hippocampal kindled Sprague-Dawley rats blocked generalized seizures and shortened the afterdischarge duration significantly. VGD also provided complete protection from focal seizures in the corneally kindled rats (ED 50 ,161 mg/kg).Conclusions: The results obtained in this study suggest that VGD has a broad spectrum of anticonvulsant activity and promising potential as a new AED.

1 Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on dierent methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer ± enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2 Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. . Racemic PID also signi®cantly increased the seizure threshold in this model. 5 Mechanistic studies showed that PID did not aect voltage-sensitive sodium channels or kainate-, GABA-or NMDA-evoked currents. 6 The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer ± enantiomer interaction. 7 This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic pro®le. The enhanced ecacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer ± enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.