Anticonvulsant Activity of Felbamate in Amygdala Kindling Model of Temporal Lobe Epilepsy in Rats

Abstract

Summary:Purpose: Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE).Methods: The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, afterdischarge (AD) duration and seizure duration either at the focal seizure threshold, or after suprathreshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test.Results: FBM at doses of 12.5-50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 PA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses.Conclusions: FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE. Key Words: Amygdala-Felbamate-Kindling.Felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) is a novel broad-spectrum epileptic drug (AED) with a favorable safety profile. Preclinical animal studies have shown that felbamate exerts anticonvulsant activity in a variety of models of epilepsy or epileptic seizures ( I ,2). FBM was also active in kainate-, pilocarpine-, and lithium-pilocarpine-induced status epilepticus (SE) in rats (3,4) and inhibited corneally kindled seizures in rats (I). In addition to its antiepileptic activity, FBM has clear-cut antiischemic properties (5,6). Clinically, FBM was the first compound demonstrated to be highly effective in patients with Lennox-Gastaut syndrome (7), but it also displayed much efficacy against partial seizures (8,9). In adults with epilepsy, -70% of cases of complex partial seizures are refractory to the currently available AEDs (lo), which emphasizes the need to develop new and more effective therapeutic strategies. An animal model that is best suited for studying drug-resistant partial epilepsy with seizures secondarily generalized is the amygdala-kindled rat (1 I). To our knowledge no inforAccepted July 14, 1997. mation on the activity of FBM in this model has yet been published to date. Therefore, we determined the anticonvulsant profile of FBM in amygdala-kindled rats. We...

Comparative Anticonvulsant and Mechanistic Profile of the Established and Newer Antiepileptic Drugs

“…For example, it is effective against MES-induced tonic extension seizures and against tonic seizures induced by the glutamate agonists NMDA and'quisqualic acid (20). It is also active against certain chemically induced clonic seizures (21) and is active in the kindled rat (22). Consistent with FBM's broad preclinical profile is its rather broad clinical spectrum.…”

Mechanisms of Action of Antiepileptic Drugs

“…Felbamate effectively inhibits maximal electroshock-, audiogenic-, pentetrazole-, picrotoxin-, N-methyl-D-aspartate-, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced convulsions and amygdala-or pentetrazolkindled seizures [25,[102][103][104][105]. Bicuculline-and strychnineevoked convulsions were, however, not affected by felbamate [25].…”

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

“…[24][25][26] A brief baseline (~10 seconds) EEG period, captured prior to the initiation of amygdala stimulation, was used as a comparator to determine the duration of primary afterdischarge activity. [24][25][26] A brief baseline (~10 seconds) EEG period, captured prior to the initiation of amygdala stimulation, was used as a comparator to determine the duration of primary afterdischarge activity.…”