Anticonvulsant effect of felbamate in the pentylenetetrazole kindling model of epilepsy in the rat

Abstract

The present study was designed to examine the ability of felbamate, a novel antiepileptic agent, to antagonize the increase in seizure severity (i.e., chemical kindling) produced by chronic treatment with initially subconvulsant doses of pentylenetetrazol (PTZ). Rats were treated with PTZ (30 mg/kg, i.p., three times a week) for 8 consecutive weeks. Two other groups of rats received felbamate (300 or 400 mg/kg, i.p.), 90 min before each dose of PTZ. Pretreatment with felbamate at either dose prevented the progression of rank of seizures during chronic treatment with PTZ. Thus, the mean seizure score by the end of the chronic treatment (0-5 scale) was 0 in vehicle treated controls, 3.3 in rats treated with PTZ alone, 1.5 in rats treated with PTZ plus felbamate (300 mg/kg, i.p.) and 0.9 in the group treated with PTZ plus felbamate (400 mg/kg, i.p.). Felbamate also antagonized the long-term increase in the sensitivity to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats. Thus, the administration of a challenge dose of isoniazid (120 mg/kg, s.c.), picrotoxin (1.5 mg/kg, i.p.) or PTZ itself (15 mg/kg, i.p.), 15 to 45 days after the end of the chronic treatment regimen, induced convulsions in > 80% of PTZ-kindled rats and in < 20% of rats treated with PTZ + felbamate (400 mg/kg). The results are discussed in terms of the multiple mechanisms that can contribute to the anticonvulsant action of felbamate in the PTZ kindling model of epilepsy.

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].…”

The ups and downs of alkyl‐carbamates in epilepsy therapy: How does cenobamate differ?

“…In addition to antiseizure activity, several alkyl‐carbamates exert significant disease‐modifying or antiepileptogenic effects in rodent models of epilepsy. For instance, felbamate counteracted the development of PTZ kindling in rats, 64 and retigabine was the most effective drug in a series of compounds at blocking rapid kindling in developing rats 65 . Similarly, carisbamate has been shown to delay amygdala kindling in rats 66 and to exert powerful disease‐modifying effects in the lithium‐pilocarpine mode, 67 but failed to affect epileptogenesis in a rat model of epilepsy precipitated by traumatic brain injury 68 .…”

Isobolographic and Subthreshold Analysis of Interactions among Felbamate and Four Conventional Antiepileptic Drugs in Pentylenetetrazole‐induced Seizures in Mice

“…Felbamate (FBM), a propanediol dicarbamate (1), proved effective against a number of convulsive procedures: maximal electroshock, audiogenic, pentylenetetrazole (PTZ)‐, picrotoxin‐, N‐ methyl‐ d‐ aspartate (NMDA)‐, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐induced convulsions and amygdala‐kindled seizures (2–5). Moreover, FBM inhibited fully developed PTZ‐kindled convulsions and prevented their progression in mice (6). Nevertheless, FBM remained ineffective against bicuculline‐ and strychnine‐evoked seizures (3).…”