Long‐lasting Antiepileptic Effects of Levetiracetam against Epileptic Seizures in the Spontaneously Epileptic Rat (SER): Differentiation of Levetiracetam from Conventional Antiepileptic Drugs

Abstract

Summary:Purpose: Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absencelike seizures.Methods: The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal's head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5-to 7-Hz spike-wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods.Results: Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected ≤3 days after the final administration, and significant inhibition of absence-like seizures was still observed 8 days after the final injection of LEV. This demonstrates long-lasting seizure protection by LEV after cessation of treatment. PHT, PB, VPA, and CBZ inhibited tonic convulsions more potently compared with LEV in SERs. The maximal antiseizure effects of these drugs were reached after the initial administration, with almost the same antiseizure effects observed through day 5, despite continued drug administration. Moreover, a long-lasting treatment effect was not observed with any of these drugs except for PHT and CBZ, both of which showed moderately prolonged antiseizure effects.Conclusions: These results show that LEV is effective in the treatment of both convulsive and absence-like seizures in SERs after single-and multiple-dose administration. Interestingly, in the 5-day administration study, it was found that the antiepileptic effects for tonic convulsions and absence-like seizures were observed both during the drug-administration period and ≤8 days a...

A New Frontier in Epilepsy: Novel Antiepileptogenic Drugs

“…In addition, when LRV is administered daily in SERs for 5 days, inhibitions of seizures are gradually increased with administration day. The inhibitory effects are unusually long-lasting; suppressive effects on convulsion are still apparent 3 days after the final drug injection, and those on absence-like seizures persist more than 6 days after termination of the administration (57). However, such unusually long effects are not observed in SERs treated with phenytoin, valproate, carbamazepine, or phenobarbital when these AEDs are administered to SER in a manner similar to LEV (Fig.…”

“…A single administration of LEV in SERs inhibits both absence-like seizures and tonic convulsions with an unusually long latency and prolonged effects (57). In addition, when LRV is administered daily in SERs for 5 days, inhibitions of seizures are gradually increased with administration day.…”

“…However, such unusually long effects are not observed in SERs treated with phenytoin, valproate, carbamazepine, or phenobarbital when these AEDs are administered to SER in a manner similar to LEV (Fig. 6) (57). When LEV is intraperitoneally (i.p.)…”

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…3 panel a). This dose of phenytoin was previously shown to reduce acute or spontaneous seizures in rodents within 2 h after a single drug administration [31,32].…”

Ethosuximide and Phenytoin Dose-Dependently Attenuate Acute Nonconvulsive Seizures after Traumatic Brain Injury in Rats

“…At doses comparable to those used in this study, PHT was found to attenuate tonic-clonic seizures and wild running in rodents following global cerebral ischemia, demonstrated anticonvulsant potency by the MES test, and reduced audiogenic seizures (AGS) and significantly decreased the number of tonic convulsions in the SER. [31][32][33][34] Unlike ETX, PHT has proven ineffective in elevating minimal electroshock seizure threshold, did not protect against metrazol-induced seizures, and did not affect the absence-like seizures in SER. 32,33 In our model, both ETX and PHT significantly attenuated NCS following TBI.…”