Comparison of the antiepileptogenic effects of an early long‐term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy

Abstract

SUMMARYPurpose: Epilepsy is a heterogeneous syndrome characterized by recurrent, spontaneous seizures; continuous medication is, therefore, necessary, even after the seizures have long been suppressed with antiepileptic drug (AED) treatments. The most disturbing issue is the inability of AEDs to provide a persistent cure, because these compounds generally suppress the occurrence of epileptic seizures without necessarily having antiepileptogenic properties. The aim of our experiments was to determine, in the WAG/Rij model of absence epilepsy, if early long-term treatment with some established antiabsence drugs might prevent the development of seizures, and whether such an effect could be sustained.Methods: WAG/Rij rats were treated for 3.5 months (starting at 1.5 months of age, before seizure onset) with either ethosuximide (ETH; drug of choice for absence epilepsy) or levetiracetam (LEV; a broad-spectrum AED with antiabsence and antiepileptogenic properties). Results: We have demonstrated that both drugs are able to reduce the development of absence seizures, exhibiting antiepileptogenic effects in this specific animal model. Discussion: These findings suggest that absence epilepsy in this strain of rats very likely follows an epileptogenic process during life and that early therapeutic intervention is possible, thereby opening a new area of research for absence epilepsy and AED treatment strategies.

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

“…In the WAG/Rij rat model of absence epilepsy, early prophylactic treatment with ethosuximide, levetiracetam, or zonisamide (but not carbamazepine) before the onset of spike-wave discharges in the EEG suppressed the development of such absence-like seizures [31][32][33], which was also subsequently observed in the GAERS model of absence epilepsy [34]. These findings suggest that models are available in which epileptogenesis can be controlled and that early treatment during development may provide a strategy for preventing genetic epilepsy in susceptible individuals.…”

Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

“…Dosage was calculated on the basis of the knowledge that rats drink, on average, 10-12 ml/100 g/day; the volume drunk was also checked weekly [44]. Drug solutions were freshly prepared, replaced 2 or 3 times a week, and bottles were wrapped in silver foil to exclude light [45,46].…”

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

“…The number, but not duration, of the SWDs was found to be markedly suppressed during 3 months of sequential recordings performed after termination of treatment, revealing an antiepileptogenic potential of ethosuximide. This observation has been reproduced in subsequent studies [17,31] and extended to another genetic animal model for human absence epilepsy-the GAERS rat [32]. Furthermore, ethosuximide also seems to prevent comorbid anxiety [32] and depression [31,33] in the genetic absence epilepsy models, based upon observations in the open field and the forced swim test, respectively.…”

“…This was first demonstrated in a strain of spontaneously epileptic rats from Kyoto University in which early long-term treatment with a therapeutically relevant dose of levetiracetam inhibited the developmental expression of tonic convulsions and SWDs associated with absence seizures [58]. Later studies in the WAG/Rij rats confirmed that early long-term treatment with a therapeutically relevant dose of levetiracetam inhibits the developmental expression of SWDs [17,33].…”

“…There is some evidence that valproate [13] and levetiracetam [14,15] may cause a delay in kindling acquisition that persists beyond the period of drug exposure, suggesting an antiepileptogenic action. In addition, long-term treatment with ethosuximide and levetiracetam has recently demonstrated a compelling ability to reduce the development of seizures in genetic animal models of absence epilepsy [16,17]. The reduction in seizures persists after the treatment is withdrawn, suggesting a true antiepileptogenic effect.…”